bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene functional networks and autism spectrum characteristics in young people with intellectual disability
Authors: Brkić Diandra , Ng-Cordell Elise , O’Brien Sinéad , Scerif Gaia , Astle Duncan , Baker Kate 
Published: May 2020

AbstractBackgroundGenes associated with Intellectual disability (ID) can be grouped into networks according to gene function. This study asked whether individuals with ID show differences in autism spectrum characteristics (ASC), depending on the functional network membership of their rare, pathogenicde novogenetic variants.MethodsChildren and young people with ID of known genetic origin were allocated to two broad functional network groups: synaptic physiology (n=29) or chromatin regulation (n=23). We applied principle components analysis to the Social Responsiveness Scale to map the structure of ASC in this population, and identified three components – Inflexibility, Social Understanding and Social Motivation. We then used Akaike Information Criterion (AIC) to test the best fitting models for predicting ASC components, including demographic factors (age, gender), non-ASC behavioural factors (global adaptive function, anxiety, hyperactivity, inattention) and gene functional networks.ResultsWe found that, when other factors are accounted for, the chromatin regulation group showed higher levels of Inflexibility. We also observed contrasting predictors of ASC within each network group. Within the chromatin regulation group, Social Understanding was associated with inattention, and Social Motivation was predicted by hyperactivity. Within the synaptic group, Social Understanding was associated with hyperactivity, and Social Motivation was linked to anxiety.ConclusionWe report that gene functional networks can predict Inflexibility, but not other ASC dimensions. Contrasting behavioural associations within each group suggests network-specific developmental pathways from genomic variation to autism. Simple classification of neurodevelopmental disorder genes as high risk or low risk for autism is unlikely to be valid or useful.
SIFNet: Electromagnetic Source Imaging Framework Using Deep Neural Networks
Authors: Sun Rui , Sohrabpour Abbas , Ye Shuai , He Bin 
Published: May 2020

AbstractElectroencephalography (EEG) and magnetoencephalography (MEG) are used to measure brain activity, noninvasively, and are useful tools for brain research and clinical management of brain disorders. Tremendous effort has been made in solving the inverse source imaging problem from EEG/MEG measurements. This is a challenging ill-posed problem, since the number of measurements is much smaller than the number of possible sources in the brain. Various methods have been developed to estimate underlying brain sources from noninvasive EEG/MEG as this can offer insight about the underlying brain electrical activity with significantly improved spatial resolution. In this work, we propose a novel data-drivenSource Imaging Frameworkusing deep learning neural networks (SIFNet), where (1) a simulation pipeline is designed to model realistic brain activation and EEG/MEG signals to train generalizable neural networks, (2) and a residual convolutional neural network is trained using the simulated data, capable of estimating source distributions from EEG/MEG recordings. The performance of our proposed SIFNet approach is evaluated in a series of computer simulations, which indicates the excellent performance of SIFNet outperforming conventional weighted minimum norm algorithms that were tested in this work. The SIFNet is further tested by analyzing interictal EEG data recorded in a clinical setting from a focal epilepsy patient. The results of this clinical data analysis indicate accurate localization of epileptogenic activity as validated by the epileptogenic zone clinically determined in this patient. In sum, the proposed SIFNet approach promises to offer an alternative solution to the EEG/MEG inverse source imaging problem, shows promising signs of being robust against measurement noise, and is easy to implement, therefore, being translatable to clinical practice.
Broadly reactive influenza antibodies are not limited by germinal center competition with high affinity antibodies
Authors: Keating Rachael , Johnson Jenny L. , Brice David C. , Labombarde Jocelyn G. , Dent Alexander L. , McGargill Maureen A. 
Published: May 2020

ABSTRACTEnhancing the generation of broadly reactive influenza antibodies is a pertinent goal towards developing a universal influenza vaccine. While antibodies that bind conserved influenza epitopes have been identified in humans, the frequency of these antibodies is typically very low. The predominant theory is that antibodies specific for conserved influenza epitopes are limited in germinal centers by competition with high affinity antibodies specific for the variable region of the virus. Here, we show that reducing germinal center formation and removing competition with high affinity antibodies was not sufficient to increase broadly reactive influenza antibodies or enhance protection against distinct influenza subtypes. These data disprove the prevailing hypothesis that broadly reactive influenza antibodies are rare due to competition in germinal centers. Additionally, levels of IgM antibodies specific for the variable region of HA persisted in mice in the absence of germinal centers, further demonstrating that immunodominance can be established independent of germinal centers. Our data also highlight the protective capacity of germinal center-independent IgM antibodies, which are not typically considered when testing correlates of protection, and offer an alternate target for delivering a universal influenza vaccine.IMPORTANCEIt is estimated that 250,000 – 650,000 individuals worldwide die each year from seasonal influenza infections. Current vaccines provide little protection against newly emerging strains. Thus, considerable effort is focused on enhancing the generation of broadly reactive influenza antibodies in order to develop a universal influenza vaccine. However, broadly reactive antibodies are rare and the factors that limit their generation are not completely understood. Our data disprove the prevailing hypothesis that broadly reactive influenza antibodies are rare due to completion in the germinal centers with antibodies to the variable HA head. Understanding the factors limiting antibodies specific for conserved regions of the influenza virus is imperative for developing a universal vaccine, which could potentially circumvent a global pandemic
A spatially-explicit model of stabilizing selection for improving phylogenetic inference
Authors: Beaulieu Jeremy M. , O’Meara Brian C. , Gilchrist Michael A. 
Published: May 2020

AbstractUltraconserved elements (UCEs) are stretches of hundreds of nucleotides with highly conserved cores flanked by variable regions. Although the selective forces responsible for the preservation of UCEs are unknown, they are nonetheless believed to contain phylogenetically meaningful information from deep to shallow divergence events. Phylogenetic applications of UCEs assume the same degree of rate heterogeneity applies across the entire locus, including variable flanking regions. We present a Wright-Fisher model of selection on nucleotides (SelON) which includes the effects of mutation, drift, and spatially varying, stabilizing selection for an optimal nucleotide sequence. The SelON model assumes the strength of stabilizing selection follows a position dependent Gaussian function whose exact shape can vary between UCEs. We evaluate SelON by comparing its performance to a simpler and spatially invariant GTR+Γmodel using an empirical dataset of 400 vertebrate UCEs used to determine the phylogenetic position of turtles. We observe much improvement in model fit of SelON over the GTR+Γmodel, and support for turtles as sister to lepidosaurs. Overall, the UCE specific parameters SelON estimates provide a compact way of quantifying the strength and variation in selection within and across UCEs. SelON can also be extended to include more realistic mapping functions between sequence and stabilizing selection as well as allow for greater levels of rate heterogeneity. By more explicitly modeling the nature of selection on UCEs, SelON and similar approaches can be used to better understand the biological mechanisms responsible for their preservation across highly divergent taxa and long evolutionary time scales.
Antibody repertoire induced by SARS-CoV-2 spike protein immunogens
Authors: Ravichandran Supriya , Coyle Elizabeth M. , Klenow Laura , Tang Juanjie , Grubbs Gabrielle , Liu Shufeng , Wang Tony , Golding Hana , Khurana Surender 
Published: May 2020

ABSTRACTMultiple vaccine candidates against SARS-CoV-2 based on viral spike protein are under development. However, there is limited information on the quality of antibody response generated following vaccination by these vaccine modalities. To better understand antibody response induced by spike protein-based vaccines, we immunized rabbits with various SARS-CoV-2 spike protein antigens: S-ectodomain (S1+S2) (aa 16-1213), which lacks the cytoplasmic and transmembrane domains (CT-TM), the S1 domain (aa 16-685), the receptor-binding domain (RBD) (aa 319-541), and the S2 domain (aa 686-1213 as control). Antibody response was analyzed by ELISA, Surface Plasmon Resonance (SPR) against different Spike proteins in native conformation, and a pseudovirion neutralization assay to measure the quality and function of the antibodies elicited by the different Spike antigens. All three antigens (S1+S2 ectodomain, S1 domain, and RBD) generated strong neutralizing antibodies against SARS-CoV-2. Vaccination induced antibody repertoire was analyzed by SARS-CoV-2 spike Genome Fragment Phage Display Libraries (SARS-CoV-2 GFPDL), which identified immunodominant epitopes in the S1, S1-RBD and S2 domains. Furthermore, these analyses demonstrated that surprisingly the RBD immunogen elicited a higher antibody titer with 5-fold higher affinity antibodies to native spike antigens compared with other spike antigens. These findings may help guide rational vaccine design and facilitate development and evaluation of effective therapeutics and vaccines against COVID-19 disease.One Sentence SummarySARS-CoV-2 Spike induced immune response
CoV3D: A database and resource for high resolution coronavirus protein structures
Authors: Gowthaman Ragul , Guest Johnathan D. , Yin Rui , Adolf-Bryfogle Jared , Schief William R. , Pierce Brian G. 
Published: May 2020

AbstractSARS-CoV-2, the etiologic agent behind COVID-19, exemplifies the general threat to global health posed by coronaviruses. The urgent need for effective vaccines and therapies is leading to a rapid rise in the number of high resolution structures of SARS-CoV-2 proteins that collectively reveal a map of virus vulnerabilities. To assist structure-based design of vaccines and therapeutics against SARS-CoV-2 and other coronaviruses, we have developed CoV3D, a database and resource for coronavirus protein structures, which is updated on a weekly basis. CoV3D provides users with comprehensive sets of structures of coronavirus proteins and their complexes with antibodies, receptors, and small molecules. Integrated molecular viewers allow users to visualize structures of the spike glycoprotein, which is the major target of neutralizing antibodies and vaccine design efforts, as well as sets of spike-antibody complexes, spike sequence variability, and known polymorphisms. In order to aid structure-based design and analysis of the spike glycoprotein, CoV3D permits visualization and download of spike structures with modeled N-glycosylation at known glycan sites, and contains structure-based classification of spike conformations, generated by unsupervised clustering. CoV3D can serve the research community as a centralized reference and resource for spike and other coronavirus protein structures, and is available at: https://cov3d.ibbr.umd.edu.
A Computational Toolset for Rapid Identification of SARS-CoV-2, other Viruses, and Microorganisms from Sequencing Data
Authors: Chen Shifu , He Changshou , Li Yingqiang , Li Zhicheng , Melançon Charles E 
Published: May 2020

ABSTRACTIn this paper, we present a toolset and related resources for rapid identification of viruses and microorganisms from short-read or long-read sequencing data. We present fastv as an ultra-fast tool to detect microbial sequences present in sequencing data, identify target microorganisms, and visualize coverage of microbial genomes. This tool is based on the k-mer mapping and extension method. K-mer sets are generated by UniqueKMER, another tool provided in this toolset. UniqueKMER can generate complete sets of unique k-mers for each genome within a large set of viral or microbial genomes. For convenience, unique k-mers for microorganisms and common viruses that afflict humans have been generated and are provided with the tools. As a lightweight tool, fastv accepts FASTQ data as input, and directly outputs the results in both HTML and JSON formats. Prior to the k-mer analysis, fastv automatically performs adapter trimming, quality pruning, base correction, and other pre-processing to ensure the accuracy of k-mer analysis. Specifically, fastv provides built-in support for rapid SARS-CoV-2 identification and typing. Experimental results showed that fastv achieved 100% sensitivity and 100% specificity for detecting SARS-CoV-2 from sequencing data; and can distinguish SARS-CoV-2 from SARS, MERS, and other coronaviruses. This toolset is available at:https://github.com/OpenGene/fastv.
Elements at the 5′ end ofXistharbor SPEN-independent transcriptional antiterminator activity
Authors: Trotman Jackson B. , Lee David M. , Cherney Rachel E. , Kim Sue O. , Inoue Kaoru , Schertzer Megan D. , Bischoff Steven R. , Cowley Dale O. , Calabrese J. Mauro 
Published: May 2020

AbstractTheXistlncRNA requires Repeat A, a conserved RNA element located in its 5′ end, to induce gene silencing during X-chromosome inactivation. Intriguingly, Repeat A is also required for the production ofXist. While silencing by Repeat A requires the protein SPEN, how Repeat A promotesXistproduction remains unclear. We report that in mouse embryonic stem cells, expression of a transgene comprising the first two kilobases ofXist(Xist-2kb) causes transcriptional readthrough of multiple downstream polyadenylation sequences. Readthrough required Repeat A and the ~750 nucleotides downstream but did not require SPEN. Despite associating with SPEN and chromatin,Xist-2kb did not robustly silence transcription, whereas a transgene comprisingXist’s first 5.5 kilobases robustly silenced transcription and read through its polyadenylation sequence. Longer, splicedXisttransgenes also induced robust silencing yet terminated efficiently. Thus, in contexts examined here,Xistrequires sequence elements beyond its first two kilobases to robustly silence transcription, and the 5′ end ofXistharbors SPEN-independent transcriptional antiterminator activity that can repress proximal cleavage and polyadenylation. In endogenous contexts, this antiterminator activity may help produce full-lengthXistRNA while rendering theXistlocus resistant to silencing by the same repressive complexes that the lncRNA recruits to other genes.
Phthiocerol dimycocerosates fromMycobacterium tuberculosisincrease the membrane activity of bacterial effectors and host receptors
Authors: Augenstreich Jacques , Haanappel Evert , Sayes Fadel , Simeone Roxane , Guillet Valérie , Mazeres Serge , Chalut Christian , Mourey Lionel , Brosch Roland , Guilhot Christophe , Astarie-Dequeker Catherine 
Published: May 2020

AbstractMycobacterium tuberculosis(Mtb) synthesizes a variety of atypical lipids that are exposed at the cell surface and help the bacterium infect macrophages and escape elimination by the cell’s immune responses. In the present study, we investigate the mechanism of action of one family of hydrophobic lipids, the phthiocerol dimycocerosates (DIM/PDIM), major lipid virulence factors. DIM are transferred from the envelope ofMtbto host membranes during infection. Using the polarity-sensitive fluorophore C-Laurdan, we visualized that DIM increase the membrane polarity of a supported lipid bilayer put in contact with mycobacteria, even beyond the site of contact. We observed that DIM activate the complement receptor 3, a predominant receptor for phagocytosis ofMtbby macrophages. DIM also increased the activity of membrane-permeabilizing effectors ofMtb, among which the virulence factor EsxA. This is consistent with previous observations that DIM helpMtbdisrupt host cell membranes. Taken together, our data show that transferred DIM spread within the target membrane, remodel lipid organization and increase the activity of host cell receptors and bacterial effectors, diverting in a nonspecific manner host cell functions. We therefore bring new insight into the molecular mechanisms by which DIM increaseMtb’scapability to escape the cell’s immune responses.
A single point mutation in thePlasmodium falciparum ftsh1metalloprotease confers actinonin resistance
Authors: Goodman Christopher D , Uddin Taher , Spillman Natalie J , McFadden Geoffrey I 
Published: May 2020

AbstractThe antibiotic actinonin kills malaria parasites (Plasmodium falciparum) by interfering with apicoplast function. Early evidence suggested that actinonin inhibited prokaryote-like post-translational modification in the apicoplast; mimicking its activity against bacteria. However, Amberg Johnson et al. (2017) identified the metalloproteaseTgFtsH1 as the target of actinonin in the related parasiteToxoplasma gondiiand implicated actinonin in the inhibition ofP. falciparumgrowth. The authors were not, however, able to recover actinonin resistant malaria parasites, leaving the specific target of actinonin uncertain. We generated actinonin resistantP. falciparumbyin vitroselection and identified a specific sequence change inPfftsH1associated with resistance. Re-Introduction of this point mutation using CRISPr-Cas9 allelic replacement was sufficient to confer actinonin resistance inP. falciparum. Our data unequivocally identifiesPfFtsH1 as the target of actinonin and suggests that actinonin should not be included in the highly valuable collection of “irresistible” drugs for combatting malaria.
A new paradigm for Prelamin A proteolytic processing by ZMPSTE24: the upstream SY^LL cleavage occurs first and there is no CaaX processing by ZMPSTE24
Authors: Nie Laiyin , Spear Eric , Babatz Timothy D. , Quigley Andrew , Dong Yin Yao , Chu Amy , Rotty Bérénice , Chalk Rod , Mukhopadhyay Shubhashish M.M. , Burgess-Brown Nicola A. , Pike Ashley C.W. , Young Stephen G. , Michaelis Susan , Carpenter Elisabeth P. 
Published: May 2020

AbstractHuman ZMPSTE24, an integral membrane zinc metalloprotease, is required for conversion of prelamin A to mature lamin A, a component of the nuclear lamina and failure of this processing causes premature ageing disorders. ZMPSTE24 has also been implicated in both type 2 diabetes mellitus and in viral-host response mechanisms, but to date its only confirmed substrate is the precursor for lamin A. Prelamin A is thought to undergo four C-terminal post-translational modifications in the following order: farnesylation, SIM tripeptide cleavage, carboxymethylation and upstream “SY^LL” cleavage. Here we present evidence that the sequence of events does not follow the accepted dogma. We assessed cleavage of long human prelamin A sequence peptides by purified human ZMPSTE24 combined with FRET and mass spectrometry to detect products. Surprisingly, we found that the “SY^LL” cleavage occurs before and independent of the C-terminal CSIM modifications. We also found that ZMPSTE24 does not perform the predicted C^SIM tripeptide cleavage, but rather it removes an IM dipeptide. ZMPSTE24 can perform a tripeptide cleavage with a canonical CaaX box (C: cysteine; a: aliphatic; X: any residue), but the C-terminus of prelamin A is not a true CaaX sequence. Regardless of the C-terminal modifications of prelamin A, ZMPSTE24 can perform upstream SY^LL cleavage, thus removing the unwanted farnesylated C-terminus. Therefore, it is failure of SY^LL cleavage, not the C-terminal processing that is the likely cause of progeroid disorders.
Delayed global feedback in the genesis and stability of spatiotemporal patterns in paced biological excitable media
Authors: Song Zhen , Qu Zhilin 
Published: May 2020

AbstractA multi-scale approach was used to investigate the roles of delayed global feedback (DGF) in the genesis and stability of spatiotemporal patterns in periodically-paced excitable media. Patterns that are temporal period-2 (P2) and spatially concordant (in-phase) or discordant (out-of-phase) were investigated. First, simulations were carried out using a generic spatiotemporal model composed of coupled FitzHugh-Nagumo units with DGF. When DGF is absent, concordant and discordant P2 patterns occur depending on initial conditions. The discordant P2 patterns are spatially random. When the DGF is negative, only concordant P2 patterns exist. When the DGF is positive, both concordant and discordant P2 patterns can occur. The discordant P2 patterns are still spatially random, but they satisfy that the global signal exhibits a temporal period-1 behavior. Second, to validate the spatiotemporal dynamics in a biological system, simulations were carried out using a 3-dimensional physiologically detailed ventricular myocyte model. This model can well capture the intracellular calcium release patterns widely observed in experiments. The properties of DGF were altered by changing ionic currents or clamping voltage. The spatiotemporal pattern dynamics of calcium release in this model match precisely with those of the generic model. Finally, theoretical analyses were carried out using a coupled map lattice model with DGF, which reveals the instabilities and bifurcations leading to the spatiotemporal dynamics and provides a general mechanistic understanding of the role of DGF in the genesis, selection, and stability of spatiotemporal patterns in paced excitable media.Author SummaryUnderstanding the mechanisms of pattern formation in biological systems is of great importance. Here we investigate the dynamical mechanisms by which delayed global feedback affects pattern formation and stability in periodically-paced biological excitable media, such as cardiac or neural cells and tissue. We focus on the formation and stability of the temporal period-2 and spatially in-phase and out-of-phase patterns. Using a multi-scale modeling approach, we show that when the delayed global feedback is negative, only the spatially in-phase patterns are stable; when the feedback is positive, both spatially in-phase and out-of-phase patterns are stable. Also, under the positive feedback, the out-of-phase patterns are spatially random but satisfy that the global signals are temporal period-1 solutions.