bluuebunny/crossref_metadata_2025 huggingface dataset:
Social network architecture and the tempo of cumulative cultural evolution
Authors: Cantor Mauricio , Chimento Michael , Smeele Simeon Q. , He Peng , Papageorgiou Danai , Aplin Lucy M. , Farine Damien R.
Published: March 2021

The ability to build upon previous knowledge—cumulative cultural evolution—is a hallmark of human societies. While cumulative cultural evolution depends on the interaction between social systems, cognition and the environment, there is increasing evidence that cumulative cultural evolution is facilitated by larger and more structured societies. However, such effects may be interlinked with patterns of social wiring, thus the relative importance of social network architecture as an additional factor shaping cumulative cultural evolution remains unclear. By simulating innovation and diffusion of cultural traits in populations with stereotyped social structures, we disentangle the relative contributions of network architecture from those of population size and connectivity. We demonstrate that while more structured networks, such as those found in multilevel societies, can promote the recombination of cultural traits into high-value products, they also hinder spread and make products more likely to go extinct. We find that transmission mechanisms are therefore critical in determining the outcomes of cumulative cultural evolution. Our results highlight the complex interaction between population size, structure and transmission mechanisms, with important implications for future research.
The contractile patterns, anatomy and physiology of the hyoid musculature change longitudinally through infancy
Authors: Mayerl C. J. , Steer K. E. , Chava A. M. , Bond L. E. , Edmonds C. E. , Gould F. D. H. , Stricklen B. M. , Hieronymous T. L. , German R. Z.
Published: March 2021

All mammalian infants suckle, a fundamentally different process than drinking in adults. Infant mammal oropharyngeal anatomy is also anteroposteriorly compressed and becomes more elongate postnatally. While suckling and drinking require different patterns of muscle use and kinematics, little insight exists into how the neuromotor and anatomical systems change through the time that infants suckle. We measured the orientation, activity and contractile patterns of five muscles active during infant feeding from early infancy until weaning using a pig model. Muscles not aligned with the long axis of the body became less mediolaterally orientated with age. However, the timing of activation and the contractile patterns of those muscles exhibited little change, although variation was larger in younger infants than older infants. At both ages, there were differences in contractile patterns within muscles active during both sucking and swallowing, as well as variation among muscles during swallowing. The changes in anatomy, coupled with less variation closer to weaning and little change in muscle firing and shortening patterns suggest that the neuromotor system may be optimized to transition to solid foods. The lesser consequences of aspiration during feeding on an all-liquid diet may not necessitate the evolution of variation in neuromotor function through infancy.
The critical role of mental imagery in human emotion: insights from fear-based imagery and aphantasia
Authors: Wicken Marcus , Keogh Rebecca , Pearson Joel
Published: March 2021

One proposed function of imagery is to make thoughts more emotionally evocative through sensory simulation, which can be helpful both in planning for future events and in remembering the past, but also a hindrance when thoughts become overwhelming and maladaptive, such as in anxiety disorders. Here, we report a novel test of this theory using a special population with no visual imagery: aphantasia. After using multi-method verification of aphantasia, we show that this condition, but not the general population, is associated with a flat-line physiological response (skin conductance levels) to reading and imagining frightening stories. Importantly, we show in a second experiment that this difference in physiological responses to fear-inducing stimuli is not found when perceptually viewing fearful images. These data demonstrate that the aphantasic individuals' lack of a physiological response when imaging scenarios is likely to be driven by their inability to visualize and is not due to a general emotional or physiological dampening. This work provides evidence that a lack of visual imagery results in a dampened emotional response when reading fearful scenarios, providing evidence for the emotional amplification theory of visual imagery.
Staphylotrichum sinense sp. nov., a new hyphomycete (Chaetomiaceae) from China
Authors: Qiao Min , Zhang Zhe , Yang Lingyan , Yu Zefen
Published: March 2021

Staphylotrichum sinense, a new hyphomycete classified in the Chaetomiaceae (Ascomycota), was isolated from soil in Jianshui county, Yunnan Province. It is characterized by globose and ochreous conidia born laterally on aerial hyphae, and micronematous, unbranched and 0–1-septate conidiophores, sometimes reduced to conidiogenous cells. Morphologically, Staphylotrichum sinense is similar to Staphylotrichum boninense, but it can be distinguished by lacking of macronematous conidiophores and having larger conidia. Phylogenetically Staphylotrichum sinense formed a single clade within Staphylotrichum species, and is closely related to Staphylotrichum boninense and Staphylotrichum brevistipitatum.
COVIDrugNet: a network-based web tool to investigate the drugs currently in clinical trial to contrast COVID-19
Authors: Menestrina Luca , Cabrelle Chiara , Recanatini Maurizio
Published: March 2021

The COVID-19 pandemic poses a huge problem of public health that requires the implementation of all available means to contrast it, and drugs are one of them. In this context, we observed an unmet need of depicting the continuously evolving scenario of the ongoing drug clinical trials through an easy-to-use, freely accessible online tool. Starting from this consideration, we developed COVIDrugNet (http://compmedchem.unibo.it/covidrugnet), a web application that allows users to capture a holistic view and keep up to date on how the clinical drug research is responding to the SARS-CoV-2 infection.

Here, we describe the web app and show through some examples how one can explore the whole landscape of medicines in clinical trial for the treatment of COVID-19 and try to probe the consistency of the current approaches with the available biological and pharmacological evidence. We conclude that careful analyses of the COVID-19 drug-target system based on COVIDrugNet can help to understand the biological implications of the proposed drug options, and eventually improve the search for more effective therapies.
COVID-19 is associated with multiple sclerosis exacerbations that are prevented by disease modifying therapies
Authors: Garjani Afagh , Middleton Rodden M , Hunter Rachael , Tuite-Dalton Katherine A , Coles Alasdair , Dobson Ruth , Duddy Martin , Hughes Stella , Pearson Owen R , Rog David , Tallantyre Emma C , Nair Roshan das , Nicholas Richard , Evangelou Nikos
Published: March 2021

Background

Infections can trigger exacerbations of multiple sclerosis (MS). The effects of the coronavirus disease 2019 (COVID-19) on MS are not known. The aim of this study was to understand the impact of COVID-19 on new and pre-existing symptoms of MS.

Methods

The COVID-19 and MS study is an ongoing community-based, prospective cohort study conducted as part of the United Kingdom MS Register. People with MS and COVID-19 were invited by email to complete a questionnaire about their MS symptoms during the infection. An MS exacerbation was defined as developing new MS symptoms and/or worsening of pre-existing MS symptoms.

Results

Fifty-seven percent (230/404) of participants had an MS exacerbation during their infection; 82 developed new MS symptoms, 207 experienced worsened pre-existing MS symptoms, and 59 reported both. Disease modifying therapies (DMTs) reduced the likelihood of developing new MS symptoms during the infection (OR 0.556, 95%CI 0.316-0.978). Participants with a higher pre-COVID-19 webEDSS (web-based Expanded Disability Status Scale) score (OR 1.251, 95%CI 1.060-1.478) and longer MS duration (OR 1.042, 95%CI 1.009-1.076) were more likely to experience worsening of their pre-existing MS symptoms during the infection.

Conclusion

COVID-19 infection was associated with exacerbation of MS. DMTs reduced the chance of developing new MS symptoms during the infection.
Sodium valproate increases activity of the sirtuin pathway resulting in beneficial effects for spinocerebellar ataxia-3in vivo
Authors: Watchon Maxinne , Luu Luan , Robinson Katherine J. , Yuan Kristy C. , De Luca Alana , Suddull Hannah J. , Tym Madelaine C. , Guillemin Gilles J. , Cole Nicholas J. , Nicholson Garth A. , Chung Roger S. , Lee Albert , Laird Angela S.
Published: March 2021

Machado-Joseph disease (MJD, also known as spinocerebellar ataxia-3) is a fatal neurodegenerative disease that impairs control and coordination of movement. Here we tested whether treatment with the histone deacetylase inhibitor sodium valproate (SV) prevented a movement phenotype that develops in larvae of a transgenic zebrafish model of the disease. We found that treatment with SV improved the swimming of the MJD zebrafish, increased levels of acetylated histones 3 and 4, but also increased expression of polyglutamine expanded human ataxin-3. Proteomic analysis of protein lysates generated from the treated and untreated MJD zebrafish also predicted that SV treatment had activated the sirtuin longevity signaling pathway and this was confirmed by findings of increased SIRT1 protein levels and sirtuin activity in SV treated MJD zebrafish and HEK293 cells expressing ataxin-3-84Q, respectively. Treatment with resveratrol (another compound known to activate the sirtuin pathway), also improved swimming in the MJD zebrafish. Co-treatment with SV alongside EX527, a SIRT1 activity inhibitor, prevented induction of autophagy by SV and the beneficial effects of SV on the movement in the MJD zebrafish, indicating that they were both dependent on sirtuin activity. These findings provide the first evidence of sodium valproate inducing activation of the sirtuin pathway. Further, they indicate that drugs that target the sirtuin pathway, including sodium valproate and resveratrol, warrant further investigation for the treatment of MJD and related neurodegenerative diseases.
A simple method to separate birds and insects in single-pol weather radar data
Authors: Nussbaumer Raphaël , Schmid Baptiste , Bauer Silke , Liechti Felix
Published: March 2021

Recent and archived data from weather radar networks are extensively used for quantification of continent-wide bird migration pattern. While discriminating birds from weather signals is well established, insect contamination is still a problem. We present a simple method combining two doppler radar products within a single Gaussian-mixture model to estimate the proportions of birds and insects within a single measurement, as well as the density and speed of birds and insects. The method can be applied to any existing archives of vertical bird profiles, such as the ENRAM repository (enram.eu) with no need to recalculate the huge amount of original polar volume data, which often are not available.
Two different cell-cycle processes determine the timing of cell division inEscherichia coli
Authors: Colin Alexandra , Micali Gabriele , Faure Louis , Lagomarsino Marco Cosentino , van Teeffelen Sven
Published: March 2021

Cells must control the cell cycle to ensure that key processes are brought to completion. InEscherichia coli, it is controversial whether cell division is tied to chromosome replication or to a replication-independent inter-division process. A recent model suggests instead thatbothprocesses may limit cell division with comparable odds in single cells. Here, we tested this possibility experimentally by monitoring single-cell division and replication over multiple generations at slow growth. We then perturbed cell width, causing an increase of the time between replication termination and division. As a consequence, replication became decreasingly limiting for cell division, while correlations between birth and division and between subsequent replication-initiation events were maintained. Our experiments support the hypothesis that both chromosome replication and a replication-independent inter-division process can limit cell division: the two processes have balanced contributions in non-perturbed cells, while our width perturbations increase the odds of the replication-independent process being limiting.
Differential condensation of sister chromatids coordinates with Cdc6 to ensure distinct cell cycle progression inDrosophilamale germline stem cell lineage
Authors: Ranjan Rajesh , Snedeker Jonathan , Wooten Matthew , Chu Carolina , Bracero Sabrina , Mouton Taylar , Chen Xin
Published: March 2021

Stem cells undergo asymmetric division to produce both a self-renewing stem cell and a differentiating daughter cell. DuringDrosophilamale germline stem cell (GSC) asymmetric division, preexisting old histones H3 and H4 are enriched in the self-renewed stem daughter cell, whereas the newly synthesized H3 and H4 are enriched in the differentiating daughter cell. However, the biological consequences in the two daughter cells resulting from asymmetric histone inheritance remained to be elucidated. In this work, we track both old and new histones throughout GSC cell cycle using high spatial and temporal resolution microscopy. We find several unique features differentiating old versus new histone-enriched sister chromatids, including nucleosome density, chromosomal condensation, and H3 Ser10 phosphorylation. These distinct chromosomal features lead to their differential association with Cdc6, an essential component of the pre-replication complex, which subsequently contributes to asynchronous initiation of DNA replication in the two resulting daughter cells. Disruption of asymmetric histone inheritance abolishes both differential Cdc6 association and asynchronous S-phase entry, demonstrating that asymmetric histone acts upstream of these critical events during cell cycle progression. Furthermore, GSC defects are detected under these conditions, indicating a connection between histone inheritance, cell cycle progression and cell fate decision. Together, these studies reveal that cell cycle remodeling as a crucial biological ‘readout’ of asymmetric histone inheritance, which precedes and could lead to other well-known readouts such as differential gene expression. This work also enhances our understanding of asymmetric histone inheritance and epigenetic regulation in other stem cells or asymmetrically dividing cells in multicellular organisms.
Explainable machine learning models of major crop traits from satellite-monitored continent-wide field trial data
Authors: Newman Saul Justin , Furbank Robert T
Published: March 2021

Four species of grass generate half of all human-consumed calories1. However, abundant biological data on species that produce our food remains largely inaccessible, imposing direct barriers to understanding crop yield and fitness traits. Here, we assemble and analyse a continent-wide database of field experiments spanning ten years and hundreds of thousands of machine-phenotyped populations of ten major crop species. Training an ensemble of machine learning models, using thousands of variables capturing weather, ground-sensor, soil, chemical and fertiliser dosage, management, and satellite data, produces robust cross-continent yield models exceeding R2= 0.8 prediction accuracy. In contrast to ‘black box’ analytics, detailed interrogation of these models reveals fundamental drivers of crop behaviour and complex interactions predicting yield and agronomic traits. These results demonstrate the capacity of machine learning models to build unified, interpretable, and explainable models of crop behaviour, and highlight the powerful role of data in the future of food.
Recurrent chromosome reshuffling and the evolution of neo-sex chromosomes in parrots
Authors: Huang Zhen , Furo Ivanete , Peona Valentina , Liu Jing , Gomes Anderson J. B. , Cen Wan , Huang Hao , Zhang Yanding , Chen Duo , Ting Xue , Chen Youling , Zhang Qiujin , Yue Zhicao , Suh Alexander , de Oliveira Edivaldo H. C. , Xu Luohao
Published: March 2021

The karyotype of most birds has remained considerably stable during more than 100 million years’ evolution, except for some groups, such as parrots. The evolutionary processes and underlying genetic mechanism of chromosomal rearrangements in parrots, however, are poorly understood. Here, using chromosome-level assemblies of three parrot genomes (monk parakeet, blue-fronted amazon, budgerigar), we uncovered frequent chromosome fusions and fissions among parrots, with most of them being lineage-specific. In particular, at least 12 chromosomes recurrently experienced inter-chromosomal fusions in different parrot lineages. Two conserved vertebrate genes,ALC1andPARP3,with known functions in the repair of double-strand breaks and maintenance of genome stability, were specifically lost in parrots. The loss ofALC1was associated with multiple deletions and an accumulation of CR1-psi, a novel subfamily of transposable elements (TEs) that recently amplified in parrots, while the loss ofPARP3was associated with an inversion. Additionally, the fusion of the ZW sex chromosomes and chromosome 11 has created a pair of neo-sex chromosomes in the ancestor of parrots, and the chromosome 25 has been further added to the sex chromosomes in monk parakeet. The newly formed neo-sex chromosomes were validated by our chromosomal painting, genomic and phylogenetic analyses. Transcriptome profiling for multiple tissues of males and females did not reveal signals of female-specific selection driving the formation of neo-sex chromosomes. Finally, we identified one W-specific satellite repeat that contributed to the unusual enlargement of the W chromosome in monk parakeet. Together, the combination of our genomic and cytogenetic analyses highlight the role of TEs and genetic drift in promoting chromosome rearrangements, gene loss and the evolution of neo-sex chromosome in parrots.
The N501Y spike substitution enhances SARS-CoV-2 transmission
Authors: Liu Yang , Liu Jianying , Plante Kenneth S. , Plante Jessica A. , Xie Xuping , Zhang Xianwen , Ku Zhiqiang , An Zhiqiang , Scharton Dionna , Schindewolf Craig , Menachery Vineet D. , Shi Pei-Yong , Weaver Scott C.
Published: March 2021

Beginning in the summer of 2020, a variant of SARS-CoV-2, the cause of the COVID-19 pandemic, emerged in the United Kingdom (UK). This B.1.1.7 variant increased rapidly in prevalence among sequenced strains, attributed to an increase in infection and/or transmission efficiency. The UK variant has 19 nonsynonymous mutations across its viral genome including 8 substitutions or deletions in the spike protein, which interacts with cellular receptors to mediate infection and tropism. Here, using a reverse genetics approach, we show that, of the 8 individual spike protein substitutions, only N501Y exhibited consistent fitness gains for replication in the upper airway in the hamster model as well as primary human airway epithelial cells. The N501Y substitution recapitulated the phenotype of enhanced viral transmission seen with the combined 8 UK spike mutations, suggesting it is a major determinant responsible for increased transmission of this variant. Mechanistically, the N501Y substitution improved the affinity of the viral spike protein for cellular receptors. As suggested by its convergent evolution in Brazil and South Africa, our results indicate that N501Y substitution is a major adaptive spike mutation of major concern.
Topographical overlapping of the Aβ and Tau pathologies in the Default mode networks predicts Alzheimer’s Disease with higher specificity
Authors: Hojjati Seyed Hani , Feiz Farnia , Ozoria Sindy , Razlighi Qolamreza R. ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: March 2021

While Amyloid-plaques and Tau-tangles are the well-recognized pathologies of Alzheimer’s disease (AD), they are more often observed in healthy individuals than in AD patients. This discrepancy makes it extremely challenging to utilize these two proteinopathies as reliable biomarkers for the early detection as well as later diagnosis of AD. Using the recent advancements in the imaging technology, our newly developed quantification methods, and publicly available neuroimaging data from 303 individuals, we hypothesize and provide preliminary evidence that topographically overlapping Aβ and Tau within the DMN play more critical roles in the underlying pathophysiology of AD than the Tau and/or Aβ pathologies. We first showed that the probability of observing overlapping Aβ and Tau is significantly higher within the DMN than outside DMN. Then we showed evidence that using Aβ and Tau overlap can increase the reliability of the prediction of healthy individuals converting to MCI and a lesser degree converting from MCI to AD. These findings shed some light on the complex pathophysiology of AD and suggest that overlapping Aβ and Tau pathologies within DMN might be a more reliable biomarker of AD for early detection and later diagnosis of the disease.
Efficacy of remdesivir in hospitalised COVID-19 patients in Japan: A large observational study using the COVID-19 Registry Japan
Authors: Tsuzuki Shinya , Hayakawa Kayoko , Uemura Yukari , Shinozaki Tomohiro , Matsunaga Nobuaki , Terada Mari , Suzuki Setsuko , Ohtsu Hiroshi , Asai Yusuke , Kitajima Koji , Saito Sho , Yamada Gen , Shibata Taro , Kondo Masashi , Izumi Kazuo , Hojo Masayuki , Mizoue Tetsuya , Yokota Kazuhisa , Nakamura-Uchiyama Fukumi , Saito Fumitake , Sugiura Wataru , Ohmagari Norio
Published: March 2021

Objectives

Although several randomised controlled trials have compared the efficacy of remdesivir with that of placebo, there is limited evidence regarding its effect in the early stage of nonsevere COVID-19 cases.

Methods

We evaluated the efficacy of remdesivir on the early stage of nonsevere COVID-19 using the COVID-19 Registry Japan, a nationwide registry of hospitalised COVID-19 patients in Japan. Two regimens (start remdesivir therapy within 4 days from admission vs. no remdesivir during hospitalisation) among patients without the need for supplementary oxygen therapy were compared by a three-step processing (cloning, censoring, and weighting) method. The primary outcome was supplementary oxygen requirement during hospitalisation. Secondary outcomes were 30-day fatality risk and risk of invasive mechanical ventilation or extracorporeal membrane oxygenation (IMV/ECMO).

Results

The data of 12,657 cases met our inclusion criteria. The ‘start remdesivir’ regimen showed a lower risk of supplementary oxygen requirement (hazard ratio: 0.861, p < 0.001). Both 30-day fatality risk and risk of IMV/ECMO introduction were not significantly different between the two regimens (hazard ratios: 1.05 and 0.886, p values: 0.070 and 0.440, respectively).

Conclusions

Remdesivir might reduce the risk of oxygen requirement during hospitalisation in the early stage of COVID-19; however, it had no positive effect on the clinical outcome and reduction of IMV/ECMO requirement.
Niche signals regulate continuous transcriptional states in hematopoietic stem cells
Authors: Fast Eva M , Sporrij Audrey , Manning Margot , da Rocha Edroaldo Lummertz , Yang Song , Zhou Yi , Guo Jimin , Baryawno Ninib , Barkas Nikolaos , Scadden David T , Camargo Fernando , Zon Leonard I
Published: March 2021

Hematopoietic stem cells (HSCs) must ensure adequate blood cell production following distinct external stressors. A comprehensive understanding ofin vivoheterogeneity and specificity of HSC responses to external stimuli is currently lacking. We performed single-cell RNA sequencing (scRNA-Seq) on functionally validated mouse HSCs and LSK (Lin-, c-Kit+, Sca1+) progenitors afterin vivoperturbation of niche signals interferon, granulocyte-colony stimulating factor (G-CSF), and prostaglandin. We identified six HSC states that are characterized by enrichment but not exclusive expression of marker genes. Niche perturbations induce novel and rapid transitions between these HSC states. Differential expression analysis within each state revealed HSC- and LSK-specific molecular signatures for each perturbation. Chromatin analysis of unperturbed HSCs and LSKs by scATAC-Seq revealed HSC-specific, cell intrinsic predispositions to niche signals. We compiled a comprehensive resource of HSC- and progenitor-specific chromatin and transcriptional features that represent important determinants of regenerative potential during stress hematopoiesis.
Standing genetic variation of the AvrPm17 avirulence gene in powdery mildew limits the effectiveness of an introgressed rye resistance gene in wheat
Authors: Mueller Marion C. , Kunz Lukas , Schudel Seraina , Kammerecker Sandrine , Isaksson Jonatan , Wyler Michele , Graf Johannes , Sotiropoulos Alexandros G. , Praz Coraline R. , Wicker Thomas , Bourras Salim , Keller Beat
Published: March 2021

Introgressions of chromosomal segments from related species into wheat are important sources of resistance against fungal diseases. The durability and effectiveness of introgressed resistance genes upon agricultural deployment is highly variable - a phenomenon that remains poorly understood as the corresponding fungal avirulence genes are largely unknown. Until its breakdown, thePm17resistance gene introgressed from rye to wheat provided broad resistance against powdery mildew (Blumeria graminis). Here, we used QTL mapping to identify the corresponding wheat mildew avirulence effectorAvrPm17. It is encoded by two paralogous genes that exhibit signatures of re-occurring gene conversion events and are members of a mildew sub-lineage specific effector cluster. Extensive haplovariant mining in wheat mildew and related sub-lineages identified several ancient virulentAvrPm17variants that were present as standing genetic variation in wheat powdery mildew prior to thePm17introgression, thereby paving the way for the rapid breakdown of thePm17resistance. QTL mapping in mildew identified a second genetic component likely corresponding to an additional resistance gene present on the 1AL.1RS translocation carryingPm17. This gene remained previously undetected due to suppressed recombination within the introgressed rye chromosomal segment. We conclude that the initial effectiveness of 1AL.1RS was based on simultaneous introgression of two genetically linked resistance genes. Our results demonstrate the relevance of pathogen-based genetic approaches to disentangle complex resistance loci in wheat. We propose that identification and monitoring of avirulence gene diversity in pathogen populations becomes an integral part of introgression breeding to ensure effective and durable resistance in wheat.

Significance Statement

Domesticated and wild wheat relatives provide an important source of new immune receptors for wheat resistance breeding against fungal pathogens. The durability of these resistance genes is variable and difficult to predict, yet it is crucial for effective resistance breeding. We identified a fungal effector protein recognised by an immune receptor introgressed from rye to wheat. We found that variants of the effector allowing the fungus to overcome the resistance are ancient. They were already present in the wheat powdery mildew gene pool before the introgression of the immune receptor and are therefore responsible for the rapid resistance breakdown. Our study demonstrates that the effort to identify new resistance genes should be accompanied by studies of avirulence genes on the pathogen side.
Defining the scope of the European Antimicrobial Resistance Surveillance network in Veterinary medicine (EARS-Vet): a bottom-up and One Health approach
Authors: Mader Rodolphe , Bourély Clémence , Amat Jean-Philippe , Broens Els M. , Busani Luca , Callens Bénédicte , Crespo Paloma , Damborg Peter , Filippitzi Maria-Eleni , Fitzgerald William , Grönthal Thomas , Haenni Marisa , Heuvelink Annet , van Hout Jobke , Kaspar Heike , Munoz Cristina , Norström Madelaine , Pedersen Karl , Pokludova Lucie , Pozzo Fabiana Dal , Slowey Rosemarie , Urdahl Anne Margrete , Vatopoulos Alkiviadis , Zafeiridis Christos , Madec Jean-Yves
Published: March 2021

Background

Building the European Antimicrobial Resistance Surveillance network in Veterinary medicine (EARS-Vet) was proposed to strengthen the European One Health antimicrobial resistance (AMR) surveillance approach.

Objectives

The objectives were to (i) define the combinations of animal species, production types, age categories, bacterial species, specimens and antimicrobials to be monitored in EARS-Vet and to (ii) determine antimicrobial test panels able to cover most combinations.

Methods

The EARS-Vet scope was defined by consensus between 26 European experts. Decisions were guided by a survey of the combinations that are relevant and feasible to monitor in diseased animals in 13 European countries (bottom-up approach). Experts also considered the One Health approach and the need for EARS-Vet to complement existing European AMR monitoring systems coordinated by the European Centre for Disease Prevention and Control (ECDC) and the European Food Safety Authority (EFSA).

Results

EARS-Vet would monitor AMR in six animal species (cattle, swine, chicken (broiler and laying hen), turkey, cat and dog), for 11 bacterial species (Escherichia coli,Klebsiella pneumoniae,Mannheimia haemolytica,Pasteurella multocida,Actinobacillus pleuropneumoniae,Staphylococcus aureus,Staphylococcus pseudintermedius,Staphylococcus hyicus,Streptococcus uberis,Streptococcus dysgalactiaeandStreptococcus suis). Relevant antimicrobials for their treatment were selected (e.g. tetracyclines) and complemented with antimicrobials of more specific public health interest (e.g. carbapenems). Three test panels of antimicrobials were proposed covering most EARS-Vet combinations of relevance for veterinary antimicrobial stewardship.

Conclusions

With this scope, EARS-Vet would enable to better address animal health in the strategy to mitigate AMR and better understand the multi-sectoral AMR epidemiology in Europe.
RS-FISH: Precise, interactive, fast, and scalable FISH spot detection
Authors: Bahry Ella , Breimann Laura , Zouinkhi Marwan , Epstein Leo , Kolyvanov Klim , Long Xi , Harrington Kyle I S , Lionnet Timothée , Preibisch Stephan
Published: March 2021

Fluorescent in-situ hybridization (FISH)-based methods are powerful tools to study molecular processes with subcellular resolution, relying on accurate identification and localization of diffraction-limited spots in microscopy images. We developed the Radial Symmetry-FISH (RS-FISH) software that accurately, robustly, and quickly detects single-molecule spots in two and three dimensions, making it applicable to several key assays, including single-molecule FISH (smFISH), spatial transcriptomics, and spatial genomics. RS-FISH allows interactive parameter tuning and scales to large sets of images as well as tera-byte sized image volumes such as entire brain scans using straight-forward distributed processing on workstations, clusters, and in the cloud.
The FDA-approved drug cobicistat synergizes with remdesivir to inhibit SARS-CoV-2 replication
Authors: Shytaj Iart Luca , Fares Mohamed , Lucic Bojana , Gallucci Lara , Tolba Mahmoud M. , Zimmermann Liv , Ayoub Ahmed Taha , Cortese Mirko , Neufeldt Christopher J. , Laketa Vibor , Chlanda Petr , Fackler Oliver T. , Boulant Steeve , Bartenschlager Ralf , Stanifer Megan , Savarino Andrea , Lusic Marina
Published: March 2021

Combinations of direct-acting antivirals are needed to minimize drug-resistance mutations and stably suppress replication of RNA viruses. Currently, there are limited therapeutic options against the Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) and testing of a number of drug regimens has led to conflicting results. Here we show that cobicistat, which is an-FDA approved drug-booster that blocks the activity of the drug metabolizing proteins Cytochrome P450-3As (CYP3As) and P-glycoprotein (P-gp), inhibits SARS-CoV-2 replication. Cell-to-cell membrane fusion assays indicated that the antiviral effect of cobicistat is exerted through inhibition of spike protein-mediated membrane fusion. In line with this, incubation with low micromolar concentrations of cobicistat decreased viral replication in three different cell lines including cells of lung and gut origin. When cobicistat was used in combination with the putative CYP3A target and nucleoside analog remdesivir, a synergistic effect on the inhibition of viral replication was observed in cell lines and in a primary human colon organoid. The cobicistat/remdesivir combination was able to potently abate viral replication to levels comparable to mock-infected cells leading to an almost complete rescue of infected cell viability. These data highlight cobicistat as a therapeutic candidate for treating SARS-CoV-2 infection and as a potential building block of combination therapies for COVID-19.
Quantitative proteomics of hamster lung tissues infected with SARS-CoV-2 reveal host-factors having implication in the disease pathogenesis and severity
Authors: Suresh Voddu , Mohanty Varshasnata , Avula Kiran , Ghosh Arup , Singh Bharti , Reddy R. Rajendra Kumar , Suryawanshi Amol Ratnakar , Raghav Sunil K. , Chattopadhyay Soma , Prasad Punit , Swain Rajeeb Kumar , Dash Rupesh , Parida Ajay , Syed Gulam Hussain , Senapati Shantibhusan
Published: March 2021

Syrian golden hamsters (Mesocricetus auratus) infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) manifests lung pathology that resembles human COVID-19 patients. In this study, efforts were made to check the infectivity of a local SARS-CoV-2 isolate in hamster model and evaluate the differential expression of lung proteins during acute infection and convalescence. The findings of this study confirm the infectivity of this isolatein vivo. Analysis of clinical parameters and tissue samples shows a similar type of pathophysiological manifestation of SARS-CoV-2 infection as reported earlier in COVID-19 patients and hamsters infected with other isolates. The lung-associated pathological changes were very prominent on the 4th day post-infection (dpi), mostly resolved by 14dpi. Here, we carried out quantitative proteomic analysis of the lung tissues from SARS-CoV-2-infected hamsters at day 4 and day 14 post infection. This resulted in the identification of 1,585 differentially expressed proteins of which 68 proteins were significantly altered among both the infected groups. Pathway analysis revealed complement and coagulation cascade, platelet activation, ferroptosis and focal adhesion as the top enriched pathways. In addition, we also identified altered expression of two pulmonary surfactant-associated proteins (Sftpd and Sftpb), known for their protective role in lung function. Together, these findings will aid in the identification of candidate biomarkers and understanding the mechanism(s) involved in SARS-CoV-2 pathogenesis.

Graphical abstract
Effect of chronic JUUL aerosol inhalation on inflammatory states of the brain, lung, heart and colon in mice
Authors: Moshensky Alex , Brand Cameron , Alhaddad Hasan , Shin John , Masso-Silva Jorge A. , Advani Ira , Gunge Deepti , Sharma Aditi , Mehta Sagar , Jahan Arya , Nilaad Sedtavut , Almarghalani Daniyah , Pham Josephine , Perera Samantha , Park Kenneth , Al-Kolla Rita , Moon Hoyoung , Das Soumita , Byun Min , Shah Zahoor , Sari Youssef , Brown Joan Heller , Crotty Alexander Laura E.
Published: March 2021

While health effects of conventional tobacco are well defined, data on vaping devices, including the most popular e-cigarette JUUL, are less established. Prior acute e-cigarette studies demonstrated inflammatory and cardiopulmonary physiology changes while chronic studies demonstrated extra-pulmonary effects, including neurotransmitter alterations in reward pathways. In this study we investigated effects of chronic flavored JUUL aerosol inhalation on inflammatory markers in brain, lung, heart, and colon. JUUL induced upregulation of cytokine and chemokine gene expression and increased HMGB1 and RAGE in the nucleus accumbens. Inflammatory gene expression increased in colon, and cardiopulmonary inflammatory responses to acute lung injury with lipopolysaccharide were exacerbated in the heart. Flavor-dependent changes in several responses were also observed. Our findings raise concerns regarding long-term risks of e-cigarette use as neuroinflammation may contribute to behavioral changes and mood disorders, while gut inflammation has been tied to poor systemic health and cardiac inflammation to development of heart disease.

One Sentence Summary

Chronic, daily inhalation of pod-based e-cigarette aerosols alters the inflammatory state across multiple organ systems in mice.
Vibrio cholerae’s mysterious Seventh Pandemic island (VSP-II) encodes novel Zur-regulated zinc starvation genes involved in chemotaxis and autoaggregation
Authors: Murphy Shannon G. , Johnson Brianna A. , Ledoux Camille M. , Dörr Tobias
Published: March 2021

Vibrio choleraeis the causative agent of cholera, a notorious diarrheal disease that is typically transmitted via contaminated drinking water. The current pandemic agent, the El Tor biotype, has undergone several genetic changes that include horizontal acquisition of two genomic islands (VSP-I and VSP-II). VSP-I and -2 presence strongly correlates with pandemicity; however, the contribution of these islands toV. cholerae’s life cycle, particularly the 26-kb VSP-II, remains poorly understood. VSP-II-encoded genes are not expressed under standard laboratory conditions, suggesting that their induction requires an unknown signal from the host or environment. One signal that bacteria encounter under both host and environmental conditions is metal limitation. While studyingV. cholerae’s zinc-starvation responsein vitro, we noticed that a mutant constitutively expressing zinc-starvation genes (Δzur) aggregates in nutrient-poor media. Using transposon mutagenesis, we found that flagellar motility, chemotaxis, and VSP-II encoded genes are required for aggregation. The VSP-II genes encode an AraC-like transcriptional activator (VerA) and a methyl-accepting chemotaxis protein (AerB). Using RNA-seq andlacZtranscriptional reporters, we show that VerA is a novel Zur target and activator of the nearby AerB chemoreceptor. AerB interfaces with the chemotaxis system to drive oxygen-dependent autoaggregation and energy taxis. Importantly, this work suggests a functional link between VSP-II, zinc-starved environments, and aerotaxis, yielding insights into the role of VSP-II in a metal-limited host or aquatic reservoir.

Author Summary

The Vibrio Seventh Pandemic island was horizontally acquired by El Tor pandemic strain, but its role in pathogenicity or environmental persistence is unknown. A major barrier to VSP-II study was the lack of stimuli favoring its expression. We show that zinc starvation induces expression of this island and describe a transcriptional network that activates a VSP-II encoded aerotaxis receptor. Importantly, aerotaxis may enableV. choleraeto locate more favorable microenvironments, possibly to colonize anoxic portions of the gut or environmental sediments.
Dual regulation of the actin cytoskeleton by CARMIL-GAP
Authors: Jung Goeh , Pan Miao , Alexander Chris , Jin Tian , Hammer John A.
Published: March 2021

CARMIL (Capping proteinArp2/3MyosinILinker) proteins are multi-domain scaffold proteins that regulate actin dynamics by regulating the activity of Capping Protein (CP). Here we characterize CARMIL-GAP, aDictyosteliumCARMIL isoform that contains a ~130 residue insert that, by homology, is a GTPase activating (GAP) domain for Rho-related GTPases. Consistently, this GAP domain bindsDictyosteliumRac1a and accelerates its rate of GTP hydrolysis. CARMIL-GAP concentrates with F-actin in phagocytic cups and at the leading edge of chemotaxing cells, and CARMIL-GAP null cells exhibit pronounced defects in phagocytosis and chemotactic streaming. Importantly, these defects are fully rescued by expressing GFP-tagged CARMIL-GAP in CARMIL-GAP null cells. Finally, rescue with versions of CARMIL-GAP that lack either GAP activity or the ability to regulate CP show that while both activities contribute significantly to CARMIL-GAP function, the GAP activity plays the bigger role. Together, our results add to the growing evidence that CARMIL proteins influence actin dynamics by regulating signaling molecules as well as CP, and that the continuous cycling of the Rho GTPase’s nucleotide state is often required to drive Rho-dependent biological processes.

SUMMARY STATEMENT

The assembly of actin filaments supports a wide array of fundamental cellular functions, including cell migration and phagocytosis. Actin assembly is controlled by a host of regulatory proteins, with Capping Protein being one of the most important. Capping Protein is in turn regulated by the CARMIL family of proteins. Actin assembly is also controlled by signaling pathways that often converge on Rho-related GTPases like Rac1. These GTPases cycle between an active, GTP-bound state and an inactive, GDP-bound state. Guanine nucleotide exchange factors (GEFs) and guanine nucleotide activating proteins (GAPs) drive Rho-related GTPases to their GTP-bound and GDP-bound states, respectively. Here we characterized a version of CARMIL that contains within it a GAP domain for Rac1. We show that CARMIL-GAP supports the actin-based processes of cell migration and phagocytosis. We also show that while CARMIL-GAP’s ability to regulate Capping Protein and the nucleotide state of Rac1 are both important for its cellular functions, its ability to regulate Rac1 via its GAP domain plays the bigger role. Finally, our data support the emerging concept that the continuous cycling of Rho GTPases between their GTP- bound and GDP-bound states is often required to drive Rho-dependent biological processes.
Insights into the controls on metabolite distributions along a latitudinal transect of the western Atlantic Ocean
Authors: Johnson Winifred M. , Kido Soule Melissa C. , Longnecker Krista , Bhatia Maya P. , Hallam Steven J. , Lomas Michael W. , Kujawinski Elizabeth B.
Published: March 2021

Metabolites, or the small organic molecules that are synthesized by cells during metabolism, comprise a complex and dynamic pool of carbon in the ocean. They are an essential form of information, linking genotype to phenotype at the individual, population and community levels of biological organization. Characterizing metabolite distributions inside microbial cells and dissolved in seawater is essential to understanding the controls on their production and fate, as well as their roles in shaping marine microbial food webs. Here, we apply a targeted metabolomics method to quantify particulate and dissolved distributions of a suite of biologically relevant metabolites including vitamins, amino acids, nucleic acids, osmolytes, and intermediates in biosynthetic pathways along a latitudinal transect in the western Atlantic Ocean. We find that, in the euphotic zone, most particulate or intracellular metabolites positively co-vary with the most abundant microbial taxa. In contrast, dissolved metabolites exhibited greater variability with differences in distribution between ocean regions. Although fewer particulate metabolites were detected below the euphotic zone, molecules identified in the deep ocean may be linked to preservation of organic matter or adaptive physiological strategies of deep-sea microbes. Based on the identified metabolite distributions, we propose relationships between certain metabolites and microbial populations, and find that dissolved metabolite distributions are not directly related to their particulate abundances.
Multiple resource limitations explain biomass-precipitation relationships in grasslands
Authors: Bharath Siddharth , Adler Peter B. , Fay Philip A. , Seabloom Eric W. , Hautier Yann , Biederman Lori , Bugalho Miguel N. , Caldeira Maria , Eskelinen Anu , Knops Johannes M.H. , McCulley Rebecca , Morgan John , Power Sally A , Risch Anita C. , Schuetz Martin , Stevens Carly J. , Ohlert Timothy , Virtanen Risto , Borer Elizabeth T.
Published: March 2021

Interannual variability in grassland primary production is strongly driven by precipitation, nutrient availability and herbivory, but there is no general consensus on the mechanisms linking these variables. If grassland biomass is limited by the single most limiting resource at a given time, then we expect that nutrient addition will not affect biomass production at arid sites. We conducted a distributed experiment manipulating nutrients and herbivores at 44 grassland sites in 8 regions around the world, spanning a broad range in aridity. We estimated the effects of 5-11 years of nutrient addition and herbivore exclusion treatments on precipitation sensitivity of biomass (proportional change in biomass relative to proportional change in rainfall among years), and the biomass in the driest year (to measure treatment effects when water was most limiting) at each site. Grazer exclusion did not interact with nutrients to influence driest year biomass or sensitivity. Nutrient addition increased driest year biomass by 74% and sensitivity by 0.12 (proportional units), and that effect did not change across the range of aridity spanned by our sites. Grazer exclusion did not interact with nutrients to influence sensitivity or driest year biomass. At almost half of our sites, the previous year's rainfall explained as much variation in biomass as current year precipitation. Overall, our distributed fertilization experiment detected co-limitation between nutrients and water governing grasslands, with biomass sensitivity to precipitation being limited by nutrient availability irrespective of site aridity and herbivory. Our findings refute the classical ideas that grassland plant performance is limited by the single most limiting resource at a site. This suggests that nutrient eutrophication will destabilize grassland ecosystems through increased sensitivity to precipitation variation.
Longitudinal single-cell epitope and RNA-sequencing reveals the immunological impact of type 1 interferon autoantibodies in critical COVID-19
Authors: van der Wijst Monique G.P. , Vazquez Sara E. , Hartoularos George C. , Bastard Paul , Grant Tianna , Bueno Raymund , Lee David S. , Greenland John R. , Sun Yang , Perez Richard , Ogorodnikov Anton , Ward Alyssa , Mann Sabrina A. , Lynch Kara L. , Yun Cassandra , Havlir Diane V. , Chamie Gabriel , Marquez Carina , Greenhouse Bryan , Lionakis Michail S. , Norris Philip J. , Dumont Larry J. , Kelly Kathleen , Zhang Peng , Zhang Qian , Gervais Adrian , Voyer Tom Le , Whatley Alexander , Si Yichen , Byrne Ashley , Combes Alexis J. , Rao Arjun Arkal , Song Yun S. ,   UCSF COMET consortium, Fragiadakis Gabriela K. , Kangelaris Kirsten , Calfee Carolyn S. , Erle David J. , Hendrickson Carolyn , Krummel Matthew F. , Woodruff Prescott G. , Langelier Charles R. , Casanova Jean-Laurent , Derisi Joseph L. , Anderson Mark S. , Ye Chun Jimmie
Published: March 2021

Type I interferon (IFN-I) neutralizing autoantibodies have been found in some critical COVID-19 patients; however, their prevalence and longitudinal dynamics across the disease severity scale, and functional effects on circulating leukocytes remain unknown. Here, in 284 COVID-19 patients, we found IFN-I autoantibodies in 19% of critical, 6% of severe and none of the moderate cases. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 COVID-19 patients, 15 non-COVID-19 patients and 11 non-hospitalized healthy controls, revealed a lack of IFN-I stimulated gene (ISG-I) response in myeloid cells from critical cases, including those producing anti-IFN-I autoantibodies. Moreover, surface protein analysis showed an inverse correlation of the inhibitory receptor LAIR-1 with ISG-I expression response early in the disease course. This aberrant ISG-I response in critical patients with and without IFN-I autoantibodies, supports a unifying model for disease pathogenesis involving ISG-I suppression via convergent mechanisms.