bluuebunny/crossref_metadata_2025 huggingface dataset:
SARS-CoV-2 susceptibility and ACE2 gene variations within diverse ethnic backgrounds
Authors: Vadgama Nirmal , Kreymerman Alexander , Campbell Jackie , Shamardina Olga , Brugger Christiane ,   Genomics England Research Consortium, Lee Richard T. , Penkett Christopher J. , Gifford Casey A. , Mercola Mark , Nasir Jamal , Karakikes Ioannis
Published: August 2021

Background

Host genetics play a major role in COVID-19 susceptibility and severity. Here, we analyse an ethnically diverse cohort of National Health Service (NHS) patients in the United Kingdom (UK) to assess the association between variants in the ACE2 locus and COVID-19 risk.

Methods

We analysed whole-genome sequencing (WGS) data of 6,274 participants who were tested for SARS-CoV-2 from the UK’s 100,000 Genomes Project (100KGP) for the presence of ACE2 coding variants and expression quantitative trait loci (eQTLs).

Findings

We identified a splice site variant (rs2285666) associated with increased ACE2 expression with an overrepresentation in SARS-CoV-2 positive patients relative to 100KGP controls (p = .015), and in hospitalised European patients relative to outpatients in intra-ethnic comparisons (p = .029). We also compared the prevalence of 288 eQTLs, of which 23 were enriched in SARS-CoV-2 positive patients. The eQTL rs12006793 had the largest effect size (d = 0.91), which decreases ACE2 expression and is more prevalent in controls, thus potentially reducing risk of COVID-19. We identified three novel nonsynonymous variants predicted to alter ACE2 function, and showed that three variants (p.K26R, p.H378R, p.Y515N) alter receptor affinity for the viral Spike (S) protein. Variants p.K26R and p.N720D are more prevalent in the European population (p < .001), but Y497H is less prevalent compared to East Asians (p = .020).

Interpretation

Our results demonstrate that the spectrum of genetic variants in ACE2 may inform risk stratification of COVID-19 patients and could partially explain the differences in disease susceptibility and severity among different ethnic groups.

Funding

The 100KGP is funded by the National Institute for Health Research and NHS England. Funding was also obtained from Stanford University, Palo Alto.
The WORC database: MRI and CT scans, segmentations, and clinical labels for 930 patients from six radiomics studies
Authors: Starmans Martijn P.A. , Timbergen Milea J.M. , Vos Melissa , Padmos Guillaume A. , Grünhagen Dirk J. , Verhoef Cornelis , Sleijfer Stefan , van Leenders Geert J.L.H. , Buisman Florian E. , Willemssen Francois E.J.A. , Koerkamp Bas Groot , Angus Lindsay , van der Veldt Astrid A.M. , Rajicic Ana , Odink Arlette E. , Renckens Michel , Doukas Michail , de Man Rob A. , IJzermans Jan N.M. , Miclea Razvan L. , Vermeulen Peter B. , Thomeer Maarten G. , Visser Jacob J. , Niessen Wiro J. , Klein Stefan
Published: August 2021

The WORC database consists in total of 930 patients composed of six datasets gathered at the Erasmus MC, consisting of patients with: 1) well-differentiated liposarcoma or lipoma (115 patients); 2) desmoid-type fibromatosis or extremity soft-tissue sarcomas (203 patients); 3) primary solid liver tumors, either malignant (hepatocellular carcinoma or intrahepatic cholangiocarcinoma) or benign (hepatocellular adenoma or focal nodular hyperplasia) (186 patients); 4) gastrointestinal stromal tumors (GISTs) and intra-abdominal gastrointestinal tumors radiologically resembling GISTs (246 patients); 5) colorectal liver metastases (77 patients); and 6) lung metastases of metastatic melanoma (103 patients). For each patient, either a magnetic resonance imaging (MRI) or computed tomography (CT) scan, collected from routine clinical care, one or multiple (semi-)automatic lesion segmentations, and ground truth labels from a gold standard (e.g., pathologically proven) are available. All datasets are multicenter imaging datasets, as patients referred to our institute often received imaging at their referring hospital. The dataset can be used to validate or develop radiomics methods, i.e., using machine or deep learning to relate the visual appearance to the ground truth labels, and automatic segmentation methods. See also the research article related to this dataset: Starmans et al.,Reproducible radiomics through automated machine learning validated on twelve clinical applications, Submitted.

Specifications Table
The potential impact of Anopheles stephensi establishment on the transmission of Plasmodium falciparum in Ethiopia and prospective control measures
Authors: Hamlet Arran , Dengela Dereje , Tongren J. Eric , Tadesse Fitsum G , Bousema Teun , Sinka Marianne , Seyoum Aklilu , Irish Seth R. , Armistead Jennifer S. , Churcher Thomas
Published: August 2021

Background

Sub-Saharan Africa has seen substantial reductions in cases and deaths due to malaria over the past two decades. While this reduction is primarily due to an increasing expansion of interventions, urbanisation has played its part as urban areas typically experience substantially less malaria transmission than rural areas. However, this may be partially lost with the invasion and establishment of Anopheles stephensi. An. stephensi, the primary urban malaria vector in Asia, was first detected in Africa during 2012 in Djibouti and was subsequently identified in Ethiopia in 2016, and later in Sudan and Somalia. In Djibouti, malaria cases have increased 30-fold from 2012 to 2019 though the impact in the wider region remains unclear.

Methods

Here we have adapted an existing model of mechanistic malaria transmission to estimate the increase in vector density required to explain the trends in malaria cases seen in Djibouti. To account for the observed plasticity in An. stephensi behaviour, and the unknowns of how it will establish in a novel environment, we sample behavioural parameters in order to account for a wide range of uncertainty. This quantification is then applied to Ethiopia, considering temperature-dependent extrinsic incubation periods, pre-existing vector-control interventions and Plasmodium falciparum prevalence in order to assess the potential impact of An. stephensi establishment on P. falciparum transmission. Following this, we estimate the potential impact of scaling up ITN (insecticide treated nets)/IRS (indoor residual spraying) and implementing piperonyl butoxide (PBO) ITNs and larval source management,, as well as their economic costs.

Results

We estimate that annual P. falciparum malaria cases could increase by 50% (95% CI 14-90) if no additional interventions are implemented. The implementation of sufficient control measures to reduce malaria transmission to pre-stephensi levels will cost hundreds of millions of USD.

Conclusions

Substantial heterogeneity across the country is predicted and large increases in vector control interventions could be needed to prevent a major public health emergency.
Distance from home to motor vehicle crash location: Implications for license restrictions among medically-at-risk older drivers
Authors: Joyce Nina R. , Khan Marzan A. , Zullo Andrew R. , Pfeiffer Melissa R. , Metzger Kristina B. , Margolis Seth A. , Ott Brian R. , Curry Allison E.
Published: August 2021

Background/Objectives

Thirty states allow licensing agencies to restrict the distance from home that “medically-at-risk” drivers are permitted to drive. However, there is little information on where older drivers crash relative to their home or how distance to crash varies by medical condition, and thus, what impact distance limits may have on motor vehicle crash rates for “medically-at-risk” drivers.

Design

Observational study of crash-involved drivers.

Setting

Medicare fee-for-service claims linked to geocoded crash locations and residential addresses from police crash reports in the state of New Jersey from 2007 through 2017.

Participants

New Jersey Medicare fee-for-service beneficiaries aged 68 years and older involved in police-reported crashes.

Measurements

The outcome was Euclidian distance from home to crash location. Covariates included driving-relevant medical conditions from Medicare claims, crash characteristics from police reports, and demographics from both sources.

Results

There were 197,122 crash-involved older drivers for whom approximately 70% of crashes occurred within 5 miles and 95% within 25 miles of the driver’s residence. The mean distance to crash was 6.0 miles. Although distance from home to the crash was generally lower among drivers with (versus without) each of the medical conditions studied, the differences were small (maximum mean difference of 2.1 miles). The largest difference in distance was by licensure status, where unlicensed/suspended drivers crashed significantly farther from home than validly licensed drivers (8.8 miles, 95% Confidence Interval [CI]: 8.4-9.1 vs 5.9 miles, 95% CI: 5.9 – 6.0).

Conclusions

Findings suggest that the majority of older adults who crash do so within a few miles from home and that the distance to crash does not differ substantially by the presence of a driving-relevant medical condition. Thus, distance restrictions may not reduce crash rates among older adults and the tradeoff between safety and mobility warrants consideration.

KEYPOINTS

30 states permit restriction of driving distance for medically-at-risk drivers

The vast majority of crashes involving older drivers occur ≤ 25 miles of home

Distance to crash does not differ markedly across driving-relevant medical conditions

Why does this matter?

Distance restrictions are likely to impact mobility and autonomy but not crash rates
Predicting anti-cancer activity in flavonoids - a graph theoretic approach
Authors: Mukwembi Simon , Nyabadza Farai
Published: August 2021

In drug design, there are two major causes of drug failure in the clinic. First, the drug has to work, and second, the drug should be safe. Identifying compounds that work for certain ailments require enormous experimental time and, in general, is cost intensive. In this paper, we are concerned with melanoma, a special type of cancer that affects the skin. In particular, we seek to provide a mathematical model that can predict the ability of flavonoids, a vast and natural class of compounds that are found in plants, in reversing or alleviating melanoma. The basis for our model is the conception of a new graph parameter called, for lack of better terminology, graph activity, which captures melanoma cancer healing properties of the flavonoids. With a superior coefficient of determination,R2= 1, the new model faithfully reproduces anti-cancer activities of some known data-sets. We demonstrate that the model can be used to rank the healing abilities of flavonoids which could be a powerful tool in the screening, and identification, of compounds for drug candidates.
Influence of age on the effectiveness and duration of protection in Vaxzevria and CoronaVac vaccines
Authors: Cerqueira-Silva Thiago , Oliveira Vinicius de Araújo , Pescarini Julia , Bertoldo Júnior Juracy , Machado Tales Mota , Flores-Ortiz Renzo , Penna Gerson , Ichihara Maria Yury , de Barros Jacson Venâncio , Boaventura Viviane S. , Barreto Mauricio L. , Werneck Guilherme Loureiro , Barral-Netto Manoel
Published: August 2021

Background

High rates of virus transmission and the presence of variants of concern can affect vaccine effectiveness (VE). Both conditions occur in low-income countries, which primarily use viral vector or inactivated virus vaccine technologies. Such countries conducted few VE analyses, and most lack the power to evaluate effectiveness in subgroups.

Methods

The present retrospective cohort study evaluated the effectiveness of Vaxzevria and CoronaVac vaccines for COVID-19-related infection in 75,919,840 Brazilian vaccinees from January 18 to July 24, 2021.

Study outcomes included documented infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19–related hospitalization, ICU admission, and death. We estimated VE using Cox regression adjusted for individual demographic characteristics.

Results

Vaccination with Vaxzevria or CoronaVac was effective against SARS-CoV-2 infection and highly effective against hospitalization, ICU admission, and death in individuals up to 79 years. From 80-89 years of age, Vaxzevria led to 89.9%(95CI:87.7-91.7) VE against death versus 67.2%(95CI:63.6-70.5) for CoronaVac. Above 90 years, 65.4%(95CI:46.1-77.8) protection was conferred to Vaxzevria-vaccinated individuals versus 33.6%(95CI:21.9-43.5) in CoronaVac-vaccinated individuals. Furthermore, the post-vaccination daily incidence rate shows a stepwise increase from younger to elder decades of life.

Conclusions

Vaxzevria demonstrated overall effectiveness against severe COVID-19 up to 89 years and CoronaVac up to 79 years of age. There is a stepwise effectiveness reduction for both vaccines for each decade of life. Our results suggest that individuals aged 80 years or older may benefit from an expedited booster dose. Ongoing evaluations, including any additional vaccines authorized, are crucial to monitoring long-term vaccine effectiveness.
HMOX1 genetic polymorphisms and outcomes in infectious disease: a systematic review
Authors: Hamilton Fergus , Somers Julia , Mitchell Ruth , Ghazal Peter , Timpson Nic
Published: August 2021

Introduction

Heme-oxygenase 1 (HMOX1) is a critical stress response gene that catalyzes the multistep oxidation of heme. A GT(n) repeat of variable length in the promoter in has been associated with a wide range of human diseases, including infections. This paper aims to summarise and systematically review associations between the length of the HMOX1 GT(n) promoter and infectious disease in humans.

Methods

A search using relevant terms was performed in PubMED and EMBASE through to 15/01/21 identifying all research that studied an association between the HMOX1 GT(n) repeat polymorphism and the incidence and/or outcome of any human infectious disease. Citations were screened for additional studies. Potential studies were screened for inclusion by two authors. Data was extracted on allele frequency, genotype, strength of association, mechanism of genotyping, and potential biases. A narrative review was performed across each type of infection.

Results

1,533 studies were identified in the search, and one via citation screening. Sixteen studies were ultimately included, seven in malaria, three in HIV, three in sepsis, and one each in pneumonia, hepatitis C, and acute respiratory distress syndrome (ARDS). Sample sizes for nearly all studies were small (biggest study, n = 1,646). Allelic definition was different across all included studies.

In malaria, three studies suggested that longer alleles were associated with reduced risk of severe malaria, particularly malaria-induced renal dysfunction, with four studies identifying a null association. In sepsis, two studies suggested an association with longer alleles and better outcomes.

Conclusions

Despite the importance of HMOX1 in survival from infection, and the association between repeat length and gene expression, the clinical data supporting an association between repeat length and incidence and/or outcome of infection remain inconclusive. The most promising data supports a potential association with protection from severe malaria, although this was not found in all studies.
Computer-delivered Cognitive Training and Transcranial Direct Current Stimulation in Patients with HIV-associated Neurocognitive Disorder: A Randomized Trial
Authors: Ownby Raymond L. , Kim Jae
Published: August 2021

Objective

HIV infection is associated with impaired cognition, and as individuals grow older, they may also experience age-related changes in mental abilities. Previous studies have shown that computer-based cognitive training (CCT) and transcranial direct current stimulation (tDCS) may be useful in improving cognition in older persons. This study evaluated the acceptability of CCT and tDCS to older adults with HIV-associated neurocognitive disorder, and assessed their impact on reaction time, attention, and psychomotor speed.

Methods

In a single-blind randomized study, 46 individuals with HIV-associated mild neurocognitive disorder completed neuropsychological assessments and six 20-minute training sessions to which they had been randomly assigned to one of the following conditions: (1) CCT with active tDCS; (2) CCT with sham tDCS, or (3) watching educational videos with sham tDCS. Immediately after training and again one month later, participants completed follow-up assessments. Outcomes were evaluated via repeated measures mixed effects models.

Results

Participant ratings of the intervention were positive. Effects on reaction time were not significant, but measures of attention and psychomotor speed suggested positive effects of the intervention.

Conclusion

Both CCT and tDCS were highly acceptable to older persons with HIV infection. CCT and tDCS may improve cognitive in affected individuals.

Registered atClinicalTrials.gov(NCT03440840).
Constitutive expression of JASMONATE RESISTANT 1 elevates content of several jasmonates and primes Arabidopsis thaliana to better withstand drought
Authors: Mahmud Sakil , Ullah Chhana , Kortz Annika , Bhattacharyya Sabarna , Yu Peng , Gershenzon Jonathan , Vothknecht Ute C.
Published: August 2021

Jasmonates have a well-documented role in balancing the trade-off between plant growth and defense against biotic stresses. However, the role of jasmonate signaling under abiotic stress is less well studied. Here, we investigated the function of JASMONATE RESISTANT 1 (JAR1) in drought stress in Arabidopsis thaliana. JAR1 converts jasmonic acid (JA) to jasmonyl-L-isoleucine (JA-Ile), the major bioactive form of jasmonates. Comparison of a newly generated over-expression line (JAR1-OE) with jar1-11, a T-DNA insertion line in the JAR1 locus, and Col-0 revealed that constitutively increased JA-Ile production results in stunted growth and a delay in flowering. Upon water limitation, JAR1-OE plants retained more water in their leaves, showed reduced wilting and recovered better from drought stress than the wild type. By contrast, jar1-11 mutant plants were hypersensitive to drought. RNA-seq analysis and hormonal profiling of plants under control and drought stress conditions provided insight into the molecular reprogramming caused by the alteration in JA-Ile content. Especially JAR1-OE plants were affected in many adaptive systems related to drought stress, including stomatal density, stomatal aperture or the formation of reactive oxygen species (ROS). Overall, our data suggest that constitutively increased expression of JAR1 can prime Arabidopsis towards improved drought tolerance.

One sentence summary

Constitutive expression of JAR1primes Arabidopsis thaliana to better withstand drought stress
Discovery of Antiviral Cyclic Peptides Targeting the Main Protease of SARS-CoV-2 via mRNA Display
Authors: Johansen-Leete Jason , Ullrich Sven , Fry Sarah E. , Frkic Rebecca , Bedding Max J. , Aggarwal Anupriya , Ashhurst Anneliese S. , Ekanayake Kasuni B. , Mahawaththa Mithun C. , Sasi Vishnu M. , Passioura Toby , Larance Mark , Otting Gottfried , Turville Stuart , Jackson Colin J. , Nitsche Christoph , Payne Richard J.
Published: August 2021

Antivirals that specifically target SARS-CoV-2 are needed to control the COVID-19 pandemic. The main protease (Mpro) is essential for SARS-CoV-2 replication and is an attractive target for antiviral development. Here we report the use of the Random nonstandard Peptide Integrated Discovery (RaPID) mRNA display on a chemically cross-linked SARS-CoV-2 Mpro dimer, which yielded several high-affinity thioether-linked cyclic peptide inhibitors of the protease. Structural analysis of Mpro complexed with a selenoether analogue of the highest-affinity peptide revealed key binding interactions, including glutamine and leucine residues in sites S1 and S2, respectively, and a binding epitope straddling both protein chains in the physiological dimer. Several of these Mpro peptide inhibitors possessed antiviral activity against SARS-CoV-2 in vitro with EC50 values in the low micromolar range. These cyclic peptides serve as a foundation for the development of much needed antivirals that specifically target SARS-CoV-2.
The Chloroflexi supergroup is metabolically diverse and representatives have novel genes for non-photosynthesis based CO2 fixation
Authors: West-Roberts Jacob A. , Matheus-Carnevali Paula B. , Schoelmerich Marie Charlotte , Al-Shayeb Basem , Thomas Alex D. , Sharrar Allison , He Christine , Chen Lin-Xing , Lavy Adi , Keren Ray , Amano Yuki , Banfield Jillian F.
Published: August 2021

The Chloroflexi superphylum have been investigated primarily from the perspective of reductive dehalogenation of toxic compounds, anaerobic photosynthesis and wastewater treatment, but remain relatively little studied compared to their close relatives within the larger Terrabacteria group, including Cyanobacteria, Actinobacteria, and Firmicutes. Here, we conducted a detailed phylogenetic analysis of the phylum Chloroflexota, the phylogenetically proximal candidate phylum Dormibacteraeota, and a newly defined sibling phylum proposed in the current study, Eulabeiota. These groups routinely root together in phylogenomic analyses, and constitute the Chloroflexi supergroup. Chemoautotrophy is widespread in Chloroflexi. Two Form I Rubisco ancestral subtypes that both lack the small subunit are prevalent in ca. Eulabeiota and Chloroflexota, suggesting that the predominant modern pathway for CO2 fixation evolved in these groups. The single subunit Form I Rubiscos are inferred to have evolved prior to oxygenation of the Earth’s atmosphere and now predominantly occur in anaerobes. Prevalent in both Chloroflexota and ca. Eulabeiota are capacities related to aerobic oxidation of gases, especially CO and H2. In fact, aerobic and anaerobic CO dehydrogenases are widespread throughout every class-level lineage, whereas traits such as denitrification and reductive dehalogenation are heterogeneously distributed across the supergroup. Interestingly, some Chloroflexota have a novel clade of group 3 NiFe hydrogenases that is phylogenetically distinct from previously reported groups. Overall, the analyses underline the very high level of metabolic diversity in the Chloroflexi supergroup, suggesting the ancestral metabolic platform for this group enabled highly varied adaptation to ecosystems that appeared in the aerobic world.
Informative RNA-base embedding for functional RNA structural alignment and clustering by deep representation learning
Authors: Akiyama Manato , Sakakibara Yasubumi
Published: August 2021

Effective embedding is being actively conducted by applying deep learning to biomolecular information. Obtaining better embedding enhances the quality of downstream analysis such as DNA sequence motif detection and protein function prediction. In this study, we adopt a pre-training algorithm for the effective embedding of RNA bases to acquire semantically rich representations, and apply it to two fundamental RNA sequence problems: structural alignment and clustering. By using the pre-learning algorithm to embed the four bases of RNA in a position-dependent manner using a large number of RNA sequences from various RNA families, a context-sensitive embedding representation is obtained. As a result, not only base information but also secondary structure and context information of RNA sequences are embedded for each base. We call this “informative base embedding” and use it to achieve accuracy superior to that of existing state-of-the-art methods in RNA structural alignment and RNA family clustering tasks. Furthermore, by performing RNA sequence alignment combining this informative base embedding with a simple Needleman-Wunsch alignment algorithm, we succeed in calculating a structural alignment in a time complexity O(n2) instead of the O(n6) time complexity of Sankoff-style algorithms.
Wolbachia in scale insects: a distinct pattern of infection frequencies and potential transfer routes via ant associates
Authors: Sanaei Ehsan , Lin Yen-Po , Cook Lyn G , Engelstädter Jan
Published: August 2021

Wolbachia is one of the most successful endosymbiotic bacteria of arthropods. Known as the “master of manipulation”, Wolbachia can induce a wide range of phenotypes in its host that can have far-reaching ecological and evolutionary consequences and may be exploited for disease and pest control. However, our knowledge of Wolbachia’s distribution and infection rate is unevenly distributed across arthropod groups such as scale insects. We fitted a distribution of within-species prevalence of Wolbachia to our data and compared it to distributions fitted to an up-to-date dataset compiled from surveys across all arthropods. The estimated distribution parameters indicate a Wolbachia infection frequency of 43.6% (at a 10% prevalence threshold) in scale insects. Prevalence of Wolbachia in scale insects follows a distribution similar to exponential decline (most species are predicted to have low prevalence infections), in contrast to the U-shaped distribution estimated for other taxa (most species have a very low or very high prevalence). We observed no significant associations between Wolbachia infection and scale insect traits. Finally, we screened for Wolbachia in scale insect’s ecological associates. We found a positive correlation between Wolbachia infection in scale insects and their ant associates, pointing to a possible route of horizontal transfer of Wolbachia.

Originality-Significance Statement

By creating metadata of Wolbachia infection in arthropods and applying a fitting an advanced mathematical model on the estimated infection frequency in scale insects, a unique pattern of infection prevalence was detected. In addition, ant-scale insect trophallaxis interaction was suggested as a plausible route of Wolbachia transfer
Characterization of the flagellar collar reveals structural plasticity essential for spirochete motility
Authors: Chang Yunjie , Xu Hui , Motaleb Md A. , Liu Jun
Published: August 2021

Spirochetes are a remarkable group of bacteria with distinct morphology and periplasmic flagella that enable motility in viscous environments, such as host connective tissues. The collar, a spirochete-specific complex of the periplasmic flagellum, is required for the unique spirochete motility, yet it has not been clear how the collar assembles and enables spirochetes to transit between complex host environments. Here, we characterize the collar complex in the Lyme disease spirochete Borrelia burgdorferi. We discover as well as delineate the distinct functions of two novel collar proteins, FlcB and FlcC, by combining subtractive bioinformatic, genetic, and cryo-electron tomography approaches. Our high-resolution in-situ structures reveal that the multi-protein collar has a remarkable structural plasticity essential not only for assembly of flagellar motors in the highly curved membrane of spirochetes but also for generation of the high torque necessary for spirochete motility.
DNA Replication-transcription conflicts do not significantly contribute to spontaneous mutations due to replication errors in Escherichia coli.
Authors: Foster Patricia L. , Niccum Brittany A. , Lee Heewook
Published: August 2021

Encounters between DNA replication and transcription can cause genomic disruption, particularly when the two meet head-on. Whether these conflicts produce point mutations is debated. This paper presents detailed analyses of a large collection of mutations generated during mutation accumulation experiments with mismatch-repair (MMR) defective Escherichia coli. With MMR absent, mutations are primarily due to DNA replication errors. Overall, there were no differences in the frequencies of base-pair substitutions or small indels (insertion and deletions ≤ 4 bp) in the coding sequences or promoters of genes oriented codirectionally versus head-on to replication. Among a subset of highly expressed genes there was a 2- to 3-fold bias for indels in genes oriented head-on to replication, but this difference was almost entirely due to the asymmetrical genomic locations of tRNA genes containing mononucleotide runs, which are hotspots for indels. No additional orientation bias in mutation frequencies occurred when MMR− strains were also defective for transcription-coupled repair (TCR). However, in contrast to other reports, loss of TCR slightly increased the overall mutation rate, meaning that TCR is antimutagenic. There was no orientation bias in mutation frequencies among the stress-response genes that are regulated by RpoS or induced by DNA damage. Thus, biases in the locations of mutational targets can account for most, if not all, apparent biases in mutation frequencies between genes oriented head-on versus co-directional to replication. In addition, the data revealed a strong correlation of the frequency of base-pair substitutions with gene length, but no correlation with gene expression levels.

IMPORTANCE

Because DNA replication and transcription occur on the same DNA template, encounters between the two machines occur frequently. When these encounters are head-to-head, genomic disruption can occur. But, whether replication-transcription conflicts contribute to spontaneous mutations is debated. Analyzing in detail a large collection of mutations generated with mismatch repair defective Escherichia coli strains, we find that across the genome there are no significant differences in mutation frequencies between genes oriented co-directionally versus head-on to replication. Among a subset of highly expressed genes there was a 2- to 3-fold bias for small insertions and deletions in head-on oriented genes, but this difference was almost entirely due to the asymmetrical locations of tRNA genes containing mononucleotide runs, which are hotspots for these mutations. Thus, biases in the positions of mutational target sequences can account for most, if not all, apparent biases in mutation frequencies between genes oriented head-on and co-directionally to replication.
Landscaping the behavioural ecology of primate stone tool use
Authors: Almeida-Warren Katarina , Matsuzawa Tetsuro , Carvalho Susana
Published: August 2021

Ecology is fundamental to the development, transmission, and perpetuity of primate technology. Previous studies on tool site selection have addressed the relevance of targeted resources and raw materials for tools, but few have considered the broader foraging landscape. In this first landscape-scale study of the ecological contexts of wild chimpanzee (Pan troglodytes verus) tool-use, we investigate the conditions required for nut-cracking to occur and persist over time at discrete locations in Bossou (Guinea). We examine this at three levels: selection, frequency of use, and inactivity. We find that, further to the presence of a nut tree and availability of raw materials, abundance of food-providing trees as well as proximity to nest sites were significant predictors of nut-cracking occurrence. This suggests that the spatial distribution of nut-cracking sites is mediated by the broader behavioural landscape and is influenced by non-extractive foraging of predictable resources, as well as non-foraging activities. Additionally, the number of functional tools was greater at sites with higher frequency of nut-cracking and was negatively correlated with site inactivity. Our findings indicate that the technological landscape of the Bossou chimpanzees shares affinities with the ‘favoured places’ model of hominin site formation and provides new insights for reconstructing ancient patterns of landscape use.

L’écologie est fondamentale pour le développement, la transmission et la pérennité de la technologie des primates. Des études antérieures ont identifié la disponibilité des ressources cibles ainsi que les matières premières pour les outils comme des facteurs influents dans la sélection des emplacements pour les activités technologiques. Cependant, il y a peu d’études qui abordent cette recherche à l’échelle du paysage et du comportement fourrager. Dans cette première étude paysagère sur l’utilisation d’outils par le chimpanzé sauvage (Pan troglodytes verus), nous recherchons les conditions écologiques qui influencent la sélection, l’utilisation et l’inactivité des emplacements utilisés pour le cassage des noix en Bossou, Guinée. Nos résultats montrent qu’en plus de la présence d’un noyer et de la disponibilité des matières premières, l’abondance d’arbres nourriciers ainsi que la proximité des sites de nidification étaient des prédicteurs significatifs de l’occurrence du cassage des noix. Cela suggère que la distribution spatiale des sites de cassage de noix est influencée par le paysage comportemental et est influencée par le fourrage non-extractive de ressources prévisibles, ainsi que par des activités non-fourragers. Nos résultats indiquent que le paysage technologique des chimpanzés de Bossou partage des affinités avec le modèle des « lieux favoris » de la formation des sites hominidés et fournit de nouvelles perspectives pour reconstruire les modes d’utilisation du paysage anciens.
Mining folded proteomes in the era of accurate structure prediction
Authors: Bayly-Jones Charles , Whisstock James
Published: August 2021

Protein structure fundamentally underpins the function and processes of numerous biological systems. Fold recognition algorithms offer a sensitive and robust tool to detect structural, and thereby functional, similarities between distantly related homologs. In the era of accurate structure prediction owing to advances in machine learning techniques, previously curated sequence databases have become a rich source of biological information. Here, we use bioinformatic fold recognition algorithms to scan the entire AlphaFold structure database to identify novel protein family members, infer function and group predicted protein structures. As an example of the utility of this approach, we identify novel, previously unknown members of various pore-forming protein families, including MACPFs, GSDMs and aerolysin-like proteins. Further, we explore the use of structure-based mining for functional inference.
Detection and phylogeny ofWolbachiain field-collectedAedes albopictusandAedes aegyptifrom Manila City, Philippines
Authors: Regilme Maria Angenica F. , Inukai Tatsuya , Watanabe Kozo
Published: August 2021

Background

Wolbachiais the most common bacterial endosymbiont of arthropods, such as the medically importantAedes albopictusand recent reports also detected inAedes aegypti. Our study showed additional support for the presence of wolbachia inAe. albopictusandAe. aegyptiusing Wolbachia specific markers,wsp, and 16S.

Main text

This study collected 12 adultAe. albopictusand 359Ae. aegyptifrom 183 households in a dengue-prone area, Manila, Philippines, between June and September 2017.Aedeslarvae (n = 509) were also collected from 17 water containers from 11 households. The DNA of theAedeslarvae and adults were screened for the presence ofWolbachiausing thewspand 16S markers, following optimized polymerase chain reaction (PCR) conditions, and sequenced. Our results showed that 3 out of 359 (0.84%) adultAe. aegyptiand 12 out of 12 (100%) adultAe. albopictuswereWolbachiapositive, whereas all larvae tested negative forWolbachia(0/509; 0%). Thewspmarker revealed sixWolbachia-positiveAe. albopictus, whereas the 16S marker showedWolbachiain threeAe. aegyptiand tenAe. albopictus

Conclusion

Our results suggest that the utilization of two Wolbachia specific markers,wspand16Sdemonstrated Wolbachia presence in individualAe. albopictusandAe. aegypti. The results of the Wolbachia infection inAe. albopictusshowed that the detected strains were from either supergroups A and B. Despite the low infection rate of Wolbachia inAe. aegypti,our results demonstrated the presence of Wolbachia in field-collectedAe. aegyptisupporting previous studies.
Long-read and chromosome-scale assembly of the hexaploid wheat genome achieves high resolution for research and breeding
Authors: Aury Jean-Marc , Engelen Stefan , Istace Benjamin , Monat Cécile , Lasserre-Zuber Pauline , Belser Caroline , Cruaud Corinne , Rimbert Hélène , Leroy Philippe , Arribat Sandrine , Dufau Isabelle , Bellec Arnaud , Grimbichler David , Papon Nathan , Paux Etienne , Ranoux Marion , Alberti Adriana , Wincker Patrick , Choulet Frédéric
Published: August 2021

The sequencing of the wheat (Triticum aestivum) genome has been a methodological challenge for many years due to its large size (15.5 Gb), repeat content, and hexaploidy. Many initiatives aiming at obtaining a reference genome of cultivar Chinese Spring have been launched in the past years and it was achieved in 2018 as the result of a huge effort to combine short-read sequencing with many other resources. Reference-quality genome assemblies were then produced for other accessions but the rapid evolution of sequencing technologies offers opportunities to reach high-quality standards at lower cost. Here, we report on an optimized procedure based on long-reads produced on the ONT (Oxford Nanopore Technology) PromethION device to assemble the genome of the French bread wheat cultivar Renan. We provide the most contiguous and complete chromosome-scale assembly of a bread wheat genome to date. Coupled with an annotation based on RNA-Seq data, this resource will be valuable for the crop community and will facilitate the rapid selection of agronomically important traits. We also provide a framework to generate high-quality assemblies of complex genomes using ONT.
Key Drivers of Ecological Assembly in the Hindgut of Atlantic Cod (Gadus morhua) when Fed with a Macroalgal Supplemented diet – How Robust Is the Gut to Taxonomic Perturbation?
Authors: Keating C. , Bolton-Warberg M. , Hinchcliffe J. , Davies R. , Whelan S. , Wan A. H. L. , Fitzgerald R. D. , Davies S. J. , Smith C. J. , Ijaz U. Z.
Published: August 2021

The microbiota in the gastrointestinal tract of any species is shaped by internal and external cues in addition to random events which can be difficult to disentangle from a range of interacting variables. Estimating ecological assembly processes can help elucidate these factors. In our study, farmed Atlantic cod (Gadus morhua) were fed a diet of 10% macroalgae supplement (Ulva rigida species [ULVA] or Ascophyllum nodosum [ASCO] or a non-amended control diet [CTRL]) over a 12-week period and the ecological assembly processes quantified. The CTRL samples showed selection (variable selection - divergence in communities related to selective environmental conditions) as a key assembly process, while dispersal limitation (limited movement results in divergent communities through stochastic processes) was a driver of the gut microbiome for fish fed the macroalgae supplemented diet at Week 12 (i.e., ASCO and ULVA). Fish from the ASCO grouping diverged into ASCO_N (normal) and ASCO_LG (lower growth), where ASCO_LG individuals found the diet unpalatable. The recruitment of new taxa over time was altered in the ASCO_LG fish, with the gut microbiome showing phylogenetic under dispersion (nepotistic recruitment of species). Finally, the gut microbiome (CTRL and ULVA only) showed increasing robustness to taxonomic disturbance over time and an increase in functional redundancy. This study advances our understanding of the ecological assembly and succession in the hindgut of juvenile Atlantic cod across dietary regimes. Understanding the processes driving ecological assembly in the gut microbiome, in fish research specifically, could allow us to manipulate the microbiome for improved health or resilience to disease for improved aquaculture production.
A yeast model of the ALS protein Matrin3 uncovers Hsp90 and its co-chaperone Sti1 as modifiers of misfolding and toxicity
Authors: Di Gregorio Sonja E. , Esmaeili Mohammad , Salem Ahmed , Duennwald Martin L.
Published: August 2021

The MATR3 gene encoding the protein Matrin3 is implicated in the pathogenesis of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Matrin3 forms neuronal cytoplasmic and nuclear inclusions in ALS-affected neurons. Additionally, 13 heterozygous missense mutations in MATR3 are identified in ALS patients. To further explore Matrin3 misfolding and toxicity, we established and characterized a yeast model. We demonstrate that wild type Matrin3 and the ALS-associated variant F115C are toxic and form inclusions in yeast. Our further characterization uncovers substantial modification of Matrin3 toxicity and inclusion formation by Hsp90 and its co-chaperones, specifically Sti1. Thus, our study demonstrates how specific branches of cellular protein quality control regulate the misfolding and toxicity of Matrin3.

Summary Statement

We established and characterized a yeast model expressing human Matrin3, a protein implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Using this yeast model and mammalian neuronal cells, we showed that Matrin3 mislocalizes and forms inclusions, is cytotoxic, and increases sensitivity to cellular stress. We also uncovered that Hsp90 and particularly its co-chaperone Sti1 alter Matrin3 toxicity.
Multi-omics investigation of Clostridioides difficile-colonized patients reveals protective commensal carbohydrate metabolism
Authors: Fishbein Skye R. S. , Robinson John I. , Hink Tiffany , Reske Kimberly A. , Newcomer Erin P. , Burnham Carey-Ann D. , Henderson Jeffrey P. , Dubberke Erik R. , Dantas Gautam
Published: August 2021

Clostridioides difficile infection (CDI) imposes a substantial burden on the health care system in the United States. Understanding the biological basis for the spectrum of C. difficile-related disease manifestations is imperative to improving treatment and prevention of CDI. Here, we investigate the correlates of asymptomatic C. difficile colonization using a multi-omics approach, comparing the fecal microbiome and metabolome profiles of patients with CDI versus asymptomatically-colonized patients. We find that microbiomes of asymptomatic patients are significantly enriched for species in the class Clostridia relative to those of symptomatic patients. Asymptomatic patient microbiomes were enriched with fucose, rhamnose, and sucrose degradation pathways relative to CDI patient microbiomes. Fecal metabolomics corroborates this result: we identify carbohydrate compounds enriched in asymptomatic patients relative to CDI patients, and correlated with a number of commensal Clostridia. Further, we reveal that across C. difficile isolates, the carbohydrates rhamnose and lactulose do not serve as robust growth substrates in vitro, corroborating their enriched detection in our metagenomic and metabolite profiling of asymptomatic individuals. We conclude that in asymptomatically-colonized individuals, carbohydrate metabolism by other commensal Clostridia may prevent CDI by inhibiting C. difficile proliferation. These insights into C. difficile colonization and putative commensal competition suggest novel avenues to develop probiotic or prebiotic therapeutics against CDI.
New insights into the evolution of SPX gene family from algae to legumes; a focus on soybean
Authors: Chegini Mahnaz Nezamivand , Ebrahimie Esmaeil , Tahmasebi Ahmad , Moghadam Ali , Eshghi Saied , Mohammadi-Dehchesmeh Manijeh , Kopriva Stanislav , Niazi Ali
Published: August 2021

Background

SPX-containing proteins have been known as key players in phosphate signaling and homeostasis. In Arabidopsis and rice, functions of some SPXs have been characterized, but little is known about their function in other plants, especially in the legumes.

Results

We analyzed SPX gene family evolution in legumes and in a number of key species from algae to angiosperms. We found that SPX harboring proteins showed fluctuations in domain fusions from algae to the angiosperms with, finally, four classes appearing and being retained in the land plants. Despite these fluctuations, Lysine Surface Cluster (KSC), and the third residue of Phosphate Binding Sites (PBS) showed complete conservation in almost all of SPXs except few proteins in Selaginella moellendorffii and Papaver sumniferum, suggesting they might have different ligand preferences. In addition, we found that the WGD/segmentally or dispersed duplication types were the most frequent contributors to the SPX expansion, and that there is a positive correlation between the amount of WGD contribution to the SPX expansion in individual species and its number of EXS genes. We could also reveal that except SPX class genes, other classes lost the collinearity relationships among Arabidopsis and legume genomes. The sub- or neo-functionalization of the duplicated genes in the legumes makes it difficult to find the functional orthologous genes. Therefore, we used two different methods to identify functional orthologs in soybean and Medicago. High variance in the dynamic and spatial expression pattern of GmSPXs proved the new or sub-functionalization in the paralogs.

Conclusion

This comprehensive analysis revealed how SPX gene family evolved from algae to legumes and also discovered several new domains fused to SPX domain in algae. In addition, we hypothesized that there different phosphate sensing mechanisms might occur in S. moellendorffii and P. sumniferum. Finally, we predicted putative functional orthologs of AtSPXs in the legumes, especially, orthologs of AtPHO1 and AtPHO1;H1, involved in long-distance Pi transportation. These findings help to understand evolution of phosphate signaling and might underpin development of new legume varieties with improved phosphate use efficiency.
Gene Expression Risk Scores for COVID-19 Illness Severity
Authors: Peterson Derick R , Baran Andrea M , Bhattacharya Soumyaroop , Branche Angela R , Croft Daniel P , Corbett Anthony M , Walsh Edward E , Falsey Ann R , Mariani Thomas J
Published: August 2021

Background

The correlates of COVID-19 illness severity following infection with SARS-Coronavirus 2 (SARS-CoV-2) are incompletely understood.

Methods

We assessed peripheral blood gene expression in 53 adults with confirmed SARS-CoV-2-infection clinically adjudicated as having mild, moderate or severe disease. Supervised principal components analysis was used to build a weighted gene expression risk score (WGERS) to discriminate between severe and non-severe COVID.

Results

Gene expression patterns in participants with mild and moderate illness were similar, but significantly different from severe illness. When comparing severe versus non-severe illness, we identified >4000 genes differentially expressed (FDR<0.05). Biological pathways increased in severe COVID-19 were associated with platelet activation and coagulation, and those significantly decreased with T cell signaling and differentiation. A WGERS based on 18 genes distinguished severe illness in our training cohort (cross-validated ROC-AUC=0.98), and need for intensive care in an independent cohort (ROC-AUC=0.85). Dichotomizing the WGERS yielded 100% sensitivity and 85% specificity for classifying severe illness in our training cohort, and 84% sensitivity and 74% specificity for defining the need for intensive care in the validation cohort.

Conclusion

These data suggest that gene expression classifiers may provide clinical utility as predictors of COVID-19 illness severity.