bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractCurative 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

AbstractBackgroundCharacterization 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.MethodsWe 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.Results436 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 RelevanceThe 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.SummaryOur 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

AbstractCOVID-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 abstractHighlightsNatural urban waters show the presence of SARS-CoV-2 RNA.Lake water receiving runoff containing SARS-CoV-2 genes reflected positive sign earlyViral 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

AbstractSARS-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

SummaryDispersal 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 abstractHighlightsTetrahymena 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

AbstractShort 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

AbstractOver 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

AbstractSevere 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

SUMMARYBackgroundREGEN-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.MethodsIn 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).FindingsBetween 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).InterpretationIn 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.FundingUK 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

AbstractBackgroundConcern 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 adultsMethods/MaterialsThis 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.ResultsThe 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.ConclusionSARS-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

SummaryHIV-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

AbstractThe 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.