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As fall classes get underway, advocates for children are sounding an alarm over the situation facing public schools in the state.
A report from the Wisconsin Council on Children and Families is critical of the impact state budget cuts have had on education policies. Council research director Jon Peacock says that “as the state has been cutting funding for schools…that’s resulting in larger class sizes and also a sharp reduction in experience for teachers.”
The report argues that spending on schools declined in Wisconsin, during a period where the national average was increased. While the state does continue to spend more on per pupil spending than the national average, the state fell from 13th highest among state to 21st between 2005 and 2013.
Peacock says the number of experienced teachers in classrooms has also seen a large drop in the past five years, after a wave of retirements following the passage of Act 10 – legislation that restricted collective bargaining for many public sector unions. Prior to the law taking effect, Peacock says about 60 percent of schools had teachers with average experience level of at least 15 years in the classroom. Now, only about 40 percent of schools hit that threshold.
The number of teachers working in Wisconsin schools also fell by almost 3,000 between 2005 and 2013, which Peacock says means more crowded classrooms and less individualized attention for students.
The report concludes that “if lawmakers continue to prioritize tax cuts above public schools, students in Wisconsin public schools will continue to have increasingly crowded classrooms and fewer experienced teachers.”
WIBA |
Coyotes captain Shane Doan is the 2011-12 recipient of the Mark Messier NHL Leadership Award, which recognizes players for the leadership on the ice and in the community.
“I am thrilled to receive the Mark Messier Leadership Award,” Doan said upon receiving the award at the NHL Awards ceremony on Wednesday in Las Vegas. “Growing up in Alberta, I was a huge fan of Mark Messier and to receive this award from one of the greatest leaders to ever play in the NHL is a tremendous honor.”
Doan was drafted by the Winnipeg Jets in 1995 and has played all 16 of his NHL seasons with the franchise. He has served as the Coyotes’ captain since 2003 and in 2011-12 helped the team to its first division title and first appearance in the Western Conference Final.
Article continues below ...
“It is hard to imagine a more worthy recipient of the Mark Messier NHL Leadership Award than Shane Doan,” said Coyotes General Manager Don Maloney. “The leadership and inspiration he displays daily in our locker room is only exceeded by his selfless giving in our community. It’s a well-deserved honor.”
Doan has long been considered one of the most selfless professional athletes in a city that is home to four major professional sports teams. He serves as an ambassador for Coyotes Charities and works with a number of organizations including: United Blood Services, Phoenix Children’s Hospital, Phoenix Rescue Mission, Flashes of Hope and Children First Academy – a kindergarten through eighth grade school for homeless children.
Messier solicits suggestions from club and league personnel and NHL fans through NHL.com in compiling a list of potential candidates. The selection of the three finalists and the ultimate winner is Messier’s choice alone. The other two finalists for the award were Los Angeles Kings forward Dustin Brown and New York Rangers forward Ryan Callahan.
Winners of the Mark Messier Leadership Award
2011-12 – Shane Doan, Phoenix Coyotes
2010-11 – Zdeno Chara, Boston Bruins
2009-10 – Sidney Crosby, Pittsburgh Penguins
2008-09 – Jarome Iginla, Calgary Flames
2007-08 – Mats Sundin, Toronto Maple Leafs
2006-07 – Chris Chelios, Detroit Red Wings |
/**
* Classes for abstracting away differences between SWT and RAP/RWT.
*
* @author dave
*
*/
package org.reldb.spoing.platform; |
Most Competitive Home Schedule In The Country
Make 2016 Deposit | 2016 Printable Schedule | Download Schedule to Calendar | All-Time Game Results | All-Time Season Results
FAYETTEVILLE, Ark. — Following a memorable finish to the 2015 season, including a dominating bowl victory, Razorback Football is primed for an exciting 2016 with arguably the most competitive home schedule in college football.
Arkansas will be the only Division-I FBS team in the country that will face four teams on its home field that were ranked in the top-25 prior to the 2015 bowl season. With the defending national champion, the defending SEC Eastern Division champion, and two SEC Western Division rivals all coming to town, Fayetteville will be the best place in the nation to watch elite college football during the months of October and November.
The Alabama Crimson Tide, Florida Gators, LSU Tigers, and Ole Miss Rebels all had compelling storylines with ties to the Razorbacks that occurred during 2015 and in previous seasons. We’ll break down each upcoming matchup in anticipation of one of the most epic home schedules in Razorback football program history.
Oct. 8, 2016: Alabama (2015 SEC Western Division and College Football Playoff champions)
We almost had ’em in Tuscaloosa in 2015 and in Fayetteville in 2014. The Hogs had a 7-3 lead in the game until the last minute of the third quarter with 100,000 ‘Bama fans holding their breath at Bryant- Denny Stadium. In 2016, Nick Saban and the Tide will be on our home turf. Donald W. Reynolds Razorback Stadium will be electric, and this is one game you will definitely not want to miss.
Oct. 15, 2016: Ole Miss
Last year’s matchup gave us the “Henry Heave”, consecutive two-point conversion attempts during overtime and a record-setting night for Brandon Allen. These are moments Razorback fans will remember for years to come, and this time, Arkansas gets to host Ole Miss during the one of the best Homecoming games this season in Division I football. During the Rebels’ most recent visit to Fayetteville in 2014, then-No. 8 Ole Miss was shut out 30-0. That’s a repeat Hogs fans most definitely will want to see.
Nov. 5, 2016: Florida (2015 SEC Eastern Division champion)
After the Razorbacks’ bye week, this will be the second-to-last home game before we finish out our 2016 slate on the road. In the past 20 years, Florida has only visited DWRRS three times, and not since 2008. Under head coach Jim McElwain, the Gators are back on a positive trajectory, and were an SEC Championship game win away from making a possible national championship playoff bid in 2015. This will be a key conference matchup for the Razorbacks and a great opportunity to see a top-ranked SEC East team face a stiff challenge at DWRRS.
Nov. 12, 2016: LSU
Arkansas closes out its 2016 home schedule against Coach Les Miles and the Tigers, whom the Razorbacks beat handily 17-0 at DWRRS in 2014. Be here to watch to see if the Hogs can retain The Boot at home and keep the team’s overall two-game win streak against LSU alive.
Experience DWRRS
The Razorback Ticket Center is currently accepting deposits for new 2016 football season tickets. A $100 deposit on new season tickets will give fans guaranteed access to available seat inventory in May. More information on the online seat selection process will be sent directly to those who make deposits. Click here for deposit details.
Current football season ticket holders do not need to place a deposit, as renewal applications are now live. Please log into your eTicket account here and click on season renewals to process your football season ticket renewal. |
package business.common.repository;
import business.common.entity.requesterentity.RequesterEntity;
import org.springframework.beans.factory.annotation.Qualifier;
import org.springframework.data.repository.CrudRepository;
import org.springframework.stereotype.Component;
import org.springframework.stereotype.Repository;
import javax.persistence.Table;
@Component
@Repository
@Table(name = "requester")
@Qualifier("RequesterRepository")
public interface RequesterRepository extends CrudRepository<RequesterEntity,Long> {
}
|
package cn.lite.flow.executor.kernel.container.impl;
import cn.lite.flow.common.model.consts.CommonConstants;
import cn.lite.flow.common.utils.FreeMarkerUtils;
import cn.lite.flow.common.utils.ParamUtils;
import cn.lite.flow.executor.common.consts.Constants;
import cn.lite.flow.executor.common.exception.ExecutorRuntimeException;
import cn.lite.flow.executor.common.utils.ExecutorLoggerFactory;
import cn.lite.flow.executor.common.utils.Props;
import cn.lite.flow.executor.kernel.conf.ExecutorMetadata;
import cn.lite.flow.executor.kernel.job.ShellProcessJob;
import cn.lite.flow.executor.model.basic.ExecutorJob;
import cn.lite.flow.executor.model.kernel.SyncContainer;
import cn.lite.flow.executor.service.ExecutorJobService;
import cn.lite.flow.executor.service.utils.ExecutorFileUtils;
import cn.lite.flow.executor.service.utils.ExecutorServiceUtils;
import org.apache.commons.io.FileUtils;
import org.apache.commons.lang3.StringUtils;
import org.slf4j.Logger;
import org.slf4j.LoggerFactory;
import java.io.File;
/**
* @description: java进程容器
* @author: yueyunyue
* @create: 2018-08-17
**/
public class FileShellContainer extends SyncContainer {
private final ShellProcessJob shellProcessJob;
private final static Logger LOG = LoggerFactory.getLogger(FileShellContainer.class);
public FileShellContainer(ExecutorJob executorJob) {
super(executorJob);
String config = executorJob.getConfig();
Props sysProps = new Props();
Props props = new Props(config);
String jobWorkspace = ExecutorMetadata.getJobWorkspace(executorJob.getId());
Logger logger = ExecutorLoggerFactory.getLogger(executorJob.getId(), jobWorkspace);
/**
* 生成脚本文件
*/
String filePath = props.getString(CommonConstants.PARAM_FILE);
String param = props.getString(CommonConstants.PARAM);
String shellName = Constants.SHELL_SCRIPT_PREFIX + executorJob.getId() + CommonConstants.POINT + Constants.SHELL_COMMAND;
String shellPath = jobWorkspace + CommonConstants.FILE_SPLIT + shellName;
try {
String shellContent = ExecutorFileUtils.getFileContent(filePath);
logger.info("job:{} get origin shell content:{}", executorJob.getId(), shellContent);
/**
* 参数不为空，通过freemarker替换关键字
*/
if(StringUtils.isNotBlank(param)){
shellContent = FreeMarkerUtils.formatString(shellContent, ParamUtils.param2Map(param));
logger.info("job:{} handle shell param:{} content:{}", executorJob.getId(), param,shellContent);
}
FileUtils.write(new File(shellPath), shellContent);
props.put(Constants.SHELL_SCRIPT_PATH, shellPath);
} catch (Throwable e) {
logger.error("job: {} write shell script error", this.executorJob.getId(), e);
throw new ExecutorRuntimeException(e.getMessage());
}
this.shellProcessJob = new ShellProcessJob(executorJob.getId(), sysProps, props, logger);
}
@Override
public void runInternal() throws Exception {
try {
shellProcessJob.run();
} finally {
}
}
@Override
public void kill() {
try {
shellProcessJob.cancel();
LOG.info("kill remote shell container executorJobId:{} get applicationId:{}", executorJob.getId(), executorJob.getApplicationId());
} catch (Throwable e) {
LOG.error("kill remote shell container, jobId:" + executorJob.getId(), e);
throw new ExecutorRuntimeException(e.getMessage());
}
}
@Override
public boolean isFailed() {
return shellProcessJob.isCanceled();
}
@Override
public boolean isSuccess() {
return shellProcessJob.isSuccess();
}
}
|
Bumps and Bruises in the Trauma Bay: A Level One Trauma Center's Analysis of Dedicated Skeletal X-Ray Imaging. The Ottawa Ankle Rule and Canadian C-Spine Rule were created to guide the utility of radiographic studies. There are no guidelines to guide X-rays within trauma. Our objective was to evaluate which findings have the highest yield for determining fractures on skeletal x-ray. A retrospective study was performed on 5050 patients at a level one trauma center from January 2018 through October 2019. 2382 patients received X-Rays. Our analysis focused on five categories: limb deformity/obvious open fracture, abrasions, hematoma/contusion/sprain, laceration, and skin tear. Standard demographic and outcome variables were collected. While the cost burden on an overwhelmed system, time in the trauma bay prior to disposition and radiation exposure has not been fully evaluated, our evidence shows that X-Rays ordered for soft tissue defects are less sensitive at identifying fracture (0.0-6.9% fracture detection rate, P = 0.00) than when ordered for limb deformity or obvious fracture. |
<reponame>thekalyan001/DMB1-CP
minimum number of characters to be inserted to convert it to palindrome
https://practice.geeksforgeeks.org/problems/form-a-palindrome2544/1#
recursion
int lcs(string a,string b,int n, int m){
if(n==0 || m==0)return 0;
if(a[n-1]==b[m-1])
return lcs(a,b,n-1,m-1)+1;
return max(lcs(a,b,n-1,m), lcs(a,b,n,m-1));
}
//bottom up
int findMinInsertions(string s){
string a=s;
reverse(a.begin(),a.end());
int lcsLen=lcs(a,s,s.size(),s.size());
return s.size()-lcsLen;
}
---------------------------------------------------------------
TLE in this also-> top down
int dp[501][501];
//TLE:-top down due to recursion stack space
int lcs(string a,string b,int n, int m){
if(n==0 || m==0)return 0;
if(a[n-1]==b[m-1])
return dp[n][m]=lcs(a,b,n-1,m-1)+1;
return dp[n][m]=max(lcs(a,b,n-1,m), lcs(a,b,n,m-1));
}
//bottom up
int findMinInsertions(string s){
memset(dp,-1,sizeof(dp));
string a=s;
reverse(a.begin(),a.end());
int lcsLen=lcs(a,s,s.size(),s.size());
return s.size()-lcsLen;
}
---------------------------------------------------------------
bottom up- ACCEPTED ☑
int lcs(string a,string b,int n){
int dp[n+1][n+1];
for(int i=0;i<=n;i++){
for(int j=0;j<=n;j++){
if(i==0 || j==0)
{dp[i][j]=0;continue;}
else if(a[i-1]==b[j-1])
dp[i][j]=dp[i-1][j-1]+1;
else
dp[i][j]=max(dp[i-1][j], dp[i][j-1]);
}
}
return dp[n][n];
}
//bottom up
int findMinInsertions(string s){
string a=s;
reverse(a.begin(),a.end());
int lcsLen=lcs(a,s,s.size());
return s.size()-lcsLen;
} |
Making sense of embodiment : simulation theories and the sharing of neural circuitry Although an increasing number of cognitive scientists are convinced that cognition is embodied, there still is relatively little agreement on what exactly that means. Notions of what it actually means for a cognizer to be embodied range from simplistic ones such as being physical or interacting with an environment to more demanding ones that consider a particular morphology or a living body prerequisites for embodied cognition. Based on experimental evidence from a range of disciplines, we argue that one of the keys to understanding the embodiment of cognition is the sharing of neural mechanisms between sensorimotor processes and higher-level cognitive processes. The latter are argued to be embodied in the sense that they make use of (partial) simulations or emulations of sensorimotor processes through the re-activation of neural circuitry also active in bodily perception and action. |
/**
* Builds the analysis. Called by the constructor and the reset method.
*/
private void constructAnalysis()
{
String ruleClassName = CurrentProperties.getInstance()
.getRuleClassName();
Rule rule = ReflectionTool
.instantiateMinimalRuleFromClassName(ruleClassName);
String ruleDescription = rule.getDisplayName();
isCompatibleRule = IntegerCellState.isCompatibleRule(ruleDescription);
if (isCompatibleRule)
{
numberOfStates = CurrentProperties.getInstance().getNumStates();
if (numberOfStates <= MAX_NUMBER_OF_STATES)
{
data = new String[numberOfStates + 1];
timeSeriesOfVolatilityList = new LinkedList[numberOfStates];
for (int i = 0; i < timeSeriesOfVolatilityList.length; i++)
{
timeSeriesOfVolatilityList[i] = new LinkedList<Point2D.Double>();
Point2D.Double point = new Point2D.Double();
point.setLocation(0, 0);
timeSeriesOfVolatilityList[i].add(point);
}
historicalPriceList = new LinkedList[numberOfStates];
for (int i = 0; i < historicalPriceList.length; i++)
{
historicalPriceList[i] = new LinkedList<Point2D.Double>();
}
}
}
createDisplayPanel();
} |
<reponame>inthemindofforrest/CodeDesignAndDataStructures
#include <vector>
#include <iostream>
void InsertionSort(std::vector<int> hsVector)
{
for (int i = 1; i < hsVector.size(); i++)
{
int Temp = hsVector[i];
int Below = i - 2;
for (; Below >= 0; Below--)
{
if (hsVector[Below] < hsVector[i] && hsVector[Below + 1] >= hsVector[i])
{
for (int Move = i; Move > Below + 1; Move--)
{
hsVector[Move] = hsVector[Move - 1];
}
hsVector[Below + 1] = Temp;
}
if (hsVector[0] >= hsVector[i])
{
for (int Move = i; Move > 0; Move--)
{
hsVector[Move] = hsVector[Move - 1];
}
hsVector[0] = Temp;
}
}
}
} |
<gh_stars>0
/**********************************************************************************************************
Copyright (c) 2002-2013 <NAME>. All rights reserved
Permission is hereby granted, free of charge, to any person obtaining a copy of this software and associated
documentation files (the Gabedit), to deal in the Software without restriction, including without limitation
the rights to use, copy, modify, merge, publish, distribute, sublicense, and/or sell copies of the Software,
and to permit persons to whom the Software is furnished to do so, subject to the following conditions:
The above copyright notice and this permission notice shall be included in all copies or substantial portions
of the Software.
THE SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED
TO THE WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT. IN NO EVENT SHALL
THE AUTHORS OR COPYRIGHT HOLDERS BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER LIABILITY, WHETHER IN AN ACTION OF
CONTRACT, TORT OR OTHERWISE, ARISING FROM, OUT OF OR IN CONNECTION WITH THE SOFTWARE OR THE USE OR OTHER
DEALINGS IN THE SOFTWARE.
************************************************************************************************************/
#ifndef __GABEDIT_TRIANGLEDRAW_H__
#define __GABEDIT_TRIANGLEDRAW_H__
#include "../Utils/Vector3d.h"
#include "../Utils/Transformation.h"
void get_color_surface(gint num,gdouble v[]);
void set_color_surface(gint num,gdouble v[]);
void TriangeShow(V3d V1,V3d V2,V3d V3,V3d N);
void IsoDraw( IsoSurface* iso);
void IsoGenLists(GLuint *positiveSurface, GLuint *negativeSurface, GLuint *nullSurface, IsoSurface* isopositive,IsoSurface* isonegative,IsoSurface* isonull);
void IsoShowLists(GLuint positiveSurface, GLuint negativeSurface, GLuint nullSurface);
void set_opacity_dlg();
void CellGenLists(GLuint *cell);
void CellShowLists(GLuint cell);
#endif /* __GABEDIT_TRIANGLEDRAW_H__ */
|
import { NormalSizes, SimpleColors } from '../../utils/prop-types';
import { NextUIThemes, NextUIThemesPalette } from '../../theme/index';
import { addColorAlpha, getNormalColor, hexToRgb } from '../../utils/color';
import { isEmpty } from '../../utils/assertion';
export type InputSize = {
heightRatio: string;
fontSize: string;
};
export const getSizes = (size?: NormalSizes) => {
const sizes: { [key in NormalSizes]: InputSize } = {
mini: {
heightRatio: '1.2',
fontSize: '.75rem',
},
small: {
heightRatio: '1.5',
fontSize: '.75rem',
},
medium: {
heightRatio: '1.687',
fontSize: '.875rem',
},
large: {
heightRatio: '1.875',
fontSize: '1rem',
},
xlarge: {
heightRatio: '2.25',
fontSize: '1.25rem',
},
};
if (!size) return sizes.medium;
return sizes[size];
};
export type InputColor = {
bgColor: string;
color: string;
placeholderColor: string;
helperColor: string;
borderColor: string;
hoverBorder: string;
shadowColor: string;
};
export const getShadowColor = (
palette: NextUIThemesPalette,
color?: SimpleColors
) => {
try {
const hexColor = getNormalColor(color, palette, palette.accents_4);
const [r, g, b] = hexToRgb(hexColor);
return `0 5px 20px -5px rgb(${r} ${g} ${b}/ 40%);`;
} catch (err) {
return 'none';
}
};
export const getColors = (
theme: NextUIThemes,
color?: SimpleColors,
status?: SimpleColors,
helperColor?: SimpleColors
): InputColor => {
const palette = theme.palette;
const isDark = theme.type === 'dark';
const normalColor = getNormalColor(color, palette);
const normalHelperColor = getNormalColor(helperColor, palette);
const normalStatusColor = getNormalColor(status, palette);
const baseProps = {
color: palette.text,
bgColor: isDark ? palette.accents_1 : palette.accents_2,
placeholderColor: isDark ? palette.accents_6 : palette.accents_3,
borderColor: palette.accents_2,
shadowColor: theme.expressiveness.shadowSmall,
};
if (status === 'default' || isEmpty(status)) {
return color === 'default'
? {
...baseProps,
helperColor: palette.text,
hoverBorder: palette.foreground,
}
: {
...baseProps,
helperColor: normalHelperColor,
hoverBorder: normalColor,
};
}
return {
...baseProps,
hoverBorder: normalColor,
helperColor: normalHelperColor,
color: normalStatusColor,
placeholderColor: addColorAlpha(normalStatusColor, 0.5),
bgColor: addColorAlpha(normalStatusColor, 0.2),
shadowColor: getShadowColor(palette, status),
};
};
|
export type DisplayFormatType = (string: string, color: string) => string;
|
import importlib
import req
import sys
import os
class leet():
arg = "leet"
session = ""
headers = ""
leet_source = ""
def __init__(self, imp):
source = os.getenv("leet_source")
if source != None:
self.leet_source = source
else:
self.leet_source = "leet-cn"
x = req.req("leet")
self.session = x.get_curl(self.leet_source)
self.headers = x.make_headers(self.session)
self.imp = imp
def get_problems(self, cat=["all"]):
req = self._get_req_imp()
problems = req.leet(self.session,self.headers,self.leet_source).get_problems(cat)
return self._format_problems(problems)
def get_topics(self):
req = self._get_req_imp()
return req.leet(self.session,self.headers,self.leet_source).get_topics()
def get_fav_list(self):
return self.get_problemset_list()
req = self._get_req_imp()
fav_list = req.leet(self.session,self.headers,self.leet_source).get_fav_list()
return self._format_fav_list(fav_list)
def get_problemset_list(self):
req = self._get_req_imp()
problemset_list = req.leet(self.session,self.headers,self.leet_source).get_problemset_list()
for item in problemset_list["categories"]["0"]:
item["cat"] = "cat"
for item in problemset_list["categories"]["1"]:
item["cat"] = "fav"
problemset_list["categories"]["0"].extend(problemset_list["categories"]["1"])
ret = problemset_list["categories"]["0"]
for item in ret:
item["name"] = item["title"]
return ret
def get_top_151_list(self):
problems = self.get_problems_of_top151()
top_list = {}
top_list["name"] = "top151"
top_list["num"] = len(problems)
ret = []
ret.append(top_list)
return ret
def get_problems_of_topic(self, topic):
req = self._get_req_imp()
topics = req.leet(self.session,self.headers,self.leet_source).get_problems_of_topic(topic)
topics["problems"] = self._format_problems(topics["problems"])
return topics
def _get_fav_list_problems(self, problems, fav_ids):
req = self._get_req_imp("leetsrc")
problems = req.leetsrc().get_fav_list_problems(problems, fav_ids)
return problems
def get_problems_of_top151(self ):
req = self._get_req_imp("leetsrc")
all_problems = self.get_problems()
problems = req.leetsrc().get_151_problems(all_problems )
return problems
def _get_problem_questions(self, question_url, cat ):
req = self._get_req_imp()
problems = req.leet(self.session,self.headers,self.leet_source).get_problemset_list_ids(question_url, cat)
ids = []
for item in problems["stat_status_pairs"]:
ids.append(item["stat"]["question_id"])
return ids
def get_problems_of_fav(self,fav_name):
fav = self.get_fav_list()
question_url = ""
for item in fav:
if fav_name in item["name"]:
question_url = item["slug"]
question_cat = item["cat"]
questions = self._get_problem_questions(question_url, question_cat)
all_problems = self.get_problems()
return self._get_fav_list_problems(all_problems, questions)
def get_problem(self, problem_id):
req = self._get_req_imp()
problem = req.leet(self.session,self.headers,self.leet_source).get_problem(problem_id)
return self._format_problem(problem)
def get_submissions(self, problem):
req = self._get_req_imp("leetsubmit")
submissions = req.leetsubmit(self.session,self.headers,self.leet_source).get_submissions(problem)
return submissions
def get_submission(self, sid):
req = self._get_req_imp("leetsubmit")
submission = req.leetsubmit(self.session,self.headers,self.leet_source).get_submission(sid)
req = self._get_req_imp("leetsubmitsrc")
submission = req.leetsubmitsrc().format_submit(submission)
problem = self.get_problem(submission['slug'])
submission['title'] = problem['title']
return submission
def test_solution(self, problem_id, title, slug, filetype, code, test_input):
req = self._get_req_imp("leetest")
result_id = req.leetest(self.session,self.headers,self.leet_source).test_solution(problem_id, slug, filetype, code, test_input )
req = self._get_req_imp("leetresult")
result = req.leetresult(self.session,self.headers,self.leet_source).check_result(result_id)
result['testcase'] = test_input.split('\n')
result['title'] = title
return result
def submit_solution(self,slug, filetype, code=None):
problem = self.get_problem(slug)
req = self._get_req_imp("leetsubmit")
result_id = req.leetsubmit(self.session,self.headers,self.leet_source).submit_solution(slug, filetype, code, problem)
req = self._get_req_imp("leetresult")
result = req.leetresult(self.session,self.headers,self.leet_source).check_result(result_id)
result['title'] = problem["title"]
return result
def _format_fav_list(self, fav_list):
req = self._get_req_imp("leetsrc")
return req.leetsrc().format_fav_list(fav_list)
def _format_problems(self, problems):
req = self._get_req_imp("leetsrc")
return req.leetsrc().format_problems(problems)
def _format_problem(self, problem):
req = self._get_req_imp("leetsrc")
return req.leetsrc().format_problem(problem)
def _get_req_imp(self,name="leetapi"):
importClass = self.arg+"."+ name
req=importlib.import_module(importClass)
return req
def get_problems( cat=["all"]):
x = leet("leet");
problems = x.get_problems()
return sorted(problems, key = lambda i: i['fid'])
def get_topics():
x = leet("leet");
topics = x.get_topics()
return topics
def get_fav_list():
x = leet("leet");
fav_list = x.get_fav_list()
return fav_list
def get_problemset_list():
x = leet("leet");
x.get_problemset_list()
def get_problems_of_topic( topic):
x = leet("leet");
topic = x.get_problems_of_topic(topic)
return topic
def get_fav_list_problems( problems, fav_ids):
x = leet("leet");
problems = x.get_fav_list_problems(problems, fav_ids)
return problems
def get_problem( problem_id):
x = leet("leet");
problem = x.get_problem(problem_id)
return problem
def get_problems_of_fav( fav_name):
x = leet("leet");
problems = x.get_problems_of_fav(fav_name)
return problems
def get_problems_of_top151( ):
x = leet("leet");
problems = x.get_problems_of_top151()
return problems
def get_top_151_list():
x = leet("leet");
lists = x.get_top_151_list()
return lists
def get_submissions(problem ):
x = leet("leet");
submissions = x.get_submissions(problem)
return submissions
def get_submission(sid ):
x = leet("leet");
submission = x.get_submission(sid)
return submission
def test_solution( problem_id, title, slug, filetype, code, test_input):
x = leet("leet");
test = x.test_solution( problem_id, title, slug, filetype, code, test_input)
return test
def submit_solution(slug, filetype, code=None):
x = leet("leet");
submit = x.submit_solution(slug, filetype, code)
return submit
if __name__ == "__main__":
x = leet("leet");
print("####################")
fav = x.get_fav_list()
print(fav)
print("####################")
fav = x.get_problems_of_fav(fav[len(fav)-2]["name"])
print(fav)
sys.exit()
problems = x.get_problems()
all_problems = problems
print("####################")
print("all problems nums:")
print(len(problems))
print("frist problems:")
print(problems)
sys.exit()
print("####################")
topics = x.get_topics()
print("all topics nums:")
print(len(topics))
print("frist topics:")
print(topics[0])
print("####################")
topic = topics[0]
print("topic name:")
print(topic["topic_name"])
topics = x.get_problems_of_topic(topic["topic_name"])
problems = topics["problems"]
print("all topics problems nums:")
print(len(problems))
print("frist topics problem:")
print(problems[0])
print("####################")
fav = x.get_fav_list()
print("all fav nums:")
print(len(fav))
print("last fav:")
print(fav[0])
print("####################")
fav_name = fav[0]["name"].replace(' ','')
fav = x.get_problems_of_fav(fav_name)
print("fav list:")
print(len(fav))
print("first fav:")
print(fav[0])
print("####################")
submissions = x.get_submissions(fav[0]['slug'])
print("first submissions :")
print(submissions[0])
print("####################")
submission = x.get_submission(submissions[0]['id'])
print("submission :")
print(submission)
print("####################")
problem = x.get_problem(fav[0]['slug'])
print("problem :")
print(problem)
print("####################")
problems = x.get_problems_of_top151()
print("num:")
print(len(problems))
print("151 problem :")
print(problems[0])
print("####################")
top_list = x.get_top_151_list()
print("151 list :")
print(top_list)
print("####################")
|
<gh_stars>0
import json
class LoadJson:
def __init__(self, payload):
self.data = json.load(payload)
self.source = self.data['source']
try:
self.api_url = self.source['api_url']
self.access_token = self.source['access_token']
self.project = self.source['project']
self.branch = self.source['branch']
except:
raise Exception("Missing required source config")
# check if also params exist
if 'params' in self.data :
self.params = self.data['params']
try:
self.target_branch = self.params['target_branch']
# Optional params
if 'delete_source' in self.params:
self.delete_source_branch = self.params['delete_source']
except:
raise Exception("Missing parameters")
# version is passed in get and put steps
if 'version' in self.data :
self.version = self.data['version']
try:
self.id = self.version['iid']
except:
raise Exception("Version not set")
|
1. The Field of the Invention
This invention relates to systems, methods, and computer program products which can be used to facilitate diagnosis and simulations of living organisms, including computing interfaces and devices capable of rendering anatomical elements and relevant information for related conditions and treatment options.
2. The Relevant Technology
Modern medical practices and information technologies have enriched and extended human life by identifying and disseminating medical information which can help individuals pursue healthy life choices and that is usable to treat a variety of medical conditions.
The application of appropriate medical treatments is often dependent upon the accuracy of medical diagnosis as well as the education that medical practitioners and patients have regarding any particular medical condition and the corresponding consequences of different treatment options.
Computing technologies can facilitate the foregoing education of medical practitioners and patients. For instance, some computing systems have been developed that are capable of identifying and rendering specific anatomy and for diagnosing and providing information related to the treatment options for particular anatomical conditions. It is now commonplace in the medical profession to see the use of multimedia systems to at least supplement the education of medical practitioners, as well as patients, regarding anatomical conditions and related treatments.
Unfortunately, the variety and complexities of biological anatomy make it difficult to present any single system or interface that is capable of accommodating the educational needs and preferences of all medical practitioners and patients. Existing interfaces and educational materials, for example, are typically generalized and fail to provide the level of personalization that is typically desired and sometimes necessary to adequately educate a patient or medical professional regarding a particular patient's anatomy, diagnosis, and/or available treatment options.
Accordingly, there remains an ongoing need for further development in the field of medicine, with particular regard to the manner in which computing systems are used for identifying and presenting information related to different anatomical conditions and treatment options. |
#ifndef STACK_H
#define STACK_H
#include <stdio.h>
#include <stdlib.h>
#include <string.h>
#include "bst.h"
struct stack{
BST* data;
struct stack *next;
};
struct Stack{
unsigned int size;
struct stack *stack;
};
typedef struct stack stack;
typedef struct Stack Stack;
Stack* create_stack();
void push(Stack* s, BST* num);
void pop(Stack* s);
BST* top(Stack* s);
int isEmpty(Stack* s);
#endif
|
<gh_stars>0
from tensorflow.keras.utils import Sequence
from ucsc_genomes_downloader.utils import expand_bed_regions
from keras_bed_sequence import BedSequence
import os
import pandas as pd
import numpy as np
from typing import Tuple
class BiologicalGapsSequence(Sequence):
def __init__(
self,
source: str,
target: str,
source_window_size: int,
target_window_size: int,
batch_size: int,
verbose: bool = True,
seed: int = 42,
elapsed_epochs: int = 0
):
"""Create new BiologicalGapsSequence.
Parameters
----------------------------------
source: str,
Assembly from which to extract the input sequences.
These sequences are centered upon the single nucleotide gaps.
target: str,
Assembly from which to extract the output sequences.
These sequences are centered upon the nucleotides corresponding to the gaps.
source_window_size: int,
Window size to use for the input.
target_window_size: int,
Window size to use for the output.
batch_size: int,
Training batch size.
verbose: bool = True,
Wethever to show or not the loading bars.
seed: int = 42,
The seed to use for shuffling the data on training epoch end.
elapsed_epochs: int = 0,
The number of elapsed epochs.
Raises
---------------------------------
ValueError,
If the dataset with given combination of source and target
is not currently available.
Returns
----------------------------------
New BiologicalGapsSequence.
"""
path = "{pwd}/datasets/{source}_{target}.bed".format(
pwd=os.path.dirname(os.path.abspath(__file__)),
source=source,
target=target
)
if not os.path.exists(path):
raise ValueError("Given combination of source '{source}' and target '{target}' is not currently available.".format(
source=source,
target=target
))
bed = pd.read_csv(path, sep="\t")
source_bed = expand_bed_regions(pd.DataFrame({
"chrom": bed.chrom,
"chromStart": bed[source],
"chromEnd": bed[source]+1,
}), source_window_size)
target_bed = expand_bed_regions(pd.DataFrame({
"chrom": bed.chrom,
"chromStart": bed[target],
"chromEnd": bed[target]+1,
}), target_window_size)
self._source_sequence = BedSequence(
source,
source_bed,
batch_size=batch_size,
verbose=verbose,
seed=seed,
nucleotides="actgn",
elapsed_epochs=elapsed_epochs
)
self._target_sequence = BedSequence(
target,
target_bed,
batch_size=batch_size,
verbose=verbose,
seed=seed,
nucleotides="actgn",
elapsed_epochs=elapsed_epochs
)
def on_epoch_end(self):
"""Shuffle private bed objects on every epoch end."""
self._source_sequence.on_epoch_end()
self._target_sequence.on_epoch_end()
def __len__(self) -> int:
"""Return length of bed generator."""
return len(self._source_sequence)
@property
def steps_per_epoch(self) -> int:
"""Return length of bed generator."""
return self._source_sequence.steps_per_epoch
@property
def batch_size(self) -> int:
"""Return batch size to be rendered."""
return self._source_sequence.batch_size
@batch_size.setter
def batch_size(self, batch_size: int):
"""Set batch size to given value."""
self._source_sequence.batch_size = batch_size
self._target_sequence.batch_size = batch_size
@property
def samples_number(self) -> int:
"""Return number of available samples."""
return self._source_sequence.samples_number
def __getitem__(self, idx: int) -> Tuple[np.ndarray, np.ndarray]:
"""Return batch corresponding to given index.
Parameters
---------------
idx: int,
Index corresponding to batch to be rendered.
Returns
---------------
Return Tuple containing X and Y numpy arrays corresponding to given batch index.
"""
# Get the input sequence
x = self._source_sequence[idx]
# Get the output sequence
y = self._target_sequence[idx]
# Get the values corresponding to gaps
nx = x[:, :, -1].astype(bool)
ny = y[:, :, -1].astype(bool)
# Filter out the 5th nucleotide (the gaps)
x = x[:, :, :4]
y = y[:, :, :4]
# Apply uniform value where the nucleotide is a gap
x[nx] = 0.25
y[ny] = 0.25
return x, y
|
On Monday, Sally Yates, the acting Attorney General, provided an example of what it means to work honorably for Donald Trump. It comes down to conducting yourself in a way that, in many cases, will result—that you know will result—in not working for him for very long. Trump fired Yates after she refused to deploy Justice Department lawyers in defense of his executive order, issued on Friday, which bans people from seven Muslim-majority countries, and refugees from anywhere in the world, from entering the United States.
Yates was an Obama holdover; she was expected to keep the Justice Department running until the Trump team had been confirmed. She might have seen herself as without a mandate. She might have thought that she had no choice but to support the new President when he signed an order that, though gussied up with a supposed temporary focus on dangerous lands, laid the basis for a religious test on immigration and for institutionalized discrimination against certain legal residents—not to mention the spectre of family division and the possible abandonment of America’s treaty obligations. When lawyers for the American Civil Liberties Union and other groups rushed to court to challenge the executive order, and U.S. Attorneys assembled lawyers to defend it, Yates could have sent federal attorneys into court, if only to go through the motions. She wouldn’t have had to do anything but mourn the harm to ordinary lives and to America’s values. Perhaps no one would have blamed her. Or she could have garnered all the praise she needed, in her circles, by resigning in a muted fashion and then, as a private citizen, writing an op-ed or giving an interview, maybe even an enraged one. Yates did something different: she decided that her job, her official position, not her policy beliefs or even the dictates of her conscience, required that she defy the President.
She did so in a letter which notes that Justice Department lawyers are “charged with advancing reasonable legal arguments that can be made supporting an Executive Order,” but that her role “as leader of this institution is different and broader. My responsibility is to ensure that the position of the Department of Justice is not only legally defensible, but is informed by our best view of what the law is after consideration of all the facts.” Those facts, she suggested, included the context and the statements that “an Administration or its surrogates” made at various points about the purpose of this executive order. She was apparently referring to the Muslim ban that Trump promised his supporters during the campaign, and to statements about giving preferential treatment to Christians, which made it clear that the notion that this action wasn’t really about religion or bigotry was a sham. Yates continued, “I am responsible for ensuring that the positions we take in court remain consistent with this institution’s solemn obligation to always seek justice and stand for what is right. At present, I am not convinced that the defense of the Executive Order is consistent with these responsibilities nor am I convinced that the Executive Order is lawful.” And so, as Yates said, "For as long as I am the Acting Attorney General, the Department of Justice will not present arguments in defense of the Executive Order, unless and until I become convinced that it is appropriate to do so." It wasn't hard to guess which of those things—staying the acting Attorney General, and becoming convinced of the appropriateness of the order—might change first.
This could all be seen as a particularly dramatic resignation letter. There can’t be any doubt that Yates was going to be out of a job soon after she sent it—this Monday Night Massacre, despite the Nixonian parallels, should come as less of a surprise than the original Saturday-night version, given everything that we already know about Trump. But, by daring Trump to fire her, and for doing her job until and despite his decision to do so, Yates made a powerful statement about the profession of politics itself. A large part of it is the ever more essential struggle to keep careerism and partisanship from blinding one to citizenship and principle. (Paul Ryan and a lot of his colleagues have failed this test.) But there is also, for those who form the moving parts of our constitutional machinery, a question of the duty one has—and to what, and to whom.
Trump has an easy answer: to him. In the White House statement regarding the matter, released on Monday night, he made it clear that he confuses constitutional obligations with personal obedience. “The acting Attorney General, Sally Yates, has betrayed the Department of Justice by refusing to enforce a legal order designed to protect the citizens of the United States,” it said. “Betrayed” is a shocking word here, particularly given the suggestion that she is indifferent to American lives, suggesting as it does that she ought to be seen as a traitor to her country, rather than a dissenter. (As a prosecutor, she helped win the conviction of Eric Rudolph, the Olympic Park bomber.) And, indeed, the statement goes on to say that Yates “is weak on borders and very weak on illegal immigration.” Does Trump really know that about her? Does he know anything about her, other than that she didn’t listen to him?
His next acting Attorney General, Dana Boente, who had been a U.S. Attorney for the Eastern District of Virginia, and was sworn in late Monday evening, has already begun to defend the ban. And the permanent Attorney General whom Trump has nominated, Senator Jeff Sessions, will be coming along as soon as he gets through the Senate. For Sessions, there won’t be any conflict: he defended a far cruder version of Trump’s ban on the campaign trail, and did so with passion. Indeed, a Washington Post story on Monday portrayed Sessions as the intellectual “Godfather” of the Trump Administration, admired by Steve Bannon and Jared Kushner alike. Sessions has for years been an extreme voice opposing immigration and, for that matter, civil-rights enforcement. In his confirmation hearings, he circumnavigated questions about religious tests by saying that some people had a religion that involved killing—and those people ought to stay out. So far, the Democrats have not been very effective at stopping Sessions. It might be time for them to try harder, with a more concerted offensive that rallies the public and, at the very least, forces whatever moderate Republicans there are left to be honest, if not ashamed, about what they are acquiescing to by confirming him.
The questions that the Democrats need to ask about the executive order should also be central to confirmation hearings for Trump’s Supreme Court nominee. “Deference” is a word that comes up a great deal in Supreme Court decisions on the adjudication of executive power. It is what courts are often asked to extend to the executive on questions of national security. Judges are supposed to trust the President, to an extent, when it comes to assertions that the country is in danger. But what if they can’t trust him, on even a basic level? And what if the President, by deference, understands only deferral to himself? The Yates story is an example of what the Attorney General can do—or what he or she can help the President to destroy. |
German Nest Competitor Tado Looks to Expand in the U.S.
Tado, which makes Internet-connected thermostats, says its new product can turn almost any AC unit into a smart device.
Is the competition among smart thermostats heating up?
German smart thermostat company Tado recently raised $13.6 million in new financing from backers Target Partners and Shortcut Ventures. CEO Christian Deilmann says the funding will be used to fuel growth in Europe and help the company expand in the United States.
Earlier this year, Google (NASDAQ:GOOGL) acquired smart thermostat startup Nest for more than $3 billion.
Unlike Nest, which offers a single thermostat that can control both heating and cooling systems, Tado offers separate thermostats and apps for heating and cooling. With Tado, Deilmann says most of the “intelligent” features are in the smartphone app and on the server.
He says these functions are enabled by geo-location signals.
And though the Google acquisition brought Nest into the spotlight in the U.S., Deilmann says the Tado product will bring something new to the market – even though both technically fall into the “smart thermostat” category.
Earlier this summer, Tado ran a successful Kickstarter campaign for its “Cooling” product. The company raised over $200,000 from 1,601 backers for the product, which the company says can turn almost any AC unit into a “smart” device. |
<reponame>RevansChen/online-judge<gh_stars>1-10
# Python3
from solution1 import allLongestStrings as f
qa = [
(["aba", "aa", "ad", "vcd", "aba"],
["aba", "vcd", "aba"]),
(["aa"],
["aa"]),
(["abc", "eeee", "abcd", "dcd"],
["eeee", "abcd"]),
(["a", "abc", "cbd", "zzzzzz", "a", "abcdef", "asasa", "aaaaaa"],
["zzzzzz", "abcdef", "aaaaaa"])
]
for *q, a in qa:
for i, e in enumerate(q):
print('input{0}: {1}'.format(i + 1, e))
ans = f(*q)
if ans != a:
print(' [failed]')
print(' output:', ans)
print(' expected:', a)
else:
print(' [ok]')
print(' output:', ans)
print()
|
PREVALENCE, RISK FACTORS, KNOWLEDGE OF HYPERTENSION AND DIETARY INTAKE OF GHANIAN NURSES IN NORTHERN REGION Mortality and morbidity of CVD hypertension coexist with undernutrition in Ghana. Little data are available to address the public health issues. Since nurses are the first line contacts with the general public and patients in providing nutrition and health education, we aimed to document nurses' prevalence, determinants, knowledge and dietary intake of hypertension in northern region of Ghana. A total of 246 nurses (74 men, 172 women) were recruited between MayJuly, 2014 to have blood pressure measured in four hospitals and complete questionnaires on their risk factors, knowledge of hypertension and dietary intake for a day. The determinants and differences in knowledge on hypertension among normotensive(<120/80mmHg, n=141, 57%), prehypertensive(120/80140/90mmHg, n=95, 39%) and hypertensive(>140/90mmHg, n=10, 4%) nurses were determined by chisquare tests using SPSS. Significant determinants of hypertension were age, rank in nursing, family history, physical activity levels and knowledge of prevention of hypertension, whereas gender, marital status, religion, BMI, and knowledge of causes, and food and hypertension did not differ among the groups. The majority (73% and 88%, resp) had inadequate K and Ca intake and excess Na, Mg, and P (57%, 74% and 72%, resp); those with inadequate calcium intake had a high odd ratio of pre/hypertension (OR=3.54; 95% CI, 1.0911.48). We conclude that nutrition and health education of nurses on risk factors; knowledge and dietary practices are needed for their own health and to empower them to help the public. |
The present invention relates generally to inkjet printers, and more particularly to an improved inkjet printhead structure.
In contrast to many other types of printers, inkjet printers provide fast, high resolution, black-and-white and color printing on a wide variety of media and at a relatively low cost. As a result, inkjet printers have become one of the most popular types of printers for both consumer and business applications. Nevertheless, inkjet technology must continuously advance to keep pace with ever-increasing customer demands for printers that print faster, at a higher resolution, and at a lower cost.
One of the more important components of an inkjet printer is the inkjet printhead. Often housed in, or mounted on, a replaceable ink cartridge, the inkjet printhead controls the application of ink to the printing medium (e.g., paper). Generally, inkjet printheads include a plurality of ink ejection mechanisms formed on a substrate. Each ink ejection mechanism includes a firing chamber with at least one ejection orifice. Each ink ejection mechanism also includes one or more firing resistors located in the firing chamber. The substrate is connected to an ink cartridge or other ink supply. Channel structures formed on the substrate direct the ink from the ink supply to the firing chambers. Control circuitry, located on the substrate and/or remote from the substrate, supplies current to the firing resistors in selected firing chambers. The ink within the selected chambers is super-heated by the firing resistors, causing the ink to be ejected through the chamber orifice toward the printing medium in the form of an ink droplet.
Conventional inkjet cartridges and printheads are well known to those of skill in the art and therefore are not described in more detail herein. Several exemplary printhead configurations are described in the following U.S. Patents, the disclosures of which are herein incorporated by reference: U.S. Pat. No. 5,636,441 to Meyer et al., entitled xe2x80x9cMethod of Forming a Heating Element for a Printheadxe2x80x9d; U.S. Pat. No. 5,682,188 to Meyer et al., entitled xe2x80x9cPrinthead with Unpassivated Heater Resistors Having Increased Resistancexe2x80x9d; and U.S. Pat. No. 6,155,675 to Nice et al., entitled xe2x80x9cPrinthead Structure and Method for Producing the Same.xe2x80x9d Inkjet printheads are typically manufactured using standard semiconductor processing methods such as are known to those of skill in the art and described in the above-referenced patents.
One problem that occurs in conventional printhead structures is damage caused to the firing resistors when a portion of an ink droplet breaks away and collapses back into the chamber and onto the resistor. Several approaches have been developed to alleviate this problem. For example, one approach involves forming the firing resistors of thicker layers that are less vulnerable to mechanical stress and impact. Another approach involves forming a protective layer over the resistors to absorb the impact. However, both approaches increase the thermal mass which must be heated to eject the ink, thereby decreasing the thermal efficiency of the ink ejection mechanism. As a result, the delay times between consecutive firings of the ejection mechanisms must be increased, thereby reducing the maximum printing speed of the printhead. Furthermore, additional protective layers increase the complexity and cost of manufacturing the printheads.
The present invention provides an improved inkjet printhead assembly adapted to reduce and/or withstand the collapse of ink back into the firing chambers. In one embodiment, the printhead assembly includes one or more firing chambers disposed on a porous substrate. An ink supply is connected to the substrate so that ink is allowed to flow through the pores of the substrate from the ink supply to the firing chamber. Thus, a substantial amount of the energy created by the impact of ink collapsing back into the firing chamber is expended within the pores of the substrate. In another embodiment, one or more firing resistors are formed in each firing chamber, and disposed adjacent the periphery of the firing chamber out of the direct impact path of collapsing ink. The peripheral firing resistors may be formed on either a porous or non-porous substrate. |
Selective Catalytic Reduction of Nitric Oxide with Propylene over Fe/Beta Catalysts Under Lean-Burn Conditions Fe/Beta catalysts were used for the selective catalytic reduction of nitric oxide with propylene (C3H6-SCR) under lean-burn conditions, which were prepared by liquid ion-exchange (LIE), solid-state ion-exchange (SIE), and incipient wet-impregnation (IWI) methods. The iron species on Fe/Beta were characterized and identified by a combination of several characterization techniques. The results showed preparation methods had a significant influence on the composition and distribution of iron species, LIE method inclined to produce more isolated Fe3+ ions at ion-exchanged sites than IWI and SIE method. C3H6-SCR activity tests demonstrated Fe/Beta(LIE) possessed remarkable catalytic activity and N2 selectivity at temperature 300450 °C. Kinetic studies of C3H6-SCR reaction suggested that isolated Fe3+ species were more active for NO reduction, whereas Fe2O3 nanoparticles enhanced the hydrocarbon combustion in excess of oxygen. According to the results of in situ DRIFTS, more isolated Fe3+ sites on Fe/Beta(LIE) would promote the formation of the key intermediates, i.e., NO2 adspecies and formate species, then led to the superior C3H6-SCR activity. The slight decrease of SCR activity after hydrothermal aging of Fe/Beta(LIE) catalyst might be due to the migration of isolated Fe3+ ions into oligomeric clusters and/or Fe2O3 nanoparticles. |
MELAKA (Bernama) -- Aida (not her real name) seemed nervous and fidgety as she held her eight-month-old baby close to her chest, clutching an immunisation brochure in her hand as she waited for the government clinic in Ayer Keroh here, to open.
She was obviously there to get her daughter immunised but still had doubts if she was doing the right thing. Apparently, she had read an article on social media stating that vaccines could cause death as they contained substances that were not only harmful but forbidden in Islam.
Out of fear, Aida did not take her baby to the clinic for the first round of immunisation when she was two months old. |
/****************************************************************************
* Name: up_shutdown
*
* Description:
* Disable the UART. This method is called when the serial
* port is closed
*
****************************************************************************/
static void rtl8721d_up_shutdown(struct uart_dev_s *dev)
{
struct rtl8721d_up_dev_s *priv = (struct rtl8721d_up_dev_s *)dev->priv;
DEBUGASSERT(priv);
DEBUGASSERT(sdrv[uart_index_get(priv->tx)]);
serial_free(sdrv[uart_index_get(priv->tx)]);
rtw_free(sdrv[uart_index_get(priv->tx)]);
sdrv[uart_index_get(priv->tx)] = NULL;
} |
<reponame>s-rajput/NextJs<filename>components/page-heading/PageHeading.tsx
//== IMPORT PACKAGE ==
import { ReactNode, ReactElement } from "react";
//== IMPORT STYLES ==
import { Box, Typography, PropTypes } from "@material-ui/core";
import PageHeadingStyles from "./PageHeadingStyles";
//== IMPORT ASSET ==
//== IMPORT VIEWS ==
//== MAIN COMPONENT ==
export interface PageHeadingInterface {
children: ReactNode;
wrapper?: boolean;
align?: PropTypes.Alignment;
}
export default function PageHeading({
children,
wrapper = true,
align = "left",
}: PageHeadingInterface): ReactElement {
/** vars */
const styles = PageHeadingStyles();
/** render */
if (wrapper) {
return (
<Box className={styles["page-heading-container"]}>
<Typography
variant={"h4"}
component={"h1"}
align={align ? align : "left"}
color={"primary"}
className={styles["page-heading-text"]}
>
{children}
</Typography>
</Box>
);
}
return (
<Box
aria-label="heading"
mb={{
xs: 1,
sm: 2,
}}
>
<Typography
variant={"h4"}
component={"h1"}
align={"left"}
color={"primary"}
>
{children}
</Typography>
</Box>
);
}
|
// set new time for callback (could actually be sooner)
// delay is relative to current time.
bool DelayCallback(bkgCallback_t *bcb, uint32_t delay)
{
if (!bcb->callback) return false;
bcb->startTime = TimDevGetTimerCount();
bcb->duration = delay;
return true;
} |
Apple's latest iPhone outperforms its 4S predecessor by a significant margin, but is matched in most areas by Samsung's Android flagship, the Galaxy S III.
ZDNet (in Germany) has examined the iPhone 5's performance using multiple benchmark tests. By way of comparison, we've included the leading Android-based competitor, Samsung's quad-core Galaxy S III (which has just received an update to Android 4.1 Jelly Bean), along with the previous-generation iPhone 4S and the iPad 3 tablet.
On test (from left): iPhone 5, iPhone 4S, iPad 3, Samsung Galaxy S III.
Geekbench bases its overall performance score on four tests: two determine the speed of the processor when handling integers and floating-point numbers (Integer, FPU) and two assess memory speed and bandwidth (Memory, Stream).
This cross-platform benchmark is well suited to analysing the performance of iOS devices, but caution is required when comparing the results on other platforms. For example, in the past, the Windows version differed from the Mac version by not using all CPU extensions, with the result that Mac OS systems delivered significantly higher scores than comparable Windows systems.
At first glance, the iPad 3's results appear particularly poor. However, this is due to the fact that the 3D graphics tests are performed at the device's native resolution, and the iPad 3 has to move over four times as many pixels (2,048 by 1,536) than the iPhone 5 (1,136 by 640). Since both devices' GPUs have similar capabilities, the iPad delivers a worse result thanks to its higher resolution — in the individual 3D Graphics test (below), the iPad 3 scored 587 points to the iPhone 5 's 1,752. On the other hand, this does reflect the performance that's actually experienced.
A different picture emerges if 3D performance is assessed at a predefined resolution (see GLBenchmark result, below). In this case, the iPad 3 delivers comparable performance to the iPhone 5. However, this finding is of little relevance in practice, as most 3D applications run with the device's native resolution. In this respect, the iPad 3 is 'suffering' for its high-resolution Retina display.
Apple's iPhone 5 offers excellent performance across the board, and is significantly faster than its iPhone 4S predecessor. The Android-based Samsung Galaxy S III delivers comparable performance in all areas except 3D games. Having said that, it beats the iPhone 5 in PassMark's PerformanceTest Mobile 2D Graphics test by some distance (see graph on page 2).
Version 4.1 of Google's operating system is largely responsible for the excellent performance of the Android smartphones: Jelly Bean has put an end to the screen freezes of the past — even on far less powerful devices than the Samsung Galaxy S III used for these tests. Unfortunately for Android users, few manufacturers have so far released Jelly Bean for their devices. The update process for the Android platform is too long and device support is restricted. By contrast, the latest iOS version is available for the three-year-old iPhone 3GS. Technically savvy Android fans can, of course, use Jelly Bean images from the developer community. If you're wary of an Android version that isn't from your phone's manufacturer, you should purchase a Google phone, for which the latest OS updates are quickly available.
This article originally appeared on ZDNet Germany as iPhone 5 im Benchmarktest. |
Internal hernia caused by the appendix adhering to the right ovary: a case report. Internal hernias are a rare condition and sometimes life-threatening, and they need an emergency exploratory laparotomy. Appendicectomy for chronic appendicitis is controversial. Without timely treatment, chronic appendicitis may develop into a ruptured appendix and an infection that spreads to other parts of the body, and other serious complications. Here we report the case of 48-year-old female who had intestinal ischemia secondary to internal hernia caused by the appendix adhering to the right ovary. Her medical history indicated a chronic, right lower abdominal pain for three years. |
The mainframe is not going away.
In fact, uptake is increasing globally and the mainframe is more flexible than ever before, while its robustness, availability and reliability improve year-on-year.
Contrary to some beliefs that the cloud will replace the mainframe, IBM Solutions sales manager Satish Babu points out that the mainframe actually supports cloud.
"There is a misconception that the cloud computing environment excludes mainframes and legacy systems," says Babu. "On the contrary, the mainframe was introduced to serve as the most robust, scaleable system ever. Now, coupled with new open standards interfaces, we can take the strengths of the mainframe into the new world.
"The mainframe is only a legacy system if it is not being used effectively. Where industry is innovating on the mainframe, its strengths enable new technologies," he says.
A recent white paper from information technology services company, Atos, notes that in spite of continual rumours of its death, the mainframe is alive and well and represents a viable and cost-effective platform for running modern IT systems.
According to Atos, mainframes are still able to run database, application, file server, Web server and firewall functions on one machine - and do so at a high level of security and reliability.
In fact, Atos explains, the greatest long-term threat to the mainframe market comes not from any weakness in the platform itself, but from the continued evolution of other platforms to a level that is 'good enough' to replace it.
The 2013 Arcati Mainframe User Survey also notes that some of the smaller sites are moving away from mainframes, not because of any particular issue with the mainframe platform, but because managers are unfamiliar with the mainframe culture.
According to Babu, cloud allows infrastructure and software to combine in a virtualised environment, and the mainframe is an infrastructure element of the overall construct.
"So they are not two different worlds," he points out. He notes that the enterprise IT environment has become increasingly complex as IT looks to move a dispersed computing environment back to a consolidated, single system of records, shared across geographical areas and devices for a lower total cost of ownership.
"You still need a mainframe, and it becomes a very viable infrastructure from which to deploy cloud services," he says.
For large enterprises with data security concerns, such as banks, this implies moving to a private cloud supported by a mainframe, he points out, adding that most of the world's top banks and largest insurance companies run mainframes.
For other enterprises, he states, the public cloud or a hybrid model may deliver the necessary benefits and economies of scale.
"We see organisations across the board moving toward the cloud," Babu says. "As virtualisation emerged, we saw less infrastructure needed. This led to standardisation, then automation, then cloud. It is all part of an incremental process of consolidation and improvement in cost containment and service delivery." |
<reponame>ned1313/flask-voting-gcp<gh_stars>0
from flask import Flask, render_template, request, Response, redirect, url_for
import sqlalchemy
from werkzeug.exceptions import abort
from . import sql
# This global variable is declared with a value of `None`, instead of calling
# `init_connection_engine()` immediately, to simplify testing. In general, it
# is safe to initialize your database connection pool when your script starts
# -- there is no need to wait for the first request.
db = None
app = Flask(__name__)
@app.before_first_request
def create_tables():
global db
db = db or sql.init_connection_engine()
# Create tables (if they don't already exist)
with db.connect() as conn:
conn.execute(
"CREATE TABLE IF NOT EXISTS polls "
"(id INT NOT NULL AUTO_INCREMENT PRIMARY KEY, created TIMESTAMP NOT NULL DEFAULT CURRENT_TIMESTAMP, "
"question VARCHAR(100) NOT NULL, answer1 VARCHAR(100) NOT NULL, votes1 INT NOT NULL, answer2 VARCHAR(100) NOT NULL, "
"votes2 INT NOT NULL, answer3 VARCHAR(100), votes3 INT, answer4 VARCHAR(100), votes4 INT );"
)
@app.route('/')
def index():
with db.connect() as conn:
polls = conn.execute(
'SELECT id, created, question'
' FROM polls p'
' ORDER BY created DESC'
).fetchall()
return render_template('polls.html', polls=polls)
@app.route('/create', methods=['GET','POST'])
def create():
if request.method == 'POST':
question = request.form['question']
answer1 = request.form['answer1']
answer2 = request.form['answer2']
answer3 = request.form['answer3']
answer4 = request.form['answer4']
error = None
if not question:
error = 'Question is required.'
if error is not None:
abort(404)
else:
stmt = sqlalchemy.text(
"INSERT INTO polls (question, answer1, answer2, answer3, answer4, votes1, votes2, votes3, votes4) "
"VALUES (:q, :a1, :a2, :a3, :a4, 0, 0, 0, 0)"
)
with db.connect() as conn:
conn.execute(
stmt,
q=question,
a1=answer1,
a2=answer2,
a3=answer3,
a4=answer4
)
return redirect(url_for('index'))
else:
return render_template('poll_create.html')
def get_poll(id):
with db.connect() as conn:
stmt = sqlalchemy.text(
"SELECT * FROM polls p WHERE p.id = :id"
)
poll = conn.execute(
stmt,
id=id
).fetchone()
if poll is None:
abort(404, f"Poll id {id} doesn't exist.")
return poll
@app.route('/poll/<int:index>', methods=['GET','POST'])
def poll_view(index):
if request.method == 'POST':
poll = get_poll(index)
vote_name = request.form["vote"]
stmt = sqlalchemy.text(
"UPDATE polls SET " + str(vote_name) + " = " + str(vote_name) + " + 1 WHERE id = :id"
)
with db.connect() as conn:
conn.execute(
stmt,
id=index
)
return redirect(url_for('poll_view', index=index))
else:
poll = get_poll(index)
return render_template('poll_view.html', poll=poll)
@app.route('/poll-delete/<int:index>')
def poll_delete(index):
stmt = sqlalchemy.text(
"DELETE FROM polls WHERE id = :id"
)
with db.connect() as conn:
conn.execute(
stmt,
id=str(index)
)
return redirect(url_for('index')) |
Traumatic Brain Injury and Stem Cells: An Overview of Clinical Trials, the Current Treatments and Future Therapeutic Approaches Traumatic brain injury represents physical damage to the brain tissue that induces transitory or permanent neurological disabilities. The traumatic injury activates an important inflammatory response, followed by a cascade of events that lead to neuronal loss and further brain damage. Maintaining proper ventilation, a normal level of oxygenation, and adequate blood pressure are the main therapeutic strategies performed after injury. Surgery is often necessary for patients with more serious injuries. However, to date, there are no therapies that completely resolve the brain damage suffered following the trauma. Stem cells, due to their capacity to differentiate into neuronal cells and through releasing neurotrophic factors, seem to be a valid strategy to use in the treatment of traumatic brain injury. The purpose of this review is to provide an overview of clinical trials, aimed to evaluate the use of stem cell-based therapy in traumatic brain injury. These studies aim to assess the safety and efficacy of stem cells in this disease. The results available so far are few; therefore, future studies need in order to evaluate the safety and efficacy of stem cell transplantation in traumatic brain injury. Introduction Traumatic brain injury (TBI) is the main cause of death in young people living in industrialized countries. TBI is a condition caused by an external mechanical force responsible for brain dysfunction. This disorder can lead to temporary damage or permanent dysfunctions that induce severe cognitive, physical, and emotional disturbances. Early intervention is important to minimize the development of brain injuries that could aggravate the patient's condition. Surgery is often necessary for patients with more serious injuries to monitor and treat high intracranial pressure (ICP), decompress the brain if intracranial pressure has increased, or remove intracranial hematomas. The management of ICP is also defined as life-saving treatment, as unstable ICP can compromise the patient's life. The ICP management is performed by extraventricular drainage, as well as by intraparenchymal catheter or combined catheter. The use of hyperosmolar substances such as mannitol and hypertonic saline solution represents a mild treatment route, currently used to reduce elevated ICP. Other practices for managing ICP can be bed elevation, hyperventilation, and barbiturate coma. The severity of the injury is clinically identified by the Glasgow Coma Scale (GCS). The GCS is a neurological rating scale used to assess patient's level of consciousness after a head injury. This scale allows evaluating visual, verbal, and motor functions. The scoring system is based on three types of response to stimuli: best eye-opening (maximum 4 points), appropriate and consistent verbal response (maximum 5 points), and best motor response (maximum 6 points). The sum of these scores gives a score between 3 and 15. According to GCS, TBI is classified as mild to score of 13-15, moderate to a score of 9-12 and severe to a score of 3-8. The TBI is characterized by a primary lesion directly related to the traumatic event that causes impaired brain function. Within a few hours of the traumatic event, a complex cascade of cellular and molecular events that characterize the secondary lesion is triggered, responsible for further death/necrosis of brain tissue. Today, pharmacological treatments of TBI is somewhat complex. Researchers are still studying new therapeutic strategies in order to reduce neurological damage. Recently, the researchers have focused their studies on the use of stem cells (SCs) as a potential therapeutic option for the treatment of TBI. Hence, considering the neuroprotective role of SCs both in tissue reconstruction and in the ability to prevent cell death, they may be useful therapeutic strategies for the treatment of TBI. In particular, neuronal stem cells (NSCs) and mesenchymal stem cells (MSCs)-such as bone marrow MCSs (BM-MSCs), adipose tissue-derived MSCs (AD-MSCs), and umbilical cord MSCs (UC-MSCs)-seem promising as new treatments for TBI. This review aims to provide an overview of the effectiveness of stem cells in the management of TBI. For this purpose, we have collected the clinical trials and the studies approved by Local Ethics Committees that use stem cell transplantation as a therapeutic treatment in patients with TBI. Traumatic Brain Injury TBI is defined as an impairment of brain function caused by mechanical damage. It represents one of the main causes of death and disability in individuals aged between 1 and 45 years. The most common causes of TBI include falls, car accidents, assaults, and sports-related injuries. According to recent incidence data, there is a higher peak among subjects in the adolescence, while a second peak is observed in the elderly. Furthermore, the incidence rates by gender show that males are at least twice more frequently affected than females. The severity of the injury is commonly classified using the GCS score. TBI is defined as mild when patients retain good neurologic function and sequelae can be resolved completely without any treatment. Conversely, moderate or severe TBI can be fatal or cause severe disability which makes the quality of life negligible. Moreover, the injuries are typically classified as open or closed injuries. The open injuries involve a fracture of the cranial theca caused by a foreign object. While the closed injuries are marked by brain damage due to indirect impact without the entry of any foreign object into the brain. Most of the TBIs observed are of the closed type; however, a small percentage is represented by open TBI, generally experienced by gunshot injuries. The TBI is characterized by two phases. The primary phase occurs at the time of exposure to external force and causes a mechanical breakdown of brain tissue. While the secondary phase has its onset hours after the traumatic event and represents the main cause of the worsening in the evolution of the TBI. In TBI the self-regulation of blood flow is lost, this determines the increase in ICP with a consequent reduction in cerebral perfusion pressure and cerebral blood flow. The break of normal cerebral blood flow occurs within 24 h of trauma and generally causes ischemic events responsible for the alteration of ionic gradients and consequent alteration of oxidative phosphorylation that leads to the accumulation of lactate. High levels of lactate cause acidosis responsible for the neuronal alteration, disruption of the blood-brain barrier and cerebral edema. This can lead to the depolarization of neurons and the excessive release of excitatory neurotransmitters such as glutamate and aspartate, which induce an alteration in the homeostasis of calcium (Ca 2+ ), potassium and sodium. The increase in intracellular Ca 2+ is responsible for activating a series of enzymes such as caspases and calpases that lead to cell death directly or indirectly through the activation of the apoptotic process. Additionally, an increase in the flow of Ca 2+ in the mitochondria is also responsible for the production of reactive oxygen species (ROS). Oxidative stress also plays an important role in the pathogenesis of TBI damage. Indeed, the production of ROS has been shown to increase the neurodegeneration process that leads to lipid peroxidation of cell membranes, particularly at the axonal level. Moreover, these events lead to the triggering of the inflammatory response characterized by macrophages, T lymphocytes, neutrophils, and glial cells that release pro-inflammatory cytokines as tumor necrosis factor-alpha (TNF), interleukin-1beta (IL-1), and interleukin-6 (IL-6). Therefore, the pathophysiology of TBI is complex, thus management, regardless of gravity, represents a great challenge. The treatment tools currently available for TBI are still not effective, with the exception of some therapies that are limited only to the reduction of secondary symptoms. Therefore, new therapeutic approaches are needed for the treatment of TBI. Stem Cells and Traumatic Brain Injury Currently, interventions to improve the lives of people with TBI in use-including drug treatments, surgeries, and rehabilitation therapy-provide poor outcomes. The use of SCs in the treatment of TBI has recently entered the clinic as a possible therapeutic application. SCs therapy is used in regenerative medicine to restore damaged neurons. SCs are cells that showed the multipotent capacity to differentiate toward different cell types and possess the capacity to renew themselves. In different preclinical studies, conducted on TBI animal models, stem cell transplantation has promoted the improvement of several neurological parameters. Specifically, NSCs and MSCs-such as BM-MSCs, AD-MSCs, and UC-MSCs-appear capable of regenerating damaged nerve tissue, as demonstrated in several in vivo studies, using animal models of TBI. NSCs derived from the lateral ventricle, the dentate gyrus of the hippocampus. Moreover, NSCs are a type of cell capable of self-renewal, they can differentiate into neurons, oligodendrocytes, and astrocytes. Additionally, NSCs are able to release cytokines and neurotrophic factors such as brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), and insulin growth-factors-1 (IGF-1). Several studies suggest that transplanted NSCs can potentially repair and integrate neurons and glial cells at the injury site, due to their ability to release crucial molecules to maintain structural and functional plasticity. NSCs, when administered in an experimental model of TBI, may be an effective, long-term treatment for neurological recovery after brain injury. The MSCs are multipotent stromal cells that can be easily harvested from a variety of tissue sources such as bone marrow, umbilical cord, adipose tissue, placenta, and oral cavity. Also, MSCs are potentially capable of differentiating into a variety of cell types including osteogenic, adipogenic, chondrogenic, and neural lineages. Moreover, MSCs according to the definition of MSCs of must be positive for CD73, CD90, and CD105 surface markers. On the contrary, MSCs must be negative for CD45, CD34, CD14, CD11b, CD79a, and CD19 and for the major histocompatibility complex class II surface molecules. MSCs promote the regeneration of damaged tissues through reducing inflammation response, recruiting local progenitor cells to replace lost cells and releasing trophic factors including BDNF, GDNF, vascular endothelial growth factors (VEGF), and nerve growth factor (NGF). Therefore, thanks to their proprieties, MSCs therapy can potentially be useful to repair damage following TBI. Indeed, it was demonstrated that MSCs are able to electively migrate to the lesioned nervous tissue of the TBI rat and following differentiate towards neurons and astrocytes, in order to repair the damaged area, with consequent enhancement the motor activity after TBI. The BM-MSCs derive from the bone marrow and showed the ability to differentiate into several cell lineage including neurons and glial cells. It was demonstrated that BM-MSCs transplantation promotes neuroplasticity and neuronal regeneration through several mechanisms. BM-MSCs showed anti-inflammatory effects by promoting the differentiation of lymphocytes. Additionally, BM-MSCs are able to release growth factors such as VEGF, BDNF, GDNF, NGF, epidermal growth factor (EGF), fibroblast growth factor (FGF), and neurotrophin-3 (NT-3), in this way leading on the repair of the lesioned area. Several preclinical studies showed that BM-MSCs release trophic factors into the damaged sites, that inhibit apoptosis, promote angiogenesis and stimulate host progenitor cells to differentiate toward neurons and astrocytes. In this way, BM-MSCs showed the ability to repair the lesioned tissue and recovered function in animal models of TBI. The UC-MSCs are obtained easily by treating the umbilical cord or the cord blood. The UM-MSCs compared to other stem cells showed several advantages such as a low immunogenicity power, less risk of rejection after transplantation, easy harvesting, and no ethical controversy. These cells secreted neutrophil activator, NT-3, BDNF, VEGF, and FGF in order to induce neuronal regeneration and neuronal vascularization in the damaged area. It was demonstrated that UM-MSCs confer trophic support in the injured, induce the microglia/macrophage to remodel of the brain, leading to significant improvement of neurological functions. The AD-MSCs are easily isolated from adipose tissue. These cells have the ability to differentiate into cell types including neurons, endothelial-derived cells, and Schwann cells. Additionally, AD-MSCs exhibit immunomodulatory properties thanks to the release of several cytokines including IL-10 and transforming growth factor-beta (TGF-). Likewise, thanks also to the release of neurotrophic factors such as BDNF and GDNF, they showed neuroprotective properties. It was demonstrated the AD-MSCs transplantation improvement motor activity in an animal model of TBI, suggesting that these cells might be considered for patients with TBI. To date, studies report that the principally used stem cell routes of administration are the intravenous route and local administration by stereotactic injections. The intravenous route has the advantage of being a non-invasive strategy, but it shows the limit that the percentage of infused cells that reaches the lesion site is very small. In addition, intravenous administration of stem cells implicates that these cells are retained by the pulmonary capillaries, thus compromising their therapeutic potential. Hence, this route of administration results not very effective due to the large dispersion of cells between the different organs of the body, which requires the administration of a large number of stem cells. Compared to intravenous administration, local infusion of stem cells by stereotaxic injections is invasive but allows to inject stem cells directly into the injury site. Therefore, this route of administration shows the advantage of reducing the number of stem cells used. However, the best route of administration has not yet been established, as each route shows its advantages and disadvantages. Role of Stem Cell in Traumatic Brain Injury: Clinical Studies In recent decades, several studies have shown the use of SCs as potential therapies in the treatment of neurological diseases such as TBI. This review provides an overview of the studies recorded on http://clinicaltrial.gov and the clinical trials approved by Local Ethics Committees. In clinicaltrial.gov we carried out the research using the terms "head injury" and "stem cells". This research led us to find 18 clinical studies. We have considered only clinical trials involving the use of stem cells as a therapeutic treatment for patients with TBI. We excluded clinical studies involving the use of drugs such as erythropoietin that stimulate the production of stem cells or other therapeutic interventions and clinical studies that involved the use of stem cells in diseases other than TBI. Additionally, on PubMed, we looked for studies approved by local ethics committees that evaluated the use of stem cells as a therapeutic treatment in patients with TBI. The keywords used for this research were "head injury", "stem cells", "clinical trial", and "human". Clinical Trials Recorded in Clinicaltrial Gov All the clinical studies (phases 1, 2, and 3) reported below have evaluated the safety and/or efficacy and tolerability of the administration from SCs in the TBI ( Table 1). Most of these trials do not yet have available results as they are still in the patient recruitment phase. A completed phase 1 clinical trial NCT00254722 was performed on 10 patients (aged 5-14 years) with acute TBI (within 24 h) diagnosed by GCS between 5 and 8. The aim of the study was to evaluate both the safety and efficacy of autologous bone marrow progenitor cell (BMPCs) transplantation in children with isolated TBI. The bone marrow samples were collected between 12-and 30-h post-injury at a dose of 3 mL/kg of body weight. The transplantation was performed by a single intravenous infusion of BMPCs at a dose by 6 10 6 mononuclear cells/kg body weight in the 36 h after the lesions. The safety of the study was determined by monitoring cerebral and systemic hemodynamic both in the collection and transplant phase. Moreover, neurological events-such as seizures, alterations in GCS, stroke, as well as secondary organ injury-in the 12 h following the transplantation and up to 21 days after treatment were evaluated, in order to assess the efficacy of treatment. The results have not yet been posted. The double-blind, controlled phase 2 study NCT02416492 has enrolled 61 male and female subjects (aged 18 years to 75 years) with chronic motor deficits secondary to TBI. The aim of the study was to evaluate the effectiveness, safety as well as tolerability in the stereotactic intracranial implantation of allogeneic modified bone marrow-derived mesenchymal stem cells (SB623). The SB623 cells are adult bone marrow cells that are transfected transitory way with a plasmid construct encoding the intracellular domain of human Notch-1. The participants were randomly divided into four groups: patients that had not received the surgical intervention (control group), and patients that received 2.5 10 6, 5 10 6, or 10 10 6 SB623 cells. The SB623 were transplanted thought stereotactic intracranial injection. The primary outcome was evaluating the motor functions by using the Fugl-Meyer Motor Scale (FMMS) from baseline to 6 months in SB623 patients compared to the control group. Besides, it was assessed both changes in the Disability Rating Scale (DRS) and gait velocity, as well as an upper limb function from baseline at 6 months. The results of the study showed a significant improvement in the motor function by changes in FMMS at week 24 in patients treated with SB623 versus the control group. Besides, five severe side events were reported in patients treated with SB623 and three in patients in the control group. In contrast, there were no differences in the rate of side events occurred during the treatment in all experimental groups. Finally, the results of this study showed that intracranial SB623 transplantation was safe and effective, thanks to motor function improvements observed 24 weeks after treatment. The cohort study NCT01575470 of 1/2 phase has enrolled 25 male and female patients (aged 18 years to 55 years) with acute serious TBI (GCS score 5-8) that showed injury at least 24 h before study start. This study was authorized by the University of Texas Health Sciences Center at Houston Committee for the Protection of Human Subjects and by the Memorial Hermann Office of Research. The goal of this trial was to assess the safety, feasibility, and efficacy of bone marrow mononuclear cells (BMMNCs) transplantation at the escalated doses. After 36 h of injury, from each patient were collected 3 to kg of bone marrow from anterior iliac crests. Before transplantation BMMNCs were tested for quality control including cell viability, nucleated cell count, gram stain, aerobic and anaerobic bacterial and fungal cultures, endotoxin and mycoplasma presence, colony-forming unit test, and multi-parameter flow cytometry analysis for cells characterization. The final doses of 6 10 6 cells/mL/kg, 9 10 6 cells/mL/kg, or 12 10 6 cells/mL/kg in 0.9% saline containing 5% of human serum albumin were infused by intravenous injections. Twenty-five participants were assigned in 5 arms: 10 patients received no interventional surgical, 5 were included in control group 1 and 5 in control group 2; this additionally control group was included in order to include participants across the time spectrum of the trials. Five patients received 6 10 6 cells/kg (low dose group), 5 patients received 9 10 6 cells/kg (medium-dose group) and 5 subjects received 12 10 6 cells/kg (high dose group). Neurological events such as seizures, changes in GCS score, cerebral vascular accident (CVA) were assessed both 12 h and 21 days after the infusion. Moreover, were assessed infectious morbidity up to 21 days after infusion and also the global functional status to assess both functional status and overall functioning in the 6 months post-injury. Additionally, inflammatory cytokines were measured in the plasma at baseline and 1 and 6 months after treatment. None of the patients manifested severe side events after collected bone marrow or after BMMNCs transplantation. After cell therapy, no serious pulmonary toxicity occurred in patients treated with a high dose of cells, but these events were not clinically significant. The cell therapy showed structural preservation of critical regions of interest brain tissue. The cytokine biomarker data showed a dose-dependent downregulation of the pro-inflammatory. Specifically, the IL-1, interferon- (IFN-), and tumor necrosis factor- (TNF-) pathway show a statistically significant decrease in concentrations compared to the baseline. These results demonstrated that cell therapy, reduce the inflammatory response to injury. Finally, the autologous BMMNCs transplantation in patients with serious TBI is safe and feasible. This BMMNCs administration showed its efficacy in terms of maintenance of critical regions of central nervous tissue, probably due to a reduction of pro-inflammatory signaling. The phase 2 interventional study NCT02525432 expected to recruit 55 male and female patients (aged 18-55 years) with acute TBI diagnosed by GCS between 5 and 8. The aim of this trial will evaluate the efficacy of intravenous BMMNCs transplantation. The patients will be divided into two groups; 33 subjects will be treated with autologous intravenous transplantation of BMMNCs within 48 post-TBI. The transplantation will be started with the lowest dose of 6 10 6 cells/kg body weight followed by a higher dose of 9 10 6 cells/kg of body weight. In contrast, 22 control patients will be undergoing a fake collection of bone marrow, as well as treated with a placebo. The primary outcome is to evaluate the macrostructural and microstructural properties both of gray matter and white matter, as well as the integrity of the regions in the corpus callosum, following the BMMNC autologous transplantation. The subjects will be evaluated by using magnetic resonance imaging (MRI) within 7-10 days at baseline, as well as to 1 and 6 months after lesions. The secondary outcome is to assess whether BMMNCs transplantation improves both functional and neurocognitive deficits, as well as the neuroinflammatory response following TBI. The subjects will be undergoing an evaluation of both size and splenic blood flow, also will be evaluated both inflammatory cytokines and infusion-related toxicity, as well as long-term safety. The toxicity and any complications associated with the infusion will be monitored within 14 days post-transplantation. Besides, both the safety and the results regarding the transplant will be evaluated after 1, 6, and 12 months from the injury. The results of this trial (estimated final data collection in October 2020) will make it possible to clarify the efficacy of BMMNCs transplantation. The non-randomized study NCT02795052 aims to recruit 300 male and female participants (aged over 18 years) with damage to the central or peripheral nervous system documented by least 6 months, including TBI. The aim of the study is to show if the autologous BM-MSCs transplantation by intravenous and intranasal administration will provide an improvement in neurological functions in patients with some neurological conditions. The participants will be divided into two experimental groups. Patients in group 1 will be treated with BM-MSCs intravenous route. While the participants in group 2 will receive BM-MSCs intravenous and intranasal (lower 1/3 of nasal passages) route. The primary outcome will be to evaluate daily activities at 3, 6, and 12 months after the administration. The secondary outcome aims to assess deficits of neurologic function. This study is still active and the results have not been published yet. The multicenter, randomized, blinded, placebo-controlled study NCT01851083 of phase 1/2 aims to recruit 50 male and female patients (aged 5-17 years) with severe TBI diagnosed by GCS between 3 and 8. The purpose of the study is to evaluate the effects of intravenous infusion of autologous BMMNCs on nervous tissue, as well as to evaluate the efficacy of cell therapy in neurocognitive and neurological function in children with severe TBI. The patients will be divided into two groups. The experimental group will be subjected to the collection of bone marrow and administration of BMMNCs in a single intravenous dose of 6 10 6 cells/kg or 10 10 6 cells/kg weight in the 48 h after lesions. Participants in the placebo group will undergo a fictitious collection of bone marrow and, subsequently, a single intravenous infusion of 0.9% sodium chloride. The primary outcome will evaluate by diffusion tensor MRI the conservation of both white and gray matter in the groups of patients treated and untreated after the trauma. The secondary outcome will measure the conservation of both the white matter and the gray matter in the CNS, as well as the improvement of functional and neurocognitive deficits. Furthermore, will be assessed the safety in the 7 days after treatment. For this trial, no result is available today. The single-arm non-randomized study NCT04063215 of phase 1/2 hopes to recruit 24 male and female patients (aged 18-55 years) with sub-acute or chronic TBI (GCS score> 2 and ≤ 6) at least of 6 months. The study aims to evaluate both the safety and the efficacy of autologous AD-MSCs transplantation; moreover, it will evaluate the neurocognitive and neurological function and neuroinflammatory response after treatment. In adult patients, 2 10 8 of AD-MSCs will be administered three times for 6 weeks. Furthermore, each infusion will be performed 14 days from the other. The primary outcomes will be evaluated by blood tests at baseline, as well as to 6 months and one year after infusion. The secondary outcomes involve an assessment of the macro and microstructural properties of the brain by MRI at baseline and 6 months post-treatment. Moreover, several tests will be performed for both functional and neuropsychological assessments at baseline, after 6 months and 1 year post-transplantation. Finally, will be assessed the inflammatory cytokines by cytometry analysis and monitoring the changes at 6 months and one year from baseline. The data from this trial will be available soon, as the final data collection is expected by August 2020. The randomized phase 1/2 study NCT02959294 aims to recruit 200 male and female participants (16-70 years of age) with mild TBI or concussion syndrome. The aim of the study will be to evaluate both the safety and efficacy of adipose-derived stromal vascular fraction (AD-cSVF) in patients with TBI and concussion syndrome. The patients enrolled in the intervention arm will undergo a microcannula harvest of AD-cSVF. The primary outcome referring to the measurement of side events at baseline and 6 months after treatment. Besides, will be assessed the clinical symptoms associated with TBI and concussion such as recurrent headaches, amnesia, behavioral change, cognitive impairment, and recurrent sleep disturbances. The secondary outcomes will be evaluated through Beck's questionnaire, in order to evaluate depression conditions. Furthermore, will be evaluated attention deficit and brain changes by MRI at baseline, 3 years, and 5 years after treatment. The results expected from this study will allow observing if the administration of AD-cSVF will be efficacy and safe for the long-term. The phase 1 study NCT02742857 will be recruiting 20 male and female patients (15 years to 65 years) which present brain death caused by TBI with axonal injury shown by MRI. The study was designed using different therapeutic interventions including MSCs transplantation, infusion of intra-thecal bioactive peptides, transcranial laser therapy, and median nerve stimulation. The aim of the study is to show the possibility of cell inversion in the case of brain death induced by TBI with diffuse axonal injury. The primary outcome will be documented by clinical examination or electroencephalogram in the 15 days' frame time. The secondary outcome is to provide a cerebrospinal fluid analysis, as well as the count and microbial evaluation. Furthermore, by using the MRI examination, both the presence of aseptic or bacterial meningitis, as well as any changes will be shown. Also, will be assessed blood pressure, pulse rate, oxygen saturation, as well as changes in breathing in the 15-day time frame. To date, no superior information is yet available. Final data collection is expected by June 2022. Clinical Trials Approved by Local Ethics Committees In this section, clinical trials published in indexed journals have been described. Many of these studies report the results obtained on treatment with stem cell therapy and provide important efficacy and safety data. The study conducted by S. Wang et al. aimed to evaluate the efficacy and safety of UC-MSCs transplantation in subjects with TBI. This trial was approved by the Medical Ethics Committee of the General Hospital of the Chinese People's Armed Police Forces (Registration no. ChiCTR-TNRC-11001528). Forty participants with TBI ascertained by magnetic resonance imaging and computed tomography were enrolled for the study. Twenty of the 40 patients were randomly assigned to the stem cell treatment group, while the other 20 subjects were assigned to the control group. Prior to enrollment in the study, 15 of the 20 patients in the interventional group and 13 of the 20 patients in the control group had undergone cranial bone flap decompression and intracranial hematoma reduction surgery. While 5 patients in the interventional group and 7 in the control group, instead, after the trauma, received conservative medical treatment. For transplantation, the UC-MSCs were used between steps 6 and 8. Before transplantation, in order to increase the safety of therapy, multiple tests were performed on UC-MSCs including, morphological evaluations, spectrofluorometric tests for the identification of cell surface markers, sterility testing, and analysis to rule out the presence of endotoxins. Patients in the stem cell group, received 2 mL of stem cell suspension that containing 1 10 7 SCs, via lumbar puncture in the lumbar 3-4 or 4-5 intervertebral space. This surgical intervention was performed four times in 5-7 days. To evaluate the efficacy of the treatment, the motor function of the limbs, the sensation, the balance and the ability to live independently, were assessed at the baseline and after 6 months of treatment (using the Fugl-Meyer Assessment and Functional Independence Measure scores). Prior to treatment, the two groups of participants showed equivalent baseline scores. After six months of treatment compared to the control group, patients treated with UC-MSCs showed a statistically significant improvement in motor function, sensitivity, and balance. The transplants patients, compared to the control group, also showed an improvement in mobility, locomotion, communication and ability to live independently. Four patients 48 h after transplantation experienced low intracranial pressure reactions with symptoms such as mild dizziness and headache. These adverse events resolved after lying down in bed or after being treated with intravenous saline infusions. In addition, during transplantation, clinical values-such as body temperature, oxygen saturation, blood pressure, and respiratory and heart rate-were monitored in all patients. No obvious anomalies were found in any subject. In conclusion, the results of this study demonstrate that the transplantation of UC-MSCs can be considered safe and can significantly improve several neurological parameters. The retrospective cohort study conducted by G.P. Liao et al. aimed to understand if BMMNCs transplantation within 48 h after trauma-induced a reduction of treatment intensity against managing elevated intracranial pressure relative in pediatric patients with severe TBI. This trial was authorized by The University of Texas Health Sciences Center at Houston Committee for the Protection of Human Subjects and approved by the Children's Memorial Hermann Office of Research. The 29 TBI patients (5-14 years) with Glasgow Coma Score 5-8 and with trauma occurring <24 h within enrollment were recruited in this study. Ten patients were assigned to a treatment group and 19 in the control group. The 3-5 mL/kg of body weight was collected from posterior or anterior iliac crests. The mononuclear cells obtained before transplantation were undergone flow cytometry analysis for cell characteristics and tested for the presence of bacterial, fungal, and mycoplasma in order to increase the safety of transplantation. The subjects in the treatment group received 6 106 autologous BMMNCs cells/kg body weight IV within 48 h of trauma. The primary outcome of this study evaluated the Pediatric Intensity Level of Therapy scale in order to quantify the treatment of elevated intracranial pressure. Secondary outcomes included the Pediatric Logistic Organ Dysfunction score and days of intracranial pressure monitoring as a surrogate for the length of neurointensive care. In the treatment group, after transplantation was observed a significant reduction in the Pediatric Intensity Level of Therapy score beginning at 24 h post-therapy compared to the control group. The same results were obtained also in the Pediatric Logistic Organ Dysfunction score following the first week of transplantation. These differences may be due to the therapeutic effect of cell therapy. In conclusion, the results of this study showed that IV autologous BMMNCs transplantation reduces therapy intensity to maintained intracranial pressure and the severity of organ damage. Additionally, these findings demonstrated that these cells are able to reduce the effects of inflammation in early post-traumatic TBI. This interventional cohort study conducted by C. Tian et al. aimed to evaluate the efficacy and safety of autologous BM-MSCs in patients with TBI. This study was authorized by the ethical committee of the Hospital and Health Bureau of City. In the trial, 97 subjects with serious TBI for at least 1 month were enrolled. Twenty-four of the 97 showed a vegetative condition; while 73 patients manifested motor activity dysfunction. About 100 mL of bone marrow were harvested from each patient from posterior iliac crests. Before transplantation, BM-MSCs were characterized by flow cytometry analysis. Finally, 1 10 6 cells/mL were administered by lumbar puncture between the lumbar vertebrae L3/L4 or L4/L5. In order to evaluate the efficacy of transplantation, 40 days after surgical intervention, the participants were followed-up for persistent vegetative state assessment and motor function analysis. None of the participants experienced severe side events. After two days of transplantation, 5 subjects showed transient fever and 2 participants perceived a slight headache. After 14 days of BM-MSCs transplantation. Thirty-eight of 97 participants showed enhancement of the TBI condition. Eleven of 24 participants before transplantation showed a vegetative state after treatment manifested enhancements in consciousness. Twenty-seven of 73 patients with motor dysfunction showed an enhancement in motor activity. Moreover, the age of participants affected the finding of cell transplantation, demonstrated that the young subjects enhancements the TBI state more than older patients. In conclusion, this study demonstrated that BM-MSCs transplantation is safe and effective in the management of serious TBI; furthermore, the early intervention in the subacute phase of this disorder showed better outcomes. Conclusions TBI is a very complex disease. Nowadays, there are no effective treatments able to reduce the effects of the primary injury, but only therapies capable of blocking their progression. In recent decades, NSCs and MSCs (BM-MSCs, AT-MSCs and UC-MSCs), have demonstrated to be a useful tool that can reduce the effects of post-traumatic brain injury. In several of the clinical studies described, BM-MSCs administrated via intravenous and via lumbar puncture, shown improvement in damaged brain areas. The same results were obtained using the UC-MSCs transplantation; however, the number of studies is fewer. Therefore, the available results encourage the use of both SCs and therapies described as useful for the treatment of TBI. The awaited outcomes and future studies will be necessary to exploit the use of cell transplantation for management TBI. |
Adult assault as a mechanism of burn injury. Assault by burning is an often unappreciated cause of burn injury. One hundred forty-eight of 3678 adults admitted to a major burn center with acute burn injuries sustained their burns as a result of an assault by another adult. High-risk groups included blacks and alcohol abusers. Patients were extremely reductant to describe the cause of their injury and to identify their assailant. In contrast to child abuse, very few cases go to court due to the patient's failure to press charges. There was no typical burn pattern, although the injury often did not coincide with the initial medical history. The presence of multiple trauma, occurring in 16% of these patients, must be excluded in the assaulted patient. |
#include "ilist.h"
#include "LZend.nuevo.h"
#include "extractorend2.h"
#include <stdlib.h>
#include <cstring>
#include "utils.h"
#define DOCid_ADD (1)
/** *******************************************************************************
* function used to parse the source posting lists that are loaded in build_il.*
* Refer to "build_il() comments below" for a more detailed description *
* Basically, it reads the len of each posting list and its values.
// *[Nwords=N]
// *[maxPostvalue]
// *[lenPost1][post11][post12]...[post1k�]
// *[lenPost2][post21][post22]...[post2k��]
// * ...
// *[lenPostN][postN1][postN2]...[postNk���]
//
* It recreates array lenList, and uint ** occList and variables maxPostValue and nlists. */
int parseAllPostingList(uint *nlists, uint **lenList, uint ***occList,
uint *maxPostValue, uint *source, uint length){
uint **occs;
uint *lens;
uint n;
register uint i,j,sourcepos,len;
if (length<2) return 1;
n=source[0];
*maxPostValue = source[1] + DOCid_ADD;
//allocating memory.
lens = (uint *) malloc (sizeof(uint) * n);
occs = (uint **) malloc (sizeof(uint *) * n);
sourcepos=2;
uint maxpostL =0;
for (i=0; i<n; i++) {
lens[i]= len = source[sourcepos++];
occs[i]= (uint *) malloc (sizeof(uint) * len);
for (j=0; j<len;j++) {
occs[i][j] = DOCid_ADD + source[sourcepos++];
if (occs[i][j] > maxpostL) maxpostL = (occs[i][j]);
}
}
if (maxpostL > *maxPostValue) *maxPostValue = maxpostL;
printf("\n **** maxpostSource = %d, maxpostComputed = %d",*maxPostValue,maxpostL);
if (length !=sourcepos) return 31;
*nlists =n;
*lenList = lens;
*occList = occs;
return 0;
}
uint encode(uint val){
uint r = 0;
uint m = 1;
for(uint i=0;i<4;i++){
r += ((val%255)+1)*m;
val = val/255;
m*=256;
}
return r;
}
uint decode(uint val){
uint r = 0;
uint m = 1;
for(uint i=0;i<4;i++){
r += ((val%256)-1)*m;
val = val/256;
m*=255;
}
return r;
}
/***************************************************************************/
/** Creates a compressed representation of a collection of text documents **/
/***************************************************************************/
/* Creates the [compressed] representation of a collection of text documents
whose text is passed as text[0..length-1]. The offset of the document
beginnings are given by docBeginnings[0..numdocs-1], whereas
docBeginnings[numdocs]== length.
Note that the *representation* is an
opaque data type. Any build option must be passed in string
build_options, whose syntax depends on the text representation.
The compressed representation must always work with some default
parameters if build_options is NULL.
The returned representation is ready to be decompressed and queried
for statistics. */
static char tmp_filename[] = "tmp_filename_il";
static char tmp_filename_rev[] = "tmp_filename_il.rev";
static char tmp_filename_sa[] = "tmp_filename_il.rev.sa";
static char tmp_filename_char[] = "tmp_filename_il.char";
static char tmp_filename_len[] = "tmp_filename_il.len";
static char tmp_filename_sources[] = "tmp_filename_il.start";
static char tmp_filename_doc[] = "tmp_filename_il.doclen";
char *error_il (int e){
return NULL;
}
/* Building the inverted list structure */
/* Creates a structure for the management of inverted lists from a
given set of posting lists.
Array source has the following format...
[Nwords=N][maxPostvalue][lenPost1][post11][post12]...[post1k]
[lenPost2][post21][post22]...[post2k]
...
[lenPostN][postN1][postN2]...[postNk]
il is an opaque data type. Any build option must be passed in string
build_options, whose syntax depends on the index. The index must
always work with some default parameters if build_options is NULL.
The returned structure is ready to be queried. */
void sourceToText(uint* source, uint length, char* filename){
printf("%d %d\n",length,source[0]);
uint tlength=0;
uint* text = (uint*) malloc(sizeof(uint)*(length-2-source[0]));
uint pos = 2;
while(pos<length){
uint len_il = source[pos];
// text[tlength]=0;
// tlength+=1;
for(uint i=0;i<len_il;i++){
text[tlength] = source[pos+i+1];
tlength += 1;
}
/*for(uint i=1;i<len_il;i++){
text[tlength] = source[pos+i+1]-source[pos+i];
tlength += 1;
}*/
pos = len_il + pos + 1;
}
for(uint i=0;i<tlength;i++){
text[i] = encode(text[i]);
}
saveText((uchar*)text, tlength*sizeof(uint), tmp_filename);
free(text);
}
unsigned int* sourceToLen(uint* source, uint length, uint* numlists, uint* maxLength){
uint tlength=0;
uint* text = new uint[source[0]];
uint pos = 2;
*maxLength = 0;
while(pos<length){
uint len_il = source[pos];
text[tlength]=len_il;
tlength += 1;
if(len_il>*maxLength)*maxLength = len_il;
pos = len_il + pos + 1;
}
*numlists = source[0];
return text;
}
int build_il (uint *source, uint length, char *build_options, void **ail){
unlink(tmp_filename);
unlink(tmp_filename_rev);
unlink(tmp_filename_sa);
unlink(tmp_filename_char);
unlink(tmp_filename_len);
unlink(tmp_filename_sources);
unlink(tmp_filename_doc);
sourceToText(source, length, tmp_filename);
//saveText(text, length, tmp_filename);
printf("**********************");
printf("\n: build_il: call to LZEND2->Parse()\n");
LZparser* p;
p = new LZEnd2(tmp_filename);
p->parse();
lzi* repr = (lzi*)malloc(sizeof(lzi));
printf("**********************");
printf("\n: build_il: call to LZEND2->ExtractorEnd2()");
repr->extractor = new ExtractorEnd2(tmp_filename, DELTA_SAMPLING);
unsigned int numlists;
unsigned int* doc_len = sourceToLen(source, length, &numlists, &(repr->maxLength));
repr->docs = numlists;
printf("**********************");
printf("\n: build_il: call to LZEND2->deltaCodes()");
repr->doc_array = new DeltaCodes(doc_len,numlists, DELTA_SAMPLING);
saveText((unsigned char*)doc_len, repr->docs*sizeof(unsigned int), tmp_filename_doc);
delete[] doc_len;
*ail = repr;
{
uint *lists = source; uint nlists=length;
fprintf(stderr,"\n ! CHECKING that the decoded lists are identical to the original ones. ");
{ //checking:: decoding a list
uint *list;
for (id=0;id < nlists;id++) {
//if ( shouldUseBitmap(il,id) ) continue;
extractList_il (repr, id, &list, &len);
//extractList (void *ail, uint id, uint **list, uint *len)
printf("\n");
for (i=0;i<len;i++){
if (list[i] != (occList[id][i]-DOCid_ADD) ) {
fprintf(stderr,"\n decoding of lists failed for %d id = %d: DIFFERENT!!: (%d,%d)\n",i,id, list[i],occList[id][i]-DOCid_ADD);
//for(i=0;i<len;i++){
// printf("(%x %x) ", list[i], occList[id][i]-DOCid_ADD);
//}
exit(0);
}
}
free(list);
}
}
fprintf(stderr,"\n ! Decoding the list of occurrences worked fine (the same as previous values) ");
}
return 0;
}
/* returns a string with the parameters available for building the method.
So that each index tells the user the available parameters. */
char *showParameters_il(){
return NULL;
}
/* Saves index on disk by using single or multiple files, having
proper extensions. */
int save_il (void *ail, char *filebasename){
char fn_base[2048];
char fn_start[2048];
char fn_len[2048];
char fn_chars[2048];
char fn_doclen[2048];
snprintf(fn_base,2048,"cp tmp_filename_il %s",filebasename);
snprintf(fn_start,2048,"cp tmp_filename_il.start %s.start",filebasename);
snprintf(fn_len,2048,"cp tmp_filename_il.len %s.len",filebasename);
snprintf(fn_chars,2048,"cp tmp_filename_il.char %s.char",filebasename);
snprintf(fn_doclen,2048,"cp tmp_filename_il.doclen %s.doclen",filebasename);
int ret;
ret = system(fn_base);
ret = system(fn_start);
ret = system(fn_len);
ret = system(fn_chars);
ret = system(fn_doclen);
return 0;
}
/* Loads index from one or more file(s) named filename, possibly
adding the proper extensions. */
int load_il (char *filebasename, void **ail){
char fn_doclen[2048];
snprintf(fn_doclen,2048,"%s.doclen",filebasename);
lzi* repr = (lzi*)malloc(sizeof(lzi));
unsigned int* doc_len = (unsigned int*)readArray(fn_doclen,(int*)(&(repr->docs)),sizeof(unsigned int));
repr->maxLength = doc_len[0];
for(unsigned int i=1;i<repr->docs;i++){
if(doc_len[i]>repr->maxLength)repr->maxLength=doc_len[i];
}
repr->doc_array = new DeltaCodes(doc_len,repr->docs, DELTA_SAMPLING);
free(doc_len);
repr->extractor = new ExtractorEnd2(filebasename, DELTA_SAMPLING);
*ail = repr;
return 0;
}
/* Frees the memory occupied by index. */
int free_il (void *ail){
delete (ExtractorEnd2*)(((lzi*)ail)->extractor);
delete (DeltaCodes*)(((lzi*)ail)->doc_array);
free(ail);
return 0;
}
/* Gives the memory occupied by index in bytes. */
int size_il(void *ail, uint *size){
*size = sizeof(lzi) + ((ExtractorEnd2*)(((lzi*)ail)->extractor))->size() + ((DeltaCodes*)(((lzi*)ail)->doc_array))->size();
return 0;
}
/* Gives the memory occupied by the index assuming an uncompressed
representation (uint **)*/
int size_il_uncompressed(void *ail, uint *size){
return 0;
}
/* Gives the length of the longest posting-list*/
int maxSizePosting_il(void *ail, uint *size){
lzi* repr = (lzi*)ail;
return repr->maxLength;
}
/* Generates estatistics about the len of the compressed posting lists */
int buildBell_il(void *ail, const char matlabfilename[]){
return 0;
}
/********************************************************/
/***** Operations (searching) with the posting lists ****/
/********************************************************/
/* Extracts the id-th list, having id \in [0..maxId-1] */
int extractList_il (void *ail, uint id, uint **list, uint *len){
DeltaCodes* doc_array = (DeltaCodes*)(((lzi*)ail)->doc_array);
unsigned int start = (doc_array->select(id)+1)*4;
unsigned int end = (doc_array->select(id+1))*4+3;
*list = (uint*)((ExtractorEnd2*)(((lzi*)ail)->extractor))->extract(start,end);
*len = (end-start+1)/4;
for(uint i=0;i<*len;i++){
//if((*list)[i]<=(*list)[i-1])(*list)[i]=(*list)[i-1]+1;
(*list)[i] = decode((*list)[i]);
}
return 0;
}
/* Extracts the id-th list, having id \in [0..maxId-1]
Assumes list has enough space previously allocated. */
int extractListNoMalloc_il (void *ail, uint id, uint *list, uint *len){
uint* aux;
extractList_il(ail, id, &aux,len);
for(uint i=0;i<*len;i++){
list[i] = aux[i];
}
free(aux);
return 0;
}
/* Sets options for searches: such as parameters, funtions to use, etc
Permits to set different algorithms for intersect2, intersectN and
if needed "fsearch-operations needed by svs-type algorithms" */
int setDefaultSearchOptions_il (void *ail, char *search_options){
return 0;
}
/* Intersects two lists given by id1 and id2 \in [0..maxId-1].
The defaultIntersect2 function must be initialized previously (svs, merge, ...)
Returns the resulting list of "intersecting positions" */
uint* intersect_aux(uint* arr1, uint len1, uint* arr2, uint len2, uint* len){
uint alen = len1<len2?len1:len2;
uint* intersect = (uint*)malloc(sizeof(uint)*alen);
//printf("\n len1= %u, len2=%u, alen is set to %u",len1,len2,alen);
uint a=0;
uint b=0;
uint count=0;
while( (a<len1) &&(b<len2)){
if(arr1[a]==arr2[b]){
intersect[count] = arr1[a];
count += 1;
a++;b++;
}else if(arr1[a]<arr2[b]){
a++;
}else{
b++;
}
}
if (!count) {free(intersect); intersect=NULL;}
*len = count;
return intersect;
}
int intersect_2_il (void *ail, uint id1, uint id2, uint *noccs, uint **occs){
uint len1;
uint* arr1;
extractList_il(ail, id1, &arr1, &len1);
uint len2;
uint* arr2;
extractList_il(ail, id2, &arr2, &len2);
*occs = intersect_aux(arr1,len1,arr2,len2,noccs);
free(arr1);
free(arr2);
//if (!(*noccs)) {free(*occs); *occs=NULL;}
return 0;
}
typedef struct {
uint pos;
uint len;
} lpair;
int lpair_compare(const void *a, const void *b) {
return ((int)(((lpair*)a)->len) - (int)(((lpair*)b)->len));
}
/* Intersects $nids$ lists given by ids in ids[], having ids[i] \in [0..maxId-1].
Returns the resulting list of "intersecting positions" */
int intersect_N_il (void *ail, uint *ids, uint nids, uint *noccs, uint **occs ){
lpair* lengths = (lpair*)malloc(sizeof(lpair)*nids);
for(unsigned int i=1;i<nids;i++){
lengths[i].pos = ids[i];
lenlist(ail, ids[i], &(lengths[i].len));
}
qsort(lengths, nids, sizeof(uint), &lpair_compare);
uint* auxArr;
uint auxLen;
intersect_2_il(ail, lengths[0].pos, lengths[1].pos, &auxLen, &auxArr);
for(unsigned int i=2;i<nids;i++){
uint len;
uint* arr;
extractList_il(ail, lengths[i].pos, &arr, &len);
auxArr = intersect_aux(auxArr,auxLen,arr,len,&auxLen);
}
free(lengths);
//if (!auxLen) {free(auxArr); auxArr=NULL;}
*occs = auxArr;
*noccs = auxLen;
return 0;
}
/* Returns the len of the id-th posting list */
int lenlist(void *ail, uint id, uint *len){
DeltaCodes* doc_array = (DeltaCodes*)(((lzi*)ail)->doc_array);
unsigned int start = doc_array->select(id)+1;
unsigned int end = doc_array->select(id+1);
*len = (end-start+1);
return 0;
}
#ifdef WITHMAIN
int main(int argc, char** argv){
lzi* ail;
load_il(argv[1],(void**)&ail);
int tlength = 92959588;
fprintf(stderr,"Encode %d %d\n",encode(tlength),decode(encode(tlength)));
fprintf(stderr,"Encode %d %d\n",encode(0),decode(encode(0)));
// uint* list = (uint*)((ExtractorEnd2*)(((lzi*)ail)->extractor))->extract(0,tlength-1);
// char ot[] = "encoded.txt";
// saveText((uchar*)list, tlength, ot);
int length;
uint* text =(uint*)readArray(argv[1],&length,sizeof(uint));
uint* source =(uint*)readArray(argv[2],&length,sizeof(uint));
uint i;
uint **occList;
uint *lenList;
uint maxPostValue;
uint nlists;
parseAllPostingList(&nlists, &lenList, &occList, &maxPostValue, source,length);
// checking that the lists are decoded successfully *************
unsigned int numlists,a;
unsigned int* doc_len = sourceToLen(source, length, &numlists, &(a));
if(numlists!=nlists)fprintf(stderr,"%d %d\n",numlists,nlists);
uint pos=0;
uint id ,len;
/*for(id=0;i<nlists;i++){
for(i=0;i<doc_len[id];i++){
if(text[pos]!=occList[id][i]-DOCid_ADD){
fprintf(stderr,"(%x %x) ", text[pos], occList[id][i]-DOCid_ADD);
}
}
}*/
fprintf(stderr,"\n ! CHECKING that the decoded lists are identical to the original ones. ");
{ //checking:: decoding a list
uint *list;
for (id=0;id < nlists;id++) {
//if ( shouldUseBitmap(il,id) ) continue;
extractList_il (ail, id, &list, &len);
//extractList (void *ail, uint id, uint **list, uint *len)
printf("\n");
for (i=0;i<len;i++){
if (list[i] != (occList[id][i]-DOCid_ADD) ) {
fprintf(stderr,"\n decoding of lists failed for %d id = %d: DIFFERENT!!: (%d,%d)\n",i,id, list[i],occList[id][i]-DOCid_ADD);
//for(i=0;i<len;i++){
// printf("(%x %x) ", list[i], occList[id][i]-DOCid_ADD);
//}
exit(0);
}
}
free(list);
}
}
fprintf(stderr,"\n ! Decoding the list of occurrences worked fine (the same as previous values) ");
fprintf(stderr,"\n ! CHECKING that the decoded lists are identical to the original ones (extract_no_malloc). ");
{ //checking:: decoding a list
uint i, id ,len;
uint *list = (uint *) malloc(sizeof(uint) * (maxPostValue+1));
for (id=0;id < nlists;id++) {
//if ( shouldUseBitmap(il,id) ) continue;
//extractList_il (*ail, id, &list, &len);
extractListNoMalloc_il(ail,id,list,&len);
//extractList (void *ail, uint id, uint **list, uint *len)
for (i=0;i<len;i++){
if (list[i] != (occList[id][i]-DOCid_ADD)) {
//fprintf(stderr,"\n decoding of lists failed for id = %d: DIFFERENT!!",id);
fprintf(stderr,"\n decoding of lists failed for id = %d: DIFFERENT!!: (%d,%d)",id, list[i],occList[id][i]-DOCid_ADD);
exit(0);
}
}
}
free(list);
}
fprintf(stderr,"\n ! Decoding the list of occurrences worked fine (the same as previous values) ");
// ****************************************************** //
}
#endif
|
Leonardo DiCaprio Oscar losing streak looks like it may be snapped this year, according to South African data scientists, Principa.
In case you didn’t know, Prinicpa happens to be the data science company that accurately predicted 91% of the 2015 Rugby World Cup match results, including South Africa’s loss in the semis.
Now, using the same tactics it did with the sports tournament, it says DiCaprio will finally be able to place a golden Oscar in his trophy cabinet for the Best Actor award this year when the ceremony takes place next Sunday, the 28th February.
Prinicpa also predicted the winners for the Best Picture, Best Director and Best Actress, the awards’ most anticipated categories.
Here are its predictions:
Best Picture: The Revenant – winning by a very slim margin over Spotlight Best Actor: Leonardo DiCaprio – winning by an 8 fold margin over Matt Damon Best Actress: Brie Larson – winning by a 6.7 fold margin over Saoirse Ronan Best Director: Alejandro González Iñárritu – winning by a very slim margin over George Miller
How did the Principa team predict this? Here’s the breakdown:
“The team have collected and analysed data spanning back to 1935 to find patterns which could help identify strong predictors of the winners. Thanks to the predictive power we’ve observed within the bookie odds and previous wins, we can make our predictions with a high-level of confidence,” Principa said.
“We learned from our Rugby World Cup initiative that when we build different models off data sources and then combine them, our predictions tended to be more accurate. As a result, for our Oscars initiative we’ve built a model off 80 years of data and then a model off more recent data and combined the two instead of using one model,” it added.
The company said the Oscars over the years have shown an affinity for movies based on true stories (The Revenant is also based on true events).
Over half of the nominated movies in any of the four main categories this year are based on a true story – the highest percentage of nominees in this genre to date – and it’s been steadily increasing over the decades.
“Regardless of how accurate our current predictions end up being on Oscar night, we have identified some very interesting patterns and trends, which reveal how our tastes are changing and how certain variables or characteristics tend to make up an Oscar winner. The data tells a story and as data scientists, we serve as story tellers,” Principa concluded.
[Source – Principa , image – YouTube |
. Between 2001-2002; in 62 cases, 33 (53%) male, 29 (47%) female, mean age 51.4 +/- 18.1 years) bronchoalveolar lavage (BAL) was performed for diagnosis of opportunistic pulmonary infection and specimens were evaluated for results of microbiological examinations. There was hematological malignancy in 18 (29%) and solid organ malignancy in 13 (21%) cases. Thirty-one (50%) cases were immunocompromised for reasons other than malignancy. By endoscopic evaluation endobronchial lesion was seen in 2 (3%) cases, indirect tumor signs were seen in 2 (3%) cases and signs of infection were seen in 11 (18%) cases. Forty-even (76%) cases were endoscopically normal. Acid-fast bacilli (AFB) direct examination was positive in 3 (5%) cases. In 4 (6%) cases mycobacterial culture was positive, Mycobacterium tuberculosis-polymerase chain reaction (PCR) was also positive in these four cases. Examination of gram-stained smears for bacteria was associated with infection in 14 (23%) cases. Bacteriologic cultures were positive for single potential pathogen in 10 (16%) cases, and for mixed pathogens in 7 (11%) cases for a total number of 17 (27%). Fungal cultures were positive in 3 (5%) cases all of which had hematological malignancy. As a result in 24 (39%) cases microbiological agent of infection is determined: in four mycobacteria, in 17 bacteria other than mycobacteria and in three fungi. |
// isEntry reports whether the given node is the entry node of a control flow
// graph.
func isEntry(n Node) bool {
for _, attr := range n.Attributes() {
if attr.Key == "entry" {
return true
}
}
return false
} |
<reponame>xiaohui100/PythonCookbook
#!/usr/bin/env python
# encoding: utf-8
"""
@author: Alfons
@contact: <EMAIL>
@file: 1.3-deque.py
@time: 2018/4/9 17:56
@version: v1.0
"""
from collections import deque
def Search(lines, pattarn, history = 5):
previous_lines = deque(maxlen = history)
for line in lines: # 文件对象可以迭代！！
if pattarn in line:
yield line, previous_lines
previous_lines.append(line)
if __name__ == "__main__":
with open("test_deque.txt", "r") as f:
for line, previous_lines in Search(f, "python"):
for pline in previous_lines:
print(pline)
print(line)
print('-' * 36)
|
First thought that comes into your mind?
Maybe MK Ultra? Maybe new experimental drugs? Maybe a secret government test on the general population?
Your guess is as good as mine, but this story is downright weird.
Something is causing first responders and some of the people they interact with to become disoriented and hallucinate – though no good explanation is apparent.
According to KIMA-TV:
This week, an emergency room in the Pacific Northwest was briefly quarantined after five people—including two police officers and a hospital worker—experienced mysterious hallucinations from an unidentified illness believed to be spread by touch. According to Oregon Live, the enigmatic incident began early Wednesday morning when a 54-year-old caregiver in North Bend, Oregon, called police to report seven or eight people “trying to take the roof off her vehicle.” Police say they found nothing, but after the caregiver reported the unseen vandals a second time, sheriff’s deputies escorted her to a nearby hospital for suspected hallucinations. Shortly afterward, however, one of the deputies began experiencing similar symptoms and returned to the hospital. Soon after that, the other deputy, a hospital worker and the caregiver’s 78-year-old patient also began hallucinating and were hospitalized.
Initially, authorities tried to explain it away by suggesting that the elderly woman was using or wearing fentanyl patches, which sometimes have a side effect of hallucinations.
But those reports proved to be incorrect, as it fails to explain how those who started hallucinating would have come into contact with, let alone spread the issue.
The Oregonian reported this, but their readers picked apart the weak case, which does little to explain the phenomenon:
A haz-mat team checked the house but found nothing suspicious. They figure it was the fentanyl, a powerful narcotic.
The 78-year-old woman uses fentanyl patches. Though all of the patches were accounted for, the deputies figured they still ended up being affected anyway, Downing said. “They think they got exposed from handling and being in the same room with everybody,” he said.
But whatever is causing hallucinations may have been spread through personal contact – though it isn’t exactly clear what the culprit may be.
Then again, one has to wonder if we are all being subjected to experimentation… perhaps to see who is affected, and how many people panic.
Exposure to electromagnetic energy has been known to cause hallucinations that are otherwise unexplainable, but that would affect only those in path of the frequency, not those who had hand-to-hand contact.
As Melissa Dykes explains, the extremely bizarre and unexplainable can be simulated and recreated in a lab using sophisticated electromagnetic technology on the brain:
Scientists Could Simulate Alien Abductions over 20 Years Ago
Here’s what they never told you about alleged alien abduction and UFO encounter experiences – the bizarre and surely unnerving experience can be induced by advanced use of stimulation of the brain and artificially tricking the neurons to fire in specific ways – using electromagnetic energy. It is a little known topic that CIA-affiliated paranormal researchers like Dr. Michael Persinger have proven experimentally. His subjects – including one journalist reporting for the New Scientist back in the early 90s – reported sudden and intense emotions and even feelings of being grabbed, stretched beyond physical limitations and dragged up a wall! They were able to simulate the entire thing in a lab…
As for whatever happened in this case…
It’s just weird, and hopefully not something that will ever happen on a widespread basis.
Read more:
VIDEOS: Mysterious Lights Spotted Over California: “Airspace Over The Pacific Is Closed To Incoming Flights”
WTF? UK Police Captures “Invisible UFO” On Thermal Camera |
The Requirement of Reversible Cysteine Sulfenic Acid Formation for T Cell Activation and Function1 Reactive oxygen intermediates (ROI) generated in response to receptor stimulation play an important role in mediating cellular responses. We have examined the importance of reversible cysteine sulfenic acid formation in naive CD8+ T cell activation and proliferation. We observed that, within minutes of T cell activation, naive CD8+ T cells increased ROI levels in a manner dependent upon Ag concentration. Increased ROI resulted in elevated levels of cysteine sulfenic acid in the total proteome. Analysis of specific proteins revealed that the protein tyrosine phosphatases SHP-1 and SHP-2, as well as actin, underwent increased sulfenic acid modification following stimulation. To examine the contribution of reversible cysteine sulfenic acid formation to T cell activation, increasing concentrations of 5,5-dimethyl-1,3-cyclohexanedione (dimedone), which covalently binds to cysteine sulfenic acid, were added to cultures. Subsequent experiments demonstrated that the reversible formation of cysteine sulfenic acid was critical for ERK1/2 phosphorylation, calcium flux, cell growth, and proliferation of naive CD8+ and CD4+ T cells. We also found that TNF- production by effector and memory CD8+ T cells was more sensitive to the inhibition of reversible cysteine sulfenic acid formation than IFN-. Together, these results demonstrate that reversible cysteine sulfenic acid formation is an important regulatory mechanism by which CD8+ T cells are able to modulate signaling, proliferation, and function. |
package com.cardpay.pccredit.intopieces.web;
import java.io.IOException;
import java.util.ArrayList;
import java.util.Date;
import java.util.HashMap;
import java.util.LinkedHashMap;
import java.util.List;
import java.util.Map;
import javax.servlet.http.HttpServletRequest;
import javax.servlet.http.HttpServletResponse;
import net.sf.json.JSONArray;
import net.sf.json.JSONObject;
import org.apache.commons.lang.StringUtils;
import org.springframework.beans.factory.annotation.Autowired;
import org.springframework.stereotype.Controller;
import org.springframework.web.bind.WebDataBinder;
import org.springframework.web.bind.annotation.InitBinder;
import org.springframework.web.bind.annotation.ModelAttribute;
import org.springframework.web.bind.annotation.RequestMapping;
import org.springframework.web.bind.annotation.RequestMethod;
import org.springframework.web.bind.annotation.RequestParam;
import org.springframework.web.bind.annotation.ResponseBody;
import org.springframework.web.multipart.MultipartFile;
import com.cardpay.pccredit.customer.constant.CustomerInforConstant;
import com.cardpay.pccredit.customer.filter.CustomerInforFilter;
import com.cardpay.pccredit.customer.model.CustomerCareersInformation;
import com.cardpay.pccredit.customer.model.CustomerInfor;
import com.cardpay.pccredit.customer.service.CustomerInforService;
import com.cardpay.pccredit.intopieces.constant.CardStatus;
import com.cardpay.pccredit.intopieces.constant.Constant;
import com.cardpay.pccredit.intopieces.constant.IntoPiecesException;
import com.cardpay.pccredit.intopieces.filter.IntoPiecesFilter;
import com.cardpay.pccredit.intopieces.filter.MakeCardFilter;
import com.cardpay.pccredit.intopieces.model.CustomerAccountData;
import com.cardpay.pccredit.intopieces.model.CustomerApplicationCom;
import com.cardpay.pccredit.intopieces.model.CustomerApplicationContact;
import com.cardpay.pccredit.intopieces.model.CustomerApplicationContactVo;
import com.cardpay.pccredit.intopieces.model.CustomerApplicationGuarantor;
import com.cardpay.pccredit.intopieces.model.CustomerApplicationGuarantorVo;
import com.cardpay.pccredit.intopieces.model.CustomerApplicationInfo;
import com.cardpay.pccredit.intopieces.model.CustomerApplicationOther;
import com.cardpay.pccredit.intopieces.model.CustomerApplicationRecom;
import com.cardpay.pccredit.intopieces.model.CustomerApplicationRecomVo;
import com.cardpay.pccredit.intopieces.model.IntoPieces;
import com.cardpay.pccredit.intopieces.model.MakeCard;
import com.cardpay.pccredit.intopieces.service.IntoPiecesService;
import com.cardpay.pccredit.product.model.AddressAccessories;
import com.cardpay.pccredit.product.model.AppendixDict;
import com.cardpay.pccredit.product.model.ProductAttribute;
import com.cardpay.pccredit.product.service.ProductService;
import com.wicresoft.jrad.base.auth.IUser;
import com.wicresoft.jrad.base.auth.JRadModule;
import com.wicresoft.jrad.base.auth.JRadOperation;
import com.wicresoft.jrad.base.constant.JRadConstants;
import com.wicresoft.jrad.base.database.id.IDGenerator;
import com.wicresoft.jrad.base.database.model.BusinessModel;
import com.wicresoft.jrad.base.database.model.QueryResult;
import com.wicresoft.jrad.base.i18n.I18nHelper;
import com.wicresoft.jrad.base.web.DataBindHelper;
import com.wicresoft.jrad.base.web.JRadModelAndView;
import com.wicresoft.jrad.base.web.controller.BaseController;
import com.wicresoft.jrad.base.web.result.JRadPagedQueryResult;
import com.wicresoft.jrad.base.web.security.LoginManager;
import com.wicresoft.util.spring.Beans;
import com.wicresoft.util.spring.mvc.mv.AbstractModelAndView;
@Controller
@RequestMapping("/intopieces/intopiecesquery/*")
@JRadModule("intopieces.intopiecesquery")
public class IntoPiecesControl extends BaseController {
@Autowired
private IntoPiecesService intoPiecesService;
@Autowired
private CustomerInforService customerInforService;
@Autowired
private ProductService productService;
@Autowired
private CustomerInforService customerInforservice;
/**
* 浏览页面
*
* @param filter
* @param request
* @return
*/
@ResponseBody
@RequestMapping(value = "browse.page", method = { RequestMethod.GET })
@JRadOperation(JRadOperation.BROWSE)
public AbstractModelAndView browse(@ModelAttribute IntoPiecesFilter filter,
HttpServletRequest request) {
filter.setRequest(request);
IUser user = Beans.get(LoginManager.class).getLoggedInUser(request);
String userId = user.getId();
filter.setUserId(userId);
QueryResult<IntoPieces> result = intoPiecesService.findintoPiecesByFilter(filter);
JRadPagedQueryResult<IntoPieces> pagedResult = new JRadPagedQueryResult<IntoPieces>(
filter, result);
JRadModelAndView mv = new JRadModelAndView(
"/intopieces/intopieces_browse", request);
mv.addObject(PAGED_RESULT, pagedResult);
return mv;
}
/**
* 查询进件
*
* @param filter
* @param request
* @return
*/
@ResponseBody
@RequestMapping(value = "queryResult.page", method = { RequestMethod.GET })
@JRadOperation(JRadOperation.BROWSE)
public AbstractModelAndView queryResult(@ModelAttribute IntoPiecesFilter filter,
HttpServletRequest request) {
filter.setRequest(request);
IUser user = Beans.get(LoginManager.class).getLoggedInUser(request);
String userId = user.getId();
filter.setUserId(userId);
QueryResult<IntoPieces> result = intoPiecesService.findintoPiecesByFilter(filter);
JRadPagedQueryResult<IntoPieces> pagedResult = new JRadPagedQueryResult<IntoPieces>(
filter, result);
JRadModelAndView mv = new JRadModelAndView(
"/intopieces/intopieces_browse", request);
mv.addObject(PAGED_RESULT, pagedResult);
return mv;
}
/**
* 审核通过进件查询
*
* @param filter
* @param request
* @return
*/
@ResponseBody
@RequestMapping(value = "applyIntopiecesQuery.page", method = { RequestMethod.GET })
@JRadOperation(JRadOperation.BROWSE)
public AbstractModelAndView applyIntopiecesQuery(@ModelAttribute IntoPiecesFilter filter,
HttpServletRequest request) {
filter.setRequest(request);
QueryResult<IntoPieces> result = intoPiecesService.findintoApplayPiecesByFilter(filter);
JRadPagedQueryResult<IntoPieces> pagedResult = new JRadPagedQueryResult<IntoPieces>(filter, result);
JRadModelAndView mv = new JRadModelAndView("/intopieces/apply_intopieces_browse", request);
mv.addObject(PAGED_RESULT, pagedResult);
return mv;
}
/**
* 制卡中心查询制卡
*
* @param filter
* @param request
* @return
*/
@ResponseBody
@RequestMapping(value = "queryCard.page", method = { RequestMethod.GET })
@JRadOperation(JRadOperation.BROWSE)
public AbstractModelAndView queryCard(@ModelAttribute MakeCardFilter filter,
HttpServletRequest request) {
filter.setRequest(request);
QueryResult<MakeCard> result = intoPiecesService.findCardByFilter(filter);
JRadPagedQueryResult<MakeCard> pagedResult = new JRadPagedQueryResult<MakeCard>(filter, result);
JRadModelAndView mv = new JRadModelAndView("/intopieces/card_browse", request);
mv.addObject(PAGED_RESULT, pagedResult);
return mv;
}
/**
* 客户经理查询制卡
*
* @param filter
* @param request
* @return
*/
@ResponseBody
@RequestMapping(value = "managerQueryCard.page", method = { RequestMethod.GET })
@JRadOperation(JRadOperation.BROWSE)
public AbstractModelAndView managerQueryCard(@ModelAttribute MakeCardFilter filter,
HttpServletRequest request) {
filter.setRequest(request);
filter.setCardOrganization(Beans.get(LoginManager.class).getLoggedInUser(request).getOrganization().getId());
QueryResult<MakeCard> result = intoPiecesService.findCardByFilter(filter);
JRadPagedQueryResult<MakeCard> pagedResult = new JRadPagedQueryResult<MakeCard>(filter, result);
JRadModelAndView mv = new JRadModelAndView("/intopieces/card_manager_browse", request);
mv.addObject(PAGED_RESULT, pagedResult);
return mv;
}
/**
* 卡片录入界面
*
* @param filter
* @param request
* @return
*/
@ResponseBody
@RequestMapping(value = "insertCard.page", method = { RequestMethod.GET })
@JRadOperation(JRadOperation.BROWSE)
public AbstractModelAndView insertCard(HttpServletRequest request) {
JRadModelAndView mv = new JRadModelAndView("/intopieces/card_input", request);
return mv;
}
/**
* 卡号保存
*
* @param request
* @return
* @throws IOException
*/
@ResponseBody
@RequestMapping(value = "saveCardData.json", method = { RequestMethod.POST })
@JRadOperation(JRadOperation.CREATE)
public Map<String, Object> saveCardData(@ModelAttribute MakeCard makeCard,
HttpServletRequest request, HttpServletResponse response) throws IOException {
response.setContentType("text/html;charset=utf-8");
Map<String, Object> map = new HashMap<String, Object>();
makeCard.setId(IDGenerator.generateID());
makeCard.setCreatedTime(new Date());
makeCard.setCreatedBy(Beans.get(LoginManager.class)
.getLoggedInUser(request).getId());
makeCard.setCardOrganizationStatus(CardStatus.ORGANIZATION_UNISSUED.toString());
makeCard.setCardCustomerStatus(CardStatus.CUSTOMER_UNISSUED.toString());
try {
intoPiecesService.saveCard(makeCard);
map.put(JRadConstants.SUCCESS, true);
map.put(JRadConstants.MESSAGE, Beans.get(I18nHelper.class)
.getMessageNotNull(Constant.SUCCESS_MESSAGE));
JSONObject obj = JSONObject.fromObject(map);
response.getWriter().print(obj.toString());
} catch (Exception e) {
e.printStackTrace();
map.put(JRadConstants.SUCCESS, false);
map.put(JRadConstants.MESSAGE, Beans.get(I18nHelper.class)
.getMessageNotNull(Constant.FAIL_MESSAGE));
JSONObject obj = JSONObject.fromObject(map);
response.getWriter().print(obj.toString());
}
return null;
}
/**
* 机构下发
*
* @param request
* @return
*/
@ResponseBody
@RequestMapping(value = "organizationIssuedCard.json", method = { RequestMethod.POST })
@JRadOperation(JRadOperation.CREATE)
public Map<String, Object> organizationIssuedCard(HttpServletRequest request, HttpServletResponse response) {
Map<String, Object> map = new HashMap<String, Object>();
try {
if(Boolean.parseBoolean(request.getParameter("flag"))){
intoPiecesService.organizationIssuedCard(request.getParameter(ID),null,CardStatus.CUSTOMER_ISSUED.toString());
}else{
intoPiecesService.organizationIssuedCard(request.getParameter(ID),CardStatus.ORGANIZATION_ISSUED.toString(),null);
}
map.put(JRadConstants.SUCCESS, true);
map.put(JRadConstants.MESSAGE, Beans.get(I18nHelper.class)
.getMessageNotNull(Constant.SUCCESS_MESSAGE));
} catch (Exception e) {
e.printStackTrace();
map.put(JRadConstants.SUCCESS, false);
map.put(JRadConstants.MESSAGE, Beans.get(I18nHelper.class)
.getMessageNotNull(Constant.FAIL_MESSAGE));
}
return map;
}
/**
* 查看卡片信息
*
* @param request
* @return
*/
@ResponseBody
@RequestMapping(value = "viewCard.page", method = { RequestMethod.GET })
@JRadOperation(JRadOperation.BROWSE)
public AbstractModelAndView viewCard(HttpServletRequest request) {
MakeCard makeCard = intoPiecesService.findMakeCardById(request.getParameter(ID));
JRadModelAndView mv = new JRadModelAndView(
"/intopieces/card_view", request);
mv.addObject("makeCard", makeCard);
return mv;
}
/**
* 选择客户信息
*
* @param filter
* @param request
* @return
*/
@ResponseBody
@RequestMapping(value = "chooseCustomerName.json", method = { RequestMethod.GET })
@JRadOperation(JRadOperation.BROWSE)
public AbstractModelAndView chooseCustomerName(HttpServletRequest request,
HttpServletResponse response) {
// TODO q?
String userId = Beans.get(LoginManager.class)
.getLoggedInUser(request).getId();
String chineseName = request.getParameter("q");
List<CustomerInfor> list = customerInforService
.findCustomerInforByName(userId,chineseName);
String json = JSONArray.fromObject(list).toString();
try {
response.getWriter().print(json);
} catch (IOException e) {
// TODO 有日志功能，在这一步应保持返回统一，出错以后查看日志
e.printStackTrace();
}
return null;
}
/**
* 选择客户信息
*
* @param filter
* @param request
* @return
*/
// TODO 选择使用JRadOperation.CREATE？
@ResponseBody
@RequestMapping(value = "chooseCustomer.page", method = { RequestMethod.GET })
@JRadOperation(JRadOperation.CREATE)
public AbstractModelAndView chooseCustomer(
@ModelAttribute CustomerInforFilter filter,
HttpServletRequest request) {
filter.setRequest(request);
filter.setUserId(Beans.get(LoginManager.class)
.getLoggedInUser(request).getId());
QueryResult<CustomerInfor> result = customerInforService
.findCustomerInforByFilter(filter);
JRadPagedQueryResult<CustomerInfor> pagedResult = new JRadPagedQueryResult<CustomerInfor>(
filter, result);
JRadModelAndView mv = new JRadModelAndView(
"/intopieces/customer_choose", request);
mv.addObject(PAGED_RESULT, pagedResult);
mv.addObject("filter", filter);
return mv;
}
/**
* 批量添加进件
*
* @param request
* @return
*/
@ResponseBody
@RequestMapping(value = "chooseCustomerById.page", method = { RequestMethod.GET })
@JRadOperation(JRadOperation.CREATE)
public AbstractModelAndView chooseCustomerById(HttpServletRequest request) {
JRadModelAndView mv = new JRadModelAndView(
"/intopieces/customer_choose_by_id", request);
return mv;
}
/**
* 根据客户信息新增进件信息，将客户相关的信息带到后面进件新增页面
*
* @param filter
* @param request
* @return
*/
@ResponseBody
@RequestMapping(value = "input.page", method = { RequestMethod.GET })
@JRadOperation(JRadOperation.CREATE)
public AbstractModelAndView input(HttpServletRequest request) {
/* 客户信息 */
CustomerInfor customerInfor = null;
/* 职业信息 */
CustomerCareersInformation customerCareersInformation = null;
/* 客户联系人 */
List<CustomerApplicationContact> customerApplicationContactList = null;
/* 客户担保人 */
List<CustomerApplicationGuarantor> customerApplicationGuarantorList = null;
/* 客户推荐人 */
List<CustomerApplicationRecom> customerApplicationRecomList = null;
/* 客户申请主表信息 */
CustomerApplicationInfo customerApplicationInfo = null;
/* 其他资料 */
CustomerApplicationOther customerApplicationOther = null;
/* 行社专栏 */
CustomerApplicationCom customerApplicationCom = null;
/* 行社专栏 */
CustomerAccountData customerAccountData = null;
/* 产品要上传的附件资料 */
List<AppendixDict> appendixDictList = null;
/* 实际上传的附件资料 */
List<AddressAccessories> addressAccessoriesList = new ArrayList<AddressAccessories>();
String tempParam = request.getParameter("intoPicesidAndCustorId");
String viewFlag = request.getParameter("viewFlag");
/*修改进件首先查询出进件信息*/
if (StringUtils.trimToNull(tempParam) != null) {
String[] tempArray = tempParam.split("_");
customerInfor = customerInforService
.findCustomerInforById(tempArray[1]);
customerApplicationInfo = intoPiecesService
.findCustomerApplicationInfoById(tempArray[0]);
if (customerInfor != null) {
customerCareersInformation = intoPiecesService
.findCustomerCareersInformationByCustomerId(customerInfor
.getId());
}
if (customerApplicationInfo != null) {
customerApplicationContactList = intoPiecesService
.findCustomerApplicationContactsByApplicationId(customerApplicationInfo
.getId());
customerApplicationGuarantorList = intoPiecesService
.findCustomerApplicationGuarantorsByApplicationId(customerApplicationInfo
.getId());
customerApplicationRecomList = intoPiecesService
.findCustomerApplicationRecomsByApplicationId(customerApplicationInfo
.getId());
customerApplicationOther = intoPiecesService
.findCustomerApplicationOtherByApplicationId(customerApplicationInfo
.getId());
customerApplicationCom = intoPiecesService
.findCustomerApplicationComByApplicationId(customerApplicationInfo
.getId());
customerAccountData = intoPiecesService
.findCustomerAccountDataByApplicationId(customerApplicationInfo
.getId());
if (customerApplicationInfo != null
&& customerApplicationInfo.getProductId() != null) {
appendixDictList = productService
.findAppendixByProductId(customerApplicationInfo
.getProductId());
addressAccessoriesList = intoPiecesService
.findAddressAccessories(
customerApplicationInfo.getId(),
customerApplicationInfo.getProductId());
}
}
} else {// 客户第一次填写进件信息
if (StringUtils.trimToNull(request.getParameter("customerId")) != null) {
customerInfor = customerInforService
.findCustomerInforById(request
.getParameter("customerId"));
} else if (StringUtils.trimToNull(request
.getParameter("customerCardId")) != null) {
customerInfor = customerInforService
.findCustomerInforByCardId(StringUtils.trim(request
.getParameter("customerCardId")));
}
if (customerInfor != null) {
customerCareersInformation = intoPiecesService
.findCustomerCareersInformationByCustomerId(customerInfor
.getId());
}
}
Map<String, String> productAttributeMap = new LinkedHashMap<String, String>();
List<ProductAttribute> list = productService.findProductAttributeByuserId(Beans.get(LoginManager.class).getLoggedInUser(request).getId());
if(list!=null&&!list.isEmpty()){
for (int i=0; i<list.size();i++) {
ProductAttribute productAttribute = list.get(i);
if (productAttribute != null) {
productAttributeMap.put(productAttribute.getId(),
productAttribute.getProductName());
}
}
if(customerApplicationInfo == null &&productAttributeMap!=null&& !productAttributeMap.isEmpty()){
appendixDictList = productService.findAppendixByProductId(list.get(0).getId());
}
}
JRadModelAndView mv = null;
if(StringUtils.trimToNull(viewFlag)!=null){
mv = new JRadModelAndView("/intopieces/customer_view", request);
if(Constant.APPROVE_INTOPICES.equals(customerApplicationInfo.getStatus())){
customerInfor = customerInforService.findCloneCustomerInforByAppId(customerApplicationInfo.getId());
if(customerInfor!=null){
customerCareersInformation = customerInforService.findCustomerCareersByCustomerId(customerInfor.getId(), customerApplicationInfo.getId());
}else{
customerCareersInformation = null;
}
}
}else{
mv = new JRadModelAndView("/intopieces/customer_input", request);
}
if(customerApplicationInfo!=null&&StringUtils.trimToNull(customerApplicationInfo.getApplyQuota())!=null){
customerApplicationInfo.setApplyQuota((Double.valueOf(customerApplicationInfo.getApplyQuota())/100)+"");
}
if(customerApplicationInfo!=null&&StringUtils.trimToNull(customerApplicationInfo.getFinalApproval())!=null){
customerApplicationInfo.setFinalApproval((Double.valueOf(customerApplicationInfo.getFinalApproval())/100)+"");
}
mv.addObject("customer", customerInfor);
mv.addObject("customerCareers", customerCareersInformation);
mv.addObject("customerApplicationContactList",
customerApplicationContactList);
mv.addObject("customerApplicationGuarantorList",
customerApplicationGuarantorList);
mv.addObject("customerApplicationRecomList",
customerApplicationRecomList);
mv.addObject("customerApplicationInfo", customerApplicationInfo);
mv.addObject("customerApplicationOther", customerApplicationOther);
mv.addObject("customerApplicationCom", customerApplicationCom);
mv.addObject("appendixDictList", appendixDictList);
mv.addObject("addressAccessoriesList", addressAccessoriesList);
mv.addObject("productAttributeMap", productAttributeMap);
mv.addObject("customerAccountData", customerAccountData);
return mv;
}
/**
* 根据客户信息新增进件信息，将客户相关的信息带到后面进件新增页面
*
* @param filter
* @param request
* @return
*/
@ResponseBody
@RequestMapping(value = "display.page", method = { RequestMethod.GET })
@JRadOperation(JRadOperation.DISPLAY)
public AbstractModelAndView display(HttpServletRequest request) {
/* 客户信息 */
CustomerInfor customerInfor = null;
/* 职业信息 */
CustomerCareersInformation customerCareersInformation = null;
/* 客户联系人 */
List<CustomerApplicationContact> customerApplicationContactList = null;
/* 客户担保人 */
List<CustomerApplicationGuarantor> customerApplicationGuarantorList = null;
/* 客户推荐人 */
List<CustomerApplicationRecom> customerApplicationRecomList = null;
/* 客户申请主表信息 */
CustomerApplicationInfo customerApplicationInfo = null;
/* 其他资料 */
CustomerApplicationOther customerApplicationOther = null;
/* 行社专栏 */
CustomerApplicationCom customerApplicationCom = null;
/* 行社专栏 */
CustomerAccountData customerAccountData = null;
/* 产品要上传的附件资料 */
List<AppendixDict> appendixDictList = null;
/* 实际上传的附件资料 */
List<AddressAccessories> addressAccessoriesList = null;
String tempParam = request.getParameter("intoPicesidAndCustorId");
String viewFlag = request.getParameter("viewFlag");
if (StringUtils.trimToNull(tempParam) != null) {// 修改进件首先查询出进件信息
String[] tempArray = tempParam.split("_");
customerInfor = customerInforService
.findCustomerInforById(tempArray[1]);
customerApplicationInfo = intoPiecesService
.findCustomerApplicationInfoById(tempArray[0]);
if (customerInfor != null) {
customerCareersInformation = intoPiecesService
.findCustomerCareersInformationByCustomerId(customerInfor
.getId());
}
if (customerApplicationInfo != null) {
customerApplicationContactList = intoPiecesService
.findCustomerApplicationContactsByApplicationId(customerApplicationInfo
.getId());
customerApplicationGuarantorList = intoPiecesService
.findCustomerApplicationGuarantorsByApplicationId(customerApplicationInfo
.getId());
customerApplicationRecomList = intoPiecesService
.findCustomerApplicationRecomsByApplicationId(customerApplicationInfo
.getId());
customerApplicationOther = intoPiecesService
.findCustomerApplicationOtherByApplicationId(customerApplicationInfo
.getId());
customerApplicationCom = intoPiecesService
.findCustomerApplicationComByApplicationId(customerApplicationInfo
.getId());
customerAccountData = intoPiecesService
.findCustomerAccountDataByApplicationId(customerApplicationInfo
.getId());
if (customerApplicationInfo != null
&& customerApplicationInfo.getProductId() != null) {
appendixDictList = productService
.findAppendixByProductId(customerApplicationInfo
.getProductId());
addressAccessoriesList = intoPiecesService
.findAddressAccessories(
customerApplicationInfo.getId(),
customerApplicationInfo.getProductId());
}
}
} else {// 客户第一次填写进件信息
if (StringUtils.trimToNull(request.getParameter("customerId")) != null) {
customerInfor = customerInforService
.findCustomerInforById(request
.getParameter("customerId"));
} else if (StringUtils.trimToNull(request
.getParameter("customerCardId")) != null) {
customerInfor = customerInforService
.findCustomerInforByCardId(StringUtils.trim(request
.getParameter("customerCardId")));
}
if (customerInfor != null) {
customerCareersInformation = intoPiecesService
.findCustomerCareersInformationByCustomerId(customerInfor
.getId());
}
}
Map<String, String> productAttributeMap = new HashMap<String, String>();
List<ProductAttribute> list = productService
.findProductAttributeByuserId(Beans.get(LoginManager.class)
.getLoggedInUser(request).getId());
for (ProductAttribute productAttribute : list) {
if (productAttribute != null) {
productAttributeMap.put(productAttribute.getId(),
productAttribute.getProductName());
}
}
JRadModelAndView mv = null;
if (StringUtils.trimToNull(viewFlag) != null) {
mv = new JRadModelAndView("/intopieces/customer_view", request);
if (!Constant.SAVE_INTOPICES.equals(customerApplicationInfo.getStatus())) {
customerInfor = customerInforService.findCloneCustomerInforByAppId(customerApplicationInfo.getId());
if (customerInfor != null) {
customerCareersInformation = customerInforService.findCustomerCareersByCustomerId(customerInfor.getId(),customerApplicationInfo.getId());
} else {
customerCareersInformation = null;
}
}
} else {
mv = new JRadModelAndView("/intopieces/customer_input", request);
}
if(customerApplicationInfo!=null&&StringUtils.trimToNull(customerApplicationInfo.getApplyQuota())!=null){
customerApplicationInfo.setApplyQuota((Double.valueOf(customerApplicationInfo.getApplyQuota())/100)+"");
}
if(customerApplicationInfo!=null&&StringUtils.trimToNull(customerApplicationInfo.getFinalApproval())!=null){
customerApplicationInfo.setFinalApproval((Double.valueOf(customerApplicationInfo.getFinalApproval())/100)+"");
}
mv.addObject("customer", customerInfor);
mv.addObject("customerCareers", customerCareersInformation);
mv.addObject("customerApplicationContactList",
customerApplicationContactList);
mv.addObject("customerApplicationGuarantorList",
customerApplicationGuarantorList);
mv.addObject("customerApplicationRecomList",
customerApplicationRecomList);
mv.addObject("customerApplicationInfo", customerApplicationInfo);
mv.addObject("customerApplicationOther", customerApplicationOther);
mv.addObject("customerApplicationCom", customerApplicationCom);
mv.addObject("appendixDictList", appendixDictList);
mv.addObject("addressAccessoriesList", addressAccessoriesList);
mv.addObject("productAttributeMap", productAttributeMap);
mv.addObject("customerAccountData", customerAccountData);
return mv;
}
/**
* 添加进件信息(保存)
*
* @param filter
* @param request
* @return
*/
@ResponseBody
@RequestMapping(value = "save.json", method = { RequestMethod.POST })
@JRadOperation(JRadOperation.CREATE)
public void save(
@ModelAttribute CustomerApplicationCom customerApplicationCom,
@ModelAttribute CustomerApplicationContactVo customerApplicationContactVo,
@ModelAttribute CustomerApplicationGuarantorVo customerApplicationGuarantorVo,
@ModelAttribute CustomerApplicationInfo customerApplicationInfo,
@ModelAttribute CustomerApplicationOther customerApplicationOther,
@ModelAttribute CustomerApplicationRecomVo customerApplicationRecomVo,
@ModelAttribute CustomerCareersInformation customerCareersInformation,
@ModelAttribute CustomerInfor customerInfor,
@ModelAttribute AddressAccessories addressAccessories,
@ModelAttribute CustomerAccountData customerAccountData,
HttpServletRequest request, HttpServletResponse response)
throws Exception {
this.saveOrUpdate(customerApplicationCom, customerApplicationContactVo,
customerApplicationGuarantorVo, customerApplicationInfo,
customerApplicationOther, customerApplicationRecomVo,
customerCareersInformation, customerInfor, addressAccessories,
customerAccountData, request, response);
}
/**
* 添加进件信息(修改)
*
* @param filter
* @param request
* @return
*/
@ResponseBody
@RequestMapping(value = "update.json", method = { RequestMethod.POST })
@JRadOperation(JRadOperation.CHANGE)
public void update(
@ModelAttribute CustomerApplicationCom customerApplicationCom,
@ModelAttribute CustomerApplicationContactVo customerApplicationContactVo,
@ModelAttribute CustomerApplicationGuarantorVo customerApplicationGuarantorVo,
@ModelAttribute CustomerApplicationInfo customerApplicationInfo,
@ModelAttribute CustomerApplicationOther customerApplicationOther,
@ModelAttribute CustomerApplicationRecomVo customerApplicationRecomVo,
@ModelAttribute CustomerCareersInformation customerCareersInformation,
@ModelAttribute CustomerInfor customerInfor,
@ModelAttribute AddressAccessories addressAccessories,
@ModelAttribute CustomerAccountData customerAccountData,
HttpServletRequest request, HttpServletResponse response)
throws Exception {
this.saveOrUpdate(customerApplicationCom, customerApplicationContactVo,
customerApplicationGuarantorVo, customerApplicationInfo,
customerApplicationOther, customerApplicationRecomVo,
customerCareersInformation, customerInfor, addressAccessories,
customerAccountData, request, response);
}
/*进件保存或者更新公共方法*/
public void saveOrUpdate(
CustomerApplicationCom customerApplicationCom,
CustomerApplicationContactVo customerApplicationContactVo,
CustomerApplicationGuarantorVo customerApplicationGuarantorVo,
CustomerApplicationInfo customerApplicationInfo,
CustomerApplicationOther customerApplicationOther,
CustomerApplicationRecomVo customerApplicationRecomVo,
CustomerCareersInformation customerCareersInformation,
CustomerInfor customerInfor,
AddressAccessories addressAccessories,
CustomerAccountData customerAccountData,
HttpServletRequest request, HttpServletResponse response)
throws Exception {
response.setContentType("text/html;charset=utf-8");
Map<String, Object> map = new HashMap<String, Object>();
Map<String, Object> paramMap = new HashMap<String, Object>();
String userId = Beans.get(LoginManager.class).getLoggedInUser(request).getId();
try {
boolean checkFlag = Boolean.valueOf(request.getParameter("checkFlag"));
/* 保存或者是申请 */
customerApplicationInfo.setStatus(StringUtils.trim(request.getParameter("operationFlag")));
/* 如果各部分信息都是新增的这里就插入进数据库 */
List<BusinessModel> list = new ArrayList<BusinessModel>();
/* 如果各部分信息已经存在就更新数据 */
List<BusinessModel> updateList = new ArrayList<BusinessModel>();
if (StringUtils.trimToNull(request
.getParameter("customerApplicationInfoId")) == null) {
customerApplicationInfo.setId(IDGenerator.generateID());
customerApplicationInfo.setApplyQuota((Integer.valueOf(customerApplicationInfo.getApplyQuota())*100)+"");
list.add(customerApplicationInfo);
} else {
customerApplicationInfo.setId(StringUtils.trim(request
.getParameter("customerApplicationInfoId")));
double temp = Double.valueOf(customerApplicationInfo.getApplyQuota());
customerApplicationInfo.setApplyQuota((temp*100)+"");
updateList.add(customerApplicationInfo);
}
if (StringUtils.trimToNull(request
.getParameter("customerApplicationComId")) != null) {
customerApplicationCom.setId(StringUtils.trim(request
.getParameter("customerApplicationComId")));
updateList.add(customerApplicationCom);
} else {
list.add(customerApplicationCom);
}
if (StringUtils.trimToNull(request
.getParameter("customerApplicationOtherId")) != null) {
customerApplicationOther.setId(StringUtils.trim(request
.getParameter("customerApplicationOtherId")));
updateList.add(customerApplicationOther);
} else {
list.add(customerApplicationOther);
}
if (StringUtils.trimToNull(addressAccessories
.getProductAccessoryName()) != null) {
String[] productAccessoryNameArray = addressAccessories
.getProductAccessoryName().split(",");
String[] appendixTypeCodeArray = addressAccessories
.getAppendixTypeCode().split(",");
if (StringUtils.trimToNull(addressAccessories
.getAddressAccessoriesId()) != null) {
String[] addressAccessoriesArray = addressAccessories
.getAddressAccessoriesId().split(",");
for (int i = 0; i < productAccessoryNameArray.length; i++) {
int flag = 0;
for (int j = 0; j < addressAccessoriesArray.length; j++) {
if (i == j) {
AddressAccessories addressAccessoriesTemp = new AddressAccessories();
addressAccessoriesTemp
.setId(addressAccessoriesArray[i]);
addressAccessoriesTemp
.setAppendixTypeCode(appendixTypeCodeArray[i]);
addressAccessoriesTemp
.setApplicationId(customerApplicationInfo
.getId());
addressAccessoriesTemp
.setProductAccessoryName(productAccessoryNameArray[i]);
addressAccessoriesTemp
.setProductId(customerApplicationInfo
.getProductId());
updateList.add(addressAccessoriesTemp);
} else {
flag++;
}
}
if (flag == addressAccessoriesArray.length) {
AddressAccessories addressAccessoriesTemp = new AddressAccessories();
addressAccessoriesTemp.setId(IDGenerator
.generateID());
addressAccessoriesTemp
.setAppendixTypeCode(appendixTypeCodeArray[i]);
addressAccessoriesTemp
.setApplicationId(customerApplicationInfo
.getId());
addressAccessoriesTemp
.setProductAccessoryName(productAccessoryNameArray[i]);
addressAccessoriesTemp
.setProductId(customerApplicationInfo
.getProductId());
list.add(addressAccessoriesTemp);
}
}
} else {
for (int m = 0; m < productAccessoryNameArray.length; m++) {
AddressAccessories addressAccessoriesTemp = new AddressAccessories();
addressAccessoriesTemp.setId(IDGenerator.generateID());
addressAccessoriesTemp
.setAppendixTypeCode(appendixTypeCodeArray[m]);
addressAccessoriesTemp
.setApplicationId(customerApplicationInfo
.getId());
addressAccessoriesTemp
.setProductAccessoryName(productAccessoryNameArray[m]);
addressAccessoriesTemp
.setProductId(customerApplicationInfo
.getProductId());
list.add(addressAccessoriesTemp);
}
}
}
if (StringUtils.trimToNull(request.getParameter("customerId")) == null) {
customerInfor.setId(IDGenerator.generateID());
customerInfor.setZipCode(StringUtils.trim(request
.getParameter("customerZipCode")));
customerCareersInformation.setCustomerId(customerInfor.getId());
customerApplicationInfo.setCustomerId(customerInfor.getId());
list.add(customerInfor);
} else {
customerInfor.setId(StringUtils.trim(request
.getParameter("customerId")));
customerInfor.setZipCode(StringUtils.trim(request
.getParameter("customerZipCode")));
customerCareersInformation.setCustomerId(customerInfor.getId());
customerApplicationInfo.setCustomerId(customerInfor.getId());
updateList.add(customerInfor);
}
if (StringUtils.trimToNull(request
.getParameter("customerCareersId")) != null) {
customerCareersInformation.setId(StringUtils.trim(request
.getParameter("customerCareersId")));
updateList.add(customerCareersInformation);
} else {
list.add(customerCareersInformation);
}
if(StringUtils.trimToNull(request
.getParameter("customerAccountDataId")) != null){
customerAccountData.setId(StringUtils.trim(request
.getParameter("customerAccountDataId")));
updateList.add(customerAccountData);
}else{
list.add(customerAccountData);
}
customerAccountData.setMainApplicationFormId(customerApplicationInfo.getId());
customerApplicationCom.setMainApplicationFormId(customerApplicationInfo.getId());
customerApplicationOther.setMainApplicationFormId(customerApplicationInfo.getId());
/* 添加联系人 */
if (customerApplicationContactVo != null&& StringUtils.trimToNull(customerApplicationContactVo.getContactName()) != null) {
String[] contactIdArray = null;
/* 以联系人姓名个数为单位计算添加联系人个数 */
String[] contactNameArray = customerApplicationContactVo.getContactName().split(",");
if (customerApplicationContactVo != null&& StringUtils.trimToNull(customerApplicationContactVo.getContactId()) != null) {
contactIdArray = customerApplicationContactVo.getContactId().split(",");
} else {
contactIdArray = new String[contactNameArray.length];
}
String[] relationshipWithApplicantArray = this.tempString(customerApplicationContactVo.getContactRelationshipWithApplicant(), contactNameArray);
String[] unitNameArray = this.tempString(customerApplicationContactVo.getContactUnitName(), contactNameArray);
String[] departmentArray = this.tempString(customerApplicationContactVo.getContactDepartment(), contactNameArray);
String[] contactPhoneArray = this.tempString(customerApplicationContactVo.getContactPhone(), contactNameArray);
String[] cellPhoneArray = this.tempString(customerApplicationContactVo.getCellPhone(), contactNameArray);
for (int i = 0; i <= contactNameArray.length - 1; i++) {
CustomerApplicationContact customerApplicationContact = new CustomerApplicationContact();
if (i < contactIdArray.length) {
customerApplicationContact.setId(StringUtils.trimToNull(contactIdArray[i]) != null ? StringUtils.trim(contactIdArray[i]) : "");
}
/* 建立表之间的主外键关联关系 */
customerApplicationContact.setMainApplicationFormId(customerApplicationInfo.getId());
customerApplicationContact.setContactName(StringUtils.trimToNull(contactNameArray[i]) != null ? StringUtils.trim(contactNameArray[i]) : "");
customerApplicationContact.setSex(StringUtils.trimToNull(request.getParameter("contactSex" + i)) != null ? StringUtils.trim(request.getParameter("contactSex" + i)): "");
customerApplicationContact.setRelationshipWithApplicant(StringUtils.trimToNull(relationshipWithApplicantArray[i]) != null ? StringUtils.trim(relationshipWithApplicantArray[i]): "");
customerApplicationContact.setUnitName(StringUtils.trimToNull(unitNameArray[i]) != null ? StringUtils.trim(unitNameArray[i]) : "");
customerApplicationContact.setDepartment(StringUtils.trimToNull(departmentArray[i]) != null ? StringUtils.trim(departmentArray[i]) : "");
customerApplicationContact.setContactPhone(StringUtils.trimToNull(contactPhoneArray[i]) != null ? StringUtils.trim(contactPhoneArray[i]) : "");
customerApplicationContact.setCellPhone(StringUtils.trimToNull(cellPhoneArray[i]) != null ? StringUtils.trim(cellPhoneArray[i]) : "");
if (StringUtils.trimToNull(customerApplicationContact.getId()) == null) {
list.add(customerApplicationContact);
} else {
updateList.add(customerApplicationContact);
}
}
}
/* 添加担保人 */
if (customerApplicationGuarantorVo != null&& StringUtils.trimToNull(customerApplicationGuarantorVo.getGuarantorMortgagorPledge()) != null) {
String[] guarantorIdArray = null;
/* 以 添加担保人姓名个数为单位计算添加联系人个数 */
String[] guarantorMortgagorPledgeArray = customerApplicationGuarantorVo.getGuarantorMortgagorPledge().split(",");
if (customerApplicationGuarantorVo != null&& customerApplicationGuarantorVo.getGuarantorId() != null) {
guarantorIdArray = customerApplicationGuarantorVo.getGuarantorId().split(",");
} else {
guarantorIdArray = new String[guarantorMortgagorPledgeArray.length];
}
String[] relationshipWithApplicantArray = this.tempString(customerApplicationGuarantorVo.getGuarantorRelationshipWithApplicant(), guarantorMortgagorPledgeArray);
String[] unitNameArray = this.tempString(customerApplicationGuarantorVo.getUnitName(), guarantorMortgagorPledgeArray);
String[] departmentArray = this.tempString(customerApplicationGuarantorVo.getDepartment(), guarantorMortgagorPledgeArray);
String[] contactPhoneArray = this.tempString(customerApplicationGuarantorVo.getGuarantorContactPhone(), guarantorMortgagorPledgeArray);
String[] cellPhoneArray = this.tempString(customerApplicationGuarantorVo.getGuarantorCellPhone(), guarantorMortgagorPledgeArray);
String[] documentNumberArray = this.tempString(customerApplicationGuarantorVo.getDocumentNumber(), guarantorMortgagorPledgeArray);
for (int i = 0; i <= guarantorMortgagorPledgeArray.length - 1; i++) {
CustomerApplicationGuarantor customerApplicationGuarantor = new CustomerApplicationGuarantor();
if (i < guarantorIdArray.length) {
customerApplicationGuarantor.setId(StringUtils.trimToNull(guarantorIdArray[i]) != null ? StringUtils.trim(guarantorIdArray[i]) : "");
}
/* 建立表之间的主外键关联关系 */
customerApplicationGuarantor.setMainApplicationFormId(customerApplicationInfo.getId());
customerApplicationGuarantor.setGuarantorMortgagorPledge(StringUtils.trimToNull(guarantorMortgagorPledgeArray[i]) != null ? StringUtils.trim(guarantorMortgagorPledgeArray[i]): "");
customerApplicationGuarantor.setSex(StringUtils.trimToNull(request.getParameter("guarantorSex" + i)) != null ? StringUtils.trim(request.getParameter("guarantorSex"+ i)) : "");
customerApplicationGuarantor.setRelationshipWithApplicant(StringUtils.trimToNull(relationshipWithApplicantArray[i]) != null ? StringUtils.trim(relationshipWithApplicantArray[i]): "");
customerApplicationGuarantor.setUnitName(StringUtils.trimToNull(unitNameArray[i]) != null ? StringUtils.trim(unitNameArray[i]) : "");
customerApplicationGuarantor.setDepartment(StringUtils.trimToNull(departmentArray[i]) != null ? StringUtils.trim(departmentArray[i]) : "");
customerApplicationGuarantor.setContactPhone(StringUtils.trimToNull(contactPhoneArray[i]) != null ? StringUtils.trim(contactPhoneArray[i]) : "");
customerApplicationGuarantor.setCellPhone(StringUtils.trimToNull(cellPhoneArray[i]) != null ? StringUtils.trim(cellPhoneArray[i]) : "");
customerApplicationGuarantor.setDocumentNumber(StringUtils.trimToNull(documentNumberArray[i]) != null ? StringUtils.trim(documentNumberArray[i]) : "");
if (StringUtils.trimToNull(customerApplicationGuarantor.getId()) == null) {
list.add(customerApplicationGuarantor);
} else {
updateList.add(customerApplicationGuarantor);
}
}
}
/* 添加推荐人 */
if (customerApplicationRecomVo != null&& StringUtils.trimToNull(customerApplicationRecomVo.getName()) != null) {
String[] recommendIdArray = null;
/* 以联系人姓名个数为单位计算添加联系人个数 */
String[] nameArray = customerApplicationRecomVo.getName().split(",");
if (customerApplicationRecomVo != null&& customerApplicationRecomVo.getRecommendId() != null) {
recommendIdArray = customerApplicationRecomVo.getRecommendId().split(",");
} else {
recommendIdArray = new String[nameArray.length];
}
String[] outletArray =this.tempString(customerApplicationRecomVo.getOutlet(), nameArray);
String[] recommendedContactPhoneArray = this.tempString(customerApplicationRecomVo.getRecommendedContactPhone(), nameArray);
String[] recommendedIdentityCardNumbArray = this.tempString(customerApplicationRecomVo.getRecommendedIdentityCardNumb(), nameArray);
for (int i = 0; i <= nameArray.length - 1; i++) {
CustomerApplicationRecom customerApplicationRecom = new CustomerApplicationRecom();
if (i < recommendIdArray.length) {customerApplicationRecom.setId(StringUtils.trimToNull(recommendIdArray[i]) != null ? StringUtils.trim(recommendIdArray[i]) : "");
}
/* 建立表之间的主外键关联关系 */
customerApplicationRecom.setMainApplicationFormId(customerApplicationInfo.getId());
customerApplicationRecom.setName(StringUtils.trimToNull(nameArray[i]) != null ? StringUtils.trim(nameArray[i]) : "");
customerApplicationRecom.setOutlet(StringUtils.trimToNull(outletArray[i]) != null ? StringUtils.trim(outletArray[i]) : "");
customerApplicationRecom.setContactPhone(StringUtils.trimToNull(recommendedContactPhoneArray[i]) != null ? StringUtils.trim(recommendedContactPhoneArray[i]) : "");
customerApplicationRecom.setRecommendedIdentityCardNumb(StringUtils.trimToNull(recommendedIdentityCardNumbArray[i]) != null ? StringUtils.trim(recommendedIdentityCardNumbArray[i]): "");
if (StringUtils.trimToNull(customerApplicationRecom.getId()) == null) {
list.add(customerApplicationRecom);
} else {
updateList.add(customerApplicationRecom);
}
}
}
customerInfor.setUserId(userId);
paramMap.put("customerId", customerInfor.getId());
paramMap.put("applicationId", customerApplicationInfo.getId());
paramMap.put("productId", customerApplicationInfo.getProductId());
paramMap.put("flag", true);
paramMap.put("customerBusinessAptitude", customerInfor.getCustomerBusinessAptitude());
paramMap.put("userId", userId);
paramMap.put("checkFlag", checkFlag);
if(!list.isEmpty()){
/* 第一次保存时做插入操作 */
intoPiecesService.saveAllInfo(list, request,userId,customerApplicationInfo.getStatus(),paramMap);
}
if(!updateList.isEmpty()){
/* 第二次保存时做更新操作 */
intoPiecesService.updateAllInfo(updateList, request,userId,customerApplicationInfo.getStatus(),paramMap);
}
map.put(JRadConstants.SUCCESS, true);
map.put(JRadConstants.MESSAGE, Beans.get(I18nHelper.class)
.getMessageNotNull(JRadConstants.CREATE_SUCCESS));
JSONObject obj = JSONObject.fromObject(map);
response.getWriter().print(obj.toString());
} catch (Exception e) {
if(e instanceof IntoPiecesException){
map.put(JRadConstants.SUCCESS, false);
map.put(JRadConstants.MESSAGE, e.getMessage());
JSONObject obj = JSONObject.fromObject(map);
response.getWriter().print(obj.toString());
}else{
// TODO 有日志功能，在这一步应保持返回统一，出错以后查看日志
e.printStackTrace();
map.put(JRadConstants.SUCCESS, false);
map.put(JRadConstants.MESSAGE, Constant.FAIL_MESSAGE);
JSONObject obj = JSONObject.fromObject(map);
response.getWriter().print(obj.toString());
}
}
}
/**
* 输入用户名模糊匹配
*
* @param filter
* @param request
* @return
*/
@ResponseBody
@RequestMapping(value = "selectByLike.json", method = { RequestMethod.GET })
@JRadOperation(JRadOperation.BROWSE)
public AbstractModelAndView selectByLike(HttpServletRequest request,
HttpServletResponse response) {
try {
intoPiecesService.selectLikeByCardId(response,
StringUtils.trim(request.getParameter("q")));
} catch (Exception e) {
// TODO 有日志功能，在这一步应保持返回统一，出错以后查看日志
e.printStackTrace();
}
// TODO 该方法永远return null??前端有ajax调用应将ajax调用方法封装，另外，返回null会带来风险
return null;
}
/**
* 删除联系人，担保人，推荐人
*
* @param filter
* @param request
* @return
*/
@ResponseBody
@RequestMapping(value = "delete.json", method = { RequestMethod.POST })
@JRadOperation(JRadOperation.BROWSE)
public Map<String,Object> delete(HttpServletRequest request,
HttpServletResponse response) throws Exception{
Map<String,Object> map = null;
try {
if(StringUtils.trimToNull(request.getParameter("value"))!=null){
intoPiecesService.delete(StringUtils.trim(request.getParameter("name")),StringUtils.trim(request.getParameter("value")));
}
map = new HashMap<String,Object>();
map.put(JRadConstants.SUCCESS, true);
map.put(JRadConstants.MESSAGE, Constant.SUCCESS_MESSAGE);
} catch (Exception e) {
e.printStackTrace();
map = new HashMap<String,Object>();
map.put(JRadConstants.SUCCESS, false);
map.put(JRadConstants.MESSAGE, Constant.FAIL_MESSAGE);
}
return map;
}
/**
* 查询产品附件列表
*
* @param filter
* @param request
* @return
* @throws IOException
*/
@ResponseBody
@RequestMapping(value = "selectProductAppendix.json", method = { RequestMethod.POST })
@JRadOperation(JRadOperation.BROWSE)
public AbstractModelAndView selectProductAppendix(
HttpServletRequest request, HttpServletResponse response)
throws IOException {
List<AppendixDict> list = null;
List<AddressAccessories> addressAccessoriesList = null;
Map<String, Object> map = null;
try {
list = productService.findAppendixByProductId(StringUtils
.trim(request.getParameter("productId")));
addressAccessoriesList = intoPiecesService.findAddressAccessories(
StringUtils.trim(request.getParameter("applicationId")),
StringUtils.trim(request.getParameter("productId")));
map = new HashMap<String, Object>();
map.put(JRadConstants.SUCCESS, true);
map.put(Constant.RESULT_LIST1, list);
map.put(Constant.RESULT_LIST2, addressAccessoriesList);
JSONObject obj = JSONObject.fromObject(map);
response.getWriter().print(obj.toString());
} catch (Exception e) {
// TODO 有日志功能，在这一步应保持返回统一，出错以后查看日志
e.printStackTrace();
map = new HashMap<String, Object>();
map.put(JRadConstants.SUCCESS, false);
map.put(JRadConstants.MESSAGE, Constant.FAIL_MESSAGE);
JSONObject obj = JSONObject.fromObject(map);
response.getWriter().print(obj.toString());
}
// TODO 该方法永远return null??前端有ajax调用应将ajax调用方法封装，另外，返回null会带来风险
return null;
}
/**
* 导出文本格式数据的接口
*
* @param filter
* @param request，response
* @return
*/
@ResponseBody
@RequestMapping(value = "importData.page")
@JRadOperation(JRadOperation.EXPORTUPLOAD)
public Map<String,Object> importData(HttpServletRequest request,
HttpServletResponse response) {
Map<String,Object> map = null;
try {
String[] intoPicesidAndCustorId = request.getParameter("intoPicesidAndCustorId").split("_");
intoPiecesService.exportData(intoPicesidAndCustorId[0],intoPicesidAndCustorId[1],response);
map = new HashMap<String,Object>();
map.put(MESSAGE, Constant.UPLOAD_SUCCESS_MESSAGE);
} catch (Exception e) {
e.printStackTrace();
}
return map;
}
/**
* 查看审批历史
*
* @param request
* @return
*/
@ResponseBody
@RequestMapping(value = "findApproveHistoryById.page", method = { RequestMethod.GET })
public AbstractModelAndView findApproveHistoryById(HttpServletRequest request) {
JRadModelAndView mv = new JRadModelAndView("/intopieces/approve_history_browse", request);
String id = request.getParameter("id");
String dataType = request.getParameter("dataType");
String ifHideUser = request.getParameter("ifHideUser");
if(StringUtils.isNotEmpty(id)){
List<ApproveHistoryForm> historyForms = intoPiecesService.findApplicationDataImport(id, dataType);
mv.addObject("historyForms", historyForms);
}
mv.addObject("ifHideUser", ifHideUser);
return mv;
}
/**
* 验证客户商业类型
*
* @param request
* @return
*/
@ResponseBody
@RequestMapping(value = "checkValue.json")
@JRadOperation(JRadOperation.BROWSE)
public Map<String, Object> checkValue(HttpServletRequest request) {
boolean flag = false;
Map<String, Object> map = new HashMap<String, Object>();
String currentUserId = Beans.get(LoginManager.class).getLoggedInUser(request).getId();
float quota = Float.valueOf(request.getParameter("applyQuota"));
String productId = request.getParameter("productId");
String value = request.getParameter("value");
try {
int i = intoPiecesService.checkValue(currentUserId,value);
if(i>0){
flag = true;
/*检查申请金额*/
if (!intoPiecesService.checkApplyQuota(quota*100, currentUserId, productId)) {
map.put(JRadConstants.SUCCESS, false);
map.put(JRadConstants.MESSAGE, CustomerInforConstant.MAX_VALUE);
return map;
}
}
if(!flag){
map.put(SUCCESS, false);
map.put(MESSAGE, CustomerInforConstant.NO_CHOICE);
}else{
map.put(SUCCESS, true);
}
} catch (Exception e) {
e.printStackTrace();
}
return map;
}
/**
* 批量导入客户基本信息页面
*
* @param request
* @return
*/
@ResponseBody
@RequestMapping(value = "importCustomerInfo.page")
@JRadOperation(JRadOperation.IMPORT)
public AbstractModelAndView importCustomerInfo(HttpServletRequest request) {
JRadModelAndView mv = new JRadModelAndView("/intopieces/customer_import", request);
return mv;
}
/**
* 批量导入客户进件信息
*
* @param request
* @return
* @throws IOException
*/
@ResponseBody
@RequestMapping(value = "importSubmit.json")
@JRadOperation(JRadOperation.IMPORT)
public Map<String, Object> importSubmit(@RequestParam(value = "file", required = false) MultipartFile file,HttpServletRequest request,HttpServletResponse response) throws IOException {
response.setContentType("text/html;charset=utf-8");
Map<String, Object> map = new HashMap<String, Object>();
try {
if(file==null||file.isEmpty()){
map.put(JRadConstants.SUCCESS, false);
map.put(JRadConstants.MESSAGE, CustomerInforConstant.IMPORTEMPTY);
return map;
}
customerInforservice.importBatchCustomerInfoByExcel(file,Beans.get(LoginManager.class).getLoggedInUser(request).getId());
map.put(JRadConstants.SUCCESS, true);
map.put(JRadConstants.MESSAGE, CustomerInforConstant.IMPORTSUCCESS);
JSONObject obj = JSONObject.fromObject(map);
response.getWriter().print(obj.toString());
} catch (Exception e) {
if(e instanceof IntoPiecesException){
map.put(JRadConstants.SUCCESS, false);
map.put(JRadConstants.MESSAGE, e.getMessage());
JSONObject obj = JSONObject.fromObject(map);
response.getWriter().print(obj.toString());
}else{
e.printStackTrace();
map.put(JRadConstants.SUCCESS, false);
map.put(JRadConstants.MESSAGE, CustomerInforConstant.IMPORTERROR);
JSONObject obj = JSONObject.fromObject(map);
response.getWriter().print(obj.toString());
}
}
return null;
}
/**
* 检查申请额度
*
* @param request
* @return
* @throws IOException
*/
@ResponseBody
@RequestMapping(value = "checkApplyQuota.json")
@JRadOperation(JRadOperation.BROWSE)
public Map<String, Object> checkApplyQuota(HttpServletRequest request) {
Map<String, Object> map = new HashMap<String, Object>();
float quota = Float.valueOf(request.getParameter("applyQuota"));
String productId = request.getParameter("productId");
String userId = Beans.get(LoginManager.class).getLoggedInUser(request).getId();
try {
if (!intoPiecesService.checkApplyQuota(quota*100, userId, productId)) {
map.put(JRadConstants.SUCCESS, false);
map.put(JRadConstants.MESSAGE, CustomerInforConstant.MAX_VALUE);
}else{
map.put(JRadConstants.SUCCESS, true);
}
} catch (Exception e) {
e.printStackTrace();
}
return map;
}
/*数组特殊处理*/
private String[] tempString(String string, String[] stringArray) {
String[] resultArray = null;
if (StringUtils.trimToNull(string) == null) {
resultArray = new String[stringArray.length];
} else {
resultArray = string.split(",");
if (resultArray.length <= stringArray.length) {
String[] temp = new String[stringArray.length];
for (int i = 0; i < temp.length; i++) {
if (i < resultArray.length) {
temp[i] = resultArray[i];
}
}
resultArray = temp;
}
}
return resultArray;
}
@InitBinder
public void initBinder(WebDataBinder binder) {
DataBindHelper.initStandardBinder(binder);
}
}
|
/// Truncate data to a given offset.
pub async fn truncate(&mut self, offset: u64) -> Result<(), IndexWriterError> {
self.byte_writer
.truncate_data_before(offset as i64)
.await
.map_err(|e| IndexWriterError::Internal {
msg: format!("failed to truncate data {:?}", e),
})
} |
Palaeoecophylostoichiometrics Searching for the Elemental Composition of the Last Universal Common Ancestor We discuss the conservation of different elemental ratios across different taxa. It may be possible to use stoichiometric and phylogenetic relationships between taxa to investigate how changes in the distribution of elements in environments such as the oceans, may have affected the evolution of life over the past ∼4 billion years particularly during the great oxidation event∼2.4 billion years ago. |
There has been significant progress in the production of high-intensity optical energy, for example in the area of laser spark plugs or cutting technology and laser-based missile defense. However, there has been little effort to protect users of such systems from accidental exposure to such high-intensity optical energy that may blind or otherwise severely injure anyone exposed to such optical energy without proper protection.
Typically, high-intensity optical energy systems use a simple case switch, which is a simple electrical switch that is opened or closed when a casing is opened. However, in some systems it may be difficult or impractical to have a case switch to indicate when an outer casing is removed. For example, for laser spark plugs, providing a casing around each plug would be impractical and lead to spacing issues, heat issues etc. Furthermore, such a sensor does little to follow the path of optical energy from the source. For example, unlike electricity, simple cuts in an optical fiber covering may do more than just cause disconnections or electrical shorts, but may leak dangerous amounts of high-intensity optical energy. Such high-intensity leaks may be particularly dangerous as they may be undetectable in current designs until damage or injury occurs. |
I was born a wildlife ecologist. Before I even know what the word meant I was sure I wanted to work with wildlife around the world. This passion was cemented when my family moved to Tanzania when I was 10. Other kids my age were cheering on Ireland at the World Cup, while we were driving through the Serengeti, watching migrations and identifying birds.
Following my dream was always going to be hard as I’m quite badly dyslexic and couldn’t get the points to go to an Irish college or university. I couldn’t do Irish for the Leaving Cert and only did five pass subjects, so I had to leavefor Hampshire in England, to do a Higher National Diploma in Wildlife Management.
This course allowed me to get into second year of a zoology degree at the University of Aberdeen.
But I always wanted to study in my own country so after my degree I stalked a Trinity College academic to see if I could study for a PhD there. As luck would have it a PhD on badgers, funded by the Department of Agriculture, came up. I spent months researching everything I could on badgers and was accepted. I really loved doing the PhD and working with farmers from all around Ireland.
In 2007, during the last year of my PhD, myself and my husband Bill started the visa process for moving to Australia. We left before the crash; it was purely a desire to travel and see more of the world.
When we moved to Australia, in a moment of madness we decided to take our cat, Freddy, with us. He was quarantined for six weeks after arriving and we used to sneak him in cans of tuna when we’d visit. We were so homesick at the time. He was our connection to home.
One day I opened the fridge and this massive cockroach fell out. Freddy and I looked at each other, he ran one way, I ran the other and we were both thinking “what the hell is that? I want to go back to Dublin”. A year to the day after we came to Australia he disappeared, which broke my heart.
I worked as a volunteer in Taronga Zoo for a year learning about Australian wildlife and applying for postdoctoral grants. Working with academics from University of New South Wales, we received a grant to reintroduce native rats which had been pushed out by black rats. The project attracted a lot of public interest. It reminded me of interacting with the farmers back home and what a buzz I get from working with the community and wildlife.
Doing this project, I spent a lot of time getting to know the local wildlife. When I’m walking through the bush I stomp hard to let the snakes know I’m coming and they move away. But you have to be very careful with funnel web and red back spiders when you are setting pitfall traps. It’s not like digging a pitfall trap in Monaghan. Digging them here can kill you.
After three years on the native rat project, I started working to help conserve koalas. Koalas are quite an urban species; 80 per cent of them are found on private land and are declining in many places due to threats such as dog attacks and vehicle strikes. Part of my work was to run a Great Koala Count, using a smartphone app that allows people to record where they see Koalas. This has been extremely successful, and will become an annual event in Australia. For someone who watched Skippy as a kid and had a koala teddy bear, I’m living the dream now, working with koalas.
My Mam and Dad and sister have been out to visit a few times, and they loved it too. But Australia just isn’t Ireland! We were in Dublin at Christmas, and seeing family and friends over pints of proper Guinness and sharing the banter reminded us of what we are missing. There is no place in the world like Ireland and we will eventually go home. I would love to work with Irish wildlife and farmers again. |
A cysteine-rich nuclear protein activates yeast metallothionein gene transcription The ACE1 gene of the yeast Saccharomyces cerevisiae is required for copper-inducible transcription of the metallothionein gene (CUP1). The sequence of the cloned ACE1 gene predicted an open reading frame for translation of a 225-amino-acid polypeptide. This polypeptide was characterized by an amino-terminal half rich in cysteine residues and positively charged amino acids. The arrangement of many of the 12 cysteines in the configuration Cys-X-Cys or Cys-X-X-Cys suggested that the ACE1 protein may bind metal ions. The carboxyl-terminal half of the ACE1 protein was devoid of cysteines but was highly acidic in nature. The ability of a bifunctional ACE1-beta-galactosidase fusion protein to accumulate in yeast cell nuclei was consistent with the possibility that ACE1 plays a direct role in the regulation of copper-inducible transcription of the yeast metallothionein gene. |
3D Facial Landmark Detection Using Deep Convolutional Neural Networks Various applications have been developed in facial research to aid the recognition of personal attributes, analysis of race, and personal authentication for the security industry and other research fields. Thus, it is possible to identify the differences in facial shape based on place of birth or country. The present study analyzes facial shape using scanned 3D facial images and investigates ways to extract facial landmarks from the 3D facial images. The detection of the facial landmark requires the normalization of the facial scale and position among in the 3D image data to analyze the facial shape. Therefore, it is difficult to obtain accurate facial landmarks from 3D facial images. Our method decomposes the task into the following three parts: (a) conversion of data from the 3D facial image to a 2D image, (b) extraction of facial landmarks from the 3D image using Convolutional Neural Network (CNN), (c) inversion of the identified facial landmarks from 2D to 3D images. In experiments, we compared the accuracy of this model for facial landmark detection. |
Field
Embodiments of the present invention relate to a laser welding head.
Related Art
When repair work is performed in a nuclear reactor, there is a place such as a narrow place which is difficult to access in the nuclear reactor. In order to increase the accessibility, a laser welding apparatus, which has small heat input and which can be made small in size, has been developed. As for a laser welding head for laser welding work to repair a nuclear reactor, various configurations have been proposed to reduce damage of the laser welding head, the damage being caused by the reflected light from a base material and the radiant heat from the molten pool.
As configurations adopted to reduce thermal damage of the laser welding head, there are proposed an underwater welding apparatus, an overlay welding apparatus, an overlay welding method for a reactor internal structure in a nuclear reactor, and the like. The proposed underwater welding apparatus includes the laser welding head configured by an aluminum alloy or a copper alloy having high thermal conductivity and therefore improves mechanical and thermal durability.
Further, in the proposed overlay welding apparatus, when the flow rate of the shielding gas is set to 6 to 14 m/s at the outlet of the shield gas injection nozzle, the proposed overlay welding apparatus recesses the surface of the molten pool and can thereby irradiate at a position closer to the base material. As a result, since welding penetration depth is increased, the proposed overlay welding apparatus can suppress occurrence of a fusion defect and a weld crack without increasing the amount of heat input.
In the overlay welding method described above, if the distance between the outlet of the shield gas injection nozzle and the molten pool is increased, the flow rate of the shielding gas is reduced, and the effect of increasing the welding penetration depth is therefore reduced. Accordingly, in the overlay welding method described above, it is required that the laser welding work is performed in a state where the shield gas injection nozzle is arranged close to the molten pool. In the state where the shield gas injection nozzle is arranged close to the molten pool, it is necessarily required that a welding wire supply nozzle which supplies a welding wire to the target is arranged close to the molten pool.
The laser light which is irradiated from the shield gas injection nozzle onto a target such as the base material is reflected by the target, and then returned to a portion of the shield gas injection nozzle and/or the welding wire supply nozzle. If the shield gas injection nozzle is arranged close to the molten pool, the influence of the reflected light on the shield gas injection nozzle and welding wire supply nozzle become large. Accordingly, there arises an event that the welding head (including the shield gas injection nozzle and the welding wire supply nozzle) is damaged by melting, deformation, deficiency or the like, and the damage should be therefore prevented.
The embodiments according to the present invention was made in consideration of the circumstances mentioned above and an object thereof is an object to provide a laser welding head capable of reducing the influence of the reflected light.
In consideration of the circumstances described above, a laser welding head in accordance with the embodiments according to the present invention includes: a shield gas injection nozzle that irradiates laser light onto a target and supplies a shielding gas to the target; and a welding wire supply nozzle that supplies a welding wire to the target, wherein the shield gas injection nozzle and the welding wire supply nozzle include a main body section and a surface layer section that covers the main body section, and at least part of the surface layer section is formed by at least one of ultra-hard alloy, cermet, ceramics and MCrAlY alloy. |
If I could summarize my world for you in one sentence, it would be: chasing my toddler. I know the back of my daughter’s scruffy blonde head anywhere: dashing across the living room, making a break for the next grocery aisle, or attempting to go up the slide (much more fun than going down). My old day job required me to attend meetings and sit in front of a computer most of the day. Now, I’m lucky if I get 10 minutes to sit down for a breather before my girl has me running to catch up with her.
I’ve never raised a child before, and given my personality, I decided to read about it. All the toddler self-help books talk about what you need to teach them: how to play with others, learn language, go potty. These books contain great advice for child rearing, but none discuss the things parents learn from toddlers. I have learned at least as much from my daughter as she has learned from me. So here are some tips for living from someone who just started her life journey:
1. It’s your duty to question everything.
Toddlers don’t take anything as a given. They don’t understand that you should eat your peas, not put them in your hair. On a more serious note, they don’t understand that running into the street can kill you, so they may bolt at any second. And when you stop them from doing something they want to do, you get the dreaded string of “whys.”
But “whys” are a good thing. They demonstrate curiosity and a thirst to understand the world. More importantly, they force us to evaluate all of our decisions. Toddlers don’t like to follow a rule with a weak “why,” and neither should adults. So if something bothers you, question it. Don’t like the answer? Channel your inner toddler and take action. You’ll feel better in the long run (especially on ethical decisions) if you always ask “why.”
2. All skills take practice, but you’ll get there eventually.
It is amazing how very little a baby can do at birth. He can’t see or hear well. Many babies struggle with the sucking reflex, so they can’t even eat well. When you watch a baby grow, it’s amazing to watch him master the ability to move and manipulate things, including himself. It literally takes years. Reasoning takes much longer. (Some parents of teenagers might argue that day never comes.) And how do we learn all of this? By doing it day in, day out for years at a time.
So as an adult, if you’re trying to learn a new skill, you’ve got to be patient and put in the time to learn something new. Toddlers thrive on doing the same things over and over again, and that’s how they become master walkers and talkers. Don’t get me wrong – toddlers are rarely patient. My daughter can cry with the best of them when she encounters a container she wants to open and can’t. But she works at it constantly until she does eventually open the box (usually to my frustrated sigh as I go find a broom).
3. There is opportunity in destruction.
Before my daughter was born, I saw the world as a place where I could create. I could find connections and establish a career. I could open up my computer and write a story. Opportunities abound in this world because I can build in it.
Toddlers like creation, but many value destruction even more. I stack blocks, my daughter knocks them down. At first, this frustrates an adult, especially when something you cherish has been ruined by your child. But there’s opportunity in destruction too. When your child scribbles marker on the wall, you have a chance to paint it a nicer color than its original boring beige. For a more adult-oriented example, perhaps you’ve been pigeonholed as a great accountant, but you’d rather be a carpenter. Casting away your old career for a new one can be more rewarding than building upon what you already have. Sometimes the greatest joy is found not in the creation, but the destruction, of something you’ve built.
4. Go outside as often as you can.
The outdoors is a magical place for a toddler. It doesn’t matter how many toys, books, and interesting things I shove in a room, it can only hold her attention for about 30 minutes (if I’m that lucky). Then I’m stuck either listening to her whine or taking her someplace else. This rule does not hold true if my toddler plays outside. We went to the beach the other weekend, and my daughter had no trouble entertaining herself for nearly 4 hours.
I used to spend a lot of time outdoors through my college years, but once I entered the “real world,” I’ve been less committed. I feel a lot healthier now that I spend more time outside with my daughter. Even if it’s just sitting on the front steps, the outdoors is at once more relaxing and exciting at the same time. It’s relaxing because natural noises lull you in the place of electronic ringtones and computer clicks. It’s exciting because all sorts of things can and do happen: you chat with your neighbors, a helicopter flies overhead, or a large butterfly catches your eye. I now value outdoor time as much as exercise and eating right.
5. Love like there’s no tomorrow.
Toddlers have little emotional restraint, and as parents, it’s our job to teach them how to work through emotions so they can live a normal life. But when it comes to love, toddlers have the right idea. They have no qualms springing a hug on you, even if it means nearly tripping you in the process. My daughter’s kiss is the best gift I have ever received in this world. She gives it at a moment’s notice, and it is always accompanied by the most genuine smile. The feeling it evokes cannot be described by ordinary words.
Imagine the world with more toddler love. It’d probably involve more chases and tickling, but I could live with that.
What have you learned from your children?
Photo by makelessnoise |
// tokenize goes through the input string and produces a list of tokens stored
// into the results attribute
func (p *parser) tokenize() {
var token Token
for token.Type != endOfStringToken {
token = p.lexer.Tokenize()
p.results = append(p.results, token)
}
} |
The Use of Social Media in Children and Adolescents: Scoping Review on the Potential Risks In recent years, social media has become part of our lives, even among children. From the beginning of COVID-19 pandemic period, media device and Internet access rapidly increased. Adolescents connected Internet alone, consulting social media, mostly Instagram, TikTok, and YouTube. During lockdown, the Internet usage allowed communication with peers and the continuity activities such as school teaching. However, we have to keep in mind that media usage may be related to some adverse consequences especially in the most vulnerable people, such as the young. Aim of the review is to focus on risks correlated to social media use by children and adolescents, identifying spies of rising problems and engaging in preventive recommendations. The scoping review was performed according to PRISMA guidelines, searching on PubMed the terms social media or social network, health, and pediatrics. Excluding articles not pertinent, we found 68 reports. Out of them, 19 were dealing with depression, 15 with diet, and 15 with psychological problems, which appeared to be the most reported risk of social media use. Other identified associated problems were sleep, addiction, anxiety, sex related issues, behavioral problems, body image, physical activity, online grooming, sight, headache, and dental caries. Public and medical awareness must rise over this topic and new prevention measures must be found, starting with health practitioners, caregivers, and websites/application developers. Pediatricians should be aware of the risks associated to a problematic social media use for the youngs health and identify sentinel signs in children as well as prevent negative outcomes in accordance with the family. Introduction Media device use is increasing year by year in Italy as well as in many other countries. An ISTAT report referred that in 2019, 85.8% of Italian adolescents aged 11-17 years regularly used smartphones, and over 72% accessed Internet via smartphones. Almost 95% of Italian families with a child had a broadband internet connection. Internet connection was mostly used to communicate with friends and to use social networks. In 2020, COVID-19 pandemic represented one of the greatest disruptions for everybody's everyday life, in Italy as well as all around the world. From the beginning of the pandemic period, media device and Internet access rapidly increased. In line, a 2021 CENSIS report revealed an even progressive increment of smartphone use by adolescents, which reached 95%. In particular, the majority of adolescents (59%) admitted they use smartphone even more frequently than in the past with a daily use of more than 3 h in 46% of cases. Adolescents connected Internet alone (59%), consulting social media, mostly Instagram Figure 1. Flow chart of the selection process. * automation tools were used: 6 records were excluded by automation tools and 3 were excluded by authors. Twenty-five records were excluded because they were not written in English, these were identified using automation tools, but then checked by authors. ** 49 records were removed because they were published before 2004, and no social network existed before that year. Of the 86 reports attained, we read the whole length articles and then excluded 20 studies. Of these twenty, 6 were excluded because not leading to any conclusion; 13 were dealing with wrong topics, such as: doctors' social media knowledge; social lock down during the pandemic; social media marketing; underage and privacy; survey on how social media is perceived by adolescents; time consumed on social media; predictor factors of problematic social media use. Finally, one was not included because it focused on parents and families. Figure 1. Flow chart of the selection process. * automation tools were used: 6 records were excluded by automation tools and 3 were excluded by authors. Twenty-five records were excluded because they were not written in English, these were identified using automation tools, but then checked by authors. ** 49 records were removed because they were published before 2004, and no social network existed before that year. Of the 86 reports attained, we read the whole length articles and then excluded 20 studies. Of these twenty, 6 were excluded because not leading to any conclusion; 13 were dealing with wrong topics, such as: doctors' social media knowledge; social lock down during the pandemic; social media marketing; underage and privacy; survey on how social media is perceived by adolescents; time consumed on social media; predictor factors of problematic social media use. Finally, one was not included because it focused on parents and families. Searching through the cited studies in the included reports, two reviews which were not initially included in the research were added. With 68 included reports analyzed, there were 15 reviews; of these two were systematic reviews, one validation study, and one editorial. Cross-sectional studies and longitudinal studies have been considered, eight and nine, respectively. Many articles reported more than one issue correlated to social media use. The most frequent problems involved mental health, followed by diet and weight problems. Table 1 Table 1. Social media health related problems in a pediatric population. This table shows the issues found in this scoping review. Depression was argued in 19 reports, being the main topic found (27.9% of the whole study). Diet associated problems were discussed in 15 reports, cyberbullying in 15, psychological problems in 14, sleep related problems in 13, addiction in 10, anxiety in 10, sex related problems in 9, behavioral problems in 7, body images distortion in 6, reduced physical activity and related problems has been reported in 5 reports, online grooming in 3 reports, sight problems in 3, also headache in 3, and dental caries in total of 2 articles. The most frequent problems found are related to mental health: depression, anxiety, and addiction. Other problems are related to sleep, diet and nutrition, cyberbullying, psychological aspects, behavioral problems, sex, body image perception, physical activity, online grooming, sight, headache, and dental caries. Time spent on social media, repetitive activities, addictive, or problematic use associated with depression, anxiety, and psychological impairment. Nevertheless, it is not possible to establish whether a causative effect exists. Domains Reference Type of Publication Highlighted Depression Sleep Anxiety Armitage R.C. et al. Letter to editor The degree of social media usage in children correlates with depression, anxiety, and perceived stress level. Bedtime access to and use of mobile devices is significantly associated with inadequate sleep in terms of quality and quantity. Investigating the impact of social media on adolescents' wellbeing is a priority due to a progressive increase in mental health problems or addiction and access to Emergency Department. As Chiu and Rutter stated, there is a positive relationship between internalizing symptoms, such as depression and anxiety, and social media use. Depression is connected to a rapidly increased of digital communication and virtual spaces, which substitute face-to-face contact by excessive smartphone use and online chatting. The more time adolescents spend on social device the higher levels of depression are found out. In this sense, social media are representing a risk factor for depression in the young. Depression, anxiety, and behavioral disorders are among the leading causes of illness and disability among adolescents. Key findings which correlate to depression regarding social media exposure are repeated activities such as checking messages, investment, and addition. The findings were similar all over the world. For example, in Sweden, spending more than 2 h on social media was associated with higher odds of feeling. In Egypt, as well, students who have problematic Internet use, have higher psychiatric comorbidities, such as depression, anxiety, and suicidal tendency. Social media addiction and more precisely Facebook addiction was linked not only to depression but even to dysthymia, so that the expression "Facebook depression" was coined to identify a relationship between depression and social networking activity. Individuals suffering from Facebook depression may be at an increased risk of social isolation and may be more vulnerable to drugs or behavioral problems. Internet penetrance and connectivity are also connected to cyberbullying which can lead to depression and suicidality. On the other side, physical activity may decrease depression and anxiety, potentially protecting the young against the harmful effect of social media abuse. At last, even if a positive correlation between internalizing symptoms and media use device is noted, Hoge states that there is also evidence that social media communication may improve mood and promote health strategies in some occasions. Finally, even if evidence revealed that social media use is linked to poor mental health, the relationship between social media and depression in adolescents is still to be completely understood. It is still unclear whether social media use leads to more depression or if these depressive symptoms cause individuals to seek out more social media, which could feed into a vicious cycle. Keles's conclusion as well suggest defining the relationship between internalizing symptoms and social media use as an association and not a causative effect. After COVID 19 Pandemic During COVID-19 pandemic, the state of emergency and social isolation determined an increase in time on screen not only as a source of online education, but to continuously access social media. According to recent data, a percentage of 48% of adolescents spent a mean of 5 h per day on social media and 12% spent more than 10 h. Moreover, with that increase in virtual time depression arose. The degree of social media usage in children is a significant predictor of depression, which increases with each additional hour of social media use. During the pandemic, depressive symptoms may have been reactive to the context of being afraid of the virus and necessitating social isolation. However, in this peculiar period, schoolchildren who increased time spent on either smartphones, social media, or gaming had significantly elevated psychological distress, such as depressive symptoms, than those with decreased time spent on these internetrelated activities. Social Media and Diet Out of the reports, 15 dealt with the association of social media use and diet [21,. The problems were related to junk food marketing (9 reports) obesity (4 reports) [21,, unhealthy eating behaviors (3 reports), and alcohol marketing (2 reports). In Table 3 the retrieved articles dealing with social media and diet, and their major findings are presented (Table 3). Exposure to the marketing of unhealthy products, on social media is associated with a higher risk of related unhealthy behaviors. Analysis of the advertising policies of the 16 largest social media platforms proved them ineffective in protecting children and adolescents from exposure to the digital marketing of unhealthy food. Reports found that children are exposed to the marketing of unhealthy foods on social media and to their persuasive techniques. Digital marketing represents a major threat for children and adolescents in Mexico, because of its persuasive techniques. Cola and soft drinks, sweetened juices and in general the so-called junk food have high followers on Facebook and Twitter.. This may cause an increase in children's immediate consumption of the promoted product, unhealthy behaviors and may led to obesity, as confirmed by several studies. Reports agree on the youth major vulnerability to unhealthy food advertisement, including digital marketing, sponsored content, influencers, and persuasive design. This contributes to the obesity epidemic. Major social media platforms do not have comprehensive policies in place to restrict the marketing of unhealthy foods on their platforms. Therefore, exposure to the marketing of unhealthy products, on social media may be considered a risk factor for related unhealthy behaviors. Analysis of the advertising policies of the 16 largest social media platforms proved them ineffective in protecting children and adolescents from exposure to the digital marketing of unhealthy food. Among social media, YouTube is particularly worrying considering the affinity of the young toward the platform. Unhealthy food advertisements predominate in YouTube content aimed towards children. In fact, analysis of advertisements encountered in YouTube videos targeted at children revealed that food and beverage ads appeared most frequently, with more than half of these promoting unhealthy foods. As confirmed by an Irish study, adolescents are very attracted to junk food advertisements and are likely to share comments on their network: generalized linear mixed models showed that advertisements for unhealthy food evoked significantly more positive responses, compared to non-food and healthy food. Of all the advertising, they see in social media, they view unhealthy food advertising posts for longer. This confirms the vulnerability of children towards ad and digital marketing. Moreover, it has been demonstrated that adolescent heavy social media users (>3 h/day) are more willing to engage with food ads compared to light social media users, and are more willing to "like" Instagram food ads featuring many "likes" versus few "likes", demonstrating the power of social norms in shaping behaviors. Adolescents interact with brands in ways that mimic interactions with friends on social media, which is concerning when brands promote unhealthy product.. There is a need of more strict policies to limit digital marketing, which is becoming more and more intense, especially towards children and adolescents. After COVID-19 Pandemic During the COVID-19 pandemic, this phenomenon even increased. In fact, the combination of staying at home, online education and social media usage have all caused screen time to surge and the food industry has been quick to identify this change in their target audience and has intensified online advertising and focused on children. The COVID-19 experience led to an increase in risk and severity of inappropriate behavioral eating habits, affecting the health and weight. Before COVID-19 Pandemic Obesity Social media is the first independent risk factor for obesity in primary school children and the second for high school students. In both primary school and high school models, children's social media use has the highest impact on child's BMI. In addition, heavy media use during preschool years is associated with small but significant increases in BMI, especially if used ≥ 2 h of media per day. After COVID-19 Pandemic Obesity and social media correlated through junk food advertisements. During COVID 19 pandemic poor quality food, energy-dense, and nutrient-poor products consumption increased, leading to the risk of overweight and obesity. The phenomenon has been called "Covibesity". Unhealthy Eating Behavior Some social media contents promote pro-anorexia messages. These messages are no longer limited to websites that can be easily monitored, but instead have been transferred to constantly changing media such as Snapchat, Twitter, Facebook, Pinterest, and Tumblr. Consequently, pro-eating disorder content has become more easily accessible by the users. Pro-anorexia website use is correlated with a higher drive for thinness, lower evaluations of their appearance, and higher levels of perfectionism, and all correlates with eating disturbances. In detail, there is a real bombardment of unhealthy messages on media promoting low-nutrition aliments and sugar-sweetened drinks. It is likely that the suboptimal quality of online information on social media platform contributes to the development of unhealthy eating attitudes and behaviors in young adolescent internet users seeking nutritional information. They look for nutritional information on internet sources such as commercial websites or social media in order to lose weight. In this occasion, they may be exposed to higher risk of eating disorders due to the high quantity of misinformation. Moreover, they may find dangerous methods to rapidly lose weight with possible harm for their health. Literature agrees on the risk of time spent on social media as well as on the poor quality and reliability of weight loss information on media. Alcohol Marketing Adolescents identify drinking brands to peculiar images of ideal adults. Brands know well this underlying psychological mechanism and promote that identity adolescents seek, with specific advertisement on social media. Studies have shown that exposure to alcohol in TV or movies is associated with initiation of this behavior. The major alcohol brands have a strong advertising presence on social media, including Facebook, Twitter, and YouTube. Several studies underlined risky health behaviors, such as illegal alcohol use or overuse. Evidence suggests that peer viewers of this content are likely to consider these behaviors as normative and desirable. Therefore, targeted advertising via social media has a significant effect on adolescent behavior. Cyberbullying Uludasdemir D. et al. Clinical study Having daily access to the Internet and the sharing of gender on social media increased the likelihood of cyber victimization. Cyberbullying may be defined as any behavior performed through electronic or digital media by individuals or groups that repeatedly communicate hostile or aggressive messages intended to inflict harm or discomfort on others. Compared to bullying, cyberbullying may be even more dangerous as victims can be reached anytime and in any place. Moreover, anonymity amplifies aggression as the perpetrator feels out of reach. Moreover, the ability to hide behind fake names provides bullies the opportunity to communicate in content and language they would not use in front of people. As confirmed by Shah et al., the anonymity of cyberbullying increases the risk for inappropriate behaviors among adolescents. In literature, cyberbullying has been identified in phone calls, text messages, pictures/video clips, emails, and messaging apps. This is a great public health concern: in Italy, 2015 ISTAT data showed that 19.8% of 11-17 years old internet users report being cyberbullied. This phenomenon is increasing. In fact, the number of adolescents being cyberbullied at least once in their life increased from 20.8% in 2010 to 33.8% in 2016. Cyberbullying has been associated with higher risks of depression, paranoia, anxiety, and suicide than the traditional form of bullying. According to a metanalysis of 34 studies, traditional bullying increased suicide ideation by a factor of 2.16, whereas cyberbullying increased it by a factor of 3.12. In adolescence, social media intense or problematic use and frequent online contact with strangers are all independently associated with cyberbullying. In this contest, social media represent a risk factor for cyberbullying and for inappropriate behavior related to it. In fact, problematic social media use is an important driver of cyberbullying victimization and perpetration, especially among girls. The highest percentage is observed in adolescents, aged 13 to 15 years as suggested by literature reviews and, in particular, by Marengo and Uludasdemir. However, Marengo also suggests that in presence of social support, the phenomenon is attenuated. Moreover, having daily access to the Internet and the sharing of gender on social media increased the likelihood of cyber victimization among adolescents aged 12-17 years. Those who use Tumblr and Snapchat were found to become victims even more frequently. For examples, in Canadians adolescents, the prevalence of loneliness was higher for daily computer-mediated communication users than non-daily users. As well as for cyberbullying, adolescents may benefit from social support, family communication, and interaction to ameliorate feelings of loneliness. Boer et al. confirmed that intense user reported more frequent psychological complaints than non-intense user as well as less family and friend support. In line with this finding, in Lithuania a problematic social media use has been associated with two times higher odds for lower life satisfaction. Moreover, an intense social media use correlated to either low school well-being and reduced social well-being (decreased family and friends support and relations). A relationship between poor life satisfaction, problematic social media use, and lack of social support was found not only in adolescents, but also in children [52,. Social media use is also correlated with conduct and emotional problems, attention deficit, peer problems, school impairments, and psychological distress. Social networks and media device use correlate to low academic outcomes, reduced concentration, and procrastination. In fact, problematic smartphone use correlates to a surface approach to learning rather than to a deep approach, leading to reduced creativity, organization skills, own thinking, and comprehension of information. After COVID-19 Pandemic During this COVID-19 pandemic, primary school children reported significantly higher psychological distress than the period prior to the COVID-19 outbreak. Studies showed that schoolchildren who increased time spent on either smartphones, social media, or gaming had significantly elevated psychological distress than those with decreased time spent on these internet-related activities. Social Media and Sleep Extended use of digital media screen time correlates with sleep impairment . Table 8 summarized the main findings (Table 8). High levels of screen time and social media use correlates to depression, anxiety, and misperception of body image, addiction, and mental health outcomes. Evidence agrees that the degree of social media usage in children is a significant predictor of anxiety and perceived stress levels and that it increases with each additional hour of social media use. Anxiety may represent a risk factor for children and adolescents' health as it influences the way they see their body, the way they feel, and it may impact on social acceptance and relations with peers. The excessive use of at least one type of screen, including television, computer, social media, and video gaming, has been connected with anxiety symptoms in the pediatric age. Furthermore, in Rutter's study a significant association between depression and anxiety with social media use has been detached. Nevertheless, it is still unclear if social media use provoke anxiety or if anxiety is the cause of excessive use of social media. Emergency department visits for mental health, including anxiety problems, has arisen since 2009, likely linked to the increased use and the harmful effect of social media. On the contrary, physical activity may protect the young against the harmful effect of social media, preventing depression and anxiety. In a scientific report, Muzaffar confirmed that an association between anxiety and social media is of note. In detail, increased adolescent generalized anxiety symptoms were associated with increased Facebook use and repetitive Facebook habits. Anxious adolescents may not be able to control their discomfort to the point that they need to regularly go back to check their previous posting on Facebook. The constant connection to social networks through digital devices, on its side, potentially contributes to feelings of anxiety. Adolescents and children suffering from social anxiety may prefer to interact with texting, instant messaging, and emailing than over faceto-face interactions. However, the behavior may increase risk in individuals vulnerable to social anxiety disorder because substituting digital media for interpersonal communication to avoid feared situations may be reinforced over time, making the person even more avoidant and worsening the symptoms and severity of social anxiety disorder. However, in some studies, not just overexposure but also underexposure to social media was associated with adolescent anxiety, depression, and suicidal ideation. After COVID-19 Pandemic Screen time and social media use have increased during the pandemic. Social media has been helpful during lockdown to keep social relationships and not to discontinuate school activities. However, an excessive Internet use may negatively affect children and adolescents' well being. So, during social lockdown, an elevated psychological distress and anxious symptoms have been described in schoolchildren who increased time spent on screen. Children who increased by 15 or 30 min daily the time spent on internet presented a high level of psychological distress. Social Media and Sex Related Problems Studies have found social media use related to sexual problematic behaviors such as early sexual activity, exposure to pornography, and sexting. [21,22,26,50,51,. Table 9 summarizes the results (Table 9). The prevalence of sex related problems cannot be accurately recorded as for a wide range of definition and sampling methods and the comparison among reports is difficult. Especially for girls, higher social media use, associated with lower family affluence and poorer body image, are key to early sexual activity. Social media use was found to be significantly associated with risky sexual behavior among pre-college students in Ethiopia. Facebook, Instagram, YouTube, and other platforms have been identified as a factor that alters adolescent's perception and influences them to engage in risky sexual behavior. Those who view sexually suggestive Facebook photos have a higher chance of having unprotected sexual intercourse and sex with strangers. Moreover, youth can be exposed to unwanted sexual material online, including unwanted nude pictures or sexually explicit videos through means such as pop-up windows or spam e-mails. Children exposed to inappropriate sexual content are prone to high-risk behaviors in subsequent sexual encounters. Sexting activities may also affect emotional and social wellbeing of adolescents; it is correlated to depression and risky health behaviors, such as substance use, alcohol consumption, and suicide. The odds of risky sexual behavior were 1.23 higher in social media user than in other students. Furthermore, on the internet, pornography is readily accessible by media device, so that Wana found out that 7% of students use social media for pornography. In most cases, adolescents admit they intentionally viewed materials. Pornographic media depict a fantasy world in which unrealistic encounters result in immediate sexual gratification, and intimate relationships are nonexistent. Repeated exposure of the adolescent brain to the world of online pornography can make it difficult for adolescents to develop mature healthy sexual relationships. Internet pornography usage has been documented in adolescents before the age of 18. Online pornography is often the first source of sex education for many adolescents, and exposure to violent pornography increases the odds of sexually aggressive behavior. Peer advice as well as substance abuse are significant predictor for risky sexual behavior. Sexting is the use of media to send nude or sexualized contents such as texts, photos, or videos. An extensive sharing of these contents through technology has been connected with a negative impact on the emotional and social wellbeing of adolescents involved. An earlier sexual debut such as the use of drugs and promiscuity have been all associated to the excessive use of sexting. It can also cause spreading of sexual content material without consent, to a third party as a method of bullying or revenge. Social Media and Behavioral Problems Out of the reports, seven explored the influence of social media and behavioral problems [22,49,64,. Table 10 outlines the highlighted findings (Table 10). Behavioral outcomes usually cover five areas, including hyperactivity/inattention, emotional symptoms, conduct problems, peer relationship, and pro-social behavior. Time spent on screen has been associated to sleeping problems, especially sleep duration, and with problematic behaviors, higher internalizing, and externalizing symptoms. Clinical Study Excessive time of media use has a strong association with emotional distress and worse behavioral outcomes. Clinical Study Association between hours of media use and behavioral problems has been documented among children aged 9-10 years old, in Japan. Clinical Study Regression analysis predicted a strong positive association of exposure to violent social/electronic media content with level of aggression of adolescents ( = 0.43). Behavioral problems Deslandes S.F. et al.. Clinical Study Online challenges are a powerful communicative resource but can involve potential self-inflicted injuries to participants, with risks ranging from minor to lethal. For children aged 10-15 years old, limited time on social media has no effect on most emotional and behavioral outcomes (and can even positively impact social relationships), while there are strong negative associations between very long hours on social media and increased emotional distress and worse behavioral outcomes, which continue for several years. In accordance to McNamee, the study by Okada conducted in Japan among children aged 9-10 years old highlighted that mobile devices usage time of less than 1 h was a protective factor for behavior problems in boys. Instead, the usage time of 1 h or more was a risk factor in girls. Among girls, a dose-response positive association was found between duration of mobile devices usage and total difficulty score. A U-shaped association was found between duration of mobile devices usage and behavioral problems in boys: moderate use of mobile devices might be a tool for relaxation or alleviating distress through interactions with peers. However, in the subscale analysis, boys who use two or more hours of mobile devices showed higher risk of emotional problems and peer problems. Moreover, the social media violent content exposure may be a risk factor for violent and aggressive behaviors. In this context, levels of aggression are directly proportional to exposure of types of violent media content. Electronic and social media showing contents with fights, stealing, dead bodies, and people's belongings being destroyed influence young viewers, as per observational-learning theory, making them believe that reacting aggressively in response to perception of any offense is acceptable. In line with Tahir's report, Maurer underlined a significant association between exposure to media violence and aggressive behavior, aggressive thoughts, angry feelings, and physiologic arousal. Media exposure is also negatively related to personal adjustment and school performance and positively related to risk-taking behaviors. Another study confirmed that longer the time spent on screens, higher the risk for behavioral problems among children 9-10 years old, and depending on the content type visualization, the risk for an aggressive and rule-breaking behavior. This association was mediated by sleep duration: longer sleep duration was associated with fewer problem behaviors. Challenges and risk-taking attitudes are frequent in child and youth culture. However, online challenges take on new meanings when mediated by digital sociability; they appear as a powerful communicative resource to reaffirm belonging, recognition, and audience adherence. They are a media strategy adopted by youth in the construction of an internetmediated identity in which risk and violence are crucial devices in building a self-image capable of maintaining an audience. Nevertheless, they can involve potential self-inflicted injuries to participants, with risks ranging from minor to even lethal. Finally, an emerging problem is the social phenomenon called Shakaiteki Hikikomori (social withdrawal). Most of them are males and they usually experience a social reclusion range from 1 to 4 years. They refuse to communicate even with their own family and spend even more than 12 h a day in front of a screen. Social Media and Body Image On social media platforms such as Facebook, Snapchat, and Instagram, body image has become an important topic. Table 11 summarized the evidence. (Table 11). People post their most flattering photos and view those of others, creating an online environment that could be damaging to body image acceptance. Spending time on social media puts adolescents under a higher risk of comparing themselves to models that are more attractive. As a result, these unfavorable social comparisons of physical appearance may exacerbate body image apprehension. Moreover, beauty trends are constantly reinforced through social media networks and image-editing tools are often used to alter images to fit beauty standards. Teenagers who, perhaps, are not aware of these digital changing made in commercial photos may become insecure of their image. This may reduce self-esteem and body satisfaction, mainly among adolescent girls, developing body image concerns, engaging in weight-modification behavior, and potentially developing eating disorders. Nowadays, adolescents, and, in particular, girls, need to fit "social media" standard for photo posting; they use to modify photos with specific programs in order to respect society beauty standard. In fact, 28% of girls aged 8-18 years admit to editing their photos to make themselves look more attractive prior to posting online. Addictive, smart phone activities of youth is directly affecting their perception of the body, also causing physical problems, eye diseases, headache, and exposure to unwanted sexual material online. In addition to social media causing body image problems, adolescents with body image misperception may look on the internet for advice on how to lose weight quickly. However, the suboptimal quality of online information contributes to the development of unhealthy eating attitudes and behaviors in young adolescents. It may be that the content of these sites promotes eating disorders by providing unhealthy weight loss advice. Furthermore, the desire of perfection and selfie mania with repeated selfie can cause depression and self-harm. This is a typical symptom of body dysmorphic disorder. Finally, this association between the use of social media, self-esteem and body image can be a correlation and not a cause-effect relation: girls with lower self-esteem and sensitive to body image complains may use social media more frequently than girls with a higher level of self-esteem. For example, users can make a "selective self-presentation" where they show themselves only in a positive way on their social media profiles. Social Media and Physical Activity Evidence supports a correlation between social media and physical activity. Excessive use of smartphones and other digital devices can also cause physical problems, such as a more sedentary lifestyle, which is positively associated with childhood obesity. In addition, non-physiological postures assumed while using smartphones may lead to cervical rigidity and muscle pain resulting in neck strain or "Tech Neck". Moreover, "texting thumb" is a form of tendinitis that comes from overusing the thumb from excessive texting, video gaming, and web browsing using a smartphone. An Australian study found that non-organized physical activity declines between 11 and 13 years, especially in children with a large increase in activities of texting, emailing, social media, and other internet use. Another study showed that problematic social media use is related to lower levels of vigorous physical activity, especially in girls. In Table 12 are listed the reports related to this topic and their major content (Table 12). Addictive, smart phone activities of youth is directly influencing their perception of the body, also causing physical problems, eye diseases, headache, and exposure to unwanted sexual material online. Physical activity Kemp B.J. et al. Clinical Study Australian children between 11 y and 13 y who had a larger increase in social media use had lower participation in overall physical activity. Online Grooming Online grooming may be defined as a situation in which an adult builds a relationship with a minor finalized to a sexual abuse using social media.. The risk of developing post-traumatic stress disorder in the victims is of note and may affect mental and well-being of children and adolescents. Children are more vulnerable online as they often escape their parents' control and may be more willing to share information or pictures about themselves than in real life. Online grooming, differently to offline sexual abuse, is simpler to perpetrate, due to internet's technology and accessibility. Furthermore, often the perpetrator misrepresents himself as another child or teenager, in order to establish a trusting relationship. Teenage girls appear to be more at risk, even if the proportion of male victims is considerable too. In general, minors with problematic internet use are at greater risk of being groomed. Sexual solicitation has been found to be more common in children spending longer time on internet on weekdays, being involved in sexting, having strangers in social networks friends list, playing online games, and chats. The risk is high even for adolescents whose curiosity and unconsciousness set them at risk of being deceived. Table 13 presents the reports related to this topic and their major content (Table 13). Social Media and Sight Studies have investigated the risk of social media on sight, in terms of visual imbalance. Evidence underlines that children can develop ocular disorders from excessive screen time, including myopia, eye fatigue, dryness, blurry vision, irritation, burning sensation, conjunctival injection, ocular redness, dry eye disease, decreased visual acuity, strain, fatigue acute acquired concomitant esotropia, and macular degeneration. During smartphone use, there is a reduction of the blink rate to 5-6/min that promotes tear evaporation and accommodation, leading to dry eye disease. In addition, excessive screen time and less time spent outdoors may lead to early development of myopia, particularly with smartphone and tablet use. Table 14 presents the reports related to this topic and their major content (Table 14). Addictive, smart phone activities of youth is directly influencing their perception of the body, also causing physical problems, eye diseases, headache, and exposure to unwanted sexual material online. Social Media and Headache There are increased complaints of headaches related to staring at a screen for too long. Reports dealing with social media and headache are listed in Table 15 (Table 15). Headache is actually the most common neurologic disorder in the population, children and adolescents included. It may negatively impact on children and adolescents' wellbeing, leading to stress, tiredness, anxiety, and bad mood. Time of usage of media device has been directly connected to headache: in particular, adolescents using more than 3 h a screen have a significantly higher risk of headache compared with those using a device for less than 2 h (p < 0.001). Spending even 2-3 h with a computer significantly increases the chance of suffering a headache in comparison with those using a computer for less than 2 h (p < 0.01). Excessive use of electronic devices is considered a risk factor, especially for the development of migraine-type headache (p < 0.05). According to recent studies, headache and somatic symptoms have been found mostly in patients with problematic social media usage, compared with non-problematic peers. There is a consistent association between the problematic use of social media and adolescent psychosomatic health. Social Media and Dental Caries The association between use of internet and social media has been studied in literature. Table 16 summarizes the main findings (Table 16). Table 16. Social media and dental caries. Reference Type of Publication Highlighted Diet Dental Caries Radesky J. et al. Clinical Study Exposure to advertising is associated with unhealthy behaviors. Children are uniquely vulnerable to the persuasive effects of advertising because of immature critical thinking skills and impulse inhibition. Ads also promote intake of foods that contribute to dental caries. Dental Caries Almoddahi D. Clinical Study Study conducted in England, Wales, and Northern Ireland. Excessive internet use is associated to dental caries, and this could be mediated by health behaviors. The association between use of internet social media to obtain oral health information and dental caries has been highlighted in Almoddahi's report. In detail, problematic internet use has been associated with unhealthy lifestyles, poor oral health behaviors, and more oral symptoms such as toothache, bleeding gums, and poor self-perceived oral health. Caries and junk food have been both connected to excessive internet use and ads. Therefore, social media may be a risk factor for caries, poor oral health, and dental outcomes. In line with Almoddahi, Radesky underlines that advertisements on social media promote intake of foods that contribute to dental caries, such as fast food and sugar beverages. Nevertheless, evidence suggests that smartphone applications may improve health and oral health when internet-based health interventions are in place. Delivering oral health information via social media may increase tooth brushing and dental outcome. Limitations From the literature, it is not possible to decide whether social media use causes internalizing symptoms and problematic behaviors examined in this manuscript or whether children and adolescents suffering from depression, anxiety, or other psychological distress are more likely to spend time on social media. We can just state that there is an association between social media use and health problems, but that is not necessarily cause-effect. Moreover, the articles included are different, ranging from reviewers to clinical studies to letters and to editors, so that it may be difficult to accurately compare them. Third, as specified in the materials and methods, we excluded reports not in English letter and not published in PubMed. Nevertheless, through our manuscript we contribute to the existing literature to highlighting the impact of social media use on adolescents, providing advices to pediatricians in everyday practice. Conclusions Social media is increasingly being used by children and adolescents, especially during COVID-19 pandemic and the health emergency. Although social media use demonstrated to be of utility, an excessive or non-correct use may be a risk factor for mental health, including depression, anxiety, and addiction. Social media use may also correlate to a non-adequate nutrition with consumption of junk food marketing leading to weight gain, obesity, dental caries, and unhealthy eating behaviors. Associations have been found also with increasing physical problems due to sedentary lifestyle, obesity, and non-physiological postures. On the other hand, social media can cause problems with body image visualization and acceptance, especially in young adolescent girls with lower self-esteem, who may look for contents for losing weight rapidly, and this can help the extension of anorexia disorders. Children and adolescents who use social media for many hours a day, are also at higher risk for behavioral problems, cyberbullying, online grooming, sleep difficulties, eye problems, (such as myopia, eye fatigue, dryness, blurry vision, irritation, burning sensation, conjunctival injection, ocular redness, and dry eye disease), and headache. Moreover, uncontrolled social media use, can lead to sexting, exposure to pornography, exposed to unwanted sexual material online, and early sexual activity. Social media users meet more online risks than their peers do, with an increased risk for those who are more digitally competence. Public and medical awareness must rise over this topic and new prevention measures must be found, starting with health practitioners, caregivers, and websites/application developers. Families should be educating on the dangers and concerns of having children and adolescence online. Prerequisite to inform families how to handle social media is to educate those responsible for training, including health practitioners. In detail, pediatricians should be reminded to screen for media exposure (amount and content) during periodic check-up visits. They need to keep in mind a potential correlation of problematic social media use with depression, obesity and unhealthy eating behavior, psychological problems, sleep disorder, addiction, anxiety, sex related problem, behavioral problem, body image, physical inactivity, online grooming, sight compromising, headache, and dental caries. Pediatricians can also counsel parents to guide children to appropriate content by consulting ratings, reviews, plot descriptions, and by a previous screening of the material. They should inform parents about the potential risk of digital commerce to facilitate junk food, poor nutrition and sweetened aliments, facilitating overweight and obesity. On the contrary, a healthy diet, adequate physical activity and sleep need to be recommended. Pediatricians may also play a role in preventing cyberbullying by educating both adolescent and families on appropriate online behaviors and on privacy respect. They should also promote a faceto-face communication and to limit online communication by social media. Pediatricians may encourage parents to develop rules and strategies about media device and social media use at home as well as in every day's life. |
<filename>Userland/Libraries/LibJS/SourceTextModule.h
/*
* Copyright (c) 2021, <NAME> <<EMAIL>>
* Copyright (c) 2022, <NAME> <<EMAIL>>
*
* SPDX-License-Identifier: BSD-2-Clause
*/
#pragma once
#include <LibJS/AST.h>
#include <LibJS/CyclicModule.h>
#include <LibJS/Forward.h>
#include <LibJS/Parser.h>
namespace JS {
// 16.2.1.6 Source Text Module Records, https://tc39.es/ecma262/#sec-source-text-module-records
class SourceTextModule final : public CyclicModule {
public:
using ImportEntry = ImportStatement::ImportEntry;
using ExportEntry = ExportStatement::ExportEntry;
static Result<NonnullRefPtr<SourceTextModule>, Vector<Parser::Error>> parse(StringView source_text, Realm&, StringView filename = {});
Program const& parse_node() const { return *m_ecmascript_code; }
virtual ThrowCompletionOr<Vector<FlyString>> get_exported_names(VM& vm, Vector<Module*> export_star_set) override;
virtual ThrowCompletionOr<ResolvedBinding> resolve_export(VM& vm, FlyString const& export_name, Vector<ResolvedBinding> resolve_set = {}) override;
Object* import_meta()
{
if (m_import_meta.is_null())
return nullptr;
return m_import_meta.cell();
}
void set_import_meta(Badge<MetaProperty>, Object* import_meta)
{
m_import_meta = make_handle(import_meta);
}
protected:
virtual Completion initialize_environment(VM& vm) override;
virtual Completion execute_module(VM& vm, Optional<PromiseCapability> capability) override;
private:
SourceTextModule(Realm&, StringView filename, bool has_top_level_await, NonnullRefPtr<Program> body, Vector<ModuleRequest> requested_modules,
Vector<ImportEntry> import_entries, Vector<ExportEntry> local_export_entries,
Vector<ExportEntry> indirect_export_entries, Vector<ExportEntry> star_export_entries,
RefPtr<ExportStatement> default_export);
NonnullRefPtr<Program> m_ecmascript_code; // [[ECMAScriptCode]]
ExecutionContext m_execution_context; // [[Context]]
Handle<Object> m_import_meta; // [[ImportMeta]]
Vector<ImportEntry> m_import_entries; // [[ImportEntries]]
Vector<ExportEntry> m_local_export_entries; // [[LocalExportEntries]]
Vector<ExportEntry> m_indirect_export_entries; // [[IndirectExportEntries]]
Vector<ExportEntry> m_star_export_entries; // [[StarExportEntries]]
RefPtr<ExportStatement> m_default_export; // Note: Not from the spec
};
}
|
<filename>src/main/java/com/vision/niosmart/consumer/ID.java
package com.vision.niosmart.consumer;
import static java.lang.annotation.RetentionPolicy.RUNTIME;
import java.lang.annotation.Documented;
import java.lang.annotation.ElementType;
import java.lang.annotation.Retention;
import java.lang.annotation.Target;
@Documented
@Retention(RUNTIME)
@Target(ElementType.PARAMETER)
public @interface ID {
}
|
<gh_stars>1-10
#include "StdAfx.h"
#include "Part.h"
static char *shader_type_string[]={
"\n#version 150\n#define SHADER_TYPE_NORMAL \n",
"\n#version 150\n#define SHADER_TYPE_BOX \n",
"\n#version 150\n#define SHADER_TYPE_EDGE \n",
"\n#version 150\n#define SHADER_TYPE_POINT \n",
"\n#version 150\n#define SHADER_TYPE_FRAME \n",
};
static int shader_type_id=0;
void Shader_base::set_shader_type(int my_shader_type_id)
{
shader_type_id=my_shader_type_id;
}
class shader_program{
public:
CString shader_file_name[MAX_SHADER_NUMBER];
struct{
int program_id,shader_id[MAX_SHADER_NUMBER];
Shader_program_variable_index variable_index;
}shader_id[sizeof(shader_type_string)/sizeof(shader_type_string[0])];
};
static int shader_program_number=0;
static shader_program shader_program[MAX_SHADER_PROGRAM_NUMBER];
static Shader_base *first_shader_pointer=NULL;
static CString directory_file_name,configure_shader_file_name,uniform_shader_file_name,vertex_shader_file_name;
void Shader_base::set_general_shader_file_name_and_max_draw_instance_number(
CString my_directory_file_name,CString my_configure_shader_file_name,
CString my_uniform_shader_file_name,CString my_vertex_shader_file_name)
{
directory_file_name=my_directory_file_name;
configure_shader_file_name=my_configure_shader_file_name;
uniform_shader_file_name=my_uniform_shader_file_name;
vertex_shader_file_name=my_vertex_shader_file_name;
}
bool Shader_base::is_same_shader(Shader_base *s,Shader_base*t)
{
if((s==NULL)||(t==NULL))
return false;
if((s->get_program_index_id())!=(t->get_program_index_id()))
return false;
if((s->class_name)!=(t->class_name))
return false;
return true;
}
int Shader_base::get_program_id(Shader_program_variable_index **variable_index)
{
int program_id;
if((program_id=shader_program[program_index_id].shader_id[shader_type_id].program_id)<0){
CString display_error_message=_T("");
for(int i=0;i<MAX_SHADER_NUMBER;i++){
if(shader_program[program_index_id].shader_id[shader_type_id].shader_id[i]<0){
for(int j=0;j<shader_program_number;j++){
if(j!=program_index_id)
if(shader_program[j].shader_id[shader_type_id].shader_id[i]>0)
if((shader_program[j].shader_file_name[i])==(shader_program[program_index_id].shader_file_name[i])){
shader_program[program_index_id].shader_id[shader_type_id].shader_id[i]=shader_program[j].shader_id[shader_type_id].shader_id[i];
break;
}
}
if(shader_program[program_index_id].shader_id[shader_type_id].shader_id[i]<0){
File_data program_code((directory_file_name)+(shader_program[program_index_id].shader_file_name[i]));
if(program_code.data_pointer()!=NULL){
CString str;
if(i==0)
program_code.insert_file_data(directory_file_name+vertex_shader_file_name);
program_code.insert_file_data(directory_file_name+uniform_shader_file_name);
program_code.insert_file_data(directory_file_name+configure_shader_file_name);
Shader_part_information *info=get_part_information();
str.Format(_T("\n#define MAX_USER_ORDER_NUMBER %d\n"),(info->max_user_order_number<5)?5:(info->max_user_order_number)); program_code.insert_data(str);
str.Format(_T("\n#define MAX_USER_PARAMETER_NUMBER %d\n"),(info->max_user_parameter_number<2)?2:(info->max_user_parameter_number)); program_code.insert_data(str);
str.Format(_T("\n#define MAX_LIGHT_NUMBER %d\n"),(MAX_LIGHT_NUMBER<2)?2:MAX_LIGHT_NUMBER); program_code.insert_data(str);
str.Format(_T("\n#define MAX_CLIP_PLANE_NUMBER %d\n"),(MAX_CLIP_PLANE_NUMBER<2)?2:MAX_CLIP_PLANE_NUMBER); program_code.insert_data(str);
program_code.insert_data(CString(shader_type_string[shader_type_id]));
shader_program[program_index_id].shader_id[shader_type_id].shader_id[i]=Graphics_system::compile_shader(display_error_message,program_code.data_pointer(),i);
}
}
}
}
program_id=Graphics_system::link_program(display_error_message,
MAX_SHADER_NUMBER,
shader_program[program_index_id].shader_id[shader_type_id].shader_id,
shader_program[program_index_id].shader_file_name);
shader_program[program_index_id].shader_id[shader_type_id].program_id=program_id;
shader_program[program_index_id].shader_id[shader_type_id].variable_index.order_parameter =Graphics_system::get_uniform_index(program_id,"order_parameter");
shader_program[program_index_id].shader_id[shader_type_id].variable_index.clip_plane_parameter =Graphics_system::get_uniform_index(program_id,"clip_plane_parameter");
const char *shadow_texture_name[]={
"shadow_texture0", "shadow_texture1", "shadow_texture2", "shadow_texture3",
"shadow_texture4", "shadow_texture5", "shadow_texture6", "shadow_texture7"
};
for(int i=0;(i<MAX_LIGHT_NUMBER)&&(i<(sizeof(shadow_texture_name)/sizeof(shadow_texture_name[0])));i++)
shader_program[program_index_id].shader_id[shader_type_id].variable_index.shadow_texture[i]=Graphics_system::get_uniform_index(program_id,shadow_texture_name[i]);
if(display_error_message!=_T("")){
static int error_sequence_id=0;
CString str;
str.Format(_T("temp\\compile_and_link_error_%d.txt"),++error_sequence_id);
str=directory_file_name+str;
ofstream f(str);
File_data::output_string(f,display_error_message);
f.close();
::ShellExecute(NULL,_T("open"),str,NULL,NULL,SW_SHOWNORMAL);
}
}
if(variable_index!=NULL)
*variable_index=&(shader_program[program_index_id].shader_id[shader_type_id].variable_index);
return program_id;
}
CString *Shader_base::get_program_file_name()
{
return &(shader_program[program_index_id].shader_file_name[0]);
}
void Shader_base::delete_all_program_object()
{
for(int j=0;j<(sizeof(shader_type_string)/sizeof(shader_type_string[0]));j++){
for(int i=0;i<shader_program_number;i++){
if(shader_program[i].shader_id[j].program_id>0)
Graphics_system::delete_program(shader_program[i].shader_id[j].program_id);
shader_program[i].shader_id[j].program_id=-1;
for(int k=0;k<MAX_SHADER_NUMBER;k++)
if(shader_program[i].shader_id[j].shader_id[k]>0){
Graphics_system::delete_shader(shader_program[i].shader_id[j].shader_id[k]);
shader_program[i].shader_id[j].shader_id[k]=-1;
}
}
}
}
Shader_base *Shader_base::system_clone_shader(Part_parameter &par)
{
Shader_base *sp,*new_sp,*bak_first_shader_pointer;
if(shader_program_number>=MAX_SHADER_PROGRAM_NUMBER)
return NULL;
for(sp=first_shader_pointer;sp!=NULL;sp=sp->next_shader)
if(sp->class_name==par.class_name){
bak_first_shader_pointer=first_shader_pointer;
new_sp=sp->clone_shader(par.directory_name,par.material_file_name);
new_sp->class_shader=sp;
new_sp->next_shader=NULL;
first_shader_pointer=bak_first_shader_pointer;
for(int i=0;i<shader_program_number;i++){
bool match_flag=true;
for(int j=0;j<MAX_SHADER_NUMBER;j++){
if(shader_program[i].shader_file_name[j]!=(par.shader_file_name[j])){
match_flag=false;
break;
}
}
if(match_flag){
new_sp->program_index_id=i;
return new_sp;
}
}
new_sp->program_index_id=shader_program_number;
for(int i=0;i<MAX_SHADER_NUMBER;i++)
shader_program[shader_program_number].shader_file_name[i]=par.shader_file_name[i];
for(int i=0;i<(sizeof(shader_type_string)/sizeof(shader_type_string[0]));i++){
for(int j=0;j<MAX_SHADER_NUMBER;j++)
shader_program[shader_program_number].shader_id[i].shader_id[j]=-1;
shader_program[shader_program_number].shader_id[i].program_id=-1;
}
shader_program_number++;
return new_sp;
}
return NULL;
}
Shader_base::Shader_base(CString my_class_name,CString my_directory_name,CString my_file_name)
{
class_name=my_class_name;
directory_name=my_directory_name;
file_name=my_file_name;
program_index_id=-1;
class_shader=this;
next_shader=first_shader_pointer;
first_shader_pointer=this;
}
Shader_base::~Shader_base()
{
}
|
// TestDeleteCreateRevert tests a weird state transition corner case that we hit
// while changing the internals of StateDB. The workflow is that a contract is
// self-destructed, then in a follow-up transaction (but same block) it's created
// again and the transaction reverted.
//
// The original StateDB implementation flushed dirty objects to the tries after
// each transaction, so this works ok. The rework accumulated writes in memory
// first, but the journal wiped the entire state object on create-revert.
func TestDeleteCreateRevert(t *testing.T) {
state, _ := New(common.Hash{}, NewDatabase(rawdb.NewMemoryDatabase()), nil)
addr := toAddr([]byte("so"))
state.SetBalance(addr, big.NewInt(1))
root, _ := state.Commit(false)
state, _ = New(root, state.db, state.snaps)
state.Suicide(addr)
state.Finalise(true)
id := state.Snapshot()
state.SetBalance(addr, big.NewInt(2))
state.RevertToSnapshot(id)
root, _ = state.Commit(true)
state, _ = New(root, state.db, state.snaps)
if state.getStateObject(addr) != nil {
t.Fatalf("self-destructed contract came alive")
}
} |
The unrelated bone marrow donor. Although the majority of bone marrow transplants (BMT) have been performed using HLA-identical sibling donors, BMT may also be successful when the donor is a haploidentical partially matched relation or a well-matched unrelated volunteer. For patients with acute lymphoblastic leukaemia or acute myeloid leukaemia, an alternative to allogeneic BMT using a sibling donor is the use of autologous marrow, although the period of follow-up for such studies is still relatively short and final assessment must await the results of randomized trials. In contrast patients with chronic myeloid leukaemia, severe aplastic leukaemia or myelodysplasia who lack suitable related donors are prime candidates for well-matched unrelated donor transplantation. In this paper we discuss the value of various methods for identifying unrelated donors, the size and costs of maintaining volunteer panels in relation to the probability of finding a matched donor for an individual patient and some of the criteria on which the choice between a mismatched family member donor and a matched unrelated donor can be based. |
Former American presidential candidate Ron Paul says states will eventually break away from the United States but the good news is that secession is already underway.
The former Texas congressman made the remarks during a speech at a pro-secession conference, titled “Breaking Away: The Case for Secession”, late last month. The video of Paul’s speech surfaced on Friday.
“I would like to start off by talking about the subject and the subject is secession and, uh, nullification, the breaking up of government, and the good news is it’s going to happen. It’s happening,” Paul told a gathering at the libertarian Mises Institute on January 24.
He said that Congress would not approve secession, but the process rather would be de facto.
“And it’s not going to be because there will be enough people in the US Congress to legislate it. It won’t happen. It will be de facto. You know, you’ll have a gold standard when the paper standard fails, and we’re getting awfully close to that. And people will have to resort to taking care of themselves. So when conditions break down, you know, there’s going to be an alternative. And I think that’s what we’re witnessing,” Paul stated.
He also said that the US central bank, which he considers responsible for many of the ills afflicting America, would end and the states would simply stop listening to federal laws they didn’t agree with.
The veteran American politician said the Federal Reserve “is going to end. There is going to be a de facto secession movement going on. The states are going to refuse to listen to some of the laws.”
He added that “the American people are waking up to that, and as far as I’m concerned, the more the merrier.”
Amid the growing anger with Washington, polls show that nearly a quarter of Americans want their states to break away from the United States and become an independent country.
The results of a Reuters/Ipsos poll released in September last year show that 24 percent of Americans strongly support or tend to support the idea of their state separating from the union.
Experts say last year’s Scottish vote for independence along with the falling public approval of the White House is increasing interest in breaking away among the American public.
GJH/GJH |
def s(x):
out=0
q=str(x)
for i in q:
out+=int(i)
return out
n=int(input())
if n<=9:
print (n)
raise SystemExit
k=len(str(n))
a=n//(10**(k-1))
if a>=2:
a=a-1
a=str(a)+'9'*(k-1)
else:
a='9'*(k-1)
a=int(a)
b=n-a
out=s(a)+s(b)
print(out) |
Change of Cerebral Blood Flow After a Successful Pharmacological Treatment of Phantom Bite Syndrome: A Case Report Background Phantom bite syndrome, a persistent complaint of an uncomfortable bite sensation with no obvious occlusal abnormal finding, recently was suggested to be related with central nervous system dysfunction. Here, we report a case of phantom bite syndrome in which the occlusal discomfort was improved with mirtazapine and aripiprazole combination parallel with regional cerebral blood flow change. Case report A 60-year-old-female patient came to our clinic with the chief complaint of a loosely bite after dental treatment and various uncomfortable sensations of body sites. One year after the medication therapy, the prosthodontic retreatment was carried out successfully, and a good outcome was obtained for over 24 months so far. In addition, a subsequent change of regional cerebral blood flow was observed in single-photon emission computed tomography: the right and left asymmetry of cerebral blood flow in the frontal lobe has disappeared along with the improvement to the symptoms improvement. Conclusions This case suggests that some central nervous system dysfunction involving dopaminergic system might be related to the pathophysiology of phantom bite syndrome. "P hantom bite syndrome" (PBS), which was first described by in the year 1976, is a persistent complaint of uncomfortable bite sensation with no obvious occlusal abnormal findings. Conventional dental treatments were repeated again and again to adjust patients' occlusion, but only worsened the symptoms. Previous studies suggested that PBS was mostly developed after dental treatment (eg, prosthodontic, restoration, orthodontic, etc). While most patients could adapt quickly to the restored occlusion, some of them were hardly and slowly to adapt and keep complaining of their discomfort. 4 Although PBS has been considered to be associated with paranoia, personality problems, or some other mental diseases, 1 not all the cases of PBS have psychiatric symptoms. Several researches have suggested a relationship between PBS and some dysfunction in the central nervous system. 5,6 In particular, a decreased blood flow of the dorsolateral prefrontal and frontopolar cortex was reported with reproduced occlusal discomfort in healthy participants using near-infrared spectroscopy. 7 Supporting the hypothesis about a relationship between PBS and central nervous system, antidepressants and antipsychotics were used for PBS management. 8 However, there is no investigation involving patients with PBS focusing on the change of cerebral blood flow before and after treatment has been reported. CASE REPORT A 60-year-old housewife complaining about her occlusal discomfort visited our clinic. She felt a pressure sensation on the maxillary anterior fixed prosthetic and numbness of her right face. She had no remarkable incidents in medical/psychiatric history and was living with her husband in a good relationship. Fifteen months before the initial visit to our clinic, after placing a porcelain fused zirconia crown on the maxillary left incisor, the patient started to feel an occlusal discomfort, which she described as "bite is loose," "heavy" sensation in her back, "twisting" sensation in her waist, and general lethargy. Even though the crown was immediately replaced by a temporary one and adjusted many times, her symptoms did not improve. Then, the dentist suggested a consult with a psychiatrist, but she refused that proposal. She believed strongly that what she needed was "correcting bite," not mental health care. At the first visit to our clinic, she brought along her own illustration to demonstrate the occlusal abnormality and blamed her "lousy bite" to the prior dentist. There she was in a presentable appearance, and a polite attitude was kept through our interview. No overreaction, manic episodes, hallucination, or any sight of delusional complaints were seen. Extraoral examination found symmetrical face and pleasant countenance. Hypertonia or tenderness of masticatory muscle, clicking, crepitus, and trismus were not observed. However, the patient kept complaining about being unable to find the "correct bite" and unstable "tapping point." No abnormalities in intraoral examination as well as in the radiographs were found. In accordance with the criteria suggested by Melis and Zawawi, 9 we diagnosed the patient as having PBS. Then a head magnetic resonance imaging and 99m Tc ethyl cysteinate dimer single-photon emission computed tomography (SPECT) were performed. The head magnetic resonance imaging showed no obvious organic change (eg, bleeding of the brain parenchyma, infarction, expansion of cerebral ventricles, etc). On the other hand, the SPECT imaging showed the asymmetrical cerebral blood flow patterns between the right and left with right-sided dominance in the frontal lobe (Fig. 1A). The assessment was carried out by a physician specialized in the field of nuclear medicine. After explaining that the symptoms might come from the central nervous system, so that any conventional dental treatment could not be mitigated, we obtained her consent for medication therapy. The patient was initially prescribed amitriptyline 10 mg/d, but she complained about many adverse effects such as "stagger," "strong nausea," or "cannot do anything." On day 7, she was switched to mirtazapine 15 mg/d. After 1 week, her appetite returned, and she felt slightly better. The staggering remained so she refused to increase the dosage of the mirtazapine. Instead, aripiprazole 1 mg/d was added on. One month after initiation of medications, the patient was aware of the improvement of "twisted body" feeling. Three months later, the occlusal discomfort improved but remained slightly. The same prescription was continued, and the symptoms stabilized until the prosthodontic retreatment was carried out one year after the initial visit. During the dental treatment, her oral complaints such as "bite was loose" and "the crown did not fit me" recurred; however, it calmed down quickly a week later with the same prescription. The crown was successfully delivered. After the symptom relief, we checked the SPECT image again and observed the previous asymmetrical regional cerebral blood flow (rCBF) pattern disappeared (Fig. 1B). At 41 months' follow-up visits, the patient remained in stable condition with the same prescription. No sight of recurrence has been observed. DISCUSSION The persistence of occlusal discomfort even after many repeated dental treatment is diagnosed as PBS 1-3 or occlusal dysesthesia. 9,10 A study revealed more than 30% of the temporomandibular disorders patients suffer from bite discomfort. 9 In our opinion, PBS might be included in such patients, although the precise prevalence is still unclear. In another study, 70% of PBS patients developed their symptoms after conventional dental treatment. 8 The exact pathophysiological mechanism of PBS remained unknown, but previous research suggested the hypothesis of biochemical abnormalities related to neurotransmitter in the brain and higher brain dysfunction correlated with the cognitive processes. 11 In this report, in order to clarify those hypotheses, the treatment course and the change in rCBF were assessed. Before the treatment, SPECT image showed the asymmetrical rCBF pattern between the right and left frontal lobe with dominance in the right side. After prescribed mirtazapine and aripiprazole combination, the cerebral blood flow pattern has been changed. From the view of drugs reaction: mirtazapine is classified as a noradrenergic and specific serotonergic antidepressant and acts like an antagonist of presynaptic 2-adrenergic autoreceptors while enhancing serotonin neurotransmission at the 5-HT 1 receptor. 12 On the other hand, aripiprazole is a partial agonist on dopamine D 2, D 3, and serotonin 1A and antagonist on serotonin A 2. 13 In this case, the monotherapy of mirtazapine did not show sufficient effects, but adding on aripiprazole resulted in a good course. This suggests the occlusal discomfort might relate to dysfunction of complex neurotransmissions involving the dopaminergic system. A remarkable phenomenon in this case is the recurrence of occlusal discomfort after restarting the prosthodontic treatment. Although the sensation existed in only a very short time, then obtained improvement without additional prescription, the prosthodontic treatment likely provoked PBS symptoms. A possible explanation here would be the alteration of sensorimotor functions following modifying dental occlusion. That study also reported that the ability to adapt new altered occlusal in rats related to asymmetrical neuroplasticity between the right and left side of the primary motor cortex of the face in the frontal lobe. 4 Therefore, the spontaneous recovery of adaptation capacity after retreatment and the asymmetrical rCBF change in the frontal lobe in this case might reflect the alternation of this condition. CONCLUSIONS We reported a case of PBS in which the occlusal discomfort was improved by mirtazapine and aripiprazole combination therapy. In the 99m Tc ethyl cysteinate dimer SPECT images taken after treatment, the right and left asymmetry of the cerebral blood flow in the frontal lobe has disappeared along with the improvement of FIGURE 1. A, The SPECT images showed the rCBF was asymmetrical between the right and left with right-sided dominance in the frontal lobe (white arrow). B, After the treatment, the asymmetrical rCBF pattern disappeared. |
/**
* Model for a request to fetch Comic from the api.
*/
public static class Request {
final String url;
public Request(String url) {
this.url = url;
}
} |
def trimWordleDict(
wordles: "list[str]",
badChars: "list[str]",
okChars: "list[wordleChar]",
placedChars: "list[wordleChar]",
) -> "list[str]":
validWordles: "list[str]" = []
word: "str"
for word in wordles:
valid: "bool" = True
for badc in badChars:
if badc in word:
valid = False
if not valid:
continue
for okc in okChars:
if (okc.ch not in word) or (word[okc.loc] == okc.ch):
valid = False
if not valid:
continue
for plc in placedChars:
if word[plc.loc] != plc.ch:
valid = False
if not valid:
continue
if valid:
validWordles.append(word)
return validWordles |
def hexdump(binary, length=16, indent="", indent_size=0, newline='\n', prefix_offset=0):
generator = chunk(binary, length)
line_frmt = "%%s%%08X: %%-%ss %%s" % ((length * 3) - 1)
out = [line_frmt % (indent * indent_size, prefix_offset + (addr * length), dump(d), d.translate(FILTER))
for addr, d in enumerate(generator)]
return newline.join(out) |
<filename>Cracking_the_Coding_Interview/strings_making_anagrams.py
#!/usr/bin/env python3
import sys
from collections import Counter
arr1 = list(input().strip())
arr2 = list(input().strip())
c1 = Counter()
c2 = Counter()
for a in arr1:
c1[a] += 1
for a in arr2:
c2[a] += 1
diff = 0
dups = c1.keys() & c2.keys()
for k, v in c1.items():
if k in dups:
m = min(c1[k], c2[k])
diff += c1[k] - m
else:
diff += c1[k]
for k, v in c2.items():
if k in dups:
m = min(c1[k], c2[k])
diff += c2[k] - m
else:
diff += c2[k]
print(diff)
|
/**
* ============LICENSE_START====================================================
* org.onap.aaf
* ===========================================================================
* Copyright (c) 2018 AT&T Intellectual Property. All rights reserved.
* ===========================================================================
* Licensed under the Apache License, Version 2.0 (the "License");
* you may not use this file except in compliance with the License.
* You may obtain a copy of the License at
*
* http://www.apache.org/licenses/LICENSE-2.0
*
* Unless required by applicable law or agreed to in writing, software
* distributed under the License is distributed on an "AS IS" BASIS,
* WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
* See the License for the specific language governing permissions and
* limitations under the License.
* ============LICENSE_END====================================================
*
*/
package org.onap.aaf.auth.hello;
import java.io.BufferedReader;
import java.io.InputStreamReader;
import javax.servlet.ServletOutputStream;
import javax.servlet.http.HttpServletRequest;
import javax.servlet.http.HttpServletResponse;
import org.onap.aaf.auth.env.AuthzTrans;
import org.onap.aaf.auth.hello.AAF_Hello.API;
import org.onap.aaf.auth.rserv.HttpCode;
import org.onap.aaf.auth.rserv.HttpMethods;
import org.onap.aaf.misc.env.Env;
import org.onap.aaf.misc.env.TimeTaken;
/**
* API Apis
* @author Jonathan
*
*/
public class API_Hello {
private static final String APPLICATION_JSON = "application/json";
protected static final byte[] NOT_JSON = "Data does not look like JSON".getBytes();
// Hide Public Constructor
private API_Hello() {}
/**
* Normal Init level APIs
*
* @param oauthHello
* @param facade
* @throws Exception
*/
public static void init(final AAF_Hello oauthHello){
////////
// Simple "GET" API
///////
oauthHello.route(HttpMethods.GET,"/hello/:perm*",API.TOKEN,new HttpCode<AuthzTrans, AAF_Hello>(oauthHello,"Hello OAuth"){
@Override
public void handle(AuthzTrans trans, HttpServletRequest req, HttpServletResponse resp) throws Exception {
resp.setStatus(200 /* OK */);
ServletOutputStream os = resp.getOutputStream();
os.print("Hello AAF ");
String perm = pathParam(req, "perm");
if (perm!=null && perm.length()>0) {
os.print('(');
os.print(req.getUserPrincipal().getName());
TimeTaken tt = trans.start("Authorize perm", Env.REMOTE);
try {
if (req.isUserInRole(perm)) {
os.print(" has ");
} else {
os.print(" does not have ");
}
} finally {
tt.done();
}
os.print("Permission: ");
os.print(perm);
os.print(')');
}
os.println();
trans.info().printf("Said 'Hello' to %s, Authentication type: %s",trans.getUserPrincipal().getName(),trans.getUserPrincipal().getClass().getSimpleName());
}
});
////////////////
// REST APIs
////////////////
////////////////
// CREATE/POST
////////////////
oauthHello.route(oauthHello.env,HttpMethods.POST,"/resthello/:id",new HttpCode<AuthzTrans, AAF_Hello>(oauthHello,"REST Hello Create") {
@Override
public void handle(AuthzTrans trans, HttpServletRequest req, HttpServletResponse resp) throws Exception {
BufferedReader br = new BufferedReader(new InputStreamReader(req.getInputStream()));
StringBuilder sb = new StringBuilder();
while (br.ready()) {
sb.append(br.readLine());
}
String content = sb.toString();
trans.info().printf("Content from %s: %s\n", pathParam(req, ":id"),content);
if (content.startsWith("{") && content.endsWith("}")) {
resp.setStatus(201 /* OK */);
} else {
resp.getOutputStream().write(NOT_JSON);
resp.setStatus(406);
}
}
},APPLICATION_JSON);
////////////////
// READ/GET
////////////////
oauthHello.route(oauthHello.env,HttpMethods.GET,"/resthello/:id",new HttpCode<AuthzTrans, AAF_Hello>(oauthHello,"REST Hello Read") {
@Override
public void handle(AuthzTrans trans, HttpServletRequest req, HttpServletResponse resp) throws Exception {
resp.setStatus(200 /* OK */);
StringBuilder sb = new StringBuilder("{\"resp\": \"Hello REST AAF\",\"principal\": \"");
sb.append(req.getUserPrincipal().getName());
sb.append('"');
String perm = pathParam(req, "perm");
trans.info().printf("Read request from %s: %s\n", pathParam(req, ":id"),perm);
if (perm!=null && perm.length()>0) {
TimeTaken tt = trans.start("Authorize perm", Env.REMOTE);
try {
sb.append(",\"validation\": { \"permission\" : \"");
sb.append(perm);
sb.append("\",\"has\" : \"");
sb.append(req.isUserInRole(perm));
sb.append("\"}");
} finally {
tt.done();
}
}
sb.append("}");
ServletOutputStream os = resp.getOutputStream();
os.println(sb.toString());
trans.info().printf("Said 'RESTful Hello' to %s, Authentication type: %s",trans.getUserPrincipal().getName(),trans.getUserPrincipal().getClass().getSimpleName());
}
},APPLICATION_JSON);
////////////////
// UPDATE/PUT
////////////////
oauthHello.route(oauthHello.env,HttpMethods.PUT,"/resthello/:id",new HttpCode<AuthzTrans, AAF_Hello>(oauthHello,"REST Hello Update") {
@Override
public void handle(AuthzTrans trans, HttpServletRequest req, HttpServletResponse resp) throws Exception {
BufferedReader br = new BufferedReader(new InputStreamReader(req.getInputStream()));
StringBuilder sb = new StringBuilder();
while (br.ready()) {
sb.append(br.readLine());
}
String content = sb.toString();
trans.info().printf("Content from %s: %s\n", pathParam(req, ":id"),content);
if (content.startsWith("{") && content.endsWith("}")) {
resp.setStatus(200 /* OK */);
resp.getOutputStream().print(content);
} else {
resp.getOutputStream().write(NOT_JSON);
resp.setStatus(406);
}
}
},APPLICATION_JSON);
////////////////
// DELETE
////////////////
oauthHello.route(oauthHello.env,HttpMethods.DELETE,"/resthello/:id",new HttpCode<AuthzTrans, AAF_Hello>(oauthHello,"REST Hello Delete") {
@Override
public void handle(AuthzTrans trans, HttpServletRequest req, HttpServletResponse resp) throws Exception {
trans.info().printf("Delete requested on %s\n", pathParam(req, ":id"));
resp.setStatus(200 /* OK */);
}
},APPLICATION_JSON);
}
}
|
A Survey of People With Parkinsons and Their Carers: The Management of Pain in Parkinsons Background: Pain in Parkinsons is problematic but under treated in clinical practice. Healthcare professionals must understand the impact of pain in Parkinsons and patient preferences for management. Objective: To understand the impact of pain in Parkinsons and to understand current management and preferences for pain management. Methods: We conducted a national survey with 115 people with Parkinsons (PwP) and 10 carers. Both closed and open questions were used. The questions focused on how pain affected the individual, healthcare professional involvement in supporting pain management, current pain management strategies and views on future pain management interventions. We used descriptive statistics to summarize closed responses and thematic analysis to summarize open question responses. Results: 70% of participants reported pain impacted their daily life. Pain had a multifactorial impact on participants, affecting movement, mood and quality of life. Improved pain management was viewed to have the potential to address each of these challenges. Pain affected a number of different sites, with low back pain and multiple sites being most frequently reported. Exercise was the most frequently noted strategy (38%) recommended by healthcare professionals for pain management. PwP would value involvement from healthcare professionals for future pain management, but also would like to self-manage the condition. Medication was not suggested as a first line strategy. Conclusions: Despite reporting engagement in some strategies to manage pain, pain still has a wide-ranging impact on the daily life of PwP. Results from this survey highlight the need to better support PwP to manage the impact of pain. Pain can affect up to 85% of people with Parkinson's (PwP) 1,2 yet is poorly recognized and managed within clinical practice, 3 which can have significant consequences on quality of life. 4 Pain is biopsychosocial and has a multifactorial impact on individuals lives, yet this has been found to not be acknowledged by healthcare professionals. 5 Despite the problem of pain, there are limited options for pain management in Parkinson's. 6 Between 50% 7 and 63% 8 of those reporting pain have not received any pharmacological or non-pharmacological treatment for their pain, which has been attributed to an inadequate awareness of clinicians. 9 There is a need to increase education concerning pain in Parkinson's for healthcare professionals and to develop options for both pharmacological and non-pharmacological management of pain. 10 Currently, it is unknown if pharmacological therapy will relieve pain in Parkinson's due to the distinct mechanisms involved with pain processing interacting with Parkinson's pathophysiology. 11 A small number of cross sectional studies have provided some detail on how PwP manage their pain. Physiotherapy and pain medication are the most frequently cited approaches. 7,8,12 However, this must be considered in the wider context of a number of individuals not receiving any treatment. There is limited literature to date exploring the impact of pain, current management strategies and the preferences of PwP for future interventions. Understanding of these factors will help to inform the development of pain management for PwP. Currently there is only a small amount of research that focuses specifically on PwP views on pain. This work aimed to enable PwP and their carers to share their experiences of pain and pain management in their own words and, importantly, to share their thoughts on what pain management interventions should look like. This survey forms part of a wider piece of patient and public involvement to inform the direction of a future research study about pain management in Parkinson's. Materials and Methods Ethics The survey was approved by Northumbria University Research Ethics committee. Informed consent was obtained at the start of the survey. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Developing the Survey In order to ensure the survey was clear and that questions focused on aspects important to PwP, we considered it vital to work with PwP to develop the survey questions. JN, AA and NR drafted questions based on existing literature and the research team's plans for a future study. The draft survey was then sent to 5 people affected by Parkinson's (3 male & 2 female; time since diagnosis: ranging between 2-15 years) who provided feedback on the clarity of questions and recommended changes. As a result of this feedback, a number of amendments were made including reducing the length of the survey, refining the focus and providing more detail for certain questions. Recruitment and Procedures The survey was administered in March 2020 by Parkinson's UK on SmartSurvey, an online survey software and questionnaire tool. Participants were recruited via Parkinson's UK Research Support Network-an online network that brings together people driven to help find a cure and better treatments for Parkinson's. The Research Support Network has around 6,000 members (as of February 2020), the vast majority of whom are PwP and partners, family members and carers of those with the condition living in the UK. An email was sent to the network inviting people to complete the survey, and the survey was also included in the Network's monthly enewsletter. The survey gathered feedback from both PwP and partners, family members and carers. The target population was those who had experience of pain. The question set was the same for the 2 groups, aside from minor variations in wording to make questions applicable. The first question required the individual to indicate if they were a person with Parkinson's or a partner, family member or carer so the appropriate question set could be shown (supplementary material). The survey consisted of 2 parts. Part 1 included 8 questions focused on how pain affected the individual (or their partner/family member/person they cared for), their experience of healthcare professional involvement in supporting pain management, current pain management strategies and views on future pain management interventions. Three questions collecting demographic information were also included. Part 2 consisted of a further 9 questions focused on feedback for the specific design of a study. Results from part 2 are not reported here. The survey did not collect any identifying information. Participants were able to skip any questions they did not wish to answer. The survey included a mixture of closed and open-ended questions. Open ended questions were deemed important to allow participants to develop responses due to the limited research in this area, and also provided an opportunity for participants to highlight any additional points they deemed relevant. Data Analysis We used descriptive statistics to characterize the sample. Categorical data were analyzed via SPSS (version 21) to generate frequencies. Open ended questions were summarized using thematic coding analysis. 12 These were informed by the aims of the research, while allowing new themes to emerge. One author (JN) read through the responses, coded these and then categorized into themes. A second author (KB) independently categorized the coded responses and a final presentation of themes was agreed through a peer debriefing meeting between the 2 authors and discussed with the wider team. Results We received responses from 115 PwP and 10 carers. Almost all the questions (except 3) were focused on the experience of the person with Parkinson's, with partners, family members and carers responding on the person's behalf. Therefore, the reporting of "participants" refers to the information captured from both groups of respondents (N 125), unless specified otherwise. All participants answered the closed questions (see Table 1 Closed Questions Please see Table 1 for details of participant characteristics. 75% of participants were aged 60 or over. 42% had been diagnosed between 2 and 5 years. A large majority of participants indicated pain impacted their daily life (70%), with 49% experiencing pain multiple times per week and 24% experiencing pain multiple times per day. The healthcare professional (HCP) with whom the highest number of participants had discussed their pain was their Parkinson's nurse (48%) followed by a general practitioner (38%) and a physiotherapist (35%). 10% of PwP discussed pain with their neurologist. Exercise was the most frequently noted mechanism by which healthcare professionals supported individuals with their pain (38%). Open Questions The open-ended questions provide detailed information regarding the current impact of pain, it's management and future management suggestions. The impact and current management of pain in Parkinson's. When asked about what pain management strategies PwP used, physical activity, paracetamol and ibuprofen were the most frequently reported. Some individuals described multiple strategies, with some participants identifying a wide range of strategies that had been tried to manage their pain. Other participants acknowledged that no management options had been successful to date or not being sure how to manage their pain. While medication was cited, some participants expressed reluctance at taking this. Parkinson's medication was not linked with pain. Five individuals noted painful muscle spasms and cramps. Some participants had tried other therapies such as massage and mindfulness. Table 2 provides a description of each of the pain management strategies and examples identified by participants. When asked if pain impacted their daily life, responses focused around describing the location of their pain and the timing of this, alongside capturing the biopsychosocial impact that this can have. Pain was reported in a number of locations, with low back pain being the most frequently reported, alongside having pain in multiple locations. Wearing off pain was noted by few participants. Pain made movement difficult for some participants, alongside having a negative impact on mood and wider daily life. Detail surrounding these open-ended responses is provided in Table 3. Pain management needs for people with Parkinson's. Participants identified the need for pain management interventions to provide pain relief. Involving healthcare professionals with pain management was deemed important, with some individuals viewing it necessary to be able to self-manage their pain or to have a combination of support and self-management. When asked an open question about future pain management medication was not mentioned as a suggestion for pain management, however some participants highlighted a non-drug approach to be the preference. Table 4 provides further detail pertaining to the nature of pain management interventions suggested by participants. Participants indicated improved pain management would provide an overall positive impact on general wellbeing, in particular improving activity and quality of life. An impact on mood, sleep and daily life were often referred to alongside improved pain management as having the potential to "change the life" of some individuals. A sense of being in control of pain was deemed important by some. Table 5 elaborates on these findings, with specific examples provided. Discussion This survey has identified the anticipated impact improved pain management strategies would have on PwP living with pain, alongside preferences on how such strategies should be delivered. Studies to date present findings on strategies that have been tried for PwP but have involved little dialogue with people about their preferences. This survey provides a direct account of what PwP would like from future pain management interventions and the potential impact they felt that this would have. Pain was highlighted as having a biopsychosocial impact, with movement, mood and daily life each being cited as being impacted by pain. Despair and despondency associated with living with pain in Parkinson's has been reported in a qualitative study (n 4). 5 This study reported individuals experiencing high levels of pain which had psychological and social impacts. Some participants tried management strategies such as exercise, while others felt this to not be possible. Having a sense of control over pain was key. A disconnect between healthcare professionals and PwP was highlighted, with individuals needs surrounding pain not addressed. 5 While small samples can be expected in this type of study, transferability of these findings is limited as a stand-alone study. The current survey adds to these findings, highlighting on a larger scale the wide-ranging impact of pain, and variation among the use of strategies. A key development with the current survey is individuals reporting how improved pain management would impact their daily life. A feeling of overall improved wellbeing including improved activity, mood and quality of life were each highlighted if pain were to be better managed. Pain can influence all aspects of someone's life 13 and be a particularly bothersome symptom. 14 Individuals in this survey noted the dominating effect of pain, and the overarching positive impact that a reduction in pain could have on daily life. Exercise is encouraged for PwP as a key aspect of the management of the condition. 3,15 The current survey identified that exercise is a frequently advised strategy by healthcare professionals to support the management of pain. At early stages of Parkinson's it has been found that activity levels are reduced compared to age matched controls. 16 Pain can be a barrier to exercise 15 and increased physical activity has been found to be associated with worse pain scores in Parkinson's. 17 Within the literature related to chronic musculoskeletal pain, avoidance of activity due to fear and reduced self-efficacy regarding managing symptoms can occur. 18 Keeping active may not seem plausible to patients with low perceived control over their pain 19 and has been identified as an issue with PwP and pain. 13 While exercise is also advocated for the management of pain in the general population 20,21 this is often in conjunction with other strategies including education and support. 22,23 Given that PwP in this survey highlighted exercise as a key strategy for reducing pain, future work to investigate pain management strategies specific to Parkinson's is necessary. Medication was also identified as a method currently used to manage pain. The most frequently cited medication was paracetamol (15% of individuals) followed by ibuprofen (11% of individuals), which follows a similar pattern to cross sectional studies, which have collected medication use data. 2,12 This type of medication use has been criticized as not targeting the central mechanisms of pain in Parkinson's. 2 Alongside this, these are not large numbers of the participants reporting medication use, and often individuals do not receive any support with pain management, including medication. 7,8 Some participants in the current survey identified a hesitance at taking medication or suggesting a non-drug approach for future management. It is important to note that in an open question about expectations for a pain management intervention, medication was not suggested as a potential strategy by participants. Healthcare professional support was valued by participants for pain management, appreciating the knowledge and advice healthcare professionals could provide being most frequently cited. A recent systematic review of pain management for PwP 6 advocates the need for further research in this area. The review demonstrated promise for pharmacological therapy focusing on Safinamide, and from 1 study, efficacy for multidisciplinary team (MDT) management. "Miscellaneous therapies" were highlighted including hydrotherapy, massage and resistance exercise, yet the quality of these studies was poor. Pain is multifactorial, 24 and individual approaches like those approaches did not reflect the biopsychosocial impact of pain. The review was comprehensive in its search, including allied health, behavioral therapy and client centered therapy, yet identified little in these areas. While MDT management had shown promise for pain 25 this was not the primary outcome or focus of this study and there was limited detail of the MDT management. A previous cross sectional survey found the greatest efficacy for pain management was reported in conjunction with treatment in a rehabilitation clinic or physiotherapy. 12 To date, there is limited literature focusing on interventions for pain management in Parkinson's. 6 Pain management in the context of wider care, with support from healthcare professionals warrants investigation given PwP identifying the wide ranging impact of pain on their daily lives and a preference for support in pain management. The participants in this study identified a number of different HCPs with whom they have discussed their pain with. In previous studies an orthopaedic doctor or general practitioner were the most frequently cited, with a small number citing neurologists. 12 In agreement, the current survey found a small number of neurologists and consultants cited. However, the Parkinson's nurse and physiotherapist were frequently referred to as those who individuals had consulted. This finding is crucial as it indicates that there is a need for a multidisciplinary approach to pain management in Parkinson's, in support of previous work. 25 HCPs working with individuals with chronic musculoskeletal pain have reported challenges in supporting people with pain and require support themselves. 26 Alongside this, literature exploring clinician attitudes and beliefs to chronic musculoskeletal pain has found HCP attitudes and beliefs to be associated with those of their patient. A biomedical orientation has a negative association with patient education, adherence to treatment guideline and activity recommendations. 27 These results of the current survey show that PwP feel HCPs have a key role to play in pain management. It is therefore important for future work to understand attitudes and beliefs among HCPs regarding pain in Parkinson's, particularly given the limited focus on pain management in current Parkinson's practice. 7,8 70% of participants reported pain influenced their daily life, which aligns with other cross sectional studies focusing on pain and Parkinson's, which report between 52% 28 and 85% 2 of people reporting pain. The current survey found 49% to experience pain daily and 24% multiple times per day. These findings are higher than previously reported of up to 21% "often" experiencing aches and pains and 6% "always" experiencing these. 29 Low back pain is frequently cited as problematic in Parkinson's 30,31 and was noted most frequently in this survey, followed by individuals experiencing pain at multiple sites. A diagnosis of the cause of pain was important to some individuals. However, given the central processes involved in pain, and PwP potentially being more predisposed to pain 32,33 a definitive diagnosis may be difficult to achieve. A diagnosis can provide legitimacy to pain, and one potential way to achieve this is to consider education regarding pain physiology. 18 This captures the biopsychosocial nature of pain, supporting participants to understand the multifactorial influences on a pain experience. The participants focused predominantly on the location of pain within this survey. Given that there are often different pain mechanisms involved with pain and Parkinson's 34 communicating these to PwP may help with understanding. A limitation of this study is the lack of measures of disease severity including Hoen and Yahr staging, MDS UPDRS and measures of non-motor symptoms such as sleep and mood. This was a non-random sample, using self-report data, which is also acknowledged as a limitation of the study. Those responding are more likely to have had a problem with pain in view of the nature of the study. Alongside this, as individuals recruited would have expressed an interest to be contacted regarding research, the population may not be entirely representative of the Parkinson's population as a whole. The relationship between pain, OFF periods and anti Parkinson medication was not specifically explored, however pain has been found to be no different between the ON and OFF state in the largest pain and Parkinson's study to date. 2 We did not use a validated scale to capture information regarding pain in Parkinson's, for example the Kings Parkinson's pain scale. 35 However, the survey was able to address the aim of this exploratory study, to identify current pain management strategies and suggestions for the future. There were responses from 10 carers within this survey and it should be acknowledged they may have differing views to the PwP themselves, though there were not sufficient data to investigate this here. Respondents were all from the United Kingdom, which has implications for the availability of services. The key strength of this study is that it has explored preferences and needs regarding pain management by directly asking PwP for their views. Feedback from a small group of PwP on the draft survey questions helped ensure that the survey focused on aspects important to PwP, and the use of open-ended questions allowed PwP to make suggestions about what pain intervention strategies should look like. Key HCPs who could be involved in pain management have also been identified, which will help when providing tailored support and guidance to healthcare professionals themselves. This study highlights the need to develop evidence surrounding how to manage pain in Parkinson's, alongside the potential impact improved management would have on PwP quality of life, movement and wellbeing. |
OAKLAND — The message at a recent town hall meeting about Coliseum City was loud and clear: East Oakland residents don’t want a development that ignores their needs and is designed for people who don’t live there.
Nearly 200 people packed into Union Baptist Temple church in the middle of the proposed Coliseum City neighborhood Saturday to discuss the future of the 800-acre area that surrounds O.co Coliseum and Oracle Arena. As the city of Oakland and Alameda County put together the Coliseum City Specific Plan, some people and organizations are speaking up about what they would like to see for their community in the near future.
She encouraged residents to be leaders, not followers, when it comes to communicating with City Hall about the needs of the community.
Several people said they hadn’t heard about the workshops hosted by the city, and they felt the votes on the development plan were made behind closed doors. As a result, Oakland United, an umbrella organization working with labor unions, environmental health groups and housing rights groups, hosted the town hall meeting so residents could “come to the table” and be heard.
The town hall offered several opportunities for people to express their points of view. There was a station to conduct video interviews and a table where people could write their thoughts and ideas on note cards. In the main event, everyone split off into 14 groups to do visualization exercises for what they would like to see happen in Coliseum City.
Some people cited churches, some cited the diversity of the area. But there was also some hesitation, as urban blight, homelessness and neglected infrastructure were part of the conversation.
E Riller worried that she wouldn’t be able to get her car out that day because the sewer drains had backed up so much from the heavy rain. “That’s an example of something the city can fix. They have the money, just not the wherewithal,” she said.
The ideas came out in a torrent: Walkable streets, accessible pathways. Access to transportation. Child care centers. Affordable and accessible transportation. People said police accountability in the area feels uneven and poorly managed and needs to be improved. Nobody seemed interested in high-end condos or boutique shops.
Donna Griggs Murphy, a longtime resident of the area, suggested a worker-owned grocery co-op and a vocational training facility. |
After an entire career spent on Spanish teams, 34-year-old Francisco Ventoso has decided to take the leap to the BMC Racing Team for 2017, the team announced today. Related Articles The Cyclingnews guide to 2016-2017 rider transfers
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Ventoso, who is nearing the end of a six-season stint with Movistar, is a former Spanish national champion and winner of two Giro d'Italia stages in recent years. Formerly a bunch sprinter, he has put more emphasis on the Classics recently, although this season's campaign was hampered when he suffered a deep gash to his leg, reportedly the result of an impact with a disc brake rotor.
BMC General Manager Jim Ochowicz sees him as a support rider for Greg Van Avermaet and for the team's Grand Tour ambitions.
"Francisco Ventoso is a very versatile rider who will fit well with BMC Racing Team's objectives," Ochowicz said in a team press release. "He is not only a strong Classics rider, but also a great support rider for the Grand Tours. Francisco has been on the professional circuit for a long time so he is experienced in the peloton and understands what needs to be done in different race scenarios, which ticks a lot of boxes for us. Francisco is also a multiple Grand Tour stage winner so when given the opportunity he also knows how to win. We look forward to seeing him in the BMC Racing Team kit in 2017."
Ventoso said he looks forward to racing with Van Avermaet.
"For me it is a great motivation to go to one of the best teams in the world and it is an honor for me to join the group of riders who will attack the Spring Classics with Greg Van Avermaet as captain," Ventoso said.
"My main goal for 2017 is to put all of my experience and my strength into the team to make BMC Racing Team even stronger. I greatly appreciate the confidence placed in me and I will give the best version of myself as a rider." |
Paclitaxel-Loaded Folate-Targeted Albumin-Alginate Nanoparticles Crosslinked with Ethylenediamine. Synthesis and In Vitro Characterization Among the different ways to reduce the secondary effects of antineoplastic drugs in cancer treatment, the use of nanoparticles has demonstrated good results due to the protection of the drug and the possibility of releasing compounds to a specific therapeutic target. The -isoform of the folate receptor (FR) is overexpressed on a significant number of human cancers; therefore, folate-targeted crosslinked nanoparticles based on BSA and alginate mixtures and loaded with paclitaxel (PTX) have been prepared to maximize the proven antineoplastic activity of the drug against solid tumors. Nanometric-range-sized particles (169 ± 28 nm296 ± 57 nm), with negative Z-potential values (between −0.12 ± 0.04 and −94.1± 0.4), were synthesized, and the loaded PTX (2.63 ± 0.193.56 ±0.13 g PTX/mg Np) was sustainably released for 23 and 27 h. Three cell lines (MCF-7, MDA-MB-231 and HeLa) were selected to test the efficacy of the folate-targeted PTX-loaded BSA/ALG nanocarriers. The presence of FR on the cell membrane led to a significantly larger uptake of BSA/ALGFol nanoparticles compared with the equivalent nanoparticles without folic acid on their surface. The cell viability results demonstrated a cytocompatibility of unloaded nanoparticleFol and a gradual decrease in cell viability after treatment with PTX-loaded nanoparticleFol due to the sustainable PTX release. Introduction Targeted treatments and personalized medicine are two of the axes of current oncology. They refer to the design of drugs that respond specifically to some genetic characteristics of each patient's cancer. More efficiency is pursued with fewer adverse effects, adapting the procedures to the characteristics of each patient. Numerous studies have focused on the development of targeted drug-delivery systems for cancer treatment in order to reduce side effects due to the unspecific effect of anticancer drugs on healthy cells. Nanocarriers based on natural polymers have the advantage of being a priori biocompatible and also biodegradable. Among biological polymers, polysaccharides have been used for therapeutic delivery systems due to their non-toxic and non-reactogenic properties, as well 98%), N-hydroxysuccinimide (NHS), N,N'-dicyclohexylcarbodiimide (DCC) were purchased from Sigma-Aldrich (Barcelona, Spain). Sodium hydroxide (NaOH), hydrochloric acid (HCl; 35%), trichloroacetic acid, ethanol absolute, ethylenediaminetetraacetic acid (EDTA), Tween ® 80, triethylamine, anhydrous di-sodium hydrogen phosphate (Na 2 HPO4), di-hydrogen potassium phosphate (KH 2 PO4), diethylether, dichloromethane (DCM) and acetonitrile (HPLC-analysis grade) were supplied by Panreac (Madrid, Spain). Bovine serum albumin (BSA, Fraction V), sodium chloride (NaCl) and disodium hydrogen phosphate dehydrated were purchased from Merck (Barcelona, Spain). Fetal bovine serum (FBS), penicillin (50 U/mL), streptomycin (50 g/mL) and 0.05% trypsin/0.53 mM EDTA were purchased from Invitrogen Life Technologies, Grand Island, NY. Dubecco's Modified Eagle Medium was purchased from Lonza Bioscience (Bornem, Belgium). Paclitaxel (Taxol) was supplied by Tocris Bioscience (Mw 889.95 > 99%). All water used in the assays was Millipore Milli Q grade. Preparation of BSA/ALG Nanoparticles Folate-targeted nanoparticles (Nps-Fol) based on bovine serum albumin (BSA) and alginate (ALG) mixtures were prepared and stabilized by amide bonds using ethylenediamine. BSA 5% (w/v) and ALG 1% (w/v) aqueous solutions were prepared in the presence of EDAC 50 mM (Sigma-Aldrich). Subsequently, several blends of BSA/ALG were obtained by mixing different volumes of the solutions prepared previously (Supplementary data Table S1). Ethylenediamine (ED) was added to each blend according to 2:1 ratio (polymer: ED, w/w) under intense stirring conditions (magnetic stirrer), and pH was then adjusted to 3 with HCl to attain amide bond formation. Stirring was maintained for 2 h and blends were finally centrifuged (10,000 rpm, 5 min; Sigma SM202 centrifuge). Pellets were freeze dried (Heto PowerDry LL1500 Freeze Dryer, Thermo Electro Corporation, Waltham, MA, USA) for 24 h at −110 C. The conjugation of folate to nanoparticles was carried out by a carbodimiide reaction with NHS-folate. The N-Hydroxysuccinimide ester of folic acid (NHS-folate) was prepared according to the method developed by Lee and co-workers. Folic acid (2.5 g) was dissolved in 50 mL of dry dimethyl sulfoxide (DMSO) plus 1.25 mL of triethylamine and reacted with NHS (1.3 g) in the presence of dicyclohexylcarbodiimide (2.35 g) overnight at room temperature. The byproduct, dicyclohexylurea, was removed by filtration. The DMSO solution was then freeze-dried, and NHS-folate was precipitated in diethylether. The final product, NHS-folate, was washed several times with anhydrous ether, dried under vacuum, and yielded a yellow powder. The conjugation of folate to nanoparticles was carried out following the method developed by Zhang and co-workers : NHS-folate (50 mg/mL) was dissolved in 3 mL DMSO and added slowly to 6 mL of the stirred nanoparticle suspension (10 mg NP/mL, pH adjusted to 10 using 1 M carbonate/bicarbonate buffer). After stirring for 3 h at room temperature, the reaction mixture was centrifuged (10,000 rpm, 10 min) in order to separate the folate conjugated nanoparticles from unreacted folic acid and other byproducts and then washed with DMSO (10,000 rpm, 10 min). Finally, folate-conjugated nanoparticles (30BSA/70ALG-Fol, 40BSA/60ALG-Fol; 50BSA/50ALG-Fol) were freeze dried for 24 h at −110 C. 2.3. Characterization of Nanoparticles 2.3.1. Composition of BSA/AlG Nanoparticles Composition of nanoparticles was determined according to the method developed by Martinez and co-workers. The composition of BSA/ALG nanoparticles was studied measuring the concentration of BSA and ALG in the supernatant obtained after the centrifugation of the samples in the synthesis process. The difference between the initial concentration of each polymer and their concentration in the supernatant was determined, to reveal the proportion of each polymer in nanoparticle formation. Concentration of alginate in the supernatant was determined by measuring the absorbance of the colored Polymers 2021, 13, 2083 4 of 18 products obtained after a hydrolysis reaction of alginate. The hydrolysis of alginate was carried out in extreme conditions (10 N HCl, 5 h, 100 C) and, after this reaction, samples were neutralized with 10 N NaOH and cooled. Absorbance of the samples was measured at 277.6 nm. A standard curve of alginate (0.5-4 mg/mL) was prepared. Concentration of BSA in the supernatant was determined using Bradford's method. The absorbance of blue-colored products of this reaction could be measured at 595 nm. To avoid interactions between alginate and Bradford reagent, the BSA in the supernatant was precipitated with 2M trichloroacetic acid (TCA). After the precipitation process, samples were centrifuged and the supernatant was removed. The pellet was suspended in 1 mL 6M urea (urea solution in 2 N HCl). A standard curve of BSA (0.125-0.5 mg/mL) was prepared. Thermogravimetric Analysis (TGA) TGA curves of BSA/ALG nanoparticles, as well as raw materials, were obtained using a Mettler Toledo thermal analyzer (TGA-SDTA 851 ®, Switzerland). Samples (3 mg) were placed onto the balance, the temperature increased from 25 to 600 C at 10 C min −1 in a nitrogen atmosphere (nitrogen flow rate of 60 cm 3 min −1 ) and the mass continuously recorded as a function of temperature. Determination of Folate-Conjugated to BSA/ALG Nanoparticles The amount of folate conjugated to the amine groups of albumin was determined by spectrophotometric analysis. A quantity of 2 mg folate-conjugated nanoparticles (Nps-Fol) were hydrolysed by trypsin (0.05 mg/mg NP) with stirring at 37 C for 2 h. After the digestion process, the quantification of folate-conjugation was performed by spectrophotometric measurement of its absorbance at 358 nm (folic acid = 8643.5 M −1 cm −1 ). Morphology, Size and Z-Potential of Nanoparticles The morphology and size of Nps and Nps-Fol were studied by Transmission Electron Microscopy (TEM) (JOEL JEM 1010 microscope from ICTS Centro Nacional de Microscopa Electrnica, UCM). Size and zeta potential measurements of Nps and Nps-Fol were performed in deionized distilled water using a backscattered quasi-elastic light scattering device (Zetatrac NPA). Data were analyzed with Microtrac Flex Software. Preparation of PTX-Folate-Conjugated Nanoparticles The paclitaxel (PTX) load into Nps-Fol was carried out as follows: a suspension of 30 mg of NPs-Fol in 1 mL of the solution 1 mg PTX/mL ethanol was prepared and incubated for 22 h using a circular rotary stirrer in darkness at room temperature. Finally, the suspension was centrifuged (12,000 rpm, 15 min), the pellet was washed with water and nanoparticles were freeze-dried. Estimation of PTX Content Two different methods were carried out in order to determine the amount of PTX loaded into Nps-Fol. One of the methods consisted of a direct extraction of the drug from PTX-loaded Nps-Fol using ethanol: 3 mg of PTX-loaded Nps-Fol were suspended in 1 mL of ethanol under stirring conditions for 5 h. After this time, the suspension was centrifuged (13,000 rpm, 5 min) and the supernatant was collected. The samples were analyzed by HPLC. The other method consisted of an enzymatic digestion of PTX-loaded Nps-Fol with trypsin and a subsequent extraction of the drug with an organic solvent: 2 mg of PTX-loaded nanoparticles was suspended in 2 mL of phosphate-buffered saline (PBS, pH 7.4), and 50 g of trypsin was added to the solution. The digestion process was performed under orbital stirring (100 rpm) at 37 C for 24 h. After this time, PTX was extracted from PBS solution by the addition of 4 mL of dichloromethane. The tubes were mixed in a vortex mixer for 10 min and then centrifuged for 10 min at 10,000 rpm. The organic phase was transferred to flask vials and evaporated to dryness. The resulting residue was reconstituted in ethanol and then quantified by the HPLC technique. The concentration of PTX was determined by high-performance liquid chromatography (HPLC) using a Spectra Physics HPLC system, Spectra 100 UV-Vis detector and a SP8800 pump. The mobile phase consisted of acetonitrile/water 60:40 (v/v) and was pumped through 25 mm 4.6 mm RP-Spherisorb ODS2 C18 column (5 mm particle size, Waters) at a flow rate of 1 mL/min. The output at 227 nm was monitored and the peak area of each sample generated by ChromQuestTM software. The calibration curve was generated using PTX solutions between 0.1 and 25 g/mL in acetonitrile/water (60:40, v/v), prepared from a PTX solution in ethanol, and a good linear correlation (r 2 = 0.99) was obtained. All quantifications were performed in triplicate. In Vitro Drug Release Studies The release of PTX from Nps-Fol was carried out in centrifuge tubes. Drug-loaded Nps-Fol (3 mg) was suspended in PBS (4 mL pH 7.4, 37 C) containing 0.1% (w/v) Tween 80 ®. Release studies were carried out in the dark with orbital shaking (100 rpm; Ecotron INFORS HT, Switzerland) for 96 h. Sink conditions were maintained during drug release experiments and all experimental conditions were performed in triplicate. At predetermined time intervals, the solutions were centrifuged at 10,000 rpm for 1 min and the supernatants collected for PTX concentration analysis. The Nps-Fol samples were dispersed in fresh PBS and placed back on the shaker. The PTX was extracted from the supernatants by DCM (1 mL) by stirring using a vortex mixer for 10 min at room temperature. The DCM layer collected was evaporated at room temperature for 24 h, and the dried PTX was dissolved in acetonitrile/water (1 mL; 60:40 (v/v)). The percentage of PTX released into the supernatant was determined by HPLC. In order to analyze the drug delivery mechanism used by the NPs-Fol, the in vitro drug release data were fitted to various kinetic models. Higuchi, Korsemeyer-Peppas, zero-order and first-order models were selected for this study, applying the following set of equations : Higuchi model where M o, M t and M ∞ corresponded to the drug amount at time zero, at a particular time and at an infinite time, respectively. The K terms referred to the release kinetic constants obtained from the linear curves of simple regression analysis. Cellular Uptake of Nanoparticles Nps and Nps-Fol (10 mg) were loaded with 6-coumarin (98%, Sigma-Aldrich, Madrid, Spain) by immersion in 1 mL of a 1 mg/mL 6-coumarin solution (dissolved in ethanol) for 24 h at room temperature in the dark and under orbital shaking. Then, the suspension was centrifuged (7000 rpm, 5 min), and the 6-coumarin-loaded NPs were washed twice with ethanol and freeze-dried for 24 h at −110 C Cellular uptake of Nps and Nps-Fol was investigated in a monolayer of MCF7, MDA-MB-231 and HeLa cells. Cells were seeded in 96 well flat-bottom plates at 10,000 cells/well for MCF7 and MDA-MB-231, and 5000 cells/well for HeLa. After 24 h, the medium was replaced with 100 L of 1% FBS medium containing 6-coumarin-loaded Nps or Np-Fol and the plates were incubated in the 5% CO2 incubator at 37 C for 2, 4 and 24 h. The concentration of nanoparticles was the equivalent to obtain a concentration of 1 M of drug, considering the PTX load of each nanoparticle composition. Thus, the concentration of 6-coumarin-loaded Nps and Nps-Fol was 0.24 mg/mL (composition 50BSA/50ALG) and 0.325 mg/mL (composition 30BSA/70ALG) respectively. As a positive control, cells were grown with 0.2 g/mL of 6-coumarin in FBS medium, in the absence of nanoparticles. At each time interval, cells were washed twice with PBS to remove any uninternalized nanoparticles and lysed with 100 L lysis reagent (PBS with 2% SDS v/v and 50 mM EDTA). Internalization of nanoparticles was evaluated by fluorimetry at 488 nm, using a spectrophotometer (Varioskan, Thermo FisherScientific, Barcelona, Spain). Calibration curves (fluorescence versus concentration) were prepared with 6-coumarin (1 ng/mL −1 g/mL) dissolved in the lysis medium in order to calculate the amount of 6-coumarin incorporated into nanoparticles. All experimental conditions were performed in quintuplicate. Fluorescence Microscopy Cellular uptake of Nps and Nps-Fol with 6-coumarin was observed by fluorescence microscopy. Cells were seeded in 24 well flat-bottom plates at 40,000 cells/well for MCF-7 and MDA-MB-231, and 20,000 cells/well for HeLa. After 24 h, the medium was replaced with 500 L of 1% FBS medium containing 6-coumarin-loaded Nps or Np-Fol and the plates were incubated in the 5% CO 2 incubator at 37 C for 4 h. Then, cells were washed twice with PBS to remove any uninternalized nanoparticles. Localization of Nps-Fol with 6-coumarin was examined by light fluorescence microscopy (Leica DMIL microscope, Leica Microsystems, Balgach, Switzerland). Cells were photographed with a Leica DFC 300FX digital camera and Leica Application Suite software was used for processing the pictures (Leica Microsystems Switzerland). Cell Viability Cell viability was evaluated by using the MTT method. All experimental conditions were performed in quintuplicate. Each experiment was carried out in triplicate. In preliminary experiments, increasing concentrations of PTX from 0.1 to 500 nM were tested in culture. The IC50 of PTX was determined in the three cell lines tested. According to that, the selected concentrations of PTX in cell viability studies were 2.5 and 7.5 nM for HeLa and MCF7 cell lines, and 7.5 and 30 nM for MDA-MB-231 cells. Cells were seeded in 96-well flat-bottom plates at 5000 cells/well in the case of MCF7 and MDA-MB-231, and at 2500 cells/well in the case of HeLa. After 24 h, the medium was replaced with 100 L medium with 1% FBS containing Nps-Fol, PTX-loaded Nps-Fol or the drug in solution. The amount of Nps-Fol was the needed to obtain a final concentration of 30, 7.5 and 2.5 nM of PTX, considering the PTX load of each nanoparticle composition; for this purpose, a nanoparticle suspension of 0.24 mg/mL of 50BSA/50ALG and 0.325 mg/mL of 30BSA/70ALG Nps-Fol, (equivalent to 1000 nM PTX) was used. After 1, 3 and 6 days, 10 L of MTT solution (5 mg/mL) were added to each well. After 2 h of incubation at 37 C, 5% CO2, each well was replaced with 100 L DMSO. The cell viability was determined by measuring the absorbance at 570 nm using a spectrophotometer (Varioskan, Thermo Fisher Scientific, Barcelona, Spain). Results are expressed as the percentage survival in relation to untreated control cells. Statistical Analysis Statistical comparisons were performed with the unpaired Student's t-test. A value of p < 0.05 was considered significant. Composition of Nanoparticles Final nanoparticle composition was determined by the concentration of BSA and ALG in the supernatant collected after centrifugation, in the synthesis process. Thus, the contribution of each polymer within the final formulation of nanoparticles was calculated by the difference between the initial concentration and the final concentration after the synthesis protocol ( Table 1). The BSA/ALG ratio was calculated considering the concentration of each polymer incorporated into nanoparticles. These results demonstrated that not all the BSA nor ALG added in the initial solution of synthesis was incorporated in the final nanoparticles. Surprisingly, an increased proportion of BSA (w/w) in the initial composition was not translated into a higher incorporation of BSA into Nps. The thermal stability of raw materials and BSA/ALG nanoparticles was studied. The TGA first derivative of the materials is plotted in Figure S1 (Supplementary Materials). The Nps showed a thermal profile different from raw materials: Nps that included more BSA in their composition (30BSA/70ALG, ratio 1:1) showed a two-step degradation process: at 217 C (close to the degradation peak of ALG) and 317 C (close to the degradation peak of BSA). However, Nps with more ALG in their composition (40BSA/60ALG, ratio 0.25:1; 50BSA/50ALG, ratio 0.5:1) showed only one degradation peak at 212 C (close to the degradation peak of ALG). These differences in thermal behavior between raw materials and the Nps would indicate the chemical interaction between both polymers in the Nps and would confirm the different ratio of polymers incorporated in each Np composition. Additionally, all Np compositions showed a mass loss above 200 C which indicated that Nps were stable to use at routine work temperatures. According to these results, the compositions 30BSA/70ALG-Fol and 50BSA/50ALG-Fol were finally chosen for further studies due to their greater content of incorporated folate. Morphology, Size and Z-Potential of Nanoparticles The morphology of 30BSA/70ALG and 50BSA/50ALG Nps was analyzed by TEM. Micrographs showed nanometric-range sized particles (<100 nm), with a spherical appearance. This morphology was maintained after folate conjugation (Figure 1). 40BSA/60ALG-Fol (p = 0.0002) and also between 50BSA/50ALG-Fol and 40BSA/60ALG-Fol (p = 0.0004). Therefore, no correlation between the amount of BSA in the nanoparticles and the extent of folate on their surface was established. According to these results, the compositions 30BSA/70ALG-Fol and 50BSA/50ALG-Fol were finally chosen for further studies due to their greater content of incorporated folate. Morphology, Size and Z-Potential of Nanoparticles The morphology of 30BSA/70ALG and 50BSA/50ALG Nps was analyzed by TEM. Micrographs showed nanometric-range sized particles (<100 nm), with a spherical appearance. This morphology was maintained after folate conjugation (Figure 1). These nanoparticles were also analyzed using quasi-elastic light scattering to characterize them in terms of mean size and surface charge ( Table 2). The results showed that all synthesized systems had a nanometric size in the range of 169 ± 28 nm and 296 ± 57 nm and a polydispersity index between 1.2 ± 0.4 and 1.8 ± 0.4. Moreover, an increase in size was observed after the incorporation of folate and the loading of paclitaxel in both nanoparticle compositions. However, these differences in size were not statistically significant. Differences in nanoparticle size among TEM photographs and DLS data can be attributed to the different characteristics of these techniques. In this way, DLS measures are realized in a water solution without stirring, and nanoparticles tend to establish interactions and aggregate, increasing the observed size. These nanoparticles were also analyzed using quasi-elastic light scattering to characterize them in terms of mean size and surface charge ( Table 2). The results showed that all synthesized systems had a nanometric size in the range of 169 ± 28 nm and 296 ± 57 nm and a polydispersity index between 1.2 ± 0.4 and 1.8 ± 0.4. Moreover, an increase in size was observed after the incorporation of folate and the loading of paclitaxel in both nanoparticle compositions. However, these differences in size were not statistically significant. Differences in nanoparticle size among TEM photographs and DLS data can be attributed to the different characteristics of these techniques. In this way, DLS measures are realized in a water solution without stirring, and nanoparticles tend to establish interactions and aggregate, increasing the observed size. Results of Z-potential analysis ( Table 2) showed a negative charge at the surface of all the tested compositions, like the results obtained in similar studies. The negative value of this parameter was increased after the conjugation of folic acid and the incorporation of PTX in both formulations, those differences were statistically significant. Estimation of PTX Content in Folate-Conjugate Nanoparticles The estimation of PTX content in each formulation was determined by two methods: extraction with ethanol and enzymatic degradation using trypsin ( Table 3). Independently of the method, results showed statistically significant differences (p < 0.05) in drug content comparing both compositions, showing a higher PTX load in 50BSA/50ALG-Fol nanoparticles. Data: mean ± S.D. (n = 3). a : significant statistical differences p < 0.05 (p = 0.002); b : significant statistical differences p < 0.05 (p = 0.03). PTX Release from Folate-Conjugated Nanoparticles (Nps-Fol) The cumulative release curve of PTX is represented in Figure 2. The maximum PTX release (82% and 88% of drug load) was achieved at 23 and 27 h from 30BSA/70ALG-Fol and 50BSA/50ALG-Fol, respectively. Drug release in the presence of Tween 80 ® occurred quickly in the first 4 h (Table 4), followed by a slower release rate in both types of nanosystem. In both stages of drug delivery, the release of PTX was faster from the 50BSA/50ALG-Fol composition. The PTX release was also evaluated in a Tween 80 ® free medium at 74 h. In this ex perimental condition, only 16% and 23% of the PTX load was released from The PTX release was also evaluated in a Tween 80 ® free medium at 74 h. In this experimental condition, only 16% and 23% of the PTX load was released from 50BSA/50ALG-Fol and 30BSA/70ALG-Fol, respectively. Cellular Uptake of Nanoparticles To evaluate the uptake of the synthesized nanosystems by cells, three different human tumor cell lines, MCF-7, MDA-MB-231 and HeLa, were selected. BSA/ALG-Fol nanoparticles and BSA/ALG nanoparticles were loaded with a fluorescent marker (6-coumarin) and added to cells in order to study their cellular uptake. The fluorescent signal into cells was quantified after 2, 4 and 24 h of incubation. Results are shown in Figure 3. As results showed, either targeted or non-targeted systems were internalized in cells. However, folateconjugated nanoparticles enhanced their uptake in the three cell lines. The 50BSA/50ALG nanoparticles were less internalized than 30BSA/70ALG. Besides the quantitative assay, the internalization of these systems was easily observed due to the green fluorescence of coumarin attached to the particles. Figure 3 shows the uptake when they were functionalized with folate (BSA50/50ALG-Fol) for 4 h, as an example of the images obtained. Besides the quantitative assay, the internalization of these systems was easily observed due to the green fluorescence of coumarin attached to the particles. Figure 3 shows the uptake when they were functionalized with folate (BSA50/50ALG-Fol) for 4 h, as an example of the images obtained. Both unloaded nanoparticles (50BSA/50ALG-Fol and 30BSA/70ALG-Fol) were cytocompatible and no significant decrease in viability (cell survival between 91% ± 6% and 89% ± 3% for MCF7; 83% ± 5% and 84% ± 13% for MDA-MB-231; 100% ± 3% and 100% ± 12% for HeLa) was observed for the three tested cell lines at longer times of exposure. Cell Viability PTX administered into 50BSA/50ALG-Fol and 30BSA/70ALG-Fol nanoparticles ( Figure 4) caused a more gradual decrease in cell viability than PTX in solution from the first day, at the highest drug concentration assayed for MCF7, MDA-MB-231 and HeLa cells. PTX administered into 50BSA/50ALG-Fol and 30BSA/70ALG-Fol nanoparticles (Figure 4) caused a more gradual decrease in cell viability than PTX in solution from the first day, at the highest drug concentration assayed for MCF7, MDA-MB-231 and HeLa cells. Discussion Paclitaxel (PTX) is one of the most common drugs used for the treatment of different types of solid tumors. PTX acts by promoting microtubule polymerization by binding to the -subunit of tubulins, which causes mitotic arrest at the G2/M phase and results in cell death by the apoptosis pathway. Besides this, PTX exhibits cytotoxic properties that lead to the inhibition of cellular growth. Both characteristics contribute to the antitumor efficacy of PTX. Since it is a hydrophobic drug, a vehicle is required to dissolve it, which causes numerous side effects, limiting its optimal clinical utility as an anticancer agent. For this reason, different nanocarriers have been prepared to improve the safety, efficacy and pharmacokinetic profile of PTX. Thus, in recent studies PTX has been encapsulated in nanoparticles, liposomes and polymeric micelles. On the other hand, the folate receptor is overexpressed on many tumors. The FR isoform is the most widely expressed of all the FR isoforms and is overexpressed (100-300 times more than in healthy cells) in a large number of cancers of epithelial origin. Besides this, the high binding affinity (K D = 0.1-1 nM) of FR for folic acid and other oxidized folates has led to the development of folate-conjugated nanosystems for targeting cancer cells. For these reasons, folic acid was selected to target tumor cells with folate-bounded drug-loaded BSA/ALG nanoparticles. Composition, Characterization and PTX Release from Folate-Conjugated Nanoparticles Nanoparticles of different BSA/ALG composition, cross-linked with ethylenediamine (ED), were synthesized. BSA was better incorporated in 30BSA/70ALG (BSA:ALG 1:1) nanoparticles; meanwhile, alginate was similarly incorporated in all compositions, which can be attributed, at least in part, to the formation of amide bonds between ED and carboxylic groups of both ALG and BSA (each BSA molecule has 58 residues of Glu and 41 residues of Asp). TGA results confirmed the different ratio of polymers incorporated in each Np composition and could also indicate the chemical interaction between both polymers in Np. Covalent attachment of folic acid to the three systems was achieved. There was no correlation between the amount of BSA in the nanoparticles and the extent of folate on their surface. Whereas 30BSA/70ALG-Fol and 50BSA/50ALG-Fol nanoparticles bound a similar amount of folic acid (FA), 40BSA/60ALG-Fol nanoparticles showed a significantly lower amount of FA attached. This fact could be related to the disposition of the amine groups of the side chain of amino acids in the nanoparticles; one BSA molecule has 60 residues of Lys and 26 residues of Arg, which can participate in FA attaching. Thus, the low amount of FA attached was the main reason to reject 40BSA/60ALG-Fol nanoparticles for later experiments. TEM micrographs showed spherical, nano-sized particles without significant differences between nanoparticles of different BSA/ALG composition or those that were FA-bounded and not. The size of the unloaded nanosystems, determined by DLS (Table 2), was larger, but not statistically significantly so, for 50BSA/50ALG-Fol (268 ± 102 nm) than for 30BSA/70ALG-Fol (189 ± 81 nm), which could be due to the larger proportion of alginate in those nanoparticles, which would induce a higher swelling of the systems. However, the value of the polydispersity index was the same for both types of nanoparticles, and it was like the values obtained for other polymeric systems. The Z-potential value of all studied nanosystems was negative ( Table 2). The presence of alginate in 30BSA/70AGL and 50BSA/50ALG nanoparticles showed lightly negative Z-potential values. The FA-bounded nanosystems significantly increased Z-potential values (−69.3 mV and −66.2 mV for 30BSA/70ALG-Fol and 50BSA/50ALG-Fol, respectively), which were very much larger than −30 mV, the Z-potential value (positive or negative value) that has been established as the minimum for obtaining a physically stable nanosuspension and avoiding nanoparticle aggregation. Besides this, when these nanosystems were loaded with PTX, Z-potential was of the same magnitude for PTX-loaded 30BSA/70ALG-Fol, and significantly larger (−94.1 mV) for PTX-loaded 50BSA/50ALG-Fol. This increase could be explained by the possible superficial distribution of part of the drug on the nanosystem. Thus, the low tendency to establish interactions among them, indicated by the Z-potential value of these unloaded and PTX-loaded FA-attached nanosystems, make them very suitable for later in vivo intravenous administration studies. The PTX load of Fol-nanosystems was determined by extraction with ethanol and afterward by the enzymatic digestion of the nanoparticles with trypsin (Table 3). No differences were observed among the results obtained by both methods. Regardless of the method used, the PTX load of 50BSA/50ALG-Fol was larger (3.56-3.28 g PTX/mg Np) than that of 30BSA/70ALG-Fol (2.63-2.42 g PTX/mg Np). Interactions between PTX and nanosystems seem to be very similar in both types of nanoparticles since the value of the PTX load obtained by the two methods is almost the same. These observed results were in contrast with the expected results, where the drug load determined by ethanol extraction should be lower than that obtained by enzymatic digestion in the case of high PTX-nanoparticle interaction. The PTX release studies showed a prolonged and faster drug release from 50BSA/50ALG-Fol nanoparticles; PTX release took place in two stages from both types of nanosystems ( Figure 3). The first stage of release was during the first four hours (Table 4), and the release was faster from 50BSA/50ALG-Fol, which could be related to a part of the drug being located more superficially as indicated by the Z-potential values. A second stage of drug release was determined up to 27 h, and PTX release was faster from 50BSA/50ALG-Fol. In no case was the total amount of the PTX load released: 88% of the PTX load was released from 50BSA/50ALG-Fol and 82% of it from 30BSA/70ALG-Fol. In all these experiments, the release conditions were favored by the presence of Tween 80 ® in the medium; however, in the absence of the surfactant, an experimental condition closer to biological systems, a slower release occurred, which would make possible a significant amount of PTX loaded into the nanoparticle-Fol to be delivered to cancer cells in vivo. Similar in vitro PTX release behavior was observed when that drug was released from nanohydrogels. In that case, a maximum release took place at 50 h, and it caused a significant decrease in cell viability of human cancer cell lines. These PTX-loaded nanoparticulated systems were subcutaneously injected in female athymic nude mice bearing HeLa human tumor xenografts, and they showed higher antitumor activity than PTX in solution. Equivalently, tamoxifen-loaded folate-targeted protein/polysaccharide-based nanoparticles, which released the drug in the first 8 h in in vitro studies, were demonstrated to be highly effective in tumor remission assays in MCF7 cell xenograft mice after intravenous administration. In that case, although in vitro drug release from nanoparticulated and folate-targeted nanoparticulated systems took place faster, the results obtained in xenograft models demonstrated the effectiveness of these types of nanosystems as an antitumoral therapy. In order to determine the predominant drug release mechanism from BSA/ALG-Fol nanoparticles, the obtained data were fitted to different physical models with a significant correlation coefficient (r 2 = 0.791-0.979) (Supplementary Materials; Table S2). According to the results, the PTX release kinetics from 50BSA/50ALG-Fol nanoparticles fitted in the order of Korsemeyer-Peppas = Higuchi = First Order > Zero Order; PTX release from 30BSA/70ALG-Fol nanoparticles fitted in the order of Korsemeyer-Peppas > Higuchi > First Order > Zero Order. The Higuchi model indicates drug diffusion from the matrix, with no matrix dissolution and constant drug diffusivity. The release of PTX from 30BSA/70ALG-Fol nanoparticles showed the lowest value of K H, which implies a slower release in comparison with 50BSA/50ALG-Fol nanoparticles. An equivalent behavior has been observed for the release of naproxen from cyclodextrin-based hydrogel matrices. The release of PTX was favored by the swelling capability of the nanoparticles, which made the diffusion of the entrapped drug easier. In the case of the Korsemeyer-Peppas model, the nanosystems showed values of the release exponent (n) different from the standard value for declaring Fickian release behavior (n = 0.43; considering spherical shape). This was 0.36 and 0.70 for 30BSA/70ALG-Fol and 50BSA/50ALG-Fol nanoparticles, respectively. The values of the n parameter lower than 0.43 can be related to a dispersion of nanoparticle sizes. For spherical particles, when the n value is between 0.43 and 0.85, an anomalous transport (non-Fickian; intermediate between Fickian and Case II transport, zero order) is considered, and then a mixed diffusion and chain relaxation mechanism takes place, which happened for PTX release from 50BSA/50ALG-Fol. This nanoparticle composition presents an acceptable fitting to the first order kinetic model. In Vitro Evaluation of Folate-Conjugated Nanoparticles in Tumor Cell Lines The presence of FRs in several human solid tumors, such as breast cancer, has been clearly demonstrated. Thus, these receptors provide an interesting therapeutic target for solid tumor treatment. PTX is widely used as a first-line treatment for patients with breast cancer. The cancer cell lines of human breast adenocarcinoma MCF-7 and MDA-MB-231 express a low and high level of folate receptor, respectively. However, whereas MCF-7 cells express estrogen receptors (ER), MDA-MB-231 cells are triple negative breast cancer (TNBC) cells; they do not express ER, progesterone receptor (PR) or the amplification of HER-2/Neu. Besides this, among the drugs used to treat stage IVB cervical cancer is PTX. HeLa cells are human cervical carcinoma cells, positive for FR, adequate to study the efficacy of these folate-targeted PTX-loaded BSA/ALG nanocarriers. Therefore, these three different cellular lines expressing folate receptors (FRs) were chosen for evaluating the effectiveness of these BSA/ALG-Fol nanoparticles. Different studies carried out by our group and other research have shown that MCF7, MDA-MB-231 and HeLa cells express different levels of FRs on their surface, meaning they can be used as an in vitro test of folate-targeted nanosystem efficacy. In general, good cytocompatibility values were obtained with the two compositions of BSA/ALG-Fol nanoparticles for the three cell lines, although a slightly lower value was observed for MDA-MB-231 cells, which can be attributed to the larger amount of nanoparticles in the experiments with this cell line. Therefore, the uptake of unloaded nanoparticle-Fol observed in these cell lines seemed not to be harmful even after six days of incubation. The presence of FRs on the cell surface led to a larger uptake in these cell lines for both nanoparticle-Fol compositions in comparison with the corresponding nanoparticle composition without folic acid bounded on their surface. A larger amount of folate receptors on the cell surface made nanoparticle-Fol uptake easier as fluorescence images of HeLa cells showed. The uptake of Nps without FA on their surface revealed there was a nonspecific uptake mechanism that would act in addition to FR-mediated internalization. In this way, different studies indicate that negative-charged nanoparticles showed high cellular uptake due to electrostatic interactions established with some parts of the cellular membrane, which would be in accordance with the negative values of the Z-potential of these BSA/ALG nanoparticles. This nonspecific uptake was lower in the case of 50BSA/50ALG nanoparticles in the three cell lines studied, and so they would be less internalized into cells without FR on their surface, like non-cancer cells. PTX-loaded nanoparticle-Fol caused a gradual decrease in cell viability values when PTX was released from both nanosystems, mainly at a higher PTX load (7.5 nM PTX for MCF7 and HeLa; 30 nM for MDA-MB-231) at a longer time of incubation. Significant differences in decreasing viability were not observed between PTX-loaded 50BSA/50ALG-Fol and 30BSA/70ALG-Fol nanoparticles in all cell lines studied. Although viability values obtained in the presence of PTX-loaded nanoparticle-Fol were similar to those of PTX in solution, it must be taken into account that the PTX amount within the cells treated with PTX-loaded nanosystems-Fol will be lower than the amount of drug available in cells treated with PTX solutions, in accordance with in vitro drug release studies. Once PTXloaded nanoparticle-Fol was taken up into cells via the FR-mediated endocytosis pathway, the unligate FR may then recycle to the cell surface at a rate in the range of 0.5-5 h. It is believed that more nanoparticles were taken up into the cells; PTX release would have take place mainly after the enzymatic degradation of nanoparticles, which would have caused a delay in the cytotoxic action of PTX-loaded nanoparticle-Fol compared to PTX in solution. Conclusions The prepared folate-targeted PTX-BSA/ALG nanoparticles seem to be a promising alternative to the conventional use of Cremophor ® EL and would reduce the drug re-sistance problem mediated by P-gp. Preliminary cellular assays have demonstrated the effectiveness of these nanosystems against cancer cells overexpressing surface folate receptors. In this respect, a reduction in cell survival was observed in a cervical carcinoma cell line, a breast adenocarcinoma ER+ cell line and a TNBC cell line, which causes a very aggressive cancer type with a difficult treatment. These results allow us to think that the synthesized folate-targeted PTX-BSA/ALG nanoparticles could be considered for further in vivo biocompatibility and tumor growth suppression studies. Data Availability Statement: The data presented in this study are available on request from the corresponding author. |
Hike by candlelight at Whitefish Dunes, ride a chairlift to watch the sunset on Rib Mountain and more to do around Wisconsin this week.
Algoma: Soar on the Shore. Watch professionals fly kites along Crescent Beach from 11 a.m. to 4 p.m. Aug. 18. There will also be food and drinks, raffles and activities for kids. See visitalgomawi.com.
Minocqua: Dragon Boat Festival. Cheer on teams of dragon boat paddlers on Lake Minocqua on Aug. 18. There will also be food and beverages for sale and kids' activities at Torpy Park. See minocquadragonboat.com.
Oconomowoc: Midwest Paddle Festival. This standup paddleboarding festival Aug. 18 at Village Green Park will include races, clinics, free demos, yoga, raffles and more. Admission is $10 for non-racers. See paddleboardspecialists.com.
Sturgeon Bay: Candlelight Hike. Walk along Whitefish Dunes State Park's Red Trail by candlelight from 7:30 to 9:30 p.m. Aug. 18, then enjoy popcorn and lemonade courtesy of the Friends groups. Pets are not permitted. See wiparks.net.
Wausau: Sunset Rides. Hop on the chairlift at the Granite Peak Ski Area for a sunset ride up Rib Mountain on Fridays and Saturdays, Aug. 17-Sept. 15. Rides are offered from 3 to 8 p.m. Tickets are $12 for adults, $8 for kids ages 6-12 and free for kids ages 3-5. See skigranitepeak.com. |
package edu.iit.hawk.atolentino.ride_management;
import static org.junit.jupiter.api.Assertions.*;
import java.text.ParseException;
import java.util.Iterator;
import org.junit.jupiter.api.AfterEach;
import org.junit.jupiter.api.BeforeEach;
import org.junit.jupiter.api.Nested;
import org.junit.jupiter.api.Test;
import edu.iit.hawk.atolentino.message_management.entities.Message;
import edu.iit.hawk.atolentino.request_information_processing.boundaries.PatchType;
import edu.iit.hawk.atolentino.request_information_processing.entities.JoinRequestInformation;
import edu.iit.hawk.atolentino.request_information_processing.entities.MessageInformation;
import edu.iit.hawk.atolentino.request_information_processing.entities.RideInformation;
import edu.iit.hawk.atolentino.request_information_processing.entities.UpdateJoinRequestInformation;
import edu.iit.hawk.atolentino.ride_management.boundaries.RideUtilities;
import edu.iit.hawk.atolentino.ride_management.interactors.RideManager;
public class RideManagerTest {
private RideManager rideManager;
private RideInformation rideInformation;
private int rid;
private static final int AID = 19;
private static final String FROM_CITY = "Barrington";
private static final String FROM_ZIP = "60010";
private static final String TO_CITY = "Milwaukee";
private static final String TO_ZIP = "53202";
private static final String DATE = "14-Apr-2020";
private static final String TIME = "09:00";
private static final String MAKE = "Audi";
private static final String MODEL = "A4";
private static final String COLOR = "Gray";
private static final String PLATE_STATE = "IL";
private static final String PLATE_SERIAL = "COVID19";
private static final int MAX_PASSENGERS = 2;
private static final double AMOUNT_PER_PASSENGER = 15.00;
private static final String CONDITIONS = "No more than one carry on per passenger. No pets.";
private boolean doesRideInformationMatch(RideUtilities r, RideInformation rideInformation) {
return (
r.getAid() == rideInformation.getAid() &&
r.getFromCity().equals(rideInformation.getFromCity()) &&
r.getFromZip().equals(rideInformation.getFromZip()) &&
r.getToCity().equals(rideInformation.getToCity()) &&
r.getToZip().equals(rideInformation.getToZip()) &&
r.getDate().equals(rideInformation.getDate()) &&
r.getTime().equals(rideInformation.getTime()) &&
r.getMake().equals(rideInformation.getMake()) &&
r.getModel().equals(rideInformation.getModel()) &&
r.getColor().equals(rideInformation.getColor()) &&
r.getPlateState().equals(rideInformation.getPlateState()) &&
r.getPlateSerial().equals(rideInformation.getPlateSerial()) &&
r.getAmountPerPassenger().equals(rideInformation.getAmountPerPassenger()) &&
r.getConditions().equals(rideInformation.getConditions())
);
}
@BeforeEach
void init() {
rideManager = new RideManager();
}
@Test
void test_searchRide_defaultGivenEmptyStringKeys_isEmpty() {
Iterator<RideUtilities> iterator = rideManager.searchRide("", "", "");
assertFalse(iterator.hasNext());
}
@Test
void test_getRidesBetweenStartDateAndEndDate_defaultGivenEmptyStringDates_isEmpty() {
assertDoesNotThrow(() -> {
Iterator<RideUtilities> iterator = rideManager.getRidesBetweenStartDateAndEndDate("", "");
assertFalse(iterator.hasNext());
});
}
@Nested
class AddRideTest {
@BeforeEach
void init() {
rideInformation = new RideInformation(
AID,
FROM_CITY,
FROM_ZIP,
TO_CITY,
TO_ZIP,
DATE,
TIME,
MAKE,
MODEL,
COLOR,
PLATE_STATE,
PLATE_SERIAL,
MAX_PASSENGERS,
AMOUNT_PER_PASSENGER,
CONDITIONS
);
rid = rideManager.addRide(rideInformation);
}
@AfterEach
void clean() {
rideManager.deleteRide(rid);
}
@Test
void test_updateRide_givenNewRideInformation_shouldUpdateRideInformation() {
String fromCity = "Chicago";
String fromZip = "60616";
String toCity = "Rockford";
String toZip = "";
String date = "30-Apr-2020";
String time = "15:00";
RideInformation rideInformation = new RideInformation(
AID,
fromCity,
fromZip,
toCity,
toZip,
date,
time,
MAKE,
MODEL,
COLOR,
PLATE_STATE,
PLATE_SERIAL,
MAX_PASSENGERS,
AMOUNT_PER_PASSENGER,
CONDITIONS
);
rideManager.updateRide(rid, rideInformation);
assertTrue(doesRideInformationMatch(rideManager.getRide(rid), rideInformation));
}
@Test
void test_searchRide_givenFROMCITY_shouldContainRID() {
Iterator<RideUtilities> iterator = rideManager.searchRide(FROM_CITY, "", "");
RideUtilities ride = null;
while(iterator.hasNext()) {
ride = iterator.next();
}
assertEquals(rid, ride.getRid());
}
@Test
void test_searchRide_givenFROMZIP_shouldContainRID() {
Iterator<RideUtilities> iterator = rideManager.searchRide(FROM_ZIP, "", "");
RideUtilities ride = null;
while(iterator.hasNext()) {
ride = iterator.next();
}
assertEquals(rid, ride.getRid());
}
@Test
void test_searchRide_givenNotUsedFromKey_shouldNotContainRID() {
Iterator<RideUtilities> iterator = rideManager.searchRide("blah", "", "");
assertFalse(iterator.hasNext());
}
@Test
void test_searchRide_givenTOCITY_shouldContainRID() {
Iterator<RideUtilities> iterator = rideManager.searchRide("", TO_CITY, "");
RideUtilities ride = null;
while(iterator.hasNext()) {
ride = iterator.next();
}
assertEquals(rid, ride.getRid());
}
@Test
void test_searchRide_givenTOZIP_shouldContainRID() {
Iterator<RideUtilities> iterator = rideManager.searchRide("", TO_ZIP, "");
RideUtilities ride = null;
while(iterator.hasNext()) {
ride = iterator.next();
}
assertEquals(rid, ride.getRid());
}
@Test
void test_searchRide_givenNotUsedToKey_shouldNotContainRID() {
Iterator<RideUtilities> iterator = rideManager.searchRide("", "blah", "");
assertFalse(iterator.hasNext());
}
@Test
void test_searchRide_givenDATE_shouldContainRID() {
Iterator<RideUtilities> iterator = rideManager.searchRide("", "", DATE);
RideUtilities ride = null;
while(iterator.hasNext()) {
ride = iterator.next();
}
assertEquals(rid, ride.getRid());
}
@Test
void test_searchRide_givenNotUsedDateKey_shouldNotContainRID() {
Iterator<RideUtilities> iterator = rideManager.searchRide("", "", "blah");
assertFalse(iterator.hasNext());
}
@Test
void test_searchRide_givenEmptyStrings_shouldContainRID() {
Iterator<RideUtilities> iterator = rideManager.searchRide("", "", "");
RideUtilities ride = null;
while(iterator.hasNext()) {
ride = iterator.next();
}
assertEquals(rid, ride.getRid());
}
@Test
void test_doesRideExist_givenRID_shouldReturnTrue() {
assertTrue(rideManager.doesRideExist(rid));
}
@Test
void test_doesRideExist_givenUnusedRid_shouldReturnFalse() {
assertFalse(rideManager.doesRideExist(-1));
}
@Test
void test_addJoinRequest_shouldBeSavedToRide() {
int aid = 2;
JoinRequestInformation joinRequestInformation = new JoinRequestInformation(aid, 2, null, null);
int jid = rideManager.addJoinRequest(rid, joinRequestInformation);
assertTrue(rideManager.doesJoinRequestExist(rid, jid));
}
@Test
void test_updateRideConfirmed_setToTrueAfterAddingJoinRequest_accountShouldBeARiderOfRide() {
int aid = 2;
JoinRequestInformation joinRequestInformation = new JoinRequestInformation(aid, 2, null, null);
int jid = rideManager.addJoinRequest(rid, joinRequestInformation);
UpdateJoinRequestInformation updateJoinRequestInformation = new UpdateJoinRequestInformation(aid, true, PatchType.RIDE_CONFIRMED);
rideManager.updateRideConfirmed(rid, jid, updateJoinRequestInformation);
assertTrue(rideManager.isAccountRiderOfRide(rid, aid));
}
@Test
void test_updateRideConfirmed_setToFalseAfterAddingJoinRequest_accountShouldNotBeARiderOfRide() {
int aid = 2;
JoinRequestInformation joinRequestInformation = new JoinRequestInformation(aid, 2, null, null);
int jid = rideManager.addJoinRequest(rid, joinRequestInformation);
UpdateJoinRequestInformation updateJoinRequestInformation = new UpdateJoinRequestInformation(aid, false, PatchType.RIDE_CONFIRMED);
rideManager.updateRideConfirmed(rid, jid, updateJoinRequestInformation);
assertFalse(rideManager.isAccountRiderOfRide(rid, aid));
}
@Test
void test_updatePickUpConfirmed_afterAddingJoinRequest_pickUpConfirmShouldBeTrue() {
int aid = 2;
JoinRequestInformation joinRequestInformation = new JoinRequestInformation(aid, 2, null, null);
int jid = rideManager.addJoinRequest(rid, joinRequestInformation);
rideManager.updatePickUpConfirmed(rid, jid);
assertTrue(joinRequestInformation.getPickUpConfirmed());
}
@Test
void test_isAccountRiderOfRide_afterSendingJoinRequest_shouldReturnFalse() {
int aid = 2;
JoinRequestInformation joinRequestInformation = new JoinRequestInformation(aid, 2, null, null);
rideManager.addJoinRequest(rid, joinRequestInformation);
assertFalse(rideManager.isAccountDriverOfRide(rid, aid));
}
@Test
void test_addMessage_shouldBeFoundInGetMessages() {
int aid = 2;
String MSG = "Hello";
int MID = rideManager.addMessage(rid, new MessageInformation(aid, MSG));
Iterator<Message> iterator = rideManager.getMessages(rid);
Message message = null;
while(iterator.hasNext()) {
message = iterator.next();
}
assertEquals(MID, message.getMid());
}
@Test
void test_getMessages_default_isEmpty() {
Iterator<Message> iterator = rideManager.getMessages(rid);
assertFalse(iterator.hasNext());
}
@Test
void test_isAccountDriverOfRide_givenAID_shouldReturnTrue() {
assertTrue(rideManager.isAccountDriverOfRide(rid, AID));
}
@Test
void test_isAccountDriverOfRide_givenNonDriverAid_shouldReturnFalse() {
assertFalse(rideManager.isAccountDriverOfRide(rid, -1));
}
@Test
void test_getRide_givenRID_shouldReturnRideMatchingRID() {
RideUtilities ride = rideManager.getRide(rid);
assertEquals(rid, ride.getRid());
}
@Test
void test_getRideDate_givenRID_shouldReturnDATE() {
assertEquals(DATE, rideManager.getRideDate(rid));
}
@Test
void test_getRidesBetweenStartDateAndEndDate_givenDATEForStartDate_shouldContainRID() {
assertDoesNotThrow(() -> {
Iterator<RideUtilities> iterator = rideManager.getRidesBetweenStartDateAndEndDate(DATE, "");
RideUtilities ride = null;
while(iterator.hasNext()) {
ride = iterator.next();
}
assertEquals(rid, ride.getRid());
});
}
@Test
void test_getRidesBetweenStartDateAndEndDate_givenEmptyString_shouldContainRID() {
assertDoesNotThrow(() -> {
Iterator<RideUtilities> iterator = rideManager.getRidesBetweenStartDateAndEndDate("", "");
RideUtilities ride = null;
while(iterator.hasNext()) {
ride = iterator.next();
}
assertEquals(rid, ride.getRid());
});
}
@Test
void test_getRidesBetweenStartDateAndEndDate_givenEndDateBeforeDATE_shouldNotContainRID() {
assertDoesNotThrow(() -> {
Iterator<RideUtilities> iterator = rideManager.getRidesBetweenStartDateAndEndDate("", "13-Apr-2020");
assertFalse(iterator.hasNext());
});
}
@Test
void test_getRidesBetweenStartDateAndEndDate_givenWrongFormatDate_shouldThrowParseException() {
assertThrows(ParseException.class, () -> {
rideManager.getRidesBetweenStartDateAndEndDate("blah", "blah");
});
}
}
}
|
Diversified Assembly and Application of Optical Fiber Spectrometer: An Instrumental Analysis Experiment : An instrumental analysis experiment Diversified assembly and application of optic fiber spectrometer is recommended for undergraduates. UV-Vis spectrometer, molecular fluorescence spectrometer, near-infrared spectrometer, Raman spectrometer, and laser-induced fluorescence spectrometer can be assembled using light source, fiber, and charge-coupled devices detector, etc. Through the practice of this experiment, the traditional optical experiment is extended. It is helpful for students to cultivate the professional skills and abilities comprehensively by hands-on assembling the optical instruments. |
/**
* An optional ant Task which emulates the Command Line Interface pack200(1).
* Note, only the most commonly used command line options are implemented here,
* users are encouraged to use the configuration file described below to set
* other Pack200 options.
*
* @version %W% %E%
* @author Kumar Srinivasan
*/
public class Pack200Task extends Pack
{
private static final String ERRMSG_ZF = "zipfile attribute must end";
protected static final String COM_PREFIX = "com.sun.java.util.jar.pack.";
private boolean doRepack = false;
private boolean doGZIP = false;
private File p200ConfigFile = null;
// Storage for the properties used by the setters.
private HashMap<String, String> propMap;
public Pack200Task()
{
// Initialize our fields
doRepack = false;
doGZIP = false;
propMap = new HashMap<String, String>();
}
// We validate our own stuff
private void validate()
throws BuildException
{
if (p200ConfigFile != null
&& (!p200ConfigFile.exists() || p200ConfigFile.isDirectory())) {
throw new BuildException("Pack200 property file attribute must "
+ "exist and not represent a directory!", getLocation());
}
if (doGZIP) {
if (!zipFile.toString().toLowerCase().endsWith(".gz")) {
throw new BuildException(ERRMSG_ZF + " with .gz extension",
getLocation());
}
} else if (doRepack) {
if (!zipFile.toString().toLowerCase().endsWith(".jar")) {
throw new BuildException(ERRMSG_ZF + " with .jar extension",
getLocation());
}
} else {
if (!zipFile.toString().toLowerCase().endsWith(".pack")
&& !zipFile.toString().toLowerCase().endsWith(".pac")) {
throw new BuildException(ERRMSG_ZF
+ "with .pack or .pac extension", getLocation());
}
}
}
/**
* Sets the repack option, ie the jar will be packed and repacked.
*/
public void setRepack(boolean value)
{
doRepack = value;
}
/**
* Sets whether the pack archive is additionally deflated with gzip.
*/
public void setGZIPOutput(boolean value)
{
doGZIP = value;
}
/**
* Sets whether the java debug attributes should be stripped
*/
public void setStripDebug(String value)
{
propMap.put(COM_PREFIX + "strip.debug", value);
}
/**
* Sets the modification time for the archive
*/
public void setModificationTime(String value)
{
propMap.put(Packer.MODIFICATION_TIME, value);
}
/**
* Sets the deflate hint for the archive
*/
public void setDeflateHint(String value)
{
propMap.put(Packer.DEFLATE_HINT, value);
}
/**
* Sets the file ordering.
*/
public void setKeepFileOrder(String value)
{
propMap.put(Packer.KEEP_FILE_ORDER, value);
}
/**
* Sets the segment limit.
*/
public void setSegmentLimit(String value)
{
propMap.put(Packer.SEGMENT_LIMIT, value);
}
/**
* Sets the effort.
*/
public void setEffort(String value)
{
propMap.put(Packer.EFFORT, value);
}
/**
* Sets the action to be taken if an unknown attribute is encountered.
*/
public void setUnknownAttribute(String value)
{
propMap.put(Packer.UNKNOWN_ATTRIBUTE, value);
}
/**
* Useful to set those Pack200 attributes which are not commonly used.
*/
public void setConfigFile(File packConfig)
{
p200ConfigFile = packConfig;
}
/**
* Set the verbosity level.
*/
public void setVerbose(String value)
{
propMap.put(COM_PREFIX + "verbose", value);
}
protected void pack()
{
/* remove extraneous logging
* this should be using some kind of ant logging service anyway
String statusStr = doRepack ? "Repack with Pack200"
: "Packing with Pack200";
System.out.println(statusStr + " " + source);
System.out.println("Source File :" + source);
System.out.println("Dest. File :" + zipFile);
if (p200ConfigFile != null)
System.out.println("Config file :" + p200ConfigFile);
*/
this.validate();
File packFile = zipFile;
try {
Pack200.Packer pkr = Pack200.newPacker();
pkr.properties().putAll(propMap);
// The config file overrides all.
if (p200ConfigFile != null) {
InputStream is = new BufferedInputStream(new FileInputStream(
p200ConfigFile));
Properties pFile = new Properties();
pFile.load(is);
is.close();
for (Map.Entry me : pFile.entrySet())
pkr.properties().put((String) me.getKey(),
(String) me.getValue());
}
if (doRepack) {
doGZIP = false;
packFile = new File(zipFile.toString() + ".tmp");
}
JarFile jarFile = new JarFile(source);
FileOutputStream fos = new FileOutputStream(packFile);
OutputStream os = (doGZIP) ? new BufferedOutputStream(
new GZIPOutputStream(fos)) : new BufferedOutputStream(fos);
pkr.pack(jarFile, os);
os.close();
jarFile.close();
if (doRepack) {
InputStream is = new BufferedInputStream(new FileInputStream(
packFile));
JarOutputStream jout = new JarOutputStream(
new BufferedOutputStream(new FileOutputStream(zipFile)));
Pack200.Unpacker unpkr = Pack200.newUnpacker();
unpkr.properties().putAll(propMap);
// The config file overrides all.
if (p200ConfigFile != null) {
InputStream pc_is = new BufferedInputStream(
new FileInputStream(p200ConfigFile));
Properties pFile = new Properties();
pFile.load(pc_is);
pc_is.close();
for (Map.Entry me : pFile.entrySet()) {
unpkr.properties().put((String) me.getKey(),
(String) me.getValue());
}
}
unpkr.unpack(is, jout);
is.close();
jout.close();
}
} catch (IOException ioe) {
ioe.printStackTrace();
throw new BuildException("Error in pack200", ioe);
} finally {
if (doRepack)
packFile.delete();
}
}
/**
* @param pack200Jar
*/
public void setDestfile(File pack200Jar)
{
zipFile = pack200Jar;
}
} |
(New York)- Even though the Chilean armed forces have admitted responsibility in the deaths of some 200 people who "disappeared" under military rule, the Chilean courts should continue to prosecute those and all other cases of the "disappeared," Human Rights Watch said today.
Chilean courts have managed to prosecute cases of the "disappeared" despite the 1978 decree granting amnesty to the armed forces for such crimes. The courts have used a jurisprudential rule that establishes a "disappearance" as a continuing crime -- one that extends beyond the period of military rule because the victims have never been found and therefore the criminal act is still underway. Some have argued that information on the victims' deaths means the amnesty decree should terminate ongoing prosecutions.
Human Rights Watch said that the information provided by the military was cryptic, and far too sparse in most cases to allow the courts to verify it. While the place where the bodies were dumped is approximated, there are no details regarding the date when the prisoners or their corpses were disposed of, whether boats or air transport were used, how the prisoners met their deaths, or what happened to their bodies after they were killed.
"It is a step forward for the armed forces to have finally owned up to what they must have known all along," said Jos?Miguel Vivanco, executive director of the Americas division of Human Rights Watch. "But without independent confirmation, no judges worth their salt could possibly close an investigation on the basis of this information. To award officers an amnesty when there is still no proof of death other than the armed forces' word would add insult to the anguish of the relatives."
The armed forces recently released a report describing the fate of 200 victims, in fulfillment of a government-sponsored agreement with human rights lawyers signed last June. Among the report's revelations was that the armed forces dumped the bodies of more than 150 prisoners into the ocean, rivers and lakes of Chile. Most of the cases included in the armed forces' list date from the first six months of the military government, before the repression was placed in the hands of a centralized apparatus, the secret police known as the DINA.
"The information is a devastating confirmation of the armed forces' responsibility for horrifying atrocities," said Vivanco. "It is particularly important as it represents the first details the armed forces have ever given about their terrible crimes, which have left deep scars in Chile."
Human Rights Watch urged President Lagos to take further steps to find the missing information, and to clarify the fate of hundreds of prisoners who "disappeared" after their abduction by the DINA, which responded ultimately to General Pinochet alone. To do this, the government must search for new methods to ensure cooperation, such as penalizing those who conceal information, or providing benefits to those who cooperate, while taking care that the courts are given the resources and support they need to investigate these horrific crimes and bring those responsible to justice. |
Mother and ChildT Cell Receptor Repertoires: Deep Profiling Study The relationship between maternal and child immunity has been actively studied in the context of complications during pregnancy, autoimmune diseases, and haploidentical transplantation of hematopoietic stem cells and solid organs. Here, we have for the first time used high-throughput Illumina HiSeq sequencing to perform deep quantitative profiling of T cell receptor (TCR) repertoires for peripheral blood samples of three mothers and their six children. Advanced technology allowed accurate identification of 5105 to 2106 TCR beta clonotypes per individual. We performed comparative analysis of these TCR repertoires with the aim of revealing characteristic features that distinguish related mother-child pairs, such as relative TCR beta variable segment usage frequency and relative overlap of TCR beta complementarity-determining region 3 (CDR3) repertoires. We show that thymic selection essentially and similarly shapes the initial output of the TCR recombination machinery in both related and unrelated pairs, with minor effect from inherited differences. The achieved depth of TCR profiling also allowed us to test the hypothesis that mature T cells transferred across the placenta during pregnancy can expand and persist as functional microchimeric clones in their new host, using characteristic TCR beta CDR3 variants as clonal identifiers. In recent years, the potential of next-generation sequencing (NGS) to reveal the full complexity of human and mouse immune receptor repertoires has inspired numerous efforts to develop optimal techniques for achieving large-scale T cell receptor (TCR) and antibody profiling and to decipher various aspects of adaptive immunity (8,9,11,. With appropriate library preparation methods, NGS techniques now make it possible to perform quantitative analysis of hundreds of thousands or millions of distinct TCR beta complementarity-determining region 3 (CDR3) variants. This individual diversity of TCR beta CDR3 variants, which is generated in the course of V-D-J recombination and the random addition and deletion of nucleotides in the thymus, largely determines the whole diversity of nave T cells and specificity of T cell immune responses. In the present study, we have used deep NGS profiling to compare TCR beta repertoires of mothers and their children. We achieved a profiling depth of 500,000-2,000,000 unique TCR beta CDR3 clonotypes per donor, and performed comparative analysis with the aim of revealing specific features of TCR repertoires that distinguish related mother-child pairs from unrelated individuals, and how these familial repertoires manifest the influence of inherited factors, such as the elements of TCR recombination machinery and human leukocyte antigens (HLA). By comparing out-of-frame (i.e., non-functional and thus not subjected to selection) and in-frame TCR beta repertoires, we also show the extent of the impact of thymic selection and the common trends in how this process shapes individual repertoires. Additionally, the profiling depth that we achieved allowed us to look for the potential presence of maternal or fetal microchimeric T cell clones that may have transmigrated through the placenta as mature / T cells and which subsequently persist in both related donors, by using characteristic TCR beta CDR3 variants as clonal identifiers. SAMPLE COLLECTION This study was approved by the ethical committee of the Federal Scientific Clinical Center of Pediatric Hematology, Oncology, and Immunology. Blood donors provided informed consent prior to participating in the study. Ten milliliters of peripheral blood samples were obtained from nine systemically healthy Caucasian donors: three mothers (average age 40 ± 4 years) and their six children (average age 11 ± 4 years). Peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll-Paque (Paneco, Russia) density gradient centrifugation. Total RNA was isolated with Trizol (Invitrogen, USA) in accordance with the manufacturer's protocol. CONTAMINATION PRECAUTIONS T cell receptor beta libraries were generated in clean PCR hoods with laminar flow, using reagents of high purity and pipette tips with hydrophobic filters. As an additional precaution, we generated the TCR beta libraries for the two groups being comparedmothers and their children -a month apart, and sequenced the two libraries in two separate Illumina runs to guarantee the absence of inter-library contamination during amplification or on the solid phase of the sequencer. PREPARING cDNA LIBRARIES FOR QUANTITATIVE TCR BETA PROFILING cDNA-based library preparation was performed essentially as described previously. Briefly, we used the Mint kit (Evrogen, Russia) for first-strand cDNA synthesis. For each donor sample, the whole amount of extracted RNA was used for cDNA synthesis, with 1.5 g of RNA per 15 l reaction volume. We incubated the mixture of RNA and priming oligonucleotide BC_R4_short (GTATCTGGAGTCATTGA), which is specific to both variants of the human TCR beta constant (TRBC) segment, at 70°C for 2 min and 42°C for 2 min for annealing. We then added the 5 -adapter for the template switch. The reaction was carried out at 42°C for 2 h, with 5 l of IP solution added after the first 40 min. Further cDNA library amplification was performed in two sequential PCRs using Encyclo PCR mix (Evrogen). To capture the maximum number of input cDNA molecules, we used the whole amount of synthesized cDNA for the first PCR amplification. The first PCR totaled 18 cycles with universal primers M1SS (AAGCAGTGGTATCAACGCA) and BC2R (TGCTTCT-GATGGCTCAAACAC), which are respectively specific to the 5adapter and a nested region of the TRBC segments. The primer annealing temperature was set at 62°C. The products of the first PCR were combined, and a 100-l aliquot was purified by QIAquick PCR purification Kit (Qiagen) and eluted by 20 l of EB buffer. The second PCR amplification was performed for 8-10 cycles with a mix of TCR beta joining (TRBJ)-specific primers and the universal primer M1S ((N) 2-4 (XXXXX)CAGTGGTATCAACGCA GAG), which is specific to the 5 -adapter and is nested relative to the M1SS primer used in the first PCR amplification. XXXXX represents a sample barcode introduced in the second PCR, and (N) 2-4 are random nucleotides that were added in order to generate diversity for better cluster identification during Illumina sequencing. Primer annealing temperature was set at 62°C. ILLUMINA HiSeq SEQUENCING PCR products carrying pre-introduced sample barcodes were mixed together in equal ratio for each of the two groups (mothers and children). Illumina adapters were ligated according to the manufacturer's protocol using NEBNext DNA Library Prep Master Mix Set for Illumina (New England Biolabs, USA). Generated libraries were analyzed using two separate Illumina HiSeq 2000 lanes in separate runs with 100 + 100 nt paired end sequencing using Illumina sequencing primers. Raw sequences deposited in NCBI SRA database (PRJNA229070). NGS DATA ANALYSIS TCR beta variable (TRBV) segment identification , CDR3 identification (based on the sequence between conserved Cys-104 and Phe-118, inclusive), clonotype clusterization and correction of reverse transcription, PCR, and sequencing errors were performed using our MiTCR software 1. The sequencing quality threshold of each nucleotide within the CDR3 region was set as Phred >25, with low-quality sequence rescue by mapping to high-quality clonotypes. The strictest "eliminate these errors" correction algorithm was employed to eliminate the maximal number of accumulated PCR and sequencing errors. STATISTICAL ANALYSIS We used Jensen-Shannon divergence (JS), which is a symmetrized version of the Kullback-Leibler divergence (KL), to quantify the similarity between the clonotype TRBV gene usage distribution in related and unrelated mother-child pairs. JS and KL are defined as follows : Where P and Q correspond to the TRBV gene segment frequency distributions of the two individuals being analyzed, and p i and q i stand for the frequency of a particular TRBV gene segment in the first and second individual, correspondingly. For statistical comparison of the JS among related and unrelated mother-child pairs, we used two-tailed, unpaired Student's t -test with P-values <0.05 considered significant. To account for multiple testing, Bonferroni-corrected P-values were used. We used linear regression to analyze dependency between TRBV-CDR3/CDR3 overlap ratio and the number of shared major histocompatibility complex I (MHC-I) alleles, and calculated the Pearson correlation coefficient. The linear model: was fit using the least-squares method. Linear regression and correlation analysis were performed using R programing language 2. HLA TYPING The samples were HLA-typed using SSP AllSet Gold HLA-ABC Low Res Kit and SSP AllSet Gold HLA-DRDQ Low Res Kit (Invitrogen) and results were processed using UniMatch software. RESULTS We obtained at least 1 10 7 TCR beta CDR3-containing sequencing reads for each mother and about 3 10 6 reads for each child. MiTCR software analysis yielded 500,000-2,000,000 distinct TCR beta CDR3 clonotypes per donor ( Table 1) -representing a significant portion of the total TCR beta diversity for an individual, which lower bound estimate constitutes~4 million. We then subjected these individual TCR beta datasets to comparative analysis in an effort to identify features that distinguish TCR beta repertoires of related mother-child pairs. TRBV GENE USAGE We analyzed the relative usage of TRBV gene segments in mother-child pairs at three levels (see Figure 1): Out-of-frame TCR beta variants The influence of genetic effects on the recombination machinery, which determines the relative frequencies of TRBV gene segment usage in TCRs generated before selection in the thymus, should be reflected by out-of-frame TCR variants that are not subjected to the pressure of further selective processes. Due to nonsensemediated decay mechanisms, RNA-based libraries generally contain a low percentage of out-of-frame TCR beta variants. Nevertheless, out-of-frame CDR3 sequences constituted 2.5% of all clonotypes (Table 1) -16,048-45,300 clonotypes per donor -which is sufficiently abundant to perform statistical analysis. These subsets were used to compare TRBV gene segment usage in related and unrelated mother-child pairs before thymic selection. At this level of out-of-frame non-functional TCR beta variants, Jensen-Shannon divergence in TRBV gene usage was comparable for related and unrelated mother-child pairs, albeit with a non-significant increase in divergence for the latter (Figure 2A; Figures 3A,B, first 2 bars). Low-frequency in-frame clonotypes The pressure of thymic selection can be tracked by comparing TRBV gene segment usage in out-of-frame TCR beta variants relative to those variants represented in nave T cells. In this work, we did not perform separate TCR profiling of FACS-sorted nave T cells. We aimed to achieve maximal depth of analysis, and sought to avoid the loss of cells and RNA and general quantitative biases that inevitably arise from the cell sorting process. We estimated the pool of TCR beta clonotypes that predominantly belong to the nave subset as follows. We used FACS analysis to identify the percentage of nave CD27 high CD45RA high CD3+ T cells for each donor. This analysis demonstrated that nave T cells constitute 40-73% of the T cell population in children and 27-55% of the T cell population in mothers (Table 1; Figure 1). Since each nave T cell clone is usually represented by minor numbers of TCR-identical cells in an individual, for the purposes of bulk analysis, we hypothesized that the subset of the low-frequency clonotypes that occupies the same share of homeostatic space as the FACS-determined share of nave T cells for that particular donor (433,293-1,797,650 clonotypes per donor) predominantly includes nave T cells. At this level of low-frequency, in-frame TCR beta clonotypes, TRBV gene segment usage was significantly less divergent compared to out-of-frame TCR beta variants, both in related and unrelated pairs (Figures 2B and 3). Additionally, TRBV gene segment usage was significantly more similar for related versus unrelated pairs (Figures 3A,B, bars 3, 4). In accordance with JS analysis, comparison within related triplets revealed equalization of the usage of particular TRBV gene segments in lowfrequency, in-frame TCR clonotypes compared to out-of-frame TCR variants (Figure 4). For example, in each triplet, we saw the usage of TRBV gene segments 12-3, 12-4, 20-1, 21-1, and 23-1 equalize in the low-frequency TCR beta clonotypes pool. We also observed an equalizing decrease in TRBV 7-3 usage in triplets A and C, and an equalizing increase in TRBV 28 usage in triplet B. Notably, the observed changes in TRBV gene segments usage were generally similar in different unrelated donors (compare Figures 4A-C), and the convergence of TRBV usage after thymic selection (difference of out-of-frame versus in-frame TRBV usage divergence) was not significantly dependent on the number of shared HLA alleles (R = 0.12, P = 0.63). High-frequency in-frame clonotypes The influence of antigen-specific reactions on selection of TRBV gene segments could be tracked by comparing TRBV gene usage in nave and antigen-experienced T cells. Following the same logic that we used above for the approximate identification of the subset of nave TCR beta clonotypes, we hypothesized that the most abundant clonotypes predominantly represent antigen-experienced T cell clones. We defined this population as clones representing >0.001% of all CDR3 sequences. Thus, the lower bound for this group was approximately an order of magnitude greater than the upper border set for the low-frequency clones in a given donor's T cell pool (Figure 1). Such delineation with a gap between the two subsets minimized"contamination"by nave TCR beta clonotypes. Still, the pool of high-frequency in-frame clonotypes could contain a portion of nave clonotypes with TCR beta CDR3 sequence variants of low complexity, that are repetitively produced in thymus due to the convergent recombination events and thus may be highly represented. This set of the 2,803-8,285 most abundant clonotypes per individual cumulatively occupied 13.9-46.2% of the homeostatic T cell space in each donor. These high-frequency TCR beta clonotypes were generally characterized by increased variability in TRBV gene segment usage, and related and unrelated mother-child pairs were nearly indistinguishable ( Figure 2C; Figures 3A,B, bars 5, 6). OVERLAP OF TCR BETA REPERTOIRES FOR RELATED AND UNRELATED MOTHER-CHILD PAIRS Several studies in recent years have revealed that unrelated individuals widely share TCR beta repertoires. However, it is presently unclear whether the repertoires of haploidentical individuals are characterized by a higher level of overlap compared to unrelated donors. Additionally, for related mother-child pairs, shared TCR beta variants could conceal microchimeric T cell clones that have been physically shared across the placenta (see below). To address these questions, we performed comparative analysis of TCR beta repertoire overlap for related and unrelated mother-child pairs by quantifying CDR3 variant identity at the amino acid level, at the nucleotide level, and at the nucleotide level in conjunction with identical TRBV and TRBJ gene segment usage (i.e., fully identical TCR beta chains). We measured overlaps separately for low-frequency and high-frequency in-frame clonotypes (as delineated in Figure 1), and all in-frame clonotypes. Table 2 shows raw, non-normalized numbers of CDR3 variants shared on average by related and unrelated mother-child pairs. Normalized results are plotted in Figure 5. For all CDR3 categories, the degree of overlap was always slightly higher for related pairs, but this difference never approached a significant level compared to unrelated pairs. The highest level of overlap was observed for high-frequency clonotypes, in agreement with the previous work. WITHIN AMINO ACID CDR3 OVERLAPS OF EXPANDED CLONOTYPES, PERCENTAGE OF CLONOTYPES WITH IDENTICAL TRBV GENES IS INCREASED FOR RELATED MOTHER-CHILD PAIRS The CDR3 region is considered to form interactions mainly with antigenic peptide, while CDR1 and CDR2 encoded in the TRBV segment are mostly responsible for MHC recognition Figure 1 for delineation of lowand high-frequency clonotypes. Please note that "All in-frame clonotypes" include not only low-frequency and high-frequency clonotypes, but also the medium-frequency ones. Some TRBV segments have nearly identical sequences taking part in CDR3 formation, so two different TRBV segments can often give rise to the same CDR3 amino acid sequence. However, in two individuals with similar or identical HLA alleles, proliferating antigen-specific clones with the same TRBV segment and CDR3 amino acid sequence that recognize the same peptide-MHC complex can be preferentially activated. Therefore, since related mother and child pairs share at least 50% of their HLA alleles, we could expect that antigen-experienced clones with identical amino acid CDR3 variants that recognize the same antigenic peptide should more often carry the same TRBV segment encoding CDR1 and CDR2 responsible for MHC recognition. To verify this hypothesis, we analyzed various repertoire pairs comprising the 10,000 most abundant amino acid CDR3 clonotypes from each individual and computed overlap in terms of shared amino acid CDR3 sequences and shared amino acid CDR3 sequences carrying the same TRBV segment (i.e., identical CDR1, 2, and 3). We then determined the ratio of TRBV-CDR3 overlap to CDR3 overlap for each mother-child pair. In all cases, the ratio was greater for related mother-child pairs (1.3-fold, ±0.16, Figure 6A). Moreover, we observed significant positive correlation of this ratio with the number of shared MHC-I alleles between individuals (R = 0.62, P < 0.006, Figure 6B; Table 3). SELECTION IN THE THYMUS DECREASES AVERAGE CDR3 LENGTH COMPARED TO THE INITIALLY GENERATED REPERTOIRE Comparison of the out-of-frame and in-frame CDR3 repertoires revealed that the former are characterized by higher average length (45.6 ± 0.4 versus 43.3 ± 0.2) and an increased number of added nucleotides (8.6 ± 0.2 versus 7.4 ± 0.1, see Figure 7A), in both mothers and children. This finding indicates that, upon recombination, the initially generated TCR beta CDR3 repertoire (the parameters of which are preserved in the non-functional out-of-frame repertoire) is characterized by higher average length, while further selection in thymus essentially shapes the repertoire toward lower CDR3 length and fewer added nucleotides. SEARCHING FOR MICROCHIMERIC CLONES TRANSFERRED ACROSS THE PLACENTA AS MATURE T CELLS It is well established that mother and child exchange cells across the placenta during pregnancy, and that the progeny of these migrating cells persist in the new host for decades after gestation. Most authors agree that lymphoid progenitor cells commonly cross the placenta to populate the new host. Some observations also indicate that mature T cells can transmigrate through the placenta (see Discussion). However, it remains to be determined whether the transferred mature T cells (hereinafter referred to as mature-microchimeric T cells) can further persist and serve as functional T cell clones in their new host. We hypothesized that the present deep sequence analysis of such a substantial portion of the maternal and fetal TCR repertoire (including the absolute majority of proliferated antigen-experienced T cell clones) could reveal the presence of transferred and multiplied functional T cell populations, albeit without the immediate ability to distinguish the direction of transfer (i.e., maternal versus fetal microchimerism). Indeed, Frontiers in Immunology | T Cell Biology microchimeric T cell clones that were initially transferred across the placenta as mature T cells (mature-microchimeric T cell clones) within a given mother-child pair should be characterized by the same TCR beta CDR3 nucleotide sequence and the same TRBV and TRBJ gene segments, which therefore could serve as a clone-specific identifier. www.frontiersin.org However,~40% of the CDR3 nucleotide variants shared between any two individuals were characterized with the same TRBV and TRBJ gene segments, in similar numbers for both related and unrelated mother-child pairs. This means 1,766-5,410 shared clonotype variants across different donor pairs (Table 2; Figure 5). This widespread sharing of identical TCR beta nucleotide variants makes the TRBV-CDR3-TRBJ identifier insufficient to distinguish clones that were physically transferred across the placenta as mature T cells with recombined TCRs from public TCRs resulting from independent convergent recombination events. Thus, if mature-microchimeric T cell clones are present, they are concealed amongst the overwhelming majority of natural public TCRs, and additional characteristics are needed to delineate them. Frontiers in Immunology | T Cell Biology It has been reported that public TCR beta clonotypes are generally characterized by a low number of added nucleotides in CDR3 (i.e., low complexity). We therefore used the number of added nucleotides as an additional selective characteristic that essentially determines the probability of convergent recombination events leading to CDR3 variants that are identical at the nucleotide level. Comparison of this characteristic for all TCR beta CDR3 nucleotide variants and those TRBV-CDR3-TRBJ nucleotide variants that were shared between unrelated motherchild pairs revealed that the latter were characterized by much lower numbers of added nucleotides ( Figure 7A). The transfer of mature T cells across the placenta should not be dependent on CDR3 length or the number of added nucleotides. In humans, it has been demonstrated that there is no significant difference between adult blood and cord blood samples in the mean number of added nucleotides. Therefore, this characteristic should be essentially identical for both feto-maternal and materno-fetal mature-microchimeric T cell clones and for the general TCR beta repertoire. If the TCR beta repertoires of related mother-child pairs carry mature-microchimeric T cell clones of interest, we would expect to observe shaping of the added nucleotide curve proportional to the contribution of such clones to the repertoire overlap ( Figure 7B). The sensitivity of this method to the percentage of maturemicrochimeric T cell clones in the shared TCR beta population is therefore limited by the natural dispersion of the added nucleotide curves for unrelated pairs. For example, if mature-microchimeric T cell clones contribute~0.3% of the TRBV-CDR3-TRBJ overlap for a mother-child pair (i.e.,~10 out of 3,000 overlapping clonotypes, out of the~1 10 6 total clonotypes sequenced from each donor), the shape of the added nucleotide curve would be indistinguishable from that of an unrelated donor pair -and therefore below the sensitivity threshold of this method. In contrast, the presence of 100 mature-microchimeric T cell clones out of 3,000 clonotypes (i.e., 3.3% of shared variants) per pair of related donors could be clearly distinguished (Figure 7B), and this can therefore be considered as the approximate sensitivity limit of the method. We subsequently determined that the presence of mature-microchimeric T cell clones is undetectable in all cases, based on the added nucleotide curves for overlapping TRBV-CDR3-TRBJ nucleotide sequences for our six related mother-child pairs ( Figure 7C). Correspondingly, the average numbers of added nucleotides in the shared TRBV-CDR3-TRBJ nucleotide variants were indistinguishable for related versus unrelated mother-child pairs (data not shown). The above-described comparison of added nucleotide curves was performed at the level of distinct TCR beta clonotypes, but not sequencing reads, so that the influence of each T cell clone's relative representation within the repertoire was excluded. Similar albeit noisier results we have obtained when performing the same analysis at the level of sequencing reads (i.e., taking into account relative clonal size). As such, we have not identified any meaningful difference between the subsets of shared TRBV-CDR3-TRBJ nucleotide variants for related versus unrelated mother-child pairs that would allow us to establish detection of a subpopulation of maturemicrochimeric T cells that have been systemically shared during pregnancy as mature nave or memory T cells, and which subsequently have engrafted and survived for years. TRBV GENE USAGE For out-of-frame TCR beta variants, which are not expressed and thus avoid any selection, TRBV gene usage was slightly more similar but generally comparable for related versus unrelated motherchild pairs (Figures 2A and 3). This indicates that inherited maternal factors associated with the TCR recombination machinery are insufficient to yield the essentially similar TRBV gene segment selection in the child. Remarkably, both within related and unrelated pairs, TRBV gene segment usage in low-frequency in-frame TCR beta clonotypes was more similar compared to that in the out-of-frame TCR beta variants (Figure 3). The equalization of the usage of TRBV gene segments in functional TCR variants (Figure 4) is probably a manifestation of selective pressure during thymic T cell selection, which should distinguish TRBV gene usage in functional TCRs from that preserved in unselected, out-of-frame TCR beta variants. This pressure on relative TRBV usage frequencies was prominent and led to significant convergence in both related (P = 0.0006) and unrelated (P = 0.0015) pairs, indicating that thymic selection essentially and similarly shapes the initial output of the TCR recombination machinery at the population level. Interestingly, thymic selection also essentially filters out the longest CDR3 variants with large numbers of added nucleotides, as can be concluded from our comparison of non-functional outof-frame and in-frame TCR beta CDR3 repertoires (Figure 7A). Modeling of added nucleotide curves for shared TRBV-CDR3-TRBJ variants between mother-child pairs based on input of mature-microchimeric TCR beta CDR3 variants in different proportions. This was derived from the curves in (A), which depict added nucleotide distributions for shared clonotypes between unrelated individuals (gray; equivalent to near-zero contribution to shared clonotypes) and for any individual repertoire (black; equivalent to 100% contribution to shared clonotypes), mixed in different proportions. Lines represent model input where mature-microchimeric TCR beta is equal to 100, 33, 3.3, or 0.3% of shared clonotypes. Shaded region shows the range for unrelated pairs. Inset shows a magnified view. (C) Added nucleotide curves for TRBV-CDR3-TRBJ variants shared in each related mother-child pair. Shaded region shows the range for unrelated pairs. Frontiers in Immunology | T Cell Biology Since TRBV gene segments encode the fragments of TCR chains that interact with MHC, we would expect that related mother-child pairs, being haploidentical (i.e., sharing at least 50% of HLA alleles), are characterized by more similar TRBV gene segment usage frequencies at the level of functional T cells compared to unrelated donor pairs due to the impact of identical HLA genes in thymic selection. Indeed, we observed that differences in TRBV gene segment usage in related versus unrelated pairs became more pronounced and statistically significant (P = 0.02) at the level of low-frequency, in-frame TCR beta CDR3 clonotypes (Figure 3). However, the general direction of TCR beta repertoire shaping was similar for related and unrelated donors, suggesting that the pressure of thymic selection is relatively homogenous in the population. The strength of this general pressure was far greater relative to the specific changes that were characteristic of related donors, which only added a minor codirectional trend (Figures 3 and 4). The subset of high-frequency TCR beta clonotypes was characterized by increased variability in TRBV segment usage, and related and unrelated mother-child pairs were indistinguishable at this level (Figures 2C and 3). This is presumably due to the fact that different antigen specificities (but not TRBV segment interaction with MHC) play a dominant role in the priming and expansion of T cell clones, and this semi-random process negates the initial correlations that we observed in TRBV gene usage at the level of nave T cells. It should be noted, however, that the above analysis refers to low-and high-frequency clonotypes, which do not fully coincide with the nave and antigen-experienced T cell subsets, respectively. It was previously demonstrated in other studies that recombinatorial biases might result in relatively high frequencies for certain nave T cell clones, whereas some memory T cell clones may occur at relatively low frequencies. Moreover, these studies have shown a substantial overlap between the nave and memory T cell repertoires, which suggests that a number of TCR beta CDR3 clonotypes could be associated with both subsets, being paired with either the same or alternative TCR alpha chains. OVERLAP OF TCR BETA REPERTOIRES We observed the greatest relative overlap of TCR beta repertoires among high-frequency clonotypes. This observation can be explained by the presence of common expanded antigenexperienced clonotypes recognizing the same antigens, as well as of high-frequency nave clonotypes carrying the TCR beta CDR3 sequence variants of low complexity that are repetitively produced in thymus and may be highly represented both within and between individuals. In all comparisons, only slightly higher numbers of shared clonotypes were observed in related versus unrelated mother-child pairs (Figure 5). This observation is in agreement with the previous report by Robins et al. where the overlap in the nave CD8+ CDR3 sequence repertoires was suggested to be independent of the degree of HLA matching based on results obtained from three related donors. Here, we have achieved a more accurate comparison by studying a larger cohort of related donors, using unbiased library preparation techniques, sequencing the samples being compared on separate Illumina lanes to protect from potential cross-sample contamination on the solid phase and performing deeper individual profiling. Even with these various methodological improvements, we still observed only a subtle trend toward increased TCR beta repertoire overlap in related individuals. However, among the shared high-frequency amino acid CDR3 variants, the percentage of TRBV-CDR3 identical clonotypes was always higher for related pairs compared to unrelated ones, and correlated with the number of identical MHC-I alleles (Figure 6). This finding indicates that optimal recognition of the particular peptide-MHC complex often requires full functional convergence of the TCR beta chain, leading to an increased share of TRBVidentical common CDR3 variants in individuals carrying the same HLA alleles. Notably, this phenomenon was observed for bulk T cell populations, where the input of CD8+ T cells was sufficient to provide correlation. This correlation would probably be much higher if we were to specifically analyze sorted CD8+ T cells. SEARCHING FOR PERSISTENT MATURE-MICROCHIMERIC CLONES In humans, maternal T cells are present in different fetal tissues, and may be present in the cord blood at a frequency of 0.1-0.5% of total T cells. This can represent hundreds of thousands or millions of cells, of which many are likely to be memory T cells capable of further clonal proliferation. Transmigration of maternal differentiated effector/memory Th1 and Th17 cells through the placenta was recently demonstrated in mouse models. Transfer of mature T cells is also possible in the opposite direction, and the presence of fetal microchimeric CD4+ and CD8+ T cells was registered in maternal blood during normal pregnancy in humans, predominantly in the third trimester when mature / T cells are circulating in the fetus at significant numbers. Such mature-microchimeric T cell clones could further affect immunity to solid tumors, influence transplantation tolerance, cause autoimmune diseases (3,4,43,, or protect the child against infections he/she has never encountered before. Recent work has demonstrated that, in general, experienced clonal T cells commonly persist in the body for many years. We have observed more than 20,000 TCR beta clonotypes that persisted in a patient for at least 7 years -from 2005 until 2012even after the patient underwent autologous HSC transplantation in 2009 . Similarly, nave T cell clones persist in the body for many years after loss of thymus functionality. Therefore, if the engraftment of mature T cell clones transferred from mother to child and/or vice versa is a systemic process, we could expect to be able to verify the presence of such clones by using characteristic TCR beta CDR3 variants as clonal identifiers. In our repertoire analysis, we did not observe maturemicrochimeric T cell clones at a level of methodological sensitivity of~100 mature-microchimeric clones per 10 6 analyzed TCR beta clonotypes. Still, this does not preclude the existence of mature T cell-based maternal or fetal microchimerism at levels below the sensitivity achieved in the current study, in minor number of individuals, or in pathological conditions such as autoimmune disease. It should be noted that deep TCR beta profiling methodology presently appears to be insufficiently sensitive for identifying www.frontiersin.org particular expanded mature-microchimeric T cell clones, due to the general abundance of common identical TCR beta clonotypes. The following combination of methods could offer a potential way forward: deep TCR beta profiling suggesting the presence of a particular expanded mature-microchimeric T cell clone, preferably with many added nucleotides within CDR3; cell sorting using a TRBV family specific antibody in order to enrich for the hypothetical microchimeric clone of interest; and realtime PCR confirmation of increased microchimerism in the sorted sample. We also believe that further development of NGS profiling methods -especially in combination with the use of live cellbased emulsion PCR to identify paired TCR alpha-beta chains, and to potentially identify TCR beta chains paired with specific HLA molecules serving as an internal marker of microchimeric clones -should greatly facilitate future studies of mature T cell microchimerism in health and disease. |
Feline XLF accumulates at DNA damage sites in a Kudependent manner Resistance to radiotherapy and chemotherapy is a common problem in the treatment of cancer in humans and companion animals, including cats. There is thus an urgent need to develop new treatments. Molecularly targeted therapies hold the promise of high specificity and significant cancerkilling effects. Accumulating evidence shows that DNA doublestrand break (DSB) repair proteins, which function in Kudependent nonhomologous DNAend joining (NHEJ), are potential target molecules for nextgeneration cancer therapies. Although cancer radioresistance in cats has been previously described, there are no reports on feline Kudependent NHEJ. Here, we cloned and sequenced feline XLF cDNA and characterized Xray repair crosscomplementing protein 4like factor (XLF), which is one of the core NHEJ proteins. We demonstrated that feline XLF localizes to the nuclei of feline cells and that feline XLF immediately accumulates at laserinduced DSB sites in a Kudependent manner. Amino acid sequence alignment analysis showed that feline XLF has only 80.9% identity with human XLF protein, while the predicted nuclear localization signal and putative 1433binding motif are perfectly conserved among human, cat, dog, chimpanzee, and mouse. These findings are consistent with the hypothesis that regulation of subcellular localization is important for the function of XLF. Furthermore, these findings may be useful in clarifying the mechanisms underlying feline Kudependent DSB repair and feline cell radioresistance, and possibly facilitate the development of new molecularly targeted therapies that target common proteins in human and feline cancers. Resistance to radiotherapy and chemotherapy is a common problem in the treatment of cancer in humans and companion animals, including cats. There is thus an urgent need to develop new treatments. Molecularly targeted therapies hold the promise of high specificity and significant cancer-killing effects. Accumulating evidence shows that DNA double-strand break (DSB) repair proteins, which function in Ku-dependent non-homologous DNA-end joining (NHEJ), are potential target molecules for next-generation cancer therapies. Although cancer radioresistance in cats has been previously described, there are no reports on feline Ku-dependent NHEJ. Here, we cloned and sequenced feline XLF cDNA and characterized X-ray repair cross-complementing protein 4-like factor (XLF), which is one of the core NHEJ proteins. We demonstrated that feline XLF localizes to the nuclei of feline cells and that feline XLF immediately accumulates at laser-induced DSB sites in a Ku-dependent manner. Amino acid sequence alignment analysis showed that feline XLF has only 80.9% identity with human XLF protein, while the predicted nuclear localization signal and putative 14-3-3binding motif are perfectly conserved among human, cat, dog, chimpanzee, and mouse. These findings are consistent with the hypothesis that regulation of subcellular localization is important for the function of XLF. Furthermore, these findings may be useful in clarifying the mechanisms underlying feline Ku-dependent DSB repair and feline cell radioresistance, and possibly facilitate the development of new molecularly targeted therapies that target common proteins in human and feline cancers. Companion animals are of tremendous importance in the lives of many people. Unfortunately, about 6 million dogs and a similar number of cats are diagnosed with cancer in the USA each year. Nickoloff et al. described that companion animal studies, under the umbrella of comparative oncology, have played key roles in the development of clinical radiotherapy throughout its more than 100-year history. They also mentioned that canine cancer models present many translational research opportunities to exploit fundamental knowledge about DNA repair to improve radiotherapy. Radiation is becoming widely available to treat tumors in companion animals such as cats and dogs. However, the effect of radiation therapy in cats seems to be very different from in dogs in terms of tumor responses as well as normal tissue toxicity. Radioresistance of cats has been observed in animal radiotherapy at veterinary hospitals. In addition, at the cellular level, feline normal fibroblasts were more radioresistant than human fibroblasts. The feline cells displayed a decreased residual amount of DNA double-strand breaks (DSBs) after potential lethal damage repair, suggesting that DNA damage induced by X-irradiation is more effectively repaired in feline cells. Thus, chemo-radiotherapy is expected to be one of the most effective treatments, not only for companion animals, but also for humans, if the nextgeneration radiosensitizers specifically targeting cancer cells in cats can be developed. Molecularly targeted therapies of cancer promisingly have a high selectivity and significant cancer-killing effects. The DSBs are the most dangerous DNA damage. There are three pathways, namely non-homologous DNA-end joining (NHEJ), homologous recombination (HR) and alternative end joining (A-EJ), for repairing DSBs in human and other mammalian cancer cells. An accessory NHEJ factor, DNA-dependent protein kinase, catalytic subunit (DNA-PKcs), has been reported to be upregulated in human tumors and radiation-resistant cell lines, suggesting that this protein has a role in tumor growth and survival. Thus, the NHEJ factors including DNA-PKcs are potential targets of drug discovery for the next-generation cancer therapies. Recently, Gemenetzidis et al. suggested that oral cancer stem cells display resistance to ionizing radiation (IR), and this correlates with elevated levels of X-ray repair cross-complementing protein 4 (XRCC4)-like factor (XLF), which is the other core NHEJ factor. Hence, XLF might be a pharmacological target in cancer therapy. However, as yet there are no drugs targeting XLF. It is important to uncover the regulatory mechanisms of DNA repair in human and companion animal cells to develop novel molecularly targeted therapies. Post-translational modifications (PTMs) and protein-protein interactions might trigger and control DNA repair processes and DNA damage response signals to repair DSBs efficiently. Recently, we cloned and characterized four cDNAs of the canine core NHEJ repair genes. However, there are no reports about mechanism of DNA repair in feline cells. Furthermore, the sequence, localization, and regulatory mechanisms of each feline core NHEJ factor, e.g. XLF or Ku70, have not been published. In this study, we first cloned feline XLF cDNA and examined its expression, localization, and recruitment to DSB sites of feline XLF proteins. In addition, we carried out comparative analysis to uncover the regulatory mechanisms which govern XLF's functions. Cloning of feline XLF Cloning of feline XLF cDNA was performed as previously described with the following modifications. Oligonucleotide primers used to amplify feline XLF cDNA from a male cat cDNA library (Zyagen, San Diego, CA, USA) were designed based on the predicted XLF genomic sequence of female cat, belonging to the species Felis catus (XM_011285546.1). PCR amplification with sense (feline XLF F1: 5 0 -GAATTCTATGGAGGAACTGGAGCAAG GTCTG-3 0 ) and antisense (feline XLF R: 5 0 -GGATCCT TAACTGAAGAGCCCCCTTAGCTTC-3 0 ) primers was performed in a TaKaRa PCR Thermal Cycler Dice (Takara Bio Inc., Otsu, Japan) using LA Taq polymerase (Takara Bio Inc.). Pre-denaturation was carried out for 5 min at 94°C. This was followed by 35 cycles of PCR amplification. Each cycle consisted of a denaturation step at 94°C for 0.5 min, annealing at 56°C for 0.5 min and extension at 72°C for 0.5 min, followed by a final extension step (4 min). PCR products were subcloned into the pCR4-TOPO vector (Thermo Fisher Scientific, Waltham, MA, USA) (pCR4-feline XLF plasmid), and the nucleotide sequences were determined by sequencing using primers, T3 and T7. XLF cDNA from pCR4-feline XLF plasmid was subcloned into the EcoRI and BamHI sites of pEYFP-C1 (pEYFP-feline XLF), and the inserts were validated by sequencing. Other PCR primers used in this study were as follows: feline XLF F11: 5 0 -CTCTAGGCCTTTCGGTTTGC-3 0, feline XLF R11: 5 0 -GCGAAGCAGATCATCCAAAT-3 0, feline XLF F2: 5 0 -CCCCACAAGGAACTGAAAACCAAC-3 0 and feline XLF R2: 5 0 -CCTTTTAGGCTGACATTAGGGCAC-3 0. These PCR primers were used to validate that the above synthetic primer sequence (feline XLF F1) is the true sequence. We confirmed that the sequence around ATG is based on the cognate sequence. X-irradiation X-irradiation was carried out as described previously. Cells were exposed to X-rays at 10 Gy at a dose rate of 0.72 Gymin 1 using the Pantak HF320S X-ray system (Shimadzu, Kyoto, Japan) operating at 200 kV, 20 mA with a filter of 0.5 mm aluminum and 0.5 mm copper. DNA damage induction using micro-laser and cell imaging Local DNA damage induction using microlaser and subsequent cell imaging was carried out as described previously. Briefly, local DSBs were induced using a 405 nm laser. Images of living or fixed cells expressing EYFP-feline XLF or EYFP alone were obtained using an FV300 confocal laser-scanning microscope system (Olympus). Immunocytochemistry was carried out using rabbit anti-Ku80 polyclonal antibody (AHP317), rabbit anti-Ku70 polyclonal antibody (H-308), a mouse anti-cH2AX monoclonal antibody (JBW301), and Alexa Fluor 568-conjugated secondary antibody (Thermo Fisher Scientific), as previously described. Phosphorylation of H2AX after X-irradiation and expression of core NHEJ factors in feline cells Histone H2AX is rapidly phosphorylated at serine 139 (cH2AX) in response to DSBs, and the reduction of cH2AX reflects DSB repair. To test whether the DSB repair pathways are intact in feline CRFK cells, we examined X-irradiation-induced H2AX phosphorylation and cH2AX reduction in extracts from CRFK cells by western blot analysis using the anti-cH2AX antibody. As shown in Fig. 1A, a high level of cH2AX was detected in extracts from CRFK cells at 1 h post-irradiation, and cH2AX reduction was detected from 1 to 6 h after X-irradiation. Mammalian cells have three DSB repair pathways, i.e. NHEJ, HR, and A-EJ, and NHEJ, but not HR and A-EJ, contributes to the fast repair within hours after irradiation to X-ray-induced DSBs. We speculate that the fast DSB repair pathway, i.e. NHEJ, might be intact in CRFK cells. Next, we examined the expression of core NHEJ factors, i.e. Ku70, Ku80, and XLF in feline (CRFK) and human cell lines. As shown in Fig. 1B,C, using each of two specific antibodies, the expression of feline XLF, Ku70 and Ku80 was detected in CRFK cells. Interestingly, the size of the feline XLF protein was greatly distinct from that of human. We speculate that the PTMs on feline XLF are different from those of human, although further studies need to clarify this. Cloning and sequence analysis of feline XLF The cDNA of the core NHEJ factors of feline species including XLF cDNA had not been cloned previously. Hence, we firstly cloned the feline XLF cDNA from a cat testis library and then sequenced it. We isolated a 900-nucleotide open reading frame encoding the protein of 299 amino acids for the first time (Fig. 2). The feline XLF sequence has been deposited at the DDBJ/ EMBL/NCBI database (accession number: LC309246). Comparative analysis of XLF sequences from different species showed that feline XLF had 80.9%, 84.9%, 82.3%, and 74.9% amino acid identity with the human, dog, chimpanzee, and mouse proteins, respectively. PTMs by phosphorylation, and protein-protein interactions of XLF as well as other core NHEJ factors might play a key role in the regulation of NHEJ pathways in human cells. As shown in Fig. 3, we found that the phosphorylation sites of DNA-PK (S245), AKT-1 (T181) and casein kinase I (CKI) (S170) in human XLF are evolutionarily conserved in cat, dog, chimpanzee, and mouse. On the contrary, the ataxia telangiectasia mutated (ATM) (S251) and CKI (T173) phosphorylation sites of human XLF are not conserved in cat, dog, and mouse. Most recently, Normanno et al. reported that the simultaneous phosphorylation of six phosphorylation sites (S132, S203, S245, S251, S263, and S266) of human XLF and the eight phosphorylation sites of human XRCC4 might be important for the regulation of both the stability and DNA bridging capacity of XRCC4-XLF complexes. First, we found that the 266th amino acid of XLF is threonine in human, chimpanzee, and mouse, but serine in cat and dog, although the amino acid in human has been previously described as serine in. Regulatory mechanisms of subcellular localization of XLF in human and cow might play an important role in the control of the NHEJ activity. We described previously that the basic amino acids in the putative nuclear localization signal (NLS) of XLF are highly conserved among humans, chimpanzee, mouse, domestic animal species including cattle, goat, horse, birds, and dogs. In this study, our data show that the putative NLS sequence is also conserved in cat (Fig. 3). It is reported that human XLF has a putative b-transducin repeat containing protein (b-TRCP)-recognizable degron motif ( 169 ESGAT 173 ) and a putative 14-3-3 binding motif ( 178 RLKTEP 183 ). We found that the 14-3-3 binding site (P183) of human XLF is evolutionarily conserved in cat, dog, chimpanzee, and mouse, whereas the putative b-TRCP-recognizable degron of human XLF is not conserved in cat as well as in dog and mouse XLF. Recently, it was reported that K180 in the putative 14-3-3 binding motif on XLF is a target for ubiquitination in human cells. We found that the target site is highly conserved among all five species examined including cat. Localization of XLF in feline cells To investigate subcellular localization of XLF in live feline cells, we generated CRFK cells transiently expressing EYFP-feline XLF. For this purpose, the expression vector pEYFP-C1 containing feline XLF (pEYFP-feline XLF) was transfected into CRFK cells (Fig. 4A). Western blotting using an anti-XLF and two anti-GFP antibodies showed that the chimeric protein was expressed in the transfected feline cells (Fig. 4B). Confocal laser microscopy demonstrated that during interphase, EYFP-feline XLF localized in the nuclei of the cells transfected with pEYFP-feline XLF (Fig. 4C). Expectedly, EYFP, used as a control, was distributed throughout the cell (with the exclusion of the nucleoli) in pEYFP-transfected CRFK cells (Fig. 4C). Immediate accumulation of Ku-dependent EYFPfeline XLF at laser-microirradiated DSB sites Previously, we and others have demonstrated that human core NHEJ proteins, such as Ku70, Ku80, XLF, and XRCC4, accumulate at DSB sites immediately after irradiation. It has never been investigated whether feline core NHEJ proteins accumulate at DSB sites immediately after DNA damage. We investigated whether, in feline cells, EYFP-feline XLF accumulates immediately at sites of DSB induced by laser microirradiation (Fig. 5A). Local DSBs in feline cells were induced using a 405 nm laser. Laser microirradiation resulted in the accumulation of EYFP-feline XLF at the microirradiated sites in live CRFK cells (Fig. 5B). To confirm if EYFP-feline XLF actually accumulated at the DSBs induced by the 405 nm laser, we immunostained the cells with an antibody against Ku70 or Ku80, a sensor of DSB. We found that EYFP-feline XLF accumulates and colocalizes with Ku70 and Ku80 at the DSB sites in CRFK cells (Fig. 5C). To examine the temporal dynamics of XLF localization, we carried out time-lapse imaging in CRFK cells transfected with pEYFP-feline XLF. We found that EYFP-feline XLF accumulates at the microirradiated sites 5 s after irradiation (Fig. 5D). Next, we examined whether Ku (heterodimer of Ku70 and Ku80) is essential for the accumulation of feline XLF. We first confirmed that EYFP-feline XLF was expressed in both CHO-K1 and Ku80-deficient CHO-K1 mutant cells (xrs-6) transfected with pEYFPfeline XLF (Fig. 6A,B). We found that EYFP-feline XLF does not accumulate at the microirradiated region in the xrs-6 cells, whereas it accumulates in CHO-K1 cells (Fig. 6C). We also confirmed whether EYFP-feline XLF accumulated at laser-induced DSB sites by immunostaining the cells with an antibody that recognizes cH2AX. As shown in Fig. 6D, EYFP-feline XLF colocalized with cH2AX at the laser-induced DSB sites in the CHO-K1 cells, but not in the xrs-6 cells, indicating that the recruitment of EYFP-feline XLF is dependent on the presence of hamster Ku in the hamster cells. Collectively, these results suggest that Ku is essential for the accumulation at DSBs of feline XLF. Discussion In the treatment of cancers in humans and companion animals such as cats, resistance to chemotherapy and. The locations of the CKI phosphorylation sites (S170 and T173), AKT phosphorylation site (T181), putative 14-3-3 binding motif (P183), DNA-PK phosphorylation site (S245), ATM phosphorylation site (S251), and ubiquitination site (K180) in the human XLF sequence are marked with asterisks. The locations of the phosphorylation sites (S132, S203, S245, S251, S263, T266), which impact both the stability and DNA bridging capacity of XRCC4-XLF complexes in the human XLF sequence, are marked with a double asterisk. radiotherapy is a common and critical problem. The DSB repair proteins, especially core NHEJ factors, are charming target molecules for new anti-cancer drugs. Human XLF is one of the core NHEJ factors, and XLF-deficient cells derived from human patients display ionizing radiation sensitivity. Hence, XLF is a possible target molecule for the development of next-generation radiosensitizers and chemotherapeutics. Chemo-radiotherapy is the most common cancer treatment modality not only in human and dogs, but also in cats. Nevertheless, feline NHEJ and core NHEJ factors including XLF of cats remain to be investigated in depth. In this study, we cloned and sequenced the cDNA of feline XLF, and characterized feline XLF protein. Our data demonstrated that feline XLF localizes in the nuclei of feline CRFK cells, and feline XLF immediately accumulates at laser-induced DSB sites, except in Ku-deficient cells. Amino acid sequence alignment analysis for XLF suggested that the spatial and temporal control mechanisms of XLF, which play key roles in NHEJ, are evolutionarily conserved between humans and cats, although the structure of protein-protein interaction motifs and the sites of PTM are not perfectly conserved. These findings might be useful for clarifying the molecular mechanisms of NHEJ and of the radioresistance of feline cells, and for the development of new radiosensitizers that target common targets against human and feline cancers. In this study, our data demonstrated that feline XLF accumulates at DSB sites in a Ku-dependent manner. Based on two impressive clinical successes of cancer treatment, DNA repair-targeted therapies have attracted considerable attention. The first strategy utilizes the synthetic lethality targeting another remaining DNA repair pathway, e.g. by poly (ADP-ribose) polymerase inhibitors for treating BRCA1/2-mutated ovarian cancers. This strategy has provided a paradigm for many current clinical strategies targeting DNA repair. The second one is a new molecular targeted therapy employing immune checkpoint inhibitors including anti-programmed cell death protein 1 (PD-1) or anti-programmed cell death 1 ligand 1 (PD-L1) mAbs and resulted in dramatic clinical responses in certain types of solid malignancies, although the antitumor response rates were not enough. PD-L1 is upregulated in the tumor cells after IR, and the adaptive response might mediate resistance to radiotherapy and treatment failure. On the basis of this, the authors proposed that irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity. Recently, Sato et al. reported that Ku70/Ku80 depletion in cancer cells substantially enhances PD-L1 upregulation after X-irradiation, suggesting that the DSB repair pathway regulates PD-L1 expression. These data suggest that further studies on the DSB repair mechanism in feline cells and the Ku-dependent accumulation of feline XLF at DSBs will be useful for developing next-generation drugs and combination therapies against cancers of both human and companion animals. A substantial amount of data indicate that tumors with differential expression of the core NHEJ factors have differential therapy responsiveness. To develop more effective DNA repair inhibitors and more efficient anti-cancer drugs, it is important to clarify the molecular and control mechanisms of DNA repair pathways in feline cells. Unfortunately, however, no information is available about these in the context of feline cells. It is proposed that XLF proteins may be novel targets for human oral cancer stem cells, because their inhibition could lead to selective killing of these cells via spontaneous DSB induction and/or amplification of DNA damage following IR. Previously, our findings suggested that two predictive motifs, i.e. the NLS and 14-3-3 binding motif, needed for the regulation of human XLF subcellular localization are conserved among human, dog, mouse, and chimpanzee. In this study, our comparative analysis showed that feline XLF had only 80.9%, 84.9%, and 74.9% amino acid identity with the human, dog, and mouse protein sequences, respectively. We found that a ubiquitination target site (K180) for human XLF, which is on the putative 14-3-3 binding motif is perfectly conserved among cat, human, and the other three species. The ubiquitination target site might be important for the regulation of XLF localization and/or functions, although further studies are needed to confirm this. Collectively, these findings support the idea that the regulatory mechanism of subcellular localization of XLF is important for the control of XLF functions in human and mammalian cells, including those of cats. Each core NHEJ factor is a potentially suitable molecular target for the development of chemotherapeutics and radiosensitizers for human cancers . Indeed, several core NHEJ factor-targeted inhibitors including DNA-PK inhibitors are in clinical development for human cancer treatment. However, as described above, there has been no report on the Ku-dependent DNA repair mechanism via NHEJ in cats. Meanwhile, a number of studies showed that lack of XLF in mice can be compensated by Rag2, 53BP1, ATM, H2AX, DNA-PKcs, Mri, and PAralog of XRCC4 and XLF (PAXX). Additionally, genetic interaction between XLF and PAXX was shown using human cells. In the present study, we firstly cloned and sequenced one of the core NHEJ genes, i.e. cDNA of feline XLF, and characterized feline XLF. Our data suggest that the mechanism of spatiotemporal regulation of XLF might be conserved in humans and cats. Our findings coupled with further studies might be useful to better understand the mechanism of the NHEJ and for the development of common DNA repairtargeted drugs against cancers of both humans and cats. |
//
// process.h
//
// Copyright (c) Microsoft Corporation. All rights reserved.
//
// This file declares the process control functionality (e.g., the exec and
// spawn families of functions).
//
#pragma once
#ifndef _INC_PROCESS // include guard for 3rd party interop
#define _INC_PROCESS
#include <corecrt.h>
#include <corecrt_startup.h>
#include <corecrt_wprocess.h>
_CRT_BEGIN_C_HEADER
// Flag values for the _spawn family of functions
#define _P_WAIT 0
#define _P_NOWAIT 1
#define _OLD_P_OVERLAY 2
#define _P_NOWAITO 3
#define _P_DETACH 4
#define _P_OVERLAY 2
// Action codes for _cwait(). The action code argument to _cwait() is ignored on
// Win32. The parameter only exists so that we do not break existing code.
#define _WAIT_CHILD 0
#define _WAIT_GRANDCHILD 1
#if _CRT_FUNCTIONS_REQUIRED
_ACRTIMP __declspec(noreturn) void __cdecl exit(_In_ int _Code);
_ACRTIMP __declspec(noreturn) void __cdecl _exit(_In_ int _Code);
_ACRTIMP __declspec(noreturn) void __cdecl _Exit(_In_ int _Code);
_ACRTIMP __declspec(noreturn) void __cdecl quick_exit(_In_ int _Code);
_ACRTIMP __declspec(noreturn) void __cdecl abort(void);
_DCRTIMP int __cdecl system(_In_opt_z_ char const* _Command);
_ACRTIMP void __cdecl _cexit(void);
_ACRTIMP void __cdecl _c_exit(void);
typedef void (__stdcall *_tls_callback_type)(void *, unsigned long, void *);
_ACRTIMP void __cdecl _register_thread_local_exe_atexit_callback(_In_ _tls_callback_type _Callback);
#endif // _CRT_FUNCTIONS_REQUIRED
// Declare DLL notification (initialization/termination) routines. The preferred
// method is for the CRT client to define DllMain(), which will automatically be
// called by the DLL entry point defined by the CRT. If the CRT client wants to
// define the DLL entry point, the client entry point must call _CRT_INIT on all
// types of notifications, as the very first thing on attach notifications and as
// the very last thing on detach notifications.
#ifdef _DECL_DLLMAIN
int __stdcall DllMain(
_In_ void* _DllHandle,
_In_ unsigned long _Reason,
_In_opt_ void* _Reserved
);
int __stdcall _CRT_INIT(
_In_ void* _DllHandle,
_In_ unsigned long _Reason,
_In_opt_ void* _Reserved
);
extern int (__stdcall* const _pRawDllMain)(void*, unsigned long, void*);
#endif
typedef void (__cdecl* _beginthread_proc_type )(void*);
typedef unsigned (__stdcall* _beginthreadex_proc_type)(void*);
_ACRTIMP uintptr_t __cdecl _beginthread(
_In_ _beginthread_proc_type _StartAddress,
_In_ unsigned _StackSize,
_In_opt_ void* _ArgList
);
_ACRTIMP void __cdecl _endthread(void);
_Success_(return != 0)
_ACRTIMP uintptr_t __cdecl _beginthreadex(
_In_opt_ void* _Security,
_In_ unsigned _StackSize,
_In_ _beginthreadex_proc_type _StartAddress,
_In_opt_ void* _ArgList,
_In_ unsigned _InitFlag,
_Out_opt_ unsigned* _ThrdAddr
);
_ACRTIMP void __cdecl _endthreadex(
_In_ unsigned _ReturnCode
);
#ifdef _CRT_USE_WINAPI_FAMILY_DESKTOP_APP
_ACRTIMP int __cdecl _getpid(void);
_DCRTIMP intptr_t __cdecl _cwait(
_Out_opt_ int* _TermStat,
_In_ intptr_t _ProcHandle,
_In_ int _Action
);
_DCRTIMP intptr_t __cdecl _execl(
_In_z_ char const* _FileName,
_In_z_ char const* _Arguments,
...);
_DCRTIMP intptr_t __cdecl _execle(
_In_z_ char const* _FileName,
_In_z_ char const* _Arguments,
...);
_DCRTIMP intptr_t __cdecl _execlp(
_In_z_ char const* _FileName,
_In_z_ char const* _Arguments,
...);
_DCRTIMP intptr_t __cdecl _execlpe(
_In_z_ char const* _FileName,
_In_z_ char const* _Arguments,
...);
_DCRTIMP intptr_t __cdecl _execv(
_In_z_ char const* _FileName,
_In_z_ char const* const* _Arguments
);
_DCRTIMP intptr_t __cdecl _execve(
_In_z_ char const* _FileName,
_In_z_ char const* const* _Arguments,
_In_opt_z_ char const* const* _Environment
);
_DCRTIMP intptr_t __cdecl _execvp(
_In_z_ char const* _FileName,
_In_z_ char const* const* _Arguments
);
_DCRTIMP intptr_t __cdecl _execvpe(
_In_z_ char const* _FileName,
_In_z_ char const* const* _Arguments,
_In_opt_z_ char const* const* _Environment
);
_DCRTIMP intptr_t __cdecl _spawnl(
_In_ int _Mode,
_In_z_ char const* _FileName,
_In_z_ char const* _Arguments,
...);
_DCRTIMP intptr_t __cdecl _spawnle(
_In_ int _Mode,
_In_z_ char const* _FileName,
_In_z_ char const* _Arguments,
...);
_DCRTIMP intptr_t __cdecl _spawnlp(
_In_ int _Mode,
_In_z_ char const* _FileName,
_In_z_ char const* _Arguments,
...);
_DCRTIMP intptr_t __cdecl _spawnlpe(
_In_ int _Mode,
_In_z_ char const* _FileName,
_In_z_ char const* _Arguments,
...);
_DCRTIMP intptr_t __cdecl _spawnv(
_In_ int _Mode,
_In_z_ char const* _FileName,
_In_z_ char const* const* _Arguments
);
_DCRTIMP intptr_t __cdecl _spawnve(
_In_ int _Mode,
_In_z_ char const* _FileName,
_In_z_ char const* const* _Arguments,
_In_opt_z_ char const* const* _Environment
);
_DCRTIMP intptr_t __cdecl _spawnvp(
_In_ int _Mode,
_In_z_ char const* _FileName,
_In_z_ char const* const* _Arguments
);
_DCRTIMP intptr_t __cdecl _spawnvpe(
_In_ int _Mode,
_In_z_ char const* _FileName,
_In_z_ char const* const* _Arguments,
_In_opt_z_ char const* const* _Environment
);
_CRT_OBSOLETE(LoadLibrary)
_DCRTIMP intptr_t __cdecl _loaddll(
_In_z_ char* _FileName
);
_CRT_OBSOLETE(FreeLibrary)
_DCRTIMP int __cdecl _unloaddll(
_In_ intptr_t _Handle
);
typedef int (__cdecl* _GetDllProcAddrProcType)(void);
_CRT_OBSOLETE(GetProcAddress)
_DCRTIMP _GetDllProcAddrProcType __cdecl _getdllprocaddr(
_In_ intptr_t _Handle,
_In_opt_z_ char* _ProcedureName,
_In_ intptr_t _Ordinal
);
#endif // _CRT_USE_WINAPI_FAMILY_DESKTOP_APP
#if _CRT_INTERNAL_NONSTDC_NAMES
#define P_WAIT _P_WAIT
#define P_NOWAIT _P_NOWAIT
#define P_OVERLAY _P_OVERLAY
#define OLD_P_OVERLAY _OLD_P_OVERLAY
#define P_NOWAITO _P_NOWAITO
#define P_DETACH _P_DETACH
#define WAIT_CHILD _WAIT_CHILD
#define WAIT_GRANDCHILD _WAIT_GRANDCHILD
#ifdef _CRT_USE_WINAPI_FAMILY_DESKTOP_APP
_CRT_NONSTDC_DEPRECATE(_cwait)
_DCRTIMP intptr_t __cdecl cwait(
_Out_opt_ int* _TermStat,
_In_ intptr_t _ProcHandle,
_In_ int _Action
);
_CRT_NONSTDC_DEPRECATE(_execl)
_DCRTIMP intptr_t __cdecl execl(
_In_z_ char const* _FileName,
_In_z_ char const* _Arguments,
...);
_CRT_NONSTDC_DEPRECATE(_execle)
_DCRTIMP intptr_t __cdecl execle(
_In_z_ char const* _FileName,
_In_z_ char const* _Arguments,
...);
_CRT_NONSTDC_DEPRECATE(_execlp)
_DCRTIMP intptr_t __cdecl execlp(
_In_z_ char const* _FileName,
_In_z_ char const* _Arguments,
...);
_CRT_NONSTDC_DEPRECATE(_execlpe)
_DCRTIMP intptr_t __cdecl execlpe(
_In_z_ char const* _FileName,
_In_z_ char const* _Arguments,
...);
_CRT_NONSTDC_DEPRECATE(_execv)
_DCRTIMP intptr_t __cdecl execv(
_In_z_ char const* _FileName,
_In_z_ char const* const* _Arguments
);
_CRT_NONSTDC_DEPRECATE(_execve)
_DCRTIMP intptr_t __cdecl execve(
_In_z_ char const* _FileName,
_In_z_ char const* const* _Arguments,
_In_opt_z_ char const* const* _Environment
);
_CRT_NONSTDC_DEPRECATE(_execvp)
_DCRTIMP intptr_t __cdecl execvp(
_In_z_ char const* _FileName,
_In_z_ char const* const* _Arguments
);
_CRT_NONSTDC_DEPRECATE(_execvpe)
_DCRTIMP intptr_t __cdecl execvpe(
_In_z_ char const* _FileName,
_In_z_ char const* const* _Arguments,
_In_opt_z_ char const* const* _Environment
);
_CRT_NONSTDC_DEPRECATE(_spawnl)
_DCRTIMP intptr_t __cdecl spawnl(
_In_ int _Mode,
_In_z_ char const* _FileName,
_In_z_ char const* _Arguments,
...);
_CRT_NONSTDC_DEPRECATE(_spawnle)
_DCRTIMP intptr_t __cdecl spawnle(
_In_ int _Mode,
_In_z_ char const* _FileName,
_In_z_ char const* _Arguments,
...);
_CRT_NONSTDC_DEPRECATE(_spawnlp)
_DCRTIMP intptr_t __cdecl spawnlp(
_In_ int _Mode,
_In_z_ char const* _FileName,
_In_z_ char const* _Arguments,
...);
_CRT_NONSTDC_DEPRECATE(_spawnlpe)
_DCRTIMP intptr_t __cdecl spawnlpe(
_In_ int _Mode,
_In_z_ char const* _FileName,
_In_z_ char const* _Arguments,
...);
_CRT_NONSTDC_DEPRECATE(_spawnv)
_DCRTIMP intptr_t __cdecl spawnv(
_In_ int _Mode,
_In_z_ char const* _FileName,
_In_z_ char const* const* _Arguments);
_CRT_NONSTDC_DEPRECATE(_spawnve)
_DCRTIMP intptr_t __cdecl spawnve(
_In_ int _Mode,
_In_z_ char const* _FileName,
_In_z_ char const* const* _Arguments,
_In_opt_z_ char const* const* _Environment
);
_CRT_NONSTDC_DEPRECATE(_spawnvp)
_DCRTIMP intptr_t __cdecl spawnvp(
_In_ int _Mode,
_In_z_ char const* _FileName,
_In_z_ char const* const* _Arguments
);
_CRT_NONSTDC_DEPRECATE(_spawnvpe)
_DCRTIMP intptr_t __cdecl spawnvpe(
_In_ int _Mode,
_In_z_ char const* _FileName,
_In_z_ char const* const* _Arguments,
_In_opt_z_ char const* const* _Environment
);
_CRT_NONSTDC_DEPRECATE(_getpid)
_ACRTIMP int __cdecl getpid(void);
#endif // _CRT_USE_WINAPI_FAMILY_DESKTOP_APP
#endif // _CRT_INTERNAL_NONSTDC_NAMES
_CRT_END_C_HEADER
#endif // _INC_PROCESS
|
While the Tour de France will be the centrepiece of Vincenzo Nibali’s 2014 season, the Astana rider looks set to make Milan-San Remo the focus of the early months of the campaign. Related Articles Fuglsang ready to help Nibali at 2014 Tour de France
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Nibali to ride Paris-Nice instead of Tirreno-Adriatico
Nibali's Tour de France not just a race against Froome
The insertion of the new climb of the Pompeiana between the Cipressa and the Poggio should tilt the balance of the race away from the sprinters and favour attackers. Nibali, who finished 3rd on the old parcours in 2012, has yet to reconnoitre the new finale, but believes that it could be to his liking.
“I have to go and see the new climb, the Pompeiana, which could be the ideal springboard,” Nibali told Gazzetta dello Sport. “Winning Milan-San Remo would be a real boost for the whole team, but I wouldn’t be satisfied just with that. Look at the Worlds: I was coming from a great since, but I still had the desire and the hunger to win.”
Nibali is currently at Astana’s first gathering ahead of the new season, in Montecatini Terme in Tuscany. While his full racing programme for 2014 is yet to be announced, Nibali effectively ruled out the prospect of returning to the Giro d’Italia to defend his crown.
“No, they’re too close – the gap between the Giro and Tour is too tight. Maybe you could do it by skipping the classics, but it would be too risky an experiment. We’ll see.”
Instead, Nibali is likely to spend an extended period at altitude and ride the Critérium du Dauphiné as preparation for the Tour, as was the case when finished 3rd overall last year. “We’re also looking at the possibility of doing two altitude training camps – one before the Dauphiné and one after,” he said.
While Michele Scarponi and Franco Pellizotti were the two most high-profile additions to Astana’s roster, Nibali will also renew his working relationship with former Liquigas trainer Paolo Slongo, who joins the Kazakh team for the new campaign.
“He knows the entire course of my development, and there’s mutual understanding between us as people,” Nibali said. “Paolo can also follow us at races as he’s a directeur sportif, and that’s no small thing. It’s not just phone calls and emails, there’s human contact too. He’s a great addition for the whole Astana team.”
Nibali and Astana will assemble for their first full training camp in Calpe, Spain from December 10 to 21, while the Sicilian is set to begin his season at the Tour de San Luis (January 20-26) and the new Dubai Tour (February 5-8), organised by RCS Sport. |
Traffic will be delayed on Highway 371 on Saturday, May 20, after cool weather stalled a road maintenance project.
One-way traffic control with a pilot car is required during the work hours between Howard Road in Anza and Barbara Trail in Aguanga. Motorists may face delays of up to 30 minutes.
Construction will take place from 7 a.m. to 3 p.m. Saturday then resume Monday, May 22 through Thursday, May 25 and, after a break for Memorial Day, May 31-Friday, June 2.
Caltrans is overseeing a $1.9 million project to apply an overlay treatment to help extend the life of the roadway. |
<reponame>jjzhang166/balancer<filename>util/regexp/glob_compat.h
#pragma once
#include <util/system/defaults.h>
#if !defined(_MSC_VER)
#include <glob.h>
#else
struct stat;
typedef struct {
int gl_pathc; /* Count of total paths so far. */
int gl_matchc; /* Count of paths matching pattern. */
int gl_offs; /* Reserved at beginning of gl_pathv. */
int gl_flags; /* Copy of flags parameter to glob. */
char **gl_pathv; /* List of paths matching pattern. */
/* Copy of errfunc parameter to glob. */
int (*gl_errfunc)(const char *, int);
/*
* Alternate filesystem access methods for glob; replacement
* versions of closedir(3), readdir(3), opendir(3), stat(2)
* and lstat(2).
*/
void (*gl_closedir)(void *);
struct dirent *(*gl_readdir)(void *);
void *(*gl_opendir)(const char *);
int (*gl_lstat)(const char *, struct stat *);
int (*gl_stat)(const char *, struct stat *);
} glob_t;
//#if __POSIX_VISIBLE >= 199209
/* Believed to have been introduced in 1003.2-1992 */
#define GLOB_APPEND 0x0001 /* Append to output from previous call. */
#define GLOB_DOOFFS 0x0002 /* Use gl_offs. */
#define GLOB_ERR 0x0004 /* Return on error. */
#define GLOB_MARK 0x0008 /* Append / to matching directories. */
#define GLOB_NOCHECK 0x0010 /* Return pattern itself if nothing matches. */
#define GLOB_NOSORT 0x0020 /* Don't sort. */
#define GLOB_NOESCAPE 0x2000 /* Disable backslash escaping. */
/* Error values returned by glob(3) */
#define GLOB_NOSPACE (-1) /* Malloc call failed. */
#define GLOB_ABORTED (-2) /* Unignored error. */
#define GLOB_NOMATCH (-3) /* No match and GLOB_NOCHECK was not set. */
#define GLOB_NOSYS (-4) /* Obsolete: source comptability only. */
//#endif /* __POSIX_VISIBLE >= 199209 */
//#if __BSD_VISIBLE
#define GLOB_ALTDIRFUNC 0x0040 /* Use alternately specified directory funcs. */
#define GLOB_BRACE 0x0080 /* Expand braces ala csh. */
#define GLOB_MAGCHAR 0x0100 /* Pattern had globbing characters. */
#define GLOB_NOMAGIC 0x0200 /* GLOB_NOCHECK without magic chars (csh). */
#define GLOB_QUOTE 0x0400 /* Quote special chars with \. */
#define GLOB_TILDE 0x0800 /* Expand tilde names from the passwd file. */
#define GLOB_LIMIT 0x1000 /* limit number of returned paths */
/* source compatibility, these are the old names */
#define GLOB_MAXPATH GLOB_LIMIT
#define GLOB_ABEND GLOB_ABORTED
//#endif /* __BSD_VISIBLE */
int glob(const char *, int, int (*)(const char *, int), glob_t *);
void globfree(glob_t *);
#endif /* _MSC_VER */
|
Maintenance of Clinical Endpoints After Discharge from a Pharmacist-Managed Risk Reduction Clinic at a Veterans Affairs Medical Center. BACKGROUND Diabetes, dyslipidemia, and hypertension are complex chronic disease states that often require close monitoring and frequent follow-up to achieve and maintain therapeutic control as determined by hemoglobin A1c (A1c), low-density lipoprotein (LDL), and blood pressure (BP). At the Charles George Veterans Affairs Medical Center (CGVAMC), physicians may refer their patients to the on-site pharmacist-managed Risk Reduction Clinic (RRC). Patients are discharged from the RRC once patient-specific therapeutic goals have been met for diabetes, dyslipidemia, and/or hypertension. This study investigated the change in A1c, LDL, and systolic blood pressure (SBP) after discharge from the CGVAMC RRC. OBJECTIVES To investigate (a) how clinical endpoints for diabetes, dyslipidemia, and hypertension change after discharge from the pharmacist-managed RRC at the CGVAMC; (b) the factors associated with worsening of monitoring parameters; and (c) the frequency of reconsultation to the RRC. METHODS In this single-center retrospective quality management study, patients were included if they had a completed consultation to the CGVAMC RRC between August 11, 2008, and January 1, 2011, for the management of type 2 diabetes, dyslipidemia, and/or hypertension. Patients were included if they were discharged from the RRC prior to October 1, 2011, due to goal attainment. Furthermore, it was required that patients have A1c, LDL, and SBP measurements, as applicable based on diagnoses, at least yearly during the first 2 years following discharge. Patients were excluded if they were discharged for any reason other than goal attainment or if they were followed by a specialty clinic related to the RRC, including the Diabetes PharmD, Diabetes MD, MIDAS (group diabetes), or MAGIC (group dyslipidemia) clinics. Data collection included patient demographics; date of and indication for consultation to the RRC; date of first RRC visit; date of discharge from the RRC; number of visits to the RRC; A1c, LDL, SBP, and weight at consultation to the RRC, at discharge, and during the 2 years following discharge from the RRC; and date of and indication for reconsultation to the RRC, as applicable. Two-tailed paired t-tests were used to compare A1c, LDL, and SBP at discharge from the RRC to A1c, LDL, and SBP during the follow-up period. Two-tailed unpaired t-tests were performed to determine which variables were associated with changes in the monitoring parameters after discharge from the RRC. RESULTS One hundred forty-nine patients were included in this study. For all patients with a diagnosis of diabetes (N = 82), A1c rose from 6.49% to 6.79% (P < 0.001) during the first year and to 7.04% (P < 0.001) during the second year following discharge. For patients diagnosed with dyslipidemia (N = 137), LDL rose after discharge from 81.5 mg/dL to 90.8 mg/dL (P < 0.001) and to 90.9 mg/dL (P < 0.001), respectively. For patients diagnosed with hypertension (N = 132), SBP rose from 126.2 mm Hg to 131.5 mm Hg (P < 0.001) and to 133.9 mm Hg (P < 0.001), respectively. An increase in A1c after discharge was associated with lower discharge A1c (P = 0.014), higher consultation weight (P = 0.009), and higher discharge weight (P = 0.042). A rise in LDL was correlated to higher consultation LDL (P = 0.006), while higher SBP was associated with lower discharge SBP (P < 0.001). Twelve percent of patients were reconsulted to the RRC. CONCLUSIONS A1c, LDL, and SBP rose after discharge from the pharmacist-managed risk reduction clinic, but these changes may not have been clinically significant based on the low reconsultation rate and values remaining close to generally accepted therapeutic goals. Patients likely to benefit from extending RRC services past goal attainment include those with higher A1c and LDL at the time of consultation and those with higher weight. As a result of this study, recommendations have been made to consider following up every 3-4 months for 2-3 additional visits for patients with baseline A1c > 8% and LDL > 115 mg/dL and those with weight > 220 pounds prior to discharging them from the CGVAMC RRC. Furthermore, we believe that all patients could benefit from extending follow-up to 6 months for 1-2 additional visits or as needed after their therapeutic goals have been reached. |
import Promise from 'bluebird';
import * as sh from 'shelljs';
/**
* Asynchronously executes a shell command and returns a promise that resolves
* with the result.
*
* The `opts` object will be passed to shelljs's `exec()` and then to Node's native
* `child_process.exec()`. The most commonly used opts properties are:
*
* - {String} cwd - A full path to the working directory to execute the `cmd` in
* - {Boolean} silent - If `true`, the process won't log to `stdout`
*
* See shell.js docs: https://github.com/shelljs/shelljs#execcommand--options--callback
* See Node docs: https://nodejs.org/api/child_process.html#child_process_child_process_exec_command_options_callback
*
* @example
*
* const execAsync = require('execAsync');
* execAsync('ls -al', { silent: true, cwd: '/Users/admin/' });
*
* @param {String} cmd - The shell command to execute
* @param {Object} opts - Any opts to pass in to exec (see shell.js docs and Node's native `exec` documentation)
* @returns {String.<Promise>} - Resolves with the command results from `stdout`
*/
const execAsync = (cmd: string, opts = {}): Promise<any> => {
return new Promise(function (resolve: (reason: string) => any, reject: (reason: string | Error) => any) {
// Execute the command, reject if we exit non-zero (i.e. error)
sh.exec(cmd, opts, function (code, stdout, stderr) {
if (code != 0) return reject(new Error(stderr));
return resolve(stdout);
});
});
};
export default execAsync; |
Prolonged culture of cells from normal human thyroid tissue and toxic goiters. Normal human thyroid cells and cells from patients with Grave's disease were cultured for 5 months (11 passages) in vitro. Both normal and diseased thyreocytes, similar in morphology, proliferated actively and responded to thyrotropin stimulation by cytoplasmic arborization of a part of the population. Slight inhibition of mitotic activity was present under the influence of thyrotropin. |
N = int(input())
es = [[] for i in range(N)]
for i in range(N-1):
a,b = map(lambda x:int(x)-1,input().split())
es[a].append(b)
es[b].append(a)
def path(s,g):
visited = [0] * N
back = [-1] * N
stack = [(s,-1)]
while stack:
a,prev = stack.pop()
visited[a] = 1
back[a] = prev
for to in es[a]:
if visited[to]: continue
if to == g:
ret = [g,a]
while back[ret[-1]] >= 0:
ret.append(back[ret[-1]])
return list(reversed(ret))
stack.append((to,a))
def fennec_win():
win_border = (N//2)+1
p = path(0,N-1)
cant_go = p[(len(p)+1)//2]
visited = [0] * N
stack = [0]
count = 0
while stack:
a = stack.pop()
visited[a] = 1
count += 1
if count >= win_border:
return True
for to in es[a]:
if visited[to] or to == cant_go: continue
stack.append(to)
return False
print('Fennec' if fennec_win() else 'Snuke')
|
A Noninvasive Method for Assessing Impaired Diastolic Suction in Patients With Dilated Cardiomyopathy Background Diastolic suction is a major determinant of early left ventricular filling in animal experiments. However, suction remains incompletely characterized in the clinical setting. Methods and Results First, we validated a method for measuring the spatio-temporal distributions of diastolic intraventricular pressure gradients and differences (DIVPDs) by digital processing color Doppler M-mode recordings. In 4 pigs, the error of peak DIVPD was 0.0±0.2 mm Hg (intraclass correlation coefficient, 0.95) compared with micromanometry. Forty patients with dilated cardiomyopathy (DCM) and 20 healthy volunteers were studied at baseline and during dobutamine infusion. A positive DIVPD (toward the apex) originated during isovolumic relaxation, reaching its peak shortly after mitral valve opening. Peak DIVPD was less than half in patients with DCM than in control subjects (1.2±0.6 versus 2.5±0.8 mm Hg, P<0.001). Dobutamine increased DIVPD in control subjects by 44% (P<0.001) but only by 23% in patients with DCM (P=NS). DIVPDs were the consequence of 2 opposite forces: a driving force caused by local acceleration, and a reversed (opposed to filling) convective force that lowered the total DIVPD by more than one third. In turn, local acceleration correlated with E-wave velocity and ejection fraction, whereas convective deceleration correlated with E-wave velocity and ventriculo:annular disproportion. Convective deceleration was highest among patients showing a restrictive filling pattern. Conclusions Patients with DCM show an abnormally low diastolic suction and a blunted capacity to recruit suction with stress. By raising the ventriculo:annular disproportion, chamber remodeling proportionally increases convective deceleration and adversely affects left ventricular filling. These previously unreported mechanisms of diastolic dysfunction can be studied by using Doppler echocardiography. |
If Hillary Clinton wasn’t above the law (as the Obama regime has thoroughly proved), she could go to jail for five years for lying to congress. She’s told so many lies under oath to Congress it’s hard to keep up. Rand Paul says that Clinton could get five years in prison for lying about selling weapons to Syria.
Hillary Clinton could get 5 years in prison for lying to congress about Syrian weapons
Secretary of State Hillary Clinton knew that the US was sending arms from Libya to Syria back in 2011, a year before the Benghazi consulate attacks. Hillary Clinton denied she knew about the weapons shipments during public testimony (under oath) in early 2013 after the Benghazi terrorist attack. Senator Rand Paul questioned Hillary Clinton about this gun running program back in January 2013 during her testimony on the Benghazi terrorist attack.
The sale of weapons to Syria is among some of the material that is expected to be released by Wikileaks (whenever they do it). That will prove she lied under oath to Congress. Of course, it wouldn’t matter, as she will never pay the price for her crimes.
Assange claims he has 1,700 e-mails proving Hillary Clinton sold weapons illegally to Syria. We’ll wait for the leak. |
/** Prints the ToS value in the hex form according to the ToS encoding. */
public static String printProfileKeyValue(MapKey key_)
{
return "src=" + key_.value.getSubset(2)
+ ",dest=" + key_.value.getSubset(1)
+ "," + classify(key_.value.getSubset(0) & DSCPMask);
} |
Differential laboratory diagnosis of hypercalcemia. It is proposed that this review will adopt the following format: establishment of hypercalcemia. This demands a discussion of the problem of normal ranges, the usage of either total calcium or ionized calcium in making this decision and where total calcium is used whether adjustment of this value for serum protein concentration should be used and if so, the formulae which have been cited to perform this. Having established hypercalcemia why is it necessary to differentiate this? This will involve reviewing those clinical situations in which differentiation of hypercalcemia has been attempted and will include an attempt to produce an up to date indication of conditions in which hypercalcemia has been described. When hypercalcemia has been established the laboratory tests which have been further used to discriminate will be divided into single tests such as N- or C- terminal parathormone, 1,25- dihydroxycholecalciferol, cyclic AMP; the combination tests which have been used including phosphate clearance, chloride vs. bicarbonate etc. proceeding to those groups which have used discriminant function to help in the decision making; dynamic testing will also be discussed particularly with reference to steroid suppression but will also include other known suppressants such as Mithramycin and Calcitonin. A final section will be included attempting to assess overall the present state of art in differentiating laboratory diagnosis of hypercalcemia and will also attempt to highlight those areas which appear to be most fruitful areas of progress in the future. |
/**
* Copyright (c) Rich Hickey. All rights reserved.
* The use and distribution terms for this software are covered by the
* Eclipse Public License 1.0 (http://opensource.org/licenses/eclipse-1.0.php)
* which can be found in the file epl-v10.html at the root of this distribution.
* By using this software in any fashion, you are agreeing to be bound by
* the terms of this license.
* You must not remove this notice, or any other, from this software.
**/
/* rich Jun 18, 2009 */
package clojure.lang;
public interface IChunk extends Indexed{
IChunk dropFirst();
Object reduce(IFn f, Object start) ;
}
|
Demonstration of a ~40 kV Si Vacuum Transistor as a Practical High Frequency and Power Device We demonstrate for the first time a vacuum transistor fabricated based upon Si operating in excess of 38 kV applied bias, a voltage normally reserved for high bandgap materials such as SiC and GaN. This is a proof of a concept demonstration of a high-performance vacuum transistor with the potential of having a semiconductor-like footprint. The device consists of a gated field emission array or an electron source, a vacuum drift region and a metal anode. Electrons are emitted from the gated field emission array into vacuum through tunneling, travel through vacuum and are collected at the anode. In this case, the vacuum determines the properties of transport and the high voltage isolation. Important figures of merit: the Baliga, Johnson and power vs. frequency figures of merit (FOMs) are theoretically derived and show the benefits of using a vacuum drift channel, especially for applications which require both high frequency and power. The origin of the improved performance comes from the high critical field of vacuum and most importantly the unbounded nature of the electron velocity due to a lack of scattering. |
Universal composite hypothesis testing: A competitive minimax approach A novel approach is presented for the long-standing problem of composite hypothesis testing. In composite hypothesis testing, unlike in simple hypothesis testing, the probability function of the observed data, given the hypothesis, is uncertain as it depends on the unknown value of some parameter. The proposed approach is to minimize the worst case ratio between the probability of error of a decision rule that is independent of the unknown parameters and the minimum probability of error attainable given the parameters. The principal solution to this minimax problem is presented and the resulting decision rule is discussed. Since the exact solution is, in general, hard to find, and a fortiori hard to implement, an approximation method that yields an asymptotically minimax decision rule is proposed. Finally, a variety of potential application areas are provided in signal processing and communications with special emphasis on universal decoding. |
#if !defined(AFX_DRAWFRAME_H__221D28C2_B68C_11D4_9F32_00C0F02A5F5D__INCLUDED_)
#define AFX_DRAWFRAME_H__221D28C2_B68C_11D4_9F32_00C0F02A5F5D__INCLUDED_
#if _MSC_VER > 1000
#pragma once
#endif // _MSC_VER > 1000
// DrawFrame.h : header file
//
/////////////////////////////////////////////////////////////////////////////
// CDrawFrame frame
class CDrawFrame : public CFrameWnd
{
DECLARE_DYNCREATE(CDrawFrame)
protected:
CDrawFrame(); // protected constructor used by dynamic creation
// Attributes
public:
//BOOL Create(LPCTSTR lpszClassName, LPCTSTR lpszWindowName, DWORD dwStyle,
// RECT& rect, CWnd* pParentWnd, UINT nID, CCreateContext* pContext = NULL);
// Operations
public:
// Overrides
// ClassWizard generated virtual function overrides
//{{AFX_VIRTUAL(CDrawFrame)
//}}AFX_VIRTUAL
// Implementation
protected:
virtual ~CDrawFrame();
// Generated message map functions
//{{AFX_MSG(CDrawFrame)
// NOTE - the ClassWizard will add and remove member functions here.
//}}AFX_MSG
DECLARE_MESSAGE_MAP()
};
/////////////////////////////////////////////////////////////////////////////
//{{AFX_INSERT_LOCATION}}
// Microsoft Visual C++ will insert additional declarations immediately before the previous line.
#endif // !defined(AFX_DRAWFRAME_H__221D28C2_B68C_11D4_9F32_00C0F02A5F5D__INCLUDED_)
|
. The influence of intravenous Flunitrazepam (0.4-0.8 mg), Benzoctamine (10-20 mg) and Placebo (NaCl 0.9%) on pO2, pCO2, forced vital capacity, forced expiratory volume and peak flow were investigated in patients with reduced lung function undergoing orthopaedic surgery under spinal anaesthesia. Both drugs depress respiration: Flunitrazepam immediately, Benzoctamine about 15 min after administration. Both drugs reduce lung function in the postoperative period. They should be administered under careful observation of patients' respiration, administration of oxygen and only in special cases where sedation is necessary to reduce psychological stress. The advantage of regional anaesthesia in patients with high risk of postoperative pulmonary failure seems worth retaining compared to general anaesthesia. |
Synthesis of Porphyrin, Chlorin and Phthalocyanine Derivatives by Azide-Alkyne Click Chemistry. The aim of this review is to provide a summary of the use of copper-catalyzed azide-alkyne cycloaddition (CuAAC) in the synthesis of porphyrin, chlorin and phthalocyanine derivatives for different types of therapeutic applications. The click reaction is a powerful and versatile tool for scientists working on the synthesis of various symmetrically and asymmetrically substituted tetrapyrrolic derivatives. For example, click chemistry is widely used for the elaboration of photosensitizer conjugates for photodynamic therapy applications. Other biological applications are also described. |
Provisional attachment has been made by the Income Tax department in more than 900 cases of properties under the Prohibition of Benami Property Transactions Act, which came into force November 1, 2016.
These attachments include plots of land, flats, shops, jewellery, vehicles, deposits in bank accounts and fixed deposits. The value of properties under attachment is more than Rs. 3,500 crore, including immovable properties of more than Rs. 2,900 crore, said a press release.
In five cases, the provisional attachments of benami properties, amounting to more than Rs. 150 crore have been confirmed by the adjudicating authority. In one such case, it was established that a real estate company had acquired about 50 acres of land, valued at more than Rs.110 crore, using the names of certain persons of no means as benamidars. This was corroborated from the sellers of the land as well as the brokers involved.
In another case, post demonetisation, two assessees were found depositing demonetised currency into multiple bank accounts in the names of their employees, associates to be ultimately remitted to their bank accounts. The total amount attempted to be remitted to the beneficial owners was about Rs. 39 crore.
In yet another case, cash of Rs. 1.11 crore was intercepted from a vehicle with a person who denied the ownership of the cash. Subsequently, no one claimed ownership of the cash and it was held to be benami property.
Earlier, the income tax department had stepped-up actions under the Prohibition of Benami Property Transactions Act, which provides for provisional attachment and subsequent confiscation of benami properties.
It also allows for prosecution, which may result in rigorous imprisonment up to 7 years and fine upto 25 percent of fair market value of the property.
The department had set-up 24 dedicated Benami Prohibition Units under its investigation directorates all over India in May, 2017 to ensure swift action in respect of benami properties. |
<filename>idempotence4j-postgres/src/main/java/com/transferwise/idempotence4j/postgres/JdbcPostgresLockProvider.java
package com.transferwise.idempotence4j.postgres;
import com.transferwise.idempotence4j.core.ActionId;
import com.transferwise.idempotence4j.core.Lock;
import com.transferwise.idempotence4j.core.LockProvider;
import com.transferwise.idempotence4j.jdbc.mapper.ActionSqlMapper;
import org.springframework.jdbc.core.JdbcTemplate;
import org.springframework.jdbc.core.namedparam.MapSqlParameterSource;
import org.springframework.jdbc.core.namedparam.NamedParameterJdbcTemplate;
import java.util.Optional;
public class JdbcPostgresLockProvider implements LockProvider {
private final NamedParameterJdbcTemplate namedParameterJdbcTemplate;
private final ActionSqlMapper sqlMapper = new ActionSqlMapper();
public JdbcPostgresLockProvider(JdbcTemplate jdbcTemplate) {
this.namedParameterJdbcTemplate = new NamedParameterJdbcTemplate(jdbcTemplate);
}
@Override
public Optional<? extends Lock> lock(ActionId actionId) {
MapSqlParameterSource parameters =new MapSqlParameterSource()
.addValue("key", actionId.getKey())
.addValue("type", actionId.getType())
.addValue("client", actionId.getClient());
return namedParameterJdbcTemplate.query(LOCK_SQL, parameters, (rs, rowNum) -> new PostgresRowLock(sqlMapper.toEntity(rs)))
.stream()
.findFirst();
}
//@formatter:off
private final static String LOCK_SQL =
"SELECT " +
"key, type, client, created_at, last_run_at, completed_at, result, result_type " +
"FROM idempotent_action " +
"WHERE " +
"key = :key " +
"AND type = :type " +
"AND client = :client " +
"FOR UPDATE " +
"SKIP LOCKED";
//@formatter:on
}
|
/*-
* Copyright (c) 2005-2007, <NAME>
* All rights reserved.
*
* Redistribution and use in source and binary forms, with or without
* modification, are permitted provided that the following conditions
* are met:
* 1. Redistributions of source code must retain the above copyright
* notice, this list of conditions and the following disclaimer.
* 2. Redistributions in binary form must reproduce the above copyright
* notice, this list of conditions and the following disclaimer in the
* documentation and/or other materials provided with the distribution.
* 3. Neither the name of the author nor the names of any co-contributors
* may be used to endorse or promote products derived from this software
* without specific prior written permission.
*
* THIS SOFTWARE IS PROVIDED BY THE AUTHOR AND CONTRIBUTORS ``AS IS'' AND
* ANY EXPRESS OR IMPLIED WARRANTIES, INCLUDING, BUT NOT LIMITED TO, THE
* IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE
* ARE DISCLAIMED. IN NO EVENT SHALL THE AUTHOR OR CONTRIBUTORS BE LIABLE
* FOR ANY DIRECT, INDIRECT, INCIDENTAL, SPECIAL, EXEMPLARY, OR CONSEQUENTIAL
* DAMAGES (INCLUDING, BUT NOT LIMITED TO, PROCUREMENT OF SUBSTITUTE GOODS
* OR SERVICES; LOSS OF USE, DATA, OR PROFITS; OR BUSINESS INTERRUPTION)
* HOWEVER CAUSED AND ON ANY THEORY OF LIABILITY, WHETHER IN CONTRACT, STRICT
* LIABILITY, OR TORT (INCLUDING NEGLIGENCE OR OTHERWISE) ARISING IN ANY WAY
* OUT OF THE USE OF THIS SOFTWARE, EVEN IF ADVISED OF THE POSSIBILITY OF
* SUCH DAMAGE.
*/
#ifndef _TIMER_H
#define _TIMER_H
#include <types.h>
#include <sys/cdefs.h>
#include <sys/list.h>
#include <sys/sysinfo.h>
#include <event.h>
/*
* Time-out element.
*/
struct timer {
struct list link; /* linkage on timer chain */
int state; /* timer state */
u_long expire; /* expiration time, in ticks */
u_long interval; /* time interval */
void (*func)(void *); /* function to call */
void *arg; /* function argument */
struct event event; /* event for this timer */
};
/* state for timer */
#define TM_ACTIVE 0x54616321 /* magic# 'Tac!' */
#define TM_STOP 0x54737421 /* magic# 'Tst!' */
/*
* Macro to compare two timer counts.
* time_after() returns true if a is after b.
*/
#define time_after(a,b) (((long)(b) - (long)(a)) < 0)
#define time_before(a,b) time_after(b,a)
#define time_after_eq(a,b) (((long)(a) - (long)(b)) >= 0)
#define time_before_eq(a,b) time_after_eq(b,a)
/*
* Macro to get the next element on timer list.
*/
#define timer_next(head) \
(list_entry(list_first(head), struct timer, link))
__BEGIN_DECLS
void timer_callout(struct timer *, u_long, void (*)(void *), void *);
void timer_stop(struct timer *);
u_long timer_delay(u_long);
int timer_sleep(u_long, u_long *);
int timer_alarm(u_long, u_long *);
int timer_periodic(thread_t, u_long, u_long);
int timer_waitperiod(void);
void timer_cancel(thread_t);
void timer_clock(void);
void timer_handler(void);
u_long timer_ticks(void);
void timer_info(struct timerinfo *);
void timer_init(void);
__END_DECLS
#endif /* !_TIMER_H */
|
// NewF5Controller creates a F5 controller
func NewF5Controller(kubeClient *unversioned.Client, watchNamespace string, conf map[string]string, configLabelKey, configLabelValue string) (backend.BackendController, error) {
f5Host := os.Getenv("F5_HOST")
f5User := os.Getenv("F5_USER")
f5Password := os.Getenv("F5_PASSWORD")
if f5Host == "" && f5User == "" && f5Password == "" {
glog.Fatalln("F5_HOST, F5_USER, F5_PASSWORD env variables not set")
} else if f5Host == "" {
glog.Fatalln("F5_HOST env variable not set")
} else if f5User == "" {
glog.Fatalln("F5_USER env variable not set")
} else if f5Password == "" {
glog.Fatalln("F5_PASSWORD env variable not set")
}
f5Session := bigip.NewSession(f5Host, f5User, f5Password)
ns := os.Getenv("POD_NAMESPACE")
if ns == "" {
ns = api.NamespaceDefault
}
ipMgr := controllers.NewIPManager(kubeClient, ns, watchNamespace, configLabelKey, configLabelValue)
if ipMgr == nil {
glog.Fatalln("NewIPManager returned nil")
}
lbControl := F5Controller{
f5: f5Session,
kubeClient: kubeClient,
watchNamespace: watchNamespace,
configMapLabelKey: configLabelKey,
configMapLabelValue: configLabelValue,
ipManager: ipMgr,
namespace: ns,
}
return &lbControl, nil
} |
Xenotransplantation in China: Present status The main obstacle to organ transplantation is the shortage of organs from deceased individuals. Especially in China, the ratio of patients on the waiting list versus the transplant recipients is 30:1. Therefore, there is an urgent need for organ donors. Genetically modified pig organs have proved to be a new source for xenotransplantation, and Chinese scientists have made considerable progress in this area during recent years. In this paper, we review four important aspects of the xenotransplantation field in China. First, a large variety of genetically modified pigs have been generated by Chinese scientists: all these genetically modified pigs and the purpose of these modifications will be summarized. Second, the preclinical research in pigtononhuman primate xenotransplantation is outlined. The survival time and major biochemical parameters for the xenografts are summarized. Third, regarding the benchtobed approach, more suitable organs have been developed for xenotransplantation in humans, and in particular, pig islet transplantation into diabetic patients as well as pigtohuman cornea and skin transplantation. Fourth, we briefly address the regulations and prospects for recruiting xenotransplantation experts in China. Based on recent progress, we anticipate that genetically modified pigs will offer suitable organs for the treatment of endstage organ diseases in humans in the near future. Given the recent influx of worldrenowned scientists in xenotransplantation to China, our country will definitely become one of the major centers of xenotransplantation research and development in the world. |
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