bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mesoderm patterning by a dynamic gradient of retinoic acid signalling
Authors: Bernheim Ségolène , Meilhac Sigolène M. 
Published: August 2020

Retinoic acid (RA), derived from vitamin A, is a major teratogen, clinically recognized in 1983. Identification of its natural presence in the embryo and dissection of its molecular mechanism of action became possible in the animal model with the advent of molecular biology, starting with the cloning of its nuclear receptor. In normal development, the dose of RA is tightly controlled to regulate organ formation. Its production depends on enzymes, which have a dynamic expression profile during embryonic development. As a small molecule, it diffuses rapidly and acts as a morphogen. Here, we review advances in deciphering how endogenously produced RA provides positional information to cells. We compare three mesodermal tissues, the limb, the somites and the heart, and discuss how RA signalling regulates antero-posterior and left–right patterning. A common principle is the establishment of its spatio-temporal dynamics by positive and negative feedback mechanisms and by antagonistic signalling by FGF. However, the response is cell-specific, pointing to the existence of cofactors and effectors, which are as yet incompletely characterized.This article is part of a discussion meeting issue ‘Contemporary morphogenesis’.
Spatial protein analysis in developing tissues: a sampling-based image processing approach
Authors: Leonavicius Karolis , Royer Christophe , Miranda Antonio M. A. , Tyser Richard C. V. , Kip Annemarie , Srinivas Shankar 
Published: August 2020

Advances in fluorescence microscopy approaches have made it relatively easy to generate multi-dimensional image volumes and have highlighted the need for flexible image analysis tools for the extraction of quantitative information from such data. Here we demonstrate that by focusing on simplified feature-based nuclear segmentation and probabilistic cytoplasmic detection we can create a tool that is able to extract geometry-based information from diverse mammalian tissue images. Our open-source image analysis platform, called ‘SilentMark’, can cope with three-dimensional noisy images and with crowded fields of cells to quantify signal intensity in different cellular compartments. Additionally, it provides tissue geometry related information, which allows one to quantify protein distribution with respect to marked regions of interest. The lightweight SilentMark algorithms have the advantage of not requiring multiple processors, graphics cards or training datasets and can be run even with just several hundred megabytes of memory. This makes it possible to use the method as a Web application, effectively eliminating setup hurdles and compatibility issues with operating systems. We test this platform on mouse pre-implantation embryos, embryonic stem cell-derived embryoid bodies and mouse embryonic heart, and relate protein localization to tissue geometry.
This article is part of a discussion meeting issue ‘Contemporary morphogenesis’.
Coordination between patterning and morphogenesis ensures robustness during mouse development
Authors: Saiz Néstor , Hadjantonakis Anna-Katerina 
Published: August 2020

The mammalian preimplantation embryo is a highly tractable, self-organizing developmental system in which three cell types are consistently specified without the need for maternal factors or external signals. Studies in the mouse over the past decades have greatly improved our understanding of the cues that trigger symmetry breaking in the embryo, the transcription factors that control lineage specification and commitment, and the mechanical forces that drive morphogenesis and inform cell fate decisions. These studies have also uncovered how these multiple inputs are integrated to allocate the right number of cells to each lineage despite inherent biological noise, and as a response to perturbations. In this review, we summarize our current understanding of how these processes are coordinated to ensure a robust and precise developmental outcome during early mouse development.This article is part of a discussion meeting issue ‘Contemporary morphogenesis'.
Digital otoscopy videos versus composite images: A reader study to compare the accuracy of ENT physicians
Authors: Binol Hamidullah , Niazi M. Khalid Khan , Essig Garth , Shah Jay , Mattingly Jameson K. , Harris Michael S. , Elmaraghy Charles , Teknos Theodoros , Taj-Schaal Nazhat , Yu Lianbo , Gurcan Metin N. , Moberly Aaron C. 
Published: August 2020

AbstractObjectivesWith the increasing emphasis on developing effective telemedicine approaches in Otolaryngology, this study explored whether a single composite image stitched from a digital otoscopy video provides acceptable diagnostic information to make an accurate diagnosis, as compared with that provided by the full video.MethodsFive Ear, Nose, and Throat (ENT) physicians reviewed the same set of 78 digital otoscope eardrum videos from four eardrum conditions: normal, effusion, retraction, and tympanosclerosis, along with the composite images generated by aSelectStitchmethod that selectively uses video frames with computer-assisted selection, as well as aStitchmethod that incorporates all the video frames. Participants provided a diagnosis for each item along with a rating of diagnostic confidence. Diagnostic accuracy for each pathology ofSelectStitchwas compared with accuracy when reviewing the entire video clip and when reviewing theStitchimage.ResultsThere were no significant differences in diagnostic accuracy for physicians reviewingSelectStitchimages and full video clips, but both provided better diagnostic accuracy thanStitchimages. The inter-reader agreement was moderate.ConclusionEqual to using full video clips, composite images of eardrums generated bySelectStitchprovided sufficient information for ENTs to make the correct diagnoses for most pathologies. These findings suggest that use of a composite eardrum image may be sufficient for telemedicine approaches to ear diagnosis, eliminating the need for storage and transmission of large video files, along with future applications for improved documentation in electronic medical record systems, patient/family counseling, and clinical training.Level of EvidenceLevel 3
Comparing the Fit of N95, KN95, Surgical, and Cloth Face Masks and Assessing the Accuracy of Fit Checking
Authors: O’Kelly Eugenia , Arora Anmol , Pirog Sophia , Ward James , Clarkson P. John 
Published: August 2020

AbstractIntroductionThe COVID-19 pandemic has made well-fitting face masks a critical piece of protective equipment for healthcare workers and civilians. While the importance of wearing face masks has been acknowledged, there remains a lack of understanding about the role of good fit in rendering protective equipment useful. In addition, supply chain constraints have caused some organizations to abandon traditional quantitative or qualitative fit testing, and instead, have implemented subjective fit checking. Our study seeks to quantitatively evaluate the level of fit offered by various types of masks, and most importantly, assess the accuracy of implementing fit checks by comparing fit check results to quantitative fit testing results.MethodsSeven participants first evaluated N95 and KN95 masks by performing a fit check. Participants then underwent quantitative fit testing wearing five N95 masks, a KN95 mask, a surgical mask, and fabric masks.ResultsN95 masks offered higher degrees of protection than the other categories of masks tested; however, it should be noted that most N95 masks failed to fit the participants adequately. Fit check responses had poor correlation with quantitative fit scores. All non-N95 masks achieved low fit scores.ConclusionFit is critical to the level of protection offered by masks. For an N95 mask to provide the promised protection, it must fit the participant. Performing a fit check was an unreliable way of determining fit.
NLRP3 inflammasome contributes to host defense againstTalaromyces marneffeiinfection
Authors: Ma Haiyan , Chan Jasper FW , Tan Yen Pei , Kui Lin , Tsang Chi-Ching , Pei Steven LC , Lau Yu-Lung , Woo Patrick CY , Lee Pamela P 
Published: August 2020

AbstractTalaromyces marneffeiis an important thermally dimorphic pathogen causing disseminated mycoses in immunocompromised individuals in southeast Asia. Previous study has suggested that NLRP3 inflammasome plays a critical role in antifungal immunity. However, the mechanism underlying the role of NLRP3 inflammasome activation in host defense againstT. marneffeiremains unclear. We show thatT. marneffeiyeasts but not conidia induce potent IL-1β response, which is differentially regulated in discrete immune cell types. Dectin-1/Syk signaling pathway mediates pro-IL-1β production, and NLRP3 inflammasome is activated to trigger the processing of pro-IL-1β into IL-1β. The activated NLRP3 inflammasome partially promotes Th1 and Th17 immune responses againstT. marneffeiyeasts.In vivo, mice with NLRP3 or caspase-1 deficiency exhibit higher mortality rate and fungal load compared to wild-type mice. Herein, our study provides the first evidence that NLRP3 inflammasome contributes to host defense againstT. marneffeiinfection, which may have implications for future antifungal therapeutic designs.
Optogenetic activation of heterotrimeric Gi proteins by LOV2GIVe— a rationally engineered modular protein
Authors: Garcia-Marcos Mikel , Parag-Sharma Kshitij , Marivin Arthur , Maziarz Marcin , Luebbers Alex , Nguyen Lien T. 
Published: August 2020

ABSTRACTHeterotrimeric G-proteins are signal transducers that mediate the action of many natural extracellular stimuli as well as of many therapeutic agents. Non-invasive approaches to manipulate the activity of G-proteins with high precision are crucial to understand their regulation in space and time. Here, we engineered LOV2GIVe, a modular protein that allows the activation of Gi proteins with blue light. This optogenetic construct relies on a versatile design that differs from tools previously developed for similar purposes, i.e. metazoan opsins, which are light-activated GPCRs. To make LOV2GIVe, we fused a peptide derived from a non-GPCR protein that activates Gαi (but not Gαs, Gαq, or Gα12) to a small plant protein domain, such that light uncages the G-protein activating module. Targeting LOV2GIVe to cell membranes allowed for light-dependent activation of Gi proteins in different experimental systems. In summary, LOV2GIVe expands the armamentarium and versatility of tools available to manipulate heterotrimeric G-protein activity.GRAPHICAL SUMMARY
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 Johnny , 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 
Published: August 2020

AbstractIn 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-CoV2 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.
Clinical Characterisation of Eleven Lateral Flow Assays for Detection of COVID-19 Antibodies in a Population
Authors: Rudolf Fabian , Kaltenbach Hans-Michael , Linnik Janina , Ruf Marie-Therèse , Niederhauser Christoph , Nickel Beatrice , Gygax Daniel , Savic Miodrag 
Published: August 2020

AbstractImportanceSerological assays can help diagnose and determine the rate of SARS-CoV-2 infections in a population.ObjectiveWe characterized and compared 11 different lateral flow assays for their performance in diagnostic or epidemiological settings.Design, Setting, ParticipantsWe used two cohorts to determine the specificity: (i) up to 350 blood donor samples from past influenza seasons and (ii) up to 110 samples which tested PCR negative for SARS-CoV-2 during the first wave of SARS-CoV-2 infections in Switzerland. The sensitivity was determined using up to 370 samples which tested PCR positive for SARS-CoV-2 during the same time and is representative for age distribution and severity.Main OutcomeWe found a single test usable for epidemiological studies in the current low-prevalence setting, all other tests showed lacking sensitivity or specificity for a usage in either epidemiological or diagnostic setting. However, orthogonal testing by combining two tests without common cross-reactivities makes testing in a low-prevalence setting feasible.ResultsNine out of the eleven tests showed specificities below 99%, only five of eleven tests showed sensitivities comparable to established ELISAs, and only one fulfilled both criteria. Contrary to previous results from lab assays, five tests measured an IgM response in >80% of the samples. We found no common cross-reactivities, which allows orthogonal testing schemes for five tests of sufficient sensitivities.Conclusions and RelevanceThis study emphasizes the need for large and diverse negative cohorts when determining specificities, and for diverse and representative positive samples when determining sensitivities of lateral flow assays for SARS-CoV-2 infections. Failure to adhere to statistically relevant sample sizes or cohorts exclusively made up of hospitalised patients fails to accurately capture the performance of these assays in epidemiological settings. Our results allow a rational choice between tests for different use cases.
FinaleDB: a browser and database of cell-free DNA fragmentation patterns
Authors: Zheng Haizi , Zhu Michelle S , Liu Yaping 
Published: August 2020

AbstractSummaryCirculating cell-free DNA (cfDNA) is a promising biomarker for the diagnosis and prognosis of many diseases, including cancer. The genome-wide non-random fragmentation patterns of cfDNA are associated with the nucleosomal protection, epigenetic environment, and gene expression in the cell types that contributed to cfDNA. However, current progress on the development of computational methods and understanding of molecular mechanisms behind cfDNA fragmentation patterns is significantly limited by the controlled-access of cfDNA whole-genome sequencing (WGS) dataset. Here, we present FinaleDB (FragmentatIoN AnaLysis of cEll-free DNA DataBase), a comprehensive database to host thousands of uniformly processed and curated de-identified cfDNA WGS datasets across different pathological conditions. Furthermore, FinaleDB comes with a fragmentation genome browser, from which users can seamlessly integrate thousands of other omics data in different cell types to experience a comprehensive view of both gene-regulatory landscape and cfDNA fragmentation patterns.Availability and implementationFinaleDB service:http://finaledb.research.cchmc.org/FinaleDB source code:https://github.com/epifluidlab/finaledb_portalandhttps://github.com/epifluidlab/finaledb_workflow.Contactlyping1986@gmail.com
Rescuing auditory temporal processing with a novel augmented acoustic environment in a mouse model of congenital SNHL
Authors: Dziorny Adam C. , Scott Luisa L. , Luebke Anne E. , Walton Joseph P. 
Published: August 2020

AbstractCongenital sensorineural hearing loss (SNHL) affects thousands of infants each year and results in significant delays in speech and language development. Previous studies have shown that early exposure to a simple augmented acoustic environment (AAE) can limit the effects of progressive SNHL on hearing sensitivity. However, SNHL is also accompanied by “hidden hearing loss” that is not assessed on standard audiological exams, such as reduced temporal processing acuity. To assess whether sound therapy may improve these hidden deficits, a mouse model of congenital SNHL was exposed to simple or temporally complex AAE. Peripheral function and sound sensitivity in auditory midbrain neurons improved following exposure to both types of AAE. However, only exposure to a novel, temporally complex AAE significantly improved a measure of temporal processing acuity, neural gap-in-noise detection in the auditory midbrain. These experiments suggest that targeted sound therapy may improve hearing outcomes for children suffering from congenital SNHL.
Early life stress programming of NG2+ glia transcriptome alters functional properties of voltage gated sodium (Nav) channels and cognitive performance
Authors: Treccani Giulia , Yigit Hatice , Lingner Thomas , Schleuβner Vanessa , Wennström Malin , Herzog David P , Fricke Markus , Wegener Gregers , Mittmann Thomas , Trotter Jacqueline , Müller Marianne B 
Published: August 2020

AbstractThe precise mechanisms underlying the detrimental effects of early life stress (ELS) on adult mental health remain still elusive. To date, most studies have exclusively targeted neuronal populations and not considered neuron-glia crosstalk as a crucially important element for the integrity of stress-related brain function. Here, we have investigated the impact of ELS on a glial subpopulation with unique properties in brain homeostasis, the NG2+ cells. ELS shifted the NG2+ transcriptome towards more mature stages, and these transcriptional effects were dependent on stress-induced glucocorticoids. The functional relevance of one candidate gene, Scn7a, could be confirmed by an increase in the density of voltage-gated sodium (Nav) channel activated currents in hippocampal NG2+ cells. Scn7a remained upregulated until adulthood in ELS animals, and these same animals displayed impaired cognitive performance. Considering that Nav channels are important for NG2+ cell-to-neuron communication, our findings suggest novel insights into the pathophysiology of stress-related mental disorders.
Mechanical Activation of MscL Revealed by a Locally Distributed Tension Molecular Dynamics Approach
Authors: Tatikonda R. R. , Anishkin A. , Sukharev S. , Vanegas J. M. 
Published: August 2020

ABSTRACTMembrane tension perceived by mechanosensitive (MS) proteins mediates cellular responses to mechanical stimuli and osmotic stresses, and it also guides multiple biological functions including cardiovascular control and development. In bacteria, MS channels function as tension-activated pores limiting excessive turgor pressure, with MscL (MS channel of large conductance) acting as an emergency release valve preventing cell lysis. Previous attempts to simulate gating transitions in MscL by either directly applying steering forces to the protein or by increasing the whole system tension were not fully successful and often disrupted the integrity of the system. We present a novel locally distributed tension molecular dynamics (LDT-MD) simulation method that allows application of forces continuously distributed among lipids surrounding the channel using a specially constructed collective variable. We report reproducible and reversible transitions of MscL to the open state with measured parameters of lateral expansion and conductivity that exactly satisfy experimental values. The LDT-MD method enables exploration of the MscL gating process with different pulling velocities and variable tension asymmetry between the inner and outer membrane leaflets. We use LDT-MD in combination with well-tempered metadynamics to reconstruct the tension-dependent free energy landscape for the opening transition in MscL.SIGNIFICANCEMembrane-embedded mechanosensitive (MS) proteins are essential for numerous biological functions including cardiovascular control and development, osmotic regulation, touch and pain sensing. In this work, we present a novel molecular dynamics simulation method that allows rapid and systematic exploration of structure, dynamics, and energetics of the mechanical transduction process in MS proteins under tightly controlled local tension distributed in the lipid rim around the protein. We provide a detailed description of the gating transition for the tension-activated bacterial mechanosensitive channel of large conductance, MscL, which is the best characterized channel of this type. MscL functions as a tension-activated emergency osmolyte release valve that limits excessive turgor pressure, prevents cell lysis and thus imparts environmental stability to most free-living bacteria.