bluuebunny/crossref_metadata_2025 huggingface dataset:
HLA-C*04:01 is a Genetic Risk Allele for Severe Course of COVID-19
Authors: January Weiner , Phillip Suwalski , Manuel Holtgrewe , Charlotte Thibeault , Müller Melina , Dimitri Patriki , Claudia Quedenau , Krüger Ulrike , Elisa T. Helbig , Lena Lippert , Paula Stubbemann , Miguel Real Luis , Macias Sanchez Juan , Pineda Juan A. , Marta Fernandez-Fuertes , Xiaomin Wang , Zehra Karadeniz , Jacopo Saccomanno , Jan-Moritz Doehn , Ralf-Harto Hübner , Bernd Hinzmann , Mauricio Salvo , Anja Blueher , Sandra Siemann , Stjepan Jurisic , Hansjuerg Beer , Jonas Rutishauser , Benedikt Wiggli , Hansruedi Schmid , Kathrin Danninger , Ronald Binder , Victor Corman M. , Barbara Mühlemann , Alice Braun , Stephan Ripke , Jones Terry C. , Norbert Suttorp , Martin Witzenrath , Stefan Hippenstiel , Tomasz Zemojtel , Carsten Skurk , Wolfgang Poller , Tatiana Borodina ,   Pa-COVID Study Group, Sander Leif E. , Dieter Beule , Ulf Landmesser , Toumy Guettouche , Florian Kurth , Bettina Heidecker
Published: December 2020

Background

Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing demand to identify predictors of severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as potential genetic host factors. We sought to evaluate this hypothesis by conducting an international multicenter study using HLA sequencing with subsequent independent validation.

Methods

We analyzed a total of 332 samples. First, we enrolled 233 patients in Germany, Spain, and Switzerland for HLA and whole exome sequencing. Furthermore, we validated our results in a public data set (United States, n=99). Patients older than 18 years presenting with COVID-19 were included, representing the full spectrum of the disease. HLA candidate alleles were identified in the derivation cohort (n=92) and tested in two independent validation cohorts (n=240).

Results

We identified HLA-C* 04:01 as a novel genetic predictor for severe clinical course in COVID-19. Carriers of HLA-C* 04:01 had twice the risk of intubation when infected with SARS-CoV-2 (hazard ratio 2.1, adjusted p-value=0.0036). Importantly, these findings were successfully replicated in an independent data set. Furthermore, our findings are biologically plausible, as HLA-C* 04:01 has fewer predicted bindings sites with relevant SARS-CoV-2 peptides as compared to other HLA alleles. Exome sequencing confirmed findings from HLA analysis.

Conclusions

HLA-C* 04:01 carriage is associated with a twofold increased risk of intubation in patients infected with SARS-CoV-2. Testing for HLA-C* 04:01 could have clinical implications to identify high-risk patients and individualize management.
Differential gene expression in scrub typhus compared to other acute febrile infections by bioinformatic approaches
Authors: Mandal Manisha , Mandal Shyamapada
Published: December 2020

Scrub typhus (ST), caused with the infection of Orientia tsutsugamushi, without eschar, is a febrile illness that mimics malaria (ML), dengue (DG), and other rickettsioses such as murine typhus (MT). Comparative analysis of microarray gene expression profiles of GSE16463 dataset, from O. tsutsugamushi infected monocytes, was performed to identify transcriptional signatures in ST discriminated from other acute febrile infections, accompanied by functional pathways and enrichment analysis in disease pathogenesis. A unique 31 ST-associated signature genes obtained in this study could help distinguish ST from other febrile illnesses DG, ML and MT. The functional pathways significantly enriched in ST disease group included translocation of ZAP-70 to immunological synapse, and phosphorylation of CD3 and TCR zeta chains, involving PTPN22 and CD3G genes, which could further help in the understanding of molecular pathophysiology of ST and discovering novel drug targets as well as vaccine developments.
Identification of Key Genes and Signaling Pathways Associated with the Progression of Glioblastoma multiform
Authors: Vastrad Basavaraj , Vastrad Chanabasayya , Kotturshetti Iranna
Published: December 2020

Genomic features have been gradually regarded as part of the basics to the clinical diagnosis, prognosis and treatment for glioblastoma multform (GBM). However, the molecular modifications taking place during the advancement of GBM remain unclear. Therefore, recognition of potential important genes and pathways in the gastric cancer progression is important to clinical practices. In the present study, gene expression dataset (GSE116520) of GBM were selected from the Gene Expression Omnibus (GEO) database and were further used to identify differentially expressed genes (DEGs). Then, pathway and Gene Ontology (GO) enrichment analyses were conducted, and a protein-protein interaction (PPI) network was constructed to explore the potential mechanism of GBM carcinogenesis. Significant modules were discovered using the PEWCC1 plugin for Cytoscape. In addition, a target gene - miRNA regulatory network and target gene - TF regulatory network in GBM were constructed using common deregulated miRNAs, TFs and DEGs. Finally, we carried on validation of hub genes by UALCAN, cBioporta, human protein atlas, ROC (Receiver operating characteristic) curve analysis, RT-PCR and immune infiltration analysis. The results indicated that a total of 947 differential expressed genes (DEGs) (477 up regulated and 470 down regulated) was identified in microarray profiles. Pathway enrichment analysis revealed that DEGs (up and down regulated) were mainly associated in reactive oxygen species degradation, ribosome, homocarnosine biosynthesis and GABAergic synapse, whereas GO enrichment analyses revealed that DEGs (up and down regulated) were mainly associated in macromolecule catabolic process, cytosolic part, synaptic signaling and synapse part as the main pathways associated in these processes. Finally, we filtered out hub genes, including MYC, ARRB1, RPL7A, SNAP25, SOD2, SVOP, ABCC3 and ABCA2, from the all networks. Validation of hub genes suggested the robustness of the above results. In conclusion, these results provided novel and reliable biomarkers for GBM, which will be useful for further clinical applications in GBM diagnosis, prognosis and targeted therapy.
Towards understanding interindividual differences in cortical morphological brain networks
Authors: Li Zhen , Li Junle , Wang Ningkai , Wang Jinhui
Published: December 2020

Individual-level morphological brain networks are becoming an important approach for studying human connectome; however, their interindividual differences are not well understood with respect to behavioral and cognitive relevance, individual identification, and genetic origin. Using three publicly available datasets that involved cross-sectional and longitudinal structural magnetic resonance scans of adults and children, we constructed four morphological brain networks for each of 1,451 images from 1,329 participants on the basis of cerebral surface-based, vertex-wise cortical thickness, fractal dimension, gyrification index and sulcal depth, respectively. The morphological index-dependent networks were further fused via multiplex network model, and fed into community detection. We found that the multiplex morphological brain networks 1) accounted for significant proportions of interindividual variance in and were predictive of multiple behavioral and cognitive domains, in particular Cognition and Motor domains (P< 0.05, corrected), 2) distinguished individuals from each other with high accuracies even for twin subjects (accuracies > 96%), and 3) exhibited low-moderate heritability with the highest for sulcal depth-based morphological brain networks. Intriguingly, compared with intra-module morphological connectivity, inter-module connections explained more behavioral and cognitive variance and were associated with higher heritability. Further comparisons revealed that multiplex morphological brain networks outperformed each type of single-layer morphological brain networks in the performance of behavioral and cognitive association and prediction, and individual identification. Finally, all the findings were generally reproducible over different datasets. Altogether, our findings indicate that interindividual differences in individual-level morphological brain networks are biologically meaningful, which underpins their usage as fingerprints for individualized studies in health and disease.
Aesthetic evaluation of the need for orthodontic treatment – Perception among university students
Authors: Alves Luís , Mesaros Anca , Ponces Maria João , Pollmann Maria Cristina Figueiredo
Published: December 2020

Introduction

Aesthetics is a relevant part of procedures in healthcare, often influencing treatment planning in tandem with a healthy function. Orthodontic treatment (OT) is one of many solutions and is, sometimes, wanted purely for aesthetic reasons. In 1989, Brook and Shaw proposed the Index of Orthodontic Treatment Need (IOTN), which has been largely used.

This study aims to verify the main motivations of university students to look for OT and, based on the Aesthetic Component of the IOTN, weigh the aesthetics influence to seek for it. It was compared the opinion of students from various areas of study - Dentistry, Science and Nature (ScN), Arts and Humanity (AtH) - at the beginning (Initiated Students) and end (Advanced Students) of their graduation; the same question was also analysed taking into account their nationalities and training schools.

Materials and Methods

In a collaboration between the University of Porto (Portugal) and the University of Medicine and Pharmacy of Cluj-Napoca (Romania), a sample of 1071 individuals was gathered. Participants responded to an online survey, based on IOTN pictures, about what would motivate them to seek OT. The ratings were analysed using the T-Test and alpha error of 5%.

Results

The results showed that the total Dentistry students registered a higher Oral Esthetical Sensibility (OES) than the total ScN and AtH students. All groups, except Dentistry Advanced Students, registered a higher OES for Self-Perception than for Perception of Others.

Discussion

Among other factors, the pictures used from the IOTN, taken in 1989, may have influenced the participants’ responses. However, it is the most used index, and it is validated.

Conclusion

In conclusion, for the studied populations, the main motivations for OT demand are primarily and respectively in this order: functional reasons, doctor’s advice, and aesthetical reasons. OES is influenced by Dentistry studies, specifically in Advanced Students. OES is not influenced by the country of the students’ origin nor the country they are graduating at.
Psychiatric morbidities and Coping strategies in patients with different Coronavirus disease-2019 severities and chronic medical diseases: A multicenter cross-sectional study
Authors: Shousha Hend Ibrahim , Madbouly Nagwan , Afify Shaimaa , Asem Noha , Maher Rabab , Moussa Suaad Sayed , Abdelazeem Amr , Youssif Eslam Mohamed , Harhira Khalid Yousef , Elmorsy Hazem , Elgarem Hassan , Omran Dalia , Hassany Mohamed , Elsayed Bassem , El kassas Mohamed
Published: December 2020

COVID-19 patients, especially those with chronic medical illnesses (CMI), may use different coping strategies, to reduce their psychological distress while facing the COVID-19 infection. The aim was to compare anxiety, depression and coping styles between patients infected with COVID-19 disease with and without CMI during the peak of COVID-19 disease in Egypt. This is a cross sectional study, that included an online survey consisting of Arabic versions of General Health Questionnaire-12, Taylor Manifest Anxiety Scale (TMAS), Beck Depression Inventory (BDI) and Brief-COPE scale. Questionnaires were distributed to adult patients with a confirmed diagnosis of SARS-CoV-2 virus infection during their quarantine in Egypt. One hundred ninety-nine patients responded to the survey, where 46.73% of them had CMI. Religion, emotional support, use of informational support and acceptance were the most used coping strategies by participants. Avoidant coping strategies were frequently used by divorced patients, home quarantined individuals, patients who developed COVID-19 related anxiety/depression and patients who didn’t receive hydroxyl-chloroquine. Approach strategies were frequently used by patients with mild COVID-19. Understanding the used coping strategies has implications for how individuals might be helped to manage their illness during the current presentation and intervene with development of serious long-term mental health conditions.
Adenovirus and RNA-based COVID-19 vaccines: perceptions and acceptance among healthcare workers
Authors: Temsah Mohamad-Hani , Barry Mazin , Aljamaan Fadi , Alhuzaimi Abdullah , Al-Eyadhy Ayman , Saddik Basema , Alrabiaah Abdulkarim , Alsohime Fahad , Alhaboob Ali , Alhasan Khalid , Alaraj Ali , Halwani Rabih , Alamro Nurah , Al-Shahrani Fatimah S , Jamal Amr , Alsubaie Sarah , Memish Ziad A , Al-Tawfiq Jaffar A
Published: December 2020

Objectives

The aim of this study was to compare the perception, confidence, hesitancy, and acceptance rate of various COVID-19 vaccine types among healthcare workers (HCWs) in Saudi Arabia, a nation with MERS-CoV experience.

Design

National cross-sectional, pilot-validated questionnaire.

Setting

Online, self-administered questionnaire among HCWs.

Participants

A total of 2,007 HCWs working in the Kingdom of Saudi Arabia participated; 75.3% completed the survey and were included in the analysis.

Intervention

Data were collected through an online survey sent to HCWs during November 1-15, 2020. The main outcome measure was HCW acceptance of COVID-19 candidate vaccines. The associated factors of vaccination acceptance were identified through a logistic regression analysis and via measurement of the level of anxiety, using the generalized anxiety disorder 7 (GAD7) scale.

Results

Among the 1512 HCWs who were included, 62.4% were women, 70.3% were between 21 and 40 years of age, and the majority (62.2%) were from tertiary hospitals. In addition, 59.5% reported knowing about at least one vaccine; 24.4% of the participants were sure about their willingness to receive the ChAdOx1 nCoV-19 vaccine, and 20.9% were willing to receive the RNA BNT162b2 vaccine. However, 18.3% reported that they would refuse to receive the Ad5-vectored vaccine, and 17.9% would refuse the Gam-COVID-Vac vaccine. Factors that influenced the differential readiness of HCWs included their perceptions of the vaccine’s efficiency in preventing the infection (33%), their personal preferences (29%), and the vaccine’s manufacturing country (28.6%).

Conclusions

Awareness by HCWs of the several COVID-19 candidate vaccines could improve their perceptions and acceptance of vaccination. Reliable sources on vaccine efficiency could improve vaccine uptake, so healthcare authorities should use reliable information to decrease vaccine hesitancy among frontline healthcare providers.
Automated processing of thermal imaging to detect COVID-19
Authors: Brzezinski Rafael Y. , Rabin Neta , Lewis Nir , Peled Racheli , Kerpel Ariel , Tsur Avishai M. , Gendelman Omer , Naftali-Shani Nili , Gringauz Irina , Amital Howard , Leibowitz Avshalom , Mayan Haim , Ben-Zvi Ilan , Heler Eyal , Shechtman Liran , Rogovski Ori , Shenhar-Tsarfaty Shani , Konen Eli , Marom Edith M. , Ironi Avinoah , Rahav Galia , Zimmer Yair , Grossman Ehud , Ovadia-Blechman Zehava , Leor Jonathan , Hoffer Oshrit
Published: December 2020

Rapid and sensitive screening tools for SARS-CoV-2 infection are essential to limit the spread of COVID-19 and to properly allocate national resources. Here, we developed a new point-of-care, non-contact thermal imaging tool to detect COVID-19, based on image-processing algorithms and machine learning analysis. We captured thermal images of the back of individuals with and without COVID-19 using a portable thermal camera that connects directly to smartphones. Our novel image processing algorithms automatically extracted multiple texture and shape features of the thermal images and achieved an area under the curve (AUC) of 0.85 in detecting COVID-19 with up to 92% sensitivity. Thermal imaging scores were inversely correlated with clinical variables associated with COVID-19 disease progression. We show, for the first time, that a hand-held thermal imaging device can be used to detect COVID-19. Non-invasive thermal imaging could be used to screen for COVID-19 in out-of-hospital settings, especially in low-income regions with limited imaging resources.

HIGHLIGHTS

Automated processing of thermal images of the back can be used to detect COVID-19 with up to 92% sensitivity.

The extracted texture features of the thermal image are associated with COVID-19 disease progression and lung injury.

A portable thermal camera that connects directly to smartphones can be used to detect COVID-19.

Non-invasive thermal imaging could be used to screen for COVID-19 in out-of-hospital settings and regions with limited imaging resources.

GRAPHICAL ABSTRACT
Analysis of genome characteristics and transmission of SARS-CoV-2 strains in North-East of Romania during the first COVID-19 outbreak
Authors: Lobiuc Andrei , Dimian Mihai , Gheorghita Roxana , Sturdza Olga , Covasa Mihai
Published: December 2020

Romania officially declared its first SARS-CoV-2 case on February 26, 2020. The first and largest COVID-19 outbreak in Romania was recorded in Suceava, N/E region of the country, and originated at the Suceava regional county hospital. Following sheltering-in-place measures, infection rates decreased, only to rise again after relaxation of measures. This study describes the incursion of SARS-CoV-2 in Suceava and other parts of Romania and analyzes the mutations and their association with clinical manifestation of the disease during the period of COVID-19 outbreak. Phylogenetic analysis indicated multiple sites of origin for SARS-CoV-2 strains in Suceava, specifically from Spain, Italy and Russia, but also other strains related to those from Czech Republic, Belgium and France. Most Suceava samples contained mutations common to European lineages, such as A20268G, however aproximately 10% of samples were missing such mutations, indicating a possible different origin. While overall genome regions ORF1ab, S and ORF7 were subject to most mutations, several recurring mutations such as C27707T were identified, and these were mainly present in severe forms of the disease. Non-synonymous mutations, such as C3225A (Thr987Asn in NSP3a domain), associated with changes in a protein responsible for decreasing viral tethering in human host were also present. Patients with diabetes and hypertension exhibited eight and three time,s respectively, higher odds ratios of acquiring severe forms of the disease and these were mainly related to C27707T mutation. These results will aid in tracing virus movement throughout Romania and identification of infectivity, virulence and pathogenicity.
Patterns of SARS-CoV-2 testing preferences in a national cohort in the United States
Authors: Romo Matthew L. , Zimba Rebecca , Kulkarni Sarah , Berry Amanda , You William , Mirzayi Chloe , Westmoreland Drew , Parcesepe Angela M. , Waldron Levi , Rane Madhura , Kochhar Shivani , Robertson McKaylee , Maroko Andrew R. , Grov Christian , Nash Denis ,   for the CHASING COVID Cohort Study Team
Published: December 2020

In order to understand preferences about SARS-CoV-2 testing, we conducted a discrete choice experiment among 4793 participants in the Communities, Households, and SARS-CoV-2 Epidemiology (CHASING COVID) Cohort Study from July 30-September 8, 2020. We used latent class analysis to identify distinct patterns of preferences related to testing and conducted a simulation to predict testing uptake if additional testing scenarios were offered. Five distinct patterns of SARS-CoV-2 testing emerged. “Comprehensive testers” (18.9%) ranked specimen type as most important and favored less invasive specimen types, with saliva most preferred, and also ranked venue and result turnaround time as highly important, with preferences for home testing and fast result turnaround time. “Fast track testers” (26.0%) ranked result turnaround time as most important and favored immediate and same day turnaround time. “Dual testers” (18.5%) ranked test type as most important and preferred both antibody and viral tests. “Non-invasive dual testers” (33.0%) ranked specimen type and test type as similarly most important, preferring cheek swab specimen type and both antibody and viral tests. “Home testers” (3.6%) ranked venue as most important and favored home-based testing. By offering less invasive (saliva specimen type), dual testing (both viral and antibody tests), and at home testing scenarios in addition to standard testing scenarios, simulation models predicted that testing uptake would increase from 81.7% to 98.1%. We identified substantial differences in preferences for SARS-CoV-2 testing and found that offering additional testing options, which consider this heterogeneity, would likely increase testing uptake.

SIGNIFICANCE

During the COVID-19 pandemic, diagnostic testing has allowed for early detection of cases and implementation of measures to reduce community transmission of SARS-CoV-2 infection. Understanding individuals’ preferences about testing and the service models that deliver tests are relevant in efforts to increase and sustain uptake of SARS-CoV-2 testing, which, despite vaccine availability, will be required for the foreseeable future. We identified substantial differences in preferences for SARS-CoV-2 testing in a discrete choice experiment among a large national cohort of adults in the US. Offering additional testing options that account for or anticipate this heterogeneity in preferences (e.g., both viral and antibody tests, at home testing), would likely increase testing uptake.

Classification

Biological Sciences (major); Psychological and Cognitive Sciences (minor)
The 100,000 most influential scientists rank: the underrepresentation of Brazilian women in academia
Authors: de Oliveira Leticia , Reichert Fernanda , Zandona Eugenia , Soletti Rossana C. , Staniscuaski Fernanda
Published: December 2020

Despite the progress observed in recent years, women are still underrepresented in science worldwide, especially at top positions. Many factors contribute to women progressively leaving academia at different stages of their career, including motherhood, harassment and conscious and unconscious discrimination. Implicit bias plays a major negative role in recognition, promotions and career advancement of female scientists. Recently, a rank on the most influential scientists in the world was created based on several metrics, including the number of published papers and citations. Here, we analyzed the representation of Brazilian scientists in this rank, focusing on gender. Female Brazilian scientists are greatly underrepresented in the rank (11% in the Top 100,000; 18% in the Top 2%). Male scientists have more self-citation than female scientists and positions in the rank varied when self-citations were included, suggesting that self-citation by male scientists increases their visibility. Moreover, male scientists had more papers never cited than female scientists. Possible reasons for this observed scenario are related to the metrics used to rank scientists, since these metrics reproduce and amplify the well-known implicit bias in peer-review and citations. Discussions on the repercussions of such ranks are pivotal to avoid deepening the gender gap in science.
Platycodin D prevents both lysosome- and TMPRSS2-driven SARS-CoV-2 infectionin vitroby hindering membrane fusion
Authors: Kim Tai Young , Jeon Sangeun , Jang Youngho , Gotina Lizaveta , Won Joungha , Ju Yeon Ha , Kim Sunpil , Jang Minwoo Wendy , Won Woojin , Park Mingu Gordon , Pae Ae Nim , Han Sunkyu , Kim Seungtaek , Lee C. Justin
Published: December 2020

An ongoing pandemic of coronavirus disease 2019 (COVID-19) is now the greatest threat to the global public health. Herbal medicines and their derived natural products have drawn much attention to treat COVID-19, but there has been no natural product showing inhibitory activity against SARS-CoV-2 infection with detailed mechanism. Here, we show that platycodin D (PD), a triterpenoid saponin abundant inPlatycodon grandiflorum(PG), a dietary and medicinal herb commonly used in East Asia, effectively blocks the two main SARS-CoV-2 infection-routes via lysosome- and transmembrane protease, serine 2 (TMPRSS2)-driven entry. Mechanistically, PD prevents host-entry of SARS-CoV-2 by redistributing membrane cholesterol to prevent membrane fusion, which can be reinstated by treatment with a PD-encapsulating agent. Furthermore, the inhibitory effects of PD are recapitulated by a pharmacological inhibition or gene-silencing ofNPC1, which is mutated in Niemann-Pick type C (NPC) patients displaying disrupted membrane cholesterol. Finally, readily available local foods or herbal medicines containing PG root show the similar inhibitory effects against SARS-CoV-2 infection. Our study proposes that PD is a potent natural product for preventing or treating COVID-19 and that a brief disruption of membrane cholesterol can be a novel therapeutic approach against SARS-CoV-2 infection.
Fitness selection of hyperfusogenic measles virus F proteins associated with neuropathogenic phenotypes
Authors: Ikegame Satoshi , Hashiguchi Takao , Hung Chuan-Tien , Dobrindt Kristina , Brennand Kristen J , Takeda Makoto , Lee Benhur
Published: December 2020

Measles virus (MeV) is resurgent and caused >200,000 deaths in 2019. MeV infection can establish a chronic latent infection of the brain that can recrudesce months to years after recovery from the primary infection. Recrudescent MeV leads to fatal subacute sclerosing panencephalitis (SSPE) or measles inclusion body encephalitis (MIBE) as the virus spreads across multiple brain regions. Most clinical isolates of SSPE/MIBE strains show mutations in the fusion (F) gene that result in a hyperfusogenic phenotypein vitroand allow for efficient spread in primary human neurons. Wild-type MeV receptor binding protein (RBP) is indispensable for manifesting these mutant F phenotypes, even though neurons lack canonical MeV receptors (CD150/SLAMF1 or Nectin-4). How such hyperfusogenic F mutants are selected for, and whether they confer a fitness advantage for efficient neuronal spread is unresolved. To better understand the fitness landscape that allows for the selection of such hyperfusogenic F mutants, we conducted a screen of ≥3.1×105MeV-F point mutants in their genomic context. We rescued and amplified our genomic MeV-F mutant libraries in BSR-T7 cells under conditions where MeV-F-T461I (a known SSPE mutant), but not wild-type MeV can spread. We recovered known SSPE mutants but also characterized at least 15 novel hyperfusogenic F mutations with a SSPE phenotype. Structural mapping of these mutants onto the pre-fusion MeV-F trimer confirm and extend our understanding of the fusion regulatory domains in MeV-F. Our list of hyperfusogenic F mutants is a valuable resource for future studies into MeV neuropathogenesis and the regulation of paramyxovirus fusion.

Significance

Measles remains a major cause of infant death globally. On rare occasions, measles virus infection of the central nervous system (CNS) leads to a fatal progressive inflammation of the brain many years after the initial infection. MeV isolates from such CNS infections harbor fusion (F) protein mutations that result in a hyperfusogenic phenotype. The small number of hyperfusogenic MeV-F mutants identified thus far limits our ability to understand how these mutations are selected in the context of CNS infections. We performed a saturating mutagenesis screen of MeV-F to identify a large set of mutants that would mimic the hyperfusogenic phenotype of MeV-F in CNS infection. Characterization of these mutants shed light on other paramyxoviruses known to establish chronic CNS infections.
Multi-cellular communities are perturbed in the aging human brain and Alzheimer’s disease
Authors: Cain Anael , Taga Mariko , McCabe Cristin , Green Gilad , Hekselman Idan , White Charles C. , Lee Dylan I. , Gaur Pallavi , Rozenblatt-Rosen Orit , Zhang Feng , Yeger-Lotem Esti , Bennett David A. , Yang Hyun-Sik , Regev Aviv , Menon Vilas , Habib Naomi , De Jager Philip L.
Published: December 2020

The role of different cell types and their interactions in Alzheimer’s disease (AD) is an open question. Here we pursued it by assembling a high-resolution cellular map of the aging frontal cortex by single nucleus RNA-seq of 24 individuals with different clinicopathologic characteristics. We used the map to infer the neocortical cellular architecture of 638 individuals profiled by bulk RNA-seq, providing the sample size necessary for identifying statistically robust associations. We uncovered diverse cell populations associated with AD, including inhibitory neuronal subtypes and oligodendroglial states. We further recovered a network of multicellular communities, each composed of coordinated subpopulations of neuronal, glial and endothelial cells, and found that two of these communities are altered in AD. Finally, we used mediation analyses to prioritize cellular changes that might contribute to cognitive decline. Thus, our deconstruction of the aging neocortex provides a roadmap for evaluating the cellular microenvironments underlying AD and dementia.
Multiethnic Prediction of Nicotine Biomarkers and Association with Nicotine Dependence
Authors: Bergen Andrew W. , McMahan Christopher S. , McGee Stephen , Ervin Carolyn M. , Tindle Hilary A. , Marchand Loïc Le , Murphy Sharon E. , Stram Daniel O. , Patel Yesha M. , Park Sungshim L. , Baurley James W.
Published: December 2020

Background

The nicotine metabolite ratio and nicotine equivalents are measures of metabolism rate and intake. Genome-wide prediction of these nicotine biomarkers will extend biomarker studies to cohorts without measured biomarkers and enable tobacco-related behavioral and exposure research.

Methods

We screened genetic variants genome-wide using marginal scans and applied statistical learning algorithms on top-ranked genetic variants and age, ethnicity and sex, and cigarettes per day (CPD) (in additional modeling) to build prediction models for the urinary nicotine metabolite ratio (uNMR) and creatinine-standardized total nicotine equivalents (TNE) in 2,239 current cigarette smokers in five ethnic groups. We predicted these nicotine biomarkers using model ensembles, and evaluated external validity using behavioral outcomes in 1,864 treatment-seeking smokers in two ethnic groups.

Results

The genomic regions with the most selected and trained variants for measured biomarkers were chr19q13.2 (uNMR, without and with CPD) and chr15q25.1 and chr10q25.3 (TNE, without and with CPD). We observed ensemble correlations between measured and predicted biomarker values for the uNMR and TNE without (with CPD) of 0.67 (0.68), and 0.65 (0.72) in the training sample. We observed inconsistency in penalized regression models of TNE (with CPD) with fewer variants at chr15q25.1 selected and trained. In treatment-seeking smokers, predicted uNMR (without CPD) was significantly associated with CPD, and predicted TNE (without CPD) with CPD, Time-To-First-Cigarette, and Fagerström total score.

Conclusions

Nicotine metabolites, genome-wide data and statistical learning approaches develop novel robust predictive models for urinary nicotine biomarkers in multiple ethnic groups. Predicted biomarker associations help define genetically-influenced components of nicotine dependence.

IMPLICATIONS

We demonstrate development of robust models and multiethnic prediction of the urinary nicotine metabolite ratio and total nicotine equivalents using statistical and machine learning approaches. Trained variants in models for both biomarkers include top-ranked variants in multiethnic genome-wide studies of smoking behavior, nicotine metabolites and related disease. Association of the two predicted nicotine biomarkers with Fagerstr□m Test for Nicotine Dependence items support models of nicotine biomarkers as predictors of physical dependence and nicotine exposure. Predicted nicotine biomarkers may facilitate tobacco-related disease and treatment research in samples with genomic data and limited nicotine metabolite or tobacco exposure data.
SARS-CoV-2 Testing in Florida, Illinois, and Maryland: Access and Barriers
Authors: Clipman Steven J. , Wesolowski Amy , Mehta Shruti H. , Agarwal Smisha , Cobey Sarah E. , Cummings Derek A.T. , Gibson Dustin G. , Labrique Alain B. , Kirk Gregory D. , Solomon Sunil S.
Published: December 2020

Objective

To characterize the SARS-CoV-2 testing cascade and associated barriers in three US states.

Methods

We recruited participants from Florida, Illinois, and Maryland (∼1000/state) for an online survey September 16 – October 15, 2020. The survey covered demographics, COVID-19 symptoms, and experiences around SARS-CoV-2 PCR testing in the prior 2 weeks. Logistic regression was used to analyze associations with outcomes of interest.

Results

Overall, 316 (10%) of 3,058 respondents wanted/needed a test in the two weeks prior to the survey. Of these, 166 (53%) were able to get tested and 156 (94%) received results; 53% waited ≥ 8 days to get results from when they wanted/needed a test. There were no significant differences by state. Among those wanting/needing a test, getting tested was significantly less common among men (aOR: 0.46) and those reporting black race (aOR: 0.53) and more common in those reporting recent travel (aOR: 3.35).

Conclusions

There is an urgent need for a national communication strategy on who should get tested and where one can get tested. Additionally, measures need to be taken to improve access and reduce turn-around-time.
A Systematic Review of the Incubation Period of SARS-CoV-2: The Effects of Age, Biological Sex, and Location on Incubation Period
Authors: Daley Caitlin , Fydenkevez Megan , Ackerman-Morris Shari
Published: December 2020

A systematic review of the incubation period of COVID-19 was compiled and analyzed from 21 quantitative studies. We investigated the incubation period of COVID-19 with regard to age, biological sex, location, and severity of the disease. Based on the data extracted, we report an overall mean and median incubation period for SARS-CoV-2 of 5.894 days and 5.598 days, respectively. The incubation period did not statistically vary for biological sex or age, but some studies suggest a longer incubation period in the young and elderly. Cases of COVID-19 in Wuhan and Hubei Province of China may have a shorter incubation period for COVID-19 but the shorter incubation period may be due to an increase in viral load. In studying coronavirus strains such as SARS and MERS, researchers have discovered an inverse relationship between incubation period length and virus severity. Taking into consideration that SARS-CoV-2 is part of the beta-coronavirus family, as well as the study mentioned above, we suggest that people who experience more severe disease due to SARS-CoV-2 may have a shorter incubation period.
Selective Targeting of Ras Mutant Cancers via a New Small Molecule
Authors: Tolani Bhairavi , Celli Anna , Yao Yanmin , Tan Yong Zi , Fetter Richard , Liem Christina R. , de Smith Adam J. , Vasanthakumar Thamiya , Bisignano Paola , Seiple Ian B. , Rubinstetin John L. , Jost Marco , Weissman Jonathan S.
Published: December 2020

Mutations in the Ras family of oncogenes are implicated in 33% of human cancers, making Ras an intensely pursued target in drug discovery. As an alternative to direct pharmacological inhibition of Ras, we looked for sensitivities in RAS mutant cells. Using a small molecule screen in cell lines with mutations in Ras and its effector Raf, we discovered 249C as a Ras-mutant selective cytotoxic agent against a spectrum of RAS-mutant cancers. By combining CRISPR chemical-genetic screening, comparative profiling and chemoproteomics, we identified that 249C binds to a unique subunit on vacuolar (V)-ATPase with nanomolar affinity, inhibiting its biochemical activity and, unexpectedly, altering V-ATPase translocation in Ras-induced macropinocytosis. Via binding to V-ATPase, 249C prevents lysosomal acidification and inhibits autophagy and macropinocytosis pathways that several Ras-driven cancers rely on for survival. In characterizing 249C’s mechanism, we show that potency varies with the identity of the RAS driver mutation highlighting a mutant-specific dependence on autophagy and macropinocytosis. Indeed, 249C potently inhibits tumor growth without adverse side effects in a mouse xenograft model ofKRAS-driven non-small cell lung cancer. These data establish proof-of-concept for targeting V-ATPase as a way to indirectly target specific Ras mutants, and provide a fundamental link between V-ATPase localization and specific Ras mutant tumor-related activity.
Partial spontaneous intersubunit rotations in actively translating ribosomes
Authors: Huang Tianhan , Choi Junhong , Prabhakar Arjun , Puglisi Joseph , Petrov Alexey
Published: December 2020

The ribosome is a molecular machine that adopts at least two global states during translation. Two main steps of translation, peptidyl transfer and translocation, are accompanied by counterclockwise and clockwise rotations of the two ribosomal subunits. However, when and why the ribosome alternates between these states remains unclear, with two well supported but conflicting hypotheses. Ribosomes may undergo a single cycle of forward and backward rotations per codon read. Alternatively, in addition to rotations caused by peptidyl transfer and translocation, ribosomes may undergo multiple full spontaneous rotations, with these rotations playing a critical role in elongation and specifically in translocation mechanism. We applied high-speed single-molecule TIRF microscopy to follow translation in real-time. Actively translating ribosomes undergopartialspontaneous rotations between three different rotational states. Spontaneous rotations are restricted prior to A-site tRNA decoding. Peptidyl transfer unlocks spontaneous rotations. Consequently, translocation proceeds via a novel rotational state induced by EF-G. Our results bridge both models and provide a coherent view of ribosome dynamics during translation.
Use of null models to compare the assembly of northeast Atlantic bacterial community in the presence of crude oil with either chemical dispersant or biosurfactant
Authors: Nikolova Christina , Ijaz Umer Zeeshan , Gutierrez Tony
Published: December 2020

The compositions of marine microbial communities in response to crude oil in the presence of biosurfactant or synthetic dispersants have been extensively studied in the last decade. Assembly processes, however, in such communities are poorly understood. In this study, we used seven different but complementing null model approaches, such as elements of metacommunity structure, Raup-Crick beta-diversity, normalised stochasticity ratio, Tucker’s null model, quantitative process estimates, lottery assembly, and phylogenetic dispersion models, to quantify the relative importance of ecological process that drive the community assembly. We found that the presence of chemical dispersant in the oil-amended microcosms induced significant temporal changes in the assembly processes that were different from the oil-only or biogenic dispersant-amended microcosms. The assembly processes in all microcosms were neither purely deterministic nor stochastic, but increasingly deterministic in dispersant-amended microcosms. Furthermore, the relative importance of determinisms varied over time and was strongest during the middle phase of incubation. Tucker’s null model revealed that phylogenetically distinct taxa might have shaped the bacterial community assembly in the different microcosms towards more niche or neutral processes. Moreover, there was faster recruitment of phylogenetically distant species in the dispersant-amended community. Drift, homogenising selection and dispersal limitation were the dominant assembly processes in all microcosms, but variable selection was only important in dispersant-amended microcosms. In conclusion, our study highlights that the assembly processes in marine bacterial communities are not static but rather dynamic, and the chemical dispersant can cause significantly different patterns of community assembly compared to non-amended or biosurfactant-amended microcosms.

Importance

The null model strategy is designed to intentionally exclude an ecological or evolutionary process of interest and create a beta diversity pattern that would be expected in the absence of this particular process – i.e. the community structure is random in respect to the process being tested. Recent advancements of bioinformatics and statistical tools have made it possible to apply theoretical macroecological concepts to microbial metagenomics in order to better understand and quantify the mechanisms and patterns controlling the complexity of microbial ecology. The conclusions from the null models can help predict the changes in microbial biodiversity and ecosystem services in oil polluted environments and therefore assist in making effective decisions with regards to what would be the best oil spill response option for similar environmental conditions.
Circular Economy of Anaerobic Biofilm Microbiomes: A Meta-Analysis Framework for Re-exploration of Amplicon Sequencing Data
Authors: Keating Ciara , Trego Anna Christine , Sloan William , O’Flaherty Vincent , Ijaz Umer Zeeshan
Published: December 2020

Use of high-throughput sequencing is widespread in efforts to understand the microbial communities in natural and engineered systems. Many built ecosystems, in particular those used for engineered wastewater treatment, have harnessed the metabolic capacity of complex microbial communities for the effective removal and recovery of organic pollutants. Recent efforts to better understand and precisely engineer such systems have increasingly used high-throughput sequencing to map the structure and function of wastewater treatment microbiomes. An enormous amount of data is readily available on online repositories such as the National Center for Biotechnology Information Short Read Archive (NCBI SRA). Here, we describe and provide an optimised meta-analysis workflow to utilise this resource to collate heterogenous studies together for anaerobic digestion research. We analysed 16S rRNA gene Illumina Miseq amplicon sequencing data from 31 anaerobic digestion studies (from high-rate digesters), including >1,300 samples. Additionally, we compare several methodological choices: extraction method, v-region, taxonomical database, and the classifier. We demonstrate that collation of data from multiple v-regions can be achieved by using only the taxa for which sequences are available in the reference databases, without losses in diversity trends. This is made possible by focusing on alternative strategies for taxonomic assignments, namely, bayesian lowest common ancestor (BLCA) algorithm which offers increased resolution to the traditional naïve bayesian classifier (NBC). While we demonstrate this using an anaerobic digestion wastewater treatment dataset, this methodology can be translated to perform meta-analysis on amplicon sequences in any field. These findings not only provide a roadmap for meta-analysis in any field, but additionally provide an opportunity to reuse extensive data resources to ultimately advance knowledge of wastewater treatment systems.

Importance

In this study, we have combined sequencing data from 31 individual studies with the purpose of identifying a meta-analysis workflow which can accurately collate data derived from sequencing different v-regions with minimal data loss and more accurate diversity patterns. While we have used Anaerobic Digestion (AD) communities for our proof-of-concept, our workflow (Fig 1) can be translated to any Illumina MiSeq meta-analysis study, in any field. Thereby, we provide the foundation for intensive data mining of existing amplicon sequencing resources. Such data-mining can provide a global perspective on complex microbial communities.

Graphical Abstract
Coalescent-based species delimitation meets deep learning: Insights from a highly fragmented cactus system
Authors: Perez Manolo F. , Bonatelli Isabel A. S. , Romeiro-Brito Monique , Franco Fernando F. , Taylor Nigel P. , Zappi Daniela C. , Moraes Evandro M.
Published: December 2020

Delimiting species boundaries is a major goal in evolutionary biology. An increasing body of literature has focused on the challenges of investigating cryptic diversity within complex evolutionary scenarios of speciation, including gene flow and demographic fluctuations. New methods based on model selection, such as approximate Bayesian computation, approximate likelihoods, and machine learning are promising tools arising in this field. Here, we introduce a framework for species delimitation using the multispecies coalescent model coupled with a deep learning algorithm based on convolutional neural networks (CNNs). We compared this strategy with a similar ABC approach. We applied both methods to test species boundary hypotheses based on current and previous taxonomic delimitations as well as genetic data (sequences from 41 loci) inPilosocereus aurisetus, a cactus species complex with a sky-island distribution and taxonomic uncertainty. To validate our method, we also applied the same strategy on data from widely accepted species from the genusDrosophila. The results show that our CNN approach has high capacity to distinguish among the simulated species delimitation scenarios, with higher accuracy than ABC. For the cactus dataset, a splitter hypothesis without gene flow showed the highest probability in both CNN and ABC approaches, a result agreeing with previous taxonomic classifications and in line with the sky-island distribution and low dispersal features ofP. aurisetus. Our results highlight the cryptic diversity within theP. aurisetuscomplex and show that CNNs are a promising approach for distinguishing complex evolutionary histories, even outperforming the accuracy of other model-based approaches such as ABC.
Daily electrical activity in the master circadian clock of a diurnal mammal
Authors: Bano-Otalora Beatriz , Moye Matthew J. , Brown Timothy M. , Lucas Robert J. , Diekman Casey O. , Belle Mino D. C.
Published: December 2020

Daily or circadian rhythms in mammals are orchestrated by a master circadian clock within the hypothalamic suprachiasmatic nuclei (SCN). Here, cell-autonomous oscillations in gene expression, intrinsic membrane properties, and synaptic communication shape the electrical landscape of the SCN across the circadian day, rendering SCN neurons overtly more active during the day than at night. This well-accepted hallmark bioelectrical feature of the SCN has overwhelmingly emerged from studies performed on a small number of nocturnal rodent species. Therefore, for the first time, we investigate the spontaneous and evoked electrical activity of SCN neurons in a diurnal mammal. To this end, we measured the electrical activity of individual SCN neurons during the day and at night in brain slices prepared from the diurnal murid rodentRhabdomys pumilioand then developed cutting-edge data assimilation and mathematical modelling approaches to uncover the underlying ionic mechanisms. We find thatR. pumilioSCN neurons were more excited in the day than at night, recapitulating the prototypical pattern of SCN neuronal activity previously observed in nocturnal rodents. By contrast, the evoked activity ofR. pumilioneurons included a prominent suppressive response that is not present in the SCN of nocturnal rodents. Our computational modelling approaches reveal transient subthreshold A-type potassium channels as the primary determinant of the suppressive response and highlight a key role for this ionic mechanism in tuning excitability of clock neurons and optimising SCN function to accommodateR. pumilio’sdiurnal niche.