bluuebunny/crossref_metadata_2025 huggingface dataset:
Phospholipase A2inhibitor-loaded micellar nanoparticles attenuate inflammation and mitigate osteoarthritis progression
Authors: Wei Yulong , Yan Lesan , Luo Lijun , Gui Tao , Amirshaghaghi Ahmad , You Tianyan , Tsourkas Andrew , Qin Ling , Cheng Zhiliang
Published: January 2021

Treating osteoarthritis (OA) remains a major clinical challenge. Despite recent advances in drug discovery and development, no disease-modifying drug for knee OA has emerged with any significant clinical success, in part due to the lack of valid and responsive therapeutic targets and poor drug delivery within knee joints. In this work, we show that the amount of secretory phospholipase A2(sPLA2) enzyme increases in articular cartilage in human and mouse OA cartilage tissues. We hypothesize that inhibition of sPLA2activity may be an effective treatment strategy for OA. To develop a sPLA2-responsive and nanoparticle (NP)-based interventional platform for OA management, we incorporated a sPLA2inhibitor (sPLA2i) into the phospholipid membrane of micelles. The engineered sPLA2i-loaded micellar nanoparticles (sPLA2i-NPs) were able to penetrate deep into the cartilage matrix, prolong retention in the joint space, and mitigate OA progression. These findings suggest that sPLA2i-NPs can be promising therapeutic agents for OA treatment.
Chromosome size affects sequence divergence between species through the interplay of recombination and selection
Authors: Tigano Anna , Khan Ruqayya , Omer Arina D. , Weisz David , Dudchenko Olga , Multani Asha S. , Pathak Sen , Behringer Richard R. , Aiden Erez L. , Fisher Heidi , MacManes Matthew D.
Published: January 2021

The structure of the genome shapes the distribution of genetic diversity and sequence divergence. To investigate how the relationship between chromosome size and recombination rate affects sequence divergence between species, we combined empirical analyses and evolutionary simulations. We estimated pairwise sequence divergence among 15 species from three different Mammalian clades -Peromyscusrodents,Musmice, and great apes - from chromosome-level genome assemblies. We found a strong significant negative correlation between chromosome size and sequence divergence in all species comparisons within thePeromyscusand great apes clades, but not theMusclade, suggesting that the dramatic chromosomal rearrangements amongMusspecies may have masked the ancestral genomic landscape of divergence in many comparisons. Our evolutionary simulations showed that the main factor determining differences in divergence among chromosomes of different size is the interplay of recombination rate and selection, with greater variation in larger populations than in smaller ones. In ancestral populations, shorter chromosomes harbor greater nucleotide diversity. As ancestral populations diverge, diversity present at the onset of the split contributes to greater sequence divergence in shorter chromosomes among daughter species. The combination of empirical data and evolutionary simulations revealed that chromosomal rearrangements, demography, and divergence times may also affect the relationship between chromosome size and divergence, and deepen our understanding of the role of genome structure on the evolution of species divergence.
The statistics ofk-mers from a sequence undergoing a simple mutation process without spurious matches
Authors: Blanca Antonio , Harris Robert S. , Koslicki David , Medvedev Paul
Published: January 2021

K-mer-based methods are widely used in bioinformatics, but there are many gaps in our understanding of their statistical properties. Here, we consider the simple model where a sequence S (e.g. a genome or a read) undergoes a simple mutation process whereby each nucleotide is mutated independently with some probability r, under the assumption that there are no spurious k-mer matches. How does this process affect the k-mers of S? We derive the expectation and variance of the number of mutated k-mers and of the number of islands (a maximal interval of mutated k-mers) and oceans (a maximal interval of non-mutated k-mers). We then derive hypothesis tests and confidence intervals for r given an observed number of mutated k-mers, or, alternatively, given the Jaccard similarity (with or without minhash). We demonstrate the usefulness of our results using a few select applications: obtaining a confidence interval to supplement the Mash distance point estimate, filtering out reads during alignment by Minimap2, and rating long read alignments to a de Bruijn graph by Jabba.
In vivo analysis of the contribution of proprotein convertases to the processing of FGF23
Authors: Rifai Omar Al , Susan-Resiga Delia , Essalmani Rachid , Creemers John W.M. , Seidah Nabil G. , Ferron Mathieu
Published: January 2021

Fibroblast growth factor 23 (FGF23) is a hormone secreted from fully differentiated osteoblasts and osteocytes that inhibits phosphate reabsorption by kidney proximal tubules. The full-length (i.e., intact) protein mediates FGF23 endocrine functions, while endoproteolytic cleavage at a consensus cleavage sequence for the proprotein convertases (PCs) inactivates FGF23. Two PCs, furin and PC5, were shown to cleave FGF23in vitroat RHTR179↓, but whether they are fulfilling this function in vivo is currently unknown. To address this question we used here mice lacking either or both furin and PC5 in cell-specific manners and mice lacking the paired basic amino acid-cleaving enzyme 4 (PACE4) in all cells. Our analysis shows that furin inactivation in osteoblasts and osteocytes results in a 25% increase in circulating intact FGF23, without any significant impact on serum phosphate levels, whether mice are maintained on a normal or a low phosphate diet. Under conditions of iron deficiency, FGF23 is normally processed in control mice, but its processing is impaired in mice lacking furin in osteoblasts and osteocytes. In contrast, FGF23 is normally cleaved following erythropoietin or IL-1β injections in mice lacking furin or both furin and PC5, and in PACE4-deficient mice. Altogether, these studies suggest that furin is only partially responsible for FGF23 cleavage under certain conditionsin vivo. The processing of FGF23 may therefore involve the redundant action of multiple PCs or of other peptidases in osteoblasts, osteocytes and hematopoietic cells.
Circadian Alterations Increase with Progression in a Patient-Derived Cell Culture Model of Breast Cancer
Authors: Lin Hui-Hsien , Taylor Stephanie R. , Farkas Michelle E.
Published: January 2021

Circadian rhythms are critical regulators of many physiological and behavioral functions; disruption of this time-tracking system can elicit the development of various diseases, including breast cancer. While multiple studies have used cell lines to study the correlation between altered circadian rhythms and cancer, these cells generally have different genetic backgrounds and do not mirror the changes that occur with disease development. Isogenic cell models can represent and recapitulate changes across cancer progression. Hence in the present study, a patient-derived breast cancer model, the 21T series, was used to evaluate changes to circadian oscillations of core clock protein transcription and translation as cells progress from normal to malignant states. Three cell lines from the series were used: H16N2, from normal breast epithelium; 21PT, from Atypical Ductal Hyperplasia; and 21MT, from Invasive Metastatic Carcinoma. Both of the cancerous cell lines are HER2 positive. We assessed the transcriptional profiles of two core circadian clock proteins, BMAL1 and PER2, which represent a positive and negative component of the molecular oscillator. In the normal H16N2 cells,BMAL1andPER2both possessed rhythmic mRNA oscillations with close to standard periods and the expected anti-phase relationship. However, in the cancerous cells, consistent changes were observed: both clock genes had periods that deviated farther from normal and did not have an anti-phase relationship. To provide a more complete understanding of circadian alterations in breast cancer, luciferase reporters and real-time luminometry should be used in future studies.
Functional Genetic Biomarkers of Alzheimer’s Disease and Gene Expression from Peripheral Blood
Authors: Ni Andrew , Sethi Amish ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2021

Detecting Alzheimer’s Disease (AD) at the earliest possible stage is key in advancing AD prevention and treatment but is challenged by normal aging processes in addition to other confounding neurodegenerative diseases. Recent genome-wide association studies (GWAS) have identified associated alleles, but it has been difficult to transition from non-coding genetic variants to underlying mechanisms of AD. Here, we sought to reveal functional genetic variants and diagnostic biomarkers underlying AD using machine learning techniques. We first developed a Random Forest (RF) classifier using microarray gene expression data sampled from the peripheral blood of 744 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. After initial feature selection, 5-fold cross-validation of the 100-gene RF classifier achieved an accuracy of 99.04%. The high accuracy of the RF classifier supports the possibility of a powerful and minimally invasive tool for screening of AD. Next, unsupervised clustering was used to validate and identify relationships among differentially expressed genes (DEGs) the RF selected revealing 3 distinct AD clusters. Results suggest downregulation of global sulfatase and oxidoreductase activities in AD through mutations in SUMF1 and SMOX respectively. Then, we used Greedy Fast Causal Inference (GFCI) to find potential causes of AD within DEGs. In the causal graph, HLA-DPB1 and CYP4A11 emerge as hub genes, furthering the discussion of the immune system’s role in AD. Finally, we used Gene Set Enrichment Analysis (GSEA) to determine the biological pathways and processes underlying the DEGs that were highly correlated with AD. Cell activation in the immune system, glycosaminoglycan (GAG) binding, vascular dysfunction, oxidative stress, and the neuronal apoptotic process were revealed to be significantly enriched in AD. This study further advances the possibility of low-cost and noninvasive genetic screening for AD while also providing potential gene targets for further experimentation.
AsmMix: A pipeline for high quality diploidde novoassembly
Authors: Wu Pei , Liu Chao , Wang Ou , Zhao Xia , Chen Fang , Cheng Xiaofang , Zhu Hongmei
Published: January 2021

In this paper, we report a pipeline, AsmMix, which is capable of producing both contiguous and high-quality diploid genomes. The pipeline consists of two steps. In the first step, two sets of assemblies are generated: one is based on co-barcoded reads, which are highly accurate and haplotype-resolved but contain many gaps, the other assembly is based on single-molecule sequencing reads, which is contiguous but error-prone. In the second step, those two sets of assemblies are compared and integrated into a haplotype-resolved assembly with fewer errors. We test our pipeline using a dataset of human genome NA24385, perform variant calling from those assemblies and then compare against GIAB Benchmark. We show that AsmMix pipeline could produce highly contiguous, accurate, and haplotype-resolved assemblies. Especially the assembly mixing process could effectively reduce small-scale errors in the long read assembly.
High prevalence of mixed and non-vaccine HPV oncogenic types and their association with higher mortality in Black women with cervical cancer
Authors: Mendoza Rachelle P. , Haidary Tahmineh , Gabutan Elmer , Zhou Yin Ying , Bukhari Zaheer , Connelly Courtney , Lee Wen-Ching , Lee Yi-Chen , Wadgaonkar Raj , Agrawal Raag , Haseeb MA , Gupta Raavi
Published: January 2021

We studied the incidence of HPV genotypes in mostly Black women with cervical carcinoma and correlated histopathologic tumor characteristics, immune markers and clinical data with survival. Disease-free survival (DFS) and overall survival (OS) were recorded for 60 months post-diagnosis. Fifty four of the 60 (90%) patients were Black and 36 (60%) were <55 years of age. Of the 40 patients with typeable HPV genotypes, 10 (25%) had 16/18 HPV genotypes, 30 (75%) had one of the non-16/18 HPV genotypes, and 20 (50%) had one of the 7 genotypes (35, 39, 51, 53, 56, 59 and 68) that are not included in the nonavalent vaccine. Mixed HPV infections (>2 types) were found in 11/40 (27.5%) patients. Patients infected with non-16/18 genotypes, including the most common genotype, HPV 35, had significantly shorter DFS and OS. PD-L1 (p=0.003), MMR expression (p=0.01), clinical stage (p=0.048), histologic grade (p=0.015) and mixed HPV infection (p=0.026) were independent predictors of DFS. A remarkably high proportion of cervical cancer cells in our patients expressed PD-L1 which opens the possibility of the use of immune checkpoint inhibitors to treat these cancers. Exclusion of the common HPV genotypes from the vaccine exacerbates mortality from cervical cancer in underserved Black patients.
Acute Endotheliitis (Type 3 Hypersensitivity Vasculitis) in Ten COVID-19 Autopsy Brains
Authors: Rhodes Roy H. , Love Gordon L. , Da Silva Lameira Fernanda , Sadough Maryam Shahmirzadi , Fox Sharon E. , Heide Richard S. Vander
Published: January 2021

Central nervous system (CNS) involvement in COVID-19 may occur through direct SARS-CoV-2 invasion through peripheral or cranial nerves or through vascular endothelial cell infection. The renin-angiotensin system may play a major part in CNS morbidity. Effects of hypoxia have also been implicated in CNS lesions in COVID-19. This communication reports on ten consecutive autopsies of individuals with death due to COVID-19 with decedent survival ranging from 30 minutes to 84 days after admission. All ten brains examined had neutrophilic microvascular endotheliitis present in variable amounts and variably distributed. Importantly, this acute stage of type 3 hypersensitivity vasculitis can be followed by fibrinoid necrosis and inner vascular wall sclerosis, but these later stages were not found. These results suggest that a vasculitis with autoimmune features occurred in all ten patients. It is possible that viral antigen in or on microvascular walls or other antigen-antibody complexes occurred in all ten patients proximate to death as a form of autoimmune vasculitis.
SARS-CoV-2 RECoVERY: a multi-platform open-source bioinformatic pipeline for the automatic construction and analysis of SARS-CoV-2 genomes from NGS sequencing data
Authors: De Sabato Luca , Vaccari Gabriele , Knijn Arnold , Ianiro Giovanni , Di Bartolo Ilaria , Morabito Stefano
Published: January 2021

Background

Since its first appearance in December 2019, the novelSevere Acute Respiratory Syndrome Coronavirus type 2(SARS-CoV-2), spread worldwide causing an increasing number of cases and deaths (35,537,491 and 1,042,798, respectively at the time of writing,https://covid19.who.int). Similarly, the number of complete viral genome sequences produced by Next Generation Sequencing (NGS), increased exponentially. NGS enables a rapid accumulation of a large number of sequences. However, bioinformatics analyses are critical and require combined approaches for data analysis, which can be challenging for non-bioinformaticians.

Results

A user-friendly and sequencing platform-independent bioinformatics pipeline, named SARS-CoV-2 RECoVERY (REconstruction of CoronaVirus gEnomes & Rapid analYsis) has been developed to build SARS-CoV-2 complete genomes from raw sequencing reads and to investigate variants. The genomes built by SARS-CoV-2 RECoVERY were compared with those obtained using other software available and revealed comparable or better performances of SARS–CoV2 RECoVERY. Depending on the number of reads, the complete genome reconstruction and variants analysis can be achieved in less than one hour. The pipeline was implemented in the multi-usage open-source Galaxy platform allowing an easy access to the software and providing computational and storage resources to the community.

Conclusions

SARS-CoV-2 RECoVERY is a piece of software destined to the scientific community working on SARS-CoV-2 phylogeny and molecular characterisation, providing a performant tool for the complete reconstruction and variants’ analysis of the viral genome. Additionally, the simple software interface and the ability to use it through a Galaxy instance without the need to implement computing and storage infrastructures, make SARS-CoV-2 RECoVERY a resource also for virologists with little or no bioinformatics skills.

Availability and implementation

The pipeline SARS-CoV-2 RECoVERY (REconstruction of COronaVirus gEnomes & Rapid analYsis) is implemented in the Galaxy instance ARIES (https://aries.iss.it).
Suppression weakens unwanted memories via a sustained reduction of neural reactivation
Authors: Meyer Ann-Kristin , Benoit Roland G.
Published: January 2021

Aversive events sometimes turn into intrusive memories. However, prior evidence indicates that such memories can be controlled via a mechanism of retrieval suppression. Here, we test the hypothesis that suppression exerts a sustained influence on memories by deteriorating their neural representations. This deterioration, in turn, would hinder their subsequent reactivation and thus impoverish the vividness with which they can be recalled. In an fMRI study, participants repeatedly suppressed memories of aversive scenes. As predicted, this process rendered the memories less vivid. Using a pattern classifier, we observed that suppression diminished the neural reactivation of scene information both globally across the brain and locally in the parahippocampal cortices. Moreover, the decline in vividness was associated with reduced reinstatement of unique memory representations in right parahippocampal cortex. These results support the hypothesis that suppression weakens memories by causing a sustained reduction in the potential to reactivate their neural representations.
Optimized CRISPR-mediated gene knock-in reveals FOXP3-independent control of human Treg identity
Authors: Lam Avery J. , Lin David T.S. , Gillies Jana K. , Uday Prakruti , Pesenacker Anne M. , Kobor Michael S. , Levings Megan K.
Published: January 2021

Treg cell therapy is a promising curative approach for a variety of immune-mediated conditions. CRISPR-based genome editing allows precise insertion of transgenes through homology-directed repair, but use in human Tregs has been limited. We report an optimized protocol for CRISPR-mediated gene knock-in in human Tregs with high-yield expansion. To establish a benchmark of human Treg dysfunction, we targeted the master transcription factor FOXP3 in naive and memory Tregs. Although FOXP3-knockout Tregs upregulated cytokine expression, effects on suppressive capacity manifested slowly and primarily in memory Tregs. Moreover, FOXP3-knockout Tregs retained their characteristic phenotype and had few changes in their DNA methylation landscape, with FOXP3 maintaining methylation at regions enriched for AP-1 binding sites. Thus, while FOXP3 is important for human Treg development, it has a limited role in maintaining mature Treg identity. Optimized gene knock-in with human Tregs will enable mechanistic studies and the development of tailored, next-generation Treg cell therapies.
Idiosyncratic purifying selection on metabolic enzymes in the long-term evolution experiment withEscherichia coli
Authors: Maddamsetti Rohan
Published: January 2021

Bacteria, Archaea, and Eukarya all share a common set of metabolic reactions. This implies that the function and topology of central metabolism has been evolving under purifying selection over deep time. Central metabolism may similarly evolve under purifying selection during longterm evolution experiments, although it is unclear how long such experiments would have to run (decades, centuries, millennia) before signs of purifying selection on metabolism appear. I hypothesized that central and superessential metabolic enzymes would show evidence of purifying selection in the long-term evolution experiment withEscherichia coli(LTEE). I also hypothesized that enzymes that specialize on single substrates would show stronger evidence of purifying selection in the LTEE than generalist enzymes that catalyze multiple reactions. I tested these hypotheses by analyzing metagenomic time series covering 62,750 generations of the LTEE. I find mixed support for these hypotheses, because the observed patterns of purifying selection are idiosyncratic and population-specific. To explain this finding, I propose the Jenga hypothesis, named after a children’s game in which blocks are removed from a tower until it falls. The Jenga hypothesis postulates that loss-of-function mutations degrade costly, redundant, and nonessential metabolic functions. Replicate populations can therefore follow idiosyncratic trajectories of lost redundancies, despite purifying selection on overall function. I tested the Jenga hypothesis by simulating the evolution of 1,000 minimal genomes under strong purifying selection. As predicted, the minimal genomes converge to different metabolic networks. Strikingly, the core genes common to all 1,000 minimal genomes show consistent signatures of purifying selection in the LTEE.

Significance Statement

Purifying selection conserves organismal function over evolutionary time. However, few studies have examined the role of purifying selection during adaptation to novel environments. I tested metabolic enzymes for purifying selection in an ongoing long-term evolution experiment withEscherichia coli.While some populations show signs of purifying selection, the overall pattern is inconsistent. To explain these findings, I propose the Jenga hypothesis, in which loss-of-function mutations first degrade costly, redundant, and nonessential metabolic functions, after which purifying selection begins to dominate. I then tested several predictions of the Jenga hypothesis using computational simulations. On balance, the simulations confirm that we should find evidence of purifying selection on the metabolic pathways that sustain growth in a novel environment.
Human Cytomegalovirus uses a Host Stress Response to Balance the Elongation of Saturated/Monounsaturated and Polyunsaturated Very Long Chain Fatty Acids
Authors: Xi Yuecheng , Lindenmayer Lena , Kline Ian , von Einem Jens , Purdy John G.
Published: January 2021

Stress and virus infection are known to regulate lipid metabolism in cells. Human cytomegalovirus infection induces fatty acid (FA) elongation and increases the cellular abundance of lipids with very long-chain FA tails (VLCFAs). While reprogramming of metabolism can be stress-related, the role of stress in HCMV reprogramming of lipid metabolism is poorly understood. In this study, we engineered cells to knockout PKR-like ER kinase (PERK) in the ER stress pathway and measured lipid changes using lipidomics to determine if PERK is needed for lipid changes associated with HCMV infection. We found that in HCMV-infected cells, PERK promotes the increase in the levels of phospholipids with saturated FA (SFA) and monounsaturated FA (MUFA) VLCFAs tails. Consistent with the SFA/MUFA lipidome changes, PERK enhances the protein levels of FA elongase 7 (ELOVL7), which elongates SFA and MUFA VLCFAs. Additionally, we found that increases in the elongation of polyunsaturated fatty acids (PUFAs) associated with HCMV infection was independent of PERK and that lipids with PUFA tails accumulated in HCMV-infected PERK knockout cells. Consistent with the PUFA lipidome changes, the protein levels of ELOVL5, which elongates PUFAs, are increased by HCMV infection through a PERK-independent mechanism. These observations show that PERK differentially regulates ELOVL7 and ELOVL5, creating a balance between the synthesis of lipids with SFA/MUFA tails and PUFA tails. Additionally, we found that PERK was necessary for virus replication and the infectivity of released viral progeny. Overall, our findings indicate that PERK—and more broadly, ER stress—may be necessary for membrane biogenesis needed to generate infectious HCMV virions.

IMPORTANCE

HCMV is a common herpesvirus that establishes lifelong persistent infections. While infection is asymptomatic in most people, HCMV causes life-threatening illnesses in immunocompromised people, including transplant recipients and cancer patients. Additionally, HCMV infection is a leading cause of congenital disabilities. HCMV replication relies on lipid synthesis. Here, we demonstrated that the ER stress mediator, PERK, controls fatty acid (FA) elongation and cellular abundance of several types of lipids following HCMV infection. Specifically, we found that PERK promotes FA elongase 7 synthesis of lipids with saturated/monounsaturated very long-chain FA tails which are important for building the viral membrane of infectious HCMV virions. Overall, our study shows that PERK is an essential host factor that supports HCMV replication and promotes lipidome changes caused by HCMV infection.
Type IV competence pili inStreptococcus pneumoniaeare highly dynamic structures that retract to promote DNA uptake
Authors: Lam Trinh , Ellison Courtney K. , Dalia Ankur B. , Eddington David T. , Morrison Donald A.
Published: January 2021

The competence pili of transformable Gram-positive species form a subset of the diverse and widespread class of extracellular filamentous organelles known as type IV pili (T4P). In Gram-negative bacteria, T4P act through dynamic cycles of extension and retraction to carry out diverse activities including attachment, motility, protein secretion, and DNA uptake. It remains unclear whether T4P in Gram-positive species exhibit this same dynamic activity, and their mechanism of action for DNA uptake remains unclear. They are hypothesized to either (1) passively form transient cavities in the cell wall to facilitate DNA passage, (2) act as static adhesins to enrich DNA near the cell surface for subsequent uptake by membrane-embedded transporters, or (3) play an active role in translocating bound DNA via their dynamic activity. Here, using a recently described pilus labeling approach, we demonstrate that pneumococcal competence pili are highly dynamic structures that rapidly extend and retract from the cell surface. By labeling ComGC with bulky adducts, we further demonstrate that pilus retraction is essential for natural transformation. Together, our results indicate that Gram-positive type IV competence pili are dynamic and retractile structures that play an active role in DNA uptake.

Short summary

Competent pneumococci kill non-competent cells on contact. Retractable DNA-binding fibers in the class of type IV pili may provide a key tool for retrieving DNA segments from cell wreckage for internalization and recombination.
Laboratory diagnostics of tomato spotted wilt virus by PCR
Authors: Morozova O.N. , Zvyagintseva D. D. , Beloshapkina O.O.
Published: January 2021

Tomato spotted wilt virus is a widespread and harmful virus. It affects a wide range of host plants. The outward signs of TSWV lesions are different on different cultures. For the early diagnosis of TSWV, molecular diagnostic methods such as PCR must be used. In the course of this work, primers were developed for the diagnosis of tomato bronzing virus by real-time PCR and classical PCR. We also compared the specificity and sensitivity of various test systems for the diagnosis of tomato bronzing virus. In the course of this comparison, it was found that the self-assembly test system and the Syntol test system can be recommended for laboratory diagnostics of tomato spotted wilt virus.
Dynamic molecular epidemiology reveals lineage-associated single-nucleotide variants that alter RNA structure in Chikungunya virus
Authors: Spicher Thomas , Delitz Markus , de Bernardi Schneider Adriano , Wolfinger Michael T.
Published: January 2021

Chikungunya virus (CHIKV) is an emerging Alphavirus which causes millions of human infections every year. Outbreaks have been reported in Africa and Asia since the early 1950s, from three CHIKV lineages: West African, East Central South African, and Asian Urban. As new outbreaks occurred in the Americas, individual strains from the known lineages have evolved, creating new monophyletic groups that generated novel geographic-based lineages. Building on a recently updated phylogeny of CHIKV, we report here the availability of an interactive CHIKV phylodynamics dataset, which is based on more than 900 publicly available CHIKV genomes. We provide an interactive view of CHIKV molecular epidemiology built on Nextstrain, a web-based visualization framework for real-time tracking of pathogen evolution. CHIKV molecular epidemiology reveals single nucleotide variants that change the stability and fold of locally stable RNA structures. We propose alternative RNA structure formation in different CHIKV lineages by predicting more than a dozen RNA elements that are subject to perturbation of the structure ensemble upon variation of a single nucleotide.
Hierarchy-guided Neural Networks for Species Classification
Authors: Elhamod Mohannad , Diamond Kelly M. , Maga A. Murat , Bakis Yasin , Bart Henry L. , Mabee Paula , Dahdul Wasila , Leipzig Jeremy , Greenberg Jane , Avants Brian , Karpatne Anuj
Published: January 2021

Species classification is an important task that is the foundation of industrial, commercial, ecological, and scientific applications involving the study of species distributions, dynamics, and evolution.

While conventional approaches for this task use off-the-shelf machine learning (ML) methods such as existing Convolutional Neural Network (ConvNet) architectures, there is an opportunity to inform the ConvNet architecture using our knowledge of biological hierarchies among taxonomic classes.

In this work, we propose a new approach for species classification termed Hierarchy-Guided Neural Network (HGNN), which infuses hierarchical taxonomic information into the neural network’s training to guide the structure and relationships among the extracted features. We perform extensive experiments on an illustrative use-case of classifying fish species to demonstrate thatHGNNoutperforms conventional ConvNet models in terms of classification accuracy, especially under scarce training data conditions.

We also observe thatHGNNshows better resilience to adversarial occlusions, when some of the most informative patch regions of the image are intentionally blocked and their effect on classification accuracy is studied.
An updated structural model of the A domain of thePseudomonas putidaXylR regulator exposes a distinct interplay with aromatic effectors
Authors: Dvořák Pavel , Alvarez-Carreño Carlos , Ciordia Sergio , Paradela Alberto , de Lorenzo Víctor
Published: January 2021

A revised model of the aromatic binding A domain of the σ54-dependent regulator XylR ofPseudomonas putidamt-2 was produced based on the known 3D structures of homologous regulators PoxR, MopR, and DmpR. The resulting frame was instrumental for mapping the large number of mutations known to alter effector specificity, which were then reinterpreted under a dependable spatial reference. Some of these changes involved the predicted aromatic-binding pocket but others occurred in distant locations, including dimerization interfaces and putative zinc-binding site. The effector pocket was buried within the protein structure and accessible from the outside only through a narrow tunnel. The model was experimentally validated by treating the cellsin vivoand the purified proteinin vitrowith benzyl bromide, which reacts with accessible nucleophilic residues on the protein surface. Proteomic analyses of the thereby tagged peptides confirmed the predicted in/out distribution of residues but also suggested that the fully-folded protein is not accessible by externally added effectors. The data thus suggested that XylR inducers assist the folding and/or the structuring of the A domain in an intramolecular non-repressive form rather than interacting dynamically with the aromatic partner once a fully structured protein is shaped.

Originality-Significance Statement

XylR is a transcriptional regulator ofPseudomonas putidastrain mt-2 which activates theupper TOL pathway promoterPufor catabolism of toluene andm-xylene upon binding of these aromatic effectors to its N-terminal A domain. While this feature has made XylR a popular platform for the development of whole-cell biosensors for aromatic compounds, the difficulty to crystallize the A domain —let alone the whole-length protein— has made structural comprehension of the effector-regulator binding quite problematic. To overcome this impasse, we have combined homology-based structural predictions of the A domain of XylR with biochemical probing of exposed amino acids on the surface of the protein, bothin vivoandin vitro. The results generally matched the effects of mutations known from previous genetic/phenotypic analyses of the protein. However, the data also suggested an intriguing mechanism of activation of XylR by effectors in which the inducer assists the shaping of the regulator in an active conformation rather than interactinga posterioriwith an already formed proteininvitro. This may in fact explain the longstanding failure to purify the protein in an effector-responsive form.
Removal of disulfide from acid stress chaperone HdeA does not wholly eliminate structure or function at low pH
Authors: Aguirre-Cardenas M. Imex , Geddes-Buehre Dane H. , Crowhurst Karin A.
Published: January 2021

HdeA is an acid-stress chaperone that operates in the periplasm of various strains of pathogenic gram-negative bacteria. Its primary function is to prevent irreversible aggregation of other periplasmic proteins when the bacteria enter the acidic environment of the stomach after contaminated food is ingested; its role is therefore to help the bacteria survive long enough to enter and infect the intestines. The mechanism of operation of HdeA is unusual in that this helical homodimer is inactive when folded at neutral pH but becomes activated at low pH after the dimer dissociates and becomes partially unfolded. Studies with chemical reducing agents have previously suggested that the intramolecular disulfide bond of HdeA aids in the maintenance of residual structure at low pH; it is believed that this residual structure is important for clustering exposed hydrophobic residues together for the purpose of binding unfolded client proteins. In order to explore its role in HdeA structure and chaperone function we performed a conservative cysteine to serine mutation of the disulfide. We found that, although residual structure is greatly diminished at pH 2 without the disulfide, it is not completely lost; conversely, the mutant is almost completely random coil at pH 6. Aggregation assays showed that mutated HdeA, although less successful as a chaperone than wild type, still maintains a surprising level of function. These studies highlight that we still have much to learn about the factors that stabilize residual structure at low pH and the role of disulfide bonds.
Human Tear Metabolomics Using Liquid Chromatography-Q Exactive-HF Mass Spectrometry
Authors: Shrestha Gauri Shankar , Vijay Ajay Kumar , Stapleton Fiona , Pickford Russell , Carnt Nicole
Published: January 2021

Aim

To putatively identify and characterise human tear metabolites in a normal subject on an untargeted platform of liquid chromatography-Q exactive-HF mass spectrometry.

Methods

Four samples of unstimulated tears were collected from both eyes on four consecutive days between 1 – 2 pm using a microcapillary tube and pooled from both eyes each day. Untargeted analysis of the tears was performed by chromatographic separation of constituent metabolites in both CSH-C18RP (Charged Surface Hybrid-C18 Reversed Phase) and SeQuant ZIC-pHILIC (Zwitterionic-polymeric Hydrophilic Interaction Liquid Chromatography) columns, followed by heated electrospray ionization (HESI) and the acquisition of mass spectra using QExactive-HF mass spectrometer. Compound Discoverer software (v2.0) was used for data analysis.

Result

Eighty-two metabolites were tentatively identified. Seventy compounds (85.4 %) were observed in all four samples with a coefficient of variation (CV) less than 25 %. Fifty-nine metabolites (71.9 %) were novel in the healthy tears. Amino acids were the most frequently detected metabolites in the tears (28 %), followed by carbohydrates (12.2 %), carboxylic acids (8.5 %), carnitines (6.1 %) and glycerophospholipids (4.9 %), respectively.

Conclusion

The current untargeted platform is capable of detecting a range of tear metabolites across several biological categories. This study provides a baseline for further ocular surface studies.
Fishing for survival: importance of shark fisheries for the livelihoods of coastal communities in Western Ghana
Authors: Seidu Issah , Brobbey Lawrence K. , Danquah Emmanuel , Oppong Samuel K. , van Beuningen David , Seidu Moro , Dulvy Nicholas K.
Published: January 2021

Small-scale shark fisheries support the livelihoods of a large number of coastal communities in developing countries. Shark meat comprises a cheap source of protein and is traded locally in many parts in developing countries, while the skins, oil, and fins are exported to the international market. This study addresses a gap in literature regarding the importance of elasmobranchs to key shark-fishing communities and the degree to which trade in shark products (meat and fins) vary in time and among fishing communities in Ghana. We interviewed 85 fishers and traders involved in shark fisheries in Axim, Dixcove, and Shama communities using semi-structured questionnaires. Fishing was the primary source of income and accounted for 58.5% of the total household income of respondents. Other important economic activities were fish processing (16.0%), fish retailing (13.3%), and small businesses (2.5%). One-third and often two-thirds of respondents generated between 80-100% of their income from shark fisheries: Axim (65%), Dixcove (68%), and Shama (35%). Shark meat consumption was common among fishers and traders and represents a substantial source of protein in the diet of the study communities. Hammerhead sharks (Sphyrnaspp) and Bull Shark (Carcharhinus leucas) have the most valuable fins and meat. Further, 75% and 95% of fishers and traders, respectively, see fishing and trading of shark meat as their last safety-net and, therefore, tend to be satisfied with their jobs. Non-fishing related livelihood streams including small businesses and transportation were the major fallback activities both fishers and traders preferred to rely on if there is a ban on the exploitation of sharks in Ghana. Overexploitation of these species will compromise food ecosystem functionality and security. Thus, any shark management strategy needs to urgently restraint mortality to sustainable levels, which, in the short-term, must take into consideration the preferred livelihood fallback options outlined by fishers and traders, and implement them to ensure the long-term benefits of the intervention.
(Counter) accounting for hybrid organising: a case of the Great Exhibition of the North
Authors: Ferry Laurence , Slack Richard
Published: January 2021

Purpose

Hybrid organising faces a fundamental challenge in managing multiple and conflicting logics. Prior studies have evidenced the performative role of accounting within such a context largely in support of neoliberal hegemony and economic logic. Mindful of such conflict and the support towards economic logic, drawing on universal accountings, this study provides insights from counter accounting and its potential to serve pluralism and the emancipation of marginalised constituencies.

Design/methodology/approach

The research examined The Great Exhibition of the North (GEOTN), England's largest event in 2018, which utilised themes of art, design and innovation to support a regeneration and economic growth agenda. This was led by NewcastleGateshead Initiative (NGI) a hybrid organisation combining logics for economic and social legacies, whose accounts are contrasted to counter accounts from a social movement; The Other Great Exhibition of the North, “OtherGEN”. The study involved 30 in-depth semi-structured interviews, detailed observation and documentation review providing account and counter account of the event.

Findings

The findings reveal that GEOTN promoted an agenda offering a duality of economic and social logics through the arts and culture delivering a lasting economic and social legacy. This employed traditional accountings and associated performance targets and measurement through a formal evaluation framework. Emergent tensions were apparent evidencing a more dominant economic logic. The purported use of culture was portrayed as artwashing by a counter account narrative enmeshed in a backdrop of austerity. This wider accounting highlights the need for reflection on logic plurality and enables challenge to the performative role of traditional accounting in hybrid organising.

Originality/value

Universal accountings, such as counter accounting, can be advanced to unpack “faked” logics duality in hybrid organising. This reveals the emancipatory potential of accountings and the need for dialogic reflection. Hybrid organising requires careful consideration of accounting as a universal praxis to support social and economic pluralism and democratic ideals.
Welfare impacts of rural credit and saving program inKurfa Cheledistrict, eastern Ethiopia: a propensity score matching estimation
Authors: Okoyo Eric N. , Wordofa Muluken Gezahegn , Hassen Jemal Y. , Bezabih Moges
Published: January 2021

Purpose

This study is conducted to evaluate the impact of rural credit on farm household income and food security.

Design/methodology/approach

A multistage random sampling procedure is implemented to select 180 (82 credit user and 98 non-credit user) households fromKurfa Cheledistrict, eastern Ethiopia. The Propensity Score Matching technique is used to estimate the impact of credit utilization on the welfare indicators.

Findings

The results of the econometric model estimation show that participation in the rural credit program was positively influenced by a household's educational status, family size, voluntary saving and participation in training related to credit and saving. On the contrary, livestock holding and extension advice were found to negatively affect participation. Furthermore, participation in rural credit program is found to increase annual income by 59% and calorie intake by 21%. These are significant results implying that participation in the rural credit and saving program improved household welfare in the study area.

Originality/value

This study is important because it shows the welfare impact of making credit program available to potential users in the study area. Moreover, for effectiveness of the credit program it is necessary to target households with relatively larger family size and those with relatively better education (to induce change among the wider farming community). It is also essential to focus on the saving behavior of the program beneficiaries and enhancing the management system by ensuring that sufficient development agents are in place.
Forget about the money? A latent profile analysis of calling and work motivation in Chinese employees
Authors: Zhang Chunyu , Hirschi Andreas
Published: January 2021

Purpose

Calling is typically associated with more intrinsic than extrinsic work motivation. This could give the impression that employees with a calling do not need or care about external rewards. To deepen the understanding of the relationship between calling and work motivation, the purpose of this paper is to test how calling is combined with different types of work motivation and how such combinations affect work outcomes differentially.

Design/methodology/approach

The authors applied latent profile analysis among Chinese employees with diverse occupations (N = 1,290), to identify calling and work motivation profiles and test their relations with work outcomes, assessed four months later.

Findings

Four profiles emerged: externally motivated low calling, moderately externally motivated calling, moderately motivated calling and highly motivated calling. Employees with weaker and stronger callings indicated being extrinsically motivated for work. Employees in the highly motivated calling profile exhibited highest job satisfaction, lowest cynicism and lowest turnover intentions, followed by employees in the moderately motivated calling profile, the moderately externally motivated calling profile and the externally motivated low calling profile.

Research limitations/implications

The findings imply that employees with a strong calling do care about external rewards and also benefit from external incentives to work.

Originality/value

This study is the first to explore the differential relationship between calling and work motivation. Moreover, the findings offer insights regarding the under-researched notion that different types of calling predict work outcomes differently.
Can board diversity predict the risk of financial distress?
Authors: Yousaf Umair Bin , Jebran Khalil , Wang Man
Published: January 2021

Purpose

The purpose of this study is to explore whether different board diversity attributes (corporate governance aspect) can be used to predict financial distress. This study also aims to identify what type of prediction models are more applicable to capture board diversity along with conventional predictors.

Design/methodology/approach

This study used Chinese A-listed companies during 2007–2016. Board diversity dimensions of gender, age, education, expertise and independence are categorized into three broad categories; relation-oriented diversity (age and gender), task-oriented diversity (expertise and education) and structural diversity (independence). The data is divided into test and validation sets. Six statistical and machine learning models that included logistic regression, dynamic hazard, K-nearest neighbor, random forest (RF), bagging and boosting were compared on Type I errors, Type II errors, accuracy and area under the curve.

Findings

The results indicate that board diversity attributes can significantly predict the financial distress of firms. Overall, the machine learning models perform better and the best model in terms of Type I error and accuracy is RF.

Practical implications

This study not only highlights symptoms but also causes of financial distress, which are deeply rooted in weak corporate governance. The result of the study can be used in future credit risk assessment by incorporating board diversity attributes. The study has implications for academicians, practitioners and nomination committees.

Originality/value

To the best of the authors’ knowledge, this study is the first to comprehensively investigate how different attributes of diversity can predict financial distress in Chinese firms. Further, this study also explores, which financial distress prediction models can show better predictive power.