bluuebunny/crossref_metadata_2025_split huggingface dataset:
The representation of priors and decisions in parietal cortex
Authors: Marshall Tom R. , Ruesseler Maria , Hunt Laurence T. , O’Reilly Jill X. 
Published: May 2021

AbstractAnimals actively sample their environment through orienting actions such as saccadic eye movements. Saccadic targets are selected based both on sensory evidence immediately preceding the saccade, and a ‘salience map’ or prior built up over multiple saccades. In the primate cortex, the selection of each individual saccade depends on competition between target-selective cells that ramp up their firing rate to saccade release. However it is less clear how a cross-saccade prior might be represented, either in neural firing or through an activity-silent mechanism such as modification of synaptic weights on sensory inputs. Here we present evidence from magnetoencephalography for two distinct processes underlying the selection of the current saccade, and the representation of the prior, in human parietal cortex. While the classic ramping decision process for each saccade was reflected in neural firing rates (measured in the event related field), a prior built up over multiple saccades was represented via modulation of the gain on sensory inputs from the preferred target, as evidenced by rapid frequency tagging. A cascade of computations over time (initial representation of the prior, followed by evidence accumulation and then updating) provides a mechanism by which a salience map may be built up across saccades in parietal cortex. It also provides insight into why evidence accumulation signals are present in parietal cortex, when inactivation of the region has been shown not to affect performance on single-trial tasks.
Classification of non-coding variants with high pathogenic impact
Authors: Moyon Lambert , Berthelot Camille , Louis Alexandra , Nguyen Nga Thi Thuy , Crollius Hugues Roest 
Published: May 2021

AbstractWhole genome sequencing is increasingly used to diagnose medical conditions of genetic origin. While both coding and non-coding DNA variants contribute to a wide range of diseases, most patients who receive a WGS-based diagnosis today harbour a protein-coding mutation. Functional interpretation and prioritization of non-coding variants represents a persistent challenge, and disease-causing non-coding variants remain largely unidentified. Depending on the disease, WGS fails to identify a candidate variant in 20-80% of patients, severely limiting the usefulness of sequencing for personalised medicine. Here we present FINSURF, a machine-learning approach to predict the functional impact of non-coding variants in regulatory regions. FINSURF outperforms state-of-the-art methods, owing to control optimisation during training. In addition to ranking candidate variants, FINSURF also delivers diagnostic information on functional consequences of mutations. We applied FINSURF to a diverse set of 30 diseases with described causative non-coding mutations, and correctly identified the disease-causative non-coding variant within the ten top hits in 22 cases. FINSURF is implemented as an online server to as well as custom browser tracks, and provides a quick and efficient solution to prioritize candidate non-coding variants in realistic clinical settings.
Membrane permeabilization is mediated by distinct epitopes in mouse and human orthologs of the necroptosis effector, MLKL
Authors: Sethi Ashish , Horne Christopher R. , Fitzgibbon Cheree , Wilde Karyn , Davies Katherine A. , Garnish Sarah E. , Jacobsen Annette V. , Samson André L. , Hildebrand Joanne M. , Wardak Ahmad , Czabotar Peter E. , Petrie Emma J. , Gooley Paul R. , Murphy James M. 
Published: May 2021

ABSTRACTNecroptosis is a lytic programmed cell death pathway with origins in innate immunity that is frequently dysregulated in inflammatory diseases. The terminal effector of the pathway, MLKL, is licensed to kill following phosphorylation of its pseudokinase domain by the upstream regulator, RIPK3 kinase. Phosphorylation provokes the unleashing of MLKL’s N-terminal four-helix bundle (4HB or HeLo) domain, which binds and permeabilizes the plasma membrane to cause cell death. The precise mechanism by which the 4HB domain permeabilizes membranes, and how the mechanism differs between species, remains unclear. Here, we identify the membrane binding epitope of mouse MLKL using NMR spectroscopy. Using liposome permeabilization and cell death assays, we validate K69 in the α3 helix, W108 in the α4 helix, and R137/Q138 in the first brace helix as crucial residues for necroptotic signaling. This epitope differs from the phospholipid binding site reported for human MLKL, which comprises basic residues primarily located in the α1 and α2 helices. In further contrast to human and plant MLKL orthologs, in which the α3-α4 loop forms a helix, this loop is unstructured in mouse MLKL in solution. Together, these findings illustrate the versatility of the 4HB domain fold, whose lytic function can be mediated by distinct epitopes in different orthologs.
Multi-omics prediction of oat agronomic and seed nutritional traits across environments and in distantly related populations
Authors: Hu Haixiao , Campbell Malachy T. , Yeats Trevor H. , Zheng Xuying , Runcie Daniel E. , Covarrubias-Pazaran Giovanny , Broeckling Corey , Yao Linxing , Caffe-Treml Melanie , Gutiérrez Lucía , Smith Kevin P. , Tanaka James , Hoekenga Owen A. , Sorrells Mark E. , Gore Michael A. , Jannink Jean-Luc 
Published: May 2021

ABSTRACTMulti-omics prediction has been shown to be superior to genomic prediction with genome-wide DNA-based genetic markers (G) for predicting phenotypes. However, most of the existing studies were based on historical datasets from one environment; therefore, they were unable to evaluate the efficiency of multi-omics prediction in multi-environment trials and distantly-related populations. To fill those gaps, we designed a systematic experiment to collect omics data and evaluate 17 traits in two oat breeding populations planted in single and multiple environments. In the single-environment trial, transcriptomic BLUP (T), metabolomic BLUP (M), G+T, G+M and G+T+M models showed greater prediction accuracy than GBLUP for 5, 10, 11, 17 and 17 traits, respectively, and metabolites generally performed better than transcripts when combined with SNPs. In the multi-environment trial, multi-trait models with omics data outperformed both counterpart multi-trait GBLUP models and single-environment omics models, and the highest prediction accuracy was achieved when modeling genetic covariance as an unstructured covariance model. We also demonstrated that omics data can be used to prioritize loci from one population with omics data to improve genomic prediction in a distantly-related population using a two-kernel linear model that accommodated both likely casual loci with large-effect and loci that explain little or no phenotypic variance. We propose that the two-kernel linear model is superior to most genomic prediction models that assume each variant is equally likely to affect the trait and can be used to improve prediction accuracy for any trait with prior knowledge of genetic architecture.
Repeated administration of 2-hydroxypropyl-β-cyclodextrin (HPβCD) attenuates the chronic inflammatory response to experimental stroke
Authors: Becktel Danielle A. , Zbesko Jacob C. , Frye Jennifer B. , Chung Amanda G. , Hayes Megan , Calderon Kylie , Grover Jeffrey W. , Li Anna , Garcia Frankie G. , Tavera-Garcia Marco A. , Schnellmann Rick G. , Wu Hsin-Jung Joyce , Nguyen Thuy-Vi V. , Doyle Kristian P. 
Published: May 2021

AbstractGlobally, more than 67 million people are living with the effects of ischemic stroke. Importantly, many stroke survivors develop a chronic inflammatory response that may contribute to cognitive impairment, a common and debilitating sequela of stroke that is insufficiently studied and currently untreatable. 2-hydroxypropyl-β-cyclodextrin (HPβCD) is an FDA-approved cyclic oligosaccharide that can solubilize and entrap lipophilic substances. The goal of the present study was to determine whether the repeated administration of HPβCD curtails the chronic inflammatory response to stroke by reducing lipid accumulation within stroke infarcts in a distal middle cerebral artery occlusion mouse model of stroke. To achieve this goal, we subcutaneously injected young adult and aged male mice with vehicle or HPβCD three times per week, with treatment beginning one week after stroke. We evaluated mice at 7 weeks following stroke using immunostaining, RNA sequencing, lipidomics, and behavioral analyses. Chronic stroke infarct and peri-infarct regions of HPβCD-treated mice were characterized by an upregulation of genes involved in lipid metabolism and a downregulation of genes involved in innate and adaptive immunity, reactive astrogliosis, and chemotaxis. Correspondingly, HPβCD reduced the accumulation of lipid droplets, T lymphocytes, B lymphocytes, and plasma cells in stroke infarcts. Repeated administration of HPβCD also preserved NeuN immunoreactivity in the striatum and thalamus and c-Fos immunoreactivity in hippocampal regions. Additionally, HPβCD improved recovery through the protection of hippocampal-dependent spatial working memory and reduction of impulsivity. These results indicate that systemic HPβCD treatment following stroke attenuates chronic inflammation and secondary neurodegeneration and prevents post-stroke cognitive decline.Significance StatementDementia is a common and debilitating sequela of stroke. Currently, there are no available treatments for post-stroke dementia. Our study shows that lipid metabolism is disrupted in chronic stroke infarcts, which causes an accumulation of uncleared lipid debris and correlates with a chronic inflammatory response. To our knowledge, these substantial changes in lipid homeostasis have not been previously recognized or investigated in the context of ischemic stroke. We also provide a proof of principle that solubilizing and entrapping lipophilic substances using HPβCD could be an effective strategy for treating chronic inflammation after stroke and other CNS injuries. We propose that using HPβCD for the prevention of post-stroke dementia could improve recovery and increase long-term quality of life in stroke sufferers.
Chicoric acid prevents neurodegeneration via microbiota-gut-brain axis in a mouse Parkinson’s disease model
Authors: Wang Ning , Pan Xin-Yue , Zhu Hong-Kang , Guo Ya-Hui , Qian He 
Published: May 2021

AbstractIt is determined that microbiota-gut-brain axis is involved in the pathogenesis of Parkinson’s Disease (PD) and may be the potential target for developing the therapeutic treatments for PD. Chicoric acid (CA) is a kind of natural polyphenolic acid compounds which are recognized as promising agents against neurodegenerative disease. Here, we investigated the influence of CA on microbiota-gut-brain axis in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) mice. The results demonstrated that oral pretreatments of CA significantly prevented the MPTP-indued motor disorders, death of nigrostriatal dopaminergic neurons and reduction in striatal neurotrophins. Sequencing results of 16S rRNA indicated the microbial dysbiosis occurred in MPTP mice, whereas CA exerted a remarkable impact on microbial diversity and microbiota compositions, as well as SCFAs production. Besides, CA pretreatment alleviated gliosis-mediated neuroinflammation and gut inflammation by suppressing TLR4/MyD88/NF-κB signaling cascade, along with preventing the colonic hyperpermeability. To conclude, CA prevented MPTP-induced neuroinflammation and neuronal degenerative processes through signaling multiple pathways of microbiota-gut-brain axis.
Meiosis-Specific Cohesin Complexes Display Distinct and Essential Roles in Mitotic ESC Chromosomes
Authors: Choi Eui-Hwan , Koh Young Eun , Yoon Seobin , Hahn Yoonsoo , Kim Keun P. 
Published: May 2021

AbstractCohesin is a chromosome-associated SMC kleisin complex that mediates sister chromatid cohesion, recombination, and most chromosomal processes during mitosis and meiosis. Through high-resolution 3D-structured illumination microscopy and functional analyses, we report multiple biological processes associated with the meiosis-specific cohesin components, REC8 and STAG3, and the distinct loss of function of meiotic cohesin during the cell cycle of embryonic stem cells (ESCs). First, we show that REC8 is translocated into the nucleus in a STAG3-dependent manner. REC8/STAG3-containing cohesin regulates chromosome topological properties and specifically maintains centromeric cohesion. Second, REC8 and mitotic cohesin RAD21 are located at adjacent sites but predominantly at nonoverlapping sites on ESC chromosomes, implying that REC8 can function independent of RAD21 in ESCs. Third, knockdown of REC8-cohesin not only leads to higher rates of premature centromere separation and stalled replication forks, which can cause proliferation and developmental defects, but also enhances compaction of the chromosome structure by hyperloading of retinoblastoma protein condensin complexes from prophase onward. We propose that the delicate balance between mitotic and meiotic cohesins may regulate ESC- specific chromosomal organization and mitotic program.
Functional characterisation of banana (Musaspp.) 2-oxoglutarate-dependent dioxygenases involved in flavonoid biosynthesis
Authors: Busche Mareike , Acatay Christopher , Martens Stefan , Weisshaar Bernd , Stracke Ralf 
Published: May 2021

AbstractBananas (Musa) are non-grass, monocotyledonous, perennial plants that are well-known for their edible fruits. Their cultivation provides food security and employment opportunities in many countries. Banana fruits contain high levels of minerals and phytochemicals, including flavonoids, which are beneficial for human nutrition. To broaden the knowledge on flavonoid biosynthesis in this major crop plant, we aimed to identify and functionally characterise selected structural genes encoding 2-oxoglutarate-dependent dioxygenases, involved in the formation of the flavonoid aglycon.Musacandidates genes predicted to encode flavanone 3-hydroxylase (F3H), flavonol synthase (FLS) and anthocyanidin synthase (ANS) were assayed. Enzymatic functionalities of the recombinant proteins were confirmedin vivousing bioconversion assays. Moreover, transgenic analyses in correspondingArabidopsis thalianamutants showed thatMusaF3H, MusaFLSandMusaANSwere able to complement the respective loss-of-function phenotypes, thus verifying functionality of the enzymesin planta.Knowledge gained from this work provides a new aspect for further research towards genetic engineering of flavonoid biosynthesis in banana fruits to increase their antioxidant activity and nutritional value.
Open issues for protein function assignment inHaloferax volcaniiand other halophilic archaea
Authors: Pfeiffer Friedhelm , Dyall-Smith Mike 
Published: May 2021

AbstractBackgroundAnnotation ambiguities and annotation errors are a general challenge in genomics. While a reliable protein function assignment can be obtained by experimental characterization, this is expensive and time-consuming, and the number of such Gold Standard Proteins (GSP) with experimental support remains very low compared to proteins annotated by sequence homology, usually through automated pipelines. Even a GSP may give a misleading assignment when used as a reference: the homolog may be close enough to support isofunctionality, but the substrate of the GSP is absent from the species being annotated. In such cases the enzymes cannot be isofunctional. Here, we examine a variety of such issues in halophilic archaea (class Halobacteria), with a strong focus on the model haloarchaeonHaloferax volcanii.ResultsAnnotated proteins ofHfx. volcaniiwere identified for which public databases tend to assign a function that is probably incorrect. In some cases, an alternative, probably correct, function can be predicted or inferred from the available evidence but this has not been adopted by public databases because experimental validation is lacking. In other cases, a probably invalid specific function is predicted by homology, and while there is evidence that this assigned function is unlikely, the true function remains elusive. We list 50 of those cases, each with detailed background information so that a conclusion about the most likely biological function can be drawn. For reasons of brevity and comprehension, only key aspects are listed in the main text, with detailed information being provided in a corresponding section of the Supplementary Material.ConclusionsCompiling, describing and summarizing these open annotation issues and functional predictions will benefit the scientific community in the general effort to improve the evaluation of protein function assignments and more thoroughly detail them. By highlighting the gaps and likely annotation errors currently in the databases, we hope this study will provide a framework for experimentalists to systematically confirm (or disprove) our function predictions or to uncover yet unexpected functions.
Correction of amblyopia in cats and mice after the critical period
Authors: Fong Ming-fai , Duffy Kevin R. , Leet Madison P. , Candler Christian T. , Bear Mark F. 
Published: May 2021

AbstractMonocular deprivation early in development causes amblyopia, a severe visual impairment. Prognosis is poor if therapy is initiated after an early critical period. However, clinical observations have shown that recovery from amblyopia can occur later in life when the non-deprived (fellow) eye is removed. The traditional interpretation of this finding is that vision is improved by relieving interocular suppression in primary visual cortex. However, an alternative explanation is that elimination of activity in the fellow eye establishes conditions in visual cortex that enable the weak connections from the amblyopic eye to gain strength. Here we show in cats and mice that temporary inactivation of the fellow eye is sufficient to promote a full and enduring recovery from amblyopia at ages when conventional treatments fail. Thus, connections serving the amblyopic eye are capable of substantial plasticity beyond the critical period, and this potential is unleashed by reversibly silencing the fellow eye.
TheArabidopsis thalianaPeptideAtlas; harnessing world-wide proteomics data for a comprehensive community proteomics resource
Authors: van Wijk Klaas J. , Leppert Tami , Sun Qi , Boguraev Sascha S. , Sun Zhi , Mendoza Luis , Deutsch Eric W. 
Published: May 2021

ABSTRACTWe developed a new resource, the Arabidopsis PeptideAtlas (www.peptideatlas.org/builds/arabidopsis/), to solve central questions about the Arabidopsis proteome, such as the significance of protein splice forms, post-translational modifications (PTMs), or simply obtain reliable information about specific proteins. PeptideAtlas is based on published mass spectrometry (MS) analyses collected through ProteomeXchange and reanalyzed through a uniform processing and metadata annotation pipeline. All matched MS-derived peptide data are linked to spectral, technical and biological metadata. Nearly 40 million out of ∼143 million MSMS spectra were matched to the reference genome Araport11, identifying ∼0.5 million unique peptides and 17858 uniquely identified proteins (only isoform per gene) at the highest confidence level (FDR 0.0004; 2 non-nested peptides ≥ 9 aa each), assigned canonical proteins, and 3543 lower confidence proteins. Physicochemical protein properties were evaluated for targeted identification of unobserved proteins. Additional proteins and isoforms currently not in Araport11 were identified, generated from pseudogenes, alternative start, stops and/or splice variants and sORFs; these features should be considered for updates to the Arabidopsis genome. Phosphorylation can be inspected through a sophisticated PTM viewer. This new PeptideAtlas is integrated with community resources including TAIR, tracks in JBrowse, PPDB and UniProtKB. Subsequent PeptideAtlas builds will incorporate millions more MS data.One sentence summaryA new web resource providing the global community with mass spectrometry-based Arabidopsis proteome information and its spectral, technical and biological metadata integrated with TAIR and JBrowse
Synaptic control of temporal processing in theDrosophilaolfactory system
Authors: Fox David , Nagel Katherine I. 
Published: May 2021

AbstractTemporal filtering of sensory stimuli is a key neural computation, but the way such filters are implemented within the brain is unclear. One potential mechanism for implementing temporal filters is short-term synaptic plasticity, which is governed in part by the expression of pre-synaptic proteins that position synaptic vesicles at different distances to calcium channels. Here we leveraged theDrosophilaolfactory system to directly test the hypothesis that short-term synaptic plasticity shapes temporal filtering of sensory stimuli. We used optogenetic activation to drive olfactory receptor neuron (ORN) activity with high temporal precision and knocked down the presynaptic priming factor unc13A specifically in ORNs. We found that this manipulation specifically decreases and delays transmission of high frequencies, leading to poorer encoding of distant plume filaments. We replicate this effect using a previously-developed model of transmission at this synapse, which features two components with different depression kinetics. Finally, we show that upwind running, a key component of odor source localization, is preferentially driven by high-frequency stimulus fluctuations, and this response is reduced by unc13A knock-down in ORNs. Our work links the extraction of particular temporal features of a sensory stimulus to the expression of particular presynaptic molecules.