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Karol G performs at Mix Live! Presented by Uforia at American Airlines Arena on June 9, 2018 in Miami.
The nominees for the 2018 Latin Grammys were announced Sept. 20. As usual, one of the most popular categories was the best new artist field, in which all nominees were extremely excited to receive such an important and once-in-a-lifetime nomination.
Billboard has gathered more details about all the 2018 hopefuls. From Karol G to Christian Nodal, meet the Latin Grammys' 2018 best new artist nominees.
Carolina Giraldo Navarro, better known by her stage name Karol G, is a Colombian reggaeton/urban singer and songwriter.
Biggest milestone: With her latest video “Culpables,” featuring Anuel AA, Karol G peaked at No. 3 on YouTube’s global chart.
On the Billboard charts: On Hot Latin Songs Karol G has eight total charted titles. Out of those, two went top 10: "Ahora Me Llama” with Bad Bunny (peaked at No. 10 on chart dated Nov. 4, 2017), and “Mi Cama” with J Balvin featuring Nicky Jam, which peaked at No. 6 on the Aug. 25, 2018-dated chart.
Why people should listen to her music: Karol G is breaking all the barriers in urban music. She has established that women can also be powerful without losing her essence.
Biggest milestone: Two Latin Grammy nominations.
On the Billboard charts: Her album Primero Soy Mexicana peaked at No. 13 on the Latin Albums Sales chart, dated May 12, 2018 and on the Regional Mexican Digital Songs Sales chart “Tu Sangre en Mi Cuerpo” peaked at No. 2 (chart dated July 8, 2017) and “La Llorona” debuted at No. 14 on the chart dated April 14, 2018 (only one charted week).
Why people should listen to her music: Angela Aguilar’s music shows Pepe Aguilar’s musical background, but she definitely has her own style as a millennial artist.
Biggest milestone: In 2017, she dropped her jazz album Nocturno.
Why people should listen to her music: Anaadi’s music style and sounds are spiritual and classic.
LosPetitFellas is an alternative musical project born in 2006 under the name of Pet Fella and led by vocalist Nicolás Barragán. Today, the band includes Sebastian Panesso (guitarist), Adrián Hidalgo (saxophonist), Nicolás Garzón (bassist), Andrés Gómez (keyboardist), Cesar Henao (drummer) and David Cortés (engineer). Their intention is to generate a positive, creative and fresh space for alternative music in the country.
Biggest milestone: Latin Grammy nomination.
Why people should listen to their music: This rock band is giving Latin alternative music a creative twist, experimenting with jazz, funk, hip-hop, soul and blues.
Nana Mendoza is an emerging artist from Mexico, and she's giving music lovers a taste of her neo-soul-meets-hip-hop-meets-R&B-meets-organic-beats sound. Nana has toured with Sin Bandera and was the lead voice of Cacho Gaytan’s project “La Manzana del Jazz.” -- J.R.
Biggest milestone: Her latest album Miradas.
Why people should listen to her music: Nana Mendoza’s music is fresh, organic and authentic.
Benjamin Walker is a Chilean singer-songwriter who has been making music since childhood and professionally sings trova. For his second album, Brotes (2017), he exhibited a style beyond the traditional trova, approaching pop.
Why people should listen to his music: His musical style is a mix of trova, bossa nova and pop.
El David Aguilar is a singer-songwriter of independent Mexican music who has been interpreting his songs throughout Mexico since 2003. He has performed his songs in Spain, France, Cuba, the United States, Argentina and Uruguay. He has recently been invited to collaborate on various projects by renowned songwriters, such as Kevin Johansen and Jorge Drexler.
Biggest milestone: Five Latin Grammy nominations in four categories: song of the year, album of the year, best new artist and best songwriter album.
Why people should listen to his music: His music is a mix of the Mexican, Brazilian and Spanish rhythms with rock-pop-folk from the '60s to the '90s.
Álex Ferreira is a Dominican singer/songwriter and has collaborated and shared the stage with artists such as Fito Páez, Jorge Drexler, Iván Ferreiro, Russian Red, Mäbu, Lori Meyers, Ximena Sariñana, Natalia Lafourcade, Gaby Moreno, Lisandro Aristimuño and Xoel López.
Why people should listen to his music: He is a Dominican singer who presents rock and pop in a particular way.
Christian Nodal is a Mexican singer-songwriter of mariachi. At age 13, he discovered that he had the ability to write songs and decided to put his feelings into words and transform them into songs. "Te Falle" is one of the songs that he made known via social networks.
Biggest milestone: Latin Grammy nominations.
On the Billboard charts: On the Regional Mexican Albums chart, Me Dejé Llevar debuted at No. 1 on chart dated Sept. 6, 2017. It remained at the penthouse for 46 weeks. The most weeks at No. 1 for an album by a male artist in the history of the chart, thus far. It has also earned the record for an album with second-most weeks ever (behind only Selena's Amor Prohibido with 97 weeks at No. 1).
Why people should listen to his music: Christian Nodal's style is mariachi fused with Norteño, without leaving aside his best instrument: the accordion.
A Colombo-Venezuelan singer-songwriter who aims to conquer the world hypnotizing everyone with traveling lyrics and fresh melodies, always making songs and everything. |
/**
* Copyright 2013-2016 <NAME>
* Test fixture for MongoDB data access classes for gedbrowser.
*/
package org.schoellerfamily.gedbrowser.persistence.mongo.fixture;
|
Much has been made in recent weeks of the shared birthday of Abraham Lincoln and Charles Darwin, two juggernauts not only of their own age, but of all the years since. New Yorker writer Adam Gopnik explores their legacies in this book-length series of essays, focusing on their abilities as writers and thinkers of the highest caliber. As Gopnik writes, "Literary eloquence is essential to liberal civilization; our heroes should be men and women possessed by the urgency of utterance." With their adherence to logic and observation, and devotion to thoughtful expression, Lincoln and Darwin in addition to everything else they accomplished helped kickstart the engine of the modern age.
1. On the origin of Lincoln's facility with words: "The frontier America of Lincoln's youth was first of all a rhetorical society, where the ability to speak in public, at length was central to social ambitions; giving a speech in 1838 in Illinois was the equivalent of putting on a play in 1598 in London, the thing you did into which everything else flowed. (We are, by turn and a writer says it with sadness essentially a society of images: a viral YouTube video, an advertising image, proliferates and sums up our desires; anyone who can't play the image game has a hard time playing any public game at all.)"
2. On the larger effects of Darwin's writing: "[T]he most important way in which Darwin altered his era was by getting people who did do science to ask a new kind of question. Some scientific revolutions have surprisingly small ideological aftershocks; Michael Faraday's discovery that electricity and magnetism are the same thing was as large a discovery as any in the history of science, but it had a paltry aftereffect...For a new scientific theory to become a model in its time, vastly influential outside its immediate claims, it has to release thinking people from a bond that they had long recognized as too narrow and help them interrogate the world in a new way."
3. On why everyone should read On the Origin of Species: "Great books of science, like all great books, are worth reading not just for what they add to objective knowledge; they are worth reading because they advance our liberal education. Just as we don't read Dante for a sneak peek at the afterlife or because we expect someday to be confronted with a diabolical architecture of circles within circles and punishments suited to our sins, we don't read Darwin because what he says is what scientists now believe much of it isn't. We read him because a book of eloquent argument and well-ordered evidence...reminds us of the powers of the human mind to bring light to darkness, make a clearing in the wood of confusion."
Rather than a biographical re-hash wise, for possibly only Jesus bests Lincoln in the number of published books devoted to a single person Gopnik offers a meditation on each man's most literary qualities: Lincoln's deceptively simple legalistic language and Darwin's crystalline powers of observation. And what could have been a gimmick (a book timed to twin bicentennials is as close as historical biographies get to a home run) becomes something more, a learned treatise that worships learning. Gone is the overly twee writing of Gopnik's memoir-inflected works (Paris to the Moon, Through the Children's Gate), and in its place is a succint, convincing, and moving account of how two men ripped mankind out of its past unreason and thrust it into a more enlightened age. Much has flowed from them. |
/// Write/associate a value/node with a defined variable. Usually called when the
/// expression has an assignment.
///
/// It is up to the caller function to ensure that the sizes are compatible, and insert
/// appropriate width operations if necessary.
pub fn write_variable(&mut self, address: MAddress, variable: VarId, value: T::ValueRef) {
radeco_trace!(
"phip_write_var|{:?}|{} ({:?})|{}",
value,
variable,
self.regfile.whole_names.get(variable as usize),
address
);
if let Some(rname) = self.regfile.whole_names.get(variable as usize) {
// XXX
self.ssa.set_register(value, rname.clone());
}
self.current_def[variable as usize].insert(address, value);
self.outputs.insert(value, variable);
radeco_trace!("Wrote: {:?} <- {:?}", variable, value);
} |
Single replacement constructs of all hydroxyl, basic, and acidic amino acids identify new function and structure-sensitive regions of the mitochondrial phosphate transport protein. The phosphate transport protein (PTP) catalyzes the proton cotransport of phosphate into the mitochondrial matrix. It functions as a homodimer, and thus residues of the phosphate and proton pores are somewhat scattered throughout the primary sequence. With 71 new single mutation per subunit PTPs, all its hydroxyl, basic, and acidic residues have now been replaced to identify these essential residues. We assayed the initial rate of pH gradient-dependent unidirectional phosphate transport activity and the liposome incorporation efficiency (LIE) of these mutants. Single mutations of Thr79, Tyr83, Lys90, Tyr94, and Lys98 inactivate transport. The spacings between these residues imply that they are located along the same face of transmembrane (TM) helix B, requiring an extension of its current model C-terminal domain by 10 residues. This extension superimposes very well onto the shorter bovine PTP helix B, leaving a 15-residue hydrophobic extension of the yeast helix B N-terminus. This is similar to the helix D and F regions of the yeast PTP. Only one transport-inhibiting mutation is located within loops: Ser158Thr in the matrix loop between helices C and D. All other transport-inhibiting mutations are located within the TM helices. Mutations that yield LIEs of <6% are all, except for four, within helices. The four exceptions are Tyr12Ala near the PTP N-terminus and Arg159Ala, Glu163Gln, and Glu164Gln in the loop between helices C and D. The PTP C-terminal segment beyond Thr214 at the N-terminus of helix E has 11 mutations with LIEs >20% and none with LIE <6%. Mutations with LIEs >20% are located near the ends of all the TM helices except TM helix D. Only a few mutations alter PTP structure (LIE) and also affect PTP transport activity. A novel observation is that Ser4Ala blocks the formation of PTP bacterial inclusion bodies. |
DLG2 Impairs dsDNA Break Repair and Maintains Genome Integrity in Neuroblastoma Background: In primary neuroblastoma, deletions on chromosome 11q are known to result in an increase in the total number of chromosomal breaks. Microhomology mediated-end joining (MMEJ) is an error-prone pathway for DNA double-strand break repair that is often upregulated in cancer. DLG2, a candidate tumor suppressor gene on chromosome 11q, has previously been implicated in DNA repair. Methods: We evaluated an association between MMEJ gene expression and neuroblastoma patient outcome, risk categorization, and 11q status using publicly available microarray data from independent neuroblastoma patient datasets. Functional studies were conducted using comet assay and H2AX phosphorylation in neuroblastoma cell lines and in the fruit y with UVC-induced DNA breaks. Results: We show that the MMEJ genes PARP1 and FEN1 are over expressed in neuroblastoma and restoration of DLG2 impairs their gene and protein expression. When exposed to UVC radiation, cells with DLG2 over expression show less DNA fragmentation and induce apoptosis in a p53 S46 dependent manner. We could also conrm that DLG2 expression results in CHK1 phosphorylation consistent with previous reports of G2/M maintenance. Conclusions: Taken together, we show that DLG2 expression increases p53 mediated apoptosis in response to genotoxicity, by maintaining S317 CHK1 phosphorylation and reducing the DNA replication machinery. added to comet assay microscope slides. The slides were allowed to harden for 15 min, lysed (pH 10; 4°C) for 1 hour in pre-chilled lysis buffer, subsequently washed 3 times in alkaline buffer and transferred into alkaline buffer for electrophoresis. The slides were run for 30 min at 1V/cm, 300 mA, washed 3 times with H 2 O, incubated for 5 min with ice cold 70% ethanol, allowed to air dry, and incubated with Vista green for visualization. Measurements and analysis were performed using Image J software version 1.52a. Data were normalized to the control transfection and expressed as a percentage of the control. Background Neuroblastoma (NB) is a tumor arising from the embryonic neural crest, later presenting in the autonomous nervous system. It is one of the most common forms of pediatric malignancies and has a disproportionately high mortality rate. Clinical screening and eventual diagnosis of NB is di cult due to the vague appearance of symptoms which is compounded by the young age of the patients. NB can be de ned by risk group, both low and intermediate NB have good treatment prospects, whereas high risk tumors are di cult to treat with current protocols. This di culty to treat results in higher incidence of refractory NB as well as higher mortality, indicating that new treatments are needed. High-risk NBs are highly aggressive, with speci c genetic lesions, copy number variations (CNV), and structural chromosomal changes. Common genetic features of NB include chromosome 1p deletion and 17q gain, whereas 11q deletion and ampli cation of the proto-oncogene MYCN account for approximately 30% and 20% of all NB cases, respectively. In NB, deletion of 11q has previously been shown to result in an increase in the number of chromosomes with DNA breaks as well as the total number of chromosomal breaks. DNA strand breaks can be repaired using different mechanisms depending on the type of break. DNA repair of single-strand breaks will often be highly successful as the DNA template still remains. In contrast, double-strand break repair can be deleterious as there is no template remaining for use during DNA repair. There are two main mechanisms by which double-strand break repair occurs: 1) Homologous Repair (HR) is highly reliable and uses the sister chromatid as a template, but can only take place during the S and G2 cell cycle phases and 2) non-homologous end joining (NHEJ) does not use a template and directly ligates the two ends of the DNA breaks, meaning that the repair mechanism can be active throughout the cell cycle, except during mitosis. In NB, the 11q-deleted region spans a number of candidate tumor suppressor genes such as ATM,H2AX, CHK1 and MRE11a, all of which are involved in DNA damage response (DDR). Recently, 11q deleted NB was shown to have abnormally low expression of Discs Large Homologue 2 (DLG2; 11q14). Low DLG2 expression has also been found in osteosarcoma and ovarian cancer. Previous results show that DLG2 can regulate the cell cycle as well as potentially regulating DNA damage repair. All of the candidate tumor suppressors spanning the 11q region have been shown to lack the second hit as per the Knudson two-hit hypothesis. It has, therefore, previously been suggested that there is a coalescence of haploinsu ciency within a single pathway. However, this has not yet been investigated. In this study, we investigate the difference in expression of genes associated with MMEJ in primary NB of various stages, and can show that some of these changes may be induced by loss of DLG2. Furthermore, we can show that DLG2 loss increases the presence of DNA double-strand breaks, and that restoration of DLG2 results in an increase in overall genomic stability. Comet assay To determine DNA damage repair post UV exposure, comet assay was performed according to the manufacturer's protocol (Abcam, Cat. ab238544). Aliquots of 10 000 cells were mixed with low melting point agarose and added to comet assay microscope slides. The slides were allowed to harden for 15 min, lysed (pH 10; 4°C) for 1 hour in pre-chilled lysis buffer, subsequently washed 3 times in alkaline buffer and transferred into alkaline buffer for electrophoresis. The slides were run for 30 min at 1V/cm, 300 mA, washed 3 times with H 2 O, incubated for 5 min with ice cold 70% ethanol, allowed to air dry, and incubated with Vista green for visualization. Measurements and analysis were performed using Image J software version 1.52a. Data were normalized to the control transfection and expressed as a percentage of the control. Quantitative PCR (qPCR) analysis Total RNA from NB cell lines and ies was extracted using the RNeasy plus mini kit® (Qiagen) according to the manufacturer's protocol. The RNA concentration was quanti ed by NanoDrop (NanoDrop Technologies) and 2 g of RNA was reverse transcribed into double stranded cDNA on a T-professional Basic Gradient thermal cycler (Biometra) using the High Capacity cDNA Reverse Transcription kit (Applied Biosystems). cDNA corresponding to 20 ng of RNA for each qPCR reaction was used. qPCR was performed on a Pikoreal qPCR System (Thermo Fisher Scienti c) in triplicate for TaqMan Human and Drosophila transcripts (Table 1), using TaqMan™ Gene Expression Master Mix (Applied Biosystems, Cat. 4318157). Quantitative gene expression data were normalized to the expression levels of the two human reference genes GAPDH and GUSB, or the y reference gene Rpl32 (Table 1) using the Livak method. Apoptosis assay Apoptosis levels were determined in the transfected NB cells to con rm the previous qPCR results by the Apo-ONE® Homogeneous Caspase-3/7 Assay (Promega) by exciting at 485nm and reading at 520nm using a FLUOstar Omega multiplate reader (BMG Labtech), as per the manufacturer's instructions. After the addition of the caspase assay, the plate was incubated for 65 min at room temperature. Apoptosis was calculated by subtracting the uorescence for the average blank background and then normalizing against the mean of the control cells. Fly strains and crosses Commercially available control white (w1118) ies (Drosophila melanogaster) and UAS-RNAi-dlg1 ies were crossed with da-GAL4 driver strain to silence gene expression. All strains were obtained from the Bloomington Drosophila Stock Center (Bloomington). Twenty female da-GAL4 ies were crossed with 10 male UAS-transgenic ies or control ies and the progeny incubated at 25 °C on standard y media. 10 ies per cross were subsequently harvested for subsequent RNA and DNA preparation. To determine the effect of UVC irradiation the crosses were subject to 30 Seconds UVC and 3 hours recovery on regular substrate. Nanopore libraries and Sequencing To prepare ONT libraries D.melanogaster gDNA was extracted with the Blood & Cell Culture DNA Kit (13323, Qiagen) using the manufacturers tissue protocol. Libraries were prepared with 1 g gDNA using the Ligation Sequencing Kit SQK-LSK109 (Oxford Nanopore Technologies) combined with native barcoding expansion 1-12 PCR free EXP-NBD104 (Oxford Nanopore Technologies) according to the manufacturer's protocol. A single 24 h sequencing run for D.melanogaster were performed with an R9.4.1MinION ow cell. Sequence alignment and quanti cation of DNA integrity To quantify DNA breakage, a strategy of global alignment between the full length of the sequenced reads and the corresponding reference genome region, where the read best aligned was chosen. Initial alignment was performed with BLASTn version 2.9.0+. A custom BLAST reference database was created from FlyBase D.melonagaster version 6.38 (FB2021_02, released April 13, 2021), ltered to only contain chromosomes. All reads passing quality control were subsequently BLASTed to this database using a gap opening and extension penalty of 1 and an e value cutoff of 1e-10. Only hits that uniquely mapped to the reference genome were considered for further downstream alignment. Global alignment was performed using the needle function from the Biopython module EMBOSS on the full length of the read and the corresponding region of the same length in the reference genome. Every mismatch, insertion and deletion were counted in these alignments. To quantify fused sequences, previously discarded reads were counted that t the following criteria: the read has exactly two BLAST hits and there is at least 10kb between the two hits to account for larger deletions in the sequenced DNA. Western blot Total protein was extracted from transfected cells in 24 well plates (1 10 5 cells/well), by aspirating the media and incubating on ice for 5 min then adding ice cold RIPA buffer (Thermo Fisher Scienti c, Cat. Statistical analysis All data are presented as Tukey's box and whisker plots showing IQR, line at the median, + at the mean with whiskers ±1.5-fold of interquartile range for at least 3 independent experiments. For all multi-group analyses, differences were determined by one-way ANOVA test followed by Holm-Sidak's multiple comparison test. For comparisons between two groups, Mann-Whitney U test was performed. A p<0.05 was considered to be statistically signi cant. All analyses were conducted using GraphPad Prism version 9.0.1 for Windows (GraphPad Software, www.graphpad.com). DLG2 enhanced DNA repair in NB cells after UVC irradiation To determine whether NB cells with or without 11q-deletion had more tendency to accumulate DNA breaks, we induced DNA breaks by exposure to UVC in combination with a forced change in DLG2 expression level. DNA integrity was assessed by exposing DLG2 transfected NB cells to UVC irradiation followed by comet assay. We could determine that silencing of DLG2 resulted in a smaller comet assay head size (68.7%, p < 0.001) and longer tail length (60.1%, p < 0.001) in 11q normal NB cells prior to UVC irradiation. Silencing DLG2 in 11q deleted cells resulted in no change in head size (15.0%, p = 0.21) but an increased tail size (33.3%, p < 0.001), indicating fewer intact DNA strands and more DNA breaks in cells with lower DLG2 levels (Fig. 2a, b). A decrease in head size (54.1%, p < 0.001) was also detected in the DLG2 over expressed cells before UVC irradiation in 11q normal NB cells. However, tail length was shown to be decreased in both 11q normal (43.2%, p < 0.001) and 11q-deleted (29.4%, p < 0.001) cells with DLG2 over expression prior to UVC irradiation, indicating a general effect on the amount of DNA breaks without inducing breaks (Fig. 2b). To determine the effect of DLG2 on DNA repair, we induced DNA breaks with UVC irradiation in 11q-deleted and 11q-normal NB cells and allowed the cells to recover for 4 hours. Using comet assay, we could determine that there was a decrease in the head size in both 11q-normal and 11qdeleted cells after irradiation in DLG2 silenced cells (20.1%, p < 0.001 and 50.4%, p < 0.001) and control samples (36.1%, p < 0.001 and 38.2%, p < 0.001); no difference was seen between the irradiated and nonirradiated samples when DLG2 was over expressed (Fig. 2a, b). There was a corresponding increase in the length of the tail in these samples; DLG2 silenced cells (83.8%, p < 0.001 and 33.9.4%, p < 0.01) and control samples (42.7%, p < 0.001 and 51.6%, p < 0.001), with no increase in the tail length of the DLG2 over expressed cells (Fig. 2b). To further investigate the presence of double-strand DNA breaks, we investigated the presence of -H2AX (Ser-139, a biomarker of DNA double-strand breaks), in DLG2 silenced, control, and DLG2 over expressed NB cells lines (SKNBE (MYCN-ampli ed), SKNAS (11q deleted) and NB69 (MYCN and 11q normal); Fig 2ce respectively), 2 and 24 hours post UVC irradiation. We could determine that -H2AX levels were moderately repressed after 2 hours and almost completely repressed after 24 hours in cells with DLG2 over expression, indicating fewer remaining DNA breaks (Fig. 2c-e). Although, some repression of -H2AX was found in SKNAS and SKNBE control cells after 24 hours ( Fig. 2c and d), -H2AX levels were constant in all cells after DLG2 silencing, thus equal amount of DNA breaks remained even 24 hours after induction ( Fig. 2c-e). To further determine the effect of UVC irradiation on DNA breakage and DLG loss we compared the DNA integrity after UVC irradiation in a Drosophila model with RNAi-silenced DLG (dmDLG knockout) to controls. We evaluated the percentage of DNA-sequences that were multiple, unique and not mapped (Fig. 2f) in control (white) and dmDLG knockout ies, 3 hours after UVC irradiation. We could ascertain that DNA from the dmDLG knockout samples had a higher percentage of non-mapped sequences compared to the control (4.33% p< 0.01; Fig. 2f). We further determined the median sequence length for the multiple, unique and not mapped sequences with dmDLG knockout ies showing a longer median read length of multiple mapped sequences (470.5bp; 45.6% increase, p< 0.05; Fig. 2g). Finally, we determined the number of multiple mapped sequence reads that contained two separate fragments from nonoverlapping (greater then 10000bp gap) sequences. We could show that knockout of dmDLG resulted in an 85.4% increase in fusion sequences, (64.95% compared to the control 35.04% ± 0.5, p < 0.001; Fig 2h). DLG2 induced apoptosis in NB cells We evaluated the effect of over expression of DLG2 on apoptosis in SKNBE (MYCN-ampli ed) and SKNAS (11q-deleted) NB cells. Overexpression of DLG2 in SKNAS cells resulted in increased mRNA expression of BAX (log2 FC = 1.47, p < 0.001) as well as decreased BCL2 expression (log2 FC = 0.713, p < 0.001); DLG2 silencing resulted in decreased mRNA expression of BCL2 (log2 FC = 0.744 p = 0.001) with no alteration in BAX expression (Fig. 3a, b). The ratio of BAX/BCL2 gene expression was determined and shown to be high in cells with DLG2 over expression (FC = 4.16, p < 0.01), with no alteration for DLG2 silenced cells (FC = 0.329, p =0.931; Fig. 3c). Caspase 3/7 activation was measured over time to determine apoptosis activity. There was no difference in caspase 3/7 activation between control cells and DLG2 transfected cells 24 hours post transfection; there was an increase in activation at 30 hours (27.8%, p < 0.001) and 54 hours (15.6%, p < 0.001), with no difference in the level of activation again at 70 hours (Fig. 3d). We could con rm that BAX gene expression changes after DLG2 over expression resulted in increased levels of BAX protein in both SKNBE and SKNAS cells, and that BCL2 protein levels were lowered in SKNAS cells (Fig. 3e). DLG2 over expression resulted in an increase in p53 and Ser46 phosphorylated p53 levels in both SKNBE (83.1%, p < 0.05 and 23.9%, p < 0.05; Fig. 3f-g) and SKNAS (45.9%, p < 0.01 and 53.4%, p < 0.01; Fig. 3h-i) cell lines. These results showed that DLG2 over expression induce apoptosis in NB cells. High DLG2 levels enhanced CHK1 phosphorylation after UVC irradiation in NB cells To determine the effect of DLG2 on DNA repair in NB, we investigated DNA damage response pathways (DDR) in NB cell lines after DLG2 silencing or DLG2 over expression and UVC irradiation. We could show a strong activation of CHK1-S317 in all cells 2 hours after UVC irradiation, with the weakest activation in DLG2 silenced cells. This activation was lost in all cells after 24 hours recovery, except in those with DLG2 over expression (Fig. 4a, b). There was no difference in basal CHK1 expression. Subsequent evaluation of CHK2-T68 phosphorylation demonstrated expression in DLG2 silenced and control cells after 2 hours of recovery for SKNBE and SKNAS but not detectable in NB69, which was lost after 24 hours of recovery; basal expression of CHK2 was unaffected in SKNBE cells, but decreased in the SKNAS and NB69 cell lines with DLG2 over expression (Fig. 4a, c). No difference in the total amount of ATM or DNA-PKCs could be determined, which were neither affected by DLG2 levels nor the time of recovery after UVC irradiation (Fig. 4a). We quanti ed the phosphorylation of S317 CHK1 and T68 CHK2 and could show that phosphorylation of CHK1-S317 decreased over time in the DLG2 silenced and the control cells (9.5%, p < 0.01 and 7.5%, p < 0.05; Fig. 4b). DLG2 over expression resulted in an increase in S317 CHK1 (9.8%, p < 0.01; Fig. 4c). The phosphorylation of T68 CHK2 decreased over time in the DLG2 silenced and the control cells (27.5%, p < 0.05 and 28.7%, p < 0.05; Fig. 4c) with no difference over time in DLG2 over expressed cells. Discussion Previous attempts have been made to determine the illusive tumor suppressor gene located on 11q, with varying success. It has previously been reported that there are two tumor suppressor genes located on chromosome 11q that could act in a combined haploinsu cient manner. Here, we investigated the convergence of DLG2 (11q14.1) and the 11q23 deleted candidate TSGs within the DNA damage repair pathway. Previous studies have shown that some of the 11q23 SRO candidate TSGs function within this pathway, the roll of DLG2 in DNA repair has only been previously suggested with bioinformatics. We have shown changes in the expression of DNA repair genes in primary NB samples with unfavorable prognosis and 11q deletion (Fig. 1a-d). As patients with 11q deleted NBs are classi ed as high risk, with poor survival and a high number of DNA breaks and chromosomal alterations, we investigated how DLG2 alters these genes of interest. We have recently shown that there are two isoforms of DLG2 expressed in NB, isoform 2 (ISO2) and isoform 7 (ISO7); and that DLG2 isoform 7 is lost in advanced staged NB. Here, we shown that DLG2-ISO7 interrupts the expression of genes associated with the DNA damage repair machinery, i.e. PARP1, FEN1,PCNA as well as induce elevated MRE11a expression (Fig. 1e), another gene located in chromosome region 11q. Inhibition of PARP1 and PCNA have previously been investigated in NB, while FEN1 is known to be up regulated in tumors with MYCN ampli cation. To further investigate these ndings, we silenced the y orthologue gene dmDLG in a Drosophila model, which subsequently resulted in increased dmFEN and dmPARP, thereby reproducing the altered PARP1 andFEN1 expression found in NB patient samples and NB cell lines (Fig. 1g). Subsequently we silenced dmDLG in the y and irradiated with UVC which resulted in increased DNA damage in the form of an increase in the number of sequences that could not be mapped, indicative of low genome integrity (Fig. 2f). Furthermore, the increased median length of multiple mapped sequence in the DNA from dmDLG silenced ies compared to control indicated that there were likely fusion-sequences present (Fig. 2g). This was con rmed by looking at the number of multiple mapped sequences that were comprised of 2 distinct fragments (Fig. 2h). The loss of dmDLG combined with UVC irradiation activated low delity DNA repair, taken with the previous results, we show that loss of dmDLG results in upregulation of MMEJ. To further investigate the effects that DLG2 has on DNA repair, we induced DNA breaks by exposing transfected cells to UVC irradiation and allowing the cells to recover. Here we could show that DLG2 maintained genome stability and integrity, whereas loss of DLG2 resulted in high fragmentation without the extra stimulus of the UVC irradiation ( Fig. 2a-b). This increase in DNA fragmentation may be the direct result of aberrantly activated endonuclease activity such as that found in FEN1 or loss of the G2/M checkpoint. After UVC stimulus, the NB cells with DLG2 loss or silencing displayed a highly unstable genome with persisting DNA strand breaks. To show that we induced double-strand breaks, we investigated phosphorylation of S139 H2AX. Here we could show that double-strand breaks were still present 24 hours after UVC irradiation when DLG2 was down regulated (Fig. 2c-e), indicating that DNA repair had not yet occurred or that FEN1-mediated genome fragmentation was actively occurring. It has previously been shown that loss of DLG2 removes the G2/M DNA damage checkpoint, maintenance of which requires CHK1 activation. Consistent with this, we show that restoration of DLG2 expression maintained S317 CHK1 phosphorylation, whereas there was a decrease in phosphorylation in the DLG2 silenced and control cells (Fig. 4). The activation of S317 CHK1 occurs primarily through ATR but it can also occur through ATM. Interestingly, there was phosphorylation of T68 CHK2 at 2 hours in the DLG2 silenced and control cells but not in the DLG2 over expressed cells. The protein was subsequently dephosphorylated after 24 hours recovery in all experiments (Fig. 4). The phosphorylation of T68 CHK2 occurs primarily by ATM, indicating that DLG2 and ATM operate within different pathways. To further complicate the mechanism, DLG2 over expression resulted in down regulation of total CHK2 expression in all cell lines except SKNBE, a MYCN ampli ed cell line. These results and the somewhat redundant nature of CHK1 and CHK2 imply that DLG2 pushes the cells towards CHK1 and away from CHK2 regulation. We subsequently investigated the effects of DLG2 on apoptosis. We could show that elevated expression of DLG2 resulted in increased total p53, the effect of which was seen in the expression of the transcriptional targets BAX and BCL2 (Fig. 3). The increased ratio of BAX/BCL2 increases the permeability of the mitochondrial membrane as BCL2 cannot inhibit BAX pore formation and leads to apoptosis. We could also detect an increase in pS46 phosphorylated p53 level, which is generally associated with severe genotoxic stress and often leads to apoptosis. Genotoxic stress is present in MYCN ampli ed NB tumors as well as 11q deleted tumors. We con rmed that there was a transient increase of the executioner caspases 3/7 post DLG2 transfection, showing that the pS46 p53 phosphorylation result in apoptosis in NB. ATM is one of the essential kinases that phosphorylates pS46 p53, in this case DLG2 might cooperate with ATM by increasing BAX expression and allow for pS46 p53 mediated binding, a key step for transcription independent apoptosis. Further studies into the coalescence of candidate 11q tumor suppressor genes are required to fully understand the causes of increased relapse and poor survival in 11q deleted NB patients. Conclusions We have shown that DLG2 over expression increases the ability to sense genotoxicity, reduce DNA replication speed, as well as increase pS46 p53 phosphorylation to induce apoptosis in both 11q deleted and MYCN ampli ed NB cells. DLG2 alters the effects of UVC irradiation on dsDNA strand breaks in NB cells. For DLG2 silenced (siDLG2), mock transfected (control) or DLG2 transfected NB69 (11q normal) and SKNAS (11q deleted) NB cells, alkaline comet assay was used to assess DNA repair by measuring a head diameter and b tail length in non-irradiated controls (black bars) and cells 4 hours post UVC irradiation (grey bars). c Presence of dsDNA breaks determined by S139 H2AX ( -H2AX), total H2AX and GAPDH as loading control, by immunoblot after 30 seconds UVC irradiation with either 2 or 24 hours recovery in DLG2 silenced (-), mock transfected (C) or DLG2 over expressed (+) c SKNBE, d SKNAS, and e NB69 cells. Effect of UVC irradiation and subsequent recovery on DNA integrity in fruit ies determined by nanopore DNA sequencing mapped to a reference genome, for control (black bars) and dmDLG silenced (gray bars) ies. Samples strati ed based on multiple mapping, uniquely mapping or non-mapping for f percentage of total reads and g median read length. h percentage of fusion sequences from the multiple mapped sequences. The data shown is representative of three experimental replicates. The data are presented as an interleaved bar chart showing the mean and SD. Signi cance was determined by two-way ANOVA with dk's multiple comparison test *P < 0.05, **P < 0.01, ***P < 0.001, ns= not signi cant. comparison test and (f-i) unpaired two-tailed Student's t-test. *P < 0.05, **P < 0.01, ***P < 0.001, ns= not signi cant. |
– Indonesian police named the editor-in-chief of The Jakarta Post as a suspect in a blasphemy case, after the newspaper published a political cartoon mocking ISIS terrorists.
Witness testimony and evidence led police to name the newspaper’s editor, Meidyatama Suryodiningrat, 47, as a suspect, for his responsibility overseeing the English-language paper, a Jakarta police spokesman identified only as Col. Rikwanto told reporters Thursday.
Suryodiningrat’s been summoned for questioning next week.
The cartoon-- published July 3-- showed an ISIS flag replaced with a skull and crossbones, and Islamic sacred phrases in Arabic, including “La ilaha Illallah,” meaning “there is none worthy of worship except Allah,” and “Allah, Mohamed and Apostle,” the South China Morning Post reported.
A Muslim group called Jakarta Preachers’ Corps alerted police to the case after The Jakarta Post issued an apology about the internationally syndicated cartoon and printed a retraction from its website and print edition.
Suryodiningrat faces five years in prison for blasphemy against a religion under the criminal code. He issued a statement Thursday, saying the newspaper did not commit a criminal act.
“What we produced was a journalistic piece that criticized the ISIS movement, which has carried out violence in the name of religion,” the statement said.
The Jakarta-based Alliance of Independent Journalists, or AJI, objected to the declaration of Suryodiningrat as suspect.
“We urge the police not to use the criminal code to deal with journalistic cases, but the press law to solve disputes related to news reports and press products,” AJI said, according to the South China Morning Post.
The case, according to AJI, was a “serious threat” to freedom of the press.
Indonesia is the world's most populous Muslim nation and its constitution guarantees freedom of speech. In recent years blasphemy cases have been filed against those seen as offending Islam. |
def nuke_logs(log_dir, target=None):
if target:
if not target.endswith('.log'):
target = target + '.log'
files = [target]
else:
files = [f for f in os.listdir(log_dir) if f.endswith(".log")]
for f in files:
try:
os.remove(os.path.join(log_dir, f))
except:
pass |
import * as _ from 'lodash';
import * as React from 'react';
import {Styles} from 'ts/types';
import {
Link,
} from 'react-router-dom';
export interface FooterProps {}
interface FooterState {}
const styles: Styles = {
icon: {
color: 'white',
fontSize: 20,
},
text: {
fontSize: 12,
},
slackIcon: {
backgroundColor: 'white',
width: 17,
height: 17,
marginTop: 1,
marginLeft: 9,
},
};
export class Footer extends React.Component<FooterProps, FooterState> {
public render() {
return (
<div className="relative" style={{backgroundColor: '#272727'}}>
<div className="mx-auto max-width-4 py3 center clearfix" style={{color: 'white'}}>
<div
className="sm-col sm-col-4 pt1 sm-center md-left-align lg-left-align sm-pb2"
style={{...styles.text}}
>
Copyright © 0xProject
</div>
<div className="sm-col sm-col-4 clearfix sm-pb2">
<div className="mx-auto" style={{width: 145}}>
<div className="col col-3 pt1">
<a href="https://github.com/0xProject" target="_blank">
<i className="zmdi zmdi-github-box" style={{...styles.icon}} />
</a>
</div>
<div className="col col-3 pt1">
<a href="https://twitter.com/0xproject" target="_blank">
<i className="zmdi zmdi-twitter-box" style={{...styles.icon}} />
</a>
</div>
<div className="col col-3 pt1">
<a href="https://www.linkedin.com/company/0xProject" target="_blank">
<i className="zmdi zmdi-linkedin-box" style={{...styles.icon}} />
</a>
</div>
<div className="col col-3 pt1">
<a href="https://slack.0xproject.com/" target="_blank">
<div className="rounded" style={{...styles.slackIcon}}>
<img src="/images/slack_icon.png" style={{width: 13}} />
</div>
</a>
</div>
</div>
</div>
<div
className="sm-col sm-col-4 pt1 sm-center md-right-align lg-right-align"
style={{...styles.text}}
>
<a
href="mailto:<EMAIL>"
className="text-decoration-none"
style={{color: 'white'}}
>
<EMAIL>
</a>
</div>
</div>
</div>
);
}
}
|
She and her husband are best known for buying a home in the segregated Shively suburb of Louisville in 1954 and then selling it to a black couple, Andrew and Charlotte Wade, the intended owners. But she also traveled throughout the Deep South aiding and writing about the struggles of blacks to get equal consideration.
Charged along with her husband with sedition for selling the house to the Wades, Braden was also labeled a Communist and traitor to her race. The house was later fire-bombed, and the Bradens were accused of that as well.
Carl Braden was found guilty of sedition and served eight months of a 15-year sentence, before a U.S. Supreme Court ruling in another case overruled the verdict. Anne Braden was never tried.
"Seeing her on film is pretty much who she was," said Mimi Pickering, longtime filmmaker for Appalshop. "She was opinionated and had her own ideas, but she also enjoyed talking to anybody and everybody. She was a good listener and really good with people. That was one of her strengths."
Pickering and Anne Lewis directed the documentary that was started in 2004, two years before Braden's death. Throughout the film, viewers see a selfless woman who fearlessly fought for the rights of black people as well as for the economically oppressed.
"She and Carl Braden were legendary in Eastern Kentucky where they organized for economic and environmental issues," Pickering said. "They organized to get white people to be a part of the civil rights movement and to understand that we are all in this together."
The reason her story is so compelling to me is that Braden could have had a safe and secure life simply by ignoring the injustice she saw around her. But she says in the film she couldn't do that.
Braden was born in Louisville in 1924, but grew up in Anniston, Ala., where one of the Freedom Riders' buses was later burned in 1961. After graduating from college, she became a journalist working in Birmingham and Louisville.
In 1948, she married Carl Braden, a journalist and union activist 10 years her senior. They had three children.
For years after the sedition charges, the family was harassed, prompting Braden to write The Wall Between, in 1958, which told of the uncertainties of that period and gave a personal view of white racism. It was a runner-up for the National Book Award.
Unable to find jobs in Louisville, the Bradens became field organizers for the Southern Conference Educational Fund, an organization based in New Orleans that solicited funds for the civil rights movement. Anne Braden wrote for the organization's monthly newspaper, The Southern Patriot, which many icons of the movement credited with getting the word out.
Anne Braden's relationship with her family was strained, Pickering said.
"Her parents loved their grandchildren but they had real difficulties with her politics for a long time, Pickering said.
Still Anne Braden "was a strongly religious woman in the Episcopal church," she said. "She took to heart the social gospel, that all people are equal. Many activists of that period have that background.
"She believed that being involved in the struggle for a better world is really what makes you divine," Pickering said. "She felt she was part of a long chain of hundreds of years of humans making a better world, and that gave her strength."
I interviewed Braden briefly in 2000 when she was a member of a panel in Frankfort discussing the civil rights movement in Kentucky. Then 75, Braden said it was "disconcerting" that she was being hailed as a hero after years of being characterized as a pariah. But, she said, the three years of tumult because of the Wade case were "probably the best thing that happened to me. It gave me opportunity to meet the cream of the crop, people who were part of the resistance movement."
When Anne and Carl Braden passed through Atlanta, they would stop at Martin and Coretta King's house, Pickering said. At one point during a discussion there, Pickering said Anne called out to Coretta, "Get out of the kitchen and come in here and sit down with us."
"She was a strategist," Pickering said. "She would sit in the background and smoke a cigarette and drink bourbon. She felt strongly that African-Americans should lead" the movement.
"As a white person," Pickering said, "I learned a lot from Anne and came to understand that for me and other whites how fundamental racial justice is to any justice in this country."
Anne Braden died in Louisville at age 81 in 2006. |
Summer Zervos’s lawsuit calls for the president-elect to either own up to “sexually inappropriate behavior” or defend himself in court.
Donald Trump has one more lawsuit on his plate. Just one week after successfully fighting a libel suit from political strategist Cheryl Jacobus, the president-elect now faces a defamation suit from Summer Zervos, a former Apprentice contestant who accused him of sexual misconduct last year.
Back in October, Zervos read a statement detailing her allegations alongside her attorney, Gloria Allred. Zervos competed on The Apprentice in Season 5, but was eliminated in the first week. She said that on two separate occasions, Trump tried to kiss her—and that during a meeting at the Beverly Hills Hotel, he groped her. Zervos was far from the first woman to accuse Trump of sexual misconduct. Trump’s response? At a rally later in October, Trump said all of his accusers were lying.
Looks like Zervos has beaten Trump to the punch. |
/**
* Class which caches created DAOs. Sometimes internal DAOs are used to support such features as auto-refreshing of
* foreign fields or collections of sub-objects. Since instantiation of the DAO is a bit expensive, this class is used
* in an attempt to only create a DAO once for each class.
*
* <p>
* <b>NOTE:</b> To use this cache, you should make sure you've added a {@link DatabaseTable#daoClass()} value to the
* annotation to the top of your class.
* </p>
*
* @author graywatson
*/
public class DaoManager {
private static Map<Class<?>, DatabaseTableConfig<?>> configMap = null;
private static Map<ClassConnectionSource, Dao<?, ?>> classMap = null;
private static Map<TableConfigConnectionSource, Dao<?, ?>> tableConfigMap = null;
private static Logger logger = LoggerFactory.getLogger(DaoManager.class);
/**
* Helper method to create a DAO object without having to define a class. This checks to see if the DAO has already
* been created. If not then it is a call through to {@link BaseDaoImpl#createDao(ConnectionSource, Class)}.
*/
public synchronized static <D extends Dao<T, ?>, T> D createDao(ConnectionSource connectionSource, Class<T> clazz)
throws SQLException {
if (connectionSource == null) {
throw new IllegalArgumentException("connectionSource argument cannot be null");
}
ClassConnectionSource key = new ClassConnectionSource(connectionSource, clazz);
Dao<?, ?> dao = lookupDao(key);
if (dao != null) {
@SuppressWarnings("unchecked")
D castDao = (D) dao;
return castDao;
}
// see if we can build it from source
dao = createDaoFromConfig(connectionSource, clazz);
if (dao != null) {
@SuppressWarnings("unchecked")
D castDao = (D) dao;
return castDao;
}
DatabaseTable databaseTable = clazz.getAnnotation(DatabaseTable.class);
if (databaseTable == null || databaseTable.daoClass() == Void.class
|| databaseTable.daoClass() == BaseDaoImpl.class) {
// see if the database type has some special table config extract method (Android)
DatabaseType databaseType = connectionSource.getDatabaseType();
DatabaseTableConfig<T> config = databaseType.extractDatabaseTableConfig(connectionSource, clazz);
Dao<T, ?> daoTmp;
if (config == null) {
daoTmp = BaseDaoImpl.createDao(connectionSource, clazz);
} else {
daoTmp = BaseDaoImpl.createDao(connectionSource, config);
}
dao = daoTmp;
logger.debug("created dao for class {} with reflection", clazz);
} else {
Class<?> daoClass = databaseTable.daoClass();
Object[] arguments = new Object[] { connectionSource, clazz };
// look first for the constructor with a class parameter in case it is a generic dao
Constructor<?> daoConstructor = findConstructor(daoClass, arguments);
if (daoConstructor == null) {
// then look for the constructor with just the ConnectionSource
arguments = new Object[] { connectionSource };
daoConstructor = findConstructor(daoClass, arguments);
if (daoConstructor == null) {
throw new SQLException(
"Could not find public constructor with ConnectionSource and optional Class parameters "
+ daoClass + ". Missing static on class?");
}
}
try {
dao = (Dao<?, ?>) daoConstructor.newInstance(arguments);
logger.debug("created dao for class {} from constructor", clazz);
} catch (Exception e) {
throw SqlExceptionUtil.create("Could not call the constructor in class " + daoClass, e);
}
}
registerDao(connectionSource, dao);
@SuppressWarnings("unchecked")
D castDao = (D) dao;
return castDao;
}
/**
* Helper method to lookup a DAO if it has already been associated with the class. Otherwise this returns null.
*/
public synchronized static <D extends Dao<T, ?>, T> D lookupDao(ConnectionSource connectionSource, Class<T> clazz) {
if (connectionSource == null) {
throw new IllegalArgumentException("connectionSource argument cannot be null");
}
ClassConnectionSource key = new ClassConnectionSource(connectionSource, clazz);
Dao<?, ?> dao = lookupDao(key);
@SuppressWarnings("unchecked")
D castDao = (D) dao;
return castDao;
}
/**
* Helper method to create a DAO object without having to define a class. This checks to see if the DAO has already
* been created. If not then it is a call through to
* {@link BaseDaoImpl#createDao(ConnectionSource, DatabaseTableConfig)}.
*/
public synchronized static <D extends Dao<T, ?>, T> D createDao(ConnectionSource connectionSource,
DatabaseTableConfig<T> tableConfig) throws SQLException {
if (connectionSource == null) {
throw new IllegalArgumentException("connectionSource argument cannot be null");
}
return doCreateDao(connectionSource, tableConfig);
}
/**
* Helper method to lookup a DAO if it has already been associated with the table-config. Otherwise this returns
* null.
*/
public synchronized static <D extends Dao<T, ?>, T> D lookupDao(ConnectionSource connectionSource,
DatabaseTableConfig<T> tableConfig) {
if (connectionSource == null) {
throw new IllegalArgumentException("connectionSource argument cannot be null");
}
TableConfigConnectionSource key = new TableConfigConnectionSource(connectionSource, tableConfig);
Dao<?, ?> dao = lookupDao(key);
if (dao == null) {
return null;
} else {
@SuppressWarnings("unchecked")
D castDao = (D) dao;
return castDao;
}
}
/**
* Register the DAO with the cache. This will allow folks to build a DAO externally and then register so it can be
* used internally as necessary.
*
* <p>
* <b>NOTE:</b> By default this registers the DAO to be associated with the class that it uses. If you need to
* register multiple dao's that use different {@link DatabaseTableConfig}s then you should use
* {@link #registerDaoWithTableConfig(ConnectionSource, Dao)}.
* </p>
*
* <p>
* <b>NOTE:</b> You should maybe use the {@link DatabaseTable#daoClass()} and have the DaoManager construct the DAO
* if possible.
* </p>
*/
public static synchronized void registerDao(ConnectionSource connectionSource, Dao<?, ?> dao) {
if (connectionSource == null) {
throw new IllegalArgumentException("connectionSource argument cannot be null");
}
addDaoToClassMap(new ClassConnectionSource(connectionSource, dao.getDataClass()), dao);
}
/**
* Remove a DAO from the cache. This is necessary if we've registered it already but it throws an exception during
* configuration.
*/
public static synchronized void unregisterDao(ConnectionSource connectionSource, Dao<?, ?> dao) {
if (connectionSource == null) {
throw new IllegalArgumentException("connectionSource argument cannot be null");
}
removeDaoToClassMap(new ClassConnectionSource(connectionSource, dao.getDataClass()), dao);
}
/**
* Same as {@link #registerDao(ConnectionSource, Dao)} but this allows you to register it just with its
* {@link DatabaseTableConfig}. This allows multiple versions of the DAO to be configured if necessary.
*/
public static synchronized void registerDaoWithTableConfig(ConnectionSource connectionSource, Dao<?, ?> dao) {
if (connectionSource == null) {
throw new IllegalArgumentException("connectionSource argument cannot be null");
}
if (dao instanceof BaseDaoImpl) {
DatabaseTableConfig<?> tableConfig = ((BaseDaoImpl<?, ?>) dao).getTableConfig();
if (tableConfig != null) {
addDaoToTableMap(new TableConfigConnectionSource(connectionSource, tableConfig), dao);
return;
}
}
addDaoToClassMap(new ClassConnectionSource(connectionSource, dao.getDataClass()), dao);
}
/**
* Clear out all of internal caches.
*/
public static synchronized void clearCache() {
if (configMap != null) {
configMap.clear();
configMap = null;
}
clearDaoCache();
}
/**
* Clear out our DAO caches.
*/
public static synchronized void clearDaoCache() {
if (classMap != null) {
classMap.clear();
classMap = null;
}
if (tableConfigMap != null) {
tableConfigMap.clear();
tableConfigMap = null;
}
}
/**
* This adds database table configurations to the internal cache which can be used to speed up DAO construction.
* This is especially true of Android and other mobile platforms.
*/
public static synchronized void addCachedDatabaseConfigs(Collection<DatabaseTableConfig<?>> configs) {
Map<Class<?>, DatabaseTableConfig<?>> newMap;
if (configMap == null) {
newMap = new HashMap<Class<?>, DatabaseTableConfig<?>>();
} else {
newMap = new HashMap<Class<?>, DatabaseTableConfig<?>>(configMap);
}
for (DatabaseTableConfig<?> config : configs) {
newMap.put(config.getDataClass(), config);
logger.info("Loaded configuration for {}", config.getDataClass());
}
configMap = newMap;
}
private static void addDaoToClassMap(ClassConnectionSource key, Dao<?, ?> dao) {
if (classMap == null) {
classMap = new HashMap<ClassConnectionSource, Dao<?, ?>>();
}
classMap.put(key, dao);
}
private static void removeDaoToClassMap(ClassConnectionSource key, Dao<?, ?> dao) {
if (classMap != null) {
classMap.remove(key);
}
}
private static void addDaoToTableMap(TableConfigConnectionSource key, Dao<?, ?> dao) {
if (tableConfigMap == null) {
tableConfigMap = new HashMap<TableConfigConnectionSource, Dao<?, ?>>();
}
tableConfigMap.put(key, dao);
}
private static <T> Dao<?, ?> lookupDao(ClassConnectionSource key) {
if (classMap == null) {
classMap = new HashMap<ClassConnectionSource, Dao<?, ?>>();
}
Dao<?, ?> dao = classMap.get(key);
if (dao == null) {
return null;
} else {
return dao;
}
}
private static <T> Dao<?, ?> lookupDao(TableConfigConnectionSource key) {
if (tableConfigMap == null) {
tableConfigMap = new HashMap<TableConfigConnectionSource, Dao<?, ?>>();
}
Dao<?, ?> dao = tableConfigMap.get(key);
if (dao == null) {
return null;
} else {
return dao;
}
}
private static Constructor<?> findConstructor(Class<?> daoClass, Object[] params) {
for (Constructor<?> constructor : daoClass.getConstructors()) {
Class<?>[] paramsTypes = constructor.getParameterTypes();
if (paramsTypes.length == params.length) {
boolean match = true;
for (int i = 0; i < paramsTypes.length; i++) {
if (!paramsTypes[i].isAssignableFrom(params[i].getClass())) {
match = false;
break;
}
}
if (match) {
return constructor;
}
}
}
return null;
}
/**
* Creates the DAO if we have config information cached and caches the DAO.
*/
private static <D, T> D createDaoFromConfig(ConnectionSource connectionSource, Class<T> clazz) throws SQLException {
// no loaded configs
if (configMap == null) {
return null;
}
@SuppressWarnings("unchecked")
DatabaseTableConfig<T> config = (DatabaseTableConfig<T>) configMap.get(clazz);
// if we don't config information cached return null
if (config == null) {
return null;
}
// else create a DAO using configuration
Dao<T, ?> configedDao = doCreateDao(connectionSource, config);
@SuppressWarnings("unchecked")
D castDao = (D) configedDao;
return castDao;
}
private static <D extends Dao<T, ?>, T> D doCreateDao(ConnectionSource connectionSource,
DatabaseTableConfig<T> tableConfig) throws SQLException {
TableConfigConnectionSource tableKey = new TableConfigConnectionSource(connectionSource, tableConfig);
// look up in the table map
Dao<?, ?> dao = lookupDao(tableKey);
if (dao != null) {
@SuppressWarnings("unchecked")
D castDao = (D) dao;
return castDao;
}
// now look it up in the class map
Class<T> dataClass = tableConfig.getDataClass();
ClassConnectionSource classKey = new ClassConnectionSource(connectionSource, dataClass);
dao = lookupDao(classKey);
if (dao != null) {
// if it is not in the table map but is in the class map, add it
addDaoToTableMap(tableKey, dao);
@SuppressWarnings("unchecked")
D castDao = (D) dao;
return castDao;
}
// build the DAO using the table information
DatabaseTable databaseTable = tableConfig.getDataClass().getAnnotation(DatabaseTable.class);
if (databaseTable == null || databaseTable.daoClass() == Void.class
|| databaseTable.daoClass() == BaseDaoImpl.class) {
Dao<T, ?> daoTmp = BaseDaoImpl.createDao(connectionSource, tableConfig);
dao = daoTmp;
} else {
Class<?> daoClass = databaseTable.daoClass();
Object[] arguments = new Object[] { connectionSource, tableConfig };
Constructor<?> constructor = findConstructor(daoClass, arguments);
if (constructor == null) {
throw new SQLException(
"Could not find public constructor with ConnectionSource, DatabaseTableConfig parameters in class "
+ daoClass);
}
try {
dao = (Dao<?, ?>) constructor.newInstance(arguments);
} catch (Exception e) {
throw SqlExceptionUtil.create("Could not call the constructor in class " + daoClass, e);
}
}
addDaoToTableMap(tableKey, dao);
logger.debug("created dao for class {} from table config", dataClass);
// if it is not in the class config either then add it
if (lookupDao(classKey) == null) {
addDaoToClassMap(classKey, dao);
}
@SuppressWarnings("unchecked")
D castDao = (D) dao;
return castDao;
}
/**
* Key for our class DAO map.
*/
private static class ClassConnectionSource {
ConnectionSource connectionSource;
Class<?> clazz;
public ClassConnectionSource(ConnectionSource connectionSource, Class<?> clazz) {
this.connectionSource = connectionSource;
this.clazz = clazz;
}
@Override
public int hashCode() {
final int prime = 31;
int result = prime + clazz.hashCode();
result = prime * result + connectionSource.hashCode();
return result;
}
@Override
public boolean equals(Object obj) {
if (obj == null || getClass() != obj.getClass()) {
return false;
}
ClassConnectionSource other = (ClassConnectionSource) obj;
if (!clazz.equals(other.clazz)) {
return false;
} else if (!connectionSource.equals(other.connectionSource)) {
return false;
} else {
return true;
}
}
}
/**
* Key for our table-config DAO map.
*/
private static class TableConfigConnectionSource {
ConnectionSource connectionSource;
DatabaseTableConfig<?> tableConfig;
public TableConfigConnectionSource(ConnectionSource connectionSource, DatabaseTableConfig<?> tableConfig) {
this.connectionSource = connectionSource;
this.tableConfig = tableConfig;
}
@Override
public int hashCode() {
final int prime = 31;
int result = prime + tableConfig.hashCode();
result = prime * result + connectionSource.hashCode();
return result;
}
@Override
public boolean equals(Object obj) {
if (obj == null || getClass() != obj.getClass()) {
return false;
}
TableConfigConnectionSource other = (TableConfigConnectionSource) obj;
if (!tableConfig.equals(other.tableConfig)) {
return false;
} else if (!connectionSource.equals(other.connectionSource)) {
return false;
} else {
return true;
}
}
}
} |
We must ensure that trade agreements are not used to open public services to private commercial activities but are used to contribute to the application of international labour standards to protect workers’ rights.
Three major agreements, and two WTO meetings, are the focus of PSI activity on trade. These issues affect many affiliates in many countries and we ask you to take action, as outlined below. For further information, please download GEN Circular 8. The circular has also been sent to all PSI affiliates.
Trade in Services Agreement (TISA)
The TISA is a new treaty to further liberalise trade and investment in services. It is the follow-up to the previous General Agreement on Trade in Services (GATS). The treaty rules would increase foreign corporate control over domestic services and would restrict governments’ ability to regulate services, essentially changing the regulation of many public, privatized or commercial services from serving the public interest to serving the profit interests of private, foreign corporations.
PSI has published a short briefing note on TISA, outlining some of the key areas that potentially would affect public sector workers in the new agreement.
The countries currently involved are: Australia, Canada, Chile, Colombia, Costa Rica, Hong Kong, Iceland, Israel, Japan, Mexico, New Zealand, Norway, Panama, Pakistan, Peru, South Korea, Switzerland, Taiwan, Turkey, the United States, and the 27 member states of the European Union. However, these negotiations will affect all PSI affiliates; if such an agreement is concluded, it will create a powerful new standard for liberalising services through trade agreements across the globe.
You can take immediate action by endorsing the sign-on letter concerning TISA, addressed to trade ministers, produced by PSI in conjunction with our allies at the Our World Is Not for Sale (OWINFS) network. Please send organisational endorsement, with country, to manicandan@gmail.com with a copy to Pauline.Chase@world-psi.org
If you are in a country involved in the TISA talks, we urge you to become involved in our activities. Please forward contact details of your union representative to Daniel.Bertossa@world-psi.org.
Trans Pacific Partnership Agreement (TPPA)
Many PSI affiliates, in partnership with civil society, have been active in opposing the harmful provisions of the TPPA. To better co-ordinate this activity, PSI affiliates have started to meet by teleconference to share information and co-ordinate our actions. The TPPA affects the following countries: Australia, Brunei Darussalam, Canada, Chile, Japan, Malaysia, Mexico, New Zealand, Peru, Singapore, Vietnam and the United States.
PSI is seeking information about trade union and civil society activity in these countries. If you are in a country that is affected by the TPPA and would like more information, or to become involved, please contact Daniel.Bertossa@world-psi.org.
Trade Facilitiation Agreement (TFA)
The TFA aims to liberalise the customs, ports and regulatory environment for imports to countries. It would create new markets in customs and shipment processing for multinational corporations. It would likely increase pressure to further privatize ports, customs operations and shipment processing, which would leave little or no space for local operators, and which has already led to a loss of jobs, downward pressure on wages and erosion of labour rights for public workers in these sectors. Further, it would restrict the policy space of sovereign governments (especially in the developing world) to pursue development, industry or fiscal objectives.
A sign-on letter is attached, addressed to members of the WTO, outlining civil society concerns with the TFA. PSI encourages all affiliates, and especially those with customs and ports workers affected by the TFA, to support the letter by sending organisational endorsement, with country, to manicandan@gmail.com and copy Pauline.Chase@world-psi.org
WTO meetings
PSI will be attending the WTO Ministerial meeting in December 2013 and will organise a forum on trade in services at the WTO Public Forum in October 2013. Please click on the meeting title links for further information.
Affiliate actions
It is vital to coordinate affiliate action in individual trade agreements and across World Trade Organization (WTO) activities and better engage our labour and civil society allies in our struggle. Please forward the name and contact details of the person in your union who deals with trade issues to Pauline.Chase@world-psi.org, indicating if you have a particular interest in any of the specific agreements or events mentioned above.
If you have any questions about PSI's trade work, please contact Daniel.Bertossa@world-psi.org. |
<reponame>marcovc/casper
/**************************************************************************\
* This file is part of CaSPER. *
* *
* Copyright: *
* 2011-2011 - <NAME> <<EMAIL>> *
* *
* 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. *
\*************************************************************************/
#ifndef CASPER_KERNEL_OBJ_GOAL_H_
#define CASPER_KERNEL_OBJ_GOAL_H_
//#include <casper/kernel/spexpr/expr.h>
namespace Casper {
namespace Detail {
template<class T>
struct Create<T,Goal>
{
Goal operator()(State& state, const T& t);
};
template<class T>
Goal Create<T,Goal>::operator()(State& state, const T& t)
{ return Goal(state,t); }
template<>
struct Create<bool,Goal>
{
Goal operator()(State& state, const bool& t)
{ return Goal(t); }
};
} // Detail
template<class Eval>
struct GoalView<Expr<Eval> > : IGoal
{
GoalView(State& state, const Expr<Eval>& e) :
g(e.toGoal(state)) {}
Goal execute() { return g; }
Goal g;
};
}
#endif /* CASPER_KERNEL_OBJ_GOAL_H_ */
|
Evaluation of the incidence of inflammatory and tumor pathology of nose and nasal sinus region Inflammatory and nasal-sinus tumor pathology is a field of great interest in rhinology worldwide. The aim of the paper is to determine the prevalence of nasal and nasal-sinus inflammatory diseases, as well as nasal and nasosinusal rhinosinusitis tumors, in association or not with inflammatory diseases, using histopathological (HP) examination. It is also desired to identify the association of chronic inflammatory pathology with the tumor one, considering inflammation and immunodeficiency as local susceptibility factors. A retrospective study was performed on a group of 254 patients hospitalized between 20182019 in Department of Otorhinolaryngology, Emergency County Hospital, Trgu Mure, Romania. Based on the clinical and HP examination, the distribution by inflammatory pathologies was made as follows: 175 nasal polyposis, 108 chronic rhinitis, 39 sinusitis strictly affecting the sinus and 28 chronic polyposis rhinosinusitis nasal and sinus association. Considering the evaluation of the incidence of benign tumor pathology, the following were found: out of the total examined cases, 4% squamous papilloma, 4% exophytic papilloma, 44% Schneiderian papilloma, 4% benign fibrous histiocytoma, 18% hemangioma, 4% hamartoma, and 4% osteoma were identified. The incidence of malignant tumors is 26% squamous cell carcinoma, 12% intestinal adenocarcinoma, 2% nonintestinal type adenocarcinoma, 2% large B-cell lymphoma, 2% plasma cell, 2% olfactory neuroblastoma, 7% malignant melanoma, 16% basal cell carcinoma. The paper draws attention to the increased incidence of tumor and inflammatory pathology both individually and in combination, considering the involvement of the clinical correlation with the HP result completed, if necessary, with immunohistochemical examinations, for a precise diagnosis. Introduction Inflammatory nasal and nasal-sinus tumor pathology is a field of great interest in rhinology worldwide, due to its increased frequency, as well as due to the many aspects related to their etiology, contradictory clinical manifestations, and the multitude of therapeutic options. The pathogenesis of chronic type rhinosinusal inflammatory diseases remains unclear, being much investigated. It is considered that the nasal mucosa suffers due to inflammatory phenomena, a degeneration known as polyps. They represent a hypertrophy of the mucosa because of the inflammatory processes. The literature talks about the fact that these formations are produced by infectious processes, and vascular changes as local disorders of the immunity of the nasal mucosa. There are also coincidences that include allergenic factors as the cause of nasal polyposis, which are of particular interest as a constitutional factor in their genesis. There are studies in the literature that demonstrate the link between nasal polyposis and allergic diseases, analyzing different parameters of humoral and cellular immunity. An impairment of cellular immunity has been shown in the literature in patients with chronic polyposis rhinosinusitis. An atypical form of chronic rhinosinusitis (CRS) is the allergic-fungal forms, characterized by the presence of eosinophils associated with fungal appearance, present in the paranasal sinuses, with or without mucosal infiltration. This condition also raises controversies about definition and etiopathogenesis. The diagnosis of this type of rhinosinusitis involves an interdisciplinary approach, including imaging, histopathology, mycology and immunological investigations, and there are controversies in the literature regarding their pathogenesis, diagnosis and treatment. Pediatric CRS is a common disorder that carries significant morbidity. The diagnosis requires sinus symptoms that persist despite standard medical therapy greater than three months. Viral infections, allergies, and anatomic differences in children lead to chronic obstruction of the ostiomeatal complex. Regarding tumors, the nasal-sinus region is much less often involved. There are various histological forms of tumors and the issue of their management is raised by the proximity of the orbit and the intracranial cavities. Histopathological (HP) examinations are the most important elements in the diagnosis of tumors, they are completed where appropriate with immunohistochemical (IHC) examinations complement the HP results. Benign tumors include more frequently of epithelial tumors than inverted papilloma, and rarer of epithelial respiratory tumors such as hamartoma, epithelial respiratory adenomatoid tumor, and seromucinous hamartoma. Regarding zonal involvement, the literature shows that all areas of the nasal cavity and paranasal sinuses may be affected, but the lateral nasal wall, maxillary and ethmoidal sinuses are the most commonly involved. The frontal sinus and sphenoid are much less frequently the starting point, which is why they sometimes remain unknown. The nasal tumors have an important role in sleep pathology together with other inflammatory pathology, as the tonsils hypertrophy. Squamous cell carcinoma (SCC) is the most common form of malignancy, with a variation for each tumor type. Classical keratinizes and nonkeratinized, but with different variations, more frequently with fusiform cells or sarcomatous and lymphoepithelial. Other epithelial tumors include adenocarcinomas, olfactory neuroblastoma, melanomas, cystic adenoid carcinoma, sarcomas, chondrosarcomas, rhabdomyosarcomas, hemoproliferative tumors, and lymphomas. Rare are malignant tumors of the soft tissue, rhabdomyosarcomas, phenotypical sarcomas, and angiosarcomas. There are special types of soft tissue tumors, borderline tumors, or tumors with reduced malignant potential, which develop, in this region, in special nasal glomangiopericytoma, individual fibrous tumors, and tumors with a very high local invasion and high risk of recurrence. Aim The aim of the paper is to determine the prevalence of nasal and nasal-sinus inflammatory diseases, as well as nasal and nasosinusal tumors, in association or not with inflammatory diseases, using HP examination. The IHC examination performed for the purpose of a definite diagnosis, came to complete the retrospective study performed. This was an exclusion criterion from the study, not being its main object. It is also desired to identify the association of chronic inflammatory pathology with the tumor one, considering inflammation and immunodeficiency as local susceptibility factors. Patients, Materials and Methods A retrospective study was performed on a group of 254 patients hospitalized between January 1, 2018 until December 31, 2019 in the Ear, Nose and Throat (ENT) Clinic, University Emergency County Hospital, Trgu Mure, Romania. The inclusion criteria were: patients who underwent surgical procedures, subsequently HP analyzed, patients with rhinosinusal pathology, patients diagnosed with chronic polyposis inflammation of the rhinosinusal region, benign and malignant tumors. In order to obtain fragments for HP analysis, patients underwent incisional or excisional biopsy. The written consent of the patient was obtained to perform the biopsy. For the performance of the statistics, the anonymous data of the patients were used, being fully respected the personal data. Tissue samples were analyzed macroscopically, were processed and microscopically visualized, stages completed or not by complementary investigation, as appropriate. Hematoxylin-Eosin (HE) staining was used for histological examination of the samples. Statistical evaluation of the data was performed on a group of 254 hospitalized patients with various nasal and nasal-sinus pathologies: chronic polyposis rhinitis, chronic polyposis sinusitis, chronic polyposis rhinosinusitis, and nasal tumor pathology, such as squamous papilloma, exophytic papilloma, Schneiderian papilloma, histiocytoma, hemangioma, hamartoma, osteoma, SCC, intestinal adenocarcinoma, basal cell carcinoma (BCC), nonintestinal type adenocarcinoma, large B-cell lymphoma, plasmacytoma, olfactory neuroblastoma, malignant melanoma. After the analysis of the demographic parameters of the lesion diagnosis, the IHC analyzes were performed. For the study realization and cases analyzes was obtained the approval of the Ethics Commission of the University Emergency County Hospital of Trgu Mure. All data collected were statistically analyzed using Statistical Package for the Social Sciences (SPSS) ver. 24, for qualitative data description or percentage for quantitative evaluation and standard deviation. The distribution by gender was made as follows: 92 (36.22%) female patients and 162 (63.78%) male patients. Based on the clinical and HP examination, the distribution by inflammatory pathologies was made as follows: 175 patients with chronic polyposis inflammatory pathologies not associated with tumors, of which 108 (62%) patients with chronic polyposis rhinitis, 39 (22%) patients with chronic polyposis sinusitis -strictly affecting the sinus and 28 (16%) patients with CRS with polypsnasal and sinus association ( Figure 1). Figure 1 -Incidence of nasal and nasal sinus inflammatory pathology. From total of 254 patients, to 175 inflammatory pathology was highlighted. The incidence of nasal and sinus tumor pathology being highlighted in 79 patients. Considering the evaluation of the incidence of benign tumor pathology, the following were found: out of the total examined cases, three (4%) patients with squamous papilloma, three (4%) patients with exophytic papilloma, 35 (44%) patients with Schneiderian papilloma, three (4%) patients with benign fibrous histiocytoma, 14 (18%) patients with hemangioma, three (4%) patients with hamartoma, and three (4%) patients with osteoma were identified. The difference was in various other types of benign tumors ( Figure 2). Figure 2 -Incidence of benign tumors with nasal and rhinosinusal localization. Out of a total of 15 patients with malignancies identified over a period of one year, the incidence by tumors was as follows: six (7%) patients with SCC, three (4%) patients with intestinal adenocarcinoma, one patient (1%) nonintestinal type adenocarcinoma, two (2%) patients with olfactory neuroblastoma, and three (4%) patients BCC with localization at the level of the nasal pyramid not being the object of our study, being still highlighted in the general statistics ( Figure 3). Figure 3 -Incidence of malignant tumor type diseases. Microscopic examination of the samples taken from the formations considered to be of the inflammatory type, described the presence or absence of eosinophilic infiltrate, Charcot-Leyden crystals and the specific appearance of fungus ball in various pathologies, as follows: in chronic polyposis, microscopic polyposis, abundant eosinophilic infiltrate was described in 62.96% of cases, 13.23% of which also associated the presence of Charcot-Leyden crystals. Fungus ball has been described in 23.81% of cases, more frequently that the literature describe. Out of the total cases, the patients diagnosed as CRSwNP, out of the total cases, 60.71% have eosinophils on microscopic examination, and 10.71% present Charcot-Leyden crystals, in one case the specific appearance of fungus ball is highlighted. In chronic polyposis sinusitis, in 41.03% were described eosinophilic infiltrate, 7.69% is associated with Charcot-Leyden crystals. Statistics show as a conclusion the description of eosinophilic infiltrate in 101 cases out of 175 evaluated. Figure 7 -Histopathological aspects of nasal intestinal adenocarcinoma, tumor with papillary architecture, with areas of ulceration and hemorrhage with exophilic growth, with conjunctival-vasculary axes converted by cylindrical stratified mucosecretory epithelium. Hematoxylin-Eosin staining, 100. Regarding the location of malignant tumors, 36.36% comprise the nasal region, 9.1% the sphenoid region and 9.1% in the ethmoidal region. Nasal sinus adenocarcinoma, identified predominantly in males, showed a dominant nasal and ethmoid sinus localization. For IHC analysis, the data related to antibodies, clones, dilution, the manufacturing company were applied according to the norms of the HP examination and represent a factor of interest of the present paper. Discussions It is noteworthy that most of the patients, 158 out of 254, are men aged between 40-69 years. The average age of patients is 51.26 years, with a standard deviation of 16.97, an age range of 3-89 years. The studied group follows a normal distribution and is heterogeneous in terms of diagnostic age. Studies in the field show similar results, both in terms of age and gender of patients. One explanation would be the fact that with age there is an immune vulnerability due to various comorbidities, and on the other hand there is a cumulative effect of inflammatory, infectious or noninfectious phenomena over time. Regarding the gender difference, it is probably due to the high prevalence of smokers over female smokers. The present study shows an increased number of nasal lesions, including the nasal wings, the nasal pyramid, and the nasal cavity itself, compared to the sinus or rhinosinusal association. BCC present located at the level of the nasal pyramid in proportion of 42.85% of the nasal pyramid, 28.57% of the nasal wings and 14.29% of the nasal vestibule was excluded from the final results, because only the nasal diseases were discussed and nasal-sinus involving the nostrils and adjacent sinus structures and do not include anything related to the structure of the nasal pyramid. The inflammatory phenomenon was more often diagnosed than the tumor one. Of the latter, 82% were benign lesions, 18% malignant tumors were identified. Regarding the inflammations of the nasal region and of the paranasal sinuses, they were represented in 62% by chronic polyposis rhinitis, 22% by chronic polyposis sinusitis and 16% by chronic polyposis rhinosinusitis. All have an increased prevalence in the population aged 40-59 years. The pathogenesis of inflammatory pathology is related to several factors: genetic (which give background), infectious or non-infectious (exposure to various irritants). In this context, frequently discussed is CRS, which is a common condition that affects health and quality of life of patients. It is associated with inferior airway affections such as asthma, or sleep breathing disorders the involvement being controversial and much analyzed. CRS is classified into two types: CRSwNP, and CRS without nasal polyps. The difference in the CRS endotype is based on the profile of inflammatory cytokines. In response to the aggression caused by inflammation, an increase in cellularity takes place locally, in order to remove harmful agents. In a study that investigated the HP profile of polyposis lesions, e.g., eosinophilic infiltrate was described in 80% of cases. In our study, 55.19% of the lesions microscopically examined had described abundant eosinophilic infiltrate. Of these, one-fifth have associated Charcot-Leyden crystals, which are formed by the fusion of eosinophilic proteins. Four cases also described fungus ball. Another study showed in 86% prevalence of eosinophil cases. Importance should be given to the type of inflammatory infiltrate. There are studies that have determined a positive association between the size of the eosinophilic infiltrate and the clinical severity of the lesion. Moreover, Arslan et al. demonstrated, in their work, that 81.8% of patients who presented eosinophilic infiltrate had postoperative recurrences, compared with 25% (who had an inflammatory infiltrate without eosinophils). The association of tumors of different types, benign or malignant with polyposis inflammatory phenomena highlighted in our study, corresponds to international multicenter studies, which show the high risk that nasal polyposis can play in triggering nasal and nasal-sinus malignancies. The definite tumor diagnosis is made following HP examination. Given the constitution of the nose and paranasal sinuses, it is understood that there is a variety of microscopic aspects, similar or not, to the tissue from which it develops, depending on the degree of differentiation of the lesion. From a HP point of view, in the tumor analysis, apart from the type of tissue, other parameters are followed, such as: invasion capacity of the tumor, constituent cells, their number, mitotic activity, different atypia, inflammatory infiltrate or associated vascularization. Lesions with a low degree of malignancy may have more numerous mitoses, which are limited to the lower third of the tissue, whose cells have different degrees of differentiation. Associated investigations in both types of pathologies include computed tomography (CT), magnetic resonance imaging (MRI), which provides excellent data on bone structural details, and tumor consistency, tumor invasion in adjacent structures. Positron emission tomography (PET)-CT is used where the tumor metastasizes to a nonspecific location relative to the primary tumor. The role of all diagnostic methods, associated with each other, represent the elaboration of therapeutic behaviors that involve first of all the intranasal approach, with the preservation of the nasal anatomical structures and implicitly of the functionality of the nasal mucosa. In certain situations, related to the clinical, HP, and imaging aspects, the external surgical approach for benign and/or especially tumor resection is absolutely necessary. When talking about the location of malignant tumors, at the nasal and sinus level, the data of our study confirm, through the values obtained -36.36% include the nasal region, 9.1% the sphenoid region, and 9.1% in the ethmoidal region, the statements of the literature. IHC analyzes are additional data in the diagnostic equation. These elements are included in the results of our study, which immunohistochemically analyzes tumors, such as melanomas, gliopericytoma, schwannomas, plasma cells, nasal neurofibromas. In this context, clinical, paraclinical data, corroborated with IHC results, lead to the possibility of a conclusive differential diagnosis. In this sense, the literature shows that although from a clinical point of view it is not very difficult to make a differential diagnosis between septal schwannoma for example and a septal neurofibroma, however, immunohistochemistry including certain specific determinations is necessary when the two clinical entities are difficult to distinguish. The literature shows that a high-grade sinonasal carcinomas are a cohort of malignant epithelial neoplasms arising in the sinonasal cavities with distinct, ominous morphological features or lacking well-differentiated features that might otherwise classify them as less biologically worrisome. The discovery of these distinct molecular tumor profiles may have significant clinical impact as targeted molecular-based therapeutics continue to evolve, and they may offer some respite for patients who have these highly aggressive cancers. Conclusions Chronic polyposis and/or tumor lesions of the rhinosinusal region are quite common conditions in clinical practice. Thus, the identification of etiological factors becomes an important objective, in order to successfully treat these pathologies. Regarding the objective of the present study, it was highlighted by microscopic examination of the lesions, supplemented by IHC techniques, the presence of inflammatory diseases in association with benign and malignant tumor pathology at the nasal and nasal-sinus level. Highlighting inflammatory diseases in association with benign or malignant tumor pathology is an important diagnostic element both clinically and pathologically. The paper draws attention to the increased incidence of tumor and inflammatory pathology both individually and in combination, considering the involvement of the clinical correlation with the HP result completed, if necessary, with IHC examinations, for a precise diagnosis. |
<reponame>teddywest32/intellij-community<filename>platform/external-system-impl/src/com/intellij/openapi/externalSystem/service/execution/ExternalSystemBeforeRunTask.java<gh_stars>0
/*
* Copyright 2000-2014 JetBrains s.r.o.
*
* 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.
*/
package com.intellij.openapi.externalSystem.service.execution;
import com.intellij.execution.BeforeRunTask;
import com.intellij.openapi.externalSystem.model.ProjectSystemId;
import com.intellij.openapi.externalSystem.model.execution.ExternalSystemTaskExecutionSettings;
import com.intellij.openapi.util.Key;
import com.intellij.openapi.util.text.StringUtil;
import org.jdom.Element;
import org.jetbrains.annotations.NotNull;
/**
* @author Vladislav.Soroka
* @since 5/30/2014
*/
public class ExternalSystemBeforeRunTask extends BeforeRunTask<ExternalSystemBeforeRunTask> {
@NotNull
private final ExternalSystemTaskExecutionSettings myTaskExecutionSettings;
public ExternalSystemBeforeRunTask(@NotNull Key<ExternalSystemBeforeRunTask> providerId, @NotNull ProjectSystemId systemId) {
super(providerId);
myTaskExecutionSettings = new ExternalSystemTaskExecutionSettings();
myTaskExecutionSettings.setExternalSystemIdString(systemId.getId());
}
@NotNull
public ExternalSystemTaskExecutionSettings getTaskExecutionSettings() {
return myTaskExecutionSettings;
}
@Override
public void writeExternal(Element element) {
super.writeExternal(element);
element.setAttribute("tasks", StringUtil.join(myTaskExecutionSettings.getTaskNames(), " "));
if (myTaskExecutionSettings.getExternalProjectPath() != null) {
element.setAttribute("externalProjectPath", myTaskExecutionSettings.getExternalProjectPath());
}
if (myTaskExecutionSettings.getVmOptions() != null) element.setAttribute("vmOptions", myTaskExecutionSettings.getVmOptions());
if (myTaskExecutionSettings.getScriptParameters() != null) {
element.setAttribute("scriptParameters", myTaskExecutionSettings.getScriptParameters());
}
}
@Override
public void readExternal(Element element) {
super.readExternal(element);
myTaskExecutionSettings.setTaskNames(StringUtil.split(StringUtil.notNullize(element.getAttributeValue("tasks")), " "));
myTaskExecutionSettings.setExternalProjectPath(element.getAttributeValue("externalProjectPath"));
myTaskExecutionSettings.setVmOptions(element.getAttributeValue("vmOptions"));
myTaskExecutionSettings.setScriptParameters(element.getAttributeValue("scriptParameters"));
}
@Override
public boolean equals(Object o) {
if (this == o) return true;
if (!(o instanceof ExternalSystemBeforeRunTask)) return false;
if (!super.equals(o)) return false;
ExternalSystemBeforeRunTask task = (ExternalSystemBeforeRunTask)o;
if (!myTaskExecutionSettings.equals(task.myTaskExecutionSettings)) return false;
return true;
}
@Override
public int hashCode() {
int result = super.hashCode();
result = 31 * result + myTaskExecutionSettings.hashCode();
return result;
}
}
|
Design and Demonstration of Autonomous Directional Drilling With a Miniature Scale Rig Drillbotics, an international student competition hosted by SPE/DSATS, directed the 2020/2021 competitors to design, build and implement a 1.5 (3.8cm) hole size, fully autonomous drilling rig capable of intersecting multiple pre-set targets within a rock sample with up to 30-degree inclination and 15-degree azimuth adjustments from the KOP. The Norwegian University of Science and Technology (NTNU) won the competition using a fixed bent Bottom Hole Assembly (BHA) and a simulated mud-motor stator with a rod inside the drillpipe transferring rotational torque from a top drive. The team designed and created a custom drill bit, bi-directional hydraulic swivel, and BHA. Trajectory control was achieved by changing the BHA bend orientation over time, rotating the drillpipe with inputs from a nonlinear Model Predictive Controller (nMPC) following a pre-planned Bezier-curve well path. Capabilities of the rig were demonstrated by drilling a 37-degree inclination well path in 6 minutes in a 60 cm sandstone replica. |
Jewel-Osco in Itasca is joining Hormel Foods in donating 33,122 jars of Skippy peanut butter to Northern Illinois Food Bank in Geneva.
The peanut butter, enough to make more than 500,000 sandwiches, arrived at the food bank on Wednesday. The donation will support the food bank's mission to lead the Northern Illinois community in solving hunger by providing nutritious meals to those in need in the area.
The donation is part of the hunger program created by the makers of Skippy peanut butter in 2018. The program involves a partnership between Hormel Foods and grocery retailers across the country and is part of the company's philanthropic efforts focused on hunger and education.
"The Skippy hunger program highlights our long-standing relationship with Jewel-Osco, and we are honored to work together to contribute to those in need," said Aly Sill, brand manager at Hormel Foods.
"We are very excited to work with Hormel Foods and the Skippy brand to donate more than 33,000 jars of peanut butter to address the problem of child hunger in the greater Chicagoland area," said Jewel-Osco President Paul Gossett. "We hope this donation will help make the holidays a little more enjoyable for individuals and families in need." |
#ifndef HASH_STRING
#define HASH_STRING
//http://www.cse.yorku.ca/~oz/hash.html
static inline unsigned long
hash_buffer(unsigned char *str)
{
unsigned long hash = 5381;
int c;
while ((c = *str++))
hash = ((hash << 5) + hash) + c; /* hash * 33 + c */
return hash;
}
#define hash_string(str) hash_buffer((unsigned char*)str)
typedef unsigned long hash_t;
#endif |
package filters
import (
log "github.com/sirupsen/logrus"
"github.com/zalando-stups/skrop/parse"
"github.com/zalando/skipper/filters"
"gopkg.in/h2non/bimg.v1"
)
// For infomations about the parameters meanings and default values have a look here:
// http://www.vips.ecs.soton.ac.uk/supported/current/doc/html/libvips/libvips-convolution.html#vips-sharpen
// SharpenName is the name of the filter
const SharpenName = "sharpen"
type sharpen struct {
Radius int
X1 float64
Y2 float64
Y3 float64
M1 float64
M2 float64
}
// NewSharpen creates a new filter of this type
func NewSharpen() filters.Spec {
return &sharpen{}
}
func (f *sharpen) Name() string {
return SharpenName
}
func (f *sharpen) CreateOptions(imageCo_ntext *ImageFilterContext) (*bimg.Options, error) {
log.Debug("Create options for sharpen ", f)
sha := bimg.Sharpen{Radius: f.Radius, X1: f.X1, Y2: f.Y2, Y3: f.Y3, M1: f.M1, M2: f.M2}
return &bimg.Options{
Sharpen: sha}, nil
}
func (f *sharpen) CanBeMerged(other *bimg.Options, self *bimg.Options) bool {
zero := bimg.Sharpen{}
//it can be merged if the background was not set (in options or in self) or if they are set to the same value
return other.Sharpen == zero || other.Sharpen == self.Sharpen
}
func (f *sharpen) Merge(other *bimg.Options, self *bimg.Options) *bimg.Options {
other.Sharpen = self.Sharpen
return other
}
func (f *sharpen) CreateFilter(args []interface{}) (filters.Filter, error) {
var err error
if len(args) != 6 {
return nil, filters.ErrInvalidFilterParameters
}
r := &sharpen{}
r.Radius, err = parse.EskipIntArg(args[0])
if err != nil {
return nil, err
}
r.X1, err = parse.EskipFloatArg(args[1])
if err != nil {
return nil, err
}
r.Y2, err = parse.EskipFloatArg(args[2])
if err != nil {
return nil, err
}
r.Y3, err = parse.EskipFloatArg(args[3])
if err != nil {
return nil, err
}
r.M1, err = parse.EskipFloatArg(args[4])
if err != nil {
return nil, err
}
r.M2, err = parse.EskipFloatArg(args[5])
if err != nil {
return nil, err
}
return r, nil
}
func (f *sharpen) Request(ctx filters.FilterContext) {}
func (f *sharpen) Response(ctx filters.FilterContext) {
HandleImageResponse(ctx, f)
}
|
//
// Created by <NAME> on 5/22/18.
//
#include <ooio.h>
#include "parseOperators.h"
#include "genoperators.h"
#include "stringTrie.h"
logical traceParse = False;
static retCode startTable(void *cl);
static retCode endTable(void *cl);
static retCode startCollection(void *cl);
static retCode endCollection(void *cl);
static retCode startArray(void *cl);
static retCode endArray(void *cl);
static retCode startEntry(const char *name, void *cl);
static retCode endEntry(const char *name, void *cl);
static retCode numEntry(double dx, void *cl);
static retCode boolEntry(logical trueVal, void *cl);
static retCode txtEntry(const char *name, void *cl);
static retCode nullEntry(void *cl);
static retCode errorEntry(const char *name, void *cl);
JsonCallBacks operEvents = {
startTable,
endTable,
startCollection,
endCollection,
startArray,
endArray,
startEntry,
endEntry,
txtEntry,
numEntry,
boolEntry,
nullEntry,
errorEntry
};
typedef enum {
initial,
inDecl,
inOper,
inAst,
inToken,
inPriorities,
inDescription,
inBkt,
inLeft,
inRight,
inSep,
inPriority,
inKeyword,
unknownState
} ParseState;
static char *stNames[] = {"initial", "inDecl", "inOper", "ast", "token", "priorities", "desc", "bracket", "left",
"right", "seperator", "priority", "keyword", "unknown"};
static OperatorStyle operatorMode(const char *name);
static ParseState fromStName(const char *name);
typedef struct {
char oper[1024]; // Operator name
char ast[1024];
OperatorStyle mode;
int priorities[4];
int numPriorities;
integer priority;
logical isKeyword;
char left[16];
char right[16];
char sep[16];
char desc[1024];
ParseState state;
} ParsingState, *statePo;
retCode startTable(void *cl) {
statePo info = (statePo) cl;
info->state = initial;
if (traceParse)
logMsg(logFile, "Starting parse of operators");
return Ok;
}
retCode endTable(void *cl) {
if (traceParse)
logMsg(logFile, "Ending parse of operators");
return Ok;
}
retCode startCollection(void *cl) {
statePo info = (statePo) cl;
if (traceParse)
logMsg(logFile, "Starting collection, state = %s", stNames[info->state]);
switch (info->state) {
case initial:
info->state = inDecl;
uniCpy((char *) &info->oper, NumberOf(info->oper), "");
uniCpy((char *) &info->sep, NumberOf(info->sep), "");
info->numPriorities = 0;
info->isKeyword = False;
break;
default:
return Error;
}
return Ok;
}
retCode endCollection(void *cl) {
statePo info = (statePo) cl;
if (traceParse)
logMsg(logFile, "Ending collection, state = %s", stNames[info->state]);
switch (info->state) {
case initial:
return Error;
case inDecl:
info->state = initial;
switch (info->mode) {
case infixOp:
genInfix(info->oper, info->ast, info->priorities[0], info->priorities[1], info->priorities[2], info->isKeyword,
info->desc);
return Ok;
case prefixOp:
genPrefix(info->oper, info->ast, info->priorities[0], info->priorities[1], info->isKeyword, info->desc);
return Ok;
case postfixOp:
genPostfix(info->oper, info->ast, info->priorities[0], info->priorities[1], info->isKeyword, info->desc);
return Ok;
case brackets:
genBracket(info->oper, info->priority, info->left, info->right, info->sep, info->desc);
return Ok;
case tokenOnly:
genToken(info->oper, info->desc, True);
return Ok;
default:
return Error;
}
default:
return Error;
}
}
retCode startArray(void *cl) {
statePo info = (statePo) cl;
if (traceParse)
logMsg(logFile, "Starting array, state = %s", stNames[info->state]);
return Ok;
}
retCode endArray(void *cl) {
statePo info = (statePo) cl;
if (traceParse)
logMsg(logFile, "Ending array, state = %s", stNames[info->state]);
return Ok;
}
retCode startEntry(const char *name, void *cl) {
statePo info = (statePo) cl;
if (traceParse)
logMsg(logFile, "Starting entry, state = %s, name=%s", stNames[info->state], name);
switch (info->state) {
case initial:
return Error;
case inDecl: {
info->state = fromStName(name);
switch (info->state) {
case inOper:
info->mode = operatorMode(name);
uniCpy(info->ast, NumberOf(info->ast), "");
return Ok;
case inAst:
return Ok;
case inPriorities:
info->numPriorities = 0;
return Ok;
case inDescription:
return Ok;
case inToken:
info->mode = tokenOnly;
return Ok;
case inBkt:
info->mode = brackets;
uniCpy(info->sep, NumberOf(info->sep), "");
return Ok;
case inKeyword:
info->isKeyword = False;
return Ok;
default:
return Error;
}
}
default:
return Error;
}
}
retCode endEntry(const char *name, void *cl) {
statePo info = (statePo) cl;
if (traceParse)
logMsg(logFile, "Ending entry, state = %s, name=%s", stNames[info->state], name);
switch (info->state) {
case initial:
return Error;
case inOper:
case inPriorities:
case inDescription:
case inToken:
case inAst:
case inLeft:
case inRight:
case inPriority:
case inSep:
case inBkt:
case inKeyword:
info->state = inDecl;
return Ok;
default:
return Error;
}
}
retCode numEntry(double dx, void *cl) {
statePo info = (statePo) cl;
if (traceParse)
logMsg(logFile, "Numeric entry, value=%d", stNames[info->state], dx);
switch (info->state) {
case inPriorities: {
if (info->numPriorities >= NumberOf(info->priorities))
return Error;
else {
info->priorities[info->numPriorities++] = (int) dx;
return Ok;
}
}
case inPriority:
info->priority = (integer) dx;
return Ok;
default:
return Error;
}
}
retCode boolEntry(logical trueVal, void *cl) {
statePo info = (statePo) cl;
if (traceParse)
logMsg(logFile, "Boolean entry, value=%d", trueVal);
switch (info->state) {
case inKeyword:
info->isKeyword = trueVal;
return Ok;
default:
return Error;
}
}
retCode txtEntry(const char *name, void *cl) {
statePo info = (statePo) cl;
if (traceParse)
logMsg(logFile, "Text entry, state = %s, name=%s", stNames[info->state], name);
switch (info->state) {
case inOper:
uniCpy(info->oper, NumberOf(info->oper), name);
return Ok;
case inLeft:
uniCpy(info->left, NumberOf(info->left), name);
return Ok;
case inRight:
uniCpy(info->right, NumberOf(info->right), name);
return Ok;
case inSep:
uniCpy(info->sep, NumberOf(info->sep), name);
return Ok;
case inDescription:
uniCpy(info->desc, NumberOf(info->desc), name);
return Ok;
case inToken:
uniCpy(info->oper, NumberOf(info->oper), name);
return Ok;
case inBkt:
uniCpy(info->oper, NumberOf(info->oper), name);
return Ok;
case inAst:
uniCpy(info->ast, NumberOf(info->ast), name);
return Ok;
default:
return Error;
}
}
retCode nullEntry(void *cl) {
return Ok;
}
retCode errorEntry(const char *name, void *cl) {
logMsg(logFile, "Error: %s", name);
return Ok;
}
static char *opModeNames[] = {
"token",
"infixOp",
"prefixOp",
"postfixOp",
"bracket"};
OperatorStyle operatorMode(const char *name) {
for (int ix = 0; ix < NumberOf(opModeNames); ix++) {
if (uniCmp(name, opModeNames[ix]) == same)
return (OperatorStyle) ix;
}
return unknownOperatorStyle;
}
ParseState fromStName(const char *name) {
for (int ix = 0; ix < NumberOf(stNames); ix++) {
if (uniCmp(name, stNames[ix]) == same)
return (ParseState) ix;
}
if (operatorMode(name) != unknownOperatorStyle)
return inOper;
return unknownState;
}
retCode parseOperators(char *fname) {
ioPo inFile = openInFile(fname, utf8Encoding);
if (inFile != NULL) {
ParsingState info = {.state=initial};
yyparse(inFile, &operEvents, &info);
return Ok;
} else {
return Fail;
}
}
|
// Copyright (c) 2011-2017 The Cryptonote developers
// Copyright (c) 2014-2017 XDN developers
// Copyright (c) 2016-2017 BXC developers
// Copyright (c) 2017 Royalties developers
// Copyright (c) 2010-2017 Kohaku developers
// Copyright (c) 2017 Wayang developers
// Distributed under the MIT/X11 software license, see the accompanying
// file COPYING or http://www.opensource.org/licenses/mit-license.php.
#pragma once
namespace CryptoNote
{
const static boost::uuids::uuid CRYPTONOTE_NETWORK = { { 0x49, 0x8A, 0xA4, 0x3A, 0xA9, 0x75, 0x5e, 0x9f, 0x25, 0x95, 0x40, 0x13, 0x50, 0x19, 0x45, 0xf1 } };
}
|
Analysis of the carboxyl-terminal peroxisomal targeting signal 1 in a homologous context in Saccharomyces cerevisiae. Most peroxisomal matrix proteins contain a carboxyl-terminal tripeptide that directs them to peroxisomes. Within limits, these amino acids may be varied, without loss of function. The specificity of this peroxisomal targeting signal (PTS1) is remarkable considering its small size and its relaxed consensus sequence. Moreover, several peroxisomal proteins have a PTS1-like signal that does not fit the reported consensus sequence. Because many of these PTS1 variants seem to be functional in a species-dependent or protein context-dependent manner, we investigated the PTS1 requirements in a homologous context, using Saccharomyces cerevisiae and endogenous peroxisomal malate dehydrogenase (MDH3). Peroxisomal import of the MDH3-PTS1 variants was tested qualitatively by the ability to complement the Deltamdh3 mutant and quantitatively by subcellular fractionation. We observed efficient import of MDH3 into peroxisomes with a large variety of PTS1 tripeptides. Many of these variants do not fit the observed PTS1 requirements for heterologously expressed proteins, which suggests that additional domains in the protein may be of decisive importance whether or not a certain PTS1 variant is recognized by the components of the peroxisomal import machinery. Because we show that dimerization of MDH3 precedes import into the organelle, these domains are most likely conformational domains. Peroxisomes are nearly ubiquitous organelles bounded by a single membrane. Their function differs from organism to organism but always includes the -oxidation of fatty acids. Peroxisomal matrix proteins are synthesized in the cytoplasm and are targeted to peroxisomes by virtue of a peroxisomal targeting signal (PTS). 1 Two types of peroxisomal targeting signals have been identified so far. The PTS1 is located at the extreme COOH terminus of a protein and was first identified in firefly luciferase, which is targeted to peroxisomes when expressed in mammalian cells. The PTS1 signal is present in the majority of the peroxisomal matrix proteins. The second per-oxisomal targeting signal (PTS2) resides at the NH 2 terminus of a protein and was first identified in thiolase. Only a limited number of peroxisomal matrix proteins are imported via this signal. The PTS1 is a remarkable targeting signal in two aspects. First, the PTS1 is very small, because it consists of only a tripeptide. Second, considering the length of the targeting signal, the PTS1 consensus sequence is relaxed. Mutational analysis of the tripeptide of luciferase resulted in the following consensus sequence: (S/A/C)(K/H/R)(L/M) (in one-letter amino acid notation) or more general: a small amino acid at the first position, a basic amino acid at the second position, and a leucine (or methionine, although this was less efficient) at the last position. These conclusions were based on an immunofluorescence import assay in transfected mammalian cells expressing the heterologous luciferase gene or hybrid genes of chloramphenicol acetyltransferase fused to luciferase. An even more relaxed consensus PTS1 was observed for import of proteins into glycosomes of trypanosomes. For these studies either luciferase was used or a hybrid protein of the COOH-terminal 6 amino acids of glycosomal phosphoglycerate kinase fused to chloramphenicol acetyltransferase. Import was determined using a selective permeabilization assay. Recent observations justified reinvestigation of the nature of the PTS1. First, PTS1-resembling sequences have now been identified in a large number of proteins (reviewed by Refs. 9 -11), and this number is rapidly increasing by the cloning of genes encoding peroxisomal proteins. Although the consensus PTS1 originally seemed to be a simple one, more and more PTS1-like sequences are identified that do not match the originally defined consensus sequence. Because these PTS1 variants were mostly found in trypanosomes and yeasts, this has been explained by species divergence. However, the recent observation that a human protein (alanine:glyoxylate aminotransferase) can also be targeted to peroxisomes of mammalian cells by PTS1 tripeptides (KKL, SSL, SQL, and NKL) that do not fit the consensus sequence makes the proposed species divergence questionable. A second reason to re-examine the nature of PTS1-dependent import is the remarkable finding that peroxisomes are able to import folded proteins. These findings may indicate that the folded structure of the protein is of decisive importance for recognition of the PTS1. All comprehensive mutation analyses of the PTS1 have been performed with either heterologously expressed peroxisomal proteins or with nonperoxisomal reporter proteins, without check on the functional competence of the imported protein. Therefore we decided to analyze the PTS1 signal in the homologous context and in a more quantitative and functional manner. To this purpose, we have made mutations in the PTS1 signal of the endogenous MDH3 protein of Saccharomyces cer-evisiae. Import of the MDH3-PTS1 mutants was qualitatively scored by the (in)ability to complement the ⌬mdh3 mutant and was quantified by subcellular fractionation. We conclude that a wide variety of PTS1 signals are functional when presented in a homologous context and discuss the implications for the interaction between the PTS1-containing protein and the PTS1 receptor. NH Epitope Tagging and Antibodies-The synthetic NH epitope tag CQDLPGNDNST (corresponding to the NH 2 terminus of the mature hem-agglutinin protein) was conjugated with maleimide bis N-hydroxysuccinimide to keyhole limpet hemocyanin and used for antibody production in rabbits. For epitope tagging, an oligonucleotide adaptor encoding the NH epitope was ligated in the SacI/BamHI site of the CTA1 expression plasmids. People interested in these epitope tagging reagents should contact P. van der Sluijs. The raising of thiolase antibodies is described in Ref. 19. Construction of MDH3-SKL/SEL/⌬KL Mutants-pMDH3-SEL was obtained by PCR on genomic DNA of S. cerevisiae using the primers 5-AAGGATCCATGGTCAAAGTCGCAATTCTTG-3 and 5-AAAAAG-CTTCATAGCTCGGAAGAGTCTACGATGAAACTC-3. After digestion of the created BamHI and HindIII sites, the fragment was cloned into the BamHI/HindIII site of pUC19 (pUC-MDH3-SEL). MDH3-SKL was made by replacing the ClaI/HindIII fragment of pUC-MDH3-SEL by the ClaI/HindIII fragment of pUC-MDH3 resulting in pUC-MDH3-SKL. The MDH⌬KL gene was obtained by PCR on genomic DNA of S. cerevisiae, using the primers 5-AAGGATCCATGGTCAAAGTCGCAA-TTCTTG-3 and 5-AAAAAGCTTCATAGCTAGGAAGAGTCTACGAT-GAAACTC-3. This fragment was cut with ClaI/HindIII and cloned into the ClaI/HindIII site of pUC-MDH3-SEL resulting in pUC-MDH3⌬KL. All constructs were verified by sequencing starting from the 3 end until the ClaI site to make sure that all genes were identical except for the PTS1. The genes were subsequently cloned in the BamHI/HindIII site behind the catalase promoter of pEL43, which is derived from pYCplac33. The multicopy plasmid used was similar to pEL43 except that it was based on pYEplac 181. Construction of MDH3-PTS1 Mutant Library-To construct a library of MDH3-PTS1 mutants, an XbaI restriction site was created by introducing a silent mutation 19 base pairs upstream of the stopcodon of the MDH3 gene. This was achieved by PCR on pWT-MDH3 (pEL102) using a universal primer and the MDH3-Xba primer 5-GAAGAGTCTA-GAATGAAACTCTTGCG-3. The obtained PCR fragment was digested with BamHI and XbaI and cloned behind the CTAI promoter of pEL43. To exclude PCR mistakes, this construct was sequenced up to the ClaI site, and the remainder of the gene was replaced with the SacI-ClaI fragment of pNH-MDH3-SKL (pEL143), resulting in NH-MDH3⌬PTS1 (pEL149). This plasmid was cut with XbaI and PstI, purified, and recirculated by ligating in the presence of the degenerated oligonucleotide adaptors (Fig. 1). The ligation mixture was transformed to a Escherichia coli MutS strain. The obtained colonies were rinsed from the plates, and plasmid DNA was isolated. This DNA was retransformed to E. coli (DH5␣), and DNA was isolated from single colonies. This was sequenced from the 3 end up to approximately 20 base pairs after the XbaI site. Although we often found unexpected mutations at the place of the introduced oligos, we never found mutations before the XbaI site. We had to sequence about 70 clones to obtain the reported random mutations in the tripeptide. The FFF and ANL tripeptides were made by using nondegenerated adaptors. After sequencing, the selected plasmids were tranformed to the ⌬mdh3 mutant. Electron Microscopy-Oleate-induced cells were fixed with 2% paraformaldehyde and 0.5% glutaraldehyde. Ultra-thin sections were prepared as described in Ref. 22. Enzyme Assays-Enzymes were measured as described earlier. Immunoprecipitations-20 ml of a culture of cells grown overnight on 0.3% glucose minimal medium was spun, and the cells were resuspended in 5 ml of minimal glycerol or oleate medium. After growing the cells for another 2 h, the cells were collected and resuspended in 1 ml of minimal glycerol medium or oleate medium with 25 Ci of 35 S-labeled methionine and cysteine. After an incubation of 1.5 h (28°C, shaking), cells were transferred in 2-ml Eppendorf tubes, spun, and resuspended in immunoprecipitation buffer (50 mM Tris (pH 7.5), 50 mM NaCl, 0.2% Triton X-100). After adding glass beads, the cells were lysed by vortexing for 30 min at 4°C. The cell debris and glassbeads were removed by a short spin. Subsequently, 100 l of a 10% protein A beads suspension (washed in HBS buffer (50 mM HEPES-NaOH (pH 7.6), 200 mM NaCl) containing 0.5% CHAPS and 2.5 l of NH-antibody were added to the cell-free lysate, and this was incubated for 1 h at 4°C while shaking. The beads were collected by a short spin, washed two times with immunoprecipitation buffer, and heated in Laemmli sample buffer. Beads were spun down, and the supernatants were then layered on a 15% SDS-polyacrylamide gel. After staining and destaining, the gels were washed in 30% methanol/phosphate-buffered saline for 5 min and then incubated in enhancer (20 g/liter of sodium salicylate in 30% methanol), dried, and subjected to fluorography. The glycerol medium appeared to be especially useful for labeling FIG. 1. MDH3 constructs used in this study. The degenerated adaptors used for random mutagenesis are printed in bold. X represents any amino acid. The nucleotide code N represents any base, whereas the nucleotide code S represents a C or G. experiments with cells that are unable to grow on oleate. For wild-type cells, the results were identical for the two media used. RESULTS MDH3 Import Is PTS1-dependent-Peroxisomal malate dehydrogenase of S. cerevisiae (MDH3) possesses the typical PTS1 tripeptide SKL at its COOH terminus. Because some PTS1-containing proteins contain additional (internal) peroxisomal targeting signals, we tested whether import of MDH3 completely relies on this tripeptide. To this purpose we made one PTS1 mutant from which the last two amino acids were deleted (MDH3⌬KL) and one PTS1 mutant in which the positively charged lysine residue was replaced by the negatively charged glutamic acid residue (MDH3-SEL). Previously, it has been shown that this substitution blocks peroxisomal import of luciferase in CV-1 cells and in S. cerevisiae. The wild-type gene (MDH3-SKL) and the mutant genes were placed under the control of the peroxisomal catalase promoter (CTA1) and transformed to ⌬mdh3 cells. Recently, we demonstrated that ⌬mdh3 cells were unable to grow on plates containing oleate as sole carbon source. Import of the MDH3-PTS1 variants was tested by the ability of the transformants to complement the growth defect of ⌬mdh3 cells. ⌬mdh3 cells transformed with MDH3-SKL regained their ability to grow on oleate plates. No growth was observed in ⌬mdh3 cells transformed with the MDH3⌬KL plasmid, indicating that the SKL tripeptide is required for import of MDH3 into peroxisomes and that no additional peroxisomal targeting signals are present in this protein (data not shown). Surprisingly, we found that ⌬mdh3 cells expressing MDH3-SEL fully regained the ability to grow on oleate. This indicates that sufficient amounts of MDH3-SEL were imported into peroxisomes to give functional complementation. To measure the efficiency of import, we determined the amount of MDH3 in peroxisomes. Wild-type cells and ⌬mdh3 transformants were induced on oleate, followed by subcellular fractionation. To eliminate the contributions of cytosolic and mitochondrial malate dehydrogenase (MDH2 and MDH1, respectively), the organellar pellet was further fractionated on a Nycodenz density gradient. Import into peroxisomes was roughly estimated by determining the distribution of MDH activity between the peroxisomal and the mitochondrial peak fractions (P and M, Fig. 2). The MDH distribution in wild-type cells was similar to the distribution observed in ⌬mdh3 cells transformed with pMDH3-SKL, indicating that the output of the endogenous MDH3 promoter is very similar to the output of the CTA1 promoter under these conditions. No bimodal MDH distribution was observed in ⌬mdh3 cells transformed with pMDH3⌬KL, which is in line with the observation that this plasmid was not able to complement the ⌬mdh3 mutant. Approximately 30% of MDH3-SEL was imported into peroxisomes, based on the P:M ratio of MDH3-SEL (P:M 0.6:1) compared with that of MDH3-SKL (P:M 2:1). Epitope Tagging of the MDH3 Protein-To determine the import of the MDH3-PTS1 variants in a more convenient and quantitative manner, we epitope-tagged the protein at its NH 2 terminus with the NH tag. After subcellular fractionation of the transformants, the amount of NH-MDH3 in the organellar pellet fraction and cytosolic supernatant fraction was determined by Western blotting using the antibody against the NH epitope, followed by 125 I-labeled protein A. The amount of 125 I labeling was quantified with a PhosphorImager. At least 90% of NH-MDH3-SKL proved to be present in the organellar pellet (Fig. 3A). No import was observed for the NH-MDH3⌬KL protein (data not shown), whereas we found that on average 50% of the NH-MDH3-SEL protein was imported into peroxisomes (Fig. 3A). These results are in agreement with the rough estimates based on the gradient analysis, indicating that the NH tag did not interfere with targeting of MDH3. Import of NH-MDH3-SEL into peroxisomes could also be demonstrated with immunoelectronmicroscopy. As shown in Fig. 4B, NH-MDH3-SEL was present inside the organelle and not just associated with it. This is consistent with the observation that (NH-)MDH3-SEL complemented the growth defect of ⌬mdh3 cells. No import was observed in ⌬mdh3 cells expressing NH-MDH3⌬KL (not shown).The tagged protein also enabled us to study the import of MDH3 in the PTS1 import mutant, pex5 (formerly named pas10), and the PTS2-import mutant, pex7 (formerly named pas7). Import of NH-MDH3-SKL was normal in pex7 cells but blocked in pex5 cells, indicating that import of this protein into peroxisomes is dependent on the presence of the PTS1 receptor (Fig. 3B). Import of MDH3-PTS1 Variants-It was remarkable that MDH3-SEL was imported into peroxisomes, because it has previously been demonstrated that luciferase-SEL or bleomycin-luciferase-SEL cannot be imported into peroxisomes of S. cerevisiae. This suggests that some targeting signals are functional in endogenous peroxisomal proteins but not in the context of heterologously expressed proteins. To test this hypothesis, we constructed MDH3-PTS1 variants with substitutions at the first, second, and third position of the tripeptide. The resulting constructs were sequenced and transformed to ⌬mdh3 cells. Import was determined by the ability of the transformants to grow on oleate and by subcellular fractionation followed by Western blotting and quantitation using a PhosphorImager (Table I). We could not find any amino acid substitution at the first position of the tripeptide that had an influence on the import efficiency. Many substitutions were also tolerated at the second position of the tripeptide. The most severe mutations obtained at this position were the negatively charged glutamic acid (E) and the small alanine (A) residue, but even the majority of these MDH3-PTS1 variants were imported. Furthermore, we found that positively charged amino acids (K/R/H) could be replaced by aromatic amino acids (Y/F) without any noticeable effect on the import efficiency. The number of functional mutations at the last position of the tripeptide was much more limited, as has also been observed in the luciferase import studies. MDH3-PTS1 variants which were imported for only 5% (SKN and SKE), were still able to complement the ⌬mdh3 mutant. No complementation (and import) was observed when the ultimate amino acid was replaced by the charged residues arginine (R) or aspartic acid (D). Because these proteins were able to complement the growth defect of a ⌬mdh2 mutant on ethanol (data not shown), this seems not to be caused by inactivation of these proteins. A phenylalanine (F) is tolerated at every position without any noticeable effect on the import efficiency (Table I). It might be that this amino acid is functional at any position as long as the other two positions are still conserved according to the "optimal" sequence SKL. This "two out of three ain't bad" rule predicted that if we mutated the entire tripeptide to phenylalanine residues, the import efficiency would decrease. This was indeed the case, although the NH-MDH3-FFF protein was still imported to some extent and able to complement the ⌬mdh3 mutant. We also tested the tripeptide ANL, which is the putative (nonconsensus) targeting signal of human peroxisomal catalase. We observed rather efficient import of MDH3-ANL, suggesting that this tripeptide functions as a valid PTS1 signal. Dimerization of MDH3-Recently, it has been shown by several elegant studies that proteins can be imported into peroxisomes in a folded (multimeric) state 31). For example, thiolase without a peroxisomal targeting signal (thiolase⌬PTS2) can be imported when expressed in wild-type cells but not when it is expressed in a thiolase disruption strain. This strongly suggested that thiolase⌬PTS2 is imported as a dimer with wild-type thiolase ("piggy-back") and hence that complete unfolding is probably not required for import into peroxisomes. A similar experiment was reported in Ref. 14. Using the same experimental setup, we tested whether dimerization of MDH3 also precedes import. To that end we transformed the plasmid pNH-MDH3⌬PTS1 to wild-type cells. The NH-MDH3⌬PTS1 protein not only contains an epitope tag to distinguish it from wild-type MDH3 but is also 7 amino acids longer than wild-type MDH3, because the COOH-terminal 5 amino acids were replaced by a peptide of 12 amino acids (Fig. 1). Because this larger protein can easily be distinguished from the shorter wild-type protein, it enabled us to verify that no recombination events had occurred between the pNH- spin. An equal percentage was layered in every lane. Pelletable thiolase was at least 75% for ⌬pex5 (⌬pas10) and less than 10% for pex7 (pas7). For this figure, the proteins were detected using NH antibodies and an alkaline phosphatase-based color staining. MDH3⌬PTS1 plasmid and the endogenous wild-type gene. Such an event could result in an NH-MDH3-SKL gene, which would hamper the analysis. The transformed cells were induced on oleate, and the amount of imported NH-MDH3⌬PTS1 was determined by subcellular fractionation followed by Western blotting using the NH antibody. Surprisingly, in contrast to the earlier reports using different proteins but a similar experimental setup, we did not find any NH-MDH3⌬PTS1 in the organellar pellet fraction (Fig. 5). One possibility is that heterodimers were not formed between WT-MDH3 and NH-MDH3⌬PTS1. Therefore, we tested the formation of heterodimers by immunoprecipitations with the NH antibody on lysates of oleate-induced wild-type cells expressing NH-MDH3⌬KL or NH-MDH3⌬PTS1 (Fig. 6). No heterodimer formation between NH-MDH3⌬PTS1 or NH-MDH3⌬KL and WT-MDH3 could be demonstrated (Fig. 6, compare first and third lanes and second and fourth lanes). Because it is possible that the modifications at the carboxyl terminus of NH-MDH3⌬PTS1 and NH-MDH3⌬KL inhibited dimerization, we tested the ability of NH-MDH3⌬KL to form dimers by using a sucrose density gradient. We found that this protein had not lost its ability to dimerize (data not shown). In addition, the NH-MDH3⌬KL protein was still active, because it was able to complement the growth defect of a ⌬mdh2 mutant on ethanol (data not shown). Another explanation for the failure to detect heterodimers is the possibility that heterodimers were disassembled during the import process. Alternatively, Because it has recently been suggested that import of some peroxisomal proteins is much faster than other peroxisomal proteins, import of WT-MDH3 might be so efficient that it does not get the chance to dimerize in the cytosol prior to import. We tested these possi-bilities by repeating the immunoprecipitations on lysates of ⌬pex5 cells transformed with NH-MDH3⌬PTS1 and NH-MDH3⌬KL. Because the PTS1 import is blocked in this mutant, dimerization of MDH3 only takes place in the cytosol. However, we were still unable to detect heterodimers, suggesting that the inability to observe heterodimers was not caused by the import process (data not shown). Taken together, these results hinted at the possibility that dimerization of MDH3 is an efficient process and that dimers are mostly formed between proteins synthesized on the same polyribosome, resulting in the formation of homodimers only. We argued that if this was indeed be the case, we might be able to increase the amount of heterodimers by expressing WT-MDH3 from a multicopy plasmid in cells expressing NH-MDH3⌬PTS1 or NH-MDH3⌬KL. Indeed, we were now able to co-immunoprecipitate WT-MDH3 with the NH antibody in lysates of these double transformants. Up to approximately 30% of NH-MDH3⌬PTS1 or NH-MDH3⌬KL had formed heterodimers with WT-MDH3 (Fig. 6, lanes 5 and 6). It can further be seen that recombination of pNH-MDH3⌬PTS1 with pWT-MDH3 did not noticeably occur, because this would have given an additional band at about the same height as NH-MDH3⌬KL. To test whether the formed heterodimers could be imported into peroxisomes, wild-type cells transformed with pNH-MDH3⌬PTS1/pWT-MDH3 were grown on oleate and fractionated. The organellar and cytosolic fractions were used for Western blotting using the NH antibody. At least 30% of NH-MDH3⌬PTS1 was now present in the organellar pellet fraction, which is in good agreement with the observed amount of heterodimers formed. To exclude that NH-MDH3⌬PTS1 was not trapped in pelletable protein aggregates caused by the overex- pression of WT-MDH3, we used the same cells for immunoelectronmicroscopy. This confirmed that NH-MDH3⌬PTS1 was indeed imported into peroxisomes when these cells were cotransformed with pWT-MDH3 (Fig. 4D). Surprisingly, the overexpression of WT-MDH3 did not lead to aggregation of the protein in the cytosol. The import machinery appeared to be perfectly capable of dealing with this large amount of PTS1containing protein, resulting in the formation of many and very large peroxisomes (Fig. 4E). Taken together, the results suggest that folding and dimerization of MDH3 precedes import into the peroxisome. DISCUSSION Degeneracy of the PTS1-The carboxyl-terminal peroxisomal targeting signal (PTS1) has been studied by extensive mutational analyses. In all these cases peroxisomal proteins from other organisms or nonperoxisomal proteins were used as reporters. This resulted in a consensus sequence to which functional PTS1s were expected to conform. Since the formulation of this consensus sequence, more and more peroxisomal proteins were identified whose PTS1-like tripeptide did not fit this consensus sequence. We therefore decided to repeat such an analysis in S. cerevisiae, using a peroxisomal protein of S. cerevisiae as reporter. Because it has been demonstrated for some PTS1-containing enzymes that deletion of the PTS1 does not block import into peroxisomes, we first demonstrated that import of MDH3 is completely dependent upon the presence of its PTS1 and the PTS1 receptor, Pex5p. Furthermore, we showed that this protein could be epitope-tagged without any noticeable effect on its import efficiency. Finally, we demonstrated that varying the COOH terminus of MDH3 did not greatly affect its activity because the nonimported variants were able to complement the growth defect on ethanol of the ⌬mdh2 mutant, which lacks the cytosolic malate dehydrogenase. This has recently also been reported by Ref. 33, which showed that deletion of the SKL tripeptide of MDH3 did not affect its specific activity. Taken together, these findings made MDH3 a reliable model protein for studying the PTS1 requirements. Although we tested only 29 out of the 60 possible amino acid substitutions, we have taken care to have representative amino acids at all positions by testing at least one positively and one negatively charged amino acid, one hydrophobic and aromatic amino acid, and one polar amino acid at each position. The results we obtained differ in several aspects from previous reports concerning the degeneracy of the PTS1 signal. (i) We did not find any amino acid substitution at the first position of the tripeptide that affected the import of MDH3. Strictly taken, the targeting signal of MDH3 is therefore not a tripeptide but a dipeptide. Especially the finding that a phenyl-alanine (F) or a proline (P) is tolerated at this position is surprising, for it is in sharp contrast to the observation that this residue should preferably be small, as has been found for luciferase expressed in mammalian cells or for the chloramphenicol acetyltransferase-glycosomal phosphoglycerate kinase fusion protein expressed in trypanosomes. We believe that the observation that many substitutions are tolerated at this position in endogenous peroxisomal proteins is more in line with the reality than the observation that this amino acid should strictly be small. Examples of this greater tolerancy in endogenous proteins are the PTS1 of human alanine:glyoxylate aminotransferase, which is KKL, and the PTS1 of peroxisomal fatty acid synthetase of S. cerevisiae (FAA2), which is EKL. Neither the EKL nor the KKL tripeptide was able to direct luciferase to peroxisomes or glycosomes. Similarly, dihydroxyacetone synthase of Hansenula polymorpha and rat and feline alanine:glyoxylate aminotransferase are targeted via the tripeptide NKL (34 -36). Also this asparagine (N) does not fit the consensus of a small residue at the first position. (ii) We found no requirement for a basic amino acid at the penultimate position as found for luciferase import in peroxisomes of mammalian cells and as observed to a lesser extent for luciferase import in glycosomes of trypanosomes. In agreement with our results are the findings that a positive residue at the penultimate position is also not required for import of the hybrid chloramphenicol acetyltransferase-glycosomal phosphoglycerate kinase protein in glycosomes of trypanosomes. It is possible that for S. cerevisiae and trypanosomes, the requirements at the penultimate position are more relaxed than for mammalian cells. However, the putative PTS1 of human catalase also does not have a positively charged residue at the second position of its PTS1-like tripeptide (ANL). Again, we therefore propose that in a homologous context many more variants are functional at this position than in a heterologous context. This notion is supported by the observation that human alanine:glyoxylate aminotransferase can be imported into peroxisomes of mammalian cells when the PTS1 of alanine:glyoxylate aminotransferase is replaced by SSL. In contrast, luciferase-SSL cannot be imported into peroxisomes of mammalian cells. Furthermore, MDH3-SEL is imported into peroxisomes of S. cerevisiae with more than 50% efficiency, whereas luciferase-SEL is not imported into peroxisomes of S. cerevisiae. (iii) Finally, we found that at the last position only hydrophobic residues result in efficient import. In agreement with previous observations, we observed that the ultimate amino acid could also be replaced by an aromatic residue. This result confirms an earlier report that the tripeptide SKF of catalase from S. cerevisiae is a legitimate PTS1 signal. Analysis of the targeting efficiency of the various MDH3-PTS1 variants is shown. Cells were grown on oleate, fractionated, and the organellar pellet and cytosolic supernatant fractions were used for Western blotting with the NH antibody. After incubation with 125 I-labeled protein A, import was quantified with a PhosphorImager. Import efficiency:, more than 80%;, between 80 and 50%;, between 20 and 5%;, less than 5% import. XKL Import SXL Import SKX Import XXX Import Importance of the Homologous Context-It is conceivable that the originally defined consensus PTS1 (a small amino acid at the first position, a positively charged amino acid at the second position, and a hydrophobic amino acid at the third position) as delineated for a heterologously expressed protein represents the most favorable PTS1 signal. This is supported by the observation that most PTS1 signals found in nature are consistent with this consensus sequence. In addition, we showed in this study that a phenylalanine (F) was tolerated at every position in the PTS1 of MDH3, without affecting the import efficiency, whereas a PTS1 consisting of the tripeptide FFF was hardly able to direct MDH3 to peroxisomes. This illustrates that only a limited number of mutations within the ideal SKL tripeptide is tolerated. It is quite often observed that certain defined targeting signals work better with one reporter protein than another. This can be explained by assuming that a targeting signal is better exposed in certain reporter proteins than others. Our results for the PTS1 seem to stress the importance of the proper reporter even further, because they imply that a much broader range of PTS1 variants is functional in endogenous peroxisomal proteins compared with heterologously expressed peroxi-somal proteins. This explains many of the encountered failures to demonstrate that certain PTS1-resembling tripeptides are able to direct a reporter protein to peroxisomes. This inability has often been explained by proposing either protein context dependence or species divergence. The importance of the homologous context explains both the observed species divergence, as well as the observed context dependence. This is probably best illustrated by the following example. The SSL tripeptide of glycosomal phosphoglycerate kinase was not able to direct a reporter protein (chloramphenicol acetyltransferase) to peroxisomes of mammalian cells, whereas chloramphenicol acetyltransferase-SKL was imported into these peroxisomes. Because both chloramphenicol acetyltransferase variants were imported into glycosomes of trypanosomes, this strongly suggests species divergence in the ability to recognize the SSL tripeptide. However, Motley et al. recently demonstrated that peroxisomes of mammalian cells were perfectly capable of importing the alanine:glyoxylate aminotransferase-SSL protein. Because luciferase-SSL was not imported in these peroxisomes, this observation would suggest that the ability to recognize the SSL tripeptide is dependent on the protein context. Similarly, glycosomal phosphoglycerate kinase has been expressed in S. cerevisiae but failed to be imported into peroxisomes. Our results in the present study show, however, that SSL can be recognized by the peroxisomal import system of S. cerevisiae provided that it is attached to an endogenous protein. The observations that signals behave either in a species-dependent manner or in a context-dependent manner or even in both are consistent with the notion that the homologous context is very important. What could be the rationale of the importance of the homologous context? It is conceivable that the interaction of peroxisomal matrix proteins with components of the peroxisomal import machinery, particularly Pex5p, is not restricted to the PTS1 but that interactions with other parts of the PTS1-containing protein are also required to ascertain that a PTS1 variant is indeed recognized as such. These "accessory sequences" may directly precede the PTS1, because it has been shown several times that a certain PTS1 tripeptide was not sufficient to direct a reporter protein to peroxisomes, whereas a hybrid protein with a longer COOH-terminal fusion was able to do so. The accessory sequences may also be further upstream of the PTS1. The observations that folding and dimerization of both thiolase and MDH3 (this study) already take place in the cytoplasm suggest that this is not restricted to some exceptional cases but rather is the default pathway for many (oligomeric) peroxisomal proteins. Therefore, it is conceivable that accessory sequences are formed by conformational epitopes within the folded protein. The interaction of these epitopes with the PTS1 receptor or with other components of the protein import machinery may be of decisive importance to determine whether a PTS1 variant is functional or not. Such interactions may be lacking when heterologously expressed proteins are used, when nonperoxisomal proteins are used, or even when mutations upstream of the PTS1 are introduced in a protein. We assume that during evolution the "ideal" PTS1 sequences may have become more degenerated, depending on the contribution of accessory sequences in binding the receptor. If this contribution is only minimal, a strong selective pressure is put on the conservation of an optimal PTS1. However, when the contribution of the accessory sequences is large, the selective pressure on keeping an optimal PTS1 is lost. There are some indications that the interactions mediated by accessory sequences are so strong that they can function as a true (though not very efficient) targeting signal. For instance, it has been reported that the PTS1-containing proteins catalase NH-MDH3⌬KL and NH-MDH3⌬PTS1 were expressed in ⌬mdh3 cells (first and second lanes), in wild-type cells (third and fourth lanes), and in wild-type cells co-expressing MDH3-SKL (fifth and sixth lanes). Cells were grown on glycerol, labeled for 2 h, and lysed as described under "Experimental Procedures." Similar results were obtained in oleate-induced cells, except that considerably less labeling was obtained in ⌬mdh3 cells. The arrowhead shows the position of WT-MDH3. and carnitine acetyltransferase of S. cerevisiae are still imported into peroxisomes when their PTS1 signal has been deleted. However, deletion of the PTS1 receptor blocks their import completely. This may indicate that these proteins contain additional domains that interact with the PTS1 receptor. Indeed, an interaction between carnitine acetyltransferase lacking its PTS1 and the PTS1 receptor Pex5p could be demonstrated using the two-hybrid assay. We were unable to demonstrate the existence of additional Pex5p interacting sequences in MDH3, because the two-hybrid interaction between MDH3-SKL and Pex5p was rather weak and already undetectable when the SKL tripeptide was replaced by SEL. Support for the existence of accessory sequences involved in binding the PTS1 receptor also comes from the observation that many nonperoxisomal proteins have carboxyl termini that fit with our observed relaxed "consensus" for functional PTS1 (di)peptides. Therefore, additional criteria are required to distinguish between genuine peroxisomal proteins and nonperoxisomal proteins. The existence of accessory sequences that mediate the binding of the PTS1 parallels the findings for nuclear protein import. Here, it has also been observed that flanking sequences of the nuclear localization sequence (NLS) modulate the import of a protein and, like the PTS1, the NLS does not have a strict consensus sequence (reviewed in Ref. 41). Moreover, both organelles can import folded proteins, and because we found that Pex5p is predominantly cytoplasmic, both import systems make use of mobile receptors. Our analysis of the PTS1 of MDH3 demonstrates that many PTS1-like signals are functional in a homologous context. Consequently, the definition of a targeting signal that it should be (i) required for import and (ii) sufficient to direct an otherwise cytosolic protein to peroxisomes may fall short for the PTS1 signal. Therefore, whether import of a peroxisomal protein truly relies on a PTS1 like signal is best tested by determining whether import requires the presence of the PTS1 receptor Pex5p. Our documentation of functional PTS1 motifs in a endogenous protein of S. cerevisiae may furthermore be useful to select putative peroxisomal proteins from the Yeast Genome Sequencing data base. Many of such proteins may previously have been overlooked, because their carboxyl termini did not fit the originally defined consensus of the PTS1. |
expected_output = {
"instance": {
2147483648: {
"sensor_type": {
"type": "yang-push periodic",
"filter_type": "xpath",
"filter_selector": "/if:interfaces-state/interface[name=\"GigabitEthernet0/0\"]/oper-status"
},
"data_collector": {
"dc0": {
"dc_type": "confd periodic",
"sub_filter": "/if:interfaces-state/interface[name=\"GigabitEthernet0/0\"]/oper-status"
}
}
}
}
}
|
Use of hybrid discrete cellular models for identification of macroscopic nutrient loss in reactiondiffusion models of tissues Macroscopic models accounting for cellular effects in natural or engineered tissues may involve unknown constitutive terms that are highly dependent on interactions at the scale of individual cells. Hybrid discrete models, which represent cells individually, were used to develop and apply techniques for modeling diffusive nutrient transport and cellular uptake to identify a nonlinear nutrient loss term in a macroscopic reactiondiffusion model of the system. Flexible and robust numerical methods were used, based on discontinuous Galerkin finite elements in space and a CrankNicolson temporal discretization. Scales were bridged via averaging operations over a complete set of subdomains yielding data for identification of a macroscopic nutrient loss term that was accurately captured via a fifthorder polynomial. Accuracy of the identified macroscopic model was demonstrated by direct, quantitative comparisons of the tissue and cellular scale models in terms of three error norms computed on a mesoscale mesh. Copyright © 2014 John Wiley & Sons, Ltd. |
Market Risk and Financial Performance of Non-Financial Companies Listed on the Moroccan Stock Exchange This study examines the effect of market risk on the financial performance of 31 non-financial companies listed on the Casablanca Stock Exchange (CSE) over the period 20002016. We utilized three alternative variables to assess financial performance, namely, the return on assets, the return on equity and the profit margin. We used the degree of financial leverage, the book-to-market ratio, and the gearing ratio as the indicators of market risk. Then, we employed the pooled OLS model, the fixed effects model, the random effects model, the difference-GMM and the system-GMM models. The results show that the different measures of market risk have significant negative influences on the companies financial performance. The elasticities are greater following the degree of financial leverage compared with the book-to-market ratio and the gearing ratio. In most cases, the firms age, the cash holdings ratio, the firms size, the debt-to-assets ratio, and the tangibility ratio have positive effects on financial performance, whereas the debt-to-income ratio and the stock turnover hurt the performance of these non-financial companies. Therefore, decision-makers and managers should mitigate market risk through appropriate strategies of risk management, such as derivatives and insurance techniques. |
Pipelining and Optimal Routing Techniques for Improving the Performance of Wireless Networks this thesis, a cross layer network design approach using effective MAC layer and optimal Network layer design has been proposed and implemented to improve the performance of the wireless networks. For this purpose, new MAC design principles have been proposed for effective scheduling and channel allocation where pipelining techniques proposed for improving the channel utilization. In addition, a new bandwidth allocation technique using partitioning has been proposed in this paper which allows varying the amount of traffic dynamically by increasing or decreasing the window size depending on the traffic. Finally, an ant colony based routing algorithm which uses cluster based routing has been proposed and implemented to match the newly designed MAC layer. |
Drug Therapy for Type 2 Diabetes OVER THE LAST several years the decisionmaking process for the treatment oftype 2 diabetes has progressed from one basic question-when should insulin be added to sulfonylurea therapy?-to a complex array of issues involving newer therapeutic regimens and a deluge of confusing and often contradictory data. Concepts such as insulin resistance, insulin sensitizers, and the peripheral effects ofantihyperglycemics now figure into the selection ofan appropriate treatment regimen. New agents offer potential advantages that often are supported with little or no scientific evidence, while older agents such as sulfonylureas and insulin are burdened with misconceptions and prejudices. In general, the balance between insulin production and insulin utilization is lost as type 2 diabetes progresses. While many patients with type 2 diabetes progress through familiar stages of impaired glucose tolerance (lGT), hyperinsulinemia, and finally pancreatic failure to meet insulin demands with resultant hyperglycemia, the normal progression may display many variations. Increased hepatic glucose output (HGO) is also a root cause for an elevated fasting plasma glucose (FPG) in type 2 diabetes. An understanding ofthis medley of causalities and an understanding ofhow each therapeutic alternative addresses each |
Anatomy as related to function and pain. In this article I have attempted to give an overview of the current aspects of anatomy relevant to understanding low back function and pain. Generally, anatomy, neuroanatomy, and mechanics of the spine are not well understood by those who examine and treat these structures. It is hoped that an improved understanding will enhance both evaluation and patient care. |
Acute recurrent bradycardia with evoked potential loss during transforaminal lumbar interbody fusion During a transforaminal lumbar interbody fusion a patient experienced acute intermittent bradycardia with manipulation of the intervertebral body space, followed by loss of somatosensory evoked potentials that did not recover. Postoperative evaluation revealed new bilateral lower extremity sensory and motor deficits. We postulate an afferent reflex arc to explain this and other reported instances of bradycardia and asystole during transforaminal lumbar interbody fusion surgery. Awareness of the association between bradycardia during lumbar spine surgery may alert anaesthetists, surgeons and neuromonitoring teams to impending neurological harm. |
(CNN) — Country singer Mindy McCready appears to have shot a dog that belonged to her late boyfriend, David Wilson, prior to shooting herself, Cleburne County Sheriff Marty Moss said Monday.
On Sunday, McCready, whose turbulent personal life overshadowed her music, was found dead on the front porch of her Arkansas home — victim, authorities said, of a self-inflicted gunshot wound.She was 37.
McCready leaves behind two sons — 6-year-old Zander and 10-month-old Zane.
“Zane and Zander are loved, cared for and comfortable with foster families at this time,” her representative told CNN in a statement.
Just a month earlier, police had paid another visit to the house in Heber Springs.
On that day, they found the infant’s father — record producer David Wilson — dead on the porch.
He too had apparently taken his own life. He too had used a gun. |
Tense and agreement in the speech of children with specific language impairment: patterns of generalization through intervention. Thirty-one children with specific language impairment participated in 48 intervention sessions designed to assist them in the use of 3rd-person singular -s or auxiliary is/are/was. Gains in the use of these target forms were significantly greater than gains on developmentally comparable morphemes serving as control forms. Untreated verb forms that mark both tense and agreement showed greater change during the intervention period than did past -ed. The findings suggest that by gaining skill in the use of morphemes that mark both tense and agreement, the children were able to identify and acquire other morphemes in the language that mark both of these features. This increase in sensitivity did not appear to apply to forms in the language that express tense only. |
Move over, Derek Zoolander! There’s a new heartthrob in town.
Ben Stiller took to Instagram on Wednesday to reveal the most recent “ridiculously good looking” addition to the cast of the “Zoolander” sequel, which is slated to hit theaters Feb. 12, 2016.
“#Zoolander2 @justinbieber,” the caption read, along with a black-and-white image of Stiller’s beloved character Derek having a "Blue Steel" face off with Bieber. But our eyes quickly drifted from the "Baby" singer's “Zoolander” impression (which was pretty good by the way) to his brown, spiky tresses. Did Bieber ditch his blonde locks for a darker look?
“"#itsawignotmynewhair,” the 21-year-old singer confirmed via a hashtag on his social media page.
Prior to the confirmation that Bieber would be strutting his stuff down the runway in “Zoolander 2,” the teen sensation teased his participation in the forthcoming comedy on Facebook.
“Working on something big right now in Europe. To learn more follow me on Fahlo. He is so hot right now,” he wrote Monday.
We’re not entirely surprised that the pop singer was cast in beloved film that first premiered in 2001. Just recently Bieber proved he had the comedy chops when he starred in Comedy Central’s the “Roast of Justine Bieber.” The singer, who claimed he wanted to change his ruffian image, took insults left and right from stars like Kevin Hart, Ludacris and even Martha Stewart.
The sandy blonde haired singer also proved he had the guts to become a model -- an underwear model, when he was chosen as the new face of Calvin Klein in January. The Canadian born artist slipped into his snug tighty whities and confidently struck a pose to promote the iconic undies in a steamy campaign ad. Looks like Derek Zoolander will definitely have some competition in 2016.
Are you excited to see Justin Bieber in “Zoolander 2”? Sound off in the comments section below with your thoughts on the “Boyfriend” singer starring alongside Ben Stiller, Owen Wilson, Will Ferrell and the rest of the gang. |
During the week following my 2011 Archibald win, one Melbourne radio announcer introduced me with the following: ''So if you can wear a horse suit and go 'neigh' you can call yourself an artist - on the line I have Ben Quilty''. I'd fired him up because I'd suggested in my Archibald acceptance speech that I felt it was time a Higher Education Contributions Scheme fee was implemented at the Australian Institute of Sport.
That was almost two years ago and I haven't stopped talking about it. Neither have I found a horse suit that fits me. Everyone pays HECS: nurses, paramedics, teachers, artists; we all pay for our education. We also pay tax from prizes won: the Archibald, Brett Whiteley Travelling Art Scholarship, all literary prizes, film prizes, prizes for excellence in education and medical research. Even the Queensland Premiers' Literary Award was taxed, until it was axed. And I didn't whinge about being thrown into a higher tax bracket when I won the Whiteley Scholarship as a young artist until I realised that at the same time I was in Paris studying, the young emerging Olympians in Salt Lake City were there for free. In fact the prizes they would receive for winning were also tax-free, and so were their education and training.
"Someone needs to point out to our sporting heroes that the spotlight is harsh but that Afghanistan is harsher." Credit:Steve Christo
My Melbourne mate on radio argued lawn bowlers couldn't make a living after competing at the Olympics and therefore shouldn't have to repay any debt to the rest of us. I gently pointed out I didn't go to art school to make money, and that school teachers sure as hell weren't making much from their full HECS-incurring degree and years of hard, thankless work in the education system. Surely if Eamon Sullivan and James Magnussen studied for nothing, then my little boy's school teacher Ms O'Rourke should also have received education for free?
I could see the headlines unfold last week as the men who embarrassed themselves in London on Stilnox and prank calls began the argument I've heard too many times before. It's always someone else's fault, the coach, team morale, always a lack of funding. When depression strikes them, inevitably someone says they need more money for therapy. Behaving well in the spotlight is a difficult thing to do for an excitable, testosterone-filled young man. Tell me about it! |
//Aca mostramos la lista de todos los semaforos actuales -----------------------------------------------------
void sem_list() {
sem_t * current = first_sem;
while (current != NULL)
{
current = current->next;
}
return;
} |
A completely integrated 1.9 GHz receiver front-end with monolithic image reject filter and VCO A 19 GHz monolithic superheterodyne receiver front-end with 300 MHz IF, on-chip tunable image reject filter and VCO is presented. The receiver was fabricated on a 0.5 um bipolar process. The 2.2 GHz VCO was realized with ground-shielded inductors. The performance is as follows: conversion gain: 25.6 dB, noise figure: 4.5 dB, image rejection: 65 dB, and phase noise of -103 dBc/Hz at 100 kHz offset. The LO-IF isolation improved compared to a previously fabricated front-end with off-chip VCO. This receiver front-end has NF, linearity, and phase noise suitable for DCS-1800. |
// Copyright 2017 The Fuchsia Authors. All rights reserved.
// Use of this source code is governed by a BSD-style license that can be
// found in the LICENSE file.
#include "le_connection_parameters.h"
namespace bt::hci_spec {
namespace {
// The length of a timeslice in the parameters, in milliseconds.
constexpr static float kTimesliceMs = 1.25f;
} // namespace
LEConnectionParameters::LEConnectionParameters(uint16_t interval, uint16_t latency,
uint16_t supervision_timeout)
: interval_(interval), latency_(latency), supervision_timeout_(supervision_timeout) {}
LEConnectionParameters::LEConnectionParameters()
: interval_(0), latency_(0), supervision_timeout_(0) {}
bool hci_spec::LEConnectionParameters::operator==(
const hci_spec::LEConnectionParameters& other) const {
return interval_ == other.interval_ && latency_ == other.latency_ &&
supervision_timeout_ == other.supervision_timeout_;
}
std::string hci_spec::LEConnectionParameters::ToString() const {
return bt_lib_cpp_string::StringPrintf("interval: %.2f ms, latency: %.2f ms, timeout: %u ms",
static_cast<float>(interval_) * kTimesliceMs,
static_cast<float>(latency_) * kTimesliceMs,
supervision_timeout_ * 10u);
}
LEPreferredConnectionParameters::LEPreferredConnectionParameters(uint16_t min_interval,
uint16_t max_interval,
uint16_t max_latency,
uint16_t supervision_timeout)
: min_interval_(min_interval),
max_interval_(max_interval),
max_latency_(max_latency),
supervision_timeout_(supervision_timeout) {}
LEPreferredConnectionParameters::LEPreferredConnectionParameters()
: min_interval_(0), max_interval_(0), max_latency_(0), supervision_timeout_(0) {}
bool LEPreferredConnectionParameters::operator==(
const LEPreferredConnectionParameters& other) const {
return min_interval_ == other.min_interval_ && max_interval_ == other.max_interval_ &&
max_latency_ == other.max_latency_ && supervision_timeout_ == other.supervision_timeout_;
}
} // namespace bt::hci_spec
|
//
// LoopMeUtility.m
// LoopMeSDK
//
// Copyright (c) 2012 LoopMe. All rights reserved.
//
#import <Foundation/Foundation.h>
typedef NS_ENUM(NSInteger, LoopMeLogLevel) {
LoopMeLogLevelError = 0,
LoopMeLogLevelDebug = 10,
LoopMeLogLevelInfo = 20,
LoopMeLogLevelOff = 30,
};
LoopMeLogLevel getLoopMeLogLevel(void);
void setLoopMeLogLevel(LoopMeLogLevel level);
void LoopMeLogDebug(NSString *format, ...);
void LoopMeLogInfo(NSString *format, ...);
void LoopMeLogError(NSString *format, ...);
@interface LoopMeLoggingSender : NSObject
@property (nonatomic) NSTimeInterval videoLoadingTimeInterval;
+ (LoopMeLoggingSender *)sharedInstance;
- (void)writeLog:(NSString *)msg;
@end
|
Firefighters are still tackling flames across the Highlands, some of which have been burning for more than 30 hours.
© STV
Wildfires in Scotland have caused at least £100,000 of damage.
Hundreds of firefighters have tackled blazes across the Highlands, with some continuing on Wednesday.
A fire in heather and gorse at the Queen's estate in Balmoral, which started on Monday, was brought under control on Tuesday afternoon.
The National Trust for Scotland said at least £100,000 of damage had been caused to its forest regeneration project, which had been hit by fire at two separate sites in the Torridon and Kintail areas.
Highlands and Islands Fire and Rescue Service said around 40 acres of trees belonging to the trust were destroyed at Torridon after the fire started on Saturday afternoon. The last fire crew left the scene just after midnight.
The Trust said its broadleaf forest included birch and hazel trees. A spokeswoman said: "We are still assessing the full extent of the damage. No buildings have been damaged and no one injured.
"Staff and volunteers have been working very hard during an extremely busy and challenging time for them."
The spokeswoman said approximately four square miles had been affected at Kintail, where part of the forest was destroyed on Sunday night, and five square miles at Torridon.
The battle against the flames continued elsewhere in Scotland. At Inverkirkaig, Highlands and Islands Fire and Rescue Service said there were "two fire fronts" this morning south of Loch Kirkaig, with a potential for four further fronts.
A helicopter has been sent to the scene to begin attacking the first front.
Two crews at Shiel Bridge were sent to the scene again to extinguish a "small area of burning" between Loch Shiel and Achnacart quarry. Parts of the area have been burning since the weekend.
On Monday night, five properties were evacuated in the area as the flames advanced. The homeowners were allowed to return to their properties on Tuesday.
A spokesman for the fire service said: "The service fully appreciates the assistance of land managers in terms of supporting helicopters and resources on the ground for some estates.
"In some areas, the mutual support provided to neighbours by fighting fires has had a significant effect on the ability to extinguish fires in their early stages, before they get too large.
"As the dry weather conditions continue, there is a continuing severe risk of further fires occurring and the public are warned to be vigilant and avoid discarding cigarette ends, lighting barbecues or other recreational activities which may result in fire outbreak."
"Following the rescue of a number of members of the public caught in the vicinity of these fires, the service would like to stress that members of the public should be aware that wildfires are very dangerous, as they spread very quickly and can change direction without warning," the spokesman added.
IN DETAIL |
import { DateRange } from 'moment-range'
import { List, Collection } from 'immutable'
import { Moment, max, min } from 'moment'
export const empty: List<DateRange> = List.of()
export function dateRangesEqual(
lhs: DateRange | undefined,
rhs: DateRange | undefined
): boolean {
return lhs && rhs
? lhs.start.millisecond() === rhs.start.millisecond() &&
lhs.end.millisecond() === rhs.end.millisecond()
: false
}
export function rangesEqual(
lhs: List<DateRange>,
rhs: List<DateRange>
): boolean {
return (
(lhs.isEmpty() && rhs.isEmpty()) ||
(lhs.size === rhs.size &&
lhs
.zipWith((l, r) => dateRangesEqual(l, r), rhs)
.every(bool => bool === true))
)
}
export function intersection(lhs: DateRange, rhs: DateRange): List<DateRange> {
return lhs.overlaps(rhs) ? List.of(lhs.intersect(rhs)) : List.of()
}
function rangesToMoments(ranges: List<DateRange>): List<Moment> {
return ranges.reduce(
(moments: List<Moment>, range: DateRange) =>
moments.concat(range.start, range.end),
List.of()
)
}
function momentsToRanges(moments: List<Moment>): List<DateRange> {
const enumerated = moments.zip(moments.keySeq())
const starts = enumerated
.filter((_, index) => index % 2 == 0)
.map(tuple => tuple[0])
const ends = enumerated
.filter((_, index) => index % 2 == 1)
.map(tuple => tuple[0])
return starts.zip(ends).map(tuple => new DateRange(tuple[0], tuple[1]))
}
function flatMap<T>(maybes: (T | undefined)[]): T[] {
const reducer = (values: List<T>, maybe: T | undefined) =>
maybe ? values.concat(maybe) : values
return maybes.reduce(reducer, List.of()).toArray()
}
function safeReduction<T>(
operation: (operands: T[]) => T,
...operands: (T | undefined)[]
): T {
return operation(flatMap(operands))
}
export function mergeUsing(
operator: (inLeft: boolean, inRight: boolean) => boolean,
lhs: List<DateRange>,
rhs: List<DateRange>
): List<DateRange> {
if (lhs.isEmpty() && rhs.isEmpty()) {
return lhs
}
let leftMoments = rangesToMoments(lhs)
let rightMoments = rangesToMoments(rhs)
const maxMoment = safeReduction(max, leftMoments.last(), rightMoments.last())
.clone()
.add(1, 'ms')
leftMoments = leftMoments.concat(maxMoment)
rightMoments = rightMoments.concat(maxMoment)
let leftIndex = 0
let rightIndex = 0
let result: List<Moment> = List.of()
let scan = safeReduction(min, leftMoments.first(), rightMoments.first())
while (scan.isBefore(maxMoment)) {
let inLeft = !(
scan.isBefore(leftMoments.get(leftIndex)) !==
(leftIndex % 2 === 1)
)
let inRight = !(
scan.isBefore(rightMoments.get(rightIndex)) !==
(rightIndex % 2 === 1)
)
let inResult = operator(inLeft, inRight) !== (result.size % 2 === 1)
if (inResult) {
result = result.concat(scan)
}
if (scan.isSame(leftMoments.get(leftIndex))) {
leftIndex = leftIndex + 1
}
if (scan.isSame(rightMoments.get(rightIndex))) {
rightIndex = rightIndex + 1
}
scan = safeReduction(
min,
leftMoments.get(leftIndex),
rightMoments.get(rightIndex)
)
}
return momentsToRanges(result)
}
|
Chimera states in ensembles of excitable FitzHugh-Nagumo systems An ensemble of nonlocally coupled excitable FitzHugh-Nagumo systems is studied. In the presence of noise the explored system can exhibit a special kind of chimera states called coherence-resonance chimera. As previously thought, noise plays principal role in forming these structures. It is shown in the present paper that these regimes appear because of the specific coupling between the elements. The action of coupling involve a spatial wave regime, which occurs in ensemble of excitable nodes even if the noise is switched off. In addition, a new chimera state is obtained in an excitable regime. It is shown that the noise makes this chimera more stable near an Andronov-Hopf bifurcation. Introduction All real systems are inevitably affected by noise. The impact of noise plays a principal role and strongly dictates the properties of the oscillatory dynamics. Noise influences lead to deterioration of the observed effects or to their complete destruction. However, this does not always lead only to destructive effects. It is known that noise can qualitatively change the oscillatory behaviour, and induce bifurcation phenomena which give rise to the appearance of new regimes of functioning. Moreover, such transitions can be accompanied by increasing of regularity with growth of the noise intensity. Such cases may include, for example, coherence or stochastic resonance. However, the affected system must have some special characteristics and properties to demonstrate new effect in the presence of noise. Noise induced effects in single oscillators are already quite well understood. Currently, most of open questions address the noise impact in networks and ensembles. Ensembles of identical and non-identical oscillators initially have a wide range of possible regimes. Thus, apart from typical synchronization, desynchronization, spatial incoherence or coherence, such systems can simultaneously demonstrate the coexistence of several modes. An example of such coexistence are chimera states. It is a spatio-temporal pattern consisting of the neighboring clusters of elements with coherent and incoherent dynamics in one network. Initially, this effect was discovered by Kuramoto and Battogtoh, and then revealed in more details by Strogatz a e-mail: nadya.i.semenova@gmail.com arXiv:1911.01862v1 5 Nov 2019 and Abrams. Since then, quite a long time has passed, and now this effect has already been found in the ensembles of many systems of various nature: phase oscillators, chaotic mappings, bistable elements, neuronal models, and many others. Usually one of the main conditions imposed on the ensemble is non-local connection, when each partial element has a finite radius of influence. Nowadays, chimera states have already been found in networks of various topologies, as well as in multilayer networks The ensemble of nonlocally coupled neuron models is considered in the present paper. The FitzHugh-Nagumo system in excitable mode is chosen as a partial element. Initially, chimera states have already been found for an ensemble of similar systems but in oscillatory regime. Later, it has been shown that chimeras can be detected in the excitable mode in the presence of noise. This effect was called coherenceresonance chimeras (CR chimera) because it combined the properties of chimeras and coherence resonance and was characterized by periodic switching of the coherent and incoherent parts position. Another feature was that CR chimera appeared only when the noise intensity belonged to a certain interval. If it was smaller, there were no oscillations in the system, but too strong noise led to complete spatial incoherence and desynchronization. This work is devoted to the study of coupling features being principal for realization of chimera states in ensembles of excitable oscillators. The comparative analysis of noise role and coupling peculiarities is carried out for the example of an ensemble of nonlocally coupled FitzHugh-Nagumo systems. In order to find out which coupling features lead to such a vulnerability of the system to noise, and whether other spatio-temporal regimes can be obtained taking these features into account. System under study In the present paper the dynamics of a one-dimensional ensemble of nonlocally coupled FitzHugh-Nagumo systems is studied numerically. The ensemble is described by the following system of equations: where u i and v i are activator and inhibitor variables of ith oscillator. The number of all nodes is N. The dynamics of partial elements depends on two parameters: and a. The first one controls the time scale in the system and a is the threshold parameter. Depending on its values, the individual FHN element can demonstrate an oscillatory (|a| < 1) or excitable (a1) regime. In oscillatory regime the system exhibits the periodic behaviour associated with the limit cycle in the phase plane. In the excitable regime all oscillations decay and there is only one stable fixed point in the phase plane. But this regime is interesting because of a coherence resonance. This effect consists in stochastically excited spiking, which is the most regular at a certain noise intensity range. The system contains white Gaussian noise source i (t) ∈ R of the intensity D. Index i indicates that the noise sources are not correlated inside the network, and each oscillator has only its own noise source. All of them have the same statistical characteristics and intensities. The components of Eq. 1 with sums describe the connectivity. Here a parameter is the coupling strength. P is the number of elements connected with each ith oscillator on the either side. Normalizing this value by the total number of elements, we get the coupling radius r = P/N. Under the sign of the sum there are two summands in each of the equations. In the first equation the parameter b uu defines the contribution of u-variables of the connected neighbours. A coefficient b uv is the same for the variables v in the first equation. Parameters b vu and b vv in the second equation have the same meaning. Thus, the parameters b uv and b vu are responsible for the cross-linking. The type of connection in Eq. 1 came from neuroscience. It is described in more detail in. Taking into account the large number of parameters, it is reasonable to enter one main operator controlling all four b-parameters. To do this, the rotational coupling matrix is introduced: Now there is only one parameter, which controls the impact of cross-linking (b uv, b vu ) and self-linking (b uu, b vv ) in the equation. Coherence-resonance chimera Chimera states in the ensembles with nonlocal coupling have been found for the same values of = /2 − 0.1 in both oscillatory and excitable regime. In this section the coupling parameters = 0.4 and r = 0.2 are fixed for coherenceresonance chimera (CR chimera). These parameters correspond to CR chimera with one incoherent and coherent domains. With smaller values of the coupling radius the number of these clusters increases. So, for r = 0.12 there are two incoherent domains in the network, and at r = 0.08 there are three of them. The chimera state exists in a quite wide range of parameter values, but at < 0.2 there is a transition to spatial incoherence. Figure 1,a shows the typical for CR chimeras space-time plot. Periodic switching the positions of incoherent areas makes it impossible to calculate statistical characteristics that involve a time realization. Therefore, the optimal characteristic for this chimera is the local order parameter, shown in Fig. 1,b. It indicates the existence of coherent and incoherent domains at one time moment and does not require the temporal evolution. The local order parameter can be obtained as follows: where the geometric phase of the jth element is defined by j = arctan(v j /u j ). The values Z k = 1 and Z k < 1 indicate coherent and incoherent domain, respectively. In this paper the parameter Z is fixed Z = 20. Figure 1,c shows the instantaneous spatial profiles (snapshots) of wave profiles in different half-periods. This panel clearly shows that the position of the incoherent part is first located on the edges of the ensemble, and then switches to the middle. Despite the seeming instability of the state, it is saved even at t = 10 6. It was obtained that for the value of = /2 − 0.1 CR chimera can be found only near an Andronov-Hopf bifurcation, at 0.995 ≤ a ≤ 1.004. The noise should have an intensity of D ∈ . Too large noise impact causes spatial incoherence. If the noise intensity is less than this interval, the ensemble does not show fluctuations. All deviations and initial conditions lead phase trajectories to a stable fixed point. On this assumption, it has been assumed earlier that coupling peculiarities at = /2 − 0.1 lead to a special position of nullclines that makes system more sensitive to noise influence. The incoherent part is incoherent due to the fact that its nodes demonstrates spikes induced exclusively by noise. The rest of the nodes, on the other hand, are spiking only because of the coupling. The nature of the switching effect has not been revealed. This work is dedicated to finding the reasons of CR chimeras. It seems that the property of these switches should also be caused by the specifics of coupling. However, in order to ensure that the effect of the coupling is not confused with the effect of noise, the latter must be excluded. To do this, set the noise intensity to D = 0. In this case the same parameters as was for CR chimeras, lead to the complete disappearance of any oscillations. The noise influence can often lead to a shift of bifurcation values. Therefore, a small variation of the parameter may lead to the CR chimeras predecessor. And this regime is found for = /2 + 0.1. Figure 2 shows the spatio-temporal profile of the new regime. On the snapshots (Fig. 2,b) some "stair" is clearly visible, and its position switches in time. If it is a stable regime existing without noise, the question arises what is the reason of these switching effect and what happens to nullclines at the same time? The location of the nullclines and information on their intersection provides the information on the location of the equilibrium states. The nullclines for one isolated FHN system can be obtained by solving a system of equationsu = 0,v = 0. It leads to the solution: u = const = −a, v(u) = u − u 3 /3. So, if a = 1.001 there is a nullcline crossing at the point u 0 = −1.001 and v 0 = u 0 − u 3 0 /3. These values correspond to the coordinates of the equilibrium state in one isolated FitzHugh-Nagumo system. However, the presence of a stable wave regime (Fig. 2) in the ensemble at the same values of parameters suggests that the equation should include the influence of the coupling. Taking into account the components of the coupling, these equations are: where C u, C v are additional values produced by the nonlocal coupling. By converting the equation onto the ensemble, we can consider what happens to the nullclines of the nodes belonging to two different stairs of observed regime (Fig. 2,c). The corresponding nullclines and projections to the phase plane are shown in Fig. 3. The gray lines in Fig. 3 represent nullclines for one isolated FHN system. The colors show the nullclines taking into account the connections for the oscillators i = 60 (red) and i = 315 (blue). Panel (a) shows that changes of nullclines for the first spiking oscillator are not essential. Initially, when the chimera states were considered, it was predicted that the incoherent part of the chimera started to spike only because of the noise, and the oscillators from the coherent domain make the path along the cycle only because of the coupling. That is why last oscillators make the spiking behaviour more coherent. Here the red oscillator i = 60 should start to move along the cycle first, but there is almost no change in its nullclines. Moreover, now there is no noise which could excite the oscillations. Nevertheless, it starts to move along the limit cycle (b). The blue oscillator belonging to the opposite stair is still near the equilibrium state. Significant changes in nullclines occur only when most of the oscillators are on the opposite side of the limit cycle (c). When all the oscillators have already begun their journey through the cycle, the blue oscillator joins them. The panel (d) clearly shows a change in its v-nullcline. This leads to destruction of the state of equilibrium. In the end, all oscillators come to the vicinity of the equilibrium state. The red oscillator made the spike first, and it turns out to be on the right side of the v-nullcline (e), and the blue one, because it was the last one, turns out to be on the left side. Next half-period, they will switch places, and the blue oscillator will be the first to start its spiking behaviour. Despite the fact that all nullclines almost coincide in projections on a phase portrait, a small deviation is enough to destroy the state of equilibrium. The summand C u affects the nullclineu = 0. It shifts it up or down depending on the sign. This affects the coordinates of the equilibrium state on the phase plane. The summand C v shifts the isoclinev = 0 left or right. It affects the existence of equilibrium point in general. If v-nullcline shifts to the right, then there will be a higher chance of oscillator goes out and starts the spiking behaviour. Finding all oscillators near the equilibrium state is accompanied by closeness of both values of C u and C v to zero. This happens when the oscillator i = 60, for which this graph is prepared, starts to spike first and last. Thus, we can assume that the oscillator that is the first one is influenced by the sign of these values. From Fig. 4 we can see that before the phase "last" both values of C u and C v of the oscillator i = 60 have very close to zero values. If we consider what happens before the phase "first", we can clearly see that the summand C v has a small negative value. When C v is less than zero, v-nullcline leads to the value u = −a + |C v |, and the nullcline shifts to the right. Let us consider what shifts the nullcline. At = /2 + 0.1 the values of the coupling matrix in the second equation are the following: b vv = cos() ≈ −0.0999, b vu ≈ −0.995. All oscillators near the state of equilibrium have almost identical v values and a small disorder of u-variables. Therefore, the main contribution is made by the following summands with cross-link: j b vu (u j − u i ). This summand has a negative strength b vu ≈ −0.995. Correspondingly, if C v is negative, all u-variables of neighbouring oscillators u j must be greater than u i. This occurs for the oscillator, which comes to the state of equilibrium last. Therefore, the same oscillator becomes the first one in the next half-period. Thus, the existence of CR chimeras is mainly caused by a special type of spatial profile. It appears in the system without noise due to the presence of cross-link in the coupling. In the case of a noisy system, there is a slight shift in the parameters at which this profile appears. The presence of an incoherent part is caused by noise exposure. The coupling leads to a special movement of nullclines, and due to the noise several oscillators have the opportunity to start moving first. At = /2 + 0.1 the values of the coupling matrix are as follows In the case of CR-chimeras = /2 − 0.1 the values of cross-link remain the same, and b uu = b vv ≈ 0.1 changes the sign to the opposite. It may give the false impression that the CR chimera can only appear when the impact of cross-linking is much larger than the impact of self-linking. As is an argument of trigonometric functions, such situation should take place when is close to /2 and 3/2. However, the chimera near 3/2 has not been found yet. Apparently, the positive sign of cross-linking parameters is important, which is negative when is about 3/2. Chimera state of type 2 This section shows that chimera state in the system under study occurs not only when is close to /2, but also for other values. The parameter was changed in the interval ∈ . It is found that at value = 5.4 the system can demonstrate chimera states too, but they qualitatively differ from those described in section 3. The new regime is given in Fig. 5. Figure 5,b shows the instantaneous spatial profile at time t = 995.8. Two breaks of spatial profile are clearly seen between top and bottom parts. The areas of spatial incoherence born near the breaks. Such an instantaneous images are typical for chimera states appearing in rings of nonlocally connected chaotic systems. For example, logistic maps, Henon maps, Rssler systems and many others [21,. Such a type of a spatial profile in some literature is called "phase chimera". However, in the ensembles of excitable systems (for example, FitzHugh-Nagumo model) this has not been encountered before. Position of incoherent and coherent domains does not change in time, and all oscillators continue to demonstrate spiking behaviour (see the space-time plot in Fig. 5,a). Due to the stationary position of the incoherent and coherent domains, it is possible to calculate mean phase velocity i and cross-correlation function k,i for this state. Figure 5,c shows mean phase velocities for each oscillator calculated as i = 2M i /∆T, i = 1,..., N, where M i is the number of complete rotations around the origin performed by the ith unit during the time interval ∆T = 10 4. Almost all values of i lie on a continuous curve. It means that all the oscillators makes their spikes with the same periodicity. Small deviations from the constant value are observed in the minima and maxima of the spatial profile, which indicates the possible dynamics with weak chaos in these regions. This feature will be discussed a while later. It may seem that each oscillator from the incoherent domain belong to top or bottom parts of spatial profile all the time. However, this is not true. At long time intervals oscillators inside incoherent parts can change their belonging. The oscillators located near the boundaries between incoherent and coherent regions are especially susceptible to this. It is very hard to see it on the space-time plots. Since the incoherent domains are now stationary, we can use the cross-correlation function, which shows temporal correlation between two oscillators (Fig. 5,d): is a deviation from the mean value. The brackets denote the time averaging. This characteristic is equal to 1 and -1 for in-phase and anti-phase oscillations respectively and is not equal to it for non-synchronized dynamics. The calculations of the cross-correlation function in Fig. 5,d is prepared in relation to the oscillator k = 175 belonging to the top coherent region (Fig. 5,b). The cross-correlation function is close to the value 1 only when comparing oscillators from one coherent part. Oscillators from the opposite coherent part are not in anti-phase with them, because the corresponding values of are not equal to -1. This can be explained by the fact that each oscillator continues to demonstrate spiking behaviour, in which it is impossible to say about the presence of phase or antiphase synchronization, they are just shifted in time. However, Fig. 5,d clearly shows that the cross correlation decreases near the boundaries between coherent and incoherent domains. This confirms that some of the oscillators there may be thrown between what a part of the profile they belong to. Another interesting feature, which is clearly indicated by the cross-correlation function, is that there is some desynchronization in the middle of one of the coherent domain. There is a local minima at i ∈ (200; 300) in Fig. 5,d. This is also one of the features of chimeras arising in ensembles of chaotic oscillators, where this type of chimeras is called amplitude ones. As usual, they have a finite life time in the center of coherent areas. The chimera state shown in Fig. 5 is obtained for the same parameter values as CR chimera but when the parameter is in a quite large range around the value 5.4. At this value the coupling matrix has values: b uu = b vv ≈ 0.6347, b uv = −b vu ≈ −0.7727. Cross-linking and self-linking have a commensurate contribution in this regime in contrast to CR chimera. Let us consider in detail the impact of noise and the parameter on the new chimera state. Fig. 6 shows the areas of existence of the new chimera on the parameter plane (, D) for two values of the parameter a = 1.001 (near an Andronov-Hopf bifurcation) and a = 1.01 (far from it). The panel (a) shows the chimera at a = 1.001. In this mode, the chimera most often coexists with weak oscillations near the equilibrium state. Random initial conditions can lead to either one, or another regime. In such bistable case the chimera can have a finite life time. However, there is a hatched region in Fig. 6,a where all considered random initial conditions bring up to the chimera. At the same time, the regime is saved even at the integration time of t = 10 6 with the integration step of h = 0.001. Experiments with further time increase were not carried out. Figure 6,b shows the area of existence of chimera states in the plane (, D) at a = 1.01. As for panel (a), several random initial conditions are considered. The chimera coexists with the equilibrium state during the whole chimera region. The clear area of stability, as it was for a = 1.001, is not found out. In both cases the most often regime at zero value of noise intensity D = 0 consists in weak oscillations near the equilibrium point. However there are rare cases when from random initial conditions the spatial profile with the breaks appears (as in Fig. 5, but without incoherent domains). At D = 0 this regime has a finite lifetime. The chimera can also be obtained, but only from specially prepared initial conditions, and it has a finite lifetime too. Another difference between the effect of noise at a=1.001 and a=1.01 is the following. The increase of the noise near the bifurcation (Fig. 6,b at a = 1.001) leads to an increase in the chimeras range of existence. It is accompanied by the appearance of clear region of stable chimera state obtained from all considered random initial conditions. Noise makes the chimera more stable. In the case of a = 1.01, the opposite is happening. Noise leads to the decrease and change of the area of existence. The number of incoherent domains in chimera state can be increased by reducing the coupling radius. In the case of chimera shown in Fig. 5 it is accompanied by the increase of the spatial wave number. Figure 7 shows main regimes obtained on the plane of coupling parameters (, r). It can be seen from the figure that at a large coupling strength and a large coupling radius r, weak oscillations near the state of equilibrium (yellow region) are observed in the system. The same effect has been found out for CR chimera. At small coupling impact the spatial incoherence and various unstable modes are observed in the ensemble (remains white in Fig. 7). Chimera states are realized between these two main areas (purple area in Fig. 7). Inside this area different wave numbers can be obtained. Here only three are indicated: K = 1 (dotted), K = 2 (diagonal hatching) and K = 3 (vertical hatching). The map of regimes is made at = 5.4, D = 0.0004. These parameter values correspond to the middle of the stable area of the chimera existence in Fig. 6. Conclusion The chimera states arising in the ring of nonlocally coupled excitable FitzHugh-Nagumo systems are considered in this article. Such system can demonstrate coherenceresonance chimera for some values of parameters. Previously, it was assumed that the chimera was caused only by noise. However, no answer was found to the question about periodic switching of the incoherent cluster position. It is shown here that the parameter, which is responsible for the influence of cross-linking and self-linking inside the coupling terms, leads to a special type of spatial and temporal dynamics even if the noise is switched off. In this case, a special spatial wave is formed. This mode is the predecessor of the CR chimera. It contains several neighbouring oscillators, which begin to make a spiking event first. The other oscillators joins them later because of the coupling. The position of the first spiking oscillators changes periodically in time. Adding noise to the system causes these oscillators to spike less regularly. This creates an incoherent cluster, and this wave regime is transforming into CR chimera. In addition, it is found that if the impact of self-linking and cross-linking is comparable ( ≈ 5.4), the system can demonstrate a chimera, which has not yet been found in the ring of FitzHugh-Nagumo systems. The spatial profile is broken into two parts, and incoherent domains are formed near these breaks. This type of chimera is very typical for the rings of chaotic oscillators and maps, but has not yet been detected for excitable systems. It is shown here that the noise near an Andronov-Hopf bifurcation makes this chimera more stable. The article discusses in detail the effect of noise and coupling parameters on this regime. |
<filename>settings_CV.py
# settings.py
def init():
global sdNum, p1, p2, p3, p4, p5, p6, p7, dir1, dir2
sdNum, p1, p2, p3, p4, p5, p6, p7, dir1, dir2 = 0, 0, 0, 0, 0, 0, 0, 0, 0, 0
|
Research on the synchronization control strategy for microgrid-connected voltage source inverter Microgrid is intended and featured to be able to operate in both grid-connected and islanded mode to ensure high quality and reliable power supply. In order to achieve stable operation of the microgrid-connected voltage source inverter (MVSI) units under paralleled or grid-connected mode, a novel synchronization method based on droop control is proposed in this paper. The difference of phase and amplitude between different MVSI units is detected and is used to calculate the output frequency and amplitude of the MVSI. This method can smooth transfer the MVSI units from standalone mode to paralleled mode. The simulation and experimental results show that the proposed method is effective in achieving paralleled operation of the MVSI units. |
<reponame>maxwass/upenn_quadrotor_share
//=================================
// include guard
#ifndef PID
#define PID
#include "utility.h"
#include "data_structs.h"
#include "logger.h"
#include "timer.h"
#include <stdio.h>
#include <stdlib.h>
#include <unistd.h>
#include <sys/time.h>
#include <time.h>
#include <math.h>
#include <fcntl.h>
#include <termios.h>
#include <stdint.h>
#include <iostream>
#include <deque>
using namespace std;
class PIDController {
private:
bool first_call_ = true;
bool FLAG, LARGE_VALUE, SMALL_VALUE = false;
float maxAllowableValue_, minAllowableValue_ = 0.000;
float maxDerivValue_ = 0.00;
float valueNew_, valueOld_, valueDeriv_ = 0.0000;
float filterValueOld_, filterValueNew_ = 0.000;
float desiredValue_ = 0.00000;
float desiredValueDeriv_ = 0.00000;
float kp_, kd_, ki_ = 0.000;
float lastDt_ = 0.1000;
float propError_,propErrorOld_, derivError_, integError_ = 0.0000;
float filterPropError_, filterPropErrorOld_, filterDerivError_, filterIntegError_ = 0.000;
float maxIntegralError_ = 10.000;
float minValue_, maxValue_ = 0.0000;
int numCalls = 0;
std::deque<float> prevValues;
//float weights[10] = {0.35, 0.25, 0.10, 0.10, .05, .05, .025, .025, .025, .025};
float weights[20] = {0.0875, 0.0875, 0.0875, 0.0875, 0.0625, 0.0625, 0.0625, 0.0625, 0.05, 0.05, 0.05, 0.05, 0.025, 0.025, 0.025, 0.025, 0.025, 0.025, 0.025, 0.025};
public:
PIDController(float kp, float kd, float ki, float desired_value, float minAllowableValue, float maxAllowableValue)
{
setDesiredValue(desired_value);
minAllowableValue_ = minAllowableValue;
maxAllowableValue_ = maxAllowableValue;
float maxDerivValue = 5.00;
maxDerivValue_ = maxDerivValue;
kp_ = kp;
kd_ = kd;
ki_ = ki;
prevValues.resize(100,0.00);
printf("END OF ALT CONSTRUCTOR\n\n");
}
float LowPassFilter(float input, float input_old, float input_old_old, float a, float b, float c)
{
float output = a * input + b * input_old + c * input_old_old;
//printf("out: %e %e %e %e %e %e %e\n", a, b, c, input, input_old, input_old_old, output);
return output;
}
void setGains(float kp, float kd, float ki)
{
kp_ = kp;
kd_ = kd;
ki_ = ki;
}
void printData(void)
{
//printf("FLAG: %i, kp: %f, kd: %f, ki: %f \n", FLAG, kp_, kd_, ki_);
printf("new value: %f, old value: %f, desiredValue_: %f, dt: %f, freq: %f \n", valueNew_, valueOld_, getDesiredValue(), lastDt_, 1/lastDt_);
printf("filterValueNew: %f, filterValueOld: %f \n\n", filterValueNew_, filterValueOld_);
//printf("Calc: Error: desired value - new value : %f, Diff: Error:propError - propErrorOld: %f Deriv Error: (Diff Error)/dt %f \n", (getDesiredValue() -valueNew_), (propError_ - propErrorOld_), (propError_ - propErrorOld_)/lastDt_);
//printf("Print: Error : %f, Deriv Error: %f, Integral Error: %f \n", propError_, derivError_, integError_);
//printf("Control Output: kp*propError: %f + kd*DerivError: %f: = %f \n\n",kp_*propError_, kd_*derivError_, this->getControlOutput());
}
void update(float valueNew, float dt)
{
if(first_call_)
{
first_call_ = false;
maxValue_ = valueNew;
minValue_ = valueNew;
lastDt_ = dt;
valueOld_ = valueNew;
valueNew_ = valueNew;
}
//record the extreme values are
if(valueNew >= maxValue_) maxValue_ = valueNew;
if(valueNew <= minValue_) minValue_ = valueNew;
//Cap and floor values
if(valueNew > maxAllowableValue_)
{
LARGE_VALUE = true;
valueNew_ = valueOld_;
}
else if(valueNew < minAllowableValue_)
{
SMALL_VALUE = true;
valueNew_ = minAllowableValue_;
}
else
{
valueNew_ = valueNew;
LARGE_VALUE = false;
SMALL_VALUE = false;
}
// printf("old value: %f, new value raw : %f, new value cap:: %f, desiredValue_: %f, dt: %f, propError_: %f, derivError_: %f \n\n\n", valueOld_, valueNew, valueNew_, getDesiredValue(), dt, desiredValue_-valueNew, - (valueNew - valueOld_)/dt);
//printData();
lastDt_ = dt;
valueDeriv_ = (valueNew_ - valueOld_)/dt;
propErrorOld_ = propError_;
propError_ = getDesiredValue() - valueNew_;
derivError_ = (propError_ - propErrorOld_)/dt;
integError_ += propError_*dt;
if(integError_ >= maxIntegralError_) integError_ = maxIntegralError_;
if(integError_ <= - maxIntegralError_) integError_ = -maxIntegralError_;
//Filter
prevValues.push_front(valueNew_);
prevValues.pop_back();
filterValueOld_ = filterValueNew_;
filterValueNew_ = calcFilterValue();
filterPropErrorOld_ = filterPropError_;
filterPropError_ = desiredValue_ - filterValueNew_;
filterDerivError_ = (filterPropError_ - filterPropErrorOld_)/dt;
filterIntegError_ += filterPropError_*dt;
if(filterIntegError_ >= maxIntegralError_) filterIntegError_ = maxIntegralError_;
if(filterIntegError_ <= - maxIntegralError_) filterIntegError_ = -maxIntegralError_;
if(filterDerivError_ >= maxDerivValue_) filterDerivError_ = maxDerivValue_;
if(filterDerivError_ <= -maxDerivValue_) filterDerivError_ = -maxDerivValue_;
valueOld_ = valueNew_;
//printf("valueNew: %f, filtValOld: %f, filtValNew: %f, filtPropError: %f, filterDerivError: %f \n", valueNew_, filterValueOld_, filterValueNew_, filterPropError_, filterDerivError_);
}
float calcFilterValue(void)
{
float output = 0.0;
numCalls = numCalls + 1;
//printf("numCalls %i: ", numCalls);
int i = 0;
int size = prevValues.size();
for (std::deque<float>::iterator it = prevValues.begin(); it!=prevValues.end(); ++it)
{
//printf("(%f * %f) + ",weights[i], *it);
//output += weights[i]*(*it);
output += (*it);
i++;
//printf(" new_output: %f, output: %f, i: %i \n",(*it), output, i);
}
output = output/size;
//printf(" = output: %f", output);
//printf("\n\n");
return output;
}
float getControlOutput(void)
{
if(FLAG)
{
if(LARGE_VALUE || SMALL_VALUE) return 0;
float output = kp_*propError_ + kd_*derivError_;// + ki_*integError_;
if(output > 10) return 10.00;
else if(output < -10) return -10.00;
return output;
}
else return 0;
}
float getMaxValue(void)
{
return maxValue_;
}
float getMinValue(void)
{
return minValue_;
}
void resetIntegral(void)
{
integError_ = 0.0;
}
void autoControlOff(void)
{
resetIntegral();
FLAG = false;
}
void autoControlOn(float desiredValue)
{
setDesiredValue(desiredValue);
//for smooth transition
valueOld_ = desiredValue;
resetIntegral();
FLAG = true;
}
bool isAutoControlOn(void)
{
return FLAG;
}
void setDesiredValue(float desiredValue)
{
//printf(" !!!!!!!!!CHANGING: before: %f after: %f !!!!!!\n\n\n", desiredValue_, desiredValue);
//usleep(1000000);
desiredValue_ = desiredValue;
}
float getFiltValue(void)
{
return this->filterValueNew_;
}
float getValue(void)
{
return valueNew_;
}
float getDesiredValue(void)
{
return desiredValue_;
}
float getValueDeriv(void)
{
return valueDeriv_;
}
float getPropError(void)
{
return propError_;
}
float getFiltPropError(void)
{
return filterPropError_;
}
float getDerivError(void)
{
return derivError_;
}
float getFiltDerivError(void)
{
return filterDerivError_;
}
float getIntegralError(void)
{
return integError_;
}
float getFiltIntegralError(void)
{
return filterIntegError_;
}
};
#endif
// __PID__
|
The disclosure relates generally to cables and more particularly to optical communication cables including an embedded element that emits light along the exterior of the cable. The disclosure also relates to light filtering viewing devices that enhance the visibility of the cable during tracing and to methods of tracing the path of such an optical communication cable within a group of cables.
Optical communication cables have seen increased use in a wide variety of electronics and telecommunications fields. Fiber optic cable assemblies may range in size and complexity from single-fiber jumpers to multi-fiber harnesses. These cable assemblies are typically used to interconnect equipment in high-speed networks, and within some high-speed networks, a large number of multiple individual cables (e.g., fiber optic patchcords) are used to interconnect various equipment, for example, within a telecommunications closet, server room, etc. As the needs of the network change or as repairs are needed, network operators frequently desire to change, move or replace cables with the network. |
A rapid and novel method for purification of ribulose 1,5-bisphosphate carboxylase from Chromatium vinosum Ribulose 1,5-bisphosphate (RuBP) carboxylase (EC 4.1.1.39) from the purple sulfur bacterium Chromatium vinosum is a large complex protein ( M r 550000) composed of 8 large (M r 55 000) and 8 small ( M r 13 000) subunits like the enzyme from higher plants. Although the catalytic function or potential has been shown to reside on the large subunit, no functional role has yet been assigned to the small subunit. The Chromatium RuBP carboxylase is of particular interest in studies of the role of small subunits because it can be reversibly dissociated into component subunits under mild conditions. The enzyme from Chromat ium has been purified by several laborious or time-consuming methods and we have been attempting to speed the purification by utilizing a new method in which samples are sedimented into a reoriented density gradient in a vertical rotor. In this paper, a rapid purification of RuBP carboxylase from C. vinosum is described that results in gel-electrophoretically homogeneous and highly active enzyme. |
PRINCETON, NJ -- Half of Americans today want the Affordable Care Act repealed or scaled back, down from 57% in January 2011. There has been essentially no change in the percentage of Americans who want the law expanded or kept as it is.
The Affordable Care Act became an integral part of the ongoing wrangling between Republicans and Democrats that led to the partial federal government shutdown on Oct. 1, with conservative Republican lawmakers initially attempting to connect any vote on funding the government to defunding the ACA. A minority of Americans would agree that the law should be totally repealed, the functional equivalent of defunding.
Mirroring the rancorous partisan debate over the ACA in Congress, views on the law are predictably split between Americans who identify as Republicans and those who identify as Democrats. A majority of Republicans (57%) say it should be repealed, with most of the rest desiring changes that would scale the law back. On the other hand, a little less than half of Democrats say the ACA should be kept as is, while 22% favor changes to expand the law. Notably, a not insubstantial 15% of Democrats want the law scaled back.
Consistent with surveys showing that Americans tilt more negatively than positively toward the Affordable Care Act, Americans remain more likely to say the law should be scaled back or repealed rather than kept as is or expanded, although only three in 10 want it repealed outright. Compared with January 2011, however, fewer Americans want the law repealed or scaled back, and more now don't have an opinion.
Results for this Gallup poll are based on telephone interviews conducted Oct. 12-13, 2013, on the Gallup Daily tracking survey, with a random sample of 1,039 adults, aged 18 and older, living in all 50 U.S. states and the District of Columbia. |
<reponame>dreammarker/oreo
package com.yedam.movie.view;
import java.io.IOException;
import java.net.MalformedURLException;
import java.net.URL;
import java.util.HashMap;
import java.util.List;
import java.util.Map;
import javax.servlet.http.HttpServletRequest;
import javax.servlet.http.HttpSession;
import org.springframework.beans.factory.annotation.Autowired;
import org.springframework.stereotype.Controller;
import org.springframework.web.bind.annotation.RequestMapping;
import org.springframework.web.servlet.ModelAndView;
import com.fasterxml.jackson.core.JsonParseException;
import com.fasterxml.jackson.core.type.TypeReference;
import com.fasterxml.jackson.databind.JsonMappingException;
import com.fasterxml.jackson.databind.ObjectMapper;
import com.yedam.movie.Paging;
import com.yedam.movie.RoomService;
import com.yedam.movie.RoomVO;
import com.yedam.movie.ScreenSearchVO;
import com.yedam.movie.ScreenService;
import com.yedam.movie.ScreenVO;
@Controller
public class ScreenController {
@Autowired
ScreenService screenService;
@Autowired
RoomService roomService;
@RequestMapping("/screeninsertgo")
public String Screengo() {
return "/nomypage/screenInsert";
}
@SuppressWarnings({ "unchecked", "rawtypes" })
@RequestMapping("/insertScreen")
public String Screeninsert(String showDt,HttpServletRequest request)
throws JsonParseException, JsonMappingException, MalformedURLException, IOException {
ObjectMapper mapper = new ObjectMapper();
HashMap<String, Object> value;
RoomVO roomvo = new RoomVO();
String theaCd = "012031\r\n" + "012053\r\n" + "012006\r\n" + "012051\r\n" + "012020\r\n" + "012034\r\n"
+ "012050\r\n" + "012022\r\n" + "012033\r\n" + "012047\r\n" + "012046\r\n" + "012045\r\n" + "012014\r\n"
+ "012018\r\n" + "012013\r\n" + "012032\r\n" + "012048\r\n" + "012015\r\n" + "012030\r\n" + "012007\r\n"
+ "012043\r\n" + "012035\r\n" + "012044\r\n" + "012042\r\n" + "012029\r\n";
String theaCd1[] = theaCd.split("\\r\\n");
showDt = request.getParameter("showDt");
System.out.println(showDt);
for (int w = 0; w < theaCd1.length; w++) {
roomvo.setTheaterId(theaCd1[w]);
ScreenVO vo = new ScreenVO();
value = mapper.readValue(new URL("http://www.kobis.or.kr/kobis/business/mast/thea/findSchedule.do?theaCd="
+ theaCd1[w] + "&showDt=" + showDt), new TypeReference<Map<String, Object>>() {
});
List<HashMap> schedule = (List<HashMap>) value.get("schedule");
System.out.println(value);
for (int i = 0; i < schedule.size(); i++) {
// roomId 값 가져와서 셋팅하기
String scrnNm = (String) schedule.get(i).get("scrnNm");
roomvo.setRoomName(scrnNm);
String roomId = roomService.roomCheck(roomvo);
System.out.println(roomId);
// 영화CD 값 가져오기
String movieCd = (String) schedule.get(i).get("movieCd");
System.out.println(movieCd);
// 영화 showTm 가져오기
String[] showTm = ((String) schedule.get(i).get("showTm")).split(",");
// 0930 ->09:30
for (int j = 0; j < showTm.length; j++) {
System.out.println(showTm[j]);
showTm[j] = showTm[j].substring(0, 2) + ":" + showTm[j].substring(2, showTm[j].length());
System.out.println(showTm[j]);
}
// 영화상영내역 insert 하기
for (int j = 0; j < showTm.length; j++) {
vo.setScreenDate(showDt); // 상영날짜
vo.setScreenStartTime(showTm[j]); // 상영시간
vo.setRoomId(roomId); // ROOMid값 가져오기
vo.setMovieId(movieCd); // 영화 CD값 세팅
System.out.println(vo + "=============================================");
if (screenService.Screencheck(vo) == null || screenService.Screencheck(vo) == "") {
System.out.println("123123123123123=====================================");
if (showTm[j] != null || showTm[j] != "") {
System.out.println("값입력");
screenService.Screeninsert(vo);
}
}
}
}
}
return "nomypage/screenInsert";
}
@RequestMapping("/checkScreen")
public ModelAndView checkScreen(ScreenSearchVO vo,Paging paging,HashMap<String,Object> map,String showDt, HttpSession session,HttpServletRequest request) {
if(request.getParameter("showDt")!=null||request.getParameter("showDt")!="") {
vo.setScreenDate(request.getParameter("showDt"));
session.setAttribute("showDt", request.getParameter("showDt"));
}
ModelAndView mv = new ModelAndView();
if(paging.getPage()==null)
paging.setPage(1);
//페이징 first,last 검색조건
vo.setFirst(paging.getFirst());
vo.setLast(paging.getLast());
vo.setScreenDate((String) session.getAttribute("showDt"));
paging.setTotalRecord(screenService.getCount(vo));
System.out.println(vo);
mv.addObject("paging",paging);
mv.addObject("List", screenService.Checkscreen(vo));
mv.setViewName("nomypage/screenInsert");
return mv;
}
}
|
US foreign policy and global standing in the 21st century: Realities and perceptions fully understood. The subjects addressed in Military Neuroscience are timelyindeed, many of the technologies that Krishnan discusses may be the subject of covert research programs in a variety of countries. When the next major conflict occurs, it is entirely possible that neurowarfare will play a very large, perhaps even decisive, role. States that are unready for a possible neurowarfare military revolution, and unable to defend against potentially devastating neurowarfare attacks, may find this to be a catastrophic vulnerability. |
Prochiral and chiral resolution in 2H NMR spectra: solutes in stretched and compressed gelatin gels. We demonstrate prochiral and chiral spectral resolution using residual H NMR quadrupolar splittings over a wide range of anisotropic conditions in liquid samples. We use a reversible gel-stretching/compressing device in a conventional high-field NMR spectrometer. We show the stability of gelatin gels as well as their unique ability to switch between multiple stretched and compressed states, thus also changing the sign of residual dipolar couplings in H and C NMR. This flexibility will be important for resolving spectra of mixtures of other chiral compounds and for structure determination of selected peptides. |
“The Favourite” is directed by Yorgos Lanthimos, who has recently gained a reputation for surrealist works like “The Lobster” and “The Killing of a Sacred Deer.” At first glance, “The Favourite” might seem like an odd choice for Lanthimos’ sensibilities, given its period setting and storyline. Yet the final product is exactly what you might expect from a surrealist filmmaker taking on a fairly standard, if rather intriguing, costume drama screenplay.
The film takes place during the reign of sickly Queen Anne, circa 1708. Sarah Churchill, the Queen’s closest friend and occasional lover, has successfully amassed immense political power by taking advantage of Anne’s maladies and unstable mind, serving essentially as a de facto ruler. Yet Churchill’s power becomes increasingly precarious as she vigorously promotes Britain’s war with France, much to the displeasure of the Tory party. Enter Abigail Hill, Sarah’s cousin brought low by an infamous father. Shortly after her arrival at court, Sarah takes her cousin under her wing, giving Abigail easy access to the Queen. Soon Abigail gains favor with the frail monarch, maneuvering to push Sarah aside, all the while using the support of the Tories to her advantage.
Here’s a blunt, overgeneralized, yet largely accurate statement: costume dramas are shockingly hard to pull off, especially in this day and age. At first glance, one might assume that this is because the stories and characters can so easily get buried beneath the costumes, make-up and sets. Yet such an assessment seems incomplete. After all, the Marvel Cinematic Universe and the Star Wars sequel trilogy are some of the most successful films in recent memory, and both employ extravagant mises-en-scène. What makes costume dramas any different? This may be pure speculation, but there seems to be a certain expectation that these films distance the audience from the characters. The set design, make-up and wardrobes don’t enhance audience engagement with the story; instead, they become historical barriers, markers of a time long since passed. The accuracy of these elements is ultimately secondary; they are a trope of the genre that must nonetheless be circumvented if the film is to stand out. Over the years, many filmmakers have tried to do just that with varying degrees of success. If you want to go back to the 1970s, Stanley Kubrick’s solution was to take the staid style of the costume drama to the extreme, transforming “Barry Lyndon” into a borderline satiric piece. More recently, the excellent “A Royal Affair” opted for a simpler but no less brilliant tactic: employing modern filmmaking techniques that feel more real and immediate. The film doesn’t dispose of absurd wigs or fancy dresses, but it makes clear that there are real human beings beneath them.
I mention all of this because “The Favourite” almost takes the lessons of “Barry Lyndon” and “A Royal Affair” to heart before discarding them entirely. As with “Barry Lyndon,” Lanthimos opts for a somewhat satiric approach to the drama in Queen Anne’s court. But whereas “Barry Lyndon” is lightly amusing, “The Favourite” revels in the surreal and the grotesque. Likewise, the film opts for modern filmmaking techniques, but takes them to the extreme. What was immersive in “A Royal Affair” becomes even more distancing in “The Favourite.” The most obvious example of this is the film’s constant use of a fisheye lens, an ultra-wide-angle lens that distorts the edges of the frame. One might initially be inclined to search for a narrative explanation for such an odd choice. After all, the use of such a wide-angle does strand the characters in the frame, emphasizing the gaping, empty spaces that surround them. However, the aforementioned distortions are too distracting, too obvious to be anything other than an authorial intervention on the part of Lanthimos. Such an intervention is the hallmark of an art film, and it is precisely what distinguishes “The Favourite” from “Barry Lyndon” or “A Royal Affair.” Like those two films, “The Favourite” clearly wants to do something different with the costume drama, but its approach is entirely its own.
But does this approach have any true purpose? Auteurs of art cinema have a particular fondness for drawing attention to themselves within their own films. In response, audience members tend to gush about their brilliance as artists. Yet as often as not, such works are the product of pure hubris. Can the same be said for Lanthimos and “The Favourite”? Perhaps, but I’d like to suggest that his techniques — such as the fisheye lens — signal to the audience that the focus is not truly on the characters or the story. Rather, the film’s mise-en-scène transforms into this sort of observational visual tapestry. For instance, the frequent usage of close-ups doesn’t encourage audience identification. Instead, the actors’ faces become yet another component in the tapestry, yet another interplay of light, shadow, movement and color. All is visual for the sake of pure visuality. |
NEW HAVEN, Conn. (AP) - Mohegan Sun, which operates one of the world's most successful casinos in Connecticut, has formed a partnership with one of the bidders hoping to run thoroughbred racing in New York state.
The Indian tribal company has teamed up with Capital Play in seeking the 20-year franchise to operate Aqueduct, Belmont and Saratoga race tracks.
"They're a fantastic partner, obviously a great success," said Karl O'Farrell, chief executive officer of Capital Play. "We're very pleased to have them as our partner. They have one of the best casino operations in the world."
Capital Play, which helped revive Australian racing, says Mohegan Sun would help in its efforts to revive horse racing in New York by making the tracks entertainment destinations as well as gambling operations. O'Farrell said that could include night clubs, comedy and top restaurants. |
Image via Wikipedia
It’s amusing when Anarchists are accused of being too ideological or outright Utopian, it is especially so when such an accusation comes from liberals or state socialists (i.e. mainstream Marxists). Why is it amusing? Because of all political perspectives, Anarchism (i.e. Libertarian Socialism) is the only one whose theories have not been refuted by history itself!
This “Utopian” accusation generally comes from two general sources. First there are those who support the current Capitalist system as is (in the 1st world countries of course) and only propose mild changes, such as more or less regulation of the economy. These would generally be the Social Democrats (or “Liberals” in US politics) or Conservatives in most political systems.
They would argue from the perspective that the Capitalist/State combination is not only “the way things are” but also the only way things can be. They would then raise such arguments as the common appeal to human nature, that Capitalism is the “end of history” – in that its superiority has been proven from an societal evolutionary perspective, that the state is necessary to ensure control from the people (i.e. representative democracy), that Capitalism provides the best benefit for all etc.
But one has to ask: who is really the ideologue here? Who is assuming an expertise of human nature in order to have some kind of unshakable base? Who is ignoring the historical forms of human societies (hint: communal) and the considerable amount of coercion required by the state in order to jump-start Capitalism? Who is absolutely oblivious the true role of the state and the real impotence of elections and government to change life for the better through normal channels, even when there is considerable popular request for social reform?
Worst of all, it’s the more than ironic result of this superior system, Capitalism, that the vast majority of people live in worse situations than they lived in pre-capitalist societies. One only has to look at the situation in the lost continent, Africa, and compare it with the pre-capitalist tribal societies, which while not great by any measure of the word, were never as bad as today. One only has to look at the current environmental obliteration, the sheer scale of unending conflict and even the relative worsening conditions of people in all nations to ask: Who is really the ideologue here?
The other great accuser of utopianism is none other than the mainstream Marxist movements of Leninism, Trotskyism, Stalinism, Maoism and the like. The younger (who somehow think itself more mature) and patronizing cousin of Anarchism.
As revolutionary anti-capitalist movements, they at least share some of the correct critical perspective on the current Capitalist system but they lose the ball when they turn around and accuse libertarian socialists of being naive for not promoting centralization, hierarchy structures and movements from above, that is, leadership from a minority of enlightened few.
The saddest thing is not that they have to misrepresent the arguments of Anarchism in order to attack their favorite straw-men (“Anarchists will not defend the revolution” being a crowd favorite), nor that they ignore what some of their own have written that basically parrots the libertarian perspective, but that they dare claim historical proof, when empirical facts have shown that their theories put in practice failed in exactly the manner that Anarchists had predicted!
Is the federalist libertarian perspective Utopian, or is the centralized authoritarian one when it fails both in theory (power corrupts, requires inhuman knowledge, leads to bureaucracy etc) and in practice? Is a bottom-up democratic society Utopian or the top-down hierarchical one who expects leaders to be practically flawless and that “real power” will somehow still remain at the hands of the people? Is the “similar means as the ends” anarchist position Utopian or is the Leninist “ends justify the means” which expects a revolution where people just passively followed orders from the enlightened few can somehow lead to a society or politically active and empowered individuals?
In the end, who is the ideologue? The one who looks at how humans currently and historically acted and interacted and makes a revolutionary theory to describe and lead to something better, or one who makes a theory which proves to be a failure in practice and then refuse to discard it? Oh, the authoritarian socialists will say that “Of course we will learn from the mistakes our historical leaders made, we of course don’t want to repeat them. Terrible tragedy” and all that, but that is no more different than the Liberals who after every Capitalist crisis declared that they will learn from the mistakes of the past and ensure a future with no Crises and depressions. And when the next disaster comes, they are always oh so surprised.
This convinces few for it’s the theory’s core of hierarchy and authority that is flawed and by refusing to review that they only doom themselves to similar results and suffering of scale.
And finally, there’s also the right-“libertarian”, pro-capitalist, free market “anarchist” camp. But those don’t generally accuse others of utopianism for they’ve probably learned that those living in glass houses don’t throw ideological stone around.
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/**
* Stops this sensor. In case this sensor has been bound to an event listener, the stop
* invokes its {@link EventListener#stop(Sensor)} method. In case of a
* {@link org.openremote.controller.protocol.ReadCommand}, the polling thread is stopped.
*
* @see org.openremote.controller.model.sensor.Sensor#start()
*/
public void stop()
{
if (isEventListener())
{
EventListener listener = (EventListener)eventProducer;
try
{
listener.stop(this);
}
catch (Throwable t)
{
log.error(
"There was an implementation error in the event listener associated with " +
"sensor ''{0}''. The event listener may not have stopped properly : {1}",
t, getName(), t.getMessage()
);
}
}
else
{
if (deviceReader != null)
{
deviceReader.stop();
}
}
} |
<filename>teach_bot.py
import dialogflow_v2 as dialogflow
from dotenv import load_dotenv
import os
import json
import copy
import logging
from tg_bot import TelegramLogsHandler
import google
import sys
logger = logging.getLogger('tg_logger')
def repack_intents(filename):
with open(filename, 'r', encoding='utf8') as q:
questions = json.load(q)
intents = []
intent = {
"display_name": None,
"messages": [{"text": {"text": [None]}}],
"training_phrases": []
}
for key in questions:
temp_intent = copy.deepcopy(intent)
temp_intent['display_name'] = key
temp_intent['messages'][0]['text']['text'][0] = questions[key]['answer']
for question in questions[key]['questions']:
training_phrase = {'parts': [{'text': question}]}
temp_intent['training_phrases'].append(training_phrase)
intents.append(temp_intent)
return intents
def load_intents_to_agent(intents, project_id):
client = dialogflow.IntentsClient()
parent = client.project_agent_path(project_id)
for intent in intents:
client.create_intent(parent, intent)
def teach_agent(project_id):
client = dialogflow.AgentsClient()
parent = client.project_path(project_id)
client.train_agent(parent)
def teach_bot(google_project_id, logger):
intents = repack_intents('questions.json')
logger.info('Intents repacked')
load_intents_to_agent(intents, google_project_id)
logger.info('Intents loaded to agent')
teach_agent(google_project_id)
logger.info('Agent taught')
def main():
load_dotenv()
tg_logger_token = os.getenv('TG_LOGGER_TOKEN')
tg_chat_id_logger = os.getenv('TG_CHAT_ID_LOGGER')
google_project_id = os.getenv('GOOGLE_PROJECT_ID')
logging.basicConfig(level=logging.INFO)
logger.addHandler(TelegramLogsHandler(tg_logger_token, tg_chat_id_logger))
try:
teach_bot(google_project_id, logger)
except google.api_core.exceptions.InvalidArgument:
logger.error(f'{__file__} Loading intents error')
sys.exit()
except google.api_core.exceptions.GoogleAPIError:
logger.error(f'{__file__} Teaching agent error')
sys.exit()
if __name__ == "__main__":
main()
|
<reponame>NarrativeCompany/narrative<gh_stars>1-10
package org.narrative.network.customizations.narrative.neo.services;
import org.narrative.common.util.UnexpectedError;
import org.narrative.common.util.ValidationHandler;
import org.narrative.network.customizations.narrative.service.api.ValidationContext;
import java.security.NoSuchAlgorithmException;
import java.util.regex.Pattern;
import static org.narrative.common.util.CoreUtils.*;
import static org.narrative.network.shared.util.NetworkCoreUtils.*;
/**
* Created by IntelliJ IDEA.
* User: jonmark
* Date: 2/23/18
* Time: 7:57 AM
*/
public class NeoUtils {
public static final int NEO_ADDRESS_LENGTH = 34;
public static final int NEO_RAW_ADDRESS_BYTE_LENGTH = 21;
public static final int NEO_ADDRESS_VERSION_BYTE = 23;
public static final Pattern NEO_SCRIPT_HASH_PATTERN = Pattern.compile("[0-9a-f]{40}", Pattern.CASE_INSENSITIVE);
public static final int NEO_TRANSACTION_ID_LENGTH = 64;
public static final Pattern NEO_TRANSACTION_ID_PATTERN = Pattern.compile("[0-9a-f]{" + NEO_TRANSACTION_ID_LENGTH + "}", Pattern.CASE_INSENSITIVE);
public static boolean isValidAddress(String address) {
try {
byte[] bytes = Base58Check.decode(address);
if (bytes == null) {
return false;
}
// bl: the address is 160 bits, so 20 bytes, plus one leading version byte.
if (bytes.length != NEO_RAW_ADDRESS_BYTE_LENGTH) {
return false;
}
// bl: the version byte is 23
// per AddressVersion: https://github.com/neo-project/neo/blob/master/neo/protocol.json
if (bytes[0] != NEO_ADDRESS_VERSION_BYTE) {
return false;
}
return true;
} catch (NoSuchAlgorithmException e) {
throw UnexpectedError.getRuntimeException("NoSuchAlgorithmException shouldn't be possible! No SHA-256?", e);
} catch (IllegalArgumentException e) {
return false;
}
}
public static boolean isProperAddressLength(String address) {
// bl: must be exactly 34 characters
return address != null && address.length() == NEO_ADDRESS_LENGTH;
}
public static boolean validateNeoAddress(ValidationHandler handler, String paramName, String fieldLabel, String neoAddress) {
if (handler.validateNotEmptyWithLabel(neoAddress, paramName, fieldLabel)) {
if (!isProperAddressLength(neoAddress)) {
handler.addWordletizedFieldError(paramName, "neoFieldsHelper.neoAddressLength");
} else if (!isValidAddress(neoAddress)) {
handler.addWordletizedFieldError(paramName, "neoFieldsHelper.neoAddressInvalid");
} else {
return true;
}
}
return false;
}
public static boolean validateNeoAddress(ValidationContext validationContext, String fieldName, String neoAddress) {
if (!isProperAddressLength(neoAddress)) {
validationContext.addFieldError(fieldName, wordlet("neoFieldsHelper.neoAddressLength"));
} else if (!isValidAddress(neoAddress)) {
validationContext.addFieldError(fieldName, wordlet("neoFieldsHelper.neoAddressInvalid"));
} else {
return true;
}
return false;
}
public static boolean validateNeoScriptHash(ValidationHandler handler, String paramName, String fieldLabel, String nrveScriptHash) {
if (handler.validateNotEmptyWithLabel(nrveScriptHash, paramName, fieldLabel)) {
return handler.validateStringWithLabel(nrveScriptHash, NEO_SCRIPT_HASH_PATTERN, paramName, fieldLabel);
}
return false;
}
public static boolean validateNeoTransactionId(ValidationHandler handler, String paramName, String fieldLabel, String transactionId) {
if (handler.validateNotEmptyWithLabel(transactionId, paramName, fieldLabel)) {
return handler.validateStringWithLabel(transactionId, NEO_TRANSACTION_ID_PATTERN, paramName, fieldLabel);
}
return false;
}
public static boolean isValidNeoTransactionId(String transactionId) {
return !isEmpty(transactionId) && NEO_TRANSACTION_ID_PATTERN.matcher(transactionId).matches();
}
}
|
The present invention relates to an object lens barrel that includes at least an object lens constructed of a plurality of lenses and retains the object lens, an object lens barrel drive unit and an optical information recording and reproducing unit.
In recent years, there has been an attempt to employ an object lens constructed of a plurality of lenses in order to achieve a high numerical aperture particularly in an optical information recording and reproducing unit.
Japanese Patent Laid-Open Publication No. HEI 4-355419 discloses an object lens barrel that includes at least an object lens for use in such an optical information recording and reproducing unit and retains the object lens. As shown in FIG. 13, this object lens barrel is provided with an object lens constructed of five lenses in total and a barrel 57 for retaining and fixing the lenses.
Such an object lens constructed of a plurality of lenses has conventionally been subjected to positioning by mechanical accuracy including the steps of determining an inter-lens distance by putting the lens surfaces of the lenses in contact with each other and performing decentering and tilting of the lenses by putting reference surfaces of the lenses in contact with the reference surface of each lens provided in the lens barrel and fixing the same.
However, there has been the problem that the object lens has not been able to bring performance into full play as an object lens because optical aberration exists merely through the positioning by mechanical accuracy.
In order to solve this problem, there has been considered a method for reducing spherical aberration by putting a ring-shaped spacer material between lenses and changing the thickness of the spacer material. However, such a method needs a lot of components and incurs an increase in weight of the object lens barrel. The inter-lens distance is specified by the thickness of the spacer material, and therefore, the inter-lens distance cannot be set to an arbitrary distance, also causing residual spherical aberration. Moreover, the fact that the object lens barrel employed for the optical information recording and reproducing unit has a heavy weight also leads to an increase in weight of the movable portion of an object lens barrel drive unit for driving the object lens barrel, consequently reducing an access speed with respect to an optical recording medium.
The present invention has been made in view of the aforementioned circumstances and has the object of providing an object lens barrel capable of easily executing inter-lens position adjustment and having a small number of components, an object lens barrel drive unit and an optical information recording and reproducing unit.
In order to achieve the above object, there is provided an object lens barrel comprising:
at least a combinational object lens constructed of a plurality of lenses including at least a first lens and a second lens, wherein `at least one of the first lens and a first lens barrel for retaining the first lens is fixed by bonding to at least one of the second lens or a second lens barrel for retaining the second lens via a spacer layer made of an adhesive.
According to the object lens barrel of the present invention, there can be executed inter-lens decentering, tilting and inter-lens distance adjustment as well as the arbitrary determination of the amount of adjustment, and therefore, the residual aberration can be reduced. Furthermore, the weight of the object lens is smaller than when a spacer of a metal or the like is employed.
Furthermore, according to the object lens drive unit of the present invention, the object lens barrel, which has a compact size and light weight, can be driven at high speed.
Furthermore, according to the optical information recording and reproducing unit of the present invention, the object lens barrel has a compact size and light weight. Therefore, high-speed access can be achieved by driving the object lens barrel at high speed. Furthermore, a high numerical aperture can be achieved, and this enables the recording and reproducing on a high-density optical recording medium. |
Personal dosimetry of the staff during treatment of neuroendocrine tumours with a high dose of Indium-111 Octreotide. BACKGROUND Therapeutic doses with Indium-111 (In-111)-DTPA-Octreotide are currently used in patients with somatostatin receptor positive tumours. It may result in tumour regression in some patients and this effect is ascribed to cell and receptor specific cytotoxicity by Auger or conversion electrons. Personnel being involved in this treatment may receive high radiation doses due to the emission of 173 keV and 247 keV photons. The aim of the present study was to assess the radiation dose to the personnel at different time intervals during treatment with Indium-111 Octreotide. METHODS Five consecutive patients suffering from a neuroendocrine tumour were included in this dosimetry study. In total, 18 treatments with Indium-111 Octreotide have been given with a mean dose of 8000 MBq every three weeks. Three dosimeters (whole body, left and right hand) and a dose rate monitor were used to register doses and dose rates during labelling, administration and in-patient follow-up and whole body scintigraphy. These procedures were performed by a pharmacist, a nuclear physician and a technologist, respectively. RESULTS The whole body dose received during the labelling procedure was 5 microSv. The mean total exposure time during administration, whole body scintigraphy and clinical follow-up was 47 minutes revealing a mean whole body dose of 45 microSv. The mean radiation dose to the hands was 60 microSv per treatment. CONCLUSIONS The radiation risk to staff members and technologists seems to be very low during in-patient treatments with high dose Indium-111 Octreotide. According to the safety regulations no special radiation protection measures or personal dosimetry is required. |
export type Topic = string;
export type OnTopicUpdatedFunc = () => void;
export type SubscribeToTopicFunc = (consumerId: number, topic: Topic, onTopicUpdated: OnTopicUpdatedFunc) => void;
export type UnsubscribeFromTopicFunc = (consumerId: number, topic: Topic) => void;
export type SubscribeToAllTopics = (consumerId: number, onTopicUpdated: OnTopicUpdatedFunc) => void;
export type UnsubscribeFromAllTopics = (consumerId: number) => void;
export type ObservedTopics = Topic[] | "all" | "none";
export type TopicSubscription = {
consumerId: number;
onTopicUpdated: OnTopicUpdatedFunc;
};
export type TopicSubscriptionsMap = {
[topic: string /* Topic */]: TopicSubscription[] | undefined;
};
export type AllTopicsSubscriptions = TopicSubscription[];
export type PubSubInnerContext<T> = {
data: T,
subscribeToTopic: SubscribeToTopicFunc;
subscribeToAllTopics: SubscribeToAllTopics;
unsubscribeFromTopic: UnsubscribeFromTopicFunc;
unsubscribeFromAllTopics: UnsubscribeFromAllTopics;
topicSubscriptionsMap: TopicSubscriptionsMap;
allTopicsSubscriptions: AllTopicsSubscriptions;
};
export type CalculateChangedTopicsFunc<T> = (prev: T, next: T) => Topic[];
|
use crate::{CodeGenDatabase, ModuleGroup};
use rustc_hash::FxHashMap;
use std::ops::Index;
use std::sync::Arc;
/// A `ModuleGroupId` refers to a single [`ModuleGroup`] in a [`ModulePartition`]
#[derive(Default, PartialEq, Eq, Clone, Debug, Hash, PartialOrd, Ord, Copy)]
pub struct ModuleGroupId(usize);
/// A `ModulePartition` defines how modules are grouped together.
#[derive(Default, PartialEq, Eq, Clone, Debug)]
pub struct ModulePartition {
groups: Vec<ModuleGroup>,
module_to_group: FxHashMap<hir::Module, ModuleGroupId>,
file_to_group: FxHashMap<hir::FileId, ModuleGroupId>,
}
impl ModulePartition {
/// Adds a new group of modules to the partition. This function panics if a module is added
/// twice in different groups.
pub fn add_group(&mut self, db: &dyn hir::HirDatabase, group: ModuleGroup) -> ModuleGroupId {
let id = ModuleGroupId(self.groups.len());
for module in group.iter() {
if self.module_to_group.insert(module, id).is_some() {
panic!("cannot add a module to multiple groups");
}
if let Some(file_id) = module.file_id(db) {
if self.file_to_group.insert(file_id, id).is_some() {
panic!("cannot add a file to multiple groups");
}
}
}
self.groups.push(group);
id
}
/// Returns the group to which the specified module belongs.
pub fn group_for_module(&self, module: hir::Module) -> Option<ModuleGroupId> {
self.module_to_group.get(&module).copied()
}
/// Returns the group to which the specified module belongs.
pub fn group_for_file(&self, file: hir::FileId) -> Option<ModuleGroupId> {
self.file_to_group.get(&file).copied()
}
/// Returns an iterator over all the groups
pub fn iter(&self) -> impl Iterator<Item = (ModuleGroupId, &ModuleGroup)> + '_ {
self.groups
.iter()
.enumerate()
.map(|(idx, group)| (ModuleGroupId(idx), group))
}
}
impl Index<ModuleGroupId> for ModulePartition {
type Output = ModuleGroup;
fn index(&self, index: ModuleGroupId) -> &Self::Output {
&self.groups[index.0]
}
}
/// Builds a module partition from the contents of the database
pub(crate) fn build_partition(db: &dyn CodeGenDatabase) -> Arc<ModulePartition> {
let mut partition = ModulePartition::default();
for module in hir::Package::all(db.upcast())
.into_iter()
.flat_map(|package| package.modules(db.upcast()))
{
let name = if module.name(db.upcast()).is_some() {
module.full_name(db.upcast())
} else {
String::from("mod")
};
partition.add_group(
db.upcast(),
ModuleGroup::new(db.upcast(), name, vec![module]),
);
}
Arc::new(partition)
}
|
<reponame>TACTfactory/harmony-core
package com.tactfactory.harmony.updater;
public interface IAddImport extends IExecutor {
}
|
THE MDC Alliance and its allies in non-governmental organisations and civil society sectors are behind the violence that broke out is some parts of the country yesterday, leading to a loss of life and destruction of property, including burning of buses and police vehicles, Government has said.
In a statement last night, Minister of State for National Security Owen Ncube said the State had activated all its security organs. By last night over 200 unruly elements had been arrested in connection with the violence, which by all looks was planned and co-ordinated through social media.
"The prevailing security situation in the country is a culmination of a well orchestrated series of events by the MDC Alliance working in cahoots with NGOs, civic society, youth organisations, pressure groups and individuals," said Minister Ncube.
"Regrettably, this has resulted in the loss of life and property, including injury to police officers and members of the public. We express our deepest condolences to the bereaving families. Full investigations are underway."
Minister Ncube said Government was aware of meetings organised by the Crisis Coalition in Zimbabwe from December 3 to 7 last year to foment disturbances in the country.
"These meetings were coordinated by Crisis Coalition and some identified foreign agents," he said.
"There were other meetings such as the one held on 11th January 2019 in Belvedere, whose agenda was to plan for the disturbance of peace and render the country ungovernable," he said.
"Pursuant to the nefarious agenda, the MDC Alliance activated its notorious terror groups which include the so-called Democratic Resistance Committees and the para-military Vanguard." Minister Ncube said yesterday's events were instructive in two ways.
"They come against the background where His Excellency the President Mnangagwa is out of the country and they are intended to undermine (kudira jecha) the ongoing re-engagement efforts of the President to market Zimbabwe at high level fora such as the World Economic Forum in Davos, Switzerland," he said.
"The events of the past 24 hours have been characterised by a well-coordinated criminal behaviour, destructive and violent pattern which included the barricading of roads, harassment of innocent members of the public, burning of cars, disruption of children's lessons in schools, forced closure of business entities, attempts to overrun police posts, destruction of property, unlawful possession and discharging of firearms in public, attacking tollgates and robbing them of cash as well as looting of shops," said Minister Ncube.
"In short, this was terrorism and total breakdown of rule of law and order which had nothing to do with the constitutional right of citizens to demonstrate peacefully as enshrined in Section 59 of the Constitution of Zimbabwe."
Minister Ncube said Government had activated all security organs to restore law and order and protect life and property.
"Government is appealing to members of the public to cooperate with the security institutions," he said.
"Government is aware of the ring leaders, their modus operandi and their funders," he said.
"Our security arms are now firmly on the ground tracking the criminals. They will be apprehended to face the full wrath of the law. In the meantime, security forces have arrested more than 200 individuals who were involved in these disturbances.
"Government urges members of the public to go about their normal day to day activities without fear as their security is guaranteed."
Minister Ncube expressed deep condolences to bereaving families and said investigations were underway. |
A Wireless In-door System for Assisting Victims and Rescue Equipments in a Disaster Management This paper presents a system based on electronic equipments, standard mobile phones and WLAN networks for managing evacuation routes, or for obtaining information about victims location and status, whenever a building collapses due to a disaster like earthquakes. The system is based on the standard Blue tooth specification to guarantee their application in indoor areas. The electronic equipments, their specifications and communication links, and the implications and viability of the entire system are analyzed in this work. |
package dev.abelab.crms.service;
import static org.assertj.core.api.Assertions.*;
import static org.junit.jupiter.api.Assertions.*;
import static org.junit.jupiter.api.TestInstance.Lifecycle.*;
import static org.junit.jupiter.params.provider.Arguments.*;
import static org.mockito.ArgumentMatchers.*;
import java.util.stream.Stream;
import org.junit.jupiter.api.Nested;
import org.junit.jupiter.api.Test;
import org.junit.jupiter.api.TestInstance;
import org.junit.jupiter.params.ParameterizedTest;
import org.junit.jupiter.params.provider.Arguments;
import org.junit.jupiter.params.provider.MethodSource;
import mockit.Expectations;
import mockit.Injectable;
import mockit.Tested;
import dev.abelab.crms.db.entity.UserSample;
import dev.abelab.crms.api.request.LoginRequest;
import dev.abelab.crms.enums.UserRoleEnum;
import dev.abelab.crms.logic.UserLogic;
import dev.abelab.crms.repository.UserRepository;
import dev.abelab.crms.exception.ErrorCode;
import dev.abelab.crms.exception.NotFoundException;
import dev.abelab.crms.exception.UnauthorizedException;
/**
* AuthService Unit Test
*/
class AuthService_UT extends AbstractService_UT {
@Injectable
UserLogic userLogic;
@Injectable
UserRepository userRepository;
@Tested
AuthService authService;
/**
* Test for login
*/
@Nested
@TestInstance(PER_CLASS)
class LoginTest {
@ParameterizedTest
@MethodSource
void 正_ユーザがログイン(final UserRoleEnum userRole) {
// setup
final var user = UserSample.builder().roleId(userRole.getId()).build();
final var requestBody = LoginRequest.builder() //
.email(user.getEmail()) //
.password(<PASSWORD>()) //
.build();
new Expectations() {
{
userRepository.selectByEmail(anyString);
result = user;
}
{
userLogic.verifyPassword(user, anyString);
result = null;
}
};
// verify
assertDoesNotThrow(() -> authService.login(requestBody));
}
Stream<Arguments> 正_ユーザがログイン() {
return Stream.of(
// 管理者
arguments(UserRoleEnum.ADMIN),
// 一般
arguments(UserRoleEnum.MEMBER));
}
@Test
void 異_メールアドレスが存在しない() {
// setup
final var user = UserSample.builder().roleId(UserRoleEnum.MEMBER.getId()).build();
final var requestBody = LoginRequest.builder() //
.email(user.getEmail()) //
.password(<PASSWORD>()) //
.build();
new Expectations() {
{
userRepository.selectByEmail(anyString);
result = new NotFoundException(ErrorCode.NOT_FOUND_USER);
}
};
// verify
final var exception = assertThrows(NotFoundException.class, () -> authService.login(requestBody));
assertThat(exception.getErrorCode()).isEqualTo(ErrorCode.NOT_FOUND_USER);
}
@Test
void 異_パスワードが間違っている() {
// setup
final var user = UserSample.builder().roleId(UserRoleEnum.MEMBER.getId()).build();
final var requestBody = LoginRequest.builder() //
.email(user.getEmail()) //
.password(<PASSWORD>()) //
.build();
new Expectations() {
{
userRepository.selectByEmail(anyString);
result = user;
}
{
userLogic.verifyPassword(user, anyString);
result = new UnauthorizedException(ErrorCode.WRONG_PASSWORD);
}
};
// verify
final var exception = assertThrows(UnauthorizedException.class, () -> authService.login(requestBody));
assertThat(exception.getErrorCode()).isEqualTo(ErrorCode.WRONG_PASSWORD);
}
}
}
|
#
# PySNMP MIB module Dell-BANNER-MIB (http://snmplabs.com/pysmi)
# ASN.1 source file:///Users/davwang4/Dev/mibs.snmplabs.com/asn1/Dell-BANNER-MIB
# Produced by pysmi-0.3.4 at Mon Apr 29 18:40:33 2019
# On host DAVWANG4-M-1475 platform Darwin version 18.5.0 by user davwang4
# Using Python version 3.7.3 (default, Mar 27 2019, 09:23:15)
#
ObjectIdentifier, Integer, OctetString = mibBuilder.importSymbols("ASN1", "ObjectIdentifier", "Integer", "OctetString")
NamedValues, = mibBuilder.importSymbols("ASN1-ENUMERATION", "NamedValues")
ConstraintsUnion, ValueSizeConstraint, SingleValueConstraint, ValueRangeConstraint, ConstraintsIntersection = mibBuilder.importSymbols("ASN1-REFINEMENT", "ConstraintsUnion", "ValueSizeConstraint", "SingleValueConstraint", "ValueRangeConstraint", "ConstraintsIntersection")
rnd, = mibBuilder.importSymbols("Dell-MIB", "rnd")
EnabledStatus, = mibBuilder.importSymbols("P-BRIDGE-MIB", "EnabledStatus")
SnmpAdminString, = mibBuilder.importSymbols("SNMP-FRAMEWORK-MIB", "SnmpAdminString")
ModuleCompliance, NotificationGroup = mibBuilder.importSymbols("SNMPv2-CONF", "ModuleCompliance", "NotificationGroup")
NotificationType, Integer32, ModuleIdentity, TimeTicks, MibScalar, MibTable, MibTableRow, MibTableColumn, iso, MibIdentifier, Bits, Counter64, Gauge32, Counter32, IpAddress, ObjectIdentity, Unsigned32 = mibBuilder.importSymbols("SNMPv2-SMI", "NotificationType", "Integer32", "ModuleIdentity", "TimeTicks", "MibScalar", "MibTable", "MibTableRow", "MibTableColumn", "iso", "MibIdentifier", "Bits", "Counter64", "Gauge32", "Counter32", "IpAddress", "ObjectIdentity", "Unsigned32")
TextualConvention, RowStatus, DisplayString = mibBuilder.importSymbols("SNMPv2-TC", "TextualConvention", "RowStatus", "DisplayString")
rlBanner = ModuleIdentity((1, 3, 6, 1, 4, 1, 89, 133))
rlBanner.setRevisions(('2007-12-16 00:00',))
if mibBuilder.loadTexts: rlBanner.setLastUpdated('200803160000Z')
if mibBuilder.loadTexts: rlBanner.setOrganization('Dell')
class BannerMessageType(TextualConvention, Integer32):
status = 'current'
subtypeSpec = Integer32.subtypeSpec + ConstraintsUnion(SingleValueConstraint(1, 2, 3))
namedValues = NamedValues(("rlBannerMOTD", 1), ("rlBannerLogin", 2), ("rlBannerExec", 3))
rlBannerMessageTable = MibTable((1, 3, 6, 1, 4, 1, 89, 133, 1), )
if mibBuilder.loadTexts: rlBannerMessageTable.setStatus('current')
rlBannerMessageEntry = MibTableRow((1, 3, 6, 1, 4, 1, 89, 133, 1, 1), ).setIndexNames((0, "Dell-BANNER-MIB", "rlBannerMessageType"), (0, "Dell-BANNER-MIB", "rlBannerMessageIndex"))
if mibBuilder.loadTexts: rlBannerMessageEntry.setStatus('current')
rlBannerMessageType = MibTableColumn((1, 3, 6, 1, 4, 1, 89, 133, 1, 1, 1), BannerMessageType())
if mibBuilder.loadTexts: rlBannerMessageType.setStatus('current')
rlBannerMessageIndex = MibTableColumn((1, 3, 6, 1, 4, 1, 89, 133, 1, 1, 2), Integer32().subtype(subtypeSpec=ValueRangeConstraint(1, 13)))
if mibBuilder.loadTexts: rlBannerMessageIndex.setStatus('current')
rlBannerMessageText = MibTableColumn((1, 3, 6, 1, 4, 1, 89, 133, 1, 1, 3), SnmpAdminString()).setMaxAccess("readwrite")
if mibBuilder.loadTexts: rlBannerMessageText.setStatus('current')
rlBannerManageTable = MibTable((1, 3, 6, 1, 4, 1, 89, 133, 2), )
if mibBuilder.loadTexts: rlBannerManageTable.setStatus('current')
rlBannerManageEntry = MibTableRow((1, 3, 6, 1, 4, 1, 89, 133, 2, 1), ).setIndexNames((0, "Dell-BANNER-MIB", "rlBannerMessageType"))
if mibBuilder.loadTexts: rlBannerManageEntry.setStatus('current')
rlBannerManageSSH = MibTableColumn((1, 3, 6, 1, 4, 1, 89, 133, 2, 1, 1), EnabledStatus()).setMaxAccess("readwrite")
if mibBuilder.loadTexts: rlBannerManageSSH.setStatus('current')
rlBannerManageTelnet = MibTableColumn((1, 3, 6, 1, 4, 1, 89, 133, 2, 1, 2), EnabledStatus()).setMaxAccess("readwrite")
if mibBuilder.loadTexts: rlBannerManageTelnet.setStatus('current')
rlBannerManageConsole = MibTableColumn((1, 3, 6, 1, 4, 1, 89, 133, 2, 1, 3), EnabledStatus()).setMaxAccess("readwrite")
if mibBuilder.loadTexts: rlBannerManageConsole.setStatus('current')
rlBannerMessageClear = MibScalar((1, 3, 6, 1, 4, 1, 89, 133, 3), BannerMessageType()).setMaxAccess("readwrite")
if mibBuilder.loadTexts: rlBannerMessageClear.setStatus('current')
mibBuilder.exportSymbols("Dell-BANNER-MIB", rlBannerMessageType=rlBannerMessageType, rlBannerManageTable=rlBannerManageTable, rlBannerMessageTable=rlBannerMessageTable, rlBannerMessageClear=rlBannerMessageClear, rlBannerMessageEntry=rlBannerMessageEntry, BannerMessageType=BannerMessageType, PYSNMP_MODULE_ID=rlBanner, rlBannerMessageIndex=rlBannerMessageIndex, rlBannerManageTelnet=rlBannerManageTelnet, rlBannerManageConsole=rlBannerManageConsole, rlBannerManageSSH=rlBannerManageSSH, rlBannerManageEntry=rlBannerManageEntry, rlBanner=rlBanner, rlBannerMessageText=rlBannerMessageText)
|
<filename>src/main/java/ru/tinkdemo/reactor/handlers/GreetingHandler.java
package ru.tinkdemo.reactor.handlers;
import org.springframework.stereotype.Component;
import org.springframework.web.reactive.function.server.ServerRequest;
import org.springframework.web.reactive.function.server.ServerResponse;
import reactor.core.publisher.Mono;
import java.util.Map;
@Component
public class GreetingHandler {
public Mono<ServerResponse> index(ServerRequest request) {
String name = request.queryParam("client")
.orElse("little hope");
return ServerResponse
.ok()
.render("index", Map.of("client", name));
}
}
|
<reponame>PushyamiKaveti/kalibr<gh_stars>1000+
#include <numpy_eigen/boost_python_headers.hpp>
#include <aslam/backend/ErrorTermTransformation.hpp>
void exportErrorTermTransformation()
{
using namespace boost::python;
using namespace aslam::backend;
class_<ErrorTermTransformation,
boost::shared_ptr<ErrorTermTransformation>,
bases<ErrorTerm> >("ErrorTermTransformation",
init<aslam::backend::TransformationExpression, sm::kinematics::Transformation, double, double>("ErrorTermTransformation(aslam::backend::TransformationExpression T, sm::kinematics::Transformation prior, double weightRotation, double weightTranslation)"))
;
}
|
Weak approximation of stochastic differential delay equations A numerical method for a class of Ito stochastic differential equations with a finite delay term is introduced. The method is based on the forward Euler approximation and is parameterised by its time step. Weak convergence with respect to a class of smooth test functionals is established by using the infinite dimensional version of the Kolmogorov equation. With regularity assumptions on coefficients and initial data, the rate of convergence is shown to be proportional to the time step. Some computations are presented to demonstrate the rate of convergence. |
package ru.job4j.filtration;
import org.junit.Test;
import java.util.List;
import static org.hamcrest.core.Is.is;
import static org.junit.Assert.assertThat;
public class SchoolTest {
@Test
public void getClassAStudentsListWithScoreBetween70And100() {
Student student1 = new Student(10);
Student student2 = new Student(20);
Student student3 = new Student(30);
Student student4 = new Student(40);
Student student5 = new Student(50);
Student student6 = new Student(60);
Student student7 = new Student(70);
Student student8 = new Student(80);
Student student9 = new Student(90);
List<Student> studentsList = List.of(student1, student2, student3, student4, student5, student6, student7, student8, student9);
School school = new School();
List<Student> result = school.collect(studentsList, s -> (s.getScore() >= 70) && (s.getScore() <= 100));
List<Student> expect = List.of(student7, student8, student9);
assertThat(result, is(expect));
}
@Test
public void getClassBStudentsListWithScoreBetween50And70() {
Student student1 = new Student(10);
Student student2 = new Student(20);
Student student3 = new Student(30);
Student student4 = new Student(40);
Student student5 = new Student(50);
Student student6 = new Student(60);
Student student7 = new Student(70);
Student student8 = new Student(80);
Student student9 = new Student(90);
List<Student> studentsList = List.of(student1, student2, student3, student4, student5, student6, student7, student8, student9);
School school = new School();
List<Student> result = school.collect(studentsList, s -> (s.getScore() >= 50) && (s.getScore() < 70));
List<Student> expect = List.of(student5, student6);
assertThat(result, is(expect));
}
@Test
public void getClassCStudentsListWithScoreBetween0And50() {
Student student1 = new Student(10);
Student student2 = new Student(20);
Student student3 = new Student(30);
Student student4 = new Student(40);
Student student5 = new Student(50);
Student student6 = new Student(60);
Student student7 = new Student(70);
Student student8 = new Student(80);
Student student9 = new Student(90);
List<Student> studentsList = List.of(student1, student2, student3, student4, student5, student6, student7, student8, student9);
School school = new School();
List<Student> result = school.collect(studentsList, s -> (s.getScore() >= 0) && (s.getScore() < 50));
List<Student> expect = List.of(student1, student2, student3, student4);
assertThat(result, is(expect));
}
}
|
<filename>src/main/java/design/mode/dm/structural/ap/v2/Client.java
package design.mode.dm.structural.ap.v2;
/**
* @author ：ex-xugaoxiang001
* @description ：适配器模式
* @copyright ： Copyright 2018 yowits Corporation. All rights reserved.
* @create ：2018/12/27 16:08
*/
public class Client {
public static void main(String[] args){
HeadsetAdapter headsetAdapter = new HeadsetAdapter(new Circular(), new TypecHeadset());
System.out.println("圆形耳机 插入");
headsetAdapter.circularPlugInEarphones();
System.out.println("type-c耳机 插入");
headsetAdapter.typecPlugInEarphones();
}
}
|
Safety of Intraovarian Injection of Human Mesenchymal Stem Cells in a Premature Ovarian Insufficiency Mouse Model Primary ovarian insufficiency (POI), a condition in which there is a loss of ovarian function before the age of 40 years, leads to amenorrhea and infertility. In our previously published studies, we demonstrated recovery of POI, correction of serum sex hormone levels, increase in the granulosa cell population, and restoration of fertility in a chemotherapy-induced POI mouse model after intraovarian transplantation of human bone marrow-derived mesenchymal stem cells (hBM-MSCs). While hBM-MSC may be a promising cell source for treatment of POI, there are few reports on the safety of stem cell-based therapy for POI. For future clinical applications, the safety of allogenic hBM-MSCs for the treatment of POI through intraovarian engraftment needs to be addressed and verified in appropriate preclinical models. In this study, we induced POI in C57/BL6 mice using chemotherapy, then treated the mice with hBM-MSCs (500,000 cells/ovary) by intraovarian injection. After hBM-MSC treatment, we analyzed the migration of engrafted cells by genomic DNA polymerase chain reaction (PCR) using a human-specific ALU repeat and by whole-body sectioning on a cryo-imaging system. We examined the possibility of transfer of human DNA from the hBM-MSCs to the resulting offspring, and compared the growth rate of offspring to that of normal mice and hBM-MSC-treated mice. We found that engrafted hBM-MSCs were detected only in mouse ovaries and did not migrate into any other major organs including the heart, lungs, and liver. Further, we found that no human DNA was transferred into the fetus. Interestingly, the engrafted cells gradually decreased in number and had mostly disappeared after 4 weeks. Our study demonstrates that intraovarian transplantation of hBM-MSCs could be a safe stem cell-based therapy to restore fertility in POI patients. Introduction Primary ovarian insufficiency (POI), also known as premature ovarian failure, is defined as an early loss of ovarian function before the age of 40 years, which usually manifests as amenorrhea and infertility. The annual incidence of POI has been steadily increasing 4,5. Approximately 70% of POI cases are idiopathic, and while evaluation is warranted to identify the underlying etiology 6, in many cases it is not clear. Iatrogenic POI secondary to chemotherapy is frequently reported and its incidence has been increasing, accounting for approximately half of the new cases of POI in women (20% to 80%) of reproductive age 7,8. Chemotherapy inhibits the growth of tumor cells; however, it also causes apoptosis of granulosa cells, follicular atresia, and decreased ovarian function, which leads to the clinical manifestations of POI. As there are no treatments that restore ovarian function in women with POI, the only option to achieve pregnancy is egg donation from a healthy donor. Recently, researchers have evaluated cell-based therapy using mesenchymal stem cells (MSCs) as a treatment option for POI-associated infertility 10,. A recent study reported that MSCs repair injured cells via paracrine activity or direct cell-to-cell interaction 15. In a previous study, we reported that transplantation of MSCs in a chemotherapy-induced POI mouse ovary corrected serum hormonal levels, restored the granulosa cell population, and stimulated ovarian follicle and angiogenesis, leading to a higher successful pregnancy rate compared to untreated POI mice. Though the therapeutic potential of MSCs in various disease conditions is well documented, safety concerns in using allogenic MSC as a biological drug remain. Several recent studies have raised concerns about potential side effects of exogenous stem cells after transplantation, such as tumor formation and neoplastic transformation 19,20. Although MSCs have proven to be a safer source of stem cells compared to other types of pluripotent stem cells 21,22, they carry an inherent risk of tumor-like mass formation 23,24. To realize the translational potential and clinical application of MSCs in the treatment of POI-associated infertility, we evaluated the safety and the potential risk of allogenic MSC treatment in a well-established preclinical mouse model of chemotherapy-induced POI 25,26. These mice show a reduced number of ovarian follicles and abnormal serum hormones level after 7 days of treatment with cyclophosphamide and busulphan. After transplantation of human bone marrow MSCs (hBM-MSCs) by direct intraovarian injection, as established in our previous study 17, we traced the migration of engrafted cells and examined the possibility of transfer of human DNA from the hBM-MSCs to offspring. Materials and Methods hBM-MSC Cell Culture hBM-MSCs were purchased from Roosterbio (Frederick, MD, USA); these cells were isolated from the bone marrow of a 29-year-old female and 26-year-old female. hBM-MSCs were cultured in the recommended cell culture medium, RoosterNourish-MSC-XF (Roosterbio, Frederick, MD, USA). At approximately 80% confluence, the cells were trypsinized using CTS TrypLE select enzyme (Gibco, Waltham, MA, USA) and serially expanded for two additional passages. At the end of the culture expansion, hBM-MSCs were collected and centrifuged at 200 g for 8 min. For intraovarian injection, 5 10 5 hBM-MSCs were resuspended with 10 ml phosphate-buffered saline (PBS). Fluorescence Labeling and Microscopy For hBM-MSC fluorescence labeling, hBM-MSCs were incubated in the culture medium containing Molday ION Rhodamine B (MIRB) at a final concentration of 30 mg/ml of medium. After 20 h of incubation, medium containing MIRB was replaced with fresh culture medium after washing with PBS. Fluorescence was observed using an EVOS FL fluorescence microscope (Thermo Fisher Scientific, Waltham, MA, USA). POI Mouse Model The experimental animal protocol in this study was approved by the University of Illinois at Chicago Animal Care Committee, and all animal experiments were performed in accordance with the ethical policy and guidelines of University of Illinois at Chicago for laboratory animals. We used the chemotherapy-induced POI animal model and hBM-MSC intraovarian injection protocol as established and described in our previous study 16,17. Briefly, female C57BL6 mice were treated with busulphan (30 mg/kg) and cyclophosphamide (120 mg/kg) by intraperitoneal injection. The control group was treated with PBS. After 7 days of chemotherapy, hBM-MSCs were transplanted into the ovary by intraovarian injection, as follows. All mice were treated preoperatively with one dose of buprenorphine (0.1 mg/kg) and anesthetized using 1% to 4% isoflurane inhalation. A small incision on the skin was made to access the ovary via the caudal abdominal cavity, and the uterine horns were traced to identify the ovary. Then, 5 10 5 hBM-MSCs resuspended in 10 ml PBS were injected into each ovary. For the control and untreated POI groups, 10 ml PBS was injected into each ovary. Seven days after hBM-MSC treatment, two female mice were housed with one C57BL6 male mouse for breeding. Pregnancy rate per group was calculated as "number of pregnant mouse/number of all mouse in group." After delivery, the postnatal pup body weight was measured at day 0, day 5, and day 10. Estrous Cycle Monitoring Estrous cycles were monitored daily for 14 days after initiation of chemotherapy to verify chemotherapy-induced POI. Daily vaginal swab samples were performed using clean and sterile cotton swabs and smeared onto a clean glass slide for staining and evaluation of estrous cycle stage. Each slide was stained with 0.1% crystal violet solution for 1 min following a published protocol 27. The estrous cycle stage was examined by bright field microscopy based on the presence or absence of nucleated epithelial cells and leukocytes 27,28. Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) RNA isolation was performed using TRIzol Reagent (Invitrogen, Waltham, MA, USA) according to the manufacturer's instructions. RNA concentration was quantified by spectrophotometry at 260 nm using Nanodrop 2000 (Thermo Fisher Scientific). A total of 1 mg of RNA was reverse transcribed to prepare cDNA using the RNA to cDNA EcoDry premix (Takara Bio, Kusatsu, Shiga, Japan). Real-time PCR was performed using the CFX96 PCR instrument with matched primers (Table 1) and Universal SYBR Green Supermix (Bio-Rad, Hercules, CA, USA). The following PCR parameters were used: initial denaturation cycle at 95 C for 3 min, followed by 40 amplification cycles at 95 C for 10 s, 56 C for 15 s, and 72 C for 1 min. The results are presented as the fold change in relative gene expression quantified using the delta-delta CT method. Human Cell Detection by Genomic DNA PCR For genomic DNA isolation, 25 to 50 mg of mouse tissue was mechanically homogenized with 1 ml DNAzol reagent (Thermo Fisher Scientific). Homogenate was centrifuged at 10,000 g for 10 min at room temperature, and the supernatant was transferred into a fresh tube. For DNA precipitation, 0.5 ml of 100% ethanol was added into the supernatant. Genomic DNA was isolated following the manufacturer's protocol. The concentration of DNA was quantified using Nanodrop 2000 (Thermo Fisher Scientific). For human cell detection by PCR, a human-specific ALU primer sequence was used as described in the litrature 29. Genomic DNA PCR was performed with ALU primers under the following conditions: one cycle of 95 for 10 min, followed by 50 cycles of 95 for 15 s, 56 for 30 s, and 72 for 30 s. The number of human cells in each sample was calculated using the correltion between CT value and cell number in the positive control sample. Fluorescence Cryo-Imaging To detect MIRB-labeled hBM-MSCs in mice, whole-animal cryo-imaging was performed on a CryoViz Instrument (BioInvision, Cleveland, OH, USA). Mice were treated with MIRB-labeled hBM-MSCs by intraovarian injection. Mice were euthanized, embedded in cyro-imaging embedding compound (BioInvision), and immediately frozen in liquid nitrogen. The frozen blocks were sent to the BioInvision Cryo-imaging lab (Mayfield Village, OH, USA) for imaging and analysis using their CryoViz Instrument. Statistical Analysis mRNA and protein levels of the examined markers were treated as continuous variables and expressed as means + standard deviations. Analysis of variance and Bonferroni's multiple-comparisons post hoc testing were used to compare the groups. The significance level was set at 5% (P < 0.05). The SPSS statistical program (version 22) was used to analyze the data. Intraovarian Engraftment of hBM-MSCs Restores Fertility in a POI Mouse Model We induced POI in mice by injecting chemotherapeutic agents (120 mg/kg of cyclophosphamide and 30 mg/kg of busulfan) via intraperitoneal injection. Estrus cycle stage was analyzed to confirm the POI induction. Through bright field microscopy of vaginal smear sample, each estrus cycle was identified (Fig. 1A). Proestrus (Fig. 1A upper-left) was presented by nucleated epithelial cells (red arrow) without leukocyte. Estrus (Fig. 1A upper-right) was identified by cornified epithelial cells (white arrow) without leukocyte. Metestrus (lower-left) showed both cornified epithelial cells Gene Sequence (white arrow) and leukocyte (black arrow) while diestrus (lower-right) showed nucleated epithelial cells (red arrow) with leukocyte (block arrow). As expected 25,26, 7 days after chemotherapy, mice showed an altered estrous cycle arrested in metestrus and diestrus, whereas normal mice maintained normal 4-to 5-day estrous cycle (Fig. 1A, B). After inducing POI, we transplanted hBM-MSCs (500,000 cells/10 ml) in each ovary. Consistent with our previous study 17, intraovarian injection of hBM-MSCs reversed abnormal ovarian morphology in the POI mice ( Fig. 1C-H), including the restoration of follicle numbers. Furthermore, we analyzed vascularization of the ovary tissue using the vascular endothelial cell marker CD31 by IHC and ovarian cell apoptosis by TUNEL assay (Fig. 1C-E). The extent of CD31-positive ovarian microvasculature was decreased in the POI mouse model (10.56% + 2.58%) and significantly recovered by hBM-MSC treatment (17.06% + 2.46%). We also analyzed the mRNA expression level of several steroidogenesis-related genes in ovary tissue (Fig. 1F, G). Expression of the ovarian granulosa cell marker FSHR was significantly decreased in the POI mouse ovary (0.35 + 0.12-fold) and this loss was reversed after hBM-MSC engraftment (1.47 + 0.39-fold, P < 0.05). The estrogen synthesis marker CYP19A1 (Cyp19) gene expression was also decreased (0.50 + 0.01-fold) in the ovaries of POI mice and restored in the hBM-MSCengrafted ovary (0.72 + 0.09-fold, P < 0.05). We also found changes in gene expression in the endometrium of the uterus of POI mice with and without hBM-MSC treatment (Fig. 1H, Supplemental Figure 1A-E). In the POI mouse, endometrial tissue showed reduced expression of ERa (0.23 + 0.08-fold), PR (0.12 + 0.02-fold), and proliferation marker Ki67 (0.60 + 0.09-fold) compared to the normal (control) mouse endometrium. Interestingly, in the hBM-MSC-engrafted POI mouse endometrium, these gene expression changes were reversed for ERa (0.52 + 0.06-fold), PR (0.38 + 0.03-fold), and Ki67 (1.01 + 0.11fold) compared to control mice. Transforming growth factor b (TGFb) gene expression, which is promoting preimplantation and angiogenesis, also restored by MSC transplantation (1.63 + 0.10-fold). The anti-apoptosis marker BCL2 gene expression, which was decreased in POI (0.44 + 0.05-fold), also increased in MSC-treated mouse (2.02 + 0.17-fold). Both angiogenesis markers vascular endothelial growth factor A (VEGFA) and a smooth muscle actin were significantly decreased in the POI model, and only VEGFA was significantly restored in the MSC-treated mouse (0.52 + 0.16-fold). Taken together, these results confirmed the phenotypic characteristics of POI mice, including estrous cycle arrest, abnormal ovarian morphology and vascularization, and low expression of marker genes in both the ovary and endometrium, and verified that hBM-MSC transplantation was able to reverse these POI-associated changes. Human Stem Cell Distribution (Detected by PCR) After Intraovarian Injection To detect engrafted human cells in the mouse body after hBM-MSC injection, we used human-specific ALU-base quantification, as reported in a previously published paper 29. We injected PBS (0 cells), 300,000 hBM-MSCs, or 500,000 hBM-MSCs into each mouse ovary. Approximately 5 min after injection, each ovary injected with a different number of hBM-MSCs was collected for genomic DNA isolation. Genomic DNA from the ovary was analyzed by real-time PCR using the human ALU sequence primer. We generated the following equation to calculate the number of human cells in mouse tissue based on the CT value from the PCR analysis ( Fig. 2A). We verified our equation by calculating the CT value of genomic DNA PCR using independent samples; the equation demonstrated 95% to 114% accuracy in quantifying human cells in mouse tissue (Fig. 2B). To analyze the human cells remaining in our POI mouse model after hBM-MSC transplantation, we collected ovary, uterus, spleen, liver, heart, and lung tissue at 14 and 28 days after transplantation (Fig. 2C, Supplemental Figure 2). On day 14 after transplantation, human cells were detected only in the ovary (approximately 170,000 + 96,000 cells). Other tissues such as uterus, spleen, liver, heart, and lung did not contain any human cells. By day 28, only one mouse was found to contain human cells in the ovary (236,000 + 3,000 cells); the remaining mice did not contain any human cells in any tissues tested. We repeated the analysis with the hBM-MSCs isolated from another donor (Supplemental Figures 2, 3) and found similar results by PCR-based human cell detection. Our calculation of the persistence of engrafted hBM-MSCs in the ovary is shown in Fig. 2D. These results suggest that after intraovarian injection, engrafted hBM-MSCs do not migrate into other tissues, with more than 50% of the engrafted hBM-MSCs disappearing within 2 weeks after transplantation and most of the engrafted hBM-MSCs vanishing within 4 weeks after transplantation. Human Stem Cell Distribution (by Ex Vivo Imaging) After Intraovarian Injection To complement our PCR-based analysis and visualize engrafted cell distribution after injection, we next traced the distribution of injected hBM-MSCs through immunofluorescence imaging. We labeled hBM-MSCs with red fluorescing MIRB. Using fluorescence microscopy, we confirmed that more than 95% of cells were successfully labeled with MIRB (Fig. 3A). MIRB-labeled hBM-MSCs were injected into the ovaries of two POI mice. One mouse was euthanized 24 h after injection, and the other mouse was euthanized on day 21 (14 days after pregnancy). Both mice were euthanized using CO 2 and freezed immediately in embedding media for ex vivo imaging. By 24 h after transplantation, most of the engrafted hBM-MSCs were located in the mouse ovary. Similar to our PCR-based analysis, at 21 days after transplantation, hBM-MSCs were present in the ovary, with no evidence of migration of labeled cells into other tissues or the embryo. These analyses demonstrated that engrafted hBM-MSCs by intraovarian injection remain in the target organ and do not migrate into other tissues. Therapeutic Effect of Transplanted hBM-MSCs on Fertility in POI Mouse Model Based on our PCR and imaging data, engrafted hBM-MSCs were not present in the POI mice beyond 28 days. To analyze the effect of hBM-MSC transplantation on pregnancy, we performed a breeding experiment. One male mouse was housed with two female mice for 10 days. After the first litter delivery, mice were allowed to recover for 2 weeks, then the next round of breeding was resumed (Fig. 4A). We analyzed the pregnancy rate (number of pregnant mice/all mice) in each round of breeding and compared the groups (Fig. 4B). In the first breeding round (7 to 42 days after hBM-MSC transplantation), the normal mouse group (control) showed an 83.3% + 15.2% pregnancy rate. The POI mouse group (POI) showed a significantly decreased pregnancy rate (16.7% + 15.2%). The hBM-MSC-treated POI mouse group (MSC) demonstrated a recovery in the pregnancy rate (58.3% + 26.5%), which was not significantly different compared to the control group. In the second round of breeding (43 to 77 days after hBM-MSC transplantation), the POI group again showed a lower pregnancy rate (16.7% + 15.2%) compared to controls, and the pregnancy rate was recovered in the MSC group (58.3% + 26.5%). Interestingly, hBM-MSC transplantation did not restore the pregnancy rate in a third round of breeding (78 to 112 days after hBM-MSC transplantation). The pregnancy rate of the MSC group in the third breeding round was 16.7% + 15.2%, significantly lower than that of the control group (66.7% + 24.2%). In a fourth breeding round (113 to 147 days after hBM-MSC transplantation), the control group mice showed a 75.0% + 20.5% of pregnancy rate; the rate was significantly lower in the POI group (16.7% + 15.2%) and MSC group (25.0% + 20.5%). We also analyzed the average number of pups per mouse in each litter between the groups (Fig. 4C). In first litter, there were 3.67 + 2.67 pups per mouse in the control group, 0.33 + 0.78 pups per mouse in the POI group, and 5.50 + 3.39 pups per mouse in the MSC group. The second litter showed a similar trend, with an average of 5.08 + 3.28 pups in the control group, a decreased number of pups in the POI group (0.92 + 2.15), and a restored number of pups in the MSC group (5.67 + 3.08). Consistent with the pregnancy rate trends, the average number of pups in the third and fourth litters was not restored in the MSC group to the numbers seen in the control group. The average number of pups in the third litter was 0.83 + 1.33 and 1.33 + 2.07 in the fourth litter in the MSC group. These results suggest that the effect of hBM-MSCs on the restoration of fertility diminishes after 78 days of cell transplantation. Effect of hBM-MSC Engraftment on Offspring Though we confirmed that engrafted hBM-MSCs do not stay in the host body beyond 4 weeks and no cells were detected in the embryo in our fluorescence imaging analysis, we evaluated the potential short-term effect of hBM-MSCs on offspring. We analyzed the presence of human DNA in mouse embryos and postnatal growth rate of pups from control mice and hBM-MSC-treated POI mice, which had been treated with hBM-MSCs from two different donors. We collected mouse embryos (7 to 10 days) and isolated genomic DNA for human-specific ALU PCR analysis (Fig. 5A-C). We did not detect any human DNA in the embryos from mice treated with hBM-MSCs from either donor. The morphology and growth rate of pups was followed out to 10 days postnatal (Fig. 5D-F). No morphologic differences were seen in the pups from the control group and the hBM-MSC-treated group. All pups were visibly active in response and movement at postnatal day 0. At postnatal day 5, we observed hair growth in pups, and around day 10, all the pups were completely covered with black fur and were actively moving. The average body weight of control group pups and the hBM-MSC-treated group pups, respectively, was 1.45 + 0.08 and 1.46 + 0.10 g at day 0, 3.09 + 0.20 g and 3.37 + 0.17 g at day 5, and 5.46 + 0.44 and 5.48 + 0.32 g at day 10, without any significant difference between the groups, signifying a normal growth rate. Taken together, intraovarian injection of hBM-MSCs did not result in human DNA integration into the offspring genome and had no effect on offspring postnatal growth. Discussion In this study, we provide preclinical evidence of the safety of intraovarian injection of hBM-MSCs in a mouse model of POI, using a well-established ALU PCR-based method for human cell detection 29. We also found that the engrafted hBM-MSCs did not migrate to any other major organs and almost disappeared from the host body by 4 weeks after transplantation. In addition, we found that the therapeutic effect of hBM-MSC transplantation on measures of fertility also diminished after 78 days of cell transplantation. Finally, we confirmed that transplanted hBM-MSCs do not affect the offspring postnatal growth rate. The ultimate goal of our study is developing treatment using hBM-MSCs for restoring fertility in human patients with POI who are typically immune competent. Before applying our findings to human patients, the therapeutic effect and persistency of hBM-MSCs should be confirmed in as matched animal model as possible. Many studies used immune-compromised mice to enhance viability of engrafted cells in animal model. However, if we use immune-compromised POI mice model, it is hard to extrapolate the persistency of hBM-MSC transplantation in an actual immune-competent patient. To establish more realistic data for persistency of hBM-MSC, we used immune-competent POI mice model instead of immunecompromised model. Numerous reports suggested that human MSCs lack tissue surface antigens (major histocompatibility complex I and MHC II) 30 as well as secrete immune-suppressive cytokines in their adjacent microenvironment such as interleukin 10 (IL-10) and TGFb1 and as such elicit no or minimal host immune rejection 15,31. Recent studies have suggested that MSCs may be a promising cell source for cell-based therapy. MSCs are easy to extract from various tissues 31, and many previous studies have revealed that MSCs repair tissue via replacing injured cells by differentiation. In addition, MSCs can stimulate tissue regeneration by promoting angiogenesis and cell viability via paracrine activity through cytokines and extracellular vesicles 15,36,37. Various studies suggested interesting interaction between the paracrine effect of MSCs and the cell surrounding environment. In the published study, it was reported that the secreted factors highly depend on the external environment and the status of MSCs 38,39. Other studies also suggested different therapeutic mechanisms of MSC treatment through inflammatory regulation. Several studies revealed that some pro-inflammatory cytokines such as interleukin 6 and tumor necrosis factor alpha can induce MSC mitochondria transfer to rescue injured cells in various cell types. According to the published studies, it appears that a pro-inflammatory environment can enhance MSC mitochondria transfer to T cells to educate immune cells and this interaction eventually leads to restored inflammation and tissue damage 43. In this connection, MSC paracrine function and mitochondrial transfer capacity are interactive and linked together to promote the tissue regeneration. For the therapeutic effect of MSCs on our POI model, our previous studies reported that intraovarian injection of MSCs restores fertility in a POI mouse model 16,17. Together, these published studies support allogeneic MSCs as a promising cell source to treat infertility in POI. Recent studies suggest that MSCs are an ideal therapeutic cell source due to their dual tissue repair and immunosuppressive properties 30,31. In these studies, MSCs were shown to regulate immune cells by secreting various cytokines such as IL10, TGFb, and VEGF 30. Despite these advantages, there are still several concerns about the use of allogeneic stem cells for transplantation, such as the risk of tumor formation. In this and our previous study, we analyzed the morphology of hBM-MSC-engrafted ovaries in multiple animals. H&E staining of the mouse ovary showed a normal appearance. Use of either an antibody for human cell-specific markers or fluorescence labeling of the injected cells has been well documented in the literature for tracking cells after inection 17,. We found engrafted hBM-MSCs only in the injected tissue (ovary), with no migration of hBM-MSCs after 28 days. Moreover, the number of hBM-MSCs found in the ovary also decreased after transplantation, and more than 95% of engrafted cells had disappeared after 28 days of transplantation. Our findings are consistent with those of previous studies, which reported that mesenchymal stem cells do not produce teratoma or germ line-transmitting chimeras because they are not pluripotent stem cells 47,48. In addition, several papers reported that mesenchymal stem cells could inhibit tumor progression 49,50. These previous studies and our result suggest that hBM-MSCs are safe for stem cells, which are not forming tumor after transplantation. Genomic integration is another major concern after allogeneic stem cell transplantation, especially when used as an infertility treatment. To address this safety issue, we analyzed human-specific sequences in various mouse tissues such as ovary, uterus, spleen, liver, heart, and lung, after hBM-MSC injection. Many studies suggest that PCR using ALU-specific primers can detect human genomic DNA in a small animal model with high sensitivity 29,51-54. Our ALU PCR analysis suggested that no human genes were incorporated into the host or embryos after hBM-MSC injection. Recent studies have reported that MSCs restore ovarian granulosa cells by secreting exosomes. Our previous study revealed that the effect of MSCs in the POI ovary involves a paracrine mechanism 18. Based on our recent data and previously published studies, we conclude that engrafted hBM-MSCs in the POI ovary does not differentiate to replace ovarian cells, but instead restores ovarian granulosa cells by secreting paracrine stimulatory factors. This study provides additional preclinical evidence that intraovarian injection of hBM-MSCs may be a promising and safe therapy for restoring ovarian function and fertility in POI patients. Today, the only option for POI patients to have a baby is through egg donation; however, this is not a solution for patients who want their own biological child. The body of evidence continues to grow regarding the safety and efficacy of allogeneic MSCs, and clinical trials are now needed to test this approach as a new option to restore ovarian function in POI patients. Conclusion In our previous studies, we reported that intraovarian injection of hBM-MSCs restores fertility in a POI mouse model. However, the safety and effect of the transplanted cells on the recipient and offspring needed to be explored. In this study, we reported that the injected hBM-MSCs stay in the ovary and do not migrate to other tissues. The number of injected hBM-MSCs decreased by more than 50% within 2 weeks and disappeared entirely in most animals within 4 weeks after injection. In addition, while hBM-MSC treatment restored fertility, the effect diminished by 78 days following cell transplantation. Moreover, we revealed a lack of genetic integration from the injected cells in the offspring of treated mice, and that hBM-MSC treatment did not affect the postnatal growth of the offspring. Taken together, this study provides further evidence that intraovarian injection of hBM-MSCs may be a safe therapy for restoring fertility in POI, and clinical trials are needed to translate this option to treat female infertility in POI patients. Understanding the distribution of engrafted hBM-MSCs and the potential for human DNA transfer to offspring after hBM-MSC transplantation in an animal model will provide key preclinical safety data required for further clinical development and future applications of hBM-MSCs to the treatment of POI-associated infertility in women. Author Contributions Hang-soo Park and Rishi Man Chugh were equally involved in the experimental design, performed most experiments and data analysis, and wrote the manuscript. Hang-soo Park performed all in vivo experiments including surgery and tissue analysis. Rishi Man Chugh prepared hBM-MSC and participated in animal surgery. Amro Elsharoud, Mara Ulin, Sahar Esfandyari, Alshimaa Aboalsoud, and Lale Bakir helped with animal surgery, tissue collection, and PCR. Ayman Al-Hendy led the entire study as a corresponding author. All authors read and approved the final manuscript. Ethical Approval The experimental animal protocol in this study was approved by the University of Illinois at Chicago Animal Care Committee (UIC ACC/19-095). Statement of Human and Animal Rights All procedures in this study were performed in accordance with the ethical policy and guidelines of University of Illinois at Chicago for laboratory animals, and experimental protocol was approved by the University of Illinois at Chicago Animal Care Committee (UIC ACC/19-095). Statement of Informed Consent There are no human subjects in this article and informed consent is not applicable. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was financially supported by a University of Chicago start-up funding to Ayman Al-Hendy. Supplemental Material Supplemental material for this article is available online. |
II. The Meanings of Pan-Islamism: The Growth of International Consciousness Among the Muslims of India and Indonesia in the Late Nineteenth and Early Twentieth Century A commentator on Muhammad Iqbal, the great poet-philosopher of.Muslim India, once wrote that Pan-Islamism is not actually defined anywhere. If true, it has not been through want of trying. Since the term Pan-Islamism became common currency in the late nineteenth century, a variety of European journalists, colonial officials and academic researchers (not to mention Muslims themselves) have striven to offer a precise interpretation of the phenomenon. But they have failed to develop any consensus, even on basic questions: what was Pan-Islamism? why was it? or even, has it ever existed? Some have considered it an essentially religious drive, others as a political mobilisation. Some observers have presented it as a movement, as a disciplined, and perhaps clandestine, organisation with active members and fixed purposes. Others have dismissed it as mere sentiment, as nothing more than the vaguest of emotional attachments between co-religionists. A number, believing that Pan-Islamism seeks to re-create a past perfection, have argued that it aims to regroup Muslims under one sovereign authority much as they had enjoyed during the Prophet's lifetime. Others, on the other hand, have sensed more modern connotations, claiming that it intends to forge an exclusive international federation of Islamic states with the very real potential for threatening non-Muslim countries. At least one Marxist writer has distinguished between progressive and reactionary strains.3 This suggests that Pan-Islamism might both nurture the longings for some distant past and be responsive to the demands of the present. |
Cooking and food are as synonymous with how we celebrate our holidays as anything else: chocolates and those chalky message hearts for Valentine’s Day, big cookouts for The 4th of July, even cake on our birthdays. But there’s one holiday above all that celebrates the coming together of family and friends to give thanks – and stuff our faces with pretty much anything we can get our hands on…as long as there’s gravy on it. It’s the same holiday that a great chef like Bob Belcher takes seriously and plans for throughout the year.
With that said…you have met Bob’s family, right?
As you can see from the following clip from Sunday night’s holiday-themed episode of Fox‘s Bob’s Burgers ‘I Bob Your Pardon,’ Bob talks turkey – or more precisely, talks to turkey. As Bob readies his roasting masterpiece, Tina, Gene and Louise head out for the town’s inaugural turkey pardoning. Two different worlds brought together by a bit of Belcher bad luck, and what starts as a good deed turns into a raging dumpster fire – with an unwelcome reporter along for the ride.
Bob’s Burgers Season 9, Episode 7 ‘I Bob Your Pardon’: The Belchers set out to save a turkey from a trip to the slaughterhouse, but when a local reporter catches wind of their schemes, the mission becomes more complicated than they had anticipated.
Bob’s Burgers‘ holiday-themed ‘I Bob Your Pardon’ airs Sunday, November 18, at 8:30 p.m. ET on Fox. |
Phase synchronization of delta and theta oscillations increase during the detection of relevant lexical information During monitoring of the discourse, the detection of the relevance of incoming lexical information could be critical for its incorporation to update mental representations in memory. Because, in these situations, the relevance for lexical information is defined by abstract rules that are maintained in memory, a central aspect to elucidate is how an abstract level of knowledge maintained in mind mediates the detection of the lower-level semantic information. In the present study, we propose that neuronal oscillations participate in the detection of relevant lexical information, based on kept in mind rules deriving from more abstract semantic information. We tested our hypothesis using an experimental paradigm that restricted the detection of relevance to inferences based on explicit information, thus controlling for ambiguities derived from implicit aspects. We used a categorization task, in which the semantic relevance was previously defined based on the congruency between a kept in mind category (abstract knowledge), and the lexical semantic information presented. Our results show that during the detection of the relevant lexical information, phase synchronization of neuronal oscillations selectively increases in delta and theta frequency bands during the interval of semantic analysis. These increments occurred irrespective of the semantic category maintained in memory, had a temporal profile specific for each subject, and were mainly induced, as they had no effect on the evoked mean global field power. Also, recruitment of an increased number of pairs of electrodes was a robust observation during the detection of semantic contingent words. These results are consistent with the notion that the detection of relevant lexical information based on a particular semantic rule, could be mediated by increasing the global phase synchronization of neuronal oscillations, which may contribute to the recruitment of an extended number of cortical regions. INTRODUCTION Executive functions have a critical role in supporting language. It has been proposed that these functions are important for language appearance during evolution (Aboitiz and Garca, 1997;Aboitiz, 2012), for language acquisition, and for its normal use (Gibson, 1998;Caplan and Waters, 1999), allowing the coordination of sensory and semantic processes across time and accommodating moment-by-moment shifts in goals and strategies (;). During the analysis/creation of the discourse, a critical role of the executive functions relates to the coordination between two different levels of semantic knowledge. One is an abstract knowledge deriving from the combination of words' content across time (propositional semantics), and the other is the low-level knowledge deriving from the incoming lexical material. Roughly, from the combinatorial operations that assemble the basic components (lexical semantic units) into larger structures -a process named "unification" -additional information is created and maintained that, in turn, is used to monitor new lexical material. This more abstract level of knowledge, or propositional semantics (Givn, 1995), generates rules that dynamically set the relevance for processed words (Sperber and Wilson, 1987, based on its own semantic information. In the definition of these rules, this abstract semantic level requires to be constantly updated with the contingent semantic information detected, in order to adapt to, and to generate, varying propositional information along the discourse (Gernsbacher, 1991(Gernsbacher,, 1995. Thus, it becomes fundamental to understand how the contingent lexical information is detected and incorporated, when it is based on a more abstract semantic representation. The notion that the referential content created during the discourse sets the specific weights to the new lexical information is contained in the psycholinguistic concept of semantic context. Context is typically viewed as information that either enhances or instantiates a context-independent core representation or as a correlated constraint in which information from higher-level representation can, in principle, inform linguistic processing to lower levels of representation (Tanenhaus and Brown-Schmidt, 2008). An important question derived from this notion is whether and how, semantic context affects lexical processing (Tanenhaus and Brown-Schmidt, 2008). From a neurobiological perspective, this debate involves questions about the architecture of the processing system and the flow of information between different types of representation. Because of the increasingly close alignment between language research and systems neuroscience, modern biological models of language processing incorporate for both, the architecture of the processing system and the flow of information, the concept of "functional-connectivity" in the brain (Pulvermller, 2002;). A known fact derived from systems neurobiology is that even for single encoded elements, the information in the brain is widely distributed, and representations may emerge by virtue of the generation of functional communications between the separated coding regions. In fact, the visualized image of a cup, for example, is totally decomposed in its elementary components before it arrives to the visual cortex, and its characteristics (borders orientation, color, texture, location, etc) are parsed in different regions of the cortex. Because of that, the mental recreation of the observed cup requires its cerebral reconstruction, a process that is apparently mediated by functionally coupling the different cortical regions decoding their characteristics, as a unique and specific temporo-spatial activity pattern (). In the context of semantic analysis, it has been proposed that the same process takes place in the brain, but in this case to create an internal memory representation that depends on the life experience, and that in the case of speech is evoked by the acoustic material listened to. This memory representation would cluster uniand multi-sensory information traces that have been ontogenically associated with the concept itself. This notion also extends to the large-scale functional communication between regions maintaining a high-level abstract representation and those generating a lower-level lexical interpretation, thus integrating the word meaning into an unfolding discourse representation. In this framework, the central question addressed here is what physiological mechanisms account for an enhancement of the lexical information defined as relevant based on specific rules deriving from more abstract semantic representations. We hypothesized that neuronal oscillations play a pivotal role in the identification and incorporation of relevant lexical information. Our overall neurobiological proposal is based on previous findings showing that: (i) there are anatomical cortical areas (particularly the dorsolateral prefontal cortex, DLPFC) supporting the function of on-line monitoring of the incoming information based on an abstract knowledge (function also defined as "using the rules of the game; " Miller, 2000;Miller and Cohen, 2001); function that has been extended to the language domain by control-based theories, which include the role of the left inferior frontal gyrus (including Broca's region) in the selection of competing semantic information (;Hagoort, 2005;;); (ii) the existence of a neural substrate in the prefrontal cortex supporting the function of defining the relevance for incoming information () in general cognitive domains, and (iii) that the oscillatory activity in the brain is an integral part of the semantic analysis (;). We propose that the identification and enhancement of contingent lexical information based on abstract knowledge is mediated by a transitory strengthening of the communication between frontal areas (monitoring and defining the relevance of semantic information) and posterior areas (decoding lexical semantics). Because oscillations enable the cortex with the necessary gating mechanisms for the generation and increase of information fluxes, by means of the establishment of phase relations (Singer, 1999;;Buzski and Draguhn, 2004;Fries, 2005;), a transient increase in the phase synchronization of the oscillatory activity could be critically involved in the recruitment and functional coupling of cortical areas for the internalization of the new information. In the present work, despite being ultimately interested in the semantic processing at the natural discursive level, we restricted our experimental approach to a controlled task in which the detection of relevance was based on inferences derived from explicit information, thus controlling for ambiguities derived from implicit aspects of decoding. Because in the context of the discourse, the relevance for the lexical semantic information can be constructed based on different aspects of the propositional semantic created, which have also subjective dependencies, the use of a naturalistic situation can hinder the interpretation of the supposed relation between an abstract semantic rule and the target lexical material. We therefore used a categorization task in which the semantic relevance for the lexical information presented was previously defined based on the congruency between a kept in mind category (abstract knowledge) and the semantic content of words aurally presented to the subject. The rationale of our experimental task was that at the base of the paradigm is the construction of abstract semantic knowledge (which in this case we recreated by the maintenance of a particular semantic category), and a specific rule that defines lexical semantic relevance (in our task, under the instruction to look for the semantic congruency). Words of different semantic categories had to be semantically analyzed but differentially responded to, thus equating the cognitive requirements of analysis and the need of motor response for all categories, which allowed us to explore the specific influence that the abstract knowledge maintained in mind has on the detection of relevant semantic information. PARTICIPANTS Sixteen right-handed native Spanish speakers (10 females), age 20-33 years, participated in the study, signing a written consent. The subjects had no history of neurological disorders, did not abuse alcohol or drugs, had normal hearing, and shared similar socioeconomic and educational levels. All subjects finalized the task and none of them reported discomfort. STIMULI AND TASK Two independent but complementary studies were separately applied to different subgroups of subjects (n = 8 each group). The first study was aimed to evaluate the effect that keeping in mind a semantic category has on the functional coupling (phase synchronization) during the analysis and detection of contingent lexical material, compared with the non-relevant (competing) lexical information. The second was a follow-up study aiming to control for specific effects of different kept in mind categories. Thus, the goal of the second study was to ascribe results of phase synchronization modulation, to the phenomenon of monitoring lexical information based on an abstract semantic representation, independent of specific semantic categories. Both studies consisted of a variation of the classical Lexical Decision Task (LDT), where Spanish words pertaining to three different semantic categories (i.e., animals, man-made objects, and abstract nouns), and pseudo-words, were presented binaurally. In the first study, subjects were informed about the inclusion of different semantic categories and pseudo-words, but only one was explicitly named (animals), and instructed to be "kept in mind" during the whole session. The behavioral task was to press one of two possible buttons, contingent to whether the heard word belonged or did not belong to the instructed category. This forced subjects to semantically analyze each word irrespective of its content or category, and also equated the motor response requirements for each word. For the second study, stimuli were presented in a block design (three blocks). Each block consisted of the presentation of words belonging to two different semantic categories and pure tones (i.e., three different categories). Categories included in each block were, man-made objects and abstract nouns; animals and pseudo-words; pseudo-words and man-made objects, respectively. Kept in mind categories for each block were, man-made objects, animals, and pseudo-words, respectively. Note that the third block contained words belonging to the first and second categories. The rationale behind this approach assumes that the first and second blocks examine the consequence of a first exposure to those stimuli, whereas the third block examines the consequence of a repetitive exposure, in which, in addition, we rotated the cognitive requirements for each category. This manipulation allowed us to evaluate the weight that the cognitive process under study has, compared to semantic categories and exposition, in the results obtained. The use of the categories "animals" and "man-made objects" was used to contrast living versus non-living categories. Abstract nouns were included to evaluate differences in the processing of non-visual conceptual information. Pseudowords and pure tones were utilized to contrast processing related to verbal non-semantic information in the case of the first one, and auditory non-verbal information for the second. All of these selections were designed to evaluate specific topographic differences between different types of semantic and non-semantic information in the context of oscillatory activity, which become the objective for a complementary study. Commercial computer programs controlled all aspects of the tasks (Stim, NeuroScan Inc., USA, for the first study; Experiment Builder, SR Research Ltd., Mississauga, Canada, for the second study). Verbal stimuli consisted of Spanish disyllabic (consonantvowel-consonant-vowel) words, and equally structured pseudowords, which contained syllables existing in the used words. The frequency of use of the words included in the stimulus set was evaluated in an independent sample of 10 subjects with equivalent educational level, using an analog scale from 1 to 10 points applied to a pool of 40 words for each category. A group of 10 words were selected for each category that were rated over seven points. Categories were defined as: man-made objects (e.g., mesa), animals (e.g., gato), abstract nouns (e.g., nota), pseudo-words (e.g., mepo) and pure tones. Each category contained 10 stimuli, which were repeated six times during the task (60 stimuli for each category). Verbal stimuli were digitized using a female voice (A/D rate = 22050 Hz, 16 bits, average duration around 500 ms); pure tones were digitally constructed (frequencies between 280 and 640 Hz; duration 500 ms) and amplitude modulated applying a symmetric envelope of 250 ms to simulate the amplitude modulation proper of syllables (Audacity® 2.0.0; free digital audio editor). The amplitude of all stimuli was normalized to equate their magnitude and presented at 80 dB SPL. Sequences of words or tones were pseudo-randomly presented (SOA: 1.7-2.3 s), preventing consecutive intra-category appearance to eliminate semantic priming effects. Stimuli were delivered through commercial earphones (NeuroScan Inc., Neuromedical Supplies, USA) to subjects seated in a comfortable chair with eyes closed, in a sound-attenuated and electrically shielded room. RECORDINGS For the first study, an 80-channel montage and two 40channel amplifiers (Quik-Cap and NuAmps, NeuroScan Inc., Neuromedical Supplies) were used for data collection. Vertical and horizontal electro oculograms were recorded. Cz served as reference for acquisition, and Afz as ground. EEG was collected continuously (A/D rate = 1000 Hz, 32 bits precision, filters = DC-100 Hz). We used Scan 4.3 software (Neurosoft Inc., USA) for initial data processing. Offline filter settings were: high pass over 0.1 Hz (Butterworth, zero phase-shift filter, 24 dB/Oct). For the second study, a 32 + 8-active channel montage and a 32 + 8-channel amplifier (BioSemi ActiveTwo System; http://www.biosemi.com) with a CMS-DRL reference system was utilized. EEG was collected continuously (A/D rate = 2048 Hz, 24 bits precision, filters = DC-1024 Hz). Channels not reaching impedance below 5 Kohms were eliminated from the analysis. Epochs were extracted in the interval from −1000 ms to 2000 ms around stimuli. Baseline activity was defined as the 500 ms preceding the stimulus presentation. Epochs containing signals in frontal channels exceeding ±100 V were eliminated, as well as signals containing great eye movements, electromyographic, or other visually identified artifacts. PHASE-SYNCHRONY ANALYSIS All subsequent analyses were carried out using MATLAB. Data was imported by means of EEGLAB toolbox package routines (Delorme and Makeig, 2004) using averaged-mastoids signal as reference. To eliminate remaining blinks, ocular, and electromyographically generated noise, the EEG signals concatenated across all trials were decomposed using Independent Component Analysis (ICA). Artifact components were visually identified, based on time series and their topographic distribution. These components were extracted and the signals re-synthesized. Then, the EEG signals of each subject were re-referenced to the average of all EEG channels. To compute phase-locking values (PLV, ), phase was obtained from the Fourier coefficients calculated by means of a short-time Fourier transform (STFT). Time-frequency decomposition was computed on the EEG epochs tapered by a sliding Hamming window, using different window lengths for specific frequency ranges (1-4 Hz: 1024 ms; 4-8 Hz: 512 ms; 10-20 Hz: 256 ms; 20-40 Hz: 128 ms) applied in steps of 50 ms. To avoid edge effects, the first and last 200 points of the time series were merged to the initial and final epochs endings points, respectively, as a flipped, reflected copy, and the regions of interest were finally defined 500 points away from the original extremes. For each computed coefficient, the phase () was obtained as the arctan of the complex number. With this angle, a complex vector of unitary magnitude was constructed. This way, a complex valued phase vector was obtained as function of electrode, time, frequency, and trial number. Phase differences between all pairs of selected electrodes were then calculated for each frequency, time and trial, and then averaged across trials. By the modulus of this complex average value, we obtained a magnitude of phase difference, which could vary between 0 (random phase relation) and 1 (constant phase relation). That is, being i (f, t, k) the phase value of electrode i, at frequency f, time t, and trial k, and j (f, t, k) the phase value of electrode j, in the same frequency, time and trial, the phase In order to eliminate volume conduction effects, phase differences of 0 or 180 were discarded previous to compute the complex average vector (). Values of phase differences were then transformed to Z-Scores normalizing at each frequency by the respective values obtained during their baseline interval, as where P (f ) is the phase difference value obtained at frequency f and each time point across trial, and f and f are the mean and standard deviation of the phase difference values during the baseline at the same frequency. Statistically significant phase-synchrony (PLV) was calculated by comparing the Z-Scores of phase differences obtained for original signals, with phase differences equally computed in epochs of shuffled signals generated by the following procedure: the signal of each trial was subdivided into windows of the same size as the windows used in the time-frequency decomposition. These windows were randomly redistributed, resulting in trials with random phase values in each electrode. Finally, a Wilcoxon test between phase differences of recorded signals and 200 shuffled signals, was then used to establish a statistical significance of the phase differences obtained during the task (). Because the topographic distribution of the scalp activity produced is specific for each semantic category (), thecomparisonofphasecoupling values betweenconditions, based on their differences of scalp distributions, is not well suited for the present study (i.e., differences between conditions could reflect inherent differences in the activity patterns generated for the lexical material analyzed, and not the cognitive effect under study). To evaluate statistical differences in the global phase synchronization between conditions, we compared the average phase synchronization values obtained at different time-frequency regions of interest (across all electrode pairs that reached a significant PLV in those windows of interest). A Kruskal-Wallis test was applied to thosetime-frequencyregions,withTukey'smultiplecomparisonswhen K-W Chi-square statistic was significant, to compare phase synchronization between conditions. To compare the effect of the experimental manipulation between the first and second studies, as they had different subjects populations and design, and to evaluate a possible interaction between tasks, we applied a Two-way analysis of variance (ANOVA) to the phase synchronization results with the factors category (attended versus not attended) and group (1 versus 2). GLOBAL FIELD POWER Global field power (GFP) was computed for each category to rule out the possibility that differences in the global phase synchronization values between categories were reflecting differences in the strength of event related evoked activity. To this end, signals were filtered between 0.01 and 20 Hz and the average event related potentials (ERP) for each subject was first computed. GFP was computed as standard deviation of the momentary potential values across electrodes (Lehmann and Skrandies, 1980) for each subject, and then averaged across all of them. RESULTS All subjects completed both tasks, while none of them reported discomfort. For the first study, the mean number of rejected epochs for each category was 17 ± 6.8, 20 ± 6.9, 17 ± 5.7, and 19 ± 6.8, respectively and the average of channels used was 58 ± 5.8 for all categories. For the second study, no epochs and channels were rejected. Because the conjunction of brain loci involved in semantic analysis is specific for each semantic category, and even for single concepts (b;), we did not select a common group of electrodes to compare between categories (see Materials and Methods). In addition, there is no published data regarding which groups of electrodes would become synchronized in our task. Moreover, modulations of phase synchronization can result as a consequence of the recruitment of new brain areas during the task, with a corresponding increase and/or reduction of phase synchronization values between different pairs of electrodes. This assumption advises against the application of any a priori criterion to select a region of interest for comparing between categories. Therefore, we evaluated the distributions of variables across all valid pairs of electrodes that reached statistically significant phase synchronizations and used the averages across electrodes to make all between-conditions comparisons. For both studies, categories were numbered as 1 (man-made objects); 2 (animals); 3 (abstract nouns), and 4 (pseudo-words). Phase synchronization during semantic analysis We first outline the results of the first study. Figure 1 shows the time-frequency charts of the average phase synchronization changes produced during the task, for each category between 1 and 20 Hz. These graphs show that the principal increment in phase synchronization after word presentations occurs, for all categories, in the delta and theta frequency bands. Also, an increment in phase synchronization at beta frequency band is apparent for all categories, which is localized in time at around 500 ms. In this case, the category number 2 (animals) corresponded to the kept in mind category. Many differential features become evident in the global phase synchronization pattern of category 2 compared to the other ones. First, whereas in categories 1, 3, and 4, delta increments concentrate in the frequency range between 1 and 2.5 Hz in the time interval between 250 and 800 ms, in the category 2, delta increment spanned continuously the frequency range between 1 and 4 Hz, and became continuous with the increment in theta band. Moreover, whilst in categories 1, 3, and 4 there is a frequency range of desynchronization between 2.5 and 4 Hz, in category 2 this is the frequency range where increments of synchrony become prominent and more prolonged. Second, in all categories there is an early increase of synchrony in theta band in the range of 5-7 Hz between 150 and 250 ms. While in all categories there is a second increment at theta band around 500 ms, in category 2 this increment is continuous between 300 and 850 ms. The values of the phase synchronization changes across the session (Z-scores) were normally distributed for all categories in the time intervals of interest. For the first study, mean and maximal Z-score values in the range of 1-3 Hz for each category, in the interval between 250 and 800 ms, were: 0.44 and 11.14; 0.68 and 16.27; 0.37 and 10.22; 0.27 and 15.13, respectively. In the interval between 500 and 800 ms, mean and maximal Z-score values in the range of 3-4 Hz for each category were: −0.06 and 12.16; 1.13 and 12.11; −0.28 and 10.26; −0.04 and 11.74, respectively. Finally, in the interval between 350 and 800 ms, mean and maximal Z-score values in the range of 4-5.5 Hz for each category were: −0.18 and 24.6; 0.67 and 21.67; −0.12 and 25.27; −0.15 and 25.93, respectively. These distributions show that the task is associated with strong modifications of the functional connectivity observed between electrodes at baseline times. This modulation is manifested through strong synchronizations and desynchronizations at different electrode pairs, latencies, and frequency bands. Overall, these synchronization modulations are best characterized as a net global increment of the inter-electrode phase synchronization for the kept in mind category, at all time intervals and frequency ranges examined (Kruskal-Wallis test, 2 = 11.82; P < 0.01; Tukey's multiple comparisons; for the average signal between 100 and 800 ms poststimulus) (Figure 2). Figure 3 shows an example of the temporal profile of phase synchronization changes that occurred between all valid pairs of electrodes during the task, for each category, in one subject. The figure displays the phase synchronization modulation that occurred in the frequency range between 4 and 6 Hz, and shows dynamic inter-electrode phase synchronization changes having an ordered temporal profile, even in the categories displaying more discrete synchrony changes. This result indicates that synchronizations and desynchronizations between electrodes occurred as ordered phenomena at specific latencies during the task. Category 2 showed the largest and prolonged increments. A parsimonious explanation for the greater global phase synchronization manifested by category 2, is that these increments were the product of volume conduction of a focal phenomenon. Category 2 (B) is characterized by a marked recruitment of new electrode pairs that increase the global phase synchronization, which could be associated to new areas becoming active during the analysis and detection of words pertaining to the relevant category. As in the average across all subjects, global phase synchronization increments not only become larger, but also more prolonged for the kept in mind semantic category (B) than for the others (A,C,D). Frontiers in Psychology | Language Sciences June 2013 | Volume 4 | Article 308 | 6 In order to address this possibility, phase differences of 0 or 180 degrees were discarded prior to computing the average phase synchronization differences between electrodes (see Materials and Methods). Also, if this was the case, it would be expected that in this category, an important proportion of the phase differences obtained between all electrodes had a value closer to 1, when compared to the other categories. To assess this possibility, we compared the distributions of the non-normalized phase difference values of all valid pairs of electrodes between categories for each time interval and frequency range of interest. Figure 4 shows the parametric, kernel-smoothed probability density functions (PDF) of phase differences, computed for each category in the time interval between 250 and 800 ms in the frequency range between 2 and 4 Hz. This figure shows that all distributions contain a similar amount of phase differences with values close to 1, and strongly suggest that the increase of the phase synchronization displayed by category 2 during the task does not occur as consequence of volume conduction effects of a local phenomenon. This was also the case for all time intervals and frequency ranges compared between different categories. These phase synchronization distributions also suggest that the overall increase of phase synchronization for the kept in mind category (Z-scores compared to baseline) does not occur principally as a result of a group of electrodes becoming particularly synchronized, but probably through a recruitment and synchronization of new areas involved in the processing of this category. This is because a greater synchronization of a similar number of electrodes for the kept in mind category, would be manifested as a change in the distribution of phase differences for that category, when compared to the others. While the distribution of phase differences of this category tends to have the greatest values (Figure 4), this is insufficient to explain the greater increment in the average phase synchronization observed for this category (Figure 2). This is also illustrated in Figure 3, where it results evident that in the case of the kept in mind category a greater number of pairs of electrodes become synchronized, compared to the others categories. Evoked activity and global field power It could also be argued that the inter-electrodes phase synchronization increment displayed at low frequencies, in the kept in mind category, were reflecting the appearance of event related evoked components associated to target detection or other types of timelocked cognitive phenomena. Whereas this possibility is unlikely considering that the modulation patterns of phase synchronization found were induced rather than evoked, we addressed this issue by computing the GFP for each category, and measured statistical differences between conditions at each poststimulus latency. Because GFP is a parametric assessment of map strength, it gives a good measure to evaluate differences in the appearance of global evoked activities between conditions. A similar profile of the GFP across time was observed for all categories. Categ 1 Categ 2 Categ 3 Categ 4 FIGURE 4 | Stronger phase synchronization for the kept in mind category is not associated to a volume conduction phenomenon. Probability density functions (PDF) of the non-normalized phase differences between electrodes, obtained in the frequency range between 2 and 4 Hz, in the interval between 250 and 800 ms for each category. This time-frequency region is where the kept in mind category manifested stronger differences with the other categories. Distributions show the existence of a similar amount of phase differences with value closer to 1 between categories. This result was replicated in each time-frequency window of interest across the task, excluding the possibility that the stronger inter-electrodes phase synchronization manifested by category 2 would be the result of a volume conduction effect. the attended one, particular evoked activities are not evidenced at any latency that could explain the strong differences found in the global phase synchronization profile between the attended and not attended conditions (see Figure 2A). We did not apply permutations analysis to evaluate specific spatial differences between conditions because, as previously mentioned, differences could be inherent to the semantic material analyzed that recruit different patterns of cortical areas, and not to the cognitive phenomenon under study. The point that we want to stress here is that there is not a global increase in the strength of the evoked activity, at any latency, as observed in the phase synchronizations patterns between conditions. Figure 6 shows the GFP obtained for each category during the task. Some intrusion of alpha oscillations in the global field activity is observed, which was found in all subjects that performed the task, with eyes closed in a light attenuated room. For all latencies after stimulus presentation, we found no statistical differences between the GFP for category 2, the attended one, compared to the other categories (Kruskal-Wallis test, P > 0.05; Tukey's multiple comparisons). These results demonstrate that the global phase synchronization differences observed between this and the other categories can not be attributed to the generation of event related evoked activity during the task. Phase synchronization In the second study, we addressed the possibility of our results being specific for the animals category or whether previous results would generalize to any semantic category, thus attributing the increment of phase synchronization to a general cognitive process of detecting relevant information for a kept in mind conceptual representation. In this case we constructed blocks of stimuli Despite the intrusive alpha activity, it can be observed that category 2 is not associated to a greater evoked activity at any latency during the task. (B) Example box and whisker plots of the average activity across subjects in the time interval between 500 and 600 ms poststimulus, when prominent differences were found in the profile of global phase synchronization between conditions. No significant differences were obtained between category 2 and the other categories at any latency across the task. Frontiers in Psychology | Language Sciences June 2013 | Volume 4 | Article 308 | 8 presentations, varying now the category to be kept in mind (see Materials and Methods). In order to compare the cognitive effect between conditions, we contrasted the results of each category when it was kept in mind, to others and the same category, when they were not relevant to the task. Time-frequency plots of the phase synchronization changes for all categories showed similar profiles to that observed in the first task, where major increments of phase synchronization were again evident at delta and theta frequency ranges (data not shown). We therefore averaged Z-score values of phase synchronization between 1 and 6 Hz, in order to evaluate the changes between conditions. Figure 7 shows the temporal profile of these changes. As in the first experiment, in the categories that were kept in mind, the detection of the relevant lexical information produced a greater global phase synchronization compared to the non-attended categories (Kruskal-Wallis test, 2 = 6.95; P < 0.01; Tukey's multiple comparisons; for the average signal between 200 and 800 ms poststimulus. Figure 7A). This phenomenon occurred irrespective of the kept in mind category. Furthermore, when we contrasted the phase synchronization changes that occurred in the same category when it was kept in mind and when it was not, significant differences occurred in the pattern of global synchronization (Figures 7A,D), showing that the increased synchronization may be attributed to the cognitive process of extracting semantic relevance for the lexical information and not to basic context free lexical processing. Interestingly, this was also observed when the kept in mind category corresponded to pseudo-words, demonstrating that our results generalize and ultimately reflect, a complex cognitive process of detecting relevant incoming information based on an abstract rule. The comparison of the phase synchronization results between both tasks (first and second studies) by means of a Two-way ANOVA with factors category (attended versus not attended) and group (1 versus 2), showed a significant effect of the category (F = 8.15; P < 0.001) and group (F = 18.16; P < 0.001) but no interaction between both factors (F = 0.37; P = 0.78). These results show that the difference of global phase synchronization between categories, i.e., the effect of attend versus not attend to categories, is maintained and independent of both studies applied. Topographic maps of phase synchronization changes Our results show that during monitoring of the semantic content of words while keeping in mind abstract semantic knowledge, increments of phase synchronization were significantly higher during the analysis of words whose content was contingent to the task. These increments were prominent at delta and theta frequency bands, and despite the fact that they displayed a specific temporo-spatial pattern for each subject, global patterns can be inferred from these changes. Whereas theta increments appear in the form of two major time epochs up to 500 ms in the nonattended categories, the second increase prolongs at least until 850 ms for the kept in mind category. We generated topographic maps of these theta increments to obtain an average image of the spatial pattern of phase relations established for each category ( Figure 8A) These maps show that the first increment at 200 ms involves principally frontal electrodes. However, for the kept in mind category these phase relations show an extended pattern involving more posterior regions (Figure 8A). At the second latency (400 ms), theta increments clearly involve more posterior regions in all categories, but again, the phase relations established Hz for all categories. While this increase was not significantly greater for category 2 compared to the others, this could be related to the fact that these increments are topographically restricted than in the other frequency bands, and statistics are applied over the whole set of electrodes. Theta Gamma in the attended category involved an increased number of electrodes compared to the other categories. We plotted maps of synchronization at gamma frequency band (around 40 Hz) because we observed an early increase around 80 ms for all categories ( Figure 8B). However this increase was not significantly higher for attended categories. This may be explained in part because the statistical tests applied considered the complete set of electrodes, and changes in this frequency band were more locally restricted. For all categories, there was a discrete increase of phase relations at this frequency band, but for the attended category, this increase concentrates at central locations, where the activity of early auditory regions tends to be projected ( Figure 8B). Delta synchronizations, as those of theta band, also showed a significantly higher and more prolonged temporal pattern for the attended categories. This phase synchronization increment spanned the period of the theta increments, which suggests the possibility that a functional relation between these frequency ranges was established. In all categories, attended and unattended, we observed a temporally localized increase of the phase synchronization in the beta band at around 500 ms (Figure 1). We hypothesize that, because of its temporal location, this activity could be related to the preparatory activity associated to motor response. Interestingly, median reaction times were higher for the attended categories (0.71, 0.8, 0.75, and 0.77 seg. respectively for each category, in the first task), which is in association to the more prolonged delta and theta increments, which in turn could be related with a time consuming processing taking place during the analysis of the words pertaining to that categories, like the internalization of phonological and/or semantic information in memory. DISCUSSION It has been widely proposed that the neurophysiological integration of sparse information in the brain is achieved by means of the synchronization of the neuronal activity across local coding regions (Singer, 1999;;Fries, 2005). As previously mentioned, oscillations enable the cortex -by establishing phase relations -with the necessary mechanisms of gating for the generation of information fluxes across brain regions (Singer, 1999;;Buzski and Draguhn, 2004;Fries, 2005;). In this context, neuronal oscillations, by means of their phase synchronization, would be critically involved in lexical decoding and integration, mediating the binding of the sparse electrical activity representing specific characteristics of the semantic construction. The main question we addressed in the present study derives from the fact that language is not interpreted as a sequence of equally weighted lexical units, but in the context of a propositional semantic that is constructed as utterances unfold. As complex conceptual information is constructed across time, an interaction is required between different levels of semantic knowledge. Early models of language analysis included the notion that the complex conceptual information created set the relevance (weight) for incoming lexical information, based mainly on the limited working memory capacities (Tanenhaus and Brown-Schmidt, 2008). Because of these limitations, it has been proposed that only specific lexical units are incorporated to update the abstract knowledge, based on the defined relevance. Considering the neurobiological substrate for supporting this function, it has been suggested that frontal areas play a crucial role in the maintenance of an abstract semantic representation, and also of the rules defining the relevance of incoming information, thus allowing the monitoring of lexical information (;Hagoort, 2005;;). The critical element we incorporate in this framework and that we tested in the present study is that phase synchronization of the oscillatory activity participates in the interaction between the different levels of semantic representations. We propose that, whereas the new lexical material is recreated in posterior sensory, motor, and multimodal areas, the matching between this information and the "relevance rules" would be produced by functionally coupling these posterior and frontal regions. When the incoming semantic information is detected as relevant, this functional coupling is strengthened in order to enhance and incorporate it to the conceptual knowledge maintained. Because phase synchronization may allow the strengthening of the functional coupling, we predict that: (i) while the semantic information is being decoded, functional bridges are established with frontal areas to detect the relevance of information, (ii) when the semantic relevance of words is detected, these established phase synchronizations selectively increase, probably recruiting new cortical areas. As we previously described, despite the fact that our hypothesis concerns the physiological mechanisms accounting for the interaction between different levels of knowledge in the natural language condition, in the present work we decided to reduce the study to a controlled condition. Whereas this clearly does not allow the generalization of the current results to natural language, it gives a first insight about the process to project future studies. In the context of our task note that, whereas we used the knowledge of a category as the more abstract level of semantics, this does not imply that we assume that semantic relevance is based on the knowledge about categories. In fact, semantic contingency could be based more on the pragmatic knowledge that defines what we are talking about (Sperber and Wilson, 1995), which could have at some moment little or nothing to do with specific categories. For example, we could be talking about the care of racehorses, in which case it could be of higher relevance to talk and incorporate the information about a horseshoe (a man-made object) than to talk about a zebra (a very related animal). Also, the hypothesis neither imposes the condition of congruence between the semantic contents to define the relevance of the information. In the case of a psychiatrist trying to catch information about the discourse of a probable schizophrenic patient, the relevant rules will probably be constructed over the base of an existent semantic incongruence. However, we cannot argue that the neural phenomena occurring in this last case would be the same as in congruent conditions, because it could be that different processes take place () given that the more natural condition of relevance in the brain is the congruence. More studies are needed to address specific aspects of the dynamic phase synchronizations generated during the processing of lexical information in the context of propositional analysis. One of these aspects relates to the specific role that different frequency bands play in the process at different latencies. As it has been recently proposed (Giraud and Poeppel, 2012) theta and gamma oscillations can play a crucial role in the extraction of the temporal properties of speech at early stages of processing, allowing an ordered output of linguistic attributes to superior cortical levels for the analyses of more complex characteristics. Because of the frequency of the syllabic units, theta plays a fundamental role in the organization of the information at these stages. Theta is also fundamental for the extraction of semantic information (;). In this context, the activity related to these different levels of processing would be probably intermingled at different temporo-spatial scales, requiring more complex analysis and/or recording tools. Considering our findings, for example, theta could be accounting for the extraction of acoustic elements in rhythmicity with the syllabic structure, as proposed by Giraud and Poeppel, and these "packages" of information can be temporally unified to construct semantic information by means of delta activity. Our results are in agreement with this scenario, because theta synchronizations appear in specific time epochs with a temporal relation with the syllabic structure (Figure 1). Both transient synchronizations can be linked by the delta synchronizations that spanned the period of both theta increments. In the case of the kept in mind category, the more prolonged second theta synchronization can be related to strengthening or a rehearsing of the phonetic information contained in syllables for its association and incorporation with the semantic information in memory. In the same category delta increments are also more prolonged accompanying theta, supporting its unifying role for semantic processing. At the same frequency band in the other categories, there is a net desynchronization phenomenon, which could be accounted for by the inhibition of the incorporation of this semantic information in memory, because of its interfering effect for the task. In any case, more refined analyses will be required in order to account for the complex spatiotemporal dynamics of these synchrony patterns across multiple cortical regions. Semantic analysis at the lexical level is explained by modern theories in terms of "co-activation of representational nodes" (;Pulvermller, 1999Pulvermller,, 2002McClelland and Rogers, 2003). This notion derives from neuroanatomical (McCarthy and Warrington, 1988;Hillis and Caramazza, 1991;Hart and Gordon, 1992;Damasio et al.,, 2004), functional (;;;;), and theoretical studies (Farah and McClelland, 1991;McClelland and Rogers, 2003). These studies show that far from being a locally restricted phenomenon, semantic processing involves the participation of several and highly distributed regions, which are proposed to contain specific parts (nodes) of a whole concept (Damasio and Damasio, 1994;a;). As pointed out originally by Wernicke (1874Wernicke ( /1977Wernicke (, 1900, the comprehension of meaning implies the recruitment of distributed neuroanatomical areas to create a unified and coherent significance. He proposed that the concept is formed by the total sum of the memory images associated with, say, a particular object. This meant that in order to comprehend meaning, a rapid temporal association had to be made between the acoustic material and the various sensory memory images representing the concept itself (Gage and Hickok, 2005). In neurophysiological terms, a temporal binding of the electrical activity representing local characteristics of whole information is required in order to construct and recognize the total pattern representing the information to be identified (). Our results are in agreement with this proposal, showing that the establishment of functional couplings across distant cortical areas is a prominent phenomenon occurring during semantic analysis, and that these functional interactions are strengthened during the cognitive requirements associated with the recognition and categorization of specific information. These findings predict that during natural language processing, the spontaneous creation of referential knowledge across the discourse would enhance the synchronization patterns of contingent lexical material, which can be the subject of future studies. |
from typing import List, Tuple, Type
import numpy as np
from continuum.datasets.base import _ContinuumDataset
from continuum.datasets.pytorch import (CIFAR10, CIFAR100, KMNIST, MNIST, FashionMNIST)
class Fellowship(_ContinuumDataset):
def __init__(
self,
dataset_list: List[Type[_ContinuumDataset]],
data_path: str = "",
train: bool = True,
download: bool = True,
):
super().__init__(data_path, download)
self.datasets = [
dataset(data_path=data_path, train=train, download=download) for dataset in dataset_list
]
def get_data(self) -> Tuple[np.ndarray, np.ndarray, np.ndarray]:
x, y, t = [], [], []
class_counter = 0
for i, dataset in enumerate(self.datasets):
data = dataset.get_data()
x.append(data[0])
y.append(data[1] + class_counter)
t.append(np.ones(len(data[0]) * i))
class_counter += len(np.unique(data[1]))
x = np.concatenate(x)
y = np.concatenate(y)
t = np.concatenate(t)
return x, y, t
class MNISTFellowship(Fellowship):
def __init__(self, data_path: str = "", train: bool = True, download: bool = True) -> None:
super().__init__(
dataset_list=[MNIST, FashionMNIST, KMNIST],
train=train,
data_path=data_path,
download=download
)
class CIFARFellowship(Fellowship):
def __init__(self, data_path: str = "", train: bool = True, download: bool = True) -> None:
super().__init__(
dataset_list=[CIFAR10, CIFAR100], train=train, data_path=data_path, download=download
)
|
/* ###
* IP: GHIDRA
*
* 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.
*/
package ghidra.app.plugin.core.analysis;
import java.math.BigInteger;
import ghidra.program.model.address.Address;
import ghidra.program.model.lang.Register;
import ghidra.program.model.lang.UnknownInstructionException;
import ghidra.program.model.listing.Instruction;
import ghidra.program.model.listing.Program;
import ghidra.program.model.mem.MemoryAccessException;
import ghidra.program.model.scalar.Scalar;
import ghidra.util.Msg;
class HexagonInstructionInfo {
Address addr;
int parseBits;
boolean endPacket;
boolean isDuplex;
boolean isImmext;
HexagonInstructionInfo.DuplexEncoding duplex1;
HexagonInstructionInfo.DuplexEncoding duplex2;
Register newValueOperandRegister;
HexagonInstructionInfo(Program program, Instruction instr, Address packetStartAddress)
throws MemoryAccessException, UnknownInstructionException {
this.addr = instr.getAddress();
endPacket = false;
isDuplex = false;
isImmext = instr.getMnemonicString().equals("A4_ext");
if (instr.getLength() != 4) {
// See comment in reallyDisassembleInstruction().
// We cleared subinsn, so all "instructions" should be 4
// bytes. Duplex instructions will appear as a 4-byte opaque
// DUPLEX temporary instruction.
throw new IllegalArgumentException("Duplex subinstruction not allowed in HexagonInstructionInfo");
}
BigInteger value = BigInteger.valueOf(((instr.getByte(1) & 0xc0) >> 6) & 0b011);
parseBits = value.intValue();
if (parseBits == 0b00) {
// This is an end of packet, and a duplex instruction
endPacket = true;
isDuplex = true;
int iclass1 = ((instr.getByte(1) & 0x20) >> 5) & 0b001;
int iclass2 = ((instr.getByte(3) & 0xe0) >> 5) & 0b111;
int iclass = (iclass2 << 1) | iclass1;
switch (iclass) {
case 0:
duplex1 = DuplexEncoding.L1;
duplex2 = DuplexEncoding.L1;
break;
case 1:
duplex1 = DuplexEncoding.L2;
duplex2 = DuplexEncoding.L1;
break;
case 2:
duplex1 = DuplexEncoding.L2;
duplex2 = DuplexEncoding.L2;
break;
case 3:
duplex1 = DuplexEncoding.A;
duplex2 = DuplexEncoding.A;
break;
case 4:
duplex1 = DuplexEncoding.L1;
duplex2 = DuplexEncoding.A;
break;
case 5:
duplex1 = DuplexEncoding.L2;
duplex2 = DuplexEncoding.A;
break;
case 6:
duplex1 = DuplexEncoding.S1;
duplex2 = DuplexEncoding.A;
break;
case 7:
duplex1 = DuplexEncoding.S2;
duplex2 = DuplexEncoding.A;
break;
case 8:
duplex1 = DuplexEncoding.S1;
duplex2 = DuplexEncoding.L1;
break;
case 9:
duplex1 = DuplexEncoding.S1;
duplex2 = DuplexEncoding.L2;
break;
case 10:
duplex1 = DuplexEncoding.S1;
duplex2 = DuplexEncoding.S1;
break;
case 11:
duplex1 = DuplexEncoding.S2;
duplex2 = DuplexEncoding.S1;
break;
case 12:
duplex1 = DuplexEncoding.S2;
duplex2 = DuplexEncoding.L1;
break;
case 13:
duplex1 = DuplexEncoding.S2;
duplex2 = DuplexEncoding.L2;
break;
case 14:
duplex1 = DuplexEncoding.S2;
duplex2 = DuplexEncoding.S2;
break;
default:
assert false;
}
}
if (parseBits == 0b11) {
endPacket = true;
}
resolveNewValueOperand(program, instr, packetStartAddress);
}
Address getAddress() {
return addr;
}
private BigInteger getNewValueOperand(Instruction instr) throws UnknownInstructionException {
Integer idx = HexagonInstructionAttributeConstants.getNewValueOperandIdx(instr);
if (idx != null) {
Object[] obj = instr.getOpObjects(idx);
assert obj.length == 1;
Object obj2 = obj[0];
if (!(obj2 instanceof Scalar)) {
Msg.error(this, "New-value operand wasn't a scalar (" + instr + ")");
throw new UnknownInstructionException("New-value operand wasn't an immediate as expected");
}
Scalar s = (Scalar) obj2;
return s.getBigInteger();
}
return null;
}
private void resolveNewValueOperand(Program program, Instruction instr, Address packetStartAddress)
throws UnknownInstructionException {
newValueOperandRegister = null;
// N.B. duplex sub-instructions still appear as one placeholder
// DUPLEX 4-byte instruction.
//
// However, duplex sub-instructions do not have new-value operands
// (not to be confused with dot-new predicates) so we can analyze
// this here
if (isDuplex) {
return;
}
BigInteger idx = getNewValueOperand(instr);
if (idx == null) {
return;
}
if (idx.intValue() == 0) {
throw new UnknownInstructionException("New-value operand value is 0");
}
if ((idx.intValue() & 0b1) != 0) {
throw new UnknownInstructionException("First bit of new-value operand is not 0");
}
int idx2 = idx.intValue();
idx2 = (idx2 >> 1) & 0b11;
Address start = instr.getAddress();
for (int i = 0; i < idx2; ++i) {
start = start.subtract(4);
if (start.compareTo(packetStartAddress) < 0) {
throw new UnknownInstructionException(
"Invalid packet has dot-new operand pointing before the beginning of the packet");
}
Instruction inst = program.getListing().getInstructionAt(start);
if (inst == null) {
throw new UnknownInstructionException();
}
if (inst.getLength() != 4) {
// sanity check that the math we did above was kosher
throw new UnknownInstructionException();
}
if (inst.getMnemonicString().equals("A4_ext")) {
// 10.10 New-Value operands
//
// “ahead” is defined here as the instruction encoded at a lower
// memory address than the consumer instruction, not counting
// empty slots or constant extenders.
start = start.subtract(4);
}
}
Instruction inst = program.getListing().getInstructionAt(start);
if (inst == null) {
throw new UnknownInstructionException();
}
extractNewValueOperandRegister(inst);
}
private void extractNewValueOperandRegister(Instruction inst) throws UnknownInstructionException {
Integer idx = HexagonInstructionAttributeConstants.getIdxOfNewValueProducer(inst);
if (idx == null) {
throw new UnknownInstructionException(
"Instruction producer for new-value operand did not have suitable register");
}
Object[] obj = inst.getOpObjects(idx);
assert obj.length == 1;
Object obj2 = obj[0];
if (!(obj2 instanceof Register)) {
Msg.error(this, "New-value producer wasn't a register (" + inst + ")");
throw new UnknownInstructionException("New-value producer wasn't a register as expected");
}
newValueOperandRegister = (Register) obj2;
}
enum DuplexEncoding {
A, L1, L2, S1, S2;
int getValue() {
switch (this) {
case A:
return 1;
case L1:
return 2;
case L2:
return 3;
case S1:
return 4;
case S2:
return 5;
}
assert false;
return -1;
}
}
}
|
package com.lingyejun.dating.chap8;
/**
* @Author: lingyejun
* @Date: 2019/12/22
* @Describe:
* @Modified By:
*/
public class Question implements PlayerService, RecordService {
@Override
public void start() {
}
@Override
public void pre() {
}
@Override
public void next() {
}
@Override
public void pause() {
}
@Override
public void stop() {
System.out.println("Question impl by self");
PlayerService.super.stop();
}
public static void main(String[] args) {
new Question().stop();
}
}
|
Q:
Как открыть в окне vim терминал
Vim разбил на 3 окна - горизонтально и вертикально. Но не могу найти инфу как первое окно(где курсор) превратить в терминал. Чтобы был терминал для запуска make и прочего. То есть работа с директорией.
A:
Если у вас свежий Vim (8.0 и новее) и он скомпилирован
с опцией +terminal, то это довольно просто:
This feature is for running a terminal emulator in a Vim window. A job can be
started connected to the terminal emulator. For example, to run a shell:
:term bash
Or to run build command:
:term make myprogram
The job runs asynchronously from Vim, the window will be updated to show
output from the job, also while editing in another window.
Документация.
Чтобы посмотреть версию Vim и опции компиляции: |
package de.martinmois.amazon.rekognition.actions;
import com.amazonaws.services.rekognition.AmazonRekognitionClient;
import com.amazonaws.services.rekognition.model.DeleteCollectionRequest;
import com.amazonaws.services.rekognition.model.DeleteCollectionResult;
import de.martinmois.amazon.rekognition.util.AmazonClientFactory;
import java.util.logging.Level;
import java.util.logging.Logger;
public class DeleteCollection {
private static final Logger LOGGER = Logger.getLogger(DeleteCollection.class.getName());
public void run(String[] args) {
if (args.length < 2) {
LOGGER.log(Level.SEVERE, "Please provide the following arguments: <collection-name>");
return;
}
try {
AmazonRekognitionClient client = AmazonClientFactory.createClient();
DeleteCollectionRequest deleteCollectionRequest = new DeleteCollectionRequest();
deleteCollectionRequest.setCollectionId(args[1]);
DeleteCollectionResult result = client.deleteCollection(deleteCollectionRequest);
LOGGER.log(Level.INFO, "Status Code: " + result.getStatusCode());
} catch (Exception e) {
LOGGER.log(Level.SEVERE, "Failed to delete collection: " + e.getLocalizedMessage());
}
}
}
|
/**
* Displays a message to the user.
*
* @param dialog the dialog
*/
public static void startDialog(Dialog dialog) {
if (instance == null) {
instance = new DialogManager();
}
instance.dialogQueue.add(dialog);
} |
// ListReleases will list releases in a bucket.
// If 'version' is provided, the list will be filtered to only releases with
// the specified version.
// If 'version' AND 'gitRef' are provided, the list will be filtered to only
// releases with the specified version built at the specified commit ref.
// Specifying 'gitRef' without 'version' is not supported.
func (b *Bucket) ListReleases(ctx context.Context, version, gitRef string) ([]Staged, error) {
stagedReleases := map[string][]*storage.ObjectHandle{}
objs := b.bucket.Objects(ctx, &storage.Query{Prefix: b.prefix + pathSuffixForVersion(version, gitRef)})
for {
objAttr, err := objs.Next()
if err == iterator.Done {
break
}
if err != nil {
return nil, err
}
obj := b.bucket.Object(objAttr.Name)
releaseName := NameForObjectPath(obj.ObjectName(), b.prefix)
stagedReleases[releaseName] = append(stagedReleases[releaseName], obj)
}
var staged []Staged
for name, objs := range stagedReleases {
rel, err := NewStagedRelease(name, b.prefix, objs...)
if err != nil {
log.Errorf("Failed to load staged release: %v", err)
continue
}
staged = append(staged, *rel)
}
return staged, nil
} |
Failure mode and effects analysis for proactive healthcare risk evaluation: A systematic literature review. RATIONALE, AIMS, AND OBJECTIVES Failure mode and effects analysis (FMEA) is a valuable reliability management tool that can preemptively identify the potential failures of a system and assess their causes and effects, thereby preventing them from occurring. The use of FMEA in the healthcare setting has become increasingly popular over the last decade, being applied to a multitude of different areas. The objective of this study is to review comprehensively the literature regarding the application of FMEA for healthcare risk analysis. METHODS An extensive search was carried out in the scholarly databases of Scopus and PubMed, and we only chose the academic articles which used the FMEA technique to solve healthcare risk analysis problems. Furthermore, a bibliometric analysis was performed based on the number of citations, publication year, appeared journals, authors, and country of origin. RESULTS A total of 158 journal papers published over the period of 1998 to 2018 were extracted and reviewed. These publications were classified into four categories (ie, healthcare process, hospital management, hospital informatization, and medical equipment and production) according to the healthcare issues to be solved, and analyzed regarding the application fields and the utilized FMEA methods. CONCLUSION FMEA has high practicality for healthcare quality improvement and error reduction and has been prevalently employed to improve healthcare processes in hospitals. This research supports academics and practitioners in effectively adopting the FMEA tool to proactively reduce healthcare risks and increase patient safety, and provides an insight into its state-of-the-art. |
//
// UIColor+Hex.h
// NovelReader
//
// Created by 沈红榜 on 2019/12/16.
// Copyright © 2019 沈红榜. All rights reserved.
//
#import <UIKit/UIKit.h>
NS_ASSUME_NONNULL_BEGIN
@interface UIColor (Hex)
+ (UIColor *)colorWithHex:(NSUInteger)hex;
@end
NS_ASSUME_NONNULL_END
|
import numpy as np
import matplotlib.pyplot as plt
from mpl_toolkits.mplot3d import Axes3D
from minisom import MiniSom
from pylab import bone, pcolor, colorbar, plot, show
from skimage import measure
def computeSOM():
points = []
lines = [line.rstrip('\n') for line in open('breast.txt')]
for i in range(len(lines)):
split = lines[i].split()
point = []
for j in range(len(split)):
point.append(float(split[j]))
points.append(point)
maxs = 0
for i in range(len(points)):
maxL = max(points[i])
if maxL > maxs:
maxs = maxL
for i in range(len(points)):
for j in range(len(points[i])):
points[i][j]=points[i][j]/maxs
som = MiniSom(30, 30, 9, sigma=0.5, learning_rate=0.7, random_seed=3)
print("Training...")
som.train_batch(points, 3000, verbose=True) # random training
print("\n...ready!")
bone()
pcolor(som.distance_map().T, cmap='gist_heat')
colorbar()
for i, x in enumerate(points):
w = som.winner(x)
plot(w[0], w[1])
show()
plt.figure(figsize=(30, 30))
# Plotting the response for each pattern in the iris dataset
plt.pcolor(som.distance_map().T, cmap='gist_heat') # plotting the distance map as background
#plt.colorbar()
for cnt, xx in enumerate(points):
w = som.winner(xx) # getting the winner
# palce a marker on the winning position for the sample xx
plt.plot(w[0]+.5, w[1]+.5, 'D', markerfacecolor='None',
markeredgecolor='C1', markersize=12, markeredgewidth=2)
plt.axis([0, 30, 0, 30])
plt.show()
plt.figure(figsize=(30, 30))
# Plotting the response for each pattern in the iris dataset
dists = som.distance_map().T.copy()
for i in range(len(dists)):
for j in range(len(dists[i])):
if dists[i][j]<0.5:
dists[i][j] = 1
else:
dists[i][j] = 0
for i in range(len(dists)):
for j in range(len(dists[i])):
dists[i][0] = 0
dists[i][len(dists)-1] = 0
dists[0][j] = 0
dists[len(dists[i])-1][j] = 0
plt.pcolor(dists, cmap='gist_heat') # plotting the distance map as background
all_labels = measure.label(dists)
blobs_labels = measure.label(dists, background=0)
plt.pcolor(blobs_labels, cmap='gist_heat') # plotting the distance map as background
plt.plot()
memberships = []
for cnt, xx in enumerate(points):
w = som.winner(xx) # getting the winner
memberships.append(all_labels[w[0],w[1]])
return memberships
def computeDistance(points, centers, j, k):
dxi = [0 for i in range(len(points))]
distSum = 0
for i in range(len(dxi)):
dxi[i] = points[i][j] - centers[i][k]
distSum += dxi[i] ** 2
return np.sqrt(distSum)
def computeMemberships(points, centers, N, C):
memberships = []
for j in range(N):
nearest = 0
min_distance = computeDistance(points, centers, j, 0)
for k in range(1, C):
distance = computeDistance(points, centers, j, k)
if distance < min_distance:
min_distance = distance
nearest = k
memberships.append(nearest)
return memberships
def computeCentersMemberships(points, centers, N, C, memberships):
centersMemberships = []
for j in range(C):
nearest = 0
min_distance = computeDistance(points, centers, 0, j)
for k in range(1, N):
distance = computeDistance(points, centers, k, j)
if distance < min_distance:
min_distance = distance
nearest = memberships[k]
centersMemberships.append(nearest)
return centersMemberships
def computeNewCenters(points, memberships, C):
new_centers = [[0] * C for i in range(len(points))]
for center in range(C):
sums = [0 for i in range(len(points))]
amount = 0
for mem in range(len(memberships)):
if memberships[mem] == center:
for i in range(len(points)):
sums[i] += points[i][mem]
amount += 1
if amount != 0:
for i in range(len(points)):
new_centers[i][center] = sums[i] / amount
return new_centers
def checkCondition(centers, new_centers, C, epsilon):
for i in range(C):
distance = computeDistance(new_centers, centers, i, i)
# print(distance)
if distance > epsilon:
return True
else:
if i == C - 1:
return False
def KMeans(points, C, centers, epsilon=0.1, show=True):
N = len(points[0])
iterations = True
# if show:
# memberships = computeMemberships(points, centers, N, C)
# # group all points by their current memberships to cluster centers
# centersMemberships = computeCentersMemberships(points, centers, N, C, memberships)
#
# # plotClustersMemberships(memberships, x, y, centersMemberships, centersX, centersY)
new_centers = [[0]*C for i in range(len(points))]
while iterations:
memberships = computeMemberships(points, centers, N, C)
# compute new positions of cluster centers
new_centers = computeNewCenters(points, memberships, C)
# check if every cluster center moved distance is smaller than epsilon
iterations = checkCondition(centers, new_centers, C, epsilon)
centers = new_centers
# group all points by their current memberships to cluster centers
memberships = computeMemberships(points, centers, N, C)
# group all points by their current memberships to cluster centers
centersMemberships = computeCentersMemberships(points, centers, N, C, memberships)
# if show:
# plotClustersEpoch(memberships, x, y, centersMemberships, new_centersX, new_centersY, centersX, centersY)
#centers = new_centers
return points, memberships, centers, centersMemberships
def plot_breast2(points, memberships):
fig = plt.figure()
axs = []
for i in range(1,4):
axs.append(fig.add_subplot(130+i, projection='3d'))
for i in range(3):
axs[i].scatter(points[i*3], points[i*3+1], points[i*3+2], c=memberships, s=20, cmap='gist_rainbow')
axs[i].set_xlabel(str(i*3))
axs[i].set_ylabel(str(i*3+1))
axs[i].set_zlabel(str(i*3+2))
plt.show()
def plot_breast(points, memberships, centers, centersMemberships):
from itertools import permutations
dimensions = [i for i in range(9)]
perm = permutations(dimensions, 3)
good = []
for permutation in list(perm):
if set(permutation) not in good:
good.append(set(permutation))
# print(len(list(good)))
# exit()
figs = [plt.figure(), plt.figure()]
for k in range(2):
# fig = plt.figure()
axs = []
for i in range(1, int(len(good)/2+1)):
axs.append(figs[k].add_subplot(6, 7, i, projection='3d'))
for i in range(int(len(good)/2)):
one, two, three = list(good[k*int(len(good)/2) + i])[0], list(good[k*int(len(good)/2) + i])[1], list(good[k*int(len(good)/2) + i])[2]
axs[i].scatter(points[one], points[two], points[three], c=memberships, s=20, cmap='gist_rainbow')
axs[i].scatter(centers[one], centers[two], centers[three], c='black', s=100)
axs[i].scatter(centers[one], centers[two], centers[three], c=centersMemberships, s=50, cmap='gist_rainbow')
axs[i].set_xlabel(str(one))
axs[i].set_ylabel(str(two))
axs[i].set_zlabel(str(three))
plt.show()
def parallelCoordinates(points, membershipsSOM):
colors = ['r', 'g', 'b', 'k', 'c', 'm', 'y', 'k', 'w']
for i in range(len(points[0])): # wymiar i
x = []
y = []
for j in range(len(points)):
x.append(j)
y.append(points[j][i]) # konkretny punkt w wymiarze i
plt.plot(x, y, c=colors[membershipsSOM[i]])
plt.show()
def load_data(path='breast.txt'):
lines = [line.rstrip('\n') for line in open(path)]
points = [[] for i in range(len(lines[0].split()))]
for i in range(len(lines)):
split = lines[i].split()
for j in range(len(split)):
points[j].append(float(split[j]))
centers = [[] for i in range(len(points))]
C = 2
for i in range(C):
for j in range(len(centers)):
centers[j].append(np.random.randint(min(points[j]), max(points[j])))
return points, centers, C
membershipsSOM = computeSOM()
points, centers, C = load_data()
# points, memberships, centers, centersMemberships = KMeans(points, C, centers, epsilon=0.1, show=True)
# plot_breast(points, memberships, centers, centersMemberships)
plot_breast2(points, membershipsSOM)
parallelCoordinates(points, membershipsSOM) |
Grammy-winning rapper Lupe Fiasco is taking a unique approach to promoting his new Drogas Wave album. The hip-hop veteran has announced his plans to fall back on doing media and press runs with the LP dropping this Friday.
Lupe went to Twitter this week to explain his disinterest in doing a traditional promo rollout for the long-awaited studio effort.
Barring any last-minute changes, Lupe is putting out his latest solo project tomorrow.
Barring any last-minute changes, Lupe’s new 24-song LP features a handful of collaborations.
Today marks the 12-year anniversary of the Chicago rap veteran’s Food & Liquor debut album. |
All brick 3br, 2ba home centrally located in the Huntington Ridge subdivision just minutes to shopping, restaurants, and schools. This home features split bedrooms, separate formal dining, and eat in breakfast area. The kitchen, formal dining area, and the living room are all open. There is a privacy fenced backyard with a screened porch and an open patio. The kitchen offers warm wood cabinets, stainless steel appliances, and tile floors. Tucked away off the kitchen area you will find the master bedroom and bathroom with large jacuzzi tub, double vanities, and separate shower. Sizes are all approx. and taken from public sources, please verify if important. |
Cognitive decline and the default American lifestyle. OBJECTIVES Upward trends in IQ, education, and mental work suggest that cognitive function among seniors should be rising strongly across cohorts. There is little sign of such improvement in recent decades, and some analyses find poorer function in the newer cohorts. This essay explores possible explanations of the anomaly. METHODS Major long-term trends that might increase cognitive impairment are reviewed, and their implications are considered. RESULTS Physical activity is declining, food is increasingly manufactured, body fat is increasing, diabetes and metabolic syndrome are on the rise, the number of prescription drugs per person is increasing, and the proportion of the population either old or obese is growing. DISCUSSION Technological and economic development may lower the cognitive function needed for survival. They also lower physical activity in daily life. Sedentary work, transportation, and leisure undermine the aerobic and metabolic fitness required for the brain to perform well. Some prescription drugs impair cognitive function, and others do so when taken for many years or in combination with others. The growing fraction of the population that is either old or obese may further lower physical activity norms and requirements and substitute medical intervention for health, accelerating a trend toward cognitive impairment. |
import { Percent as V2Percent, Trade as TradeV2 } from '@uniswap/sdk'
import {
Percent,
Token as UniswapToken,
TokenAmount,
TradeType,
} from '@uniswap/sdk-core'
import { FeeAmount } from '@uniswap/v3-sdk'
import {
contractAddresses,
isAddress,
Token,
VanillaVersion,
} from '@vanilladefi/core-sdk'
import { VanillaV1Router02__factory } from '@vanilladefi/trade-contracts/typechain/vanilla_v1.1/factories/VanillaV1Router02__factory'
import { BigNumber, ethers, providers, Signer } from 'ethers'
import { formatUnits, getAddress } from 'ethers/lib/utils'
import {
blockDeadlineThreshold,
chainId,
epoch,
usdcWethPoolAddress,
vnlDecimals,
} from './contracts'
import {
convertVanillaTokenToUniswapToken,
getAllTokens,
usdc,
weth,
} from './tokens'
import vanillaRouter from './types/abis/vanillaRouter.json'
import {
Operation,
RewardEstimate,
RewardResponse,
TokenPriceResponse,
V3Trade,
} from './types/trade'
import {
constructTrade as constructV2Trade,
tryParseAmount,
} from './uniswap/v2/trade'
import { getSpotPrice } from './uniswap/v3/spotPrice'
import { constructTrade as constructV3Trade } from './uniswap/v3/trade'
/**
* Queries the Vanilla router for eligible rewards if given token was
* sold now and with given price
*
* @param version - Vanilla version
* @param owner - token owner address
* @param signerOrProvider - an ethersjs signer(read/write) or provider(readonly)
* @param tokenSold - The sold token in Vanilla's token format
* @param tokenReceived - The received token in Vanilla's token format
* @param amountSold - Unparsed amount sold as a decimal string
* @param amountReceived - Unparsed amount received as a decimal string
* @returns the amount of rewards ($VNL) the trade would result in
*/
export const estimateReward = async (
version: VanillaVersion,
owner: string,
signerOrProvider: Signer | providers.Provider,
tokenSold: Token,
tokenReceived: Token,
amountSold: string,
amountReceived: string,
): Promise<RewardResponse | null> => {
const [parsedAmountSold, parsedAmountReceived] = [
tryParseAmount(amountSold, tokenSold),
tryParseAmount(amountReceived, tokenReceived),
]
let reward: RewardResponse | null = null
if (
parsedAmountReceived &&
parsedAmountSold &&
parsedAmountReceived.greaterThan('0') &&
parsedAmountSold.greaterThan('0') &&
isAddress(owner)
) {
const router =
version === VanillaVersion.V1_0
? new ethers.Contract(
contractAddresses.vanilla[VanillaVersion.V1_0]?.router || '',
JSON.stringify(vanillaRouter.abi),
signerOrProvider,
)
: VanillaV1Router02__factory.connect(
contractAddresses.vanilla[VanillaVersion.V1_1]?.router || '',
signerOrProvider,
)
try {
reward = await router.estimateReward(
owner,
tokenSold.address,
parsedAmountReceived?.raw.toString(),
parsedAmountSold?.raw.toString(),
)
} catch (e) {
console.error('estimateReward', e)
reward = null
}
}
return reward
}
/**
* Get the pricedata struct that contains the average price and block number of
* a token, together with the owned amount.
*
* @param version - Vanilla version
* @param owner - token owner address
* @param signerOrProvider - an ethersjs signer(read/write) or provider(readonly)
* @param tokenAddress - token contract address
* @returns Vanilla token data for given owner
*/
export const getPriceData = async (
version: VanillaVersion,
owner: string,
signerOrProvider: Signer | providers.Provider,
tokenAddress: string,
): Promise<TokenPriceResponse | null> => {
const router =
version === VanillaVersion.V1_0
? new ethers.Contract(
contractAddresses.vanilla[VanillaVersion.V1_0]?.router || '',
JSON.stringify(vanillaRouter.abi),
signerOrProvider,
)
: VanillaV1Router02__factory.connect(
contractAddresses.vanilla[VanillaVersion.V1_1]?.router || '',
signerOrProvider,
)
let priceData: TokenPriceResponse | null
try {
priceData = await router.tokenPriceData(owner, tokenAddress)
} catch (e) {
priceData = null
}
return priceData
}
/**
* Estimates gas for given trade
*
* @param version - Vanilla version
* @param trade - A Vanilla trade object
* @param signerOrProvider - an ethersjs signer(read/write) or provider(readonly)
* @param operation - Buy/Sell
* @param token0 - The bought token (Buy) or the sold token (Sell)
* @param slippageTolerance - Allowed slippage for the trade
* @returns Estimated gas limit in wei
*/
export const estimateGas = async (
version: VanillaVersion,
trade: TradeV2 | V3Trade,
signerOrProvider: Signer | providers.Provider,
operation: Operation,
token0: Token,
slippageTolerance: Percent | V2Percent,
): Promise<BigNumber> => {
const routerV1_0 = new ethers.Contract(
contractAddresses.vanilla[VanillaVersion.V1_0]?.router || '',
JSON.stringify(vanillaRouter.abi),
signerOrProvider,
)
const routerV1_1 = VanillaV1Router02__factory.connect(
contractAddresses.vanilla[VanillaVersion.V1_1]?.router || '',
signerOrProvider,
)
let gasEstimate: BigNumber = BigNumber.from('0')
try {
if (signerOrProvider && trade) {
let block: providers.Block
const signer = signerOrProvider as Signer
if (signer && signer.provider) {
block = await signer.provider.getBlock('latest')
} else {
const provider = signerOrProvider as providers.Provider
block = await provider.getBlock('latest')
}
const blockDeadline = block.timestamp + blockDeadlineThreshold
const gasPrice = await signerOrProvider.getGasPrice()
if (version === VanillaVersion.V1_0 && routerV1_0) {
const normalizedSlippageTolerance = new V2Percent(
slippageTolerance.numerator,
slippageTolerance.denominator,
)
const normalizedTrade = trade as TradeV2
if (operation === Operation.Buy) {
gasEstimate = await routerV1_0.estimateGas.depositAndBuy(
token0.address,
normalizedTrade
?.minimumAmountOut(normalizedSlippageTolerance)
.raw.toString(),
blockDeadline,
{
value: normalizedTrade?.inputAmount.raw.toString(),
gasPrice: gasPrice,
},
)
} else {
gasEstimate = await routerV1_0.estimateGas.sellAndWithdraw(
token0.address,
normalizedTrade?.inputAmount.raw.toString(),
normalizedTrade
?.minimumAmountOut(normalizedSlippageTolerance)
.raw.toString(),
blockDeadline,
{
gasPrice: gasPrice,
},
)
}
} else if (version === VanillaVersion.V1_1 && routerV1_1) {
const normalizedTrade = trade as V3Trade
const normalizedSlippageTolerance = slippageTolerance as Percent
if (operation === Operation.Buy) {
const buyOrder = {
token: token0.address,
useWETH: false,
numEth: normalizedTrade.inputAmount.raw.toString(),
numToken: normalizedTrade
.minimumAmountOut(normalizedSlippageTolerance)
.raw.toString(),
blockTimeDeadline: blockDeadline,
fee: 3000,
}
gasEstimate = await routerV1_1.estimateGas.executePayable(
[routerV1_1.interface.encodeFunctionData('buy', [buyOrder])],
{
value: normalizedTrade.inputAmount.raw.toString(),
gasPrice: gasPrice,
},
)
} else {
const sellOrder = {
token: token0.address,
useWETH: false,
numEth: normalizedTrade
.minimumAmountOut(normalizedSlippageTolerance)
.raw.toString(),
numToken: normalizedTrade.inputAmount.raw.toString(),
blockTimeDeadline: blockDeadline,
fee: 3000,
}
gasEstimate = await routerV1_1.estimateGas.executePayable(
[routerV1_1.interface.encodeFunctionData('sell', [sellOrder])],
{ gasPrice: gasPrice },
)
}
}
}
} catch (e) {
console.error('estimateGas', e)
}
return gasEstimate
}
/**
* Adds a reasonable threshold on top of
* estimated gas limits to guarantee execution
*
* @param value - estimated gas limit
* @returns gas limit with added threshold in wei
*/
export function calculateGasMargin(value: BigNumber): BigNumber {
return value.mul(BigNumber.from(10000 + 2500)).div(BigNumber.from(10000))
}
/**
* Gets user positions with embedded
* price data in Vanilla's token format
*
* @param version - Vanilla version
* @param address - user address
* @param tokens - list of tokens to query in Vanilla's token format
* @param provider - an ethersjs provider (readonly)
* @returns tokens with price data
*/
export async function getUserPositions(
version: VanillaVersion,
address: string,
tokens?: Token[],
provider?: providers.Provider,
): Promise<Token[]> {
const checkSummedAddress = isAddress(address)
const million = 1000000
const allTokens = tokens || getAllTokens(version)
const [ETHPrice] = await getSpotPrice(
usdcWethPoolAddress,
convertVanillaTokenToUniswapToken(usdc),
convertVanillaTokenToUniswapToken(weth),
)
let positions: Token[] = []
if (checkSummedAddress && vanillaRouter) {
positions = await Promise.all(
allTokens.map(async (token) => {
// Fetch price data from Vanilla router
let tokenSum: BigNumber = BigNumber.from(0)
const priceResponse: TokenPriceResponse | null = await getPriceData(
version,
checkSummedAddress,
provider || providers.getDefaultProvider(),
token.address,
)
if (priceResponse) {
tokenSum = priceResponse.tokenSum
if (!tokenSum.isZero()) {
// VNL governance token
const vnlToken = new UniswapToken(
chainId,
getAddress(contractAddresses.vanilla[version]?.vnl || ''),
vnlDecimals,
)
// Construct helpers for upcoming calculations
const parsedUniToken = new UniswapToken(
Number(token.chainId),
getAddress(token.address),
Number(token.decimals),
)
// Construct token amount from Vanilla router reported amounts
const tokenAmount = new TokenAmount(
parsedUniToken,
tokenSum.toString(),
)
// Owned amount. By default, use the total owned amount.
// If zero, exclude from user's owned tokens
const parsedOwnedAmount = tokenAmount.greaterThan('0')
? tokenAmount.toSignificant()
: undefined
// Parse value of owned token in USD
const parsedValue =
tokenAmount.greaterThan('0') && token.price
? parseFloat(tokenAmount.toSignificant()) *
token.price *
Number(ETHPrice.toSignificant(3))
: 0
// Get current best trade from Uniswap to calculate available rewards
let trade: TradeV2 | V3Trade | null = null
try {
if (version === VanillaVersion.V1_0) {
trade = await constructV2Trade(
provider || providers.getDefaultProvider(),
tokenAmount.toSignificant(),
weth,
token,
TradeType.EXACT_INPUT,
)
} else if (version === VanillaVersion.V1_1) {
trade = await constructV3Trade(
provider || providers.getDefaultProvider(),
tokenAmount.toSignificant(),
weth,
token,
TradeType.EXACT_INPUT,
)
}
} catch (e) {
console.error('Could not construct trade: ', e)
}
// Amount out from the trade as a Bignumber gwei string and an ether float
const amountOut = trade?.outputAmount.raw ?? undefined
const parsedAmountOut =
amountOut && formatUnits(amountOut.toString(), weth.decimals)
let reward: RewardResponse | null = null
// Get reward estimate from Vanilla router
reward = parsedAmountOut
? await estimateReward(
version,
address,
provider || providers.getDefaultProvider(),
token,
weth,
tokenAmount.toSignificant(),
parsedAmountOut,
)
: null
let vpc: string | null = null
if (reward?.vpc) {
// Parse VPC
const vpcNum = reward?.vpc.toNumber() ?? 0
vpc = (vpcNum / million).toString()
}
// Calculate HTRS
const priceData = await getPriceData(
version,
address,
provider || providers.getDefaultProvider(),
token.address,
)
const blockNumber = await (
provider || providers.getDefaultProvider()
).getBlockNumber()
const avgBlock =
priceData?.weightedBlockSum.div(priceData?.tokenSum) ??
BigNumber.from('0')
const bhold = BigNumber.from(blockNumber.toString()).sub(avgBlock)
const btrade = epoch
? BigNumber.from(blockNumber.toString()).sub(epoch)
: BigNumber.from('0')
let htrs = '0'
try {
htrs = (
bhold
.mul(bhold)
.mul(million)
.div(btrade.mul(btrade))
.toNumber() / million
).toString()
} catch (e) {
console.error('Could not calculate HTRS: ', e)
}
// Parse the minimum profitable price from the reward estimate
let profitablePrice: string | undefined
let usedEstimate: keyof RewardEstimate = 'medium'
if (version === VanillaVersion.V1_0 && reward?.profitablePrice) {
profitablePrice = formatUnits(reward.profitablePrice)
} else if (version === VanillaVersion.V1_1 && reward?.estimate) {
switch (Number(token.fee)) {
case FeeAmount.LOW:
usedEstimate = 'low'
break
case FeeAmount.MEDIUM:
usedEstimate = 'medium'
break
case FeeAmount.HIGH:
usedEstimate = 'high'
break
default:
usedEstimate = 'medium'
}
profitablePrice = formatUnits(
reward?.estimate[usedEstimate].profitablePrice,
)
}
// Calculate profit percentage
let profitPercentage = 0
try {
profitPercentage =
reward && profitablePrice && parsedAmountOut
? -(
parseFloat(profitablePrice) - parseFloat(parsedAmountOut)
) / parseFloat(profitablePrice)
: 0
} catch (e) {
console.error(
'Could not calculate profit percentage. Falling back to 0: ',
e,
)
}
// Parse the available VNL reward
let parsedVnl = 0
if (version === VanillaVersion.V1_0 && reward?.reward) {
parsedVnl = parseFloat(
new TokenAmount(
vnlToken,
reward.reward.toString(),
).toSignificant(),
)
} else if (version === VanillaVersion.V1_1 && reward?.estimate) {
parsedVnl = parseFloat(
new TokenAmount(
vnlToken,
reward.estimate[usedEstimate].reward.toString(),
).toSignificant(),
)
}
return {
...token,
owned: parsedOwnedAmount,
ownedRaw: tokenAmount.raw.toString(),
value: parsedValue,
htrs: htrs,
vpc: vpc,
profit: profitPercentage,
vnl: parsedVnl,
}
} else {
return token
}
} else {
return token
}
}),
)
positions = positions.filter((token) => token.owned)
}
return positions
}
|
CircPSMC3 suppresses the proliferation and metastasis of gastric cancer by acting as a competitive endogenous RNA through sponging miR-296-5p Background Circular RNAs (circRNAs) are a class of non-coding RNAs with a loop structure, but its functions remain largely unknown. Growing evidence has revealed that circRNAs play a striking role as functional RNAs in the progression of malignant disease. However, the precise role of circRNAs in gastric cancer (GC) remains unclear. Methods CircRNAs were determined by human circRNA array analysis and quantitative reverse transcription polymerase reaction. Luciferase reporter, RNA pull down, and fluorescence in situ hybridization assays were employed to test the interaction between circPSMC3 and miR-296-5p. Ectopic over-expression and siRNA-mediated knockdown of circPSMC3, proliferation, migration and invasion in vitro, and in vivo experiment of metastasis were used to evaluate the function of circPSMC3. Results CircPSMC3 rather than liner PSMC3 mRNA was down-regulated in GC tissues, corresponding plasmas from GC patients as well as GC cell lines compared to normal controls. Lower circPSMC3 expression in GC patients was correlated with higher TNM stage and shorter overall survival. Over-expression of circPSMC3 and miR-296-5p inhibitor could inhibit the tumorigenesis of gastric cancer cells in vivo and vitro whereas co-transfection of circPSMC3 and miRNA-296-5p could counteract this effect. Importantly, we demonstrated that circPSMC3 could act as a sponge of miR-296-5p to regulate the expression of Phosphatase and Tensin Homolog (PTEN), and further suppress the tumorigenesis of gastric cancer cells. Conclusion Our study reveals that circPSMC3 can serve as a novel potential circulating biomarker for detection of GC. CircPSMC3 participates in progression of gastric cancer by sponging miRNA-296-5p with PTEN, providing a new insight into the treatment of gastric cancer. Electronic supplementary material The online version of this article (10.1186/s12943-019-0958-6) contains supplementary material, which is available to authorized users. Introduction Gastric cancer (GC) is the fifth most common cancer in the world and the third most common cause of cancer death worldwide. It tends to metastasize into neighboring tissues and organs through lymph nodes and generate more cancer cells through the blood. Although there have been many advancements in the diagnosis and treatment of GC, recurrence and metastasis are still occurring at high rates. Improvements in clinical care for these patients are limited by the lack of clarity surrounding the molecular mechanism in GC development. Thus, it is urgently necessary to explore new potential biomarkers and their molecular mechanisms to better understand the pathophysiology of gastric malignancies. Circular RNAs (circRNAs) are a new class of endogenous non-coding RNAs characterized by covalently closed loops without 5 to 3 polar or polyadenylation tails. Previous studies have shown that circRNAs are formed by the back-splicing of pre-mRNA transcripts from genes with five different forms. CircRNAs are stable, conserved and abundant in various cancer tissues or cell lines, as tissue/developmental stage-specific circRNAs are usually notable. Kuei-Yang Hsiao et al. found that circRNA CCDC66 could promote the progression and metastasis of colon cancer. Studies on the molecular mechanism of circRNAs indicate that circRNAs can act as a competitive endogenous RNA (ceRNA) to regulate downstream genes associated with diseases by binding to miRNAs. Xuetao Cao et al. found that circMTO1 might regulate the progression of hepatocellular carcinoma (HCC) by regulating the expression of p21 as a sponge of oncogenic miR-9, which can be used as a potential target for HCC therapy and a prognostic indicator for low patient survival. Zhenyu Zhong et al. indicated that circMYLK could act as ceRNA of miR-29a, further promoting the progression of Epithelial-Mesenchymal Transition (EMT) in bladder cancer by activating VEGFA/VEGFR2 and Ras/ERK signaling pathways. MicroRNAs (miRNAs), as a conserved small regulatory non-coding RNA, have been demonstrated to involve many biological functions in different diseases. Many studies have reported that miRNAs can regulate by different circRNAs and lncRNAs to further regulate gene expression. Yawei Li et al. found that circHIPK3, which contains two key binding sites of miR-558, directly regulates miR-558 function to inhibit heparanase (HPSE) expression. Their findings suggest that circHIPK3 acts as a "miRNA sponge" and identifies circHIPK3 as a new therapeutic target for patients with bladder cancer. In this study, based on the results of circRNA arrays, we identified a circular RNA termed circPSMC3 derived from PSMC3 gene. CircPSMC3 was down-regulated in tissues, corresponding plasmas from GC patients as well as GC cell lines and could act as a sponge of miRNA-296-5p to regulate the expression of Phosphatase and Tensin Homolog (PTEN), and further suppress the tumorigenesis of GC cells. Our findings provide insight into the treatment of gastric cancer and reveal a novel potential circulating biomarker for detection of GC. Cell cultures and patient tissues Human gastric cancer cell lines (BGC823, MGC803, SGC7901, AGS, and MKN45) were purchased from Shanghai Institutes for Biological Sciences, China. The human gastric epithelial cell line GES-1 was obtained from the Cancer Institute and Hospital of the Chinese Academy of Medical Sciences (Beijing, China). All cell lines were cultured in RPMI 1640 medium (Gibco, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum (Gibco, Vienna, Austria) and in a humidified incubator containing 5% CO 2 at 37°C. One hundred and-six samples of GC tissues were matched to adjacent normal tissues and 10 ml preoperative blood venous blood were collected from the GC patients treated in Department of General Surgery, Nanjing Hospital, Nanjing Medical University during 2013 to 2016 in accordance with the Helsinki Declaration. Twenty-one samples of 10 ml normal venous blood were randomly obtained from the 50-90 years old individuals without any underlying diseases in physical examination center of Nanjing Hospital during 2015 to 2016. All these specimens were frozen in liquid nitrogen and stably stored at − 80°C until RNA extraction. Histological and pathological diagnoses of these specimens were confirmed and classified by two experienced clinical pathologists. Informed consent from these patients has been obtained before specimen collection. This project was approved by the Ethics Committee of Nanjing Medical University. Quantitative reverse transcription polymerase reaction (qRT-PCR) According to the manufacturer's protocol, total RNAs from tissues, plasma and cells were isolated by using TRIzol reagent (Invitrogen, CA, USA). For circRNA and mRNA, cDNA was synthesized by using reverse transcription kit (Takara, Otsu, Japan) and for miRNA, total RNAs were reversed using RiboBio reverse transcription kit (Guangzhou, China). Quantification of mRNA and circular RNA was performed by using a SYBR Green PCR Kit (Takara, Otsu, Japan), and miRNA PCR was performed by using a SYBR Green PCR Kit (RiboBio,Guangzhou, China). All primer sequences were designed and synthesized by Genery (Nanjing, China). CircPSMC3 expression level was detected using the following primer pair: 5-GTTTAGGGTCCCTGCCCTTTG-3 (Forward, or F) and 5-GTGTTGGGCTGGAAGCCATC-3 (Reverse, or R). The primer pair of PSMC3 is 5-AGACGCTGC CCACAGAGTATG -3 (F) and 5-CTTTTGGAG GTTGGATCCCC-3 (R). GAPDH was used to normalize the mRNA and circRNA expression levels and U6 was used to normalize the miRNA expression levels before calculation. RNase R treatment Total RNA (10 g) of gastric cancer cell lines was mixed with 40 U RNase R at 37°C for 2 h. To assess the stability of circPSMC3 and line PSMC3 mRNA, the expression levels were determined by using qRT-PCR. Plasmids construction and stable transfection To isolate stable human gastric cancer cells over-expressing circPSMC3, circPSMC3 cDNA was synthesized cloned into pcD-ciR and pcDNA3 vector and lentivirus (Hanheng, Shanghai, China). According to the manufacturer's instructions, human gastric cancer cell lines, MGC803 and BGC823 were infected with lentivirus at a multiplicity of infection of 50. All cell lines were followed by selection with 2 g/mL puromycin for 2 weeks. Luciferase reporter assay The wild-type and mutant fragments in 3-UTR of circPSMC3 related with miRNA-296-5p binding site were designed, synthesized and inserted into pGL3-basic vectors (Realgene, Nanjing, China), then pGL3-basic vectors and miRNA-296-5p mimics or inhibitor or circPSMC3 overexpressing lentivirus were co-transfected to 293 T cell respectively. After 48 h, according to the manufacturer's instructions, luciferase activity in co-transfected cells were collected and detected by the dual-luciferase reporter assay system (Promega). Biotin-coupled probe RNA pull down assay Biotin-coupled probe RNA pull down assay was performed. To pull down the miRNA by circRNA, MGC803 and BGC823 with transfected with miRNA-296-5p mimics were lysed and incubated with Biotin-coupled probe of circPSMC3 which was pre-bound on magnetic beads. For 2 h, target RNA was pulled by the RNeasy Mini Kit (QIA-GEN, Germany). Then the pull-down product was extracted, reversed and placed through q-PCR. To pull down the circRNA by miRNA, MGC803 and BGC823 with circPSMC3 over-expression and Biotin-coupled probe of miRNA-296-5p were processed through the same protocol. Fluorescence in situ hybridization (FISH) The fluorescence in situ hybridization assay was performed to detect the presence of circPSMC3 and miRNA-296-5p by using Fluorescence in Situ Hybridization Kit (RiboBio, Guangzhou, China). CircPSMC3 was captured with Cy5-labeled probe and miRNA-296-5p was captured with Cy3-labeled probe respectively. After prehybridization, circPSMC3 probe and miRNA-296-5p probe were hybridized in prepared hybridization buffer in MGC803 cells. Nuclei were marked by staining with 4,6-diamidino-2-phenylindole (DAPI). Confocal microscopy was used to better visualize the presence of circPSMC3 and miRNA-296-5p. Cell counting kit-8 proliferation assay and 5-Ethynyl-20deoxyuridine (EdU) incorporation assay GC cells were seeded in 96 wells with the density of 4000 cells per well. Seeded cells were treated with 10 l of CCK8 solution (Ribobio, Guangzhou, China) after cultured at 0 h, 24 h, 48 h, 72 h, 96 h, respectively. Then the absorbance of cells at each time was analyzed at 450 nM by microplate reader according to the manufacturer's instructions (Synergy4; BioTek, Winooski, VT, USA). The EdU assay was performed to assess the proliferation of cells by using a Cell-Light EdU DNA Cell Proliferation Kit (RiboBio, Guangzhou, China). GC cells were plated in 24 wells and were cultured for 24 h. These two cell lines were fixed using 4% paraformaldehyde after incubation with 50 mM EdU solution for 2 h. Then according to the manufacturer's protocol, cell lines were sealed with Apollo Dye Solution and Hoechst 33342 in order. The EdU cell lines were photographed and counted under an Olympus FSX100 microscope (Olympus, Tokyo, Japan). Transwell migration and invasion assays For this assay, according to the manufacturer's protocol, GC cells were seeded in upper chambers with 200 l of serum-free medium. The transwell chamber (Corning, NY, USA) was paved with matrigel mix (BD Biosciences, San Jose, CA, USA) for invasion assays and without matrigel mix for migration assays. The bottom chamber was filled with medium and 10% FBS as a gastric cancer cell chemoattractant. After incubation for 24 h, the upper chambers were fixed and then stained by crystal violet (Kaigen, Nanjing, China) for 15 min. For visualization, the cell lines were photographed and counted in different five fields. Cell apoptosis assays GC cells were stained with FITC and PI from the Annexin V-FITC/Propidium Iodide (PI) Apoptosis Detection Kit (BD Biosciences #556547). FACScan (BD Biosciences, San Jose, CA, USA) was used to analysis stained cells and all apoptosis data of different cell lines was analyzed by Flowjo V10 software (Tree Star, San Francisco, CA, USA). Xenografts in mice The animal assay was approved by the animal management committee of Nanjing Medical University, and all experimental procedures and animal care were in accordance with the institutional ethics guidelines for animal experiments. To create the xenograft tumor model, 20 5-week-old male nude mice were separated randomly into over-circPSMC3 group and NC group (n = 10 for each group). About 1 10 7 circPSMC3 over-expressing MGC803 cells were subcutaneously injected into the axilla of the nude mice respectively. The volume of all injected nude mice was measured every 3 days by using digital calipers. After 35 days, all injected nude mice were sacrificed, excised tumor weights were measured and tumor tissues were studied by hematoxylin and eosin (H&E) and IHC staining. To produce the nude mice metastasis model, 20 5-week-old male nude mice were separated randomly into over-circPSMC3 group and NC group (n = 10 for each group). About 2 10 6 circPSMC3 over-expressing MGC803 cells were tail-vein injected into 20 5-week-old male BALB/c nude mice respectively. Six weeks later, the nude mice were sacrificed; pulmonary metastases nodules were counted by three pathologists after the lungs were removed by experienced surgeons. The lungs removed were studied by using hematoxylin-eosin staining. Statistical analysis The analyses were mainly performed by using SPSS 19.0 (IBM, SPSS, and Chicago, IL, USA) and p-value < 0.05 was demarcated to be statistically significant. Comparison of continuous data was analyzed using an independent t-test between the two groups, whereas categorical data was analyzed by the chi-square test. Kaplan-Meier method was mainly used to assess the survival rate and analyzed by using log rank test. CircPSMC3 is significantly down regulated in gastric cancer and associated with poor prognosis To investigate the role of circRNAs in the development of gastric cancer, the circRNA expression signatures in gastric cancer plasma were explored by using circRNA microarray analysis using plasma samples from 10 GC patients, including 5 patients with no lymph node metastasis and the other 5 patients with lymph node metastasis, and 5 normal individuals. The result showed that 6405 circRNAs in lymph node metastasis group and normal group (Fig. 1a) and 3443 circRNA in lymph node metastasis group and no lymph node metastasis group (Fig. 1b) were significantly altered with fold change > 2.0 and P < 0.05. GO pathway analysis suggest that these differentially expressed circRNAs are relevant to several vital physiological processes, molecular functions, and critical signaling pathways in two groups ( Fig. 1c-d). We selected a total of 6 circRNAs based on the multiple fold difference in circRNA microarray and then verified the findings in a small sample of plasmas by using qRT-PCR as well as the structure, length, and source of circRNA (Additional file 1: Figure S1a). Results showed that a novel circRNA named circPSMC3, which has never been reported in previous literature, has a significantly lower expression in GC plasmas compared to normal controls, which was then picked out for further study. The spliced mature sequence length of circPSMC3 derived from the PSMC3 gene is 502 bp according to circbase database (http://www.circbase.org/) (Fig. 1e) and circPSMC3 is derived from exons, while no other subtypes of circPSMC3 are found. The stability of circPSMC3 was evaluated and results showed that circPSMC3 harbors a loop structure with the resistance to digestion by RNase R (Fig. 1f ), while PSMC3 mRNA could be degraded by RNase R (Fig. 1g). Given that the tremendous diagnostic and therapeutic role of circRNAs in GC, we explored the clinical value of circPSMC3 by detecting its expression in GC samples. Results indicated circPSMC3 had significantly lower expression in GC plasmas (Fig. 1h), tissues (Fig. 1i) and cells (Fig. 1j) compared to normal controls. In addition, circPSMC3 expression was lower in preoperative blood from GC patients with lymph node metastasis compared to those patients without lymph node metastasis (Fig. 1h). Clinicopathological features showed that down-expression of circPSMC3 was negatively associated with TNM stage ( Table 1, P = 0.000) and lymphatic metastasis (Table 1, P = 0.021). However, circPSMC3wa not associated with the gender, age, size, or histological grade. Furthermore, the area under the ROC curve (AUC) of circPSMC3 in distinguishing GC plasmas and normal ones was 0.9326 (Fig. 1k) and the cut-off value was − 9.965 with the sensitivity of 85.85% and specificity of 95.24%. Kaplan-Meier overall survival curve revealed that patients with lower circPSMC3 expression showed a reduced overall survival time (Fig. 1l). CircPSMC3 plays a suppression role in gastric cancer cells in vitro To evaluate the role of circPSMC3 in GC cells, three siR-NAs against circPSMC3 were designed to silence circPSMC3 without influencing PSMC3 mRNA level in BGC823 and SGC7901 cells (Additional file 1: Figure S1b-1d) and finally si-circPSMC3#1 was chosen for the following experiment with its high inhibitory efficiency. The circular transcript expression vector circPSMC3 was successfully constructed in MGC803 and AGS cells (Fig. 2a), as it could increase circPSMC3 expression level rather than PSMC3 mRNA (Additional file 1: Figure S1e-1f). The results of CCK-8 and EdU assay showed that si-circPSMC3 could promote cell proliferation in BGC823 and SGC7901 cell lines, whereas over-expression of circPSMC3 (named circ-PSMC3) might inhibit cell proliferation in MGC823 and AGS cell lines (Fig. 2b-c). Wound healing assay showed that silencing of circPSMC3 significantly increased the cell mobility, while over-expression of circPSMC3 might inhibit the cell mobility (Fig. 2d). The result of cell invasion assay showed that down regulation of circPSMC3 significantly increased cell invasion and CircPSMC3 directly binds to miR-296-5p and suppresses miR-296-5p activity Given that circRNAs could bind to different miRNAs and regulate downstream genes, we found that circPSMC3 possessed a complementary sequence to miR-296-5p seed region by bioinformatics analysis through Circinteractome database (https://circinteractome.nia.nih.gov/). To confirm the website prediction, the biotin-coupled probe pull-down assay was performed and the results showed miR-296-5p and circPSMC3 were detected in the circPSMC3 pulled-down pellet compared with the control group (Fig. 3a). Furthermore, the result of FISH indicated that circPSMC3 was co-localized with miR-296-5p in the cytoplasm of MGC803 cell lines (Fig. 3b). In addition, luciferase reporters with either the wild type circPSMC3 sequence (WT) or the sequence with mutated binding sites of miR-296-5p (Mut) into the 3 UTR of renilla luciferase showed that miR-296-5p over-expression could significantly reduce the luciferase activities of WT reporter rather than mutant one (Fig. 3c). QRT-PCR further confirmed that circPSMC3 knockdown could increase the miR-296-5p level and circ-PSMC3 had an opposite role in GC cell lines (Fig. 3d). However, miR-296-5p failed to influence circPSMC3 level (Fig. 3e). Collectively, these revealed that circPSMC3 could bind to miR-296-5p to further regulate its expression level. This interaction was confirmed by performing luciferase reporter assays. The results showed that the over-expression of miR-296-5p could significantly reduce the activity of a luciferase reporter compared to miR-NC and the inhibition of the miR-296-5p may evidently increase the luciferase activity compared with inh-NC with wild type PTEN sequence (WT), however, these effect disappeared with mutated binding sites of miR-296-5p (Mut) (Fig. 4a). The knockdown or over-expression model of miR-296-5p was successfully established (Additional file 1: Figure S1g-1 h). We found that miR-296-5p over-expression significantly reduced the PTEN mRNA levels in GC cells (Fig. 4b). Western blot further confirmed that transfection of miR-296-5p mimics could reduce PTEN expression (Fig. 4c). These results showed that miR-296-5p could negatively regulate the expression of PTEN. The role of miR-296-5p on the GC cell proliferation, viability, invasion, and migration was evaluated. The results indicated that over-expression of miR-296-5p promoted the proliferation (Fig. 4d-e), migration (Fig. 4f) and invasion (Fig. 4g) of GC cells. However, down expression of miR-296-5p might exert an opposite effect (Fig. 4d). These results suggest that miR-296-5p could target PTEN and further promote the development of GC partially. CircPSMC3 suppresses the proliferation and invasion of gastric cancer by sponging miR-296-5p to regulate PTEN In order to further explore the interaction among circPSMC3, miR-296-5p and PTEN, we performed luciferase reporter assays. The data showed that the over-expression of circPSMC3 could significantly increase the activity of a luciferase reporter, however, the co-transfection of circPSMC3 and miR-296-5p may eliminate this effect with wild type PTEN sequence (WT), and these effects disappeared with mutated binding sites of miR-296-5p (Mut) (Fig. 5a). Moreover, we found that circ-PSMC3 significantly increased the PTEN mRNA levels, whereas co-transfection of circ-PSMC3 and miR-296-5p may cancel out this effect in MGC803 and AGS cells (Fig. 5b). Western blot showed that circ-PSMC3 could promote PTEN expression, while co-transfection of circ-PSMC3 and miR-296-5p had no effect on PTEN level (Fig. 5c). These results demonstrated that circPSMC3 could regulate PTEN expression by acting as a competing endogenous RNA to sponge miR-296-5p. Results of the malignant behavior of circPSMC3 and miR-296-5p on GC cell proliferation, viability, invasion migration and metastasis indicated that the circ-PSMC3 could inhibit proliferation, invasion and migration of GC cells. However, co-transfection of circPSMC3 and miR-296-5p may counteract this effect (Fig. 5d-h). These results of experiments suggested that CircPSMC3 suppresses the proliferation, invasion and migration of gastric cancer cells by sponging miR-296-5p to regulate PTEN. Circ-PSMC3 inhibits the growth and metastasis of gastric cancer in vivo To explore the association between circPSMC3 and the growth as well as metastasis of gastric cancer in vivo, MGC803 cells transfected with circPSMC3 and GFP was injected into nude mice to established xenograft tumor model and metastasis nude mice model (Fig. 6a). In xenograft tumor model, we found that over expressing of circPSMC3 generated a negative effect on the volume of nude mice (Fig. 6b) as well as the weight (Fig. 6c). Ectopic over-expression of circPSMC3 inhibited metastasis in the lung compared to normal expression of circPSMC3 (Fig. 6d). Taken together, we illustrated that the over-expression of circPSMC3 could inhibit the proliferation, invasion and metastasis of GC cells and then suppress the progression of GC by sponging miR-296-5p to regulate PTEN expression (Fig. 6e). Discussion Deep sequencing combined with novel bioinformatics approaches led to the discovery that a significant portion of the human transcriptome is spliced into RNA loops. The growth curves of cells were measured after transfection with circPSMC3 vector or Mock vector or si-circ or si-NC by using CCK-8 assays. c EdU assays of GC cells transfected with control or circPSMC3 siRNAs or circPSMC3 vector or Mock were performed to evaluate cell proliferation. d Cell motility was examined in cells transfected with circPSMC3 vector or Mock vector or si-circ or si-NC by wound healing assay. e Cell invasion assays were performed in cells transfected with control or circPSMC3 siRNAs or circPSMC3 vector or Mock. Data indicate mean ± SD of at least three independent experiments. *p < 0.05, **p < 0.01, ***p < 0.001, Scale bar, 100 mm biogenesis of circRNAs and possible mechanisms involving them. Some of these discoveries have shown that circRNAs are very stable, abundant and present a tissue-specific expression pattern. In our study, we confirmed that circPSMC3 was significantly lower expressed in GC plasmas, tissues and cells compared to normal controls. Clinicopathological features illustrated that down expression of circPSMC3 was negatively associated with TNM stage and lymphatic metastasis, with a reduced overall survival time for GC patients. More and more studies have explored the relationship between circRNAs and the development of gastric cancer from a clinical perspective and investigated its application as a tumor biomarker in clinic. For example, Xie Y et al. detected the expression levels of hsa_circ_0074362 in 127 gastric cancer tissues and paired adjacent normal tissues by quantitative reverse transcription-polymerase chain reaction. Results showed hsa_circ_0074362 levels were significantly down regulated in gastric cancer tissues, gastritis tissues and gastric cancer cell lines and were associated with lymphatic metastasis, which may be a potential biomarker of gastric cancer. However, most of the studies only detect the expression of circRNAs from cancer tissues and adjacent tissue. Only a small number of studies detect the expression of circRNAs from preoperative blood in GC patients and the sample size is small. The results of our study make circPSMC3 an ideal noninvasive biomarker for the diagnosis and prognosis of gastric cancer. We demonstrated that miR-296-5p targets PTEN and promotes the proliferation and invasion of GC cells. Current studies show that miR-296-5p plays a role in a c d e b Fig. 3 CircPSMC3 directly binds to miR-296-5p and suppresses miR-296-5p activity. a Lysates from MGC803 and AGS cells with circPSMC3 vector were subjected to biotinylation-cirPSMC3 pull down assay, and expression levels of circPSMC3 and miR-296-5p were measured by qRT-PCR. b The Schematic of circPSMC3 wild-type (WT) and mutant (Mut) luciferase reporter vectors. c The relative luciferase activities were analyzed in 293 T cells co-transfected with miR-296-5p mimics or miR-NC and luciferase reporter vectors psiCHECK2-circPSMC3-WT or psiCHECK2-circPSMC3-Mut. d The expressions of miR-296-5p were analyzed by using qRT-qPCR in cells transfected with circPSMC3 or mock vector or si-circ or si-NC vector. e The expression levels of circPSMC3 were determined with qRT-qPCR in cells transfected with miR-296-5p mimics or inhibitor. Data indicate mean ± SD, n 3. **P < 0.01, ***P < 0.001 cancers. For example, Lee H et al. observed that miR-296-5p promoted the invasion of various glioblastomas cells. From results obtained from Ago2 immunoprecipitation and luciferase assays, they found that miR-296-5p downregulated CASP8 and NGFR through direct interaction between seed sequence of the miRNA and 3'UTR of the target mRNA. Collectively, their results implicated miR-296-5p as a potential cause of invasiveness in cancer and identifies miR-296-5p as a promising therapeutic target for glioblastomas. Maia D reported miR-296-5p expression is associated with resistance to radiotherapy and tumor recurrence in early stage laryngeal squamous cell carcinoma, showing the feasibility of this marker as a novel prognostic factor for this malignancy. Furthermore, miR-296-5p expression could be helpful in the identification of tumors resistant to radiotherapy, thus informing treatment plans. Interestingly, Lee KH reported that miR-296-5p has a tumor-suppressive role by targeting Pin1. This suggested that there are likely prognostic and clinical applications of miR-296-5p in prostate cancer therapy. In gastric cancer, Li T et al. showed miR-296-5p over-expression significantly promoted GC cell growth and attenuated the CDX1-induced anti-growth effects by recurring cell cycle distribution and apoptotic status, whereas knockdown of miR-296-5p decreased GC cell growth, which is consistent with our result. There The relative expressions of PTEN mRNA were evaluated by using qRT-qPCR in cells transfected with the miR-296-5p mimics or inhibitors respectively. c The relative expressions of PTEN protein were evaluated by using western blot in cells transfected with the miR-296-5p mimics. d The growth curves of cells were measured after transfection with miR-296-5p mimics or inhibitor by using CCK-8 assays. e EdU assays of GC cells transfected with miR-296-5p mimics or miR-NC were performed to evaluate cell proliferation. f Cell motility was examined in cells transfected with miR-296-5p mimics or miR-NC by wound healing assay. g Cell invasion or migration assays were performed in cells transfected with miR-296-5p mimics or miR-NC by using using transwell chamber with or without matrigel respectively. Data indicate mean ± SD of at least three independent experiments. *p < 0.05, **p < 0.01, ***p < 0.001, Scale bar, 100 mm translation and/or stability of target mRNAs. For example, cir-ITCH (Itchy E3 ubiquitin protein ligase) was reported to sponge miR-7, miR-17, and miR-214, leading to the upregulation of ITCH and the inhibition of WNT signaling in esophageal squamous cell carcinoma. Li X found that hsa_circ_103809 could bind to miR-620 and negatively regulates miR-620 expression, further inhibiting the proliferation and invasion abilities of hepatocellular carcinoma cells. In our research, we discovered that the over-expression of circPSMC3 could inhibit the proliferation, invasion and metastasis of GC cells. Furthermore, it can suppress the progression of GC by regulating miR-296-5p and PTEN expression. Functional inactivation of the tumor suppressor protein PTEN has been detected in multiple cases of GC, and already shown to be closely linked to the development, progression and prognosis of the disease. Inactivation of PTEN can be attributed to gene mutation, loss of heterozygosity, promoter hypermethylation, microRNA-mediated regulation of gene expression, and post-translational phosphorylation. PTEN is also involved in mechanisms regulating tumor resistance to chemotherapy. The expression levels of PTEN mRNA were analyzed using RT-qPCR in MGC803 and AGS cells were co-transfected withcircPSMC3 vector or Mock and miR-296-5p mimics or miR-NC. c The expression levels of PTEN protein were analyzed using Western blot in MGC803 and AGS cells were co-transfected with circPSMC3 vector or Mock and miR-296-5p mimics or miR-NC. d The growth curves of cells were measured after co-transfected with circPSMC3 and miR-296-5p mimics by using CCK-8 assays. e EdU assays of GC cells co-transfected with circPSMC3 and miR-296-5p mimics were performed to evaluate cell proliferation. f The cell apoptosis ability was evaluated by using apoptosis assay in cells co-transfected with circPSMC3 and miR-296-5p mimics. g Cell motility was examined in cells co-transfected with circPSMC3 and miR-296-5p mimics by wound healing assay. h Cell invasion or migration assays were performed in cells co-transfected with circPSMC3 and miR-296-5p mimics by using transwell chamber with or without matrigel respectively. Data indicate mean ± SD of at least three independent experiments. *p < 0.05, **p < 0.01, ***p < 0.001, Scale bar, 100 mm could increase PI3K/Akt signaling by directly down regulating PTEN, thus promoting the proliferation and invasion of gastric cancer cells. Liu T found that Circ-ZFR and PTEN were low-expressed whereas miR-107 and miR-130a were high-expressed in GC tissues and cells. There are targeted relationships and interactions between miR-130a/miR-107 and ZFR/PTEN. Circ-ZFR inhibits GC cell propagation, cell cycle and promoted apoptosis by sponging miR-107/miR-130a, while miR-107/miR-130a promoted GC cell propagation and prevented apoptosis through targeting PTEN. Circ-ZFR inhibited cell proliferation and facilitated apoptosis in GC by sponging miR-130a/miR-107 and modulating PTEN. Circ-ZFR curbed GC tumor growth and affected p53 protein expression in vivo. To our knowledge, this is the first study to investigate the role of circPSMC3 in gastric cancer. Not only that, this is also the first article to study the relationship between miR-296-5p and PTEN. These findings may bring light to the treatment of GC. There are several limitations to the interpretation of our study results. Firstly, our study uses GC samples taken from an ethnically homogenous population and expects further sample size and more validation from different regions. Secondly, our study examines the ability of circPSMC3 to bind to miR-296-5p, but there may be other miRNAs that binds circPSMC3 to regulate the occurrence and progression of GC. Thirdly, whether circPSMC3 regulates the development of GC through other mechanisms such as protein binding requires further investigation. We hope that a follow-up study will elucidate a deeper understanding of the therapeutic potential of circPSMC3. Conclusion Our study identifies a new circular RNA, termed circPSMC3 that is down-regulated in tissues, corresponding plasmas from GC patients as well as GC cell lines and can act as a sponge of miRNA-296-5p to regulate the expression of PTEN. Our findings reveal a novel potential circulating biomarker for detection of GC. Additional file Additional file 1: Figure S1. |
Students cognitive style in mathematical thinking process The process of mathematical thinking in learning mathematics is very important. One internal factor that affects it is cognitive style. The purpose of this study is to describe how each students cognitive style performs mathematical thinking processes. The types of cognitive styles studied are field dependent (FD) and field independent (FI). This research is a literature study by examining journals related to cognitive style and students mathematical thinking abilities. The results of journals review show that students with FI cognitive style analyze and orient analytically to process information and are able to process information using mathematical notation and their own language, and are able to model problems using image visualization. Students with FD cognitive styles adopt a global orientation to understand and process information. In solving mathematical problems, students with FI cognitive style were better than students with FD cognitive style. Introduction One of the life skills that needs to be developed through the education process is thinking skills. The ability of a person to be able to succeed in his life is partly determined by his thinking skills, especially in the effort to solve life's problems he faces. Mathematics is one of the subjects in schools that is able to develop students' thinking processes. Mathematics learning emphasizes the process of thinking, attitudes, curiosity and enjoy learning mathematics. Logical thinking skills is important in learning mathematics. It is expected that the teacher is able to develop the students' thinking skills through appropriate learning methods. An effective method for training students' thinking skills according to their individual characteristics. But in fact, learning mathematics today is still less effective for this purpose. One internal factor that influences students' thinking processes is cognitive style. The ability to think is closely related to the way a person processes and organizes information in his cognitive activities. In processing this information, each person has a different way according to their own cognitive style. Hamzah explained Woolfok's study, that in the cognitive style, there is a different way to see, recognize and organize information. Based on psychological differences, according to Prabawa and Zaenuri's study, there are two classifications of cognitive styles namely Field Dependent (FD) and Field Independent (FI). FD individuals are types of individuals who think globally and tend to be passive, while FI individuals are types of individuals who understand and process information analytically. The purpose in this article is to describe the mathematical thinking process of students in terms of cognitive style, based on the results of research that has been done. Method This research is a literature study by examining 16 journals, proceedings, and books related to cognitive style and students' mathematical thinking abilities. The results of this literature review will be used to identify how students' mathematical thinking processes with field dependent and field independent cognitive styles in mathematics learning. I selected articles that published from 2006 to 2018, where the cognitive style of students in mathematical thinking began to be widely researched in Indonesia and internationally. Cognitive Style Cognitive style is an individual preferred and habitual approach to organizing and representing information, which subsequently affects the way in which one perceives and responds to events and ideas. Allport defined cognitive styles as the habitual way in which an individual processes different information, while Friend and Cole have expanded the definition of cognitive styles to include the way in which the individual perceives, codes, saves and recalls information. According to Saracho, cognitive styles include stable attitudes, choices, or habit strategies that distinguish individual styles from feeling, remembering, thinking and solving problems. Different researchers identified different types of cognitive styles such as field dependent and field-independent, reflective and impulsive, wholist and serialist, verbalizer and visualizer. This is only a very small sample of the different types of cognitive styles that one encounters in the literature. A study conducted by Riding and Cheema reviewed over 30 methods of defining cognitive style and concluded that most could be grouped within two fundamental independent cognitive style dimensions, the verbal-imagery dimension and the wholistic-analytic dimension. This paper will be discussed about field independent (FI) and field dependent (FD) cognitive style. According to Desmita, the character of learning in students who have independent field cognitive style is may need help focusing attention on material with social content, it may need to be taught how the context to understand social information, tends have self-goals that are defined and reinforcement, are not affected by criticism, can develop their own structure in unstructured situations, and are usually better able to solve problems without explicit instructions and guidance. In contrast to the independent field cognitive style, the character of learning in students who have a field dependent cognitive style is it is easier to understand learning material by containing social content, has a better memory for social problems, has a structure, objectives, and reinforcement that are clearly defined, are more influenced by criticism, have great difficulty in learning structured material, may need to be taught how to use mnemonics, tend to accept given organizations and are unable to organize again, and may require clearer instructions on how to solve the problem. Rahman and Ahmar mentioned the implications of students' cognitive styles in learning of fieldindependent and field-dependent are as follows: Students with the cognitive style of fieldindependent learn mathematics individually, enabling them to provide better responses, and are more independent. Those with this cognitive style are more likely to learn mathematics by intrinsic motivation and are inclined to work to satisfy their own ambition. Students with the cognitive style of fielddependent learn mathematics in a group and frequently interact with their teacher, requiring extrinsic reinforcement. For those with this cognitive style, a teacher is required to design what should be undertaken and how to undertake it. Such students require guidance from the teacher and motivation is such reward and encouragement. Mathematical Thinking Processes Siswono explained that thinking is a mental activity experienced by someone when faced with a problem that must be resolved. Meanwhile, Ormrod defines the thought process as a way of mentally responding to information or an event. So, the mathematical thinking process can be interpreted as a mental activity to process information or solve mathematical problems. 3 Ngilawajan states that thinking is information processing. When children perceive, encode, represent, and store information from the world around them, then they are doing a thought process. For can stimulate and train students' thinking skills in learning mathematics, it is necessary to use appropriate methods or techniques in learning that can stimulate students to use all the potential think that is owned. Problem solving is one way in learning to train students to think and this has been proven by experts through a number of studies. Scusa mentions five mathematical thinking processes: 1) problem solving as a process, 2) the process of reasoning and proof. 3) the communication process 4) the process of representation, dan 5) making connections as a process skill. Students' cognitive style in mathematical thinking processes Amstrong mentioned the characteristics of FD and FI cognitive styles. FD individuals adopt a global orientation to perceiving and processing information; passively conform to the influence of the field or context; adopt an inter-personal approach to problem solving; and prefer to work in unstructured situations. At the other extreme, target items are perceived as being separate from the surrounding context (field independent, FI). FI individuals adopt an analytical orientation to perceiving and processing information; experience target items as discrete from their field or context; value precision and attention to detail; adopt an impersonal approach to problem solving; and prefer structured situations. The results of Agoestanto's research about mathematics critical thinking students in junior high school based on cognitive style are: the ability to think critically mathematical junior high school students are still; in terms of cognitive styles critical thinking skills mathematical junior high school students with a higher FI cognitive styles of the students FD; From the aspect of student's critical thinking aspect with FI cognitive style is better than the FD on the viability inference, assumptions, deduction, and argument evaluation. The research which is conducted by Almolhodaei found that FI way of thinking may promote higher performance in math's problem solving compared with FD way. Moreover, as was discussed, students with an FI cognitive style demonstrated higher results than FD ones in tackling the complexity of word problems, according to presented study. However, differences in performance in word problem exam were significantly higher than ordinary exam. Based on the analysis of obtained data that in solving the problem with Polya's steps, field dependent subjects are able to understand the problem but still uses mathematical language that resembles the problem, unable to devise a plan on a particular problem that requires deeper analysis, unable to carry out the plan properly on certain questions that require more analysis and look back the answer but cannot correct the mistake. Based on the findings of Marifatun, Sulistyorini, and Ahmad, in problem solving activities, field independent subject can understand the problem well, the subject can write down the elements that are known and asked from the problem completely and correctly. While the subject of the dependent field category can understand the problem quite well; the subject can write the elements that are known and asked from the problem well but still use everyday sentences. The research results of Udiyono and Yuwono, there is a positive correlation between cognitive style and students' learning achievement on geometry subject. The coefficient determination is r 2 =0.6209. It means the increase and decrease of students' learning result on geometry subject 62.09% can be explained by cognitive style with linear correlation equation Y= -2.9650 + 4.6513X. The mean score of students FD is 16 while students FI is 59.5385. It means students FI has better learning achievement than students FD on geometry subject. Conclusion Mathematical thinking process is a mental activity to process information or solve mathematical problems. While the way of receiving and processing information, attitudes towards information and habits related to the learning environment are called cognitive styles. There are two kinds of cognitive styles namely field dependent (FD) and independent field (FI). |
Automatic Detection and Classification of Laser Welding Defects Laser welding is one of the most common methods used in joining metal materials. However, welding errors are usually encountered during the welding process due to external factors. The detection and correct classification of these welding faults are of great importance for the reliability of the weld and the material which was welded. Traditionally, welding error detection is usually handed by visual inspection. However, visual inspection is an error-prone and slow process. In this study, an image processing and machine learning based method is proposed to automatically detect welding defects. The welded materials are divided into sub-images and each sub-image is examined for defect detection and defect type classification. The study has been examined in 2 aspects as 2-class classification and 3- class classification. As a result of the study, an average of 90% precision is obtained with Logistic Regression (LR) and 91% precision is obtained with the Support Vector Machine (SVM) in the 2-class classification process. As for the 3-class classification, an average of 91% precision is obtained with the LR, and 93% precision values are obtained with the SVM. |
export const countProperty = (obj : any) : number => {
var count = 0;
for (let p in obj) {
count ++;
}
return count;
} |
import { Component, OnInit, Input, trigger, state, transition, style, animate } from '@angular/core';
import { Http, Response, Headers } from '@angular/http';
import { Observable } from 'rxjs/Observable';
import { Partner } from '../../_models';
import { PartnerService } from '../../_services';
@Component({
templateUrl: './partners-list.component.html',
host: {
'[@routeAnimation]': 'true',
'[style.display]': "'block'",
},
animations: [
trigger('routeAnimation', [
state('*', style({transform: 'translateX(0)', opacity: 1})),
transition('void => *', [
style({transform: 'translateX(-100%)', opacity: 0}),
animate(300)
]),
transition('* => void', animate(300, style({transform: 'translateX(100%)', opacity: 0})))
])
]
})
export class PartnerListComponent implements OnInit {
@Input() partners: Partner[];
constructor(
private http: Http,
private partnerService: PartnerService
) {
this.partners = [];
}
ngOnInit() {
this.partnerService.getAll()
.subscribe(partnersJson => this.partners.push(...partnersJson));
}
}
|
// try to pop n integers from stack
func popNInt(s *stack.Stack, n int) ([]int, error) {
items := make([]int, n)
for i := 0; i < n; i++ {
n, err := popInt(s)
if err != nil {
return nil, err
}
items[i] = n
}
return items, nil
} |
An IDL to SDL 2000 compiler Distributed systems evolution has led telecommunication management network (TMN) systems to use object-oriented middleware paradigm, mainly CORBA (Common Object Request Broker Architecture). CORBA only includes a mechanism for defining object interfaces not for specifying the behaviour of these objects. The behaviour of a TMN system has to follow concrete and restrictive specifications, which are not reflected in CORBA IDL, at least not in a clear and unambiguously way. It is in this situation where the advantage of using an FDT (Formal Description Technique) like SDL (Specification and Description Language) appears. This work is the first step towards the overall goal of formally specifying the behaviour of the objects implementing management IDL interfaces. 1 IDL to SDL Mapping Formalising an IDL to SDL mapping is the first requirement because there is not a standard IDL-SDL mapping. An IDL to SDL compiler was developed in order to automate this translation. It translates IDL specifications into SDL structures that have to be completed with corresponding finite-state machines to obtain the desired behaviour. In some guidelines to translate IDL elements into SDL96,, constructions are given. Guidelines related to predefined types, synchronous and asynchronous methods have been used. New rules based on SDL2000 new characteristics (exceptions, interfaces, direct use of ASN.1 concepts like CHOICE or OPTIONAL) have been developed. And some ideas from other IDL mappings have been adopted for those SDL types that are not inmediately translatable. IDL to SDL mapping gives us the possibility to obtain SDL skeletons corresponding to a given IDL definition. Applying this mapping to generic management interfaces from it will be obtained a generic SDL skeleton. This can be used as a base for SDL systems of specific management interfaces developed using the guidelines in. Next step towards the overall objective is to define the behaviour of these skeletons. |
Does elevated CO2 alter silica uptake in trees? Human activities have greatly altered global carbon (C) and Nitrogen (N) cycling. In fact, atmospheric concentrations of carbon dioxide (CO2) have increased 40% over the last century and the amount of N cycling in the biosphere has more than doubled. In an effort to understand how plants will respond to continued global CO2 fertilization, long-term free-air CO2 enrichment experiments have been conducted at sites around the globe. Here we examine how atmospheric CO2 enrichment and N fertilization affects the uptake of silicon (Si) in the Duke Forest, North Carolina, a stand dominated by Pinus taeda (loblolly pine), and five hardwood species. Specifically, we measured foliar biogenic silica concentrations in five deciduous and one coniferous species across three treatments: CO2 enrichment, N enrichment, and N and CO2 enrichment. We found no consistent trends in foliar Si concentration under elevated CO2, N fertilization, or combined elevated CO2 and N fertilization. However, two-thirds of the tree species studied here have Si foliar concentrations greater than well-known Si accumulators, such as grasses. Based on net primary production values and aboveground Si concentrations in these trees, we calculated forest Si uptake rates under control and elevated CO2 concentrations. Due largely to increased primary production, elevated CO2 enhanced the magnitude of Si uptake between 20 and 26%, likely intensifying the terrestrial silica pump. This uptake of Si by forests has important implications for Si export from terrestrial systems, with the potential to impact C sequestration and higher trophic levels in downstream ecosystems. INTRODUCTION We are currently conducting a global experiment by exposing Earth's biosphere to atmospheric carbon dioxide (CO 2 ) concentrations unseen since the early Miocene, some 23 million years ago (Pearson and Palmer, 2000). From the start of the Industrial Revolution we have increased CO 2 concentrations by approximately 40% (Pearson and Palmer, 2000) and in the spring of 2014 CO 2 levels officially exceeded 400 ppm at the Mauna Loa Observatory. This grand experiment will continue for the foreseeable future, as over the next century CO 2 concentrations are expected to increase further. The impact of increased CO 2 concentrations on the terrestrial biosphere has received much research attention over the last several decades. In particular, recent research has focused on how plants have and will respond to rapid CO 2 concentration increases in combination with other regional and global climate changes, including warming air temperature and increased N availability (Norby and Luo, 2004;Ainsworth and Long, 2005;;). Among numerous other impacts, CO 2 enrichment can also alter plant stoichiometry. Exposure to elevated CO 2 concentrations can cause declines in leaf nutrients, such as N and phosphorus, as well as trace element concentrations (). The mechanism driving this decline is unclear but it has been attributed to nutrient limitation, increased non-structural carbohydrates, lower transpiration rates, or changes in nutrient allocation patterns (Roberntz and Linder, 1999). A compilation of studies on herbaceous and woody plants found that elevated CO 2 concentrations decreased foliar element concentrations by up to 15%. Research on rice, a key global crop, found similar declines in essential elements such as N, magnesium, and iron. Such declines in plant elemental concentrations could have serious repercussions for higher trophic levels, including exacerbation of human malnutrition. A meta-analysis by Cotrufo et al. (1998a) found that aboveground N content declined on average by 14% under high CO 2 concentrations. Changes in the N content of litter have also been shown to alter rates of decomposition and thus nutrient cycling within terrestrial ecosystems (b). However, changes in foliar elemental composition could also have largescale impacts on the cycling and transport of nutrients from land to the sea. Silicon (Si) is the seventh-most-abundant element in the universe and the second-most abundant element in soils, the mineral substrate for most of terrestrial plant life (Epstein, 1994;Trguer and De La Rocha, 2013). In the ocean, Si is a key nutrient required for diatoms and is used by many species of sponges, radiolarians, silicoflagellates, choanoflagellates, and even picocyanobacteria (). Of particular importance are diatoms, as they form the base of many productive marine food webs and they sequester significant amounts of C to the deep ocean. In fact, a recent modeling effort contributes 50% of global ocean productivity to diatoms (Rousseaux and Gregg, 2013). The primary source of Si to the ocean is the transport of dissolved and biogenic silica (BSi; SiO 2 ) via rivers, which together account for 78% of the net annual Si oceanic inputs (Trguer and De La Rocha, 2013). The Si transported by rivers ultimately comes from the weathering of the lithosphere, which is dependent on complex interactions between climate, geology, and biology (Bluth and Kump, 1994;Conley, 2002;). Recently there has been emphasis on the role of biology in altering the timing and magnitude of Si export, specifically in terms of biological uptake by terrestrial vegetation (Conley, 2002;Fulweiler and Nixon, 2005;;Carey and Fulweiler, 2013b) and the role of human activities in directly altering watershed Si export (;Fulweiler, 2012a, 2013b;). Plants readily absorb dissolved silica (DSi), also known as silicic acid (H 4 SiO 4 ), the dominant form of Si in soil solutions. DSi is taken up with water and carried in the transpiration stream where, with the evaporation of water, it becomes supersaturated and precipitated as BSi or phytoliths. Si provides numerous benefits to vegetation including increased resistance to bacteria, fungi, and grazers, as well protection from desiccation and metal toxicity (Hodson and Evans, 1995;Epstein, 1999;). Si is found throughout plants, from their roots to their shoots, but peak concentrations are generally observed at the transpiration termini. In fact, Si can compose 10% or more of the dry weight, exceeding those concentrations of well-known macronutrients (i.e., N and potassium; Epstein, 1994). In turn, the accumulation of Si by terrestrial vegetation over the seasonal cycle has the capacity to regulate the watershed export of Si to coastal ecosystems as plants grow and senesce (Fulweiler and Nixon, 2005;Carey and Fulweiler, 2013b). Alternatively, because BSi is 7-20 times more soluble than mineral silicates (a), plants may also provide an important source of Si on biological times scales. Within this context we wanted to determine if trees exposed to elevated CO 2 concentrations would exhibit a decline in foliar Si content like those observed for other elements. To do this, we analyzed BSi concentrations of leaf samples from coniferous and deciduous trees from the Duke free-air CO 2 enrichment (FACE) experiments in North Carolina. Additionally, we examined Si content under nitrogen (N) enrichment, as well as under the combined impact of CO 2 and N enrichment. This is the first study to specifically examine the role of CO 2 and N enrichment on Si content in trees. MATERIALS AND METHODS The Duke Face experiment is located in a Pinus taeda L. (P. taeda, loblolly pine) plantation at Duke University in North Carolina (35 58 N, 79 06 W). This plantation was established in 1983 and is characterized as having moderately low-fertility and acidic clay loam (). In addition to the dominant pine, deciduous species present include Acer rubrum (A. rubrum, red maple), Cercis canadensis (C. Canadensis, red bud), Cornus florida (C. florida, dogwood), Liquidambar styraciflua (L. styraciflua, sweet gum), and Ulmus alata (U. alata, winged Elm). Mean annual precipitation is 1145 mm. This study was conducted on leaves collected from CO 2 and N enrichment experiments that took place between 1996 and 2006. The technical details of these studies have been published previously (e.g., ;;;). Briefly, triplicate 30 m diameter treatment plots were exposed to current +200 ppm of CO 2 above ambient during daylight hours in the growing season. Control plots (n = 3) were treated in a similar manner but with the addition of ambient air instead of CO 2 (). In 1998, two of these plots were divided in half and N fertilization began (11.2 g N m −2 y −1 as urea). For more detailed information on the experimental design see http://face.env.duke.edu. For this analysis we used dried green leaf samples from P. taeda and the five broadleaf species listed above, collected in 2002-2003 and 2006, respectively. P. taeda samples (n = 31) were separated and ground into a powder using a mortar and pestle. The premilled deciduous samples (n = 98) each contained composites of several individuals. Biogenic Si concentrations were determined using a wet alkaline chemical extraction in a 1% Na 2 CO 3 solution (Demaster, 1981;Conley and Schelske, 2001). Duplicate samples were weighed to approximately 30 mg (between 28 and 34 mg) and digested in flat bottomed polyethylene bottles in a shaker bath at 85 C and 100 rpm for four hours. We used a Seal AA3 flow injection autoanalyzer to colorimetrically determine DSi from the BSi aliquots using the molybdenum blue colorimetric method (Strickland and Parsons, 1972). Standards made of sodium hexafluorosilicate (Na 2 SiF 6 ) as well as external standards were used throughout the analysis to check accuracy and were always within 4% of the expected value. We report all BSi values as %Si by dry weight. All statistical analyses were completed using JMP Pro 10.0 and significance was judged with an alpha of 0.05. BSi concentrations across species and treatments exhibited equal variances according to several commonly used unequal variance tests (O'Brien = 0.6385, Brown-Forsythe = 0.3196, Levene = 0.1978). To explore potential drivers of BSi concentrations we used a linear mixed effects model to address if the BSi concentrations were different across species and treatment alone and combined. In this model we treated station as a random effect to assess the potential random station effects of the block design used at the Duke FACE experiment. We used an ANOVA to further explore differences in BSi concentrations across species and followed it by a post hoc means comparison with Tukey's test for honestly significant differences (HSD). RESULTS Across all sample types and treatments BSi values ranged from 0.05 to 3.01 %Si dry wt., with a median of 0.82 %Si dry wt. and mean of 0.98 %Si dry wt. C. florida exhibited the lowest and least variable BSi concentrations, while U. alata had the highest (Table 1; Figure 1). While some species did exhibit a decline in foliar BSi concentrations under elevated CO 2, we found no statistically significant effect of treatment on foliar BSi concentrations ( Table 1). In fact, our least squared model showed no effect of treatments, station, or treatment by species. Because of the lack of statistical difference in plant BSi concentrations across all experimental treatments, we averaged Frontiers in Plant Science | Functional Plant Ecology BSi concentrations by species. Clear species differences exist (Figure 1), as the majority of species are statistically different from one another (p < 0.0001). The exceptions are that P. taeda, A. rubrum, and L. styraciflua are not statistically different from each other, but they are statistically different from C. florida, C. canadensis, and U. alata. U. alata exhibited BSi concentrations statistically higher than all other species (p < 0.0001). In all cases, except for C. and C. canadensis, the mean Si foliar content suggests active accumulation (i.e., %Si above 0.46%; Figure 1). DISCUSSION In this study we examined foliar BSi concentrations in five deciduous and one coniferous species across three treatments: CO 2 enrichment, N enrichment, and N and CO 2 enrichment. We expected to see a decrease in Si content as CO 2 increased, compared to the control group, as this phenomenon has been observed for a range of other elements such as N, phosphorus, iron, and zinc. In four species (P. taeda, C. canadensis, A. rubrum, L. styraciflua) we did observe a decline in BSi concentrations under elevated CO 2 but none of them were statistically significant ( Table 1). The largest decrease of 35% was observed in C. canadensis while the others ranged from 7 to 15%. These declines are on par with those reported for essential elements in other plant species and thus, the lack of significance may simply be due to a limited sample number. In one species, U. alata, we observed a small, non-significant increase in BSi concentrations under CO 2 enrichment ( Table 1). We know of only one other study that examined the impact of elevated CO 2 on plant BSi concentrations. In that study of cotton (Gossypium hirsutum L.cv. Deltapine 77), the Si concentrations increased by 26%, although the results were also not significant (). We observed a decline in BSi concentrations in N enriched trees compared to the control ranging from 8 to 50%, but none were statistically significant (Table 1). Similarly, no significant differences between BSi concentration in CO 2 enriched vs. N enriched were found for any of the species. The combined impact of N and CO 2 enrichment again exhibited mixed results. For three species (A. rubrum, L. styraciflua, U. alata) we observed BSi declines from 12 to 21% and in one species (C. canadensis) we observed an increase of 60% (Table 1). Previous work at this same site found no significant differences in leaf N, phosphorus, C, lignin, or total non-structural carbohydrates under elevated CO 2 (). This is in contrast to other studies that found decreases in N and increases in C concentrations in other tree species (quaking aspen, Populus tremuloides and paper birch, Betula papyrifera; ). Elevated CO 2 concentrations also decreased concentrations of N, potassium, phosphorus, and sulfur in Norway spruce (Picea abies L. Karst; Roberntz and Linder, 1999). From these and many other studies, foliar chemistry response to elevated CO 2 and N appears to be site-specific. Additionally, although we did not observe statistically significant effects, the trends we document may be ecologically important. For example, Si provides defense against herbivory and the 15% decline we observed in A. rubrum could impact feeding preferences of vertebrate and invertebrate consumers. The lack of significance may be in part driven by our sample numbers www.frontiersin.org and thus, a larger study with more data may produce different results. Silicon uptake by plants is divided into three broad categories (active, passive, or rejective). In active accumulation, plants acquire more Si than they would through water uptake alone. In rejective accumulation, also known as excluder accumulation, Si is taken up at a slower rate than water. Finally, in passive accumulation, water and Si have similar uptake rates (Raven, 1983;b). Plants are assigned one of these categories according to various definitions, a thorough discussion of which is beyond the scope of this paper, but see Carey and Fulweiler in this Special Issue for a full description. Briefly, previous definitions have been based on Si concentrations in aboveground tissues, on the ratio of Si to calcium, and on the relationship between porewater Si concentration and aboveground tissue Si concentrations (e.g., Jones and Handreck, 1967;;a, respectively). More recent work has focused on the presence/absence of Si transporter genes in roots (Lsi1 and Lsi2) and shoots (Lsi6) of rice ). Research on accumulation modes in trees is surprisingly lacking. Cornelis et al. (2010b) observed both passive and rejective Si accumulation growth in coniferous tree saplings grown hydroponically. And a decrease in Si concentration with depth was observed in a temperate coniferous forest and designated as active accumulation (). Adult trees likely rely more heavily on groundwater and thus, in order to precisely determine the mode of Si accumulation, measurements of Si concentrations in groundwater, porewater, and within the tree are needed. Unfortunately, this is beyond the scope of this paper. Therefore, we apply the simplest definition that describes accumulation status as a function of Si concentration in the aboveground tissue alone: active accumulators as >0.46% Si by wt., passive accumulators as between 0.25 and 0.46% Si by wt., and excluders as <0.25% Si by wt. (b;Street-Perrott and Barker, 2008). We acknowledge the limitations of this definition, as aboveground BSi tissue concentrations can be impacted by numerous factors, such as porewater DSi availability and external stressors. However, given our dataset, it is the one most appropriate for us to use. Defining Si accumulation status in trees by linking Si concentrations in aboveground vegetation to changes in porewater and groundwater, and locating Si transporter genes within trees are important areas of future research. We observed a wide range in foliar BSi concentrations ( Table 1). The low Si concentrations found in C. florida may indicate that these trees excluded H 4 SiO 4. Overall however, the BSi concentrations observed in the Duke forest are 40 to 150% higher than those previously reported for similar species (). One reason for higher concentrations found in the Duke Forest could be the different soil and climate in North Carolina compared to the majority of studies reported in Hodson et al., which were dominated by northern temperate field sites. Our samples could also have higher BSi concentrations because of the land use legacy at the Duke Face site. In 1983, just 13 years before these experiments started, the forest was cut, trunks were removed, and the remaining material was burned (). The impact of land use change and disturbance on Si cycling is an emerging topic. From what we currently know, greater DSi losses have been observed following deforestation (;). The median and mean BSi concentration (0.81 and 0.98 %Si dry wt., respectively) of the species we studied here is higher than many well-known actively Si accumulating groups, including those found in grasses (Poaceae) and sedges (Cyperaceae; Jones and Handreck, 1967;Raven, 1983;Ma and Takahashi, 2002). Uptake by forest trees has been hypothesized as a mechanism responsible for both the clear seasonal cycle of Si concentrations in stream water (Fulweiler and Nixon, 2005) and the observation of forested watersheds exporting significantly less Si than watersheds dominated by urban-land uses Fulweiler, 2012a, 2013b). Given these data, and the known limitations of Si accumulation definitions, we can only hypothesize that this forest is actively accumulating Si. Regardless, the high Si concentrations we observed support the idea that forests are a critical component in regulating the flux of Si from land to the sea. DUKE FACE SI UPTAKE The impact of elevated CO 2, N, and combined elevated CO 2 and N led to an approximately 28% increase in net primary production (NPP) at the Duke Face site between 1996and 2004(. We used the mean NPP over this period to estimate the amount of Si taken up by the Duke forest for the control and elevated CO 2 treatments. We focused on the CO 2 treatment because we do not have BSi concentrations for the P. taeda under N fertilization or the combined elevated CO 2 and N fertilization treatments. Additionally, biomass at this site is dominated by P. taeda, which comprises ∼98% of the tree basal area (). We calculated foliar Si:C ratios by dividing the treatment specific median %Si value of either P. taeda alone or all the species together by 0.47, as C concentrations in biomass are well constrained between 45 and 50%. We then multiplied this Si:C ratio by the known amount of C in each treatment to get a treatment specific Si foliar uptake value (Conley, 2002;Carey and Fulweiler, 2012b). We estimated woody biomass Si uptake using the mean temperate woody biomass %Si of 0.08 (Fulweiler and Nixon, 2005) and again divided by 0.47. We then prorated the amount of Si by the proportion of leaves (30%) versus woody biomass (70%) in a typical forest to determine a total Si uptake rate (Figure 2; ). Although we observed a decline in Si concentrations under elevated CO 2, the total amount of Si taken up by P. taeda was 26% higher at elevated CO 2 where NPP was significantly higher compared to ambient CO 2 (control: 194 kmol Si km −2, elevated CO 2 : 251 kmol Si km −2 ). Together with the hardwood species, Si uptake rate was 20% higher in the elevated compared to ambient CO 2 treatment, although absolute rates of uptake were higher than P. taeda alone (elevated CO 2 = 313 kmol km −2 y −1 ; ambient CO 2 = 266 kmol Si km −2, Figure 2). These values are on the high end of those reported for forested systems but well within the reported range. For example, Grard et al. reported 157 kmol Si km −2 for a Douglas fir forest in France, while Meunier et al. reported an uptake of over 3400 kmol Si km −2 in a bamboo forest. A review of FACE experiments found that irrespective of ecosystem type, aboveground production increased in the presence of higher CO 2 and trees were more responsive than herbaceous vegetation (). Other studies have found similar increases in global terrestrial production (;). In addition, Pan et al. found that global forest biomass has increased in established forests. Such changes in primary productivity will also alter Si cycling. In fact, Si accumulating vegetation accounts for 55% of terrestrial NPP (33 Gton C y −1 ) an amount similar to the C sequestered by marine diatoms (Carey and Fulweiler, 2012b). This terrestrial Si pump has important implications for global climate, as Si cycling helps to control atmospheric CO 2 concentrations through a variety of mechanisms, including chemical weathering of mineral silicates and C occlusion in soil phytoliths (Berner and Berner, 1997;Parr and Sullivan, 2005). In addition, this vegetation also plays a critical role in modulating the amount and timing of Si export from watersheds to downstream receiving waters Fulweiler, 2012a, 2013b), which has direct implications for marine C dynamics. Here, we show that anthropogenically driven enhanced NPP may result in an increase in the terrestrial Si pump as forests take up more Si. In turn, the increased terrestrial Si sink may alter Si availability in aquatic systems. Diatoms require N and Si on a one to one molar basis. Thus, the ratio of N to phosphorus to Si (N:P:Si) helps to control the composition and abundance of phytoplankton species assemblages. Human activities, such as fertilizer use and land use change have increased N and P loading to coastal systems worldwide. Phytoplankton respond to these elevated nutrients by increased productivity. At first, diatoms will bloom until all the Si is consumed at which point other non-Si requiring species will flourish (). The enhanced Si uptake by forests under elevated CO 2 may be another way in which humans are altering nutrient stoichiometry in coastal receiving waters. Missing from this discussion is the mechanism driving our findings that CO 2 and/or N additions have no significant impact on Si accumulation in aboveground biomass. Of course, with more data and different study sites we might observe a significant impact of these factors on Si accumulation rates in forest or other terrestrial vegetation types. In fact, a recent study found higher Si concentrations in the porewater, sediment, roots, and occasionally the aboveground biomass of a heavily N enriched salt marsh (Carey and Fulweiler, 2013a). Certainly other factors such as changes in water availability and growing season length, as well as warming temperatures, are all factors that might influence foliar BSi accumulation. Here we propose an alternative idea for exploration: we hypothesize that in ecosystems with altered transpiration rates, corresponding changes to leaf Si concentrations will also be observed because Si is delivered to vegetation via water. Higher transpiration rates should, if passive or active accumulation is occurring, result in higher Si concentration in leaves, as Si is typically concentrated at transpiration termini. Conversely, if transpiration rates decline, then less Si will be deposited. Experimental work on Douglas fir saplings found higher Si concentrations that were attributed to greater transpiration in those seedlings (b). However, at the Duke FACE experimental site no changes in transpiration were observed and maybe this is why we observed no significant changes in Si concentration (). Complicating these simple ideas is the original hypothesis that motivated this work -enhanced CO 2 lowers elemental composition of leaves such as N, phosphorus, and potassium. Thus, quantifying the interplay between structural changes in vegetation and transpiration rates, as well as water availability under future climate change scenarios, will be a critical next step in our understanding of climate change impacts on terrestrial Si cycling. CONCLUSION Our data of BSi concentrations in 6 species from the Duke FACE Experiment does not support our initial hypothesis that elevated CO 2 concentrations would decrease foliar Si content. In fact, we observed no consistent or significant impact of any of the treatments on foliar Si content. However, according to the simplest definition based on aboveground tissue Si concentrations, we did find evidence that four out of the six tree species we studied may be active Si accumulators. These tree species had Si concentrations higher than some of the most well-known Si accumulators (e.g., grasses and sedges). Further, the higher NPP values observed under elevated CO 2 resulted in higher Si uptake rates under elevated CO 2 conditions in the Duke forest. Based on this analysis we hypothesize that anthropogenic change, specifically elevated atmospheric CO 2 concentrations, may increase biological Si pumping in forests, increasing the magnitude of the terrestrial Si pump. ACKNOWLEDGMENTS This research was supported in part by the Sloan Foundation in a fellowship to Robinson W. Fulweiler. The Duke Forest FACE was supported by his study was supported by the US Department of Energy (Grant No. DE-FG02-95ER62083) through the Office of Biological and Environmental Research (BER) and its National Institute for Global Environmental Change (NIGEC), Southeast Regional Center (SERC) at the University of Alabama, and by the US Forest Service through both the Southern Global Climate Change Program and the Southern Research Station. Adrien C. Finzi acknowledges ancillary support from the US NSF www.frontiersin.org (DEB0236356). Thanks to Jeffrey Pippen for his assistance with the field sampling at Duke. We also thank Ken Czapla for training Timothy J. Maguire on the Seal Autoanalyzer and running many of the Si samples. We thank Hollie Emery for her statistical guidance. We thank our two reviewers who provided helpful suggestions and edits that improved our manuscript. |
Emotional determinants of infant-mother attachment. The present study examined the assumption that emotion-related characteristics of mothers and infants contribute to the development of infant-mother attachment in the first year of life. Mothers' emotion and personality characteristics were assessed with expressive-behavior ratings and self-report scales. Infant characteristics were measured by emotion and temperament questionnaires (mother report) and objective coding of facial expressions of emotions. Attachment classifications were determined by means of the Strange Situation procedure, and a continuous-variable index of attachment security was derived by a discriminant function procedure. Mothers' emotion experiences, expressive behaviors, and personality traits were significant predictors of the level of security of the infant-mother attachment. Infants' expressive and temperamental characteristics as rated by their mothers were also significant predictors of attachment security. |
Effect of audit committee characteristics on relationship between financial distress and income maximization actions The study aims to obtain empirical evidence regarding the influence of audit committee characteristics on the relationship between financial distress and income maximization actions. The population in the current study are companies listed on the Indonesia Stock Exchange from 2015 to 2018. The sampling technique used non-probability sampling with a purposive sampling method to get 37 observation periods as research samples. The data analysis technique uses moderated regression analysis. The test results prove that high financial expertise can weaken the influence of financial distress on income maximization actions. This study also finds empirical evidence that the frequency of meetings is not a moderating effect of financial distress on income maximization. The third hypothesis testing shows that the independence of the audit committee can moderate the relationship between financial distress on income maximization. |
. Health and illness in modern societies are often understood as moral or normative categories. The author proposes an anthropological, not mutually excluding concept. A case study shows that even a severe illness with shortened life-expectation and -quality can provide new possibilities and confer fulfilment and happiness for the people affected on condition that they and their caregivers have an open-minded attitude ("serendipity"), sense of coherence, empowerment and orientation towards "recovery" as a new concept of healthiness at their disposal. The challenges for mental health services are being discussed. |
<gh_stars>10-100
// Copyright (c) 2014-2018 LG Electronics, Inc.
//
// 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.
//
// SPDX-License-Identifier: Apache-2.0
#ifndef CORE_SERVICE_SENDER_H_
#define CORE_SERVICE_SENDER_H_
#include <string>
#include "web_app_base.h"
#include "web_app_manager.h"
class ServiceSender {
public:
virtual ~ServiceSender() = default;
virtual void PostlistRunningApps(std::vector<ApplicationInfo>& apps) = 0;
virtual void PostWebProcessCreated(const std::string& app_id,
const std::string& instance_id,
uint32_t pid) = 0;
virtual void ServiceCall(const std::string& url,
const std::string& payload,
const std::string& app_id) = 0;
virtual void CloseApp(const std::string& id) = 0;
};
#endif // CORE_SERVICE_SENDER_H_
|
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