bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimates of the rate of infection and asymptomatic COVID-19 disease in a population sample from SE England
Authors: Wells Philippa M. , Doores Katie J. , Couvreur Simon , Nunez Rocio Martinez , Seow Jeffrey , Graham Carl , Acors Sam , Kouphou Neophytos , Neil Stuart J.D. , Tedder Richard S. , Matos Pedro M. , Poulton Kate , Lista Maria Jose , Dickenson Ruth E. , Sertkaya Helin , Maguire Thomas J.A. , Scourfield Edward J. , Bowyer Ruth C. E. , Hart Deborah , O’Bryne Aoife , Steel Kathyrn J.A. , Hemmings Oliver , Rosadas Carolina , McClure Myra O. , Capedevilla-pujol Joan , Wolf Jonathan , Ourselin Sebastien , Brown Matthew A. , Malim Michael H. , Spector Tim , Steves Claire J. 
Published: July 2020

AbstractBackgroundUnderstanding of the true asymptomatic rate of infection of SARS-CoV-2 is currently limited, as is understanding of the population-based seroprevalence after the first wave of COVID-19 within the UK. The majority of data thus far come from hospitalised patients, with little focus on general population cases, or their symptoms.MethodsWe undertook enzyme linked immunosorbent assay characterisation of IgM and IgG responses against SARS-CoV-2 spike glycoprotein and nucleocapsid protein of 431 unselected general-population participants of the TwinsUK cohort from South-East England, aged 19-86 (median age 48; 85% female). 382 participants completed prospective logging of 14 COVID-19 related symptoms via the COVID Symptom Study App, allowing consideration of serology alongside individual symptoms, and a predictive algorithm for estimated COVID-19 previously modelled on PCR positive individuals from a dataset of over 2 million.FindingsWe demonstrated a seroprevalence of 12% (51participants of 431). Of 48 seropositive individuals with full symptom data, nine (19%) were fully asymptomatic, and 16 (27%) were asymptomatic for core COVID-19 symptoms: fever, cough or anosmia. Specificity of anosmia for seropositivity was 95%, compared to 88% for fever cough and anosmia combined. 34 individuals in the cohort were predicted to be Covid-19 positive using the App algorithm, and of those, 18 (52%) were seropositive.InterpretationSeroprevalence amongst adults from London and South-East England was 12%, and 19% of seropositive individuals with prospective symptom logging were fully asymptomatic throughout the study. Anosmia demonstrated the highest symptom specificity for SARS-CoV-2 antibody response.FundingNIHR BRC, CDRF, ZOE global LTD, RST-UKRI/MRC
Back to school: use of Dried Blood Spot for the detection of SARS-CoV-2-specific immunoglobulin G (IgG) among schoolchildren in Milan, Italy
Authors: Amendola Antonella , Bianchi Silvia , Gori Maria , Barcellini Lucia , Colzani Daniela , Canuti Marta , Giacomet Vania , Fabiano Valentina , Folgori Laura , Zuccotti Gian Vincenzo , Tanzi Elisabetta 
Published: July 2020

AbstractSerological surveillance is necessary to the reestablishment of school activities in safe conditions and to avoid school-related outbreaks. In this study, DBS (Dried Blood Spots) have proven to be a simple, rapid and reliable sample collection tool for detecting antibodies against SARS-CoV-2 by ELISA test compared to matched serum samples from venous sampling (R2=0.9553; Pearson’s coefficient=0.98; Cohen’s unweighted k=0.93; overall agreement=96.2%). This approach may facilitate sample collection from schoolchildren for serological surveys useful to an adequate risk-assessment.
Analysis: The potential health and economic impact of dexamethasone treatment for patients with COVID-19
Authors: Águas Ricardo , Mahdi Adam , Shretta Rima , Horby Peter , Landray Martin , White Lisa ,   the CoMo Consortium
Published: July 2020

AbstractDexamethasone has been shown to reduce mortality in hospitalised COVID-19 patients needing oxygen and ventilation by 18% and 36%, respectively. Here, we estimate the potential number of lives saved and life years gained if this treatment would be rolled out in the UK and globally, as well as its cost-effectiveness of implementing this intervention. We estimate that, for the UK, approximately 12,000 [4,250 - 27,000] lives could be saved by January 2021. Assuming that dexamethasone has a similar effect size in settings where access to oxygen therapies is limited, this would translate into approximately 650,000 [240,000 - 1,400,000] lives saved globally. If dexamethasone acts differently in these settings, the impact could be less than half of this value. To estimate the full potential of dexamethasone in the global fight against COVID-19, it is essential to perform clinical research in settings with limited access to oxygen and/or ventilators, e.g. in low and middle-income countries.
Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection
Authors: Townsend Liam , Dyer Adam H. , Jones Karen , Dunne Jean , Kiersey Rachel , Gaffney Fiona , O’Connor Laura , Mooney Aoife , Leavy Deirdre , Ridge Katie , King Catherine , Cox Fionnuala , O’Brien Kate , Dowds Joanne , Sugrue Jamie A , Hopkins David , Byrne Patricia , Kingston Tara , Cheallaigh Cliona Ni , Nadarajan Parthiban , McLaughlin Anne Marie , Bourke Nollaig M , Bergin Colm , O’Farrelly Cliona , Bannan Ciaran , Conlon Niall 
Published: July 2020

AbstractFatigue is a common symptom in those presenting with symptomatic COVID-19 infection. However, it is unknown if COVID-19 results in persistent fatigue in those recovered from acute infection. We examined the prevalence of fatigue in individuals recovered from the acute phase of COVID-19 illness using the Chalder Fatigue Score (CFQ-11). We further examined potential predictors of fatigue following COVID-19 infection, evaluating indicators of COVID-19 severity, markers of peripheral immune activation and circulating pro-inflammatory cytokines. Of 128 participants (49.5 ± 15 years; 54% female), more than half reported persistent fatigue (52.3%; 45/128) at 10 weeks (median) after initial COVID-19 symptoms. There was no association between COVID-19 severity (need for inpatient admission, supplemental oxygen or critical care) and fatigue following COVID-19. Additionally, there was no association between routine laboratory markers of inflammation and cell turnover (leukocyte, neutrophil or lymphocyte counts, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, C-reactive protein) or pro-inflammatory molecules (IL-6 or sCD25) and fatigue post COVID-19. Female gender and those with a pre-existing diagnosis of depression/anxiety were over-represented in those with fatigue. Our findings demonstrate a significant burden of post-viral fatigue in individuals with previous SARS-CoV-2 infection after the acute phase of COVID-19 illness. This study highlights the importance of assessing those recovering from COVID-19 for symptoms of severe fatigue, irrespective of severity of initial illness, and may identify a group worthy of further study and early intervention.
A test of the Baldwin Effect: Differences in both constitutive expression and inducible responses to parasites underlie variation in host response to a parasite
Authors: Fuess Lauren , Weber Jesse N. , den Haan Stijn , Steinel Natalie C. , Shim Kum Chuan , Bolnick Daniel I. 
Published: July 2020

ABSTRACTDespite the significant effect of host-parasite interactions on both ecological systems and organism health, there is still limited understanding of the mechanisms driving evolution of host resistance to parasites. One model of rapid evolution, the Baldwin Effect, describes the role of plasticity in adaptation to novel conditions, and subsequent canalization of associated traits. While mostly applied in the context of environmental conditions, this theory may be relevant to the evolution of host resistance to novel parasites. Here we test the applicability of the Baldwin Effect to the evolution of resistance in a natural system using threespine stickleback fish (Gasterosteus aculeatus) and their cestode parasiteSchistochephalus solidus. We leverage a large transcriptomic data set to describe the response toS. solidusinfection by three different genetic crosses of stickleback, from a resistant and a tolerant population. Hosts mount a multigenic response to the parasite that is similar among host genotypes. In addition, we document extensive constitutive variation in gene expression among host genotypes. However, although many genes are both infection-induced and differentially expressed between genotypes, this overlap is not more extensive than expected by chance. We also see little evidence of canalization of infection-induced gene expression in the derived resistant population. These patterns do not support the Baldwin Effect, though they illustrate the importance of variation in both constitutive expression and induced responses to parasites. Finally, our results improve understanding of the cellular mechanisms underlying a putative resistance phenotype (fibrosis). Combined, our results highlight the importance of both constitutive and inducible variation in the evolution of resistance to parasites, and identify new target genes contributing to fibrosis. These findings advance understanding of host-parasite interactions and co-evolutionary relationships in natural systems.
FasterCryptococcusmelanization increases virulence in experimental and human cryptococcosis
Authors: de Sousa Herdson Renney , de Oliveira Getúlio Pereira , de Oliveira Frazão Stefânia , de Melo Gorgonha Kaio Cesar , Rosa Camila Pereira , Melgaço Garcez Emãnuella , Lucas Joaquim , Correia Amabel Fernandes , de Freitas Waleriano Ferreira , Borges Higor Matos , Paes Hugo Costa , Trilles Luciana , Lazera Marcia dos Santos , Pinto Vitor Laerte , Felipe Maria Sueli Soares , Casadevall Arturo , Silva-Pereira Ildinete , Albuquerque Patrícia , Nicola André Moraes 
Published: July 2020

AbstractCryptococcusspp. are important human pathogens responsible for about 180,000 deaths per year. Studying their virulence attributes can lead to better cryptococcosis prevention and treatment. In this work, we systematically investigated virulence attributes ofCryptococcusspp. clinical isolates and correlated them with patient data. We collected 66C. neoformansand 19C. gattiiisolates from Brazilian patients and analyzed multiple phenotypes related with their capsule, production of laccase, melanin and extracellular vesicles. We also tested their virulence inGalleria mellonellaand ability to evade macrophage LC3-associated phagocytosis (LAP). All phenotypes analyzed varied widely among the isolates, butC. neoformansisolates tended to melanize faster and more intensely and produce thinner capsules in comparison withC. gattii. We also observed correlations that match previous studies, such as that between secreted laccase – but not total melanin production – and disease outcome in patients. The most striking results, though, came from our measurements ofCryptococcuscolony melanization kinetics, which followed a sigmoidal curve for most isolates. Faster melanization correlated positively with LAP evasion, virulence inG. mellonellaand worse prognosis in humans. These results suggest that the speed of melanization, more than the total amount of melaninCryptococcusspp. produces, is crucial for virulence.Graphical abstract
Biallelic mutation ofCLRN2causes non-syndromic hearing loss in humans
Authors: Vona Barbara , Mazaheri Neda , Lin Sheng-Jia , Dunbar Lucy A , Maroofian Reza , Azaiez Hela , Booth Kevin T. , Vitry Sandrine , Rad Aboulfazl , Varshney Pratishtha , Fowler Ben , Beetz Christian , Alagramam Kumar N. , Murphy David , Shariati Gholamreza , Sedaghat Alireza , Houlden Henry , VijayKumar Shruthi , Smith Richard J. H. , Haaf Thomas , El-Amraoui Aziz , Bowl Michael R. , Varshney Gaurav K. , Galehdari Hamid 
Published: July 2020

AbstractDeafness, the most frequent sensory deficit in humans, is extremely heterogenous with hundreds of genes probably involved. Clinical and genetic analyses of an extended consanguineous family with pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identifyCLRN2, encoding a tetraspan protein as a new deafness gene. Homozygosity mapping followed by exome sequencing identified a 15.2 Mb locus on chromosome 4p15.32p15.1 containing a missense pathogenic variant inCLRN2(c.494C>A, NM_001079827.2) segregating with the disease. Usingin vitroRNA splicing analysis, we show that theCLRN2c.494C>A mutation leads to two events: 1) the substitution of a highly conserved threonine (uncharged amino acid) to lysine (charged amino acid) at position 165, p.(Thr165Lys), and 2) aberrant splicing, with the retention of intron 2 resulting in a stop codon after 26 additional amino acids, p.(Gly146Lysfs*26). Expression studies and phenotyping of newly produced zebrafish and mouse models deficient for clarin 2 further confirm that clarin 2, expressed in the inner ear hair cells, is essential for normal organization and maintenance of the auditory hair bundles, and for hearing function. Together, our findings identifyCLRN2as a new deafness gene, which will impact future diagnosis and treatment for deaf patients.
Preferential activation of the posterior Default-Mode Network with sequentially predictable task switches
Authors: Araña-Oiarbide Garazi , Daws Richard E. , Lorenz Romy , Violante Ines R. , Hampshire Adam 
Published: July 2020

AbstractThe default-mode network (DMN) has been primarily associated with internally-directed and self-relevant cognition. This perspective is expanding to recognise its importance in executive behaviours like switching. We investigated the effect different task-switching manipulations have on DMN activation in two studies with novel fMRI paradigms. In the first study, the paradigm manipulated visual discriminability, visuo-perceptual distance and sequential predictability during switching. Increased posterior cingulate/precuneus (PCC/PrCC) activity was evident during switching; critically, this was strongest when the occurrence of the switch was predictable. In the second study, we sought to replicate and further investigate this switch-related effect with a fully factorial design manipulating sequential, spatial and visual-feature predictability. Whole-brain analysis again identified a PCC/PrCC-centred cluster that was more active for sequentially predictable versus unpredictable switches, but not for the other predictability dimensions. We propose PCC/PrCC DMN subregions may play a prominent executive role in mapping the sequential structure of complex tasks.
APOBEC2 is a Transcriptional Repressor required for proper Myoblast Differentiation
Authors: Lorenzo Jose Paulo , Molla Linda , Ibarra Ignacio L. , Ruf Sandra , Ridani Jana , Subramani Poorani Ganesh , Boulais Jonathan , Harjanto Dewi , Vonica Alin , Di Noia Javier M. , Dieterich Christoph , Zaugg Judith B. , Papavasiliou F. Nina 
Published: July 2020

ABSTRACTThe activation induced cytidine deaminase/apolipoprotein B editing complex (AID/APOBEC) family comprises several nucleic acid editors with roles ranging from antibody diversification to mRNA editing. APOBEC2, an evolutionarily conserved member of this family, has neither an established substrate nor a mechanism of action, however genetic evidence suggests functional relevance in tissues such as muscle. Here, we demonstrate that in muscle, APOBEC2 does not have any of the attributed molecular functions of the AID/APOBEC family, such as RNA editing, DNA demethylation, or DNA mutation. Instead, we show that APOBEC2 occupies chromatin at promoter regions of certain genes, whose expression is repressed during muscle cell differentiation. We further demonstrate that APOBEC2 on one hand binds promoter region DNA directly and in a sequence specific fashion, while on the other it interacts with HDAC transcriptional corepressor complexes. Therefore, APOBEC2, by actively repressing the expression of non-myogenesis pathway genes, plays a key role in enforcing the proper establishment of muscle cell fate.
Unfolding of the chromatin fiber driven by overexpression of bridging factors
Authors: Malhotra Isha , Oyarzún Bernardo , Mognetti Bortolo Matteo 
Published: July 2020

AbstractNuclear molecules control the functional properties of the chromatin fiber by shaping its morphological properties. The biophysical mechanisms controlling how bridging molecules compactify the chromatin are a matter of debate. On the one side, bridging molecules could cross-link faraway sites and fold the fiber through the formation of loops. Interacting bridging molecules could also mediate long-range attractions by first tagging different locations of the fiber and then undergoing microphase separation. Using a coarse-grained model and Monte Carlo simulations, we study the conditions leading to compact configurations both for interacting and non-interacting bridging molecules. In the second case, we report on an unfolding transition at high densities of the bridging molecules. We clarify how this transition, which disappears for interacting bridging molecules, is universal and controlled by entropic terms. In general, chains are more compact in the case of interacting bridging molecules since, in this case, interactions are not valence-limited. However, this result is conditional on the ability of our simulation methodology to relax the system towards its ground state. In particular, we clarify how, unless using reaction dynamics that change the length of a loop in a single step, the system is prone to remain trapped in metastable, compact configurations featuring long loops.
A polycomb-independent role of EZH2 in TGFβ1-damaged epithelium triggers a fibrotic cascade with mesenchymal cells
Authors: Le Huy Quang , Hill Matthew Alexander , Kollak Ines , Skronska-Wasek Wioletta , Schroeder Victoria , Wirth Johannes , Schruf Eva , Quast Karsten , Herrmann Franziska Elena , Thomas Matthew James , Garnett James Peter 
Published: July 2020

AbstractTo restore organ homeostasis, a myriad of cell types need to activate rapid and transient programs to adjust cell fate decisions and elicit a collective behaviour. Characterisation of such programs are imperative to elucidate an organ’s regenerative capacity and its aberrant repair in disease. By modelling epithelial-mesenchymal crosstalk, we provide direct evidence for transforming growth factor β1 (TGFβ1)-damaged epithelium initiating a bi-directional fibrotic cascade with the mesenchyme. Strikingly, TGFβ1-damaged epithelia facilitates the release of Enhancer of Zester Homolog 2 (EZH2) from Polycomb Repressive Complex 2 (PRC2) to establish a novel fibrotic transcriptional complex of EZH2, RNA-polymerase II (POL2) and nuclear actin. Perturbing this complex by disrupting epithelial EZH2 or actomyosin remodelling abrogates the fibrotic crosstalk. The liberation of EZH2 from PRC2 is accompanied by an EZH2-EZH1 switch to preserve global H3K27me3 occupancy. Our results reveal an important non-canonical function of EZH2, paving the way for therapeutic interventions in fibrotic disease.
PLEKHA4 Promotes Wnt/β-catenin Signaling-Mediated G1/S Transition and Proliferation in Melanoma
Authors: Shah Adnan Shami , Cao Xiaofu , White Andrew C. , Baskin Jeremy M. 
Published: July 2020

ABSTRACTMelanoma patients incur substantial mortality, despite promising recent advances in targeted therapies and immunotherapies. In particular, inhibitors targeting BRAF-mutant melanoma can lead to resistance, and no targeted therapies exist for NRAS-mutant melanoma, motivating the search for additional therapeutic targets and vulnerable pathways. Here, we identify a regulator of Wnt/β-catenin signaling, PLEKHA4, as a factor required for melanoma proliferation and survival. PLEKHA4 knockdown in vitro leads to lower Dishevelled levels, attenuated Wnt/β-catenin signaling, and a block of progression through the G1/S cell cycle transition. In mouse xenograft models, inducible PLEKHA4 knockdown attenuated tumor growth in BRAF- and NRAS-mutant melanomas and synergized with the clinically used inhibitor encorafenib in a BRAF-mutant model. As an E3 ubiquitin ligase regulator with both lipid and protein binding partners, PLEKHA4 presents several opportunities for targeting with small molecules. Our work identifies PLEKHA4 as a promising drug target for melanoma and clarifies a controversial role for Wnt/β-catenin signaling in the control of melanoma proliferation.
Vascular calcification has a role in acute non-renal phosphate clearance
Authors: Turner Mandy E , Lansing Austin P , Jeronimo Paul S , Lee Lok Hang , Svajger Bruno A , Zelt Jason GE , Forster Corey M , Petkovich Martin P , Holden Rachel M , Adams Michael A 
Published: July 2020

AbstractRationaleNon-renal extravasation of phosphate from the circulation and transient accumulation into tissues and extracellular fluid is a regulated process of acute phosphate homeostasis that is not well understood. Following oral consumption of phosphate, circulating levels normalize long before urinary excretion has been completed. This process is especially relevant in the setting of chronic kidney disease (CKD), where phosphate exposure is prolonged due to inefficient kidney excretion. Furthermore, CKD-associated dysregulation of mineral metabolism exacerbates pathological accumulation of phosphate causing vascular calcification (VC).ObjectiveDetermine whether the systemic response to acute phosphate challenges is altered by the development and progression of VC.Methods/ResultsAcute circulating and tissue deposition of an acute phosphate challenge was assessed in two rat models of VC using radio-labelled phosphate tracer. In an adenine-induced model of CKD with VC, animals with VC had a blunted elevation of circulating33PO4following oral phosphate administration and the discordant deposition could be traced to the calcifying vasculature. In a non-CKD model of VC, VC was induced with 0.5ug/kg calcitriol and then withdrawn. The radio-labelled phosphate challenge was given to assess for vascular preference for phosphate uptake with and without the presence of an active calcification stimulus. The new transport to the calcifying vasculature correlates to the pre-existing burden of calcification, and can be substantially attenuated by removing the stimulus for calcification. The accrual is stimulated by a phosphate challenge, and not present in the same degree during passive disposition of circulating phosphate.ConclusionsOur data indicate that calcifying arteries alter the systemic disposition of a phosphate challenge and acutely deposit substantial phosphate. This study supports the importance of diet as it relates to acute fluctuations of circulating phosphate and the importance of bioavailability and meal-to-meal management in CKD patients as a mediator of cardiovascular risk.
Time-resolved proteomic profiling of the ciliary Hedgehog response reveals that GPR161 and PKA undergo regulated co-exit from cilia
Authors: May Elena A. , Kalocsay Marian , D’Auriac Inès Galtier , Gygi Steven P. , Nachury Maxence V. , Mick David U. 
Published: July 2020

ABSTRACTThe primary cilium is a signaling compartment that interprets Hedgehog signals through changes of its protein, lipid and second messenger compositions. Here, we combine proximity labeling of cilia with quantitative mass spectrometry to unbiasedly profile the time-dependent alterations of the ciliary proteome in response to Hedgehog. This approach correctly identifies the three factors known to undergo Hedgehog-regulated ciliary redistribution and reveals two such additional proteins. First, we find that a regulatory subunit of the cAMP-dependent protein kinase (PKA) rapidly exits cilia together with the G protein-coupled receptor GPR161 in response to Hedgehog; and we propose that the GPR161/PKA module senses and amplifies cAMP signals to modulate ciliary PKA activity. Second, we identify the putative phosphatase Paladin as a cell type-specific regulator of Hedgehog signaling that enters primary cilia upon pathway activation. The broad applicability of quantitative ciliary proteome profiling promises a rapid characterization of ciliopathies and their underlying signaling malfunctions.