bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic and kinetic analysis of novel Nitrospinae enriched by cell sorting
Authors: Mueller Anna J. , Jung Man-Young , Strachan Cameron R. , Herbold Craig W. , Kirkegaard Rasmus H. , Wagner Michael , Daims Holger 
Published: June 2020

AbstractChemolithoautotrophic nitrite-oxidizing bacteria (NOB) are key players in global nitrogen and carbon cycling. Members of the phylum Nitrospinae are the most abundant, known NOB in the oceans. To date, only two closely affiliated Nitrospinae species have been isolated, which are only distantly related to the environmentally abundant uncultured Nitrospinae clades. Here, we applied live cell sorting, activity screening, and subcultivation on marine nitrite-oxidizing enrichments to obtain novel marine Nitrospinae. Two binary cultures were obtained, each containing one Nitrospinae strain and one alphaproteobacterial heterotroph. The Nitrospinae strains represent two new genera, and one strain is more closely related to environmentally abundant Nitrospinae than previously cultured NOB. With an apparent half-saturation constant of 8.7±2.5 µM, this strain has the highest affinity for nitrite among characterized marine NOB, while the other strain (16.2±1.6 µM) andNitrospina gracilis(20.1±2.1 µM) displayed slightly lower nitrite affinities. The new strains andN. gracilisshare core metabolic pathways for nitrite oxidation and CO2fixation but differ remarkably in their genomic repertoires of terminal oxidases, use of organic N sources, alternative energy metabolisms, osmotic stress and phage defense. The new strains, tentatively named “CandidatusNitrohelix vancouverensis” and “CandidatusNitronauta litoralis”, shed light on the niche differentiation and potential ecological roles of Nitrospinae.
Modeling the variability of the electromotor command system of pulse electric fish
Authors: Lareo Ángel , Varona Pablo , Rodríguez Francisco B. 
Published: June 2020

AbstractMormyrids, a family of weakly electric fish, use electric pulses for communication and for extracting information from the environment (active electroreception). The electromotor system controls the timing of pulse generation. Ethological studies have described several sequences of pulse intervals (SPIs) which are related to distinct behaviors (e.g. mating or exploratory behaviors). Accelerations, scallops, rasps, and cessations are four SPI patterns reported in these fish, each showing characteristic temporal structures and large variability. This paper presents a computational model of the electromotor command circuit that reproduces SPI patterns as a function of the inputs to the model while keeping the same internal network configuration. The topology of the model is based on a simplified representation of the network with four neuron clusters (nuclei). An initialad hoctuned configuration (S-T) was built to reproduce nucleus characteristics and network topology as described by detailed morphological and electrophysiological studies. Then, a genetic algorithm (GA) was developed and applied to automatically tune the synaptic parameters of the model connectivity. Two different configurations obtained from the GA are presented here: one optimized to a set of synthetic examples of SPI patterns (S-GA) and another configuration adjusted to patterns recorded from freely-behavingGnathonemus Petersiispecimens (R-GA). Robustness analyses to input variability were performed to discard overfitting and assess validity. Results show that the set of SPI patterns are consistently reproduced, both for synthetic data and for recorded data. This model can be used as a tool to test novel hypotheses regarding temporal structure in electrogeneration.
Unravelling the debate on heme effects in COVID-19 infections
Authors: Hopp Marie-Thérèse , Domingo-Fernández Daniel , Gadiya Yojana , Detzel Milena S. , Schmalohr Benjamin F. , Steinbock Francèl , Imhof Diana , Hofmann-Apitius Martin 
Published: June 2020

AbstractThe SARS-CoV-2 outbreak was recently declared a worldwide pandemic. Infection triggers the respiratory tract disease COVID-19, which is accompanied by serious changes of clinical biomarkers such as hemoglobin and interleukins. The same parameters are altered during hemolysis, which is characterized by an increase in labile heme. We present two approaches that aim at analyzing a potential link between available heme and COVID-19 pathogenesis. Four COVID-19 related proteins, i.e. the host cell proteins ACE2 and TMPRSS2 as well as the viral protein 7a and S protein, were identified as potential heme binders. We also performed a detailed analysis of the common pathways induced by heme and SARS-CoV-2 by superimposition of knowledge graphs covering heme biology and COVID-19 pathophysiology. Herein, focus was laid on inflammatory pathways, and distinct biomarkers as the linking elements. Finally, the results substantially improve our understanding of COVID-19 infections and disease progression of patients with different clinical backgrounds and expand the diagnostic and treatment options.
The plant endoplasmic reticulum is both receptive and responsive to pathogen effectors
Authors: Breeze Emily , Vale Victoria , McLellan Hazel , Godiard Laurence , Grant Murray , Frigerio Lorenzo 
Published: June 2020

AbstractThe endoplasmic reticulum (ER) is the entry point to the secretory pathway and, as such, is critical for adaptive responses to biotic stress, when the demand for de novo synthesis of immunity-related proteins and signalling components increases significantly. Comprised of a network of interconnected tubules and cisternae, the architecture of the ER is highly pleomorphic and dynamic, rapidly remodelling to meet new cellular requirements. During infection with the hemi-biotrophic phytopathogen, Pseudomonas syringae pv. tomato DC3000, the ER in cells immediately adjacent to established bacterial colonies condenses into ‘knot-like’ structures, reminiscent of fenestrated sheets. Based on known temporal dynamics of pathogen effector delivery and initial bacterial multiplication, the timing of these observed morphological changes is rapid and independent of classical elicitor activation of pathogen-triggered immunity. To further investigate a role for ER reconfiguration in suppression of plant immunity we identified a conserved C-terminal tail-anchor domain in a set of pathogen effectors known to localize to the ER and used this protein topology in an in silico screen to identify putative ER-localised effectors within the effectorome of the oomycete Phytophthora infestans. Subsequent characterization of a subset of 15 candidate tail-anchored P. infestans effectors revealed that 11 localised to the ER and/or Golgi. Notably, transient expression of an ER-localised effector from the closely related oomycete, Plasmopara halstedii, reconfigured the ER network, revealing intimate association of labelled ER with perinuclear chloroplasts and clusters of chloroplasts, potentially facilitating retrograde signalling during plant defence.
Engineered extracellular vesicle decoy receptor-mediated modulation of the IL6 trans-signalling pathway in muscle
Authors: Conceição Mariana , Forcina Laura , Wiklander Oscar P. B. , Gupta Dhanu , Nordin Joel Z. , McClorey Graham , Mäger Imre , Görgens André , Lundin Per , Musarò Antonio , Wood Matthew J. A. , Andaloussi Samir EL , Roberts Thomas C. 
Published: June 2020

AbstractThe cytokine interleukin 6 (IL6) is a key mediator of inflammation that contributes to skeletal muscle pathophysiology. IL6 activates target cells by two different mechanisms, the classical and transsignalling pathways. While classical signalling is associated with the anti-inflammatory activities of the cytokine, the IL6 trans-signalling pathway mediates chronic inflammation and is therefore a target for therapeutic intervention. Extracellular vesicles (EVs) are natural, lipid-bound nanoparticles, with potential as targeted delivery vehicles for therapeutic macromolecules. Here, we engineered EVs to express IL6 signal transducer (IL6ST) decoy receptors to selectively inhibit the IL6 trans-signalling pathway. The potency of the IL6ST decoy receptor EVs was optimized by inclusion of a GCN4 dimerization domain and a peptide sequence derived from syntenin-1 which targets the decoy receptor to EVs. The resulting engineered EVs were able to efficiently inhibit activation of the IL6 transsignalling pathway in reporter cells, while having no effect on the IL6 classical signalling. IL6ST decoy receptor EVs, were also capable of blocking the IL6 trans-signalling pathway in C2C12 myoblasts and myotubes, thereby inhibiting the phosphorylation of STAT3 and partially reversing the anti-differentiation effects observed when treating cells with IL6/IL6R complexes. Treatment of a Duchenne muscular dystrophy mouse model with IL6ST decoy receptor EVs resulted in a reduction in STAT3 phosphorylation in the quadriceps and gastrocnemius muscles of these mice, thereby demonstratingin vivoactivity of the decoy receptor EVs as a potential therapy. Taken together, this study reveals the IL6 trans-signalling pathway as a promising therapeutic target in DMD, and demonstrates the therapeutic potential of IL6ST decoy receptor EVs.
BoardION: real-time monitoring of Oxford Nanopore Technologies devices
Authors: Bruno Aimeric , Aury Jean-Marc , Engelen Stefan 
Published: June 2020

AbstractSummaryOne of the main advantages of the Oxford Nanopore Technology (ONT) is the possibility of sequencing in real time. However, the ONT sequencing interface is not sufficient to explore the quality of sequencing data in depth and existing tools do not take full advantage of real-time data streaming. We present BoardION, an interactive web application, dedicated to sequencing platforms, for real-time monitoring of all ONT sequencing devices (MinION, Mk1C, GridION and PromethION). BoardION allows users to easily explore sequencing metrics and optimize the quantity and the quality of the generated data during the experiment. It also enables the comparison of several flowcells to evaluate the library preparation protocols or the quality of input samples.AvailabilitySource code and a Docker image are available athttp://www.genoscope.cns.fr/boardion/Contactstefan.engelen@genoscope.cns.fr
Designed peptides as potential fusion inhibitors against SARA-CoV-2 coronavirus infection
Authors: Chen Ke , Bai Shihao , Zou Xin , Hao Jie , Da Lin-tai , Han Ze-Guang 
Published: June 2020

ABSTRACTInspired by fusion-inhibitory peptides from heptad repeat 1 (HR1) and heptad repeat 2 (HR2) domains from human immuno-deficiency virus type 1 (HIV-1) envelope glycoprotein gp41 and severe acute respiratory syndrome-coronavirus (SARS-CoV) based on viral fusogenic mechanism in the present work, we provided a similar approach to design the synthesized peptides against the entry into host cells of SARA-CoV-2 virus that causes 2019 novel coronavirus disease (COVID-19). These peptides derived from HR1 and HR2 of SARA-CoV-2 spike protein were further tested for their interaction and potential fusion possibility through circular dichroism spectrum. Here we used the peptide COVID-2019-HR1P1 (40 amino acids) as the target, which was derived from HR1 of SARA-CoV-2 spike protein, while the designed peptides including COVID-2019-HR2P1 (37 amino acids), COVID-2019-HR2P2 (32 amino acids) and others derived from HR2 of SARA-CoV-2 were tested for their binding to COVID-2019-HR1P1. Interestingly, results showed that both COVID-2019-HR2P1 and COVID-2019-HR2P2 can form the complex with COVID-2019-HR1P1, respectively. This implied that these designed peptides could play an important role in blocking SARA-CoV-2 entry into mammalian host cells via viral fusogenic mechanism, and thus could be used for preventing SARA-CoV-2 infection.
The impact of viral transport media on PCR assay results for the detection of nucleic acid from SARS-CoV-2 and other viruses
Authors: Kirkland P.D. , Frost M.J. 
Published: June 2020

AbstractDuring the 2020 SARS-Cov-2 pandemic, there has been an acute shortage of viral transport medium. Many different products have been used to meet the demands of large-scale diagnostic and surveillance testing. The stability of SARS-Cov-2 RNA was assessed in several commercially produced transport media and an in-house solution. Coronavirus RNA was rapidly destroyed in the commercial transport media though the deleterious effects on intact virus were limited. Similar results were obtained for a Type A influenza virus. There was reduced detection of both virus and nucleic acid when a herpesvirus sample and purified DNA were tested. Collectively these data showed that the commercial viral transport media contained nucleases or similar substances and may seriously compromise diagnostic and epidemiological investigations.Recommendations to include foetal bovine serum as a source of protein to enhance the stabilising properties of viral transport media are contraindicated. Almost all commercial batches of foetal bovine serum contain pestiviruses and at times other bovine viruses. In addition to the potential for there to be nucleases in the transport medium, the presence of these viruses and other extraneous nucleic acid in samples may compromise the interpretation of sequence data. The inclusion of foetal bovine serum presents a biosecurity risk for the movement of animal pathogens and renders these transport media unsuitable for animal disease diagnostic applications. While these transport media may be suitable for virus culture purposes, there could be misleading results if used for nucleic acid-based tests. Therefore, these products should be evaluated to ensure fitness for purpose.
Discovery and fine-mapping of kidney function loci in first genome-wide association study in Africans
Authors: Fatumo Segun , Chikowore Tinashe , Kalyesubula Robert , Nsubuga Rebecca N , Asiki Gershim , Nashiru Oyekanmi , Seeley Janet , Crampin Amelia C , Nitsch Dorothea , Smeeth Liam , Kaleebu Pontiano , Nyirenda Moffat , Burgess Stephen , Franceschini Nora , Morris Andrew P , Tomlinson Laurie , Newton Robert 
Published: June 2020

AbstractGenome-wide association studies (GWAS) for kidney function have uncovered hundreds of risk loci, primarily in populations of European ancestry. We conducted the first GWAS of estimated glomerular filtration rate (eGFR) in Africa in 3288 Ugandans and replicated the findings in 8224 African Americans. We identified two loci associated with eGFR at genome-wide significance (p<5×10−8). The most significantly associated variant (rs2433603, p=2.4×10−9) inGATMwas distinct from previously reported signals. A second association signal mapping nearHBB(rs141845179, p=3.0×10−8) was not significant after conditioning on a previously reported SNP (rs334) for eGFR. However, fine-mapping analyses highlighted rs141845179 to be the most likely causal variant at the HBB locus (posterior probability of 0.61). A trans-ethnic GRS of eGFR constructed from previously reported lead SNPs was not predictive into the Ugandan population, indicating that additional large-scale efforts in Africa are necessary to gain further insight into the genetic architecture of kidney disease.
Comparative analysis of non structural protein 1 of SARS-CoV2 with SARS-CoV1 and MERS-CoV: An in silicostudy
Authors: Chaudhuri Ankur 
Published: June 2020

AbstractThe recently emerged SARS-CoV2 caused a major pandemic of coronavirus disease (COVID-19). Non structural protein 1 (nsp1) is found in all beta coronavirus that causes several severe respiratory diseases. This protein is considered as a virulence factor and has an important role in pathogenesis. This study aims to elucidate the structural conformations of non structural protein 1 (nsp1), prediction of epitope sites and identification of important residues for targeted therapy against COVID-19. In this study, molecular modelling coupled with molecular dynamics simulations were performed to analyse the conformational change of nsp1 of SARS-CoV1, SARS-CoV2 and MERS-CoV at molecular level. Principal component analysis escorted by free energy landscape revealed that SARS-CoV2 nsp1 protein shows greater flexibility, compared to SARS-CoV1 and MERS-CoV nsp1. From the sequence alignment, it was observed that 28 mutations are present in SERS-CoV2 nsp1 protein compared to SERS-CoV1 nsp1. Several B-cell and T-cell epitopes were identified by immunoinformatics approach. SARS-CoV2 nsp1 protein binds with the interface region of the palm and finger domain of POLA1 by using hydrogen bond and salt bridge interactions. These findings can be used to develop therapeutics specific against COVID-19.
SOX2 is required independently in both stem and differentiated cells for pituitary tumorigenesis inp27null mice
Authors: Moncho-Amor Veronica , Chakravarty Probir , Galichet Christophe , Matheu Ander , Lovell-Badge Robin , Rizzoti Karine 
Published: June 2020

AbstractLoss of P27 predominantly results in development of murine pituitary intermediate lobe (IL) tumours. We previously showed that the pleiotropic protein P27 can drive repression of the transcription factorSox2. This interaction plays an important role during development ofp27-/-IL tumours because loss of one copy ofSox2diminishes tumorigenesis. Here, we have explored the cellular origin and mechanisms underlying melanotroph tumorigenesis inp27-/-IL. We show that IL hyperplasia is associated with reduced cellular differentiation, while levels of SOX2 increase in both stem cells (SC) and melanotrophs. Using loss-of-function and lineage tracing approaches, we demonstrate that SOX2 is required cell-autonomously inp27-/-melanotrophs and SCs for tumorigenesis. This is supported by studies deleting theSox2regulatory region 2 (Srr2), which is the target of P27 repressive action. Single cell transcriptomic analysis reveals that activation of a SOX2-dependent MAPK pathway in SCs is important forp27-/-tumorigenesis. Our data highlight different roles of SOX2 following loss ofp27, according to the cellular context. Furthermore, we uncover a tumor-promoting function for SCs, which is SOX2-dependant. In conclusion, our results imply that targeting SCs, in addition to tumour cells themselves, may represent an efficient anti-tumoral strategy in certain contexts.
Lipid suppressed and tissue-fraction corrected metabolic distributions in human central brain structures using 2D1H Magnetic Resonance Spectroscopic Imaging at 7 tesla
Authors: Bhogal Alex A. , Broeders Tommy A.A. , Morsinkhof Lisan , Edens Mirte , Nassirpour Sahar , Chang Paul , Klomp Dennis , Vinkers Christiaan H. , Wijnen Jannie P. 
Published: June 2020

ABSTRACTMagnetic resonance spectroscopic imaging (MRSI) has the potential to add a layer of understanding of the neurobiological mechanisms underlying brain diseases, disease progression, and treatment efficacy. Limitations related to metabolite fitting of low SNR data, signal variations due to partial volume effects, acquisition and extra-cranial lipid artefacts, along with clinically relevant aspects such as scan-time constraints, are among the factors that hinder the widespread implementation ofin vivoMRSI. The aim of this work was to address these factors and to develop an acquisition, reconstruction and post-processing pipeline to derive lipid suppressed metabolite values based on Free Induction Decay (FID-MRSI) measurements made using a 7 tesla MR scanner. Anatomical images were used to perform high-resolution (1mm3) partial-volume correction to account for grey matter, white matter and cerebral-spinal fluid signal contributions. Implementation of automatic quality control thresholds and normalization of metabolic maps from 23 subjects to the MNI standard atlas facilitated the creation of high-resolution average metabolite maps of several clinically relevant metabolites in central brain regions, while accounting for macromolecular distributions. Reported metabolite values include glutamate, choline, (phospo)creatine, myo-inositol, glutathione, N-acetyl aspartyl glutamate(and glutamine) and N-acetyl aspartate. MNI-registered average metabolite maps facilitate group-based analysis; thus offering the possibility to mitigate uncertainty in variable MRSI.
Biased Auditory Nerve Central Synaptopathy Exacerbates Age-related Hearing Loss
Authors: Wang Meijian , Zhang Chuangeng , Lin Shengyin , Wang Yong , Seicol Benjamin J. , Ariss Robert W. , Xie Ruili 
Published: June 2020

SUMMARYSound information is transmitted from the cochlea to the brain by different subtypes of spiral ganglion neurons (SGN), which show varying degrees of vulnerbility under pathological conditions. It remains unclear how information from these SGNs reassemble among target neurons in the cochlear nucleus (CN) at the auditory nerve (AN) central synapses, and how different synapses change during hearing loss. Combining immunohistochemistry with electrophysiology, we investigated the giant endbulb of Held synapses and their postsynaptic bushy neurons in mice under normal hearing and age-related hearing loss (ARHL). We found that calretinin-expressing and non-calretinin-expressing endbulbs converge at continuously different ratios onto bushy neurons with varying physiological properties. Endbulbs degenerate during ARHL, and the degeneration is more severe in non-calretinin-expressing synapses, which correlates with a gradual decrease in neuronal subpopulation predominantly innervated by these inputs. Our findings suggest that biased AN central synaptopathy and shifted CN neuronal composition underlie reduced auditory input and altered central auditory processing during ARHL.
Reverse-engineering Recurrent Neural Network solutions to a hierarchical inference task for mice
Authors: Schaeffer Rylan , Khona Mikail , Meshulam Leenoy ,   International Brain Laboratory, Fiete Ila Rani 
Published: June 2020

AbstractWe study how recurrent neural networks (RNNs) solve a hierarchical inference task involving two latent variables and disparate timescales separated by 1-2 orders of magnitude. The task is of interest to the International Brain Laboratory, a global collaboration of experimental and theoretical neuroscientists studying how the mammalian brain generates behavior. We make four discoveries. First, RNNs learn behavior that is quantitatively similar to ideal Bayesian baselines. Second, RNNs perform inference by learning a two-dimensional subspace defining beliefs about the latent variables. Third, the geometry of RNN dynamics reflects an induced coupling between the two separate inference processes necessary to solve the task. Fourth, we perform model compression through a novel form of knowledge distillation on hidden representations – Representations and Dynamics Distillation (RADD)– to reduce the RNN dynamics to a low-dimensional, highly interpretable model. This technique promises a useful tool for interpretability of high dimensional nonlinear dynamical systems. Altogether, this work yields predictions to guide exploration and analysis of mouse neural data and circuity.