bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using real-time data to guide decision-making during an influenza pandemic: a modelling analysis
Authors: Haw David J. , Biggerstaff Matthew , Prasad Pragati , Walker Joseph , Grenfell Bryan , Arinaminpathy Nimalan 
Published: June 2021

AbstractInfluenza pandemics typically occur in multiple waves of infection, often associated with initial emergence of a novel virus, followed (in temperate regions) by a later resurgence accompanying the onset of the annual influenza season. Here, we examined whether data collected from an initial pandemic wave could be informative, for the need to implement non-pharmaceutical measures in any resurgent wave. Drawing from the 2009 H1N1 pandemic in 10 states in the USA, we calibrated simple mathematical models of influenza transmission dynamics to data for virologically confirmed hospitalisations during the initial ‘spring’ wave. We then projected pandemic outcomes (cumulative hospitalisations) during the fall wave, and compared these projections with data. Model results show reasonable agreement for all states that reported a substantial number of cases in the spring wave. Using this model we propose a probabilistic decision framework that can be used to determine the need for pre-emptive measures such as postponing school openings, in advance of a fall wave. This work illustrates how model-based evidence synthesis, in real-time during an early pandemic wave, could be used to inform timely decisions for pandemic response.
Paraoxonase and acylated homoserine lactones in urine from patients with urinary tract infections-- relationship to microbial diversity by 16S rRNA gene sequencing
Authors: Lafleur John , Meisel Jacquelyn S. , Commichaux Seth , Amdur Richard L. , Pop Mihai , Silby Mark W. 
Published: June 2021

AbstractParaoxonase (PON) comprises a trio of mammalian enzymes that have been reported to have a number of roles including the inhibition of bacterial virulence and biofilm formation by microorganisms that quorum sense with acylated homoserine lactones (AHLs). PON have previously been reported to inhibit P. aeruginosa biofilm formation in mammalian airways and skin. An innate immune role for PON in urinary tract infection has not previously been reported. We performed western blots for PON1 in urine from patients with urinary tract infection (UTI), and also tested UTI urine for the presence of AHLs using a cellular reporter system. Urine sample microbiota was assessed through sequencing of the 16S rRNA marker gene. We report here that PON1 was not found in the urine of control subjects, however, in patients with UTI, PON1 was associated with the presence of E. coli in urine. AHLs, but not PON, were found in the bulk urine of those with P. aeruginosa UTI. Microbial consortia of PON positive UTI urine was found to be distinct from PON negative UTI urine; differentially over-represented bacteria in PON positive samples included a number of environmental opportunists. We hypothesize that PON may inhibit the quorum sensing activity of AHLs in UTI, as has previously described in skin and airways.
High-affinity, neutralizing antibodies to SARS-CoV-2 can be made in the absence of T follicular helper cells
Authors: Chen Jennifer S. , Chow Ryan D. , Song Eric , Mao Tianyang , Israelow Benjamin , Kamath Kathy , Bozekowski Joel , Haynes Winston A. , Filler Renata B. , Menasche Bridget L. , Wei Jin , Alfajaro Mia Madel , Song Wenzhi , Peng Lei , Carter Lauren , Weinstein Jason S. , Gowthaman Uthaman , Chen Sidi , Craft Joe , Shon John C. , Iwasaki Akiko , Wilen Craig B. , Eisenbarth Stephanie C. 
Published: June 2021

AbstractT follicular helper (Tfh) cells are the conventional drivers of protective, germinal center (GC)-based antiviral antibody responses. However, loss of Tfh cells and GCs has been observed in patients with severe COVID-19. As T cell-B cell interactions and immunoglobulin class switching still occur in these patients, non-canonical pathways of antibody production may be operative during SARS-CoV-2 infection. We found that both Tfh-dependent and -independent antibodies were induced against SARS-CoV-2 as well as influenza A virus. Tfh-independent responses were mediated by a population we call lymph node (LN)-Th1 cells, which remain in the LN and interact with B cells outside of GCs to promote high-affinity but broad-spectrum antibodies. Strikingly, antibodies generated in the presence and absence of Tfh cells displayed similar neutralization potency against homologous SARS-CoV-2 as well as the B.1.351 variant of concern. These data support a new paradigm for the induction of B cell responses during viral infection that enables effective, neutralizing antibody production to complement traditional GCs and even compensate for GCs damaged by viral inflammation.One-Sentence SummaryComplementary pathways of antibody production mediate neutralizing responses to SARS-CoV-2.
A combination of RBD and NTD neutralizing antibodies limits the generation of SARS-CoV-2 spike neutralization-escape mutants
Authors: Haslwanter Denise , Dieterle M. Eugenia , Wec Anna Z. , O’Brien Cecilia M. , Sakharkar Mrunal , Florez Catalina , Tong Karen , Rappazzo C. Garrett , Lasso Gorka , Vergnolle Olivia , Wirchnianski Ariel S. , Bortz Robert H. , Laudermilch Ethan , Fels J. Maximilian , Mengotto Amanda , Malonis Ryan J. , Georgiev George I. , Quiroz Jose A. , Wrapp Daniel , Wang Nianshuang , Dye Kathryn E. , Barnhill Jason , Dye John M. , McLellan Jason S. , Daily Johanna P. , Lai Jonathan R. , Herbert Andrew S. , Walker Laura M. , Chandran Kartik , Jangra Rohit K. 
Published: June 2021

AbstractMost known SARS-CoV-2 neutralizing antibodies (nAbs), including those approved by the FDA for emergency use, inhibit viral infection by targeting the receptor-binding domain (RBD) of the spike (S) protein. Variants of concern (VOC) carrying mutations in the RBD or other regions of S reduce the effectiveness of many nAbs and vaccines by evading neutralization. Therefore, therapies that are less susceptible to resistance are urgently needed. Here, we characterized the memory B-cell repertoire of COVID-19 convalescent donors and analyzed their RBD and non-RBD nAbs. We found that many of the non-RBD-targeting nAbs were specific to the N-terminal domain (NTD). Using neutralization assays with authentic SARS-CoV-2 and a recombinant vesicular stomatitis virus carrying SARS-CoV-2 S protein (rVSV-SARS2), we defined a panel of potent RBD and NTD nAbs. Next, we used a combination of neutralization-escape rVSV-SARS2 mutants and a yeast display library of RBD mutants to map their epitopes. The most potent RBD nAb competed with hACE2 binding and targeted an epitope that includes residue F490. The most potent NTD nAb epitope included Y145, K150 and W152. As seen with some of the natural VOC, the neutralization potencies of COVID-19 convalescent sera were reduced by 4-16-fold against rVSV-SARS2 bearing Y145D, K150E or W152R spike mutations. Moreover, we found that combining RBD and NTD nAbs modestly enhanced their neutralization potential. Notably, the same combination of RBD and NTD nAbs limited the development of neutralization-escape mutantsin vitro, suggesting such a strategy may have higher efficacy and utility for mitigating the emergence of VOC.ImportanceThe US FDA has issued emergency use authorizations (EUAs) for multiple investigational monoclonal antibody (mAb) therapies for the treatment of mild to moderate COVID-19. These mAb therapeutics are solely targeting the receptor binding domain of the SARS-CoV-2 spike protein. However, the N-terminal domain of the spike protein also carries crucial neutralizing epitopes. Here, we show that key mutations in the N-terminal domain can reduce the neutralizing capacity of convalescent COVID-19 sera. We report that a combination of two neutralizing antibodies targeting the receptor binding and N-terminal domains may have higher efficacy and is beneficial to combat the emergence of virus variants.
Deep integrative models for large-scale human genomics
Authors: Sigurdsson Arnór I. , Westergaard David , Winther Ole , Lund Ole , Brunak Søren , Vilhjálmsson Bjarni J. , Rasmussen Simon 
Published: June 2021

ABSTRACTPolygenic risk scores (PRSs) are expected to play a critical role in achieving precision medicine. Currently, PRS predictors are generally based on linear models using summary statistics, and more recently individual-level data. However, these predictors mainly capture additive relationships and are limited in data modalities they can use. Here, we developed a deep learning framework (EIR) for PRS prediction which includes a model, genome-local-net (GLN), specifically designed for large scale genomics data. The framework supports multi-task (MT) learning, automatic integration of other clinical and biochemical data, and model explainability. When applied to individual level data in the UK Biobank, we found that GLN outperformed LASSO for a wide range of diseases and in particularly autoimmune diseases. Furthermore, we show that this was likely due to modelling epistasis, and we showcase this by identifying widespread epistasis for Type 1 Diabetes. Furthermore, we trained PRS by integrating genotype, blood, urine and anthropometrics and found that this improved performance for 93% of 290 diseases and disorders considered. Finally, we found that including genotype data provided better calibrated PRS models compared to using measurements alone. EIR is available athttps://github.com/arnor-sigurdsson/EIR.
An efficient GUI-based clustering software for simulation and Bayesian cluster analysis of single-molecule localization microscopy data
Authors: Kutz Saskia , Zehrer Ando C. , Svetlitckii Roman , Balta Gülce S. Gülcüler , Galli Lucrezia , Kleber Susanne , Martin-Villalba Ana , Ewers Helge 
Published: June 2021

ABSTRACTLigand binding of membrane proteins triggers many important cellular signaling events by the lateral aggregation of ligand-bound and other membrane proteins in the plane of the plasma membrane. This local clustering can lead to the co-enrichment of molecules that create an intracellular signal or bring sufficient amounts of activity together to shift an existing equilibrium towards the execution of a signaling event. In this way, clustering can serve as a cellular switch. The underlying uneven distribution and local enrichment of the signaling cluster's constituting membrane proteins can be used as a functional readout. This information is obtained by combining single-molecule fluorescence microscopy with cluster algorithms that can reliably and reproducibly distinguish clusters from fluctuations in the background noise to generate quantitative data on this complex process.Cluster analysis of single-molecule fluorescence microscopy data has emerged as a proliferative field, and several algorithms and software solutions have been put forward. However, in most cases, such cluster algorithms require multiple analysis parameters to be defined by the user, which may lead to biased results. Furthermore, most cluster algorithms neglect the individual localization precision connected to every localized molecule, leading to imprecise results. Bayesian cluster analysis has been put forward to overcome these problems, but so far, it has entailed high computational cost, increasing runtime drastically. Finally, most software is challenging to use as they require advanced technical knowledge to operate.Here we combined three advanced cluster algorithms with the Bayesian approach and parallelization in a user-friendly GUI and achieved up to an order of magnitude faster processing than for previous approaches. Our work will simplify access to a well-controlled analysis of clustering data generated by SMLM and significantly accelerate data processing. The inclusion of a simulation mode aids in the design of well-controlled experimental assays.
Rostral Anterior Cingulate Activations inversely relate to Reward Payoff Maximation & predict Depressed Mood
Authors: Balasubramani Pragathi Priyadharsini , Diaz-Delgado Juan , Grennan Gillian , Alim Fahad , Zafar-Khan Mariam , Maric Vojislav , Ramanathan Dhakshin , Mishra Jyoti 
Published: June 2021

AbstractChoice selection strategies and decision making are typically investigated using multiple-choice gambling paradigms that require participants to maximize reward payoff. However, research shows that performance in such paradigms suffers from individual biases towards the frequency of gains to choose smaller local gains over larger longer term gain, also referred to as melioration. Here, we developed a simple two-choice reward task, implemented in 186 healthy human adult subjects across the adult lifespan to understand the behavioral, computational, and neural bases of payoff maximization versus melioration. The observed reward choice behavior on this task was best explained by a reinforcement learning model of differential future reward prediction. Simultaneously recorded and source-localized electroencephalography (EEG) showed that diminished theta-band activations in the right rostral anterior cingulate cortex (rACC) correspond to greater reward payoff maximization, specifically during the presentation of cumulative reward information at the end of each task trial. Notably, these activations (greater rACC theta) predicted depressed mood symptoms, thereby showcasing a reward processing marker of potential clinical utility.Significance StatementThis study presents cognitive, computational and neural (EEG-based) analyses of a rapid reward-based decision-making task. The research has the following three highlights. 1) It teases apart two core aspects of reward processing, i.e. long term expected value maximization versus immediate gain frequency melioration based choice behavior. 2) It models reinforcement learning based behavioral differences between individuals showing that observed performance is best explained by differential extents of reward prediction. 3) It investigates neural correlates in 186 healthy human subjects across the adult lifespan, revealing specific theta band cortical source activations in right rostral anterior cingulate as correlates for maximization that further predict depressed mood across subjects.
Integrative transcriptomics reveals ectopic lipid homeostasis mechanisms in non-endocrine cells of the teleost pituitary
Authors: Ager-Wick Eirill , Maugars Gersende , Krogh Kristine von , Nourizadeh-Lillabadi Rasoul , Siddique Khadeeja , Fontaine Romain , Weltzien Finn-Arne , Henkel Christiaan 
Published: June 2021

AbstractDirecting both organismal homeostasis and physiological adaptation, the pituitary is a key endocrine gland in all vertebrates. It communicates the needs of the organism to different organs by secreting hormones into the bloodstream. Here, we have used the model fish medaka to investigate the developmental dynamics in the pituitary using a comprehensive RNA-seq time series. By linking developmental expression trends to single-cell RNA-seq profiles, we show how the transcriptional activities of cell types change during sexual maturation. One of the most prominent changes is the decline of the non-endocrine folliculo-stellate cell populations, and especially of rare cells expressing genes encoding secreted lipid transport proteins. As these genes are typically associated with the liver, this reveals the existence of unexpected connections between endocrine communication, lipid homeostasis, and sexual maturation.
SARS-CoV-2 Alpha, Beta and Delta variants display enhanced Spike-mediated Syncytia Formation
Authors: Rajah Maaran Michael , Hubert Mathieu , Bishop Elodie , Saunders Nell , Robinot Remy , Grzelak Ludivine , Planas Delphine , Dufloo Jérémy , Gellenoncourt Stacy , Bongers Alice , Zivaljic Marija , Planchais Cyril , Guivel-Benhassine Florence , Porrot Françoise , Mouquet Hugo , Chakrabarti Lisa , Buchrieser Julian , Schwartz Olivier 
Published: June 2021

AbstractSevere COVID-19 is characterized by lung abnormalities, including the presence of syncytial pneumocytes. Syncytia form when SARS-CoV-2 spike protein expressed on the surface of infected cells interacts with the ACE2 receptor on neighbouring cells. The syncytia forming potential of spike variant proteins remain poorly characterized. Here, we first assessed Alpha and Beta spread and fusion in cell cultures. Alpha and Beta replicated similarly to D614G reference strain in Vero, Caco-2, Calu-3 and primary airway cells. However, Alpha and Beta formed larger and more numerous syncytia. Alpha, Beta and D614G fusion was similarly inhibited by interferon induced transmembrane proteins (IFITMs). Individual mutations present in Alpha and Beta spikes differentially modified fusogenicity, binding to ACE2 and recognition by monoclonal antibodies. We further show that Delta spike also triggers faster fusion relative to D614G. Thus, SARS-CoV-2 emerging variants display enhanced syncytia formation.SynopsisThe Spike protein of the novel SARS-CoV-2 variants are comparative more fusogenic than the earlier strains. The mutations in the variant spike protein differential modulate syncytia formation, ACE2 binding, and antibody escape.The spike protein of Alpha, Beta and Delta, in the absence of other viral proteins, induce more syncytia than D614GThe ACE2 affinity of the variant spike proteins correlates to their fusogenicityVariant associated mutations P681H, D1118H, and D215G augment cell-cell fusion, while antibody escape mutation E484K, K417N and Δ242-244 hamper it.Variant spike-mediated syncytia formation is effectively restricted by IFITMs
Endogenous retroviruses co-opted as divergently transcribed regulatory elements shape the regulatory landscape of embryonic stem cells
Authors: Bakoulis Stylianos , Krautz Robert , Alcaraz Nicolas , Salvatore Marco , Andersson Robin 
Published: June 2021

AbstractTransposable elements are an abundant source of transcription factor binding sites and favorable genomic integration may lead to their recruitment by the host genome for gene regulatory functions. However, it is unclear how frequent co-option of transposable elements as regulatory elements is, to which regulatory programs they contribute and how they compare to regulatory elements devoid of transposable elements. Here, we report a transcription initiation-centric, in-depth characterization of the transposon-derived regulatory landscape of mouse embryonic stem cells. We demonstrate that a substantial number of transposable elements, in particular endogenous retroviral elements, carry open chromatin regions that are divergently transcribed into unstable RNAs in a cell-type specific manner, and that these elements contribute to a sizable proportion of active enhancers and gene promoters. We further show that transposon subfamilies contribute differently and distinctly to the pluripotency regulatory program through their repertoires of transcription factor binding sites, shedding light on the formation of regulatory programs and the origins of regulatory elements.
INDEHISCENT regulates explosive seed dispersal
Authors: Galstyan Anahit , Sarchet Penny , Campos-Martin Rafael , Adibi Milad , Nikolov Lachezar A. , Antón Miguel Pérez , Rambaud-Lavigne Léa , Gan Xiangchao , Hay Angela 
Published: June 2021

AbstractHow traits evolve to produce novelty or stasis is an open question in biology. We investigate this question in Cardamine hirsuta, a relative of Arabidopsis thaliana that employs explosive fracture to disperse its seeds. This trait evolved through key morphomechanical innovations that distinguish the otherwise very similar, dehiscent fruit of these two species. Using CRISPR/Cas9, we show that dehiscence zone formation is absolutely required for explosive fracture in C. hirsuta, and is controlled by the bHLH transcription factor INDEHISCENT (IND). Using mutant screens, we identified the MADS-box transcription factor FRUITFULL (FUL) as a negative regulator of IND in C. hirsuta. Although FUL function is conserved in C. hirsuta, the consequences of IND mis-expression differ in ful mutants of C. hirsuta versus A. thaliana. In ful mutants of both species, valve tissue is replaced by dehiscence zone tissue, which comprises two distinct cell types: lignified layer and separation layer cells. While A. thaliana ful mutants develop stunted fruit with ectopic lignified layer cells, C. hirsuta ful mutants have elongated fruit with ectopic separation layer cells. We show that IND dose determines the proportion of these two cell types in ectopic dehiscence zones. We also show that the extent of ectopic lignification caused by IND mis-expression determines fruit length. Our findings indicate developmental system drift in the conserved gene network patterning dehiscent fruit in two related Brassicaceae species.
Litter characteristics and helping context during early life shape the responsiveness of the stress axis in a wild cooperative breeder
Authors: Cohas Aurélie , Bichet Coraline , Garcia Rébecca , Pardonnet Sylvia , Lardy Sophie , Rey Benjamin 
Published: June 2021

AbstractStress responses have evolved to quickly and appropriately deal with environmental stressors in order to secure or restore homeostasis. Since the regulation of stress hormones plays a key adaptive role, the regulatory processes controlling stress hormones levels may be under high selective pressure. The social environment during early life (parents and litter characteristics) strongly affects ontogeny of the hypothalamic-pituitary-adrenal (HPA) axis. In cooperative breeders, offspring are also confronted with helpers but whether and how variation in the helping context can affect HPA axis responsiveness of offspring remains unanswered. Combining dexamethasone suppression and adrenocorticotropic hormone stimulation tests, we investigated the link between the social environment and the characteristics of the HPA axis at the early stages of life in wild Alpine marmots. We show that when raised in the presence of helpers, marmot pups exhibit a greater capacity not only to mount, but also to turn off a stress response. The capacity to mount a stress response was also higher as the pups were raised in large litters. Determining impacts of such social modulation of the HPA axis functioning on individual fitness would make an important contribution to our understanding of the evolution of cooperative breeding.