bluuebunny/crossref_metadata_2025 huggingface dataset:
The sensitivity of respiratory tract specimens for the detection of SARS-CoV-2: A protocol for a living systematic review and meta-analysis
Authors: Moore Adam J. , Nakahata Maura I. , Kalinich Chaney C. , Nyhan Kate , Bromberg Daniel J. , Shi Xiaoting , Ko Albert I. , Grubaugh Nathan D. , Casanovas-Massana Arnau , Wyllie Anne L.
Published: July 2020

Background

Highly sensitive, non-invasive, and easily accessible diagnostics for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are essential for the control of the Coronavirus Disease 2019 (COVID-19) pandemic. There is a clear need to establish a gold standard diagnostic for SARS-CoV-2 infection in humans using respiratory tract specimens.

Methods

Searches will be conducted in the bibliographic databases Medline, Embase, bioRxiv, medRxiv, F1000, ChemRxiv, PeerJ Preprints, Preprints.org, Beilstein Archive, and Research Square. Relevant government documents and grey literature will be sought on the FDA’s Emergency Use Authorizations website, the ECDC’s website, and the website of the Foundation for Innovative New Diagnostics. Finally, papers categorized as diagnosis papers by the EPPI Centre’s COVID-19 living systematic map will be added to our screening process; those papers are tagged with the diagnosis topic based on human review, rather than database searches, and thus this set of papers might include ones that have not been captured by our search strategy.
Genome-wide association meta-analysis supports genes involved in valve and cardiac development to associate with mitral valve prolapse
Authors: Yu Mengyao , Kyryachenko Sergiy , Debette Stephanie , Amouyel Philippe , Schott Jean-Jacques , Tourneau Thierry Le , Dina Christian , Norris Russell A , Hagège Albert A. , Jeunemaitre Xavier , Bouatia-Naji Nabila
Published: July 2020

Objective

Mitral valve prolapse (MVP) is a common cardiac valve disease, which affects 1 in 40 in the general population. Previous GWAS have identified six risk loci for MVP. But these loci explained only partially the genetic risk for MVP. We aim to identify additional risk loci for MVP by adding a dataset from the UK Biobank.

Approaches and Results

We re-analyzed 1,007/1,469 cases and 479/862 controls from the MVP-France study and the MVP-Nantes study, respectively. We re-imputed genotypes using HRC and TOPMed, and found this latter to perform better in terms of accuracy in the lower ranges of minor allele frequency (MAF) below 0.1. We then incorporated 434 MVP cases and 4,527 controls from the UKBiobank and conducted a meta-analysis GWAS including ∼2000 MVP cases and over 6,800 controls for ∼8 million genotyped or imputed common SNPs (MAF>0.01). We replicated the association on chr2 and now provide a finer association map nearTNS1. We identified three suggestive risk loci, all driven by common variants on Chr1 (SYT2), Chr8 (MSRA), and Chr19 (FBXO46). Gene-based association using MAGMA revealed 15 risk genes for MVP includingGLIS1, TGFB2, ID2, TBX5, MSRA, andDMPK. Extensive functional annotation showed that genes associated with MVP are highly expressed in cardiovascular tissues, especially heart, and are involved in cardiac development and potentially aging.

Conclusions

We report an updated meta-analysis GWAS for MVP using dense imputation coverage and an improved case-control sample. We describe several loci and genes with MVP spanning biological mechanisms highly relevant to MVP, especially during valve and heart development.

TOC category - basic and population studies

TOC subcategory - Arteriosclerosis, Thrombosis, and Vascular Biology

Highlights

Provide high coverage meta-analysis of GWAS based on TOPMed imputation involving ∼8 million common variants in ∼2000 MVP patients and ∼6800 controls.

Low frequency variant contributed little to the association of the genes mentioned, where the associations were driven by common variants

Several association loci involve genes related to cardiac development and potentially aging.
Exposure assessment for airborne transmission of SARS-CoV-2 via breathing, speaking, coughing and sneezing
Authors: Schijven Jack , Vermeulen Lucie C. , Swart Arno , Meijer Adam , Duizer Erwin , de Roda Husman Ana Maria
Published: July 2020

Background

Evidence for indoor airborne transmission of SARS-CoV-2 is accumulating. If SARS-CoV-2 also spreads via aerosols, this has implications for measures taken to limit transmission.

Objectives

The aim of this study is to assess exposure to airborne SARS-CoV-2 particles from breathing, speaking, coughing and sneezing in an indoor environment.

Methods

An exposure assessment model was developed to estimate numbers of SARS-CoV-2 particles in aerosol droplets, expelled during breathing, speaking, coughing and sneezing by an infected person in an unventilated indoor environment, and subsequent inhalation by one or more persons. Scenarios encompass a range of virus concentrations, room sizes and exposure times.

Results

The calculated total volume of expelled aerosol droplets was highest for a sneeze, followed by a cough and speaking for 20 minutes, and lastly breathing for 20 minutes. A few to as much as tens of millions of virus particles were expelled. Exposure probability strongly depends on the viral concentration in mucus, as well as on the scenario. Exposure probabilities were generally below 1% at a virus concentration in mucus below 105 per mL for all scenarios, increasing steeply at different higher concentrations. According to nose / throat swab data collected from patients, 75%, 50% and 5% of infected individuals carry an estimated number of SARS-CoV-2 per mL mucus of at least 105, 106 and 108, respectively.

Discussion

Exposure to SARS-CoV-2 via aerosols generated during breathing, speaking, coughing and sneezing in an unventilated indoor environment is possible. This study forms a basis to estimate probabilities of exposure to SARS-Cov-2 by airborne transmission in indoor spaces. As long as it is uncertain what fraction of the airborne virus particles is infectious and as long as a dose response relation is lacking, it is recommended to be precautious.
The reproduction number R for COVID-19 in England: Why hasn’t “lockdown” been more effective?
Authors: Grant Alastair
Published: July 2020

The reproduction number R, the average number of people that a single individual with a contagious disease infects, is central to understanding the dynamics of the COVID-19 epidemic. Values greater than one correspond to increasing rates of infection, and values less than one indicate that control measures are being effective. Here, we summarise how changes in the behaviour of individuals alter the value of R. We also use matrix models that correctly recreate distributions of times that individuals spend incubating the disease and being infective to demonstrate the accuracy of a simple approximation to estimate R directly from time series of case numbers, hospital admissions or deaths. The largest uncertainty is that the generation time of the infection is not precisely known, but this challenge also affects most of the more complex methods of calculating R. We use this approximation to examine changes in R in response to the introduction of “lockdown” restrictions in England. This suggests that there was a substantial reduction in R before large scale compulsory restrictions on economic and social activity were imposed on 23rd March 2020. From mid-April to mid-June decline of the epidemic at national and regional level has been relatively slow, despite these restrictions (R values clustered around 0.81). However, these estimates of R are consistent with the relatively high average numbers of close contacts reported by confirmed cases combined with directly measured attack rates via close interactions. This implies that a significant portion of transmission is occurring in workplaces; overcrowded housing or through close contacts that are not currently lawful, routes on which nationwide lockdown will have limited impact.
Clinical Characteristics of Recurrent-positive Coronavirus Disease 2019 after Curative Discharge: a retrospective analysis of 15 cases in Wuhan China
Authors: Chen Lan , Zhang Zhen-Yu , Zhang Xiao-Bin , Zhang Su-Zhen , Han Qiu-Ying , Feng Zhi-Peng , Fu Jian-Guo , Xiao Xiong , Chen Hui-Min , Liu Li-Long , Chen Xian-Li , Lan Yu-Pei , Zhong De-Jin , Hu Lan , Wang Jun-Hui , Yin Zhen-Yu
Published: July 2020

In China, the patients with previously negative RT-PCR results again test positive during the post-discharge isolation period. We aimed to determine the clinical characteristics of these “recurrent-positive” patients. We retrospectively reviewed the data of 15 recurrent-positive patients and 107 control patients with non-recurrent, moderate COVID-19 treated in Wuhan, China. Clinical data and laboratory results were comparatively analyzed. We found that recurrent-positive patients had moderate disease. The rate of recurrent-positive disease in our hospital was 1.87%. Recurrent-positive patients were significantly younger (43(35-54) years) than control patients (60(43-69) years) (P=0.011). The early LOS (length of stay in hospital before recurrence) was significantly longer in recurrent-positive patients (36(34-45) days) than in control patients (15(7-30) days) (P =0.001). The time required for the first conversion of RT-PCR results from positive to negative was significantly longer in recurrent-positive patients (14(10-17) days) than in control patients (6(3-9) days) (P =0.011). Serum COVID-19 antibody levels were significantly lower in recurrent-positive patients than in control patients (IgM: 13.69 ± 4.38 vs. 68.10 ± 20.85 AU/mL, P = 0.015; IgG: 78.53 ± 9.30 vs. 147.85 ± 13.33 AU/mL, P < 0.0001). Recurrent-positive patients were younger than control patients. The early LOS (length of stay in hospital before recurrence) was significantly longer in recurrent-positive group than that in control group. COVID-19 IgM/IgG antibody levels were significantly lower in recurrent-positive group than those in control group, which might explain why the virus RNA RT-PCR was positive after the initial “clinical cure”(with three times of virus RNA RT-PCR negative). The virus might not be fully eliminated because of the lower IgG level and their later replicating might result in recurrent-positive virus RNA RT-PCR.
Curve-fitting approach for COVID-19 data and its physical background
Authors: Nishimoto Yoshiro , Inoue Kenichi
Published: July 2020

Forecast of the peak-out and settling timing of COVID-19 at an early stage should help the people how to cope with the situation. Curve-fitting method with an asymmetric log-normal function has been applied to daily confirmed cases data in various countries. Most of the curve-fitting could show good forecasts, while the reason has not been clearly shown. The K value has recently been proposed which can provide good reasoning of curve-fitting mechanism by corresponding a long and steep slope on the K curve with fitting stability. Since K can be expressed by a time differential of logarithmic total cases, the physical background of the above correspondence was discussed in terms of the growth rate in epidemic entropy.
Prediction of COVID-19 Active and Total Cases After a Fall and Rise of Cases
Authors: Viswanath Narayanan C.
Published: July 2020

During the progress of the COVID-19, many countries have observed that their active cases tend to rise again after falling for some time. This may cause some mathematical models like the one discussed in [2] tend to make errors in the future prediction. We discuss a simple method to better the future prediction in such cases. This method is applied on the active and total cases data for the countries USA and Canada. In the case of Canada, the method succeeded in predicting the date when the active cases began to decrease. In the case of USA, a major improvement in prediction was observed when the method was applied: the predicted active and total cases are 1465602 and 2729015 for June 30; whereas the actual values are 1455400 and 2728856. We also give the active and total cases prediction for Canada and the USA for the first week of July 2020.
Association of SARS-CoV-2 Genomic Load with COVID-19 Patient Outcomes
Authors: Zacharioudakis Ioannis M. , Prasad Prithiv J. , Zervou Fainareti N. , Basu Atreyee , Inglima Kenneth , Weisenberg Scott A. , Aguero-Rosenfeld Maria E.
Published: July 2020

Rationale

The Infectious Diseases Society of America has identified the use of SARS-CoV-2 genomic load for prognostication purposes as a key research question.

Objectives

We explored the SARS-CoV-2 genomic load as a risk factor for adverse patient outcomes.

Methods

A retrospective cohort study among adult patients admitted to the hospital between March 31st to April 10th, 2020 with COVID-19 pneumonia was conducted. We segregated patients into 3 genomic load groups: low (Cycle threshold (Ct) ≥35), intermediate (25<Ct<35), and high (Ct≤ 25) using real-time polymerase chain reaction.

Measurements

A composite outcome of death, intubation, and/or extracorporeal membrane oxygenation was used. Secondary outcomes included the severity of pneumonia on admission, as measured by the Pneumonia Severity Index (PSI).

Main Results

Of 457 patients with COVID-19 pneumonia from March 31st to April 10th, 2020, 316 met inclusion criteria. Included patients were followed for a median of 25days (IQR 21-28). High genomic load at presentation was associated with higher Charlson Comorbidity Index (p=0.005), transplant recipient status (p<0.001), and duration of illness less than 7 days (p=0.005). Importantly, patients with high genomic load were more likely to reach the primary endpoint (p=0.001), and had higher PSI scores on admission (p=0.03). In multivariate analysis, a high genomic load remained an independent predictor of the primary outcome. Results remained significant in sensitivity analyses.

Conclusions

Our findings suggest that a high genomic load of SARS-CoV-2 at the time of admission is an independent predictor of adverse outcomes, that above and beyond age, comorbidity, and severity of illness on presentation, may be used to risk-stratify patients, and call for a quantitative diagnostic assay to become available.
Assessing the burden of COVID-19 amongst healthcare workers in Mexico City: A data-driven call to action
Authors: Antonio-Villa Neftali Eduardo , Bello-Chavolla Omar Yaxmehen , Vargas-Vázquez Arsenio , Fermín-Martínez Carlos A. , Márquez-Salinas Alejandro , Pisanty-Alatorre Julio , Bahena-López Jessica Paola
Published: July 2020

BACKGROUND

Health-care workers (HCWs) could be at increased occupational risk for SARS-CoV-2 infection due to increased exposure. Information regarding the burden of COVID-19 epidemic in HCWs living in Mexico is scarce. Here, we aimed to explore the epidemiology, symptoms, and risk factors associated with adverse outcomes in HCWs in Mexico City.

METHODS

We explored data collected by the National Epidemiological Surveillance System in Mexico City, in HCWs who underwent real-time RT-PCR test. We explored COVID-19 outcomes in HCWs and the performance of symptoms to detect SARS-CoV-2 infection.

RESULTS

As of September 20th, 2020, 57,758 HCWs were tested for SARS-CoV-2 and 17,531 were confirmed (30.35%); 6,610 were nurses (37.70%), 4,910 physicians (28.0%), 267 dentists (1.52%) and 5,744 laboratory personnel and other HCWs (32.76%). Overall, 2,378 HCWs required hospitalization (4.12%), 2,648 developed severe COVID-19 (4.58%), and 336 required mechanical-ventilatory support (0.58%). Lethality was recorded in 472 (0.82%) cases. We identified 635 asymptomatic SARS-CoV-2 infections (3.62%). Compared with general population, HCWs had higher incidence, testing, asymptomatic and mortality rates. No individual symptom offers adequate performance to detect SARS-CoV2. Older HCWs with chronic non-communicable diseases and severe respiratory symptoms were associated with higher risk for adverse outcome; physicians were at higher risk compared with nurses and other HCWs.

CONCLUSIONS

We report a high prevalence of SARS-CoV-2 infection in HCWs in Mexico City. Symptoms as a screening method is not efficient to discern those HCWs with a positive PCR-RT test. Particular attention should focus on HCWs with risk factors to prevent adverse outcomes.
Association of Sickle Cell Trait with Risk and Mortality of COVID-19: Results from the UK Biobank
Authors: Resurreccion W. Kyle , Shi Zhuqing , Wei Jun , Na Rong , Zheng S. Lilly , Hulsizer Joseph , Struve Clay , Helfand Brian T. , Khandekar Janardan , Caplan Michael S. , Xu Jianfeng
Published: July 2020

We tested the hypothesis that patients with sickle cell trait (SCT), a common condition in individuals of African descent, have increased risk and mortality for coronavirus disease (COVID-19) in the UK Biobank. By June 17, 2020, 1,550 of 7,668 (20%) tested subjects were positive for COVID-19, including 298 (19%) deaths. Blacks had higher rates than Whites for COVID-19 infections (79/222=36% vs. 1,342/7,010=19%,P=1.28×10−9). Among Blacks, SCT carriers did not have higher infection rates (5/15=33%) than non-SCT carriers (74/207=36%),P=1.00. However, SCT carriers had a trend of higher death rates (2/5=40%) than non-SCT carriers (12/74=16%), although not statistically significant (P=0.21).
Early COVID-19 Interventions Failed to Replicate 1918 St. Louis vs. Philadelphia Outcomes in the United States
Authors: Jalali Aliea M. , Peterson Brent M. , Galbadage Thushara
Published: July 2020

The Coronavirus disease 2019 (COVID-19) pandemic has elicited an abrupt pause in the United States in multiple sectors of commerce and social activity. As the US faces this health crisis, the magnitude, and rigor of their initial public health response was unprecedented. As a response, the entire nation shutdown at the state-level for the duration of approximately one to three months. These public health interventions, however, were not arbitrarily decided, but rather, implemented as a result of evidence-based practices. These practices were a result of lessons learned during the 1918 influenza pandemic and the city-level non-pharmaceutical interventions (NPIs) taken across the US. During the 1918 pandemic, two model cities, St. Louis, MO, and Philadelphia, PA, carried out two different approaches to address the spreading disease, which resulted in two distinctly different outcomes. Our group has evaluated the state-level public health response adopted by states across the US, with a focus on New York, California, Florida, and Texas, and compared the effectiveness of reducing the spread of COVID-19. Our assessments show that while the states mentioned above benefited from the implementations of early preventative measures, they inadequately replicated the desired outcomes observed in St. Louis during the 1918 crisis. Our study indicates that there are other factors, including health disparities that may influence the effectiveness of public health interventions applied. Identifying more specific health determinants may help implement targeted interventions aimed at preventing the spread of COVID-19 and improving health equity.
COVID-19 associated anxiety enhances tinnitus
Authors: Xia Li , He Gang , Feng Yong , Yu Xiaoxu , Zhao Xiaolong , Chen Zhengnong , Yin Shankai , Wang Jian , Fan Jiangang , Dong Chuan
Published: July 2020

Objectives

To investigate if the anxiety associated with COVID-19 is a promoting factor to tinnitus.

Methods

A retrospective research design was used to compare the clinical characteristics of tinnitus between the patients in 2020 under pandemic pressure and those from the matching period in 2019. While anxiety was quantified using the Zung’s Self-rating Anxiety Scale (SAS), tinnitus severity was evaluated using the Tinnitus Handicap Inventory (THI) questionnaire and the test of minimum masking level (MML). The assessments were repeated after the sound therapy plus educational counselling (STEC) and compared with EC alone therapy.

Results

A large increase in anxiety was evident in 2020 in both case rate and SAS. The treatment of both methods was less effective in 2020. SAS, THI and MML were all deteriorated after the EC alone treatment in 2020, while an improvement was seen in 2019. This suggests that EC alone could not counteract the stress by COVID-19 at all, and the stress, if not managed well, can significantly increase the severity of tinnitus and associated anxiety.

Conclusions

By using the EC subgroup in virtual control, we conclude that anxiety can serve as a promoting factor to tinnitus. We believe that this is the first study report that confirm the causative/promotive role of anxiety on tinnitus.
The potential role of miR-21-3p in coronavirus-host interplay
Authors: Nersisyan Stepan , Engibaryan Narek , Gorbonos Aleksandra , Kirdey Ksenia , Makhonin Alexey , Tonevitsky Alexander
Published: July 2020

Host miRNAs are known as important regulators of virus replication and pathogenesis. They can interact with various viruses by several possible mechanisms including direct binding the viral RNA. Identification of human miRNAs involved in coronavirus-host interplay is becoming important due to the ongoing COVID-19 pandemic. In this work we performed computational prediction of high-confidence direct interactions between miRNAs and seven human coronavirus RNAs. In order to uncover the entire miRNA-virus interplay we further analyzed lungs miRNome of SARS-CoV infected mice using publicly available miRNA sequencing data. We found that miRNA miR-21-3p has the largest probability of binding the human coronavirus RNAs and being dramatically up-regulated in mouse lungs during infection induced by SARS-CoV. Further bioinformatic analysis of binding sites revealed high conservativity of miR-21-3p binding regions within RNAs of human coronaviruses and their strains.
BAZ2A association with H3K14ac is required for the transition of prostate cancer cells into a cancer stem-like state
Authors: Peña-Hernández Rodrigo , Aprigliano Rossana , Frommel Sandra , Pietrzak Karolina , Steiger Seraina , Roganowicz Marcin , Bizzarro Juliana , Santoro Raffaella
Published: July 2020

Prostate cancer (PCa) is one of the most prevalent cancers in men. Cancer stem cells are thought to be associated with PCa relapse. Here we show that BAZ2A is required for the transition of PCa cells into a cancer stem-like state. BAZ2A genomic occupancy in PCa cells coincides with H3K14ac enriched chromatin regions. This association is mediated by BAZ2A-bromodomain (BAZ2A-BRD) that specifically binds H3K14ac. BAZ2A associates with inactive enhancers marked by H3K14ac and repressing transcription of genes frequently silenced in aggressive and poorly differentiated PCa. BAZ2A-mediated repression is also linked to EP300 that acetylates H3K14ac. BAZ2A-BRD mutations or treatment with inhibitors abrogating BAZ2A-BRD/H3K14ac interaction impair the transition of PCa cells into a stem-like state. Furthermore, pharmacological inactivation of BAZ2A-BRD impairsPten-loss oncogenic transformation of prostate organoids. Our findings indicate a role of BAZ2A-BRD in PCa stem cell features and suggest potential epigenetic-reader therapeutic strategies to target BAZ2A in aggressive PCa.
Red-light is an environmental effector for mutualism between begomovirus and its vector whitefly
Authors: Zhao Pingzhi , Zhang Xuan , Gong Yuqing , Xu Dongqing , Wang Ning , Sun Yanwei , Liu Shu-Sheng , Deng Xing-Wang , Kliebenstein Daniel J. , Zhou XuePing , Fang Rong-Xiang , Ye Jian
Published: July 2020

Environments such as light condition influence the spread of infectious diseases by affecting insect vector behavior. However, whether and how light affects the host defense which further affect insect preference and performance, remains unclear, nor has been demonstrated how pathogens co-adapt light condition to facilitate vector transmission. We previously showed that begomoviral βC1 inhibits MYC2-mediated jasmonate signaling to establish plant-dependent mutualism with its insect vector. Here we show red-light as an environmental catalyzer to promote mutualism of whitefly-begomovirus by stabilizing βC1, which interacts with PHYTOCHROME-INTERACTING FACTORS (PIFs) transcription factors. PIFs positively control plant defenses against whitefly by directly binding to the promoter of terpene synthase genes and promoting their transcription. Moreover, PIFs integrates light and jasmonate signaling by interaction with MYC2, and co-regulation the transcription of terpene synthase genes. However, begomovirus encoded βC1 inhibit PIFs’ and MYC2’ transcriptional activity via disturbing their dimerization, thereby impairing plant defenses against whitefly-transmitted begomoviruses. Our results thus describe how a viral pathogen hijacks host light signaling to enhance the mutualistic relationship with its insect vector.

Author summary

Climate change is driving disease rapidly spread, esp. for global distribution of insect-borne diseases. This paper reports red-light as an environmental factor to promote insect vector olfactory orientation behavior and increase viral disease transmission. Plant virus adapts the supplemental red lighting practice in modern agricultural greenhouse production under protection, therefore enhancing disease spreading globally.
Different Perspective of Machine Learning Technique to Better Predict Breast Cancer Survival
Authors: Kumar Kaushal , Singh Vijay Vikram , Ramaswamy Ramakrishna
Published: July 2020

Machine 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

Immune 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.
Population-level differences in the neural substrates supporting Statistical Learning
Authors: Orpella Joan , Assaneo M. Florencia , Ripollés Pablo , Noejovich Laura , López-Barroso Diana , de Diego-Balaguer Ruth , Poeppel David
Published: July 2020

The ability to extract regularities from the environment is arguably an adaptive characteristic of intelligent systems. In the context of speech, statistical learning is thought to be an important mechanism for language acquisition. By considering individual differences in speech auditory-motor synchronization, an independent component analysis of fMRI data revealed that the neural substrates of statistical word form learning are not fully shared across individuals. While a network of auditory and superior pre/motor regions is universally activated in the process of learning, a fronto-parietal network is instead additionally and selectively engaged by some individuals, boosting their performance. Furthermore, interfering with the use of this network via articulatory suppression (producing irrelevant speech during learning) normalizes performance across the entire sample. Our work provides novel insights on language-related statistical learning and reconciles previous contrasting findings, while highlighting the need to factor in fundamental individual differences for a precise characterization of cognitive phenomena.
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

Advances 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

Autophagy 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

The 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

Background

BRG1 (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.

Results

Our 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.

Conclusions

Our 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

This 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

Objectives

To assess the performance (sensitivity and specificity) of the Abbott Architect SARS-CoV-2 IgG antibody assay across three clinical settings.

Methods

Antibody 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.

Results

Performance 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.

Conclusions

The 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

BACKGROUND AND AIMS

Inflammation 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 RESULTS

In 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.

CONCLUSIONS

Our 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

The 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.