bluuebunny/crossref_metadata_2025 huggingface dataset:
Following the Trail of One Million Genomes: Footprints of SARS-CoV-2 Adaptation to Humans
Authors: Akther Saymon , Bezrucenkovas Edgaras , Li Li , Sulkow Brian , Di Lia , Pante Desiree , Martin Che L. , Luft Benjamin J. , Qiu Weigang
Published: May 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has accumulated genomic mutations at an approximately linear rate since it first infected human populations in late 2019. Controversies remain regarding the identity, proportion, and effects of adaptive mutations as SARS-CoV-2 evolves from a bat-to a human-adapted virus. The potential for vaccine-escape mutations poses additional challenges in pandemic control. Despite being of great interest to therapeutic and vaccine development, human-adaptive mutations in SARS-CoV-2 are masked by a genome-wide linkage disequilibrium under which neutral and even deleterious mutations can reach fixation by chance or through hitchhiking. Furthermore, genome-wide linkage equilibrium imposes clonal interference by which multiple adaptive mutations compete against one another. Informed by insights from microbial experimental evolution, we analyzed close to one million SARS-CoV-2 genomes sequenced during the first year of the COVID-19 pandemic and identified putative human-adaptive mutations according to the rates of synonymous and missense mutations, temporal linkage, and mutation recurrence. Furthermore, we developed a forward-evolution simulator with the realistic SARS-CoV-2 genome structure and base substitution probabilities able to predict viral genome diversity under neutral, background selection, and adaptive evolutionary models. We conclude that adaptive mutations have emerged early, rapidly, and constantly to dominate SARS-CoV-2 populations despite clonal interference and purifying selection. Our analysis underscores a need for genomic surveillance of mutation trajectories at the local level for early detection of adaptive and immune-escape variants. Putative human-adaptive mutations are over-represented in viral proteins interfering host immunity and binding host-cell receptors and thus may serve as priority targets for designing therapeutics and vaccines against human-adapted forms of SARS-CoV-2.
A human antibody that broadly neutralizes betacoronaviruses protects against SARS-CoV-2 by blocking the fusion machinery
Authors: Pinto Dora , Sauer Maximilian M. , Czudnochowski Nadine , Low Jun Siong , Tortorici M. Alejandra , Housley Michael P. , Noack Julia , Walls Alexandra C. , Bowen John E. , Guarino Barbara , Rosen Laura E. , di Iulio Julia , Jerak Josipa , Kaiser Hannah , Islam Saiful , Jaconi Stefano , Sprugasci Nicole , Culap Katja , Abdelnabi Rana , Foo Caroline , Coelmont Lotte , Bartha Istvan , Bianchi Siro , Silacci-Fregni Chiara , Bassi Jessica , Marzi Roberta , Vetti Eneida , Cassotta Antonino , Ceschi Alessandro , Ferrari Paolo , Cippà Pietro E. , Giannini Olivier , Ceruti Samuele , Garzoni Christian , Riva Agostino , Benigni Fabio , Cameroni Elisabetta , Piccoli Luca , Pizzuto Matteo S. , Smithey Megan , Hong David , Telenti Amalio , Lempp Florian A. , Neyts Johan , Havenar-Daughton Colin , Lanzavecchia Antonio , Sallusto Federica , Snell Gyorgy , Virgin Herbert W. , Beltramello Martina , Corti Davide , Veesler David
Published: May 2021

The repeated spillovers of β-coronaviruses in humans along with the rapid emergence of SARS-CoV-2 escape variants highlight the need to develop broad coronavirus therapeutics and vaccines. Five monoclonal antibodies (mAbs) were isolated from COVID-19 convalescent individuals and found to cross-react with multiple β-coronavirus spike (S) glycoproteins by targeting the stem helix. One of these mAbs, S2P6, cross-reacts with more than twenty human and animal β-coronavirus S glycoproteins and broadly neutralizes SARS-CoV-2 and pseudotyped viruses from the sarbecovirus, merbecovirus and embecovirus subgenera. Structural and functional studies delineate the molecular basis of S2P6 cross-reactivity and broad neutralization and indicate that this mAb blocks viral entry by inhibiting membrane fusion. S2P6 protects hamsters challenged with SARS-CoV-2 (including the B.1.351 variant of concern) through direct viral neutralization and Fc-mediated effector functions. Serological and B cell repertoire analyses indicate that antibodies targeting the stem helix are found in some convalescent donors and vaccinees but are predominantly of narrow specificity. Germline reversion of the identified cross-reactive mAbs revealed that their unmutated ancestors are specific for the endemic OC43 or HKU1 viruses and acquired enhanced affinity and breadth through somatic mutations. These data demonstrate that conserved epitopes in the coronavirus fusion machinery can be targeted by protective antibodies and provide a framework for structure-guided design of pan-β-coronavirus vaccines eliciting broad protection.
Multimodal Analysis Reveals Differential Immuno-Metabolic Features in Lung Squamous Cell Carcinoma and Adenocarcinoma
Authors: Leitner Brooks P. , Ospanova Shyryn , Beisenbayeva Aray , Givechian Kevin B. , Politi Katerina , Perry Rachel J.
Published: May 2021

Background

The relationship between systemic metabolism, immune function, and lung cancer is complex and remains poorly defined. Seemingly paradoxically, overweight and obesity confer an improved response to immune checkpoint inhibition in non-small cell lung cancer (NSCLC); however, it is not known whether excess body weight or adiposity impacts the immunometabolic tumor microenvironment.

Methods

Utilizing three complementary National Cancer Institute-funded open-source databases containing 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (PET-CT) images for tumor and tissue glucose uptake, adipose tissue and skeletal muscle mass, histology annotated with tumor infiltrating leukocytes, and tumor RNA sequencing, we performed a retrospective cross-sectional analysis to examine phenotypic, metabolic, and genomic intersections of adiposity and tumor immune-metabolism in patients with lung adenocarcinoma (LUAD) versus squamous cell carcinoma (LUSC).

Results

Our data reveal distinct immunometabolomic features of LUSC as compared to LUAD: visceral fat content was negatively correlated with both tumor glucose uptake and leukocyte infiltration. Subcutaneous and visceral adiposity conferred different effects on the tumor genetic landscapes in both tumor types. LUSC tumors showed greater gene expression pathways related to pyruvate, glucose, amino acid, and lipid metabolism, in addition to significantly greater 18F-FDG uptake compared with LUAD, suggesting deeper metabolic regulation within the LUSC tumor microenvironment.

Conclusions

Several immunometabolomic characteristics of LUSC and LUAD differ, including tumor glucose uptake and the associated metabolic pathways in the tumor, as well as the impact of visceral adiposity on tumor metabolism. These data may highlight opportunities to advance mechanistically targeted precision medicine approaches by better understanding the interplay between metabolic, immunologic, and genomic factors in lung cancer treatment.
Severity assessment of single dose Oxford–AstraZeneca vaccinated individuals infected with SARS CoV-2 in the Southeast Bangladesh
Authors: Rana Eaftekhar Ahmed , Dutta Pronesh , Islam Md. Sirazul , Nizami Tanvir Ahmad , Das Tridip , Chowdhury Sharmin , Das Goutam Buddha
Published: May 2021

The present global endeavor to uncover the most effective vaccines against severe acute respiratory syndrome coronavirus (SARS-CoV-2) that can tremendously prevent transmission, infection and significantly reduce public health risk. COVID-19 vaccination program is underway in different parts of the world including Bangladesh but till to date there is no available health data revealed among the vaccinated peoples. We conducted a cross-sectional study from February 15 to April 15, 2021 to assess the health status of 1st dose Oxford-AstraZeneca vaccinated individuals infected with SARS CoV-2. Standard virological method, real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) was performed to detect SARS-CoV-2 and the different health parameters from vaccinated individuals were collected through direct mobile phone contact using pre-structured questionnaires. A total of 6146 suspected samples were tested and 1752 were found positive for SARS-CoV-2, of them 200 individuals were identified who received 1st dose of COVID-19 vaccine. Within the test period, majority of male (65.6%) and female (34.4%) carried moderate numbers of viruses which comprise between 30.01-35 cyclic threshold (ct) values. Among the vaccinated individuals, 165 (82.5%; 95% CI: 76.51 - 87.5) persons were not hospitalized and 177 (88.5%; 95% CI: 83.24 - 92.57) did not show any respiratory difficulties. Only a few (16) (8%; 95% CI: 4.64 - 12.67) of COVID-19 positive patients needed extra oxygen support and 199 (99.5%; 95% CI: 97.25 - 99.99) individuals didn’t require any intensive care unit (ICU) interference. Overall, oxygen saturation was recorded around 96.8% and respiratory difficulties did not extend more than 5 days, irrespective of age and sex during the infection period. Within the vaccinated COVID-19 positive individuals 113 (56.5%; 95% CI: 49.33 - 63.48) and 111(55.5%; 95% CI: 48.32 - 62.51) persons have normal physiological taste and smell. However, we have found a larger proportion of vaccinated persons (129) (64.5%; 95% CI: 57.44 - 71.12) carrying different comorbidity, among them high blood pressure 36 (27.9%; 95% CI, 20.37 - 36.48) and diabetes 32 (24.8%; 95% CI: 17.63 - 33.18) were found more prevalent. Moreover, the significant finding of the present study was 199 (99.5%; 95% CI: 97.25 - 99.99) vaccinated individuals survived with good health conditions and became negative in RT-qPCR. The authors suggest that health risk assessment among the COVID-19 vaccinated persons when infected with SARS-CoV-2 is crucial and time demanding task for the whole world. However, the present study illustrates that the administration of the 1st dose Oxford-AstraZeneca vaccine significantly reduces health risk during the COVID-19 infection period.
In-solution buffer-free digestion for the analysis of SARS-CoV-2 RBD proteins allows a full sequence coverage and detection of post-translational modifications in a single ESI-MS spectrum
Authors: Espinosa Luis Ariel , Ramos Yassel , Andújar Ivan , Torres Enso Onill , Cabrera Gleysin , Martín Alejandro , González Diamilé , Chinea Glay , Becquet Mónica , González Isabel , Canaán-Haden Camila , Nelson Elías , Rojas Gertrudis , Pérez-Massón Beatriz , Pérez-Martínez Dayana , Boggiano Tamy , Palacio Julio , Lozada-Chang Sum Lai , Hernández Lourdes , de la Luz Hernández Kathya Rashida , Markku Saloheimo , Marika Vitikainen , Valdés-Balbín Yury , Santana-Medero Darielys , Rivera Daniel G. , Vérez-Bencomo Vicente , Emalfarb Mark , Tchelet Ronen , Guillén Gerardo , Limonta Miladys , Pimentel Eulogio , Ayala Marta , Besada Vladimir , González Luis Javier
Published: May 2021

Subunit vaccines based on the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2, are among the most promising strategies to fight the COVID-19 pandemic. The detailed characterization of the protein primary structure by mass spectrometry (MS) is mandatory, as described in ICHQ6B guidelines. In this work, several recombinant RBD proteins produced in five expression systems were characterized using a non-conventional protocol known as in-solution buffer-free digestion (BFD). In a single ESI-MS spectrum, BFD allowed very high sequence coverage (≥ 99 %) and the detection of highly hydrophilic regions, including very short and hydrophilic peptides (2-8 amino acids), the His6-tagged C-terminal peptide carrying several post-translational modifications at Cys538such as cysteinylation, glutathionylation, cyanilation, among others. The analysis using the conventional digestion protocol allowed lower sequence coverage (80-90 %) and did not detect peptides carrying some of the above-mentioned post-translational modifications. The two C-terminal peptides of a dimer [RBD(319-541)-(His)6]2linked by an intermolecular disulfide bond (Cys538-Cys538) with twelve histidine residues were only detected by BFD. This protocol allows the detection of the four disulfide bonds present in the native RBD and the low-abundance scrambling variants, free cysteine residues, O-glycoforms and incomplete processing of the N-terminal end, if present. Artifacts that might be generated by the in-solution BFD protocol were also characterized. BFD can be easily implemented and we foresee that it can be also helpful to the characterization of mutated RBD.
Sexual selection and sexual size dimorphism in animals
Authors: Janicke Tim , Fromonteil Salomé
Published: May 2021

Sexual selection is often considered as a critical evolutionary force promoting sexual size dimorphism (SSD) in animals. However, empirical evidence for a positive relationship between sexual selection on males and male-biased SSD received mixed support depending on the studied taxonomic group and on the method used to quantify sexual selection. Here, we present a meta-analytic approach accounting for phylogenetic non-independence to test how standardized metrics of the opportunity and strength of pre-copulatory sexual selection relate to SSD across a broad range of animal taxa comprising up to 102 effect sizes from 64 species. We found that SSD was correlated with the sex difference in the opportunity for sexual selection but not with the sex difference in the Bateman gradient. These findings suggest that pre-copulatory sexual selection plays a limited role for the evolution of sexual size dimorphism in a broad phylogenetic context.
Bisphenol A derivatives act as novel coactivator binding inhibitors for estrogen receptor β
Authors: Iwamoto Masaki , Masuya Takahiro , Hosose Mari , Tagawa Koki , Ishibashi Tomoka , Yoshihara Eiji , Downes Michael , Evans Ronald M. , Matsushima Ayami
Published: May 2021

Bisphenol A and its derivatives are recognized endocrine disruptors based on their complex effects on estrogen receptor (ER) signaling. While the effects of bisphenol derivatives on ERα have been thoroughly evaluated, how these chemicals affect ERβ signaling is not well understood. Herein, we identified novel ERβ ligands by screening a chemical library of bisphenol derivatives. Many of the compounds identified showed intriguing dual activities as ERα agonists and ERβ antagonists. Docking simulations suggested that these compounds act as coactivator binding inhibitors (CBIs). Direct binding experiments using wild-type and mutated ERβ demonstrated the presence of a second ligand interaction position at the coactivator binding site in ERβ. Our study is the first to propose that bisphenol derivatives act as CBIs, presenting a critical view point for future ER signaling-based drug development.
Aggregation is a context-dependent constraint on protein evolution
Authors: Monti Michele , Armaos Alexandros , Fantini Marco , Pastore Annalisa , Tartaglia Gian Gaetano
Published: May 2021

Solubility is a requirement for many cellular processes. Loss of solubility and aggregation can lead to the partial or complete abrogation of protein function. Thus, understanding the relationship between protein evolution and aggregation is an important goal. Here, we analysed two deep mutational scanning experiments to investigate the role of protein aggregation in molecular evolution. In one data set, mutants of a protein involved in RNA biogenesis and processing, human TAR DNA binding protein 43 (TDP-43), were expressed in S. cerevisiae. In the other data set, mutants of a bacterial enzyme that controls resistance to penicillins and cephalosporins, TEM-1 beta-lactamase, were expressed in E. coli under the selective pressure of an antibiotic treatment. We found that aggregation differentiates the effects of mutations in the two different cellular contexts. Specifically, aggregation was found to be associated with increased cell fitness in the case of TDP-43 mutations, as it protects the host from aberrant interactions. By contrast, in the case of TEM-1 beta-lactamase mutations, aggregation is linked to a decreased cell fitness due to inactivation of protein function. Our study shows that aggregation is an important context-dependent constraint of molecular evolution and opens up new avenues to investigate the role of aggregation in different cellular contexts.
SARS-COV-2 Recombinant Receptor-Binding-Domain (RBD) Induces Neutralising Antibodies Against Variant Strains of SARS-CoV-2 and SARS-CoV-1
Authors: John Law Lok Man , Logan Michael , Joyce Michael , Landi Abdolamir , Hockman Darren , Crawford Kevin , Johnson Janelle , LaChance Gerald , Saffran Holly , Shields Justin , Hobart Eve , Brassard Raelynn , Arutyunova Elena , Pabbaraju Kanti , Croxen Matthew , Tipples Graham , Lemieux M Joanne , Tyrrell Lorne , Houghton Michael
Published: May 2021

SARS-CoV-2 is the etiological agent of COVID19. There are currently several licensed vaccines approved for human use and most of them are targeting the spike protein (or virion) in the virion envelope to induce protective immunity. Recently, variants that spread more quickly have emerged. There is evidence that some of these variants are less sensitive to neutralizationin vitro, but it is not clear whether they can evade vaccine induced protection. In this study, we tested the utility of SARS-CoV-2 spike RBD as a vaccine antigen and explore the effect of formulation with Alum/MPLA or AddaS03 adjuvants. Our results indicate RBD induces high titers of neutralizing antibodies and activates strong cellular immune responses. There is also significant cross-neutralisation of variants B1.1.7 and B.1.351 and to a lesser extent, SARS-CoV-1. These results indicate that recombinant RBD can be a viable candidate as a stand-alone vaccine or as a booster shot to diversify our strategy for COVID19 protection.
The Fluorescent Dye 1,6-Diphenyl-1,3,5-Hexatriene Binds to Amyloid Fibrils Formed by Human Amylin and Provides a New Probe of Amylin Amyloid Kinetics
Authors: Li Ming-Hao , Manathunga Lakshan , London Erwin , Raleigh Daniel P.
Published: May 2021

The fluorescent dye 1,6-diphenyl-1,3,5-hexatriene (DPH) is widely used as a probe of membrane order. We show that DPH also interacts with amyloid fibrils formed by human amylin (also known as islet amyloid polypeptide) in solution and this results in a 100-fold increase in DPH fluorescence for a sample of 20μM human amylin and 0.25 μM DPH. No increase in DPH fluorescence is observed with the non-amyloidogenic rat amylin or with freshly dissolved, non-fibrillar human amylin. The time course of amyloid formation by amylin was followed by monitoring the fluorescence of added DPH as a function of time and was similar to that monitored by the standard fluorescent probe thioflavin-T. The inclusion of DPH in the buffer did not perturb the time course of amyloid formation under the conditions examined and the time course was independent of the range of DPH concentrations tested (0.25 to 5 μM). Maximum final fluorescence intensity is observed at substoichiometric ratios of DPH to amylin. No significant increase in fluorescence was observed during the lag phase of amyloid formation, and the implications for the structure of amylin pre-fibril oligomers are discussed. Human amylin contains three aromatic residues. A triple aromatic to leucine mutant forms amyloid and DPH binds to the resulting fibrils, indicating that interactions with aromatic side chains are not required for DPH amylin amyloid interactions. DPH may be especially useful for studies on mutant amylins and other polypeptides in which changes in charged residues might complicate interpretation of thioflavin-T fluorescence.
ScreenGarden: A shinyR application for fast and easy analysis of plate-based high-throughput screens
Authors: Klemm Cinzia , Howell Rowan M. S. , Thorpe Peter H.
Published: May 2021

Colony growth on solid media is a simple and effective measure for high-throughput genomic experiments such as yeast-two hybrid, Synthetic Genetic Arrays and Synthetic Physical Interaction screens. The development of robotic pinning tools has facilitated the experimental design of these assays, and different imaging software can be used to automatically measure colony sizes on plates. However, comparison to control plates and statistical data analysis is often laborious and pinning issues or plate specific growth effects can lead to the detection of false positive growth defects. We have developed ScreenGarden, a shinyR application, to enable easy, quick and robust data analysis of plate-based high throughput assays.
Decentralized Brain Age Estimation using MRI Data
Authors: Basodi Sunitha , Raja Rajikha , Ray Bhaskar , Gazula Harshvardhan , Liu Jingyu , Verner Eric , Calhoun Vince D.
Published: May 2021

Recent studies have demonstrated that neuroimaging data can be used to predict brain age, as it captures information about the neuroanatomical and functional changes the brain undergoes during development and the aging process. However, researchers often have limited access to neuroimaging data because of its challenging and expensive acquisition process, thereby limiting the effectiveness of the predictive model. Decentralized models provide a way to build more accurate and generalizable prediction models, bypassing the traditional data-sharing methodology. In this work, we propose a decentralized method for brain age estimation and evaluate it on three different feature sets, including both volumetric and voxelwise structural MRI data as well as resting functional MRI data. The results demonstrate that a decentralized brain age model can achieve similar performance compared to the models trained with all the data in one location.
Characterization of the gene repertoire and environmentally driven expression patterns in Tanner crab (Chionoecetes bairdi)
Authors: Crandall Grace , Jensen Pamela C. , White Samuel J. , Roberts Steven
Published: May 2021

Tanner crab (Chionoecetes bairdi) are an economically important species that is threatened by ocean warming and Bitter Crab Disease, which is caused by an endoparasitic dinoflagellate,Hematodinium. Little is known about disease transmission or its link to host mortality, or how ocean warming will affect pathogenicity or host susceptibility. To provide a transcriptomic resource for the Tanner crab, we generated a suite of RNA-seq libraries encompassing pooled hemolymph samples from crab displaying differing infection statuses and maintained at different temperatures (ambient (7.5°C), elevated (10°C), or decreased (4°C)). After assembling a transcriptome and performing a multifactor differential gene expression analysis, we found genes influenced by temperature in relation to infection, and detected some of those genes over time at the individual level using RNAseq data from one crab. Biological processes associated with those genes include lipid storage, transcription, response to oxidative stress, cell adhesion, and morphogenesis. Alteration in lipid storage and transcription provide insight into how temperature impacts energy allocation inHematodiniuminfected crabs. Alteration in expression patterns in genes associated with morphogenesis could suggest hemocytes were changing morphology and/or type in response to temperature. This project provides insight into howHematodiniuminfection could influence crab physiology as oceans warm.
An improved fluorescent noncanonical amino acid for measuring conformational distributions using time-resolved transition metal ion FRET
Authors: Zagotta William N. , Sim Brandon S. , Nhim Anthony K. , Raza Marium M. , Evans Eric G.B. , Venkatesh Yarra , Jones Chloe M. , Mehl Ryan A. , Petersson E. James , Gordon Sharona E.
Published: May 2021

With the recent explosion in high-resolution protein structures, one of the next frontiers in biology is elucidating the mechanisms by which conformational rearrangements in proteins are regulated to meet the needs of cells under changing conditions. Rigorously measuring protein energetics and dynamics requires the development of new methods that can resolve structural heterogeneity and conformational distributions. We have previously developed steady-state transition metal ion fluorescence resonance energy transfer (tmFRET) approaches using a fluorescent noncanonical amino acid donor (Anap) and transition metal ion acceptor, to probe conformational rearrangements in soluble and membrane proteins. Here, we show that the fluorescent noncanonical amino acid Acd has superior photophysical properties that extend its utility as a donor for tmFRET. Using maltose binding protein (MBP) expressed in mammalian cells as a model system, we show that Acd is comparable to Anap in steady-state tmFRET experiments and that its long, single-exponential lifetime is better suited for probing conformational distributions using time-resolved FRET. These experiments reveal differences in heterogeneity in the apo and holo conformational states of MBP and produce accurate quantification of the distributions among apo and holo conformational states at subsaturating maltose concentrations. Our new approach using Acd for time-resolved tmFRET sets the stage for measuring the energetics of conformational rearrangements in soluble and membrane proteins in near-native conditions.
Microbiome differential abundance methods produce disturbingly different results across 38 datasets
Authors: Nearing Jacob T. , Douglas Gavin M. , Hayes Molly , MacDonald Jocelyn , Desai Dhwani , Allward Nicole , Jones Casey M. A. , Wright Robyn , Dhanani Akhilesh , Comeau André M. , Langille Morgan G. I.
Published: May 2021

Identifying differentially abundant microbes is a common goal of microbiome studies. Multiple methods have been applied for this purpose, which are largely used interchangeably in the literature. Although it has been observed that these tools can produce different results, there have been very few large-scale comparisons to describe the scale and significance of these differences. In addition, it is challenging for microbiome researchers to know which differential abundance tools are appropriate for their study and how these tools compare to one another. Here, we have investigated these questions by analyzing 38 16S rRNA gene datasets with two sample groups for differential abundance testing. We tested for differences in amplicon sequence variants and operational taxonomic units (referred to as ASVs for simplicity) between these groups with 14 commonly used differential abundance tools. Our findings confirmed that these tools identified drastically different numbers and sets of significant ASVs, however, for many tools the number of features identified correlated with aspects of the tested study data, such as sample size, sequencing depth, and effect size of community differences. We also found that the ASVs identified by each method were dependent on whether the abundance tables were prevalence-filtered before testing. ALDEx2 and ANCOM produced the most consistent results across studies and agreed best with the intersect of results from different approaches. In contrast, several methods, such as LEfSe, limma voom, and edgeR, produced inconsistent results and in some cases were unable to control the false discovery rate. In addition to these observations, we were unable to find supporting evidence for a recent recommendation that limma voom, corncob, and DESeq2 are more reliable overall compared with other methods. Although ALDEx2 and ANCOM are two promising conservative methods, we argue that those researchers requiring more sensitive methods should use a consensus approach based on multiple differential abundance methods to help ensure robust biological interpretations.
LYRUS: A Machine Learning Model for Predicting the Pathogenicity of Missense Variants
Authors: Lai Jiaying , Yang Jordan , Gamsiz Uzun Ece D. , Rubenstein Brenda M. , Sarkar Indra Neil
Published: May 2021

Single amino acid variations (SAVs) are a primary contributor to variations in the human genome. Identifying pathogenic SAVs can aid in the diagnosis and understanding of the genetic architecture of complex diseases, such as cancer. Most approaches for predicting the functional effects or pathogenicity of SAVs rely on either sequence or structural information. Nevertheless, previous analyses have shown that methods that depend on only sequence or structural information may have limited accuracy. Recently, researchers have attempted to increase the accuracy of their predictions by incorporating protein dynamics into pathogenicity predictions. This study presents < Lai Yang Rubenstein Uzun Sarkar > (LYRUS), a machine learning method that uses an XGBoost classifier selected by TPOT to predict the pathogenicity of SAVs. LYRUS incorporates five sequence-based features, six structure-based features, and four dynamics-based features. Uniquely, LYRUS includes a newly-proposed sequence co-evolution feature called variation number. LYRUS’s performance was evaluated using a dataset that contains 4,363 protein structures corresponding to 20,307 SAVs based on human genetic variant data from the ClinVar database. Based on our dataset, the LYRUS classifier has a higher accuracy, specificity, F-measure, and Matthews correlation coefficient (MCC) than alternative methods including PolyPhen2, PROVEAN, SIFT, Rhapsody, EVMutation, MutationAssessor, SuSPect, FATHMM, and MVP. Variation numbers used within LYRUS differ greatly between pathogenic and neutral SAVs, and have a high feature weight in the XGBoost classifier employed by this method. Applications of the method to PTEN and TP53 further corroborate LYRUS’s strong performance. LYRUS is freely available and the source code can be found at https://github.com/jiaying2508/LYRUS.
Data-driven modeling predicts gene regulatory network dynamics during the differentiation of multipotential progenitors
Authors: Handzlik Joanna Elzbieta , Manu
Published: May 2021

Cellular differentiation during hematopoiesis is guided by gene regulatory networks (GRNs) thought to be organized as a hierarchy of bistable switches, with antagonism between Gata1 and PU.1 driving red- and white-blood cell differentiation. We utilized high temporal-resolution gene-expression data from in vitro erythrocyte-neutrophil differentiation and a predictive data-driven dynamical modeling framework to learn the architecture and dynamics of gene regulation in a comprehensive twelve-gene GRN. The inferred genetic architecture is densely interconnected rather than hierarchical. The analysis of model dynamics revealed that neutrophil differentiation is driven by C/EBPα and Gfi1 rather than PU.1. This prediction is supported by the sequence of gene up-regulation in an independent mouse bone marrow scRNA-Seq dataset. These results imply that neutrophil differentiation is not driven by the Gata1-PU.1 switch but by neutrophil-specific genes instead. More generally, this work shows that data-driven dynamical modeling can uncover the causality of developmental events that might otherwise be obscured.
Discovery of novel ID2 antagonists from pharmacophore-based virtual screening as potential therapeutics for glioma
Authors: Zhong Genshen , Wang Yichun , Wang Qi , Wu Minna , Liu Yichuang , Sun Shitao , Li Zhenli , Hao Jinle , Dou Peiyuan , Lin Bin
Published: May 2021

Glioma, especially the most aggressive type glioblastoma multiforme, is one of the central nervous system malignant cancer with a poor prognosis. Traditional treatments are mainly surgery combined with radiotherapy and chemotherapy, which is still not satisfactory. Therefore, it is of great clinical significance to find new therapeutic agents. Served as an inhibitor of differentiation, protein ID2 (inhibitor of DNA binding 2) plays an important role in neurogenesis, neovascularization and malignant development of gliomas. It has been shown that ID2 affects the malignant progression of gliomas through different mechanisms. In this study, a pharmacophore-based virtual screening was carried out and 16 hit compounds were purchased for pharmacological evaluations on their ID2 inhibitory activities. Based on the cytotoxicity of these small-molecule compounds, two compounds were shown to effectively inhibit the viability of glioma cells in the low micromolar range. Among them, AK-778-XXMU was chosen for further study due to its better solubility in water. A SPR assay proved the high affinity between AK-778-XXMU and ID2 protein with the KD value as 129 nM. The plausible binding mode in the biding site of ID2 was studied by molecular docking. Subsequently, the cancer-suppressing potency of the compound was characterized both in vitro and in vivo. The data demonstrated that compound AK-778-XXMU is a potent ID2 antagonist which has the potential to be developed as a therapeutic agent against glioma.

Highlights

Two pharmacophores were built from the first-in-class pan-ID antagonists AGX51

A pharmacophore-based virtual screening was carried out and 16 hit compounds were purchased for pharmacological evaluations in glioma inhibition

Compound AK-778-XXMU was identified to be a potent ID2 antagonist in the low submicromolar range (KD: 159 nM)
High-precision mapping of nuclear pore-chromatin interactions reveals new principles of genome organization at the nuclear envelope
Authors: Tyagi Swati , Capitanio Juliana S. , Xu Jiawei , Chen Fei , Sharma Rahul , Huang Jialiang , Hetzer Martin W.
Published: May 2021

The role of nuclear pore complexes (NPCs) in genome organization remains poorly characterized due to technical limitations in probing genome-wide protein-DNA interactions specific to the nuclear periphery. Here, we developed a new sensitive method, NPC-DamID, which combinesin vitroreconstitution of nuclear import and DamID technology. The fixation-free method identifies chromatin interactions at the NPCs in intact nuclei from cells and tissues. We found that NPCs are preferentially associated with common and hierarchically arranged super-enhancers (SEs) across multiple cell types. We also uncovered phase-separated condensates at NPCs that compartmentalize and concentrate transcriptional coactivators and structural proteins at SE-regulated genes. Our results support NPCs as anchoring sites for SE regulatory hubs and cell-type-specific transcriptional control.
Dynamic Interactions of Fully Glycosylated SARS-CoV-2 Spike Protein with Various Antibodies
Authors: Cao Yiwei , Choi Yeol Kyo , Frank Martin , Woo Hyeonuk , Park Sang-Jun , Yeom Min Sun , Seok Chaok , Im Wonpil
Published: May 2021

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a public health crisis, and the vaccines that can induce highly potent neutralizing antibodies are essential for ending the pandemic. The spike (S) protein on the viral envelope mediates human angiotensin-converting enzyme 2 (ACE2) binding and thus is the target of a variety of neutralizing antibodies. In this work, we built various S trimer-antibody complex structures on the basis of the fully glycosylated S protein models described in our previous work, and performed all-atom molecular dynamics simulations to get insight into the structural dynamics and interactions between S protein and antibodies. Investigation of the residues critical for S-antibody binding allows us to predict the potential influence of mutations in SARS-CoV-2 variants. Comparison of the glycan conformations between S-only and S-antibody systems reveals the roles of glycans in S-antibody binding. In addition, we explored the antibody binding modes, and the influences of antibody on the motion of S protein receptor binding domains. Overall, our analyses provide a better understanding of S-antibody interactions, and the simulation-based S-antibody interaction maps could be used to predict the influences of S mutation on S-antibody interactions, which will be useful for the development of vaccine and antibody-based therapy.
Predicted UV-C Sensitivity of Human and Non-human Vertebrate (+) ssRNA Viruses
Authors: Pendyala Brahmaiah , Patras Ankit
Published: May 2021

Epidemic and pandemic infectious diseases caused by RNA viruses constitute a significant hazard to human and animal health. Disinfection is an essential aspect of infection prevention and control measures. In this study, we estimated UV-C sensitivity of 83 human and veterinary pathogenic (+) ssRNA viruses by developed pyrimidine dinucleotide frequency-based genomic model. The data showed that the avian infectious bronchitis virus (genus: γ-coronavirus) with an estimated D90 value of 17.8 J/m2 was highly UV sensitive, whereas Salivirus NG-J1 (genus: salivirus) with a D90 value of 346.4 J/m2 was highly UV resistant. Overall, the trend of UV-C sensitivity of (+) ssRNA virus families followed as Coronaviridae < Flaviviridae < Togadoviridae < Arteriviridae, Matonaviridae, Astroviridae < Caciviridae < Picornaviridae < Nodaviridae < Herpeviridae. The results revealed that the enveloped viral families (Coronaviridae, Flaviviridae, Togadoviridae Arteriviridae, and Matonaviridae) are more UV-C sensitive than other nonenveloped families. Further validation of the model estimated UV sensitivity with literature available experimental data showed good agreement of predicted values. The estimates presented here could make it possible to reasonably predict UV-C disinfection efficiency of human and veterinary pathogenic viruses, which need specific biosafety requirements and/or difficult to cultivate in lab conditions.
Willingness to pay for traditional, complementary and alternative medicine (TCAM) among Malaysian adults
Authors: Koh M.Z.Y. , Goh Yen-Nee
Published: May 2021

Purpose

Health plays a crucial role in the daily lives and supporting health is the important role of medicine. With the availability of traditional, complementary and alternative medicine (TCAM), the demands and willingness to pay among users are increasing. Hence, this study aims to determine the psychological factors influencing the willingness to pay for TCAM among Malaysian adults.

Design/methodology/approach

In total, 300 completed self-administered questionnaires were collected from Malaysian adults using a purposive sampling method through intercepts at public health-care facilities. A structural equation modelling approach using partial least square was used to test the hypotheses.

Findings

The findings show that attitude, subjective norms, perceived price and knowledge have a significant impact on willingness to pay for TCAM. Surprisingly, there was no relationship found between perceived behavioural control and health consciousness on willingness to pay for TCAM.

Originality/value

The findings of this study are expected to provide better insights into TCAM use among Malaysian adults. The results are also important to encourage health-care institutions and practitioners to educate the general public on the safety of TCAM to ensure more health benefits to the users.
The cubic S-curve relationship between board independence and intellectual capital efficiency: does firm size matter?
Authors: Kweh Qian Long , Lu Wen-Min , Ting Irene Wei Kiong , Thi My Le Hanh
Published: May 2021

Purpose

First, this study assesses firms’ efficiency of transforming intellectual capital (IC) components into firm performance. Second, this study examines (1) cubic S-curve relationship between board independence and IC efficiency and (2) how firm size moderates the cubic S-curve relationship.

Design/methodology/approach

This study employs a stochastic nonparametric envelopment of data (StoNED) framework to estimate IC efficiency, which is derived from the estimation process of transforming structural, relational and human capitals into accounting- and market-based performance indicators. This study conducts regression analyses on 1,104 firm-year observations of Taiwanese semiconductor firms over the period of 2011–2018.

Findings

StoNED results suggest that sample firms' IC efficiency can be relatively improved by approximately 80%. Regression results indicate that a cubic S-curve relationship between board independence and IC efficiency exists, and firm size moderates the nonlinear effects.

Practical implications

Overall, this study highlights the importance of examining the nonlinear effect of board independence on IC efficiency from the perspective of agency theory, and the moderating effect from firm size, which may suggest availability of resources from the resource-based view of the firm.

Originality/value

This study contributes to the literature through the innovative application of an efficiency-based tool for evaluating IC efficiency. The cubic S-curve relationship between board independence and IC efficiency also points to the policy concerning the appropriate number of independent directors on board.
How a doer persuade a donor? Investigating the moderating effects of behavioral biases in donor acceptance of donation crowdfunding
Authors: P. Theerthaana , Lysander Manohar Hansa
Published: May 2021

Purpose

The concept of donation crowdfunding has been drawing enormous attention as it connects donors worldwide in a shorter time at a relatively lower cost. This paper aims to integrate two unified theories, namely, behavioral finance and unified theory of acceptance and use of technology model, to investigate on the motivators and deterrents that influence prospective donors to adopt and use donation crowdfunding. The study also substantiates the significance of donors’ behavioral biases through the moderating effect in the crowdfunding adoption process.

Design/methodology/approach

The study used survey method for data collection and the data set was obtained from the sample of respondents belonging to India and Bangladesh. The proposed structural equation modeling is tested using SPSS 23.0 and AMOS 23.0.

Findings

The study reveals that performance expectancy, effort expectancy, facilitating conditions and trust significantly enhance the intention to adopt donation crowdfunding. Also, biases including overconfidence bias, herding bias and regret aversion bias are found to have significant moderating effects on the relationship between the behavioral intention to adopt donation crowdfunding and use behavior.

Practical implications

By investigating motivators and deterrents of the adoption of donation crowdfunding, the study renders lucrative insights for the donation crowdfunders in devising a donation fundraising campaign that motivates the prospective donors to provide financial contribution.

Originality/value

The study establishes its novelty in explaining the adoption behavior of donation crowdfunding with behavioral bias moderators as a theoretical paradigm. Furthermore, the unified theory of acceptance and use of technology model is extended by introducing, the variable “trust,” while studying the adoption behavior of donation crowdfunding.
Synthesis and evaluation of epoxy resin modified by hyperbranched polyester of caprylic acid and hexanoic acid
Authors: Shi Jiahao , Weng Ling , Wang Xiaoming , Sun Xue , Du Shuqiang , Gao Feng , Zhang Xiaorui
Published: May 2021

Purpose

Epoxy resin (EP) is a kind of thermosetting resin, and its application is usually limited by poor toughness. In this case, a type of new flexible chain blocking hyperbranched polyester (HBP) was designed and synthesized. The purpose of this study is to enhance the toughness and dielectric properties of EP.

Design/methodology/approach

P-toluene sulfonic acid was used as the catalyst, with dimethy propionic acid as the branch unit and pentaerythritol as the core in the experiment. Then,n-hexanoic acid andn-caprylic acid were, respectively, put to gain HBP with an-hexanoic acid andn-caprylic acid capped structure. The microstructure, mechanical properties, insulation properties and dielectric properties of the composite were characterized for the purpose of finding the appropriate proportion of HBP.

Findings

HBP enhanced the toughness of epoxy-cured products by interpenetrating polymer network structure between the flexible chain of HBP and the EP molecular chain. Meanwhile, HBP reduced the ε and tgδ of the epoxy anhydride-cured product by reducing the number of polar groups per unit volume of the EP through free volumes.

Research limitations/implications

Yet EP is a kind of thermosetting resin, which is widely used in coating, aerospace, electronics, polymer composites and military fields, but it is usually limited by poor toughness. In a word, it is an urgent priority to develop new EP with better toughness and mechanical properties.

Originality/value

At present, HBP has been applied as a new kind of toughening strategy and as a modifier for EP. According to the toughening mechanism of HBP modified EP, the free volume of HBP creates a space for the EP molecule to move around when loaded. Moreover, the free volume could cause the dielectric constant of EP to diminish by reducing the content of polarizable groups. Meanwhile, the addition of HBP with flexible chains grafted to the EP could develop an interpenetrating network structure, thus further enhancing the toughness of EP
Household‐level poverty, consumption poverty thresholds, income inequality and quality of lives in sub‐Saharan Africa
Authors: Ekeocha Davidmac O. , Iheonu Chimere O.
Published: May 2021

Poverty and income inequality are the twin greatest menaces in sub‐Saharan Africa (SSA) with significant prevalence. This study decomposed their significance and probabilities in determining the quality of life (QOL) of individuals and households in SSA while controlling for household demographics. The household‐level poverty (HLP) index and the indexes for QOL indicators were constructed from the national demographic and health surveys (DHS) for SSA countries. Data on consumption poverty thresholds and income inequality are from the global consumption and income project (GCIP) over 1985–2015. Findings reveal that, while the HLP index elicits more rural poverty across regions, consumption poverty thresholds are more urbanized and persistent across regions, except for Central Africa. The results for income inequality were found to be Gini −0.4396 and Atkinson index −0.4437, and more urbanized across regions. Furthermore, we found that SSA has made giant strides towards achieving sustainable development goals (SDGs) 6 and 3 but no information on the quality of healthcare. However, abysmal likelihoods exist for SDGs 4, 7 and 8 in SSA. Similarly, abysmal probabilities were also found for households’ access to adequate housing, a good environment and insurance coverage. Indeed, SDG‐4 is more significant for achieving SDG‐8. HLP stand as a significant bottleneck to achieving SDG‐7 and adequate housing, while income inequality mars SDG‐3 targets and sustainable environmental conditions in SSA. Policy options are discussed.