bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between Psychotropic Medications Functionally Inhibiting Acid Sphingomyelinase and reduced risk of Intubation or Death among Individuals with Mental Disorder and Severe COVID-19: an Observational Study
Authors: Hoertel Nicolas , Sánchez-Rico Marina , Gulbins Erich , Kornhuber Johannes , Carpinteiro Alexander , Abellán Miriam , de la Muela Pedro , Vernet Raphaël , Beeker Nathanaël , Neuraz Antoine , Delcuze Aude , Alvarado Jesús M. , Meneton Pierre , Limosin Frédéric 
Published: February 2021

ABSTRACTPrior preclinical and clinical evidence suggests that the acid sphingomyelinase (ASM)/ceramide system may provide a useful framework for better understanding SARS-CoV-2 infection and the repurposing of psychotropic medications with functional inhibition of acid sphingomyelinase, called FIASMA psychotropic medications, against COVID-19. We examined the potential usefulness of FIASMA psychotropic medication use among patients with mental disorder hospitalized for severe COVID-19, in an observational multicenter retrospective study conducted at AP-HP Greater Paris University hospitals. Of 545 adult patients with mental disorder hospitalized for severe COVID-19, 164 (30.1%) received a psychotropic FIASMA medication at study baseline, which was defined as the date of hospital admission for COVID-19. The primary endpoint was a composite of intubation or death. We compared this endpoint between patients who received a psychotropic FIASMA medication at baseline and those who did not in time-to-event analyses adjusted for sociodemographic characteristics, psychiatric and other medical comorbidity, and psychotropic and other medications. The primary analysis was a Cox regression model with inverse probability weighting (IPW). There was a significant association between FIASMA psychotropic medication use at baseline and reduced risk of intubation or death both in the crude analysis (HR=0.42; 95%CI=0.31-0.57; p<0.01) and in the primary IPW analysis (HR=0.50; 95%CI=0.37-0.67; p<0.01). This association remained significant in multiple sensitivity analyses. Exploratory analyses suggested that this association was not specific to one FIASMA psychotropic class or medication. These results suggest the usefulness of the ASM/ceramide system framework in COVID-19. Double-blind controlled randomized clinical trials of these medications for COVID-19 are needed.
Predicted epitope binding core motifs and common amino acid polymorphisms distinguish protective- from susceptibility-associated HLA alleles in leishmaniasis
Authors: de Vrij Nicky , Meysman Pieter , Gielis Sofie , Adriaensen Wim , Laukens Kris , Cuypers Bart 
Published: February 2021

AbstractSusceptibility for leishmaniasis is largely dependent on genetic- and immune factors of the host. Despite the previously described association of human leukocyte antigen (HLA) gene cluster variants as genetic susceptibility factors, little is known on the mechanisms that mediate these associations. To characterize the functionality underpinning these associations between HLA and disease, we predicted the epitope binding repertoires for all known leishmaniasis-associated HLA variants collected in a thorough literature review. We identified several amino acid polymorphisms in the HLA sequences that distinguished protective-from risk-associated HLA-DRB1 alleles. Proteome-wide and multi-species T cell epitope binding predictions were carried out across these alleles, enabling us to map the effects on the epitope binding repertoires. The protective-associated HLA-DRB1 alleles were characterized by common binding core motifs, which map to the identified amino acid polymorphisms. These results strongly suggest that polymorphism in the HLA region, resulting in differential antigen presentation, affects the association between HLA and leishmaniasis disease development. Finally, we established a valuable open-access resource of putative epitopes, of which a set of 14 HLA-unrestricted strong-binding epitopes, conserved across species, were prioritized for further epitope discovery in the search for novel subunit-based vaccines.
Determining the pathogenicity of MUT gene variant by mini-gene splicing assay
Authors: Wang Yanyun , Sun Yun , Jiang Tao 
Published: February 2021

AbstractObjectiveTo perform gene mutation splicing analysis on 12 suspected pathogenic MMUT/MUT gene mutation sites to verify the pathogenicity of the mutation.MethodsWild-type and mutant minigenes were inserted into pcMINI vector, and total 5 wild-type recombinant vectors and 12 mutant recombinant vectors were constructed. The total RNA in 293T cells was extracted after the recombinant vectors were transfected into 293T cell line. Then PCR products were detected by agarose gel electrophoresis and analyzed by sequencing.ResultsRT-PCR and sequencing results showed that among 12 mutations, 9 mutations (c.419T>C, 469G>T, c.470T>A, c.626dupC, c.693C>G, c.976A>G, c.1009T>C, c.1777G>T and c.1874A>C) did not affect the gene splicing, and the other 3 mutations (c.454C>T, c.421G>A and c.2125-3C>G) all affected mRNA splicing.ConclusionIn recent case reports of MMUT/MUT gene mutation sites, variant of uncertain significance (VUS) variation is very common. In this study, the pathogenicity of three mutation sites is confirmed by the mini-gene method.
Distinguishing dopamine and calcium responses using XNA-nanotube sensors for improved neurochemical sensing
Authors: Gillen Alice J. , Antonucci Alessandra , Reggente Melania , Morales Daniel , Boghossian Ardemis A. 
Published: February 2021

AbstractTo date, the engineering of single-stranded DNA-SWCNT (DNA-SWCNT) optical biosensors have largely focused on creating sensors for new applications with little focus on optimising existing sensors for in vitro and in vivo conditions. Recent studies have shown that nanotube fluorescence can be severely impacted by changes in local cation concentrations. This is particularly problematic for neurotransmitter sensing applications as spatial and temporal fluctuations in the concentration of cations, such as Na+, K+, or Ca2+, play a central role in neuromodulation. This can lead to inaccuracies in the determination of neurotransmitter concentrations using DNA-SWCNT sensors, which limits their use for detecting and treating neurological diseases.Herein, we present new approaches using locked nucleic acid (LNA) to engineer SWCNT sensors with improved stability towards cation-induced fluorescence changes. By incorporating LNA bases into the (GT)15-DNA sequence, we create sensors that are not only more resistant towards undesirable fluorescence modulation in the presence of Ca2+ but that also retain their capabilities for the label-free detection of dopamine. The synthetic biology approach presented in this work therefore serves as a complementary means for enhancing nanotube optoelectronic behavior, unlocking previously unexplored possibilities for developing nano-bioengineered sensors with augmented capabilities.
Early embryogenesis and organogenesis in the annelidOwenia fusiformis
Authors: Carrillo-Baltodano Allan Martín , Seudre Océane , Guynes Kero , Martín-Durán José María 
Published: February 2021

AbstractBackgroundAnnelids are a diverse group of segmented worms within Spiralia, whose embryos exhibit spiral cleavage and a variety of larval forms. While most modern embryological studies focus on species with unequal spiral cleavage nested in Pleistoannelida (Sedentaria + Errantia), a few recent studies looked intoOwenia fusiformis, a member of the sister group to all remaining annelids and thus a key lineage to understand annelid and spiralian evolution and development. However, the timing of early cleavage and detailed morphogenetic events leading to the formation of the idiosyncratic mitraria larva ofO. fusiformisremain largely unexplored.ResultsO. fusiformisundergoes equal spiral cleavage where the first quartet of animal micromeres are slightly larger than the vegetal macromeres. Cleavage results in a coeloblastula approximately five hours post fertilization (hpf) at 19 °C. Gastrulation occurs via invagination and completes four hours later, with putative mesodermal precursors and the chaetoblasts appearing 10 hpf at the dorsoposterior side. Soon after, at 11 hpf, the apical tuft emerges, followed by the first neurons (as revealed by the expression ofelav1andsynaptotagmin1) in the apical organ and the prototroch by 13 hpf. Muscles connecting the chaetal sac to various larval tissues develop around 18 hpf and by the time the mitraria is fully formed at 22 hpf, there are FMRFamide+neurons in the apical organ and prototroch, the latter forming a prototrochal ring. As the mitraria feeds, it grows in size and the prototroch expands through active proliferation. The larva becomes competent after ∼3 weeks post fertilization at 15 °C, when a conspicuous juvenile rudiment has formed ventrally.ConclusionsO. fusiformisembryogenesis is similar to that of other equal spiral cleaving annelids, supporting that equal cleavage is associated with the formation of a coeloblastula, gastrulation via invagination, and a feeding trochophore-like larva in Annelida. The nervous system of the mitraria larva forms earlier and is more complex than previously recognised and develops from anterior to posterior, which is likely an ancestral condition to Annelida. Altogether, our study identifies the major developmental events duringO. fusiformisontogeny, defining a conceptual framework for future investigations.
A neural circuit basis for binasal input-enhanced chemosensory avoidance
Authors: Sy Samuel K. H. , Chan Danny C. W. , Chan Roy C. H. , Lyu Jing , Li Zhongqi , Wong Kenneth K. Y. , Choi Chung Hang Jonathan , Mok Vincent C. T. , Lai Hei-Ming , Hu Yu , Ko Ho 
Published: February 2021

SummaryOur understanding of how bilaterian animals utilize parallel input channels from paired sensory organs to optimize chemosensory behavior and the underlying neural circuit mechanisms are limited. Here we developed microfluidics-based behavioral and brainwide imaging platforms to study the neural integration of binasal inputs and chemosensory avoidance in larval zebrafish. We show that larval zebrafish efficiently escape from cadaverine-carrying streams by making more frequent swim bouts and larger undirected turns. Binasal inputs are strictly required for the nasal input-dependent component of klinokinesis, while each nasal input additively enhances angular orthokinesis. Throughout brain regions, including those along the olfactory processing pathways, a distributed neural representation with a wide spectrum of ipsilateral-contralateral nasal stimulus selectivity is maintained. Nonlinear sensory information gain with bilateral signal convergence is especially prominent in neurons weakly encoding unilateral cadaverine stimulus, and associated with stronger activation of sensorimotor neurons in the downstream brain regions. Collectively, these results provide insights into how the vertebrate model sums parallel input signals to guide chemosensory avoidance behavior.
Unraveling micro-architectural modulations in neural tissue upon ischemia by Correlation Tensor MRI
Authors: Alves Rita , Henriques Rafael Neto , Kerkelä Leevi , Chavarrías Cristina , Jespersen Sune N , Shemesh Noam 
Published: February 2021

ABSTRACTNoninvasively detecting and characterizing modulations in cellular scale micro-architecture is a desideratum for contemporary neuroimaging. Diffusion MRI (dMRI) has become the mainstay methodology for probing microstructure, and, in ischemia, its contrasts have revolutionized stroke management. However, the biological underpinnings of the contrasts observed in conventional dMRI in general and in ischemia in particular are still highly debated since the markers only indirectly reporter on microstructure. Here, we present Correlation Tensor MRI (CTI), a method that rather than measuring diffusion, harnesses diffusion correlations as its source of contrast. We show that CTI can resolve the sources of diffusional kurtosis, which in turn, provide dramatically enhanced specificity and sensitivity towards ischemia. In particular, the sensitivity towards ischemia nearly doubles, both in grey matter (GM) and white matter (WM), and unique signatures for neurite beading, cell swelling, and edema are inferred from CTI. The enhanced sensitivity and specificity endowed by CTI bodes well for future applications in biomedicine, basic neuroscience, and in the clinic.
Preprints in motion: tracking changes between preprint posting and journal publication during a pandemic
Authors: Brierley Liam , Nanni Federico , Polka Jessica K , Dey Gautam , Pálfy Máté , Fraser Nicholas , Coates Jonathon Alexis 
Published: February 2021

AbstractAmidst the COVID-19 pandemic, preprints in the biomedical sciences are being posted and accessed at unprecedented rates, drawing widespread attention from the general public, press and policymakers for the first time. This phenomenon has sharpened longstanding questions about the reliability of information shared prior to journal peer review. Does the information shared in preprints typically withstand the scrutiny of peer review, or are conclusions likely to change in the version of record? We assessed preprints from bioRxiv and medRxiv that had been posted and subsequently published in a journal through 30th April 2020, representing the initial phase of the pandemic response. We utilised a combination of automatic and manual annotations to quantify how an article changed between the preprinted and published version. We found that the total number of figure panels and tables changed little between preprint and published articles. Moreover, the conclusions of 7.2% of non-COVID-19-related and 17.2% of COVID-19-related abstracts undergo a discrete change by the time of publication, but the majority of these changes do not qualitatively change the conclusions of the paper.
Daily orexinergic modulation of the rat superficial layers of the superior colliculus – implications for intrinsic clock activities in the visual system
Authors: Chrobok Lukasz , Jeczmien-Lazur Jagoda Stanislawa , Bubka Monika , Pradel Kamil , Klekocinska Aleksandra , Klich Jasmin Daniela , Rahim Amalia Ridla , Myung Jihwan , Kepczynski Mariusz , Lewandowski Marian Henryk 
Published: February 2021

AbstractThe orexinergic system delivers excitation for multiple brain centres to facilitate behavioural arousal, with its malfunction resulting in narcolepsy, somnolence, and notably, visual hallucinations. Since the circadian clock underlies the daily arousal, a timed coordination is expected between the orexin system and its target subcortical visual system, including the superior colliculus (SC). Here, we use a combination of electrophysiological, immunohistochemical, and molecular approaches across 24 h, together with the neuronal tract tracing methods in rodents to elucidate the daily coordination between the orexin system and the superficial layers of the SC. We find the daily orexinergic innervation onto the SC, coinciding with the daily silencing of spontaneous firing in this visual brain area. We identify autonomous daily and circadian expression of clock genes in the SC, which may underlie these day-night changes. Additionally, we establish the lateral hypothalamic origin of orexin innervation to the SC and that the SC neurons robustly respond to orexin A via OX2 receptor in both excitatory and GABAA receptor-dependent inhibitory manners. Together, our evidence supports that the clock coordination between the orexinergic input and its response in the SC provides arousal-related excitation needed to detect sparse visual information during the behaviourally active phase.
Multiple PDZ Domain Protein Maintains Patterning of the Apical Cytoskeleton in Sensory Hair Cells
Authors: Jarysta Amandine , Tarchini Basile 
Published: February 2021

SUMMARYSound transduction occurs in the hair bundle, the apical compartment of sensory hair cells in the inner ear. The hair bundle is formed of stereocilia aligned in rows of graded heights. It was previously shown that the GNAI-GPSM2 complex is part of a developmental blueprint that defines the polarized organization of the apical cytoskeleton in hair cells, including stereocilia distribution and elongation. Here we report a novel and critical role for Multiple PDZ domain (MPDZ) protein during apical hair cell morphogenesis. We show that MPDZ is enriched at the hair cell apical membrane, and required there to maintain the proper segregation of apical blueprints proteins, including GNAI-GPSM2. Loss of the blueprint coincides with misaligned stereocilia inMpdzmutants, and results in permanently misshapen hair bundles. Graded molecular and structural defects along the cochlea can explain the profile of hearing loss inMpdzmutants, where deficits are most severe at high frequencies.
DNA-Encoded Multivalent Display of Protein Tetramers on Phage: Synthesis and In Vivo Aplications
Authors: Lima Guilherme M. , Atrazhev Alexey , Sarkar Susmita , Sojitra Mirat , Reddy Revathi , Macauley Matthew S. , Monteiro Gisele , Derda Ratmir 
Published: February 2021

AbstractPhage display links phenotype of displayed polypeptides with DNA sequence in phage genome and offers a universal method for discovery of proteins with novel properties. Injection of phage-displayed libraries in living organisms further provides a unique and powerful approach to optimize biochemical, pharmacological and biological properties of the displayed peptides, antibodies and other proteins in vivo. However, over 60% of the proteome is comprised of multi-domain proteins, and display of large multi-subunit proteins on phages remains a challenge. Majority of protein display systems are based on monovalent phagemid constructs but methods for robust display of multiple copies of large proteins are scarce. Here, we describe a DNA-encoded display of a ∼200 kDa tetrameric protein tetrameric L-asparaginase on M13 phage produced by ligation of SpyCatcher-Asparaginase fusion (ScA) to prospectively barcoded phage clones displaying SpyTag peptide. Starting from the SpyTag display on p3 minor coat protein or p8 major coat protein yielded constructs with five copies of ScA displayed on p3 (ScA5-phage) and 50 copies of ScA on p8 protein (ScA50-phage). ScA remained active after conjugation. It could be easily produced directly from lysates of bacteria that express ScA. Display constructs of different valency can be injected into mice and analyzed by deep-sequencing of the DNA barcodes associated phage clones. In these multiplexed studies, we observed a density-dependent clearance rate in vivo. A known clearance mechanism of L-asparaginase is endocytosis by phagocytic cells. Our observations, thus, link the increase in density of the displayed protein with the increased rate of the endocytosis by cells in vivo. In conclusion, we demonstrate that a multivalent display of L-asparaginase on phage could be used to study the circulation life of this protein in vivo and such approach opens the possibility to use DNA sequencing to investigate multiplexed libraries of other multi-subunit proteins in vivo.Abstract Graphic
Kinetic Interval Measurement: A Tool to Characterize Thermal Reversion Dynamics of Light-switchable Fluorescent Proteins
Authors: von Trotha Tassilo , Jöhr Res , Fischer Jonas , Schendel Leonard C. , Gaub Hermann E. , Kluger Carleen 
Published: February 2021

AbstractLight-switchable proteins like Light-Oxygen-Voltage (LOV) domains can be used to control protein interactions and have been applied in vivo to manipulate cell behavior. The switching between dark and light state of LOV domains depends on temperature or their chemical microenvironment and can be tuned by point mutations. Here, we present a method called Kinetic Interval Measurement (KIM) to quantify the thermal reversion dynamics of light-switchable proteins by using a custom microplate reader. We show that this versatile method can be used to determine the reversion half-life of the excited state of LOV proteins in a reproducible, fast and simple manner consuming only small amounts of protein. The sensitivity of the method allows to report on changes in temperature and imidazole concentration as well as the photoswitching dynamics of LOV proteins in living cells.
A Ratio-Dependent Model of Replicator-Genetic Parasite Coevolution Demonstrates Instability of the Parasite-Free State
Authors: Berezovskaya Faina , Karev Georgy P. , Koonin Eugene V. 
Published: February 2021

AbstractNearly all organisms on earth are hosts to diverse genetic parasites including viruses and various types of mobile genetic elements. The emergence and persistence of genetic parasites was hypothesized to be an intrinsic feature of biological evolution. Here we examine this proposition by analysis of a ratio-dependent Lotka-Volterra type model of replicator(host)-parasite coevolution where the evolutionary outcome depends on the ratio of the host and parasite numbers. In a large, unbounded domain of the space of the model parameters, which include the replicator carrying capacity, the damage inflicted by the parasite, the replicative advantage of the parasites, and its mortality rate, the parasite-free equilibrium takes the form of a saddle and accordingly is unstable. Therefore, the evolutionary outcome is either the stable coexistence of the replicator and the parasite or extinction of both. Thus, the results of ratio-dependent model analysis are compatible with the hypothesis that genetic parasites are inherent to life.
Unraveling the role of MADS transcription factor complexes in apple tree dormancy using sequential DAP-seq
Authors: Falavigna Vítor da Silveira , Severing Edouard , Lai Xuelei , Estevan Joan , Farrera Isabelle , Hugouvieux Véronique , Revers Luís Fernando , Zubieta Chloe , Coupland George , Costes Evelyne , Andrés Fernando 
Published: February 2021

AbstractBackgroundThe effect of global warming on dormancy and flowering patterns of crop trees threatens world-wide fruit production and food security. In Rosaceous tree species, it is believed that a group of genes encoding MADS transcription factors (TFs) controls temperature-mediated dormancy cycle. These genes are similar toSHORT VEGETATIVE PHASE(SVP) fromArabidopsis thalianaand referred asDORMANCY-ASSOCIATED MADS-BOX(DAM) genes.ResultsBy making use of apple tree (Malusxdomestica) as a model for Rosaceous species, we have investigated the function of MADS TFs during the dormancy cycle. We found that MdDAM and other dormancy related MADS TFs form multimeric complexes with MdSVPa, and that MdSVPa is essential for the transcriptional complex activity. Then, for the first time in non-model plant species, we performed sequential DNA Affinity Purification sequencing (seq-DAP-seq) to define the genome-wide binding sites of these MADS TF complexes. Target genes associated with the binding sites were identified by combining seq-DAP-seq data with transcriptomics datasets obtained by the inducible glucocorticoid receptor expression system, and reanalyzing preexisting data related to dormancy cycle in apple trees.ConclusionWe have determined a gene regulatory network formed by MdSVPa-containing complexes that regulate the dormancy cycle in apple trees in response to environmental cues. Key genes identified with our genomic approach and the elucidated regulatory relationships provide leads for breeding fruit trees better adapted to changing climate conditions. Moreover, we provide novel molecular evidence on the evolutionary functional segregation between DAM and SVP proteins in the Rosaceae family.