bluuebunny/crossref_metadata_2025 huggingface dataset:
Juvenile ecology drives adult morphology in two insect orders
Authors: Rühr Peter T. , van de Kamp Thomas , Faragó Tomáš , Hammel Jörg U. , Wilde Fabian , Borisova Elena , Edel Carina , Frenzel Melina , Baumbach Tilo , Blanke Alexander
Published: June 2021

Most animals undergo ecological niche shifts between distinct life phases, but such shifts can result in adaptive conflicts of phenotypic traits. Metamorphosis can reduce these conflicts by breaking up trait correlations, allowing each life phase to independently adapt to its ecological niche. This process is called adaptive decoupling. It is, however, yet unknown to what extent adaptive decoupling is realized on a macroevolutionary scale in hemimetabolous insects and if the degree of adaptive decoupling is correlated with the strength of ontogenetic niche shifts. It is also unclear whether the degree of adaptive decoupling is correlated with phenotypic disparity. Here, we quantify nymphal and adult trait correlations in 219 species across the whole phylogeny of earwigs and stoneflies to test whether juvenile and adult traits are decoupled from each other. We demonstrate that adult head morphology is largely driven by nymphal ecology, and that adult head shape disparity has increased with stronger ontogenetic niche shifts in some stonefly lineages. Our findings implicate that the hemimetabolan metamorphosis in earwigs and stoneflies does not allow for high degrees of adaptive decoupling, and that high phenotypic disparity can even be realized when the evolution of distinct life phases is coupled.
DNA metabarcoding reveals trophic niche diversity of micro and mesozooplankton species
Authors: Novotny Andreas , Zamora-Terol Sara , Winder Monika
Published: June 2021

Alternative pathways of energy transfer guarantee the functionality and productivity in marine food webs that experience strong seasonality. Nevertheless, the complexity of zooplankton interactions is rarely considered in trophic studies because of the lack of detailed information about feeding interactions in nature. In this study, we used DNA metabarcoding to highlight the diversity of trophic niches in a wide range of micro- and mesozooplankton, including ciliates, rotifers, cladocerans, copepods and their prey, by sequencing
16-
and
18S rRNA
genes. Our study demonstrates that the zooplankton trophic niche partitioning goes beyond both phylogeny and size and reinforces the importance of diversity in resource use for stabilizing food web efficiency by allowing for several different pathways of energy transfer. We further highlight that small, rarely studied zooplankton (rotifers and ciliates) fill an important role in the Baltic Sea pelagic primary production pathways and the potential of ciliates, rotifers and crustaceans in the utilization of filamentous and picocyanobacteria within the pelagic food web. The approach used in this study is a suitable entry point to ecosystem-wide food web modelling considering species-specific resource use of key consumers.
Retrospective screening of routine respiratory samples revealed undetected community transmission and missed intervention opportunities for SARS-CoV-2 in the United Kingdom
Authors: Chappell Joseph G. , Tsoleridis Theocharis , Clark Gemma , Berry Louise , Holmes Nadine , Moore Christopher , Carlile Matthew , Sang Fei , Debebe Bisrat J. , Wright Victoria , Irving William L. , Thomson Brian J. , Boswell Timothy C. J. , Willingham Iona , Joseph Amelia , Smith Wendy , Khakh Manjinder , Fleming Vicki M. , Lister Michelle M. , Howson-Wells Hannah C. , Holmes Edward C. , Loose Matthew W. , Ball Jonathan K. , McClure C. Patrick ,   on behalf of the COG-UK consortium
Published: June 2021

In the early phases of the SARS coronavirus type 2 (SARS-CoV-2) pandemic, testing focused on individuals fitting a strict case definition involving a limited set of symptoms together with an identified epidemiological risk, such as contact with an infected individual or travel to a high-risk area. To assess whether this impaired our ability to detect and control early introductions of the virus into the UK, we PCR-tested archival specimens collected on admission to a large UK teaching hospital who retrospectively were identified as having a clinical presentation compatible with COVID-19. In addition, we screened available archival specimens submitted for respiratory virus diagnosis, and dating back to early January 2020, for the presence of SARS-CoV-2 RNA. Our data provides evidence for widespread community circulation of SARS-CoV-2 in early February 2020 and into March that was undetected at the time due to restrictive case definitions informing testing policy. Genome sequence data showed that many of these early cases were infected with a distinct lineage of the virus. Sequences obtained from the first officially recorded case in Nottinghamshire - a traveller returning from Daegu, South Korea – also clustered with these early UK sequences suggesting acquisition of the virus occurred in the UK and not Daegu. Analysis of a larger sample of sequences obtained in the Nottinghamshire area revealed multiple viral introductions, mainly in late February and through March. These data highlight the importance of timely and extensive community testing to prevent future widespread transmission of the virus.
Sex-specific transcriptional differences and loss of gene imprinting in pancreatic neuroendocrine tumors
Authors: Ivanov Nikolay A. , Grigorev Kirill , Fahey Thomas J. , Finnerty Brendan M. , Mason Christopher E. , Min Irene M.
Published: June 2021

Pancreatic neuroendocrine tumors (PNETs) occur more frequently in men and are associated with higher mortality in males; however, the molecular basis for these sexual dimorphisms is unclear. Here, we demonstrate that PNETs are associated with the emergence of unique sex-specific transcriptomic differences that are not observed in non-neoplastic pancreatic islet tissues. We also show that while widespread sex-specific differences are present in the DNA methylation landscapes of control pancreatic islets, they are erased in PNETs. This includes a loss of imprinting with regards to many genes. These results implicate an emergence of sex-associated genetic and epigenetic dysregulations in PNETs.
Systematic review and meta-analysis of the prevalence of coronavirus in the world: One health approach is urgent
Authors: Faustino Ricardo , Faria Miguel , Teixeira Mónica , Palavra Filipe , do Céu Costa Maria , Sargento Paulo
Published: June 2021

Coronaviruses have been responsible for major epidemic crises in 2003 with SARS-CoV-1, in 2012 with MERS-CoV and in 2019 with SARS-CoV-2 (COVID-19), causing serious atypical pneumonia in humans. We intend, with this systematic analysis and meta-analysis, to clarify the prevalence of the various strains of coronavirus in different animal species. For this purpose, we carried out an electronic survey using Pubmed’s Veterinary Science search tool to conduct a systematic assessment of published studies reporting the prevalence of different strains of coronavirus in different animal species between 2015 and 2020. We conducted different analysis to assess sensitivity, publication bias, and heterogeneity, using random and fixed effects. The final meta-analysis included 42 studies for systematic review and 29 in the meta-analysis. For the geographic regions with a prevalence greater than or equal to 0.20 (Forest plot overall; prevalence = 0.20, p < 0.01, Q = 10476.22 and I2 = 100%), the most commonly detected viruses were: enteric coronavirus (ECoV), pigeon-dominant coronavirus, (PdCoV), Avian coronavirus M41, Avian coronavirus C46, Avian coronavirus A99, Avian coronavirus JMK, MERS-CoV, Bovine coronavirus, Ro-BatCoV GCCDC1, Alphacoronavirus, Betacoronavirus, Deltacoronavirus, Gamacoronavirus and human coronaviruses (HCoVs). The wide presence of different strains of coronavirus in different animal species on all continents demonstrates the great biodiversity and ubiquity of these viruses.

The most recent epidemiological crises caused by coronavirus demonstrates our unpreparedness to anticipate and mitigate emerging risks, as well as the need to implement new epidemiological surveillance programs for viruses. Combined with the need to create advanced training courses in One Health, this is paramount in order to ensure greater effectiveness in fighting the next pandemics.
A convolutional-recurrent neural network approach to resting-state EEG classification in Parkinson’s disease
Authors: Lee Soojin , Hussein Ramy , Ward Rabab , Wang Z. Jane , McKeown Martin J.
Published: June 2021

Background

Parkinson’s disease (PD) is expected to become more common, particularly with an aging population. Diagnosis and monitoring of the disease typically rely on the laborious examination of physical symptoms by medical experts, which is necessarily limited and may not detect the prodromal stages of the disease.

New Method

We propose a lightweight (∼20K parameters) deep learning model, to discriminate between resting-state EEG recorded from people with PD and healthy controls. The proposed CRNN model consists of convolutional neural networks (CNN) and a recurrent neural network (RNN) with gated recurrent units (GRUs). The 1D CNN layers are designed to extract spatiotemporal features across EEG channels, which are subsequently supplied to the GRUs to discover temporal features pertinent to the classification.

Results

The CRNN model achieved 99.2% accuracy, 98.9% precision, and 99.4% recall in classifying PD from healthy controls (HC). Interrogating the model, we further demonstrate that the model is sensitive to dopaminergic medication effects and predominantly uses phase information of the EEG signals.

Comparison with Existing Methods

The CRNN model achieves superior performance compared to baseline machine learning methods and other recently proposed deep learning models.

Conclusion

The approach proposed in this study adequately extracts the spatial and temporal features in multi-channel EEG signals that enable the accurate differentiation between PD and HC. It has excellent potential for use as an oscillatory biomarker for assisting in the diagnosis and monitoring of people with PD. Future studies to further improve and validate the model’s performance in clinical practice are warranted.
Factors associated with COVID-19 susceptibility and severity in patients with multiple sclerosis: A systematic review
Authors: Barzegar Mahdi , bagherieh Sara , Houshi Shakiba , Hashemi Mozhgan Sadat , Pishgahi Ghasem , Afshari-Safavi Alireza , Mirmosayyeb Omid , Shaygannejad Vahid , Zabeti Aram
Published: June 2021

Background

We conducted this systematic review to identify factors associated with coronavirus disease (COVID-19) susceptibility and outcomes among people with multiple sclerosis (MS).

Methods

Available studies from PubMed, Scopus, EMBASE, Web of Science, and gray literature including reference list and conference abstracts were searched from December 1, 2019, through April 12, 2021. We included cross-sectional, case-control, and cohort studies that reported risk factors of contracting COVID-19 or its outcome in patients with MS on univariate or multivariate regression analyses.

Results

Out of the initial 2719 records and 1553 conference abstracts, a total of 20 studies were included. Factors associated with COVID-19 susceptibility were reported in 11 studies and risk factors for infection outcomes were discussed in 10. History of contact with an infected is strongly suggested as a risk factor for COVID-19 susceptibility. Other factors that could be associated with contracting infection are younger age, relapsing course, and anti-CD20 agents. The evidence suggests that increasing age, greater MS severity, treatment with anti-CD20 agents, previous use of corticosteroids, and specific comorbidities (obesity and coronary artery disease) could be independently associated with worse infection outcomes. Male sex is likely to be a risk factor for more severe disease. The black or African American race was reported as a possible risk factor.

Conclusion

Due to a paucity of research and methodological issues, no risk factors for COVID-19 susceptibility and outcomes neither be confirmed nor excluded. Further large studies are needed to address factors associated with COVID-19 susceptibility and severity.
Clonal hematopoiesis in sickle cell disease
Authors: Liggett L. Alexander , Cato Liam D. , Weinstock Joshua S. , Zhang Yingze , Nouraie Seyed Mehdi , Gladwin Mark T. , Garrett Melanie E. , Ashley-Koch Allison , Telen Marilyn J. , Custer Brian , Kelly Shannon , Dinardo Carla Luana , Sabino Ester C. , Loureiro Paula , Carneiro-Proietti Anna Bárbara , Maximo Cláudia ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Reiner Alexander P. , Abecasis Gonçalo R. , Williams David A. , Natarajan Pradeep , Bick Alexander G. , Sankaran Vijay G.
Published: June 2021

Curative gene therapies for sickle cell disease (SCD) are currently undergoing clinical evaluation. However, the occurrence of several myeloid malignancy cases in these trials has prompted safety concerns. Individuals with SCD are predisposed to myeloid malignancies, but the underlying causes remain undefined. Clonal hematopoiesis (CH) is a pre-malignant condition that also confers significant predisposition to myeloid cancers. While it has been speculated that CH may play a role in SCD-associated cancer predisposition, no data addressing this issue have been reported. Here, we leverage 74,190 whole-genome sequences to robustly study CH in SCD. While we have sufficient power to detect increased rates of CH, we find no variation in rate or clone properties between individuals affected by SCD and controls. These results should help guide ongoing efforts that seek to better define the risk factors underlying myeloid malignancy predisposition in SCD and help ensure that curative therapies can be more safely applied.
Antibody Responses to SARS-CoV-2 after Infection or Vaccination in Children and Young Adults with Inflammatory Bowel Disease
Authors: Dailey Joelynn , Kozhaya Lina , Dogan Mikail , Hopkins Dena , Lapin Blaine , Herbst Katherine , Brimacombe Michael , Grandonico Kristen , Karabacak Faith , Schreiber John , Liang Bruce Tsan-Liang , Salazar Juan C. , Unutmaz Derya , Hyams Jeffrey S.
Published: June 2021

Background

Characterization of neutralization antibodies to SARS-CoV-2 infection or vaccination in children and young adults with inflammatory bowel disease (IBD) receiving biologic therapies is crucial.

Methods

We performed a prospective longitudinal cohort study evaluating SARS-CoV-2 Spike protein receptor binding domain (S-RBD) IgG positivity along with consistent clinical symptoms in patients with IBD receiving infliximab or vedolizumab. Serum was also obtained following immunization with approved vaccines. IgG antibody to the spike protein binding domain of SARS-CoV-2 was assayed with a fluorescent bead-based immunoassay that takes advantage of the high dynamic range of fluorescent molecules using flow cytometry. A sensitive and high-throughput neutralization assay that incorporates SARS-CoV-2 Spike protein onto a lentivirus and measures pseudoviral entry into ACE2 expressing HEK-293 cells was used.

Results

436 patients were enrolled (mean age 17 years, range 2-26 years, 58% male, 71% Crohn’s disease, 29% ulcerative colitis, IBD-unspecified). 44 (10%) of enrolled subjects had SARS-CoV-2 S-RBD IgG antibodies. Compared to non-IBD adults (ambulatory) and hospitalized pediatric patients with PCR documented SARS-CoV-2 infection, S-RBD IgG antibody levels were significantly lower in the IBD cohort and by 6 months post infection most patients lacked neutralizing antibody. Following vaccination (n=33) patients had a 15-fold higher S-RBD antibody response in comparison to natural infection, and all developed neutralizing antibodies to both wild type and variant SARS-CoV-2.

Conclusions and Relevance

The lower and less durable SARS-CoV-2 S-RBD IgG response to natural infection in IBD patients receiving biologics puts them at risk of reinfection. The robust response to immunization is likely protective.

Our study showed a low and poorly durable SARS-CoV-2 S-RBD neutralizing IgG response to natural infection in IBD patients receiving biologics potentially putting them at risk of reinfection. However, they also had a robust response to immunization that is likely protective
The Spectre of SARS-CoV-2 in the Ambient Urban Natural Water in Ahmedabad and Guwahati: A Tale of Two Cities
Authors: Kumar Manish , Mazumder Payal , Deka Jyoti Prakash , Srivastava Vaibhav , Mahanta Chandan , Gupta Shilangi , Goswami Ritushmit , Joshi Madhvi , Ramanathan AL.
Published: June 2021

COVID-19 positive patients can egest live SARS-CoV-2 virus through faecal matter and urine, raising concerns about viral transmission through faecal-oral route and/or contaminated aerosolized water. These worries are heightened in many low and middle income nations, where raw sewage is often dumped into surface waterways and open defecation betide. In this manuscript we attempt to discern the presence of SARS-CoV-2 genetic material (ORF-1ab, N and S genes) in two urban cities of India viz., Ahmedabad, in western India with ∼12 WWTPs and Guwahati, in north-east of the country with no such plants. 25.8% and 20% of the surface water samples had detectable SARS-CoV-2 RNA load in Ahmedabad and Guwahati. N-gene>S-gene>ORF-1ab-gene were readily detected in surface water of Ahmedabad, whereas, no such significant trend was found in the case of Guwahati. The high concentration of gene (ORF-1ab – 800 copies/L for Sabarmati river, Ahmedabad and S-gene – 565 copies/L for Bharalu urban river, Guwahati) found in natural waters indicates low sanitation and have various health and ecological consequences that should be investigated further.

Graphical abstract

Highlights

Natural urban waters show the presence of SARS-CoV-2 RNA.

Lake water receiving runoff containing SARS-CoV-2 genes reflected positive sign early

Viral RNA in surface water reflects inadequate sanitation and wastewater management.

Residence time and transmission owing to viral RNA in natural waters needs further research.
High efficacy of therapeutic equine hyperimmune antibodies against SARS-CoV-2 variants of concern
Authors: Moreira-Soto Andres , Arguedas Mauricio , Brenes Hebleen , Buján Willem , Corrales-Aguilar Eugenia , Díaz Cecilia , Echeverri Ann , Flores-Díaz Marietta , Gómez Aarón , Hernández Andrés , Herrera María , León Guillermo , Macaya Román , Kühne Arne , Molina-Mora José Arturo , Mora Javier , Sanabria Alfredo , Sánchez Andrés , Sánchez Laura , Segura Álvaro , Segura Eduardo , Solano Daniela , Soto Claudio , Stynoski Jennifer L. , Vargas Mariángela , Villalta Mauren , Reusken Chantal B E M , Drosten Christian , Gutiérrez José María , Alape-Girón Alberto , Drexler Jan Felix
Published: June 2021

SARS-CoV-2 variants of concern (VoC) show reduced neutralization by vaccine-induced and therapeutic monoclonal antibodies. We tested therapeutic equine polyclonal antibodies (pAbs) against four VoC (alpha, beta, epsilon and gamma). We show that equine pAbs efficiently neutralize VoC, suggesting they are an effective, broad coverage, low-cost and a scalable COVID-19 treatment.
Plastic cell morphology changes during dispersal
Authors: Junker Anthony D. , Jacob Staffan , Philippe Hervé , Legrand Delphine , Pearson Chad G.
Published: June 2021

Dispersal is the movement of organisms from one habitat to another that potentially results in gene flow. It is often found to be plastic, allowing organisms to adjust dispersal movements depending on environmental conditions. A fundamental aim in ecology is to understand the determinants underlying dispersal and its plasticity. We utilized 22 strains of the ciliate Tetrahymena thermophila to determine if different phenotypic dispersal strategies co-exist within a species and which mechanisms underlie this variability. We quantified the cell morphologies impacting cell motility and dispersal. Distinct differences in innate cellular morphology and dispersal rates were detected, but no universally utilized combinations of morphological parameters correlate with dispersal. Rather, multiple distinct and plastic morphological changes impact cilia-dependent motility during dispersal, especially in proficient dispersing strains facing challenging environmental conditions. Combining ecology and cell biology experiments, we show that dispersal can be promoted through a panel of plastic motility-associated changes to cell morphology and motile cilia.

Graphical abstract

Highlights

Tetrahymena thermophila exhibits intra-specific diversity in morphology and dispersal.

Cell motility behavior during dispersal changes with cilia length and cell shape.

Cells from proficient dispersing strains transiently change basal body and cilia position.

Starvation-induced dispersal triggers increased basal body and cilia density and caudal cilium formation in rapid-swimming cells.
STRipy: a graphical application for enhanced genotyping of pathogenic short tandem repeats in sequencing data
Authors: Halman Andreas , Dolzhenko Egor , Oshlack Alicia
Published: June 2021

Short tandem repeats (STRs) are highly polymorphic with high mutation rates and expansions of STRs have been implicated as the causal variant in diseases. The application of genome sequencing in patients has recently allowed many new discoveries with over 50 disease causing loci known to date. There are several tools which allow genotyping of STRs from high-throughput sequencing (HTS) data. However, running these tools out of the box only allow around half of the known disease-causing loci to be genotyped, with lengths often limited to either read or fragment length which is less than the pathogenic cut-off for some diseases. While analysis tools can be customised to genotype extra loci, this requires proficiency in bioinformatics to set up, use, and analyse the resulting data, limiting their widespread usage by other researchers and clinicians.

To address these issues, we have created a new software called STRipy that has an intuitive graphical interface and requires no specific skills for usage, thus significantly simplifying detection of STRs expansions from human HTS data. STRipy is able to target all known disease-causing STRs with genotyping performed with an established tool, ExpansionHunter, that is incorporated into the software. We have created additional functionality into STRipy to work with long alleles exceeding the fragment length.

STRipy was validated using over 60 thousand simulated samples and was shown to work on whole genome sequencing of biological samples with pathogenic variants. Finally, we have used STRipy to acquire genotypes of pathogenic loci for thousands of samples from various populations which are provided to the user along with the data from the literature to assist with results interpretation. We believe the simplicity and breadth of STRipy will increase the testing of STR diseases in current datasets resulting in further diagnoses of rare diseases caused by STRs expansions.
The Genetic Architecture of Strawberry Yield and Fruit Quality Traits
Authors: Cockerton Helen M. , Karlström Amanda , Johnson Abigail W. , Li Bo , Stavridou Eleftheria , Hopson Katie J. , Whitehouse Adam B. , Harrison Richard J.
Published: June 2021

Over the last two centuries breeders have drastically modified the fruit quality of strawberries through artificial selection. However, there remains significant variation in quality across germplasm with scope for further improvements to be made. We report extensive phenotyping of fruit quality and yield traits in a multi-parental strawberry population to allow genomic prediction and QTL identification, thereby enabling the description of genetic architecture to inform the efficacy of implementing advanced breeding strategies.

A trade-off was observed between two essential traits: sugar content and class one yield. This result highlights an established dilemma for strawberry breeders and a need to uncouple the relationship, particularly under June-bearing, protected production systems comparable to this study. A large effect QTL was associated with perceived acidity and pH whereas multiple loci were associated with firmness, we therefore recommend the implementation of both MAS and genomic prediction to capture the observed variation respectively.

Ultimately, our results suggest that the best method to improve strawberry yield is through selecting parental lines based upon the number of marketable fruit produced per plant. Strawberry number metrics were less influenced by environmental fluctuations and had a larger additive genetic component when compared to mass traits. As such, selecting using “number” traits should lead to faster genetic gain. Finally, we identify a large effect locus associated with an increase in class one fruit.
Molecular dynamics analysis of fast-spreading severe acute respiratory syndrome coronavirus 2 variants and their effects in the interaction with human angiotensin-converting enzyme 2
Authors: de Souza Anacleto Silva , de Freitas Amorim Vitor Martins , Guardia Gabriela D A , dos Santos Felipe R C , dos Santos Filipe F , de Souza Robson Francisco , de Araujo Juvenal Guilherme , Huang Yihua , Ge Pingju , Jiang Yinan , Paudel Prajwal , Ulrich Henning , Galante Pedro A F , Guzzo Cristiane Rodrigues
Published: June 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is evolving with mutations in the Spike protein, especially in the receptor-binding domain (RBD). The failure of public health measures to contain the spread of the disease in many countries has given rise to novel viral variants with increased transmissibility. However, key questions about how quickly the variants can spread and whether they can cause a more severe disease remain unclear. Herein, we performed a structural investigation using molecular dynamics simulations and determined dissociation constant (KD) values using surface plasmon resonance (SPR) assays of three fastspreading SARS-CoV-2 variants, Alpha, Beta and Gamma ones, as well as genetic factors in the host cells that may be related to the viral infection. Our results suggest that the SARS-CoV-2 variants facilitate their entry into the host cell by moderately increased binding affinities to the human ACE2 receptor, different torsions in hACE2 mediated by RBD variants, and an increased Spike exposure time to proteolytic enzymes. We also found that other host cell aspects, such as gene and isoform expression of key genes for the infection (ACE2, FURIN and TMPRSS2), may have few contributions to the SARS-CoV-2 variants infectivity. In summary, we concluded that a combination of viral and host cell factors allows SARS-CoV-2 variants to increase their abilities to spread faster than wild-type.

Abstract Figure
Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
Authors:   RECOVERY Collaborative Group, Horby Peter W , Mafham Marion , Peto Leon , Campbell Mark , Pessoa-Amorim Guilherme , Spata Enti , Staplin Natalie , Emberson Jonathan R , Prudon Benjamin , Hine Paul , Brown Thomas , Green Christopher A , Sarkar Rahuldeb , Desai Purav , Yates Bryan , Bewick Tom , Tiberi Simon , Felton Tim , Baillie J Kenneth , Buch Maya H , Chappell Lucy C , Day Jeremy N , Faust Saul N , Jaki Thomas , Jeffery Katie , Juszczak Edmund , Lim Wei Shen , Montgomery Alan , Mumford Andrew , Rowan Kathryn , Thwaites Guy , Weinreich David M , Haynes Richard , Landray Martin J
Published: June 2021

Background

REGEN-COV is a combination of 2 monoclonal antibodies (casirivimab and imdevimab) that bind to two different sites on the receptor binding domain of the SARS-CoV-2 spike protein. We aimed to evaluate the efficacy and safety of REGEN-COV in patients admitted to hospital with COVID-19.

Methods

In this randomised, controlled, open-label platform trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus a single dose of REGEN-COV 8g (casirivimab 4g and imdevimab 4g) by intravenous infusion (REGEN-COV group). The primary outcome was 28-day mortality assessed first among patients without detectable antibodies to SARS-CoV-2 at randomisation (seronegative) and then in the overall population. The trial is registered with ISRCTN (50189673) andclinicaltrials.gov(NCT04381936).

Findings

Between 18 September 2020 and 22 May 2021, 9785 patients were randomly allocated to receive usual care plus REGEN-COV or usual care alone, including 3153 (32%) seronegative patients, 5272 (54%) seropositive patients and 1360 (14%) patients with unknown baseline antibody status. In the primary efficacy population of seronegative patients, 396 (24%) of 1633 patients allocated to REGEN-COV and 451 (30%) of 1520 patients allocated to usual care died within 28 days (rate ratio 0·80; 95% CI 0·70-0·91; p=0·0010). In an analysis involving all randomised patients (regardless of baseline antibody status), 944 (20%) of 4839 patients allocated to REGEN-COV and 1026 (21%) of 4946 patients allocated to usual care died within 28 days (rate ratio 0·94; 95% CI 0·86-1·03; p=0·17). The proportional effect of REGEN-COV on mortality differed significantly between seropositive and seronegative patients (p value for heterogeneity = 0·001).

Interpretation

In patients hospitalised with COVID-19, the monoclonal antibody combination of casirivimab and imdevimab (REGEN-COV) reduced 28-day mortality among patients who were seronegative at baseline.

Funding

UK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).
Serological prevalence of SARS-CoV-2 antibody among children and young age (between age 2-17 years) group in India: An interim result from a large multi-centric population-based seroepidemiological study
Authors: Misra Puneet , Kant Shashi , Guleria Randeep , Rai Sanjay K ,   WHO Unity Seroprevalence study team of AIIMS
Published: June 2021

Background

Concern has been raised in India regarding the probable third wave of COVID-19 where children and young age group is thought to get affected the most. There is a lack of serological prevalence data in this age group. We have some interim data from our research for WHO unity protocol, which might help policymakers and the research community to answer such questions based on evidence. Hence, we conducted a study to compare the COVID -19 sero-positivity rate between children and adults

Methods/Materials

This is part of an ongoing large multi-centric population-based sero-epidemiological study. The study is being conducted in five selected states with a proposed total sample size of 10,000. We have data of 4,500 participants at the time of midterm analysis from four states of India. Total serum antibody against SARS-CoV-2 virus was assessed qualitatively by using a standard ELISA kit. Here we are reporting the interim data of serological prevalence among children aged between 2 to 17 years along with a comparison with ≥18-year old participants.

Results

The data collection period was from 15th March 2021 to 10th June 2021. Total available data was of 4,509 participants out of which <18 years were 700 and ≥18 years was 3,809. The site-wise number of available data among the 2-17 year age group were 92, 189, 165, 146 and 108 for the site of Delhi urban resettlement colony, Delhi rural (Villages in Faridabad district under Delhi NCR), Bhubaneswar rural, Gorakhpur rural and Agartala rural area respectively. The seroprevalence was 55.7% in the <18 years age group and 63.5% in the ≥ 18 year age group. There was no statistically significant difference in prevalence between adult and children.

Conclusion

SARS-CoV-2 sero-positivity rate among children was high and were comparable to the adult population. Hence, it is unlikely that any future third wave by prevailing COVID-19 variant would disproportionately affect children two years or older.
Changes at V2 apex of HIV-1 Clade C trimer enhance elicitation of autologous neutralizing and broad V1V2-scaffold antibodies
Authors: Sahoo Anusmita , Hodge Edgar A. , LaBranche Celia , Styles Tiffany Turner , Shen Xiaoying , Cheedarla Narayanaiah , Shiferaw Ayalnesh , Ozorowski Gabriel , Lee Wen-Hsin , Ward Andrew B. , Tomaras Georgia D. , Montefiori David C. , Irvine Darrell J. , Lee Kelly K. , Amara Rama Rao
Published: June 2021

HIV-1 clade C envelope immunogens that elicit both neutralizing and non-neutralizing V1V2-scaffold specific antibodies (protective correlates from RV144 human trial) are urgently needed due to the prevalence of this clade in the most impacted regions worldwide. To achieve this, we introduced structure-guided changes followed by consensus-C sequence-guided optimizations at the V2-region to generate UFO-v2-RQH173 trimer. This improved the abundance of native-like trimers and carried an intrinsic dynamic V2-loop. Following immunization of rabbits, the wild-type protein failed to elicit any autologous neutralizing antibodies but UFO-v2-RQH173 elicited both autologous neutralizing and broad V1V2-scaffold antibodies. The variant with 173Y modification in V2-region, most prevalent among HIV-1 sequences, showed decreased ability in displaying native-like V1V2 epitope with time in-vitro and elicited antibodies with lower neutralizing and higher V1V2-scaffold activities. Our results identify a clade C C.1086-UFO-v2-RQH173 trimer capable of eliciting improved neutralizing and V1V2-scaffold antibodies, and reveal the importance of V2-region in tuning this.
Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain
Authors: Dedek Annemarie , Xu Jian , Lorenzo Louis-Étienne , Godin Antoine G. , Kandegedara Chaya M. , Glavina Geneviève , Landrigan Jeffrey A. , Lombroso Paul J. , De Koninck Yves , Tsai Eve C. , Hildebrand Michael E.
Published: June 2021

The prevalence and severity of many chronic pain syndromes differ across sex, and recent studies have identified differences in immune signalling within spinal nociceptive circuits as a potential mediator. Although it has been proposed that sex-specific pain mechanisms converge once they reach neurons within the superficial dorsal horn (SDH), direct investigations using rodent and human preclinical pain models have been lacking. Here, we discovered that in the Freund’s Adjuvantin vivomodel of inflammatory pain, where both male and female rats display tactile allodynia, a pathological coupling between KCC2-dependent disinhibition and NMDA receptor potentiation within SDH neurons was observed in male but not female rats. Unlike males, the neuroimmune mediator, BDNF, failed to downregulate inhibitory signalling elements (KCC2 and STEP61) and upregulate excitatory elements (pFyn, GluN2B, and pGluN2B) in female rats, resulting in no effect ofex vivoBDNF on synaptic NMDA receptor responses in female lamina I neurons. Importantly, this sex difference in spinal pain processing was conserved from rodents to humans. As in rodents,ex vivospinal treatment with BDNF downregulated markers of disinhibition and upregulated markers of facilitated excitation in SDH neurons from male but not female human organ donors. Ovariectomy in female rats recapitulated the male pathological pain neuronal phenotype, with BDNF driving a coupling between disinhibition and NMDA receptor potentiation in adult lamina I neurons following the prepubescent elimination of sex hormones in females. This discovery of sexual dimorphism in a central neuronal mechanism of chronic pain across species provides a foundational step towards a better understanding and treatment for pain in both sexes.
Mineral crystal thickness in calcified cartilage and subchondral bone in healthy and osteoarthritic knees
Authors: Finnilä Mikko A.J. , Das Gupta Shuvashis , Turunen Mikael J. , Kestilä Iida , Turkiewicz Aleksandra , Lutz-Bueno Viviane , Folkesson Elin , Holler Mirko , Ali Neserin , Hughes Velocity , Isaksson Hanna , Tjörnstrand Jon , Önnerfjord Patrik , Guizar-Sicairos Manuel , Saarakkala Simo , Englund Martin
Published: June 2021

Osteoarthritis (OA) is the most common joint disease globally. In OA, articular cartilage degradation is often accompanied with sclerosis of the subchondral bone. However, the association between OA and tissue mineralization at the nanostructural level is currently not understood. Especially, it is technically challenging to identify calcified cartilage, where relevant but poorly understood pathological processes like tidemark multiplication and advancement occur. Here, we used state-of-the-art micro-focus small-angle X-ray scattering with high 5µm spatial resolution to determine mineral crystal thickness in human subchondral bone and calcified cartilage. Specimens with a wide spectrum of OA severities were acquired from the medial and lateral compartments of medial compartment knee OA patients (n=15) and cadaver knees (n=10). For the first time, we identified a well-defined layer of calcified cartilage associated with pathological tidemark multiplication, containing 0.32nm thicker crystals compared to the rest of calcified cartilage. In addition, we found 0.2nm thicker mineral crystals in both tissues of the lateral compartment in OA compared with healthy knees, indicating a loading-related disease process since the lateral compartment is typically less loaded in medial compartment knee OA. Furthermore, the crystal thickness of the subchondral bone was lower with increasing histopathological OA severity. In summary, we report novel changes in mineral crystal thickness during OA. Our data suggest that unloading in the knee is associated with the growth of mineral crystals, which is especially evident in the calcified cartilage. In the subchondral bone, mineral crystals become thinner with increasing OA severity, which indicates new bone formation with sclerosis.

One Sentence Summary

Mineral crystal thickness increases with osteoarthritis in the lateral condyle that is typically unloaded.
Honey bees cannot sense harmful concentrations of metal pollutants in food
Authors: Monchanin Coline , de Brito Sanchez Maria Gabriela , Lecouvreur Loreleï , Boidard Océane , Méry Grégoire , Silvestre Jérôme , Roux Gaël Le , Baqué David , Elger Arnaud , Barron Andrew B. , Lihoreau Mathieu , Devaud Jean-Marc
Published: June 2021

Whether animals can actively avoid food contaminated with harmful compounds through taste is key to understand their ecotoxicological risks. Here, we investigated the ability of honey bees to perceive and avoid food resources contaminated with common metal pollutants known to impair their cognition at low concentrations (lead, zinc and arsenic). In behavioural assays, bees did not discriminate food contaminated with field-realistic concentrations of these metals. Bees only reduced their food consumption and displayed aversive behaviours at very high, unrealistic concentrations of lead and zinc that they perceived through their antennae and proboscis. Electrophysiological analyses confirmed that high concentrations of the three metals in sucrose solution induced a reduced neural response to sucrose in their antennae. Our results thus show that honey bees can avoid metal pollutants in their food, but only at very high concentrations above regulatory levels. Their inability to detect lower, yet harmful, concentrations in a field-realistic range suggests that metal pollution is a major threat for pollinators.
Phosphatidylserine Receptors Enhance SARS-CoV-2 Infection: AXL as a Therapeutic Target for COVID-19
Authors: Bohan Dana , Van Ert Hanora , Ruggio Natalie , Rogers Kai J. , Badreddine Mohammad , Aguilar Briseño José A. , Chavez Roberth Anthony Rojas , Gao Boning , Stokowy Tomasz , Christakou Eleni , Micklem David , Gausdal Gro , Haim Hillel , Minna John , Lorens James B. , Maury Wendy
Published: June 2021

AUTHOR SUMMARY

Phosphatidylserine (PS) receptors are PS binding proteins that mediate uptake of apoptotic bodies. Many enveloped viruses utilize this PS/PS receptor mechanism to adhere to and internalize into the endosomal compartment of cells and this is termed apoptotic mimicry. For viruses that have a mechanism(s) of endosomal escape, apoptotic mimicry is a productive route of virus entry. We evaluated if PS receptors serve as cell surface receptors for SARS-CoV-2 and found that the PS receptors, AXL, TIM-1 and TIM-4, facilitated virus infection when low concentrations of the SARS-CoV-2 cognate receptor, ACE2, was present. Consistent with the established mechanism of PS receptor utilization by other viruses, PS liposomes competed with SARS-CoV-2 for binding and entry. We demonstrated that this PS receptor enhances SARS-CoV-2 binding to and infection of an array of human lung cell lines and is an under-appreciated but potentially important host factor facilitating SARS-CoV-2 entry.
Derlin rhomboid pseudoproteases employ substrate engagement and lipid distortion function for retrotranslocation of ER multi-spanning membrane substrates
Authors: Nejatfard Anahita , Wauer Nicholas , Bhaduri Satarupa , Conn Adam , Gourkanti Saroj , Singh Narinderbir , Kuo Tiffany , Kandel Rachel , Amaro Rommie E. , Neal Sonya E.
Published: June 2021

Nearly one-third of proteins are initially targeted to the endoplasmic reticulum (ER) membrane where they are correctly folded, assembled, and then delivered to their final cellular destinations. In order to prevent the accumulation of misfolded membrane proteins, ER associated degradation (ERAD) moves these clients from the ER membrane to the cytosol; a process known as retrotranslocation. Our recent work in S. cerevisiae has revealed a derlin rhomboid pseudoprotease, Dfm1, is involved in the retrotranslocation of ubiquitinated ERAD membrane substrates. In this study, we sought to understand the mechanism associated with Dfm1’s actions and found that Dfm1’s conserved rhomboid residues are critical for membrane protein retrotranslocation. Specifically, we identified several retrotranslocation-deficient Loop 1 mutants that display impaired binding to membrane substrates. Furthermore, Dfm1 has retained the lipid thinning functions of its rhomboid protease predecessors to facilitate in the removal of ER membrane substrates. We find this substrate engagement and lipid thinning feature is conserved in its human homolog, Derlin-1. Utilizing interaction studies and molecular dynamics simulations, this work reveals that derlin rhomboid pseudoproteases employ novel mechanisms of substrate engagement and lipid thinning for catalyzing extraction of multi-spanning membrane substrates.
Accurate and fast cell marker gene identification with COSG
Authors: Dai Min , Pei Xiaobing , Wang Xiu-Jie
Published: June 2021

Accurate cell classification is the groundwork for downstream analysis of single-cell sequencing data, yet how to identify marker genes to distinguish different cell types still remains as a big challenge. We developed COSG as a cosine similarity-based method for more accurate and scalable marker gene identification. COSG is applicable to single-cell RNA sequencing data, single-cell ATAC sequencing data and spatially resolved transcriptome data. COSG is fast and scalable for ultra-large datasets of million-scale cells. Application on both simulated and real experimental datasets demonstrates the superior performance of COSG in terms of both accuracy and efficiency as compared with other available methods. Marker genes or genomic regions identified by COSG are more indicative and with greater cell-type specificity.
Tracking SARS-CoV-2 Spike Protein Mutations in the United States (2020/01 – 2021/03) Using a Statistical Learning Strategy
Authors: Zhao Lue Ping , Lybrand Terry P. , Gilbert Peter B. , Hawn Thomas R. , Schiffer Joshua T. , Stamatatos Leonidas , Payne Thomas H. , Carpp Lindsay N. , Geraghty Daniel E. , Jerome Keith R.
Published: June 2021

The emergence and establishment of SARS-CoV-2 variants of interest (VOI) and variants of concern (VOC) highlight the importance of genomic surveillance. We propose a statistical learning strategy (SLS) for identifying and spatiotemporally tracking potentially relevant Spike protein mutations. We analyzed 167,893 Spike protein sequences from US COVID-19 cases (excluding 21,391 sequences from VOI/VOC strains) deposited at GISAID from January 19, 2020 to March 15, 2021. Alignment against the reference Spike protein sequence led to the identification of viral residue variants (VRVs), i.e., residues harboring a substitution compared to the reference strain. Next, generalized additive models were applied to model VRV temporal dynamics, to identify VRVs with significant and substantial dynamics (false discovery rate q-value <0.01; maximum VRV proportion > 10% on at least one day).

Unsupervised learning was then applied to hierarchically organize VRVs by spatiotemporal patterns and identify VRV-haplotypes. Finally, homology modelling was performed to gain insight into potential impact of VRVs on Spike protein structure. We identified 90 VRVs, 71 of which have not previously been observed in a VOI/VOC, and 35 of which have emerged recently and are durably present. Our analysis identifies 17 VRVs ∼91 days earlier than their first corresponding VOI/VOC publication. Unsupervised learning revealed eight VRV-haplotypes of 4 VRVs or more, suggesting two emerging strains (B1.1.222 and B.1.234). Structural modeling supported potential functional impact of the D1118H and L452R mutations. The SLS approach equally monitors all Spike residues over time, independently of existing phylogenic classifications, and is complementary to existing genomic surveillance methods.
APRIL drives a co-ordinated but diverse response as a foundation for plasma cell longevity
Authors: Stephenson Sophie , Care Matthew A , Doody Gina M , Tooze Reuben M
Published: June 2021

Antibody secreting cells (ASCs) survive in niche microenvironments, but cellular responses driven by particular niche signals are incompletely defined. The TNF superfamily member APRIL provides a niche signal that can support the transition of transitory plasmablasts into long-lived plasma cells. Here we explore how APRIL helps to establish the biological programs that promote life in the niche, by studying the initial response of primary human plasmablast to APRIL. Under conditions allowing the maturation of ex vivo or in vitro generated plasmablasts, we find that APRIL drives activation of ERK, p38 and JNK. This is accompanied by a classical NFκB response. Under these conditions induction of AKT phosphorylation is also observed with similar kinetics, paralleled by FOXO1 phosphorylation and nuclear exclusion. Time course gene expression data resolve the downstream co-ordinated transcriptional response. The APRIL-signal propagates via immediate early genes and classical NFκB responsive targets to converge onto modules of MYC- and OCT2-regulated gene expression linked to cell growth, as well as leading to enhanced expression of ICAM1 and SQSTM1 associated with adhesion and metabolic/stress responses. Thus, APRIL drives a combination of multiple transcriptional programs that co-ordinate cell growth, stress response and adhesion in human ASCs, providing a broad foundation to support plasma cell longevity.