bluuebunny/crossref_metadata_2025_split huggingface dataset:
Different Perspective of Machine Learning Technique to Better Predict Breast Cancer Survival
Authors: Kumar Kaushal , Singh Vijay Vikram , Ramaswamy Ramakrishna 
Published: July 2020

AbstractMachine learning (ML) plays a key job in the guide of cancer diagnosis and identification. The researcher has implemented different algorithms of ML for the prediction of breast cancer. Some researchers recommend their algorithms are more accurate, faster, and easier than others. My study relies on recently developed machine learning algorithms like genetic algorithms and deep belief nets. I’m interested to build a framework to precisely separate among benign and malignant tumors. We’ve optimized the training algorithm. During this unique circumstance, we applied the genetic algorithm procedure to settle on the main genuine highlights and perfect boundary estimations of the AI classifiers. The examinations rely upon affectability, cross-validation, precision, and ROC curve. Among all the varying kinds of classifiers used in this paper genetic programming is the premier viable model for highlight determination and classifier.
PD-L1 glycosylation and its impact on binding to clinical antibodies
Authors: Benicky Julius , Sanda Miloslav , Brnakova Kennedy Zuzana , Grant Oliver C. , Woods Robert J. , Zwart Alan , Goldman Radoslav 
Published: July 2020

AbstractImmune checkpoint inhibitors, including PD-L1/PD-1, are key regulators of immune response and promising targets in cancer immunotherapy. N-glycosylation of PD-L1 affects its interaction with PD-1 but little is known about the distribution of glycoforms at its four NXS/T sequons. We optimized LC-MS/MS methods using collision energy modulation for the site-specific resolution of specific glycan motifs. Using these methods, we demonstrate that PD-L1 expressed on the surface of breast cancer cells carries mostly complex glycans with high proportion of polyLacNAc structures at the N219 sequon. PD-L1 from whole cell lysate contained, in addition, large proportion of high mannose glycans at all sites. Contrary to the full-length protein, the secreted form of PD-L1 expressed in breast cancer or HEK293 cells demonstrated minimum N219 occupancy and low contribution of the polyLacNAc structures. Molecular modeling of PD-L1/PD-1 interaction with N-glycans suggests that glycans at the N219 site of PD-L1 and N74 and N116 of PD-1 are involved in glycan-glycan interactions, but the impact of this potential interaction on the protein function remains at this point unknown. In addition, the interaction of PD-L1 with clinical antibodies is also affected by glycosylation. In conclusion, our study demonstrates that PD-L1 expressed in the MDA-MB-231 breast cancer cells carries polyLacNAc glycans mostly at the N219 sequon which displays the highest variability in occupancy and is most likely to directly influence the interaction with PD-1.
An integrative oncogene-dependency map identifies unique vulnerabilities of oncogenic EGFR, KRAS, and RIT1 in lung cancer
Authors: Vichas Athea , Nkinsi Naomi T. , Riley Amanda , Parrish Phoebe C.R. , Duke Fujiko , Chen Jenny , Fung Iris , Watson Jacqueline , Rees Matthew , Lee John K. , Piccioni Federica , Hatch Emily M. , Berger Alice H. 
Published: July 2020

ABSTRACTAdvances in precision oncology have transformed cancer therapy from broadly-applied cytotoxic therapy to personalized treatments based on each tumor’s unique molecular alterations. Here we investigate the oncogene-specific dependencies conferred by lung cancer driver variants ofKRAS, EGFR, andRIT1. Integrative analysis of genome-wide CRISPR screens in isogenic cell lines identified shared and unique vulnerabilities of each oncogene. The non-identical landscape of dependencies underscores the importance of genotype-guided therapies to maximize tumor responses. Combining genetic screening data with small molecule sensitivity profiling, we identify a unique vulnerability ofRIT1-mutant cells to loss of spindle assembly checkpoint regulators. This sensitivity may be related to a novel role of RIT1 in mitosis; we find that oncogenic RIT1M90Ialters mitotic timing via weakening of the spindle assembly checkpoint. In addition, we uncovered a specific cooperation of mutantRIT1with loss of Hippo pathway genes. In human lung cancer,RIT1mutations and amplifications frequently co-occur with loss of Hippo pathway gene expression. These results provide the first genome-wide atlas of oncogenicRIT1-cooperating factors and genetic dependencies and identify components of the RAS pathway, spindle assembly checkpoint, and Hippo/YAP1 network as candidate therapeutic targets inRIT1-mutant lung cancer.
ULK1 forms distinct oligomeric states and nanoscopic structures during autophagy initiation
Authors: Banerjee Chiranjib , Mehra Dushyant , Song Daihyun , Mancebo Angel , Kim Do-Hyung , Puchner Elias M. 
Published: July 2020

AbstractAutophagy induction involves extensive molecular and membrane reorganization. Despite significant progress, the mechanism underlying autophagy initiation remains poorly understood. Here, we used quantitative Photoactivated Localization Microscopy with single-molecule sensitivity to analyze the nanoscopic distribution of endogenous ULK1, the kinase that triggers autophagy. Under amino acid starvation, ULK1 formed large clusters containing up to 161 molecules at the endoplasmic reticulum. Cross-correlation analysis revealed that ULK1 clusters engaging in autophagosome formation require 30 or more molecules. The ULK1 structures with more than the threshold number contained varying levels of Atg13, Atg14, Atg16, LC3B, GEC1 and WIPI2. We found that ULK1 activity is dispensable for the initial clustering of ULK1, but necessary for the subsequent expansion of the clusters, which involves interaction with Atg14, Atg16, and LC3B and relies on Vps34 activity. This quantitative analysis at the single molecule level has provided unprecedented insights into the behavior of ULK1 during autophagy initiation.
DNA methylation in the upstream CpG island of the GPER locus and its relationship with GPER expression in colon cancer cell lines
Authors: Pal Uttariya , Ghosh Sujasha , Limaye Anil Mukund 
Published: July 2020

AbstractThe seven-transmembrane G-protein coupled estrogen receptor (GPER) relays short-term non-genomic responses in target cells and tissues. It is a proposed tumor suppressor, which frequently undergoes down-modulation in primary tumors of the breast, ovary, and endometrium. A study by Liu and co-workers reported the loss of GPER expression in colorectal cancer and attributed it to DNA methylation-dependent silencing. The present study is based on the hypothesis that GPER expression is inversely correlated with methylation in the upstream CpG island (upCpGi) in the GPER locus. Methylation in the upCpGi was analysed by bisulfite sequencing and correlated with GPER expression in a panel of colon cancer cell lines The bisulfite sequencing results show the presence of a differentially methylated region (DMR) comprising of the downstream eight CpGs of the upCpGi. Methylation in the DMR correlated inversely with GPER expression. We compared two cell lines, namely SW620 and COLO-320DM, in terms of their viability in response to varying concentrations of G1, a GPER specific agonist, which is known to induce cell cycle arrest and apoptosis in colon cancer cell lines. SW-620 cells, which had the least methylated DMR and the highest level of GPER expression, showed significant loss of viability with 1 μM G1. On the other hand, COLO-320DM, which had the most methylated DMR and the lowest level of GPER expression, did not show a significant response to 1 μM G1. At 5 μM G1, SW620 cells showed a greater reduction in viability than COLO-320DM cells. Our study demonstrates the inverse correlation between DNA methylation in the DMR and GPER expression. GPER is a non-canonical form of estrogen receptor, and estrogen is believed to exert its oncoprotective effect in the colon via GPER. DNA methylation-dependent silencing of GPER may, at least in part, the underlying reason behind the loss of estrogen’s oncoprotective effect in the colon. Future studies should explore the utility of DNA methylation in the upCpGi, particularly the DMR, in diagnosis or prognosis.
BRG1 promotes transcriptional patterns that are permissive to proliferation in cancer cells
Authors: Giles Katherine A. , Gould Cathryn M. , Achinger-Kawecka Joanna , Page Scott G. , Kafer Georgia , Luu Phuc-Loi , Cesare Anthony J. , Clark Susan J. , Taberlay Phillippa C. 
Published: July 2020

ABSTRACTBackgroundBRG1 (encoded bySMARCA4) is a catalytic component of the SWI/SNF chromatin remodelling complex, with key roles in modulating DNA accessibility. Dysregulation of BRG1 is observed, but functionally uncharacterised, in a wide range of malignancies. We have probed the functions of BRG1 on a background of prostate cancer to investigate how BRG1 controls gene expression programs and cancer cell behaviour.ResultsOur investigation ofSMARCA4revealed that BRG1 is universally overexpressed in 486 tumours from The Cancer Genome Atlas prostate cohort, as well as in a complementary panel of 21 prostate cell lines. Next, we utilised a temporal model of BRG1 depletion to investigate the molecular effects on global transcription programs. Unexpectedly, depleting BRG1 had no impact on alternative splicing and conferred only modest effect on global expression. However, of the transcriptional changes that occurred, most manifested as down-regulated expression. Deeper examination found the common thread linking down-regulated genes was involvement in proliferation, including several known to increase prostate cancer proliferation (KLK2,PCAT1andVAV3). Interestingly, the promoters of genes driving proliferation were bound by BRG1 as well as the oncogenic transcription factors, AR and FOXA1. We also noted that BRG1 depletion repressed genes involved in cell cycle progression and DNA replication but intriguingly, these pathways operated independently of AR and FOXA1. In agreement with transcriptional changes, depleting BRG1 conferred G1 arrest.ConclusionsOur data have revealed that BRG1 has capacity to drive oncogenesis by coordinating oncogenic pathways dependent on BRG1 for proliferation, cell cycle progression and DNA replication.
Psychiatric symptoms, risk, and protective factors among university students in quarantine during the COVID-19 pandemic in China
Authors: Sun Shufang , Goldberg Simon B. , Lin Danhua , Qiao Shan , Operario Don 
Published: July 2020

AbstractThis study investigated psychiatric symptoms (depression, anxiety, and traumatic stress) during state-enforced quarantine among university students in China. We conducted a cross-sectional survey with 1,912 university students during March and April 2020. Psychiatric symptoms in the mild or higher range based on clinical cut-offs were alarmingly prevalent: 67.05% reported traumatic stress symptoms, 46.55% had depressive symptoms, and 34.73% reported anxiety symptoms. Further, 19.56% endorsed some degree of suicidal ideation. We explored factors that may contribute to poor psychological health as well as those that may function as protective factors. Risk and protective factors examined included demographic variables, two known protective factors for mental health (mindfulness, perceived social support), four COVID-specific factors (COVID-19 related efficacy, perceived COVID-19 threat, perceived COVID-19 societal stigma, COVID-19 prosocial behavior) and screen media usage. Across psychiatric symptom domains, mindfulness was associated with lower symptom severity, while COVID-19 related financial stress, perceived COVID-19 societal stigma, and perceived COVID-19 threat were associated with higher symptom severity. COVID-19 threat and COVID-19 stigma showed main and interactive effects in predicting all mental health outcomes, with their combination associated with highest symptom severity. Average screen media device usage was 6 hours and usage was positively associated with depression. Female gender and COVID-19 prosocial behavior were associated with higher anxiety, while COVID-19 self-efficacy associated with lower anxiety symptoms. Study limitations and implications for treatment and prevention of affective disorders during crisis are discussed.
Kinetics and performance of the Abbott Architect SARS-CoV-2 IgG antibody assay
Authors: Hamilton Fergus , Muir Peter , Attwood Marie , Noel Alan , Vipond Barry , Hopes Richard , Moran Ed , Maskell Nick , Warwick Deborah , Albur Mahableshwar , Turner Jonathan , MacGowan Alasdair , Arnold David 
Published: July 2020

ObjectivesTo assess the performance (sensitivity and specificity) of the Abbott Architect SARS-CoV-2 IgG antibody assay across three clinical settings.MethodsAntibody testing was performed on three clinical cohorts of COVID-19 disease: hospitalised patients with PCR confirmation, hospitalized patients with a clinical diagnosis but negative PCR, and symptomatic healthcare workers (HCW’s). Pre-pandemic respiratory infection sera were tested as negative controls. The sensitivity of the assay was calculated at different time points (<5 days, 5-9 days, 10-14 days, 15-19 days, >20 days, >42 days), and compared between cohorts.ResultsPerformance of the Abbot Architect SARS-CoV-2 assay varied significantly between cohorts. For PCR confirmed hospitalised patients (n = 114), early sensitivity was low: <5 days: 44.4% (95%CI: 18.9%-73.3%), 5-9 days: 32.6% (95%CI, 20.5%-47.5%), 10-14 days: 65.2% (95% CI 44.9%-81.2%), 15-20 days: 66.7% (95% CI: 39.1%-86.2%) but by day 20, sensitivity was 100% (95%CI, 86.2-100%).In contrast, 17 out of 114 symptomatic healthcare workers tested at >20 days had negative results, generating a sensitivity of 85.1% (95%CI, 77.4% - 90.5%). All pre-pandemic sera were negative, a specificity of 100%. Seroconversion rates were similar for PCR positive and PCR negative hospitalised cases.ConclusionsThe sensitivity of the Abbot Architect SARS-CoV-2 IgG assay increases over time, with sensitivity not peaking until 20 days post symptoms. Performance varied markedly by setting, with sensitivity significantly worse in symptomatic healthcare workers than in the hospitalised cohort. Clinicians, policymakers, and patients should be aware of the reduced sensitivity in this setting.
Timing of PCR and Antibody Testing in Patients with COVID-19 associated dermatologic manifestations
Authors: Freeman Esther E. , McMahon Devon E. , Fox Lindy P. , Fassett Marlys S. 
Published: July 2020

A recent study from Spain noted 40 patients with chilblain-like lesions in suspected COVID-19.1 None tested PCR positive for SARS-CoV-2, but 30% had detectable antibodies. The rapid increase in chilblain/pernio-like cases during the COVID-19 pandemic is likely SARS-CoV-2-associated. The relationship between skin symptom onset and COVID-19 PCR/antibody test timing, however, remains uncharacterized.We established an international registry for cutaneous manifestations of COVID-19.2, 3 Providers reported time between dermatologic symptom onset and positive/negative COVID-19 laboratory results, when available.From 8 April-30 June, 2020, 906 laboratory-confirmed or suspected COVID-19 cases with dermatologic manifestations were reported, 534 of which were chilblains/pernio.3 Among PCR-tested patients, 57%(n=208) overall and 15%(n=23) of chilblains/pernio cases were PCR-positive. Antibody positivity was 37%(n=39) overall and 19%(n=15) for chilblains/pernio.We evaluated 163 patients with timing information on PCR and/or antibody testing (Table 1). For patients with suspected COVID-19 and any cutaneous manifestation, PCR-positive testing occurred median 6 (IQR 1-14) days after dermatologic symptoms started while PCR-negative testing occurred median 14 (IQR 7-24) days later. For patients with pernio/chilblains, PCR-positivity was noted 8 (IQR 5-14) days after symptoms and negativity median 14 (IQR 7-28) days later. Antibody testing (IgM or IgG) was positive median 30 (IQR 19-39) days after symptom onset for all dermatologic manifestations and 27 (IQR 24-33) days after chilblains/pernio onset.Like Hubiche et al, our data highlight the low frequency of SARS-CoV-2 PCR+ testing in COVID-19 patients with cutaneous manifestations. Positive predictive values for COVID-19 PCR are influenced by viral shedding kinetics, which are difficult to assess in non-respiratory presentations.4 Our data reveal that early PCR testing is more likely to be positive than later testing, even when date-of-onset is defined by cutaneous manifestations rather than systemic symptoms.Most COVID-19 antibody data are from systemically-ill patients; the kinetics of antibody production in mild-to-moderate COVID-19 infections remain unclear.5 Here, positive antibodies resulted median 30 days from disease onset, beyond the frequently used 14-21 day testing window. In outpatients with true infection, many factors influence the likelihood of a positive antibody result: antibody production, test availability, assay sensitivity, and timing of care-seeking in relation to symptom-onset. These variables influence our interpretation of individual test results and our understanding of the association between pernio and COVID-19.More population-level testing data is necessary to optimize diagnostic test timing. Positive identification of COVID-19 in minimally-symptomatic patients, including patients with skin findings, is critical to the public health effort.
Chronic exposure to IL6 leads to deregulation of glycolysis and fat accumulation in the zebrafish liver
Authors: Singh Manoj K , Jayarajan Rijith , Varshney Swati , Upadrasta Sindhuri , Singh Archana , Yadav Rajni , Scaria Vinod , Sengupta Shantanu , Shanmugam Dhanasekaran , Shalimar  , Sivasubbu Sridhar , Gandotra Sheetal , Sachidanandan Chetana 
Published: July 2020

AbstractBACKGROUND AND AIMSInflammation is a constant in Non-Alcoholic Fatty Liver Disease (NAFLD) and is usually considered a consequence. We propose that inflammation can be a cause for NAFLD. Obesity is strongly associated with (NAFLD), but not always. NAFLD in lean individuals is more common in certain populations, especially Asian-Indians. Lean healthy Indians also have a higher basal circulating IL6 suggesting a link with inflammation. We propose that inflammation-induced fatty liver could be relevant for studying obesity-independent NAFLD. Commonly used high-fat diet-induced NAFLD animal models are not ideal for testing this hypothesis.APPROACH AND RESULTSIn this study we used a transgenic zebrafish with chronic systemic overexpression of human IL6 (IL6-OE) and found accumulation of triglyceride in the liver. We performed comparative transcriptomics and proteomics on the IL6-OE liver and found an expression signature distinct from the diet-based NAFLD models. We discovered a deregulation of glycolysis/gluconeogenesis pathway, especially a robust down regulation of the glycolytic enzymealdolase bin the IL6-OE liver. Metabolomics of the IL6-OE liver showed accumulation of hexose monophosphates and their derivatives, which can act as precursors for triglyceride synthesis. Patients with the genetic disease Hereditary Fructose Intolerance (HFI) caused byALDOLASE Bdeficiency also have a higher propensity to develop fatty liver disease.CONCLUSIONSOur study demonstrates a causative role for inflammation in intrahepatic lipid accumulation. Further, our results suggest that IL6-driven repression of glycolysis/gluconeogenesis, specificallyaldolase b, may be a novel mechanism for development of fatty liver, especially in obesity-independent NAFLD.
NCBP3 is a productive mRNP component
Authors: Dou Yuhui , Barbosa Isabelle , Jiang Hua , Iasillo Claudia , Molloy Kelly R. , Schulze Wiebke Manuela , Cusack Stephen , Schmid Manfred , Le Hir Hervé , LaCava John , Jensen Torben Heick 
Published: July 2020

AbstractThe nuclear Cap Binding Complex (CBC), consisting of Nuclear Cap Binding Protein 1 (NCBP1) and 2 (NCBP2), associates with the nascent 5’cap of RNA polymerase II transcripts and impacts RNA fate decisions. Recently, the C17orf85 protein, also called NCBP3, was suggested to form an alternative CBC by replacing NCBP2. However, applying protein-protein interaction screening of NCBP1, 2 and 3, we find that the interaction profile of NCBP3 is distinct. Whereas NCBP1 and 2 identify known CBC interactors, NCBP3 primarily interacts with components of the Exon Junction Complex (EJC) and the TRanscription and EXport (TREX) complex. NCBP3-EJC associationin vitroandin vivorequires EJC core integrity and thein vivoRNA binding profiles of EJC and NCBP3 overlap. We further show that NCBP3 competes with the RNA degradation factor ZC3H18 for binding CBC-bound transcripts, and that NCBP3 positively impacts the nuclear export of polyadenylated RNAs and the expression of large multi-exonic transcripts. Collectively, our results place NCBP3 with the EJC and TREX complexes in supporting the productive fate of mRNA.
MOD: A novel machine-learning optimal-filtering method for accurate and efficient detection of subthreshold synaptic eventsin vivo
Authors: Zhang Xiaomin , Schlögl Alois , Vandael David , Jonas Peter 
Published: July 2020

AbstractTo understand the mechanisms of information coding in single neurons, it is necessary to analyze subthreshold synaptic events, action potentials (APs), and the interrelation between these two forms of activity in different behavioral states. However, detecting excitatory postsynaptic potentials (EPSPs) or currents (EPSCs) in awake, behaving animals remains challenging, because of unfavorable signal-to-noise ratio, high frequency, fluctuating amplitude, and variable time course of synaptic events. Here, we developed a new method for synaptic event detection, termed MOD (Machine-learningOptimal-filteringDetection-procedure), which combines concepts of supervised machine learning and optimal Wiener filtering. First, experts were asked to manually score short epochs of data. Second, the algorithm was trained to obtain the optimal filter coefficients of a Wiener filter and the optimal detection threshold. Third, scored and unscored data were processed with the optimal filter, and events were detected as peaks above threshold. Finally, the area under the curve (AUC) of the receiver operating characteristics (ROC) curve was used to quantify accuracy and efficiency of detection. Additionally, cross-validation was performed to exclude overfitting of the scored data, a potential concern with machine-learning approaches. We then challenged the new detection method with EPSP tracesin vivoin mice during spatial navigation and EPSC tracesin vitroin slices under conditions of enhanced transmitter release. When benchmarked using a (1−AUC)−1metric, MOD outperformed previous methods (template-fit and deconvolution) by a factor of up to 3. Thus, MOD may become an important tool for large-scale analysis of synaptic activityin vivoandin vitro.HighlightsA new method for detection of synaptic events, termed MOD, is describedThe method combines the concepts of supervised machine learning and optimal filteringThe method is useful for analysis of bothin vitroandin vivodata setsMOD outperforms previously published methods for synaptic event detection by a factor of up to 3