bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic-variant hotspots and hotspot clusters in the human genome facilitating adaptation while increasing instability
Authors: Long Xi , Xue Hong 
Published: October 2020

AbstractBackgroundGenetic variants, underlining phenotypic diversity, are known to distribute unevenly in the human genome. A comprehensive understanding of the distributions of different genetic variants is important for insights into genetic functions and disorders.MethodsHerein, a sliding-window scan of regional densities of eight kinds of germline genetic variants, including single-nucleotide-polymorphisms (SNPs) and four size-classes of copy-number-variations (CNVs) in the human genome has been performed.ResultsThe study has identified 44,379 hotspots with high genetic-variant densities, and 1,135 hotspot clusters comprising more than one type of hotspots, accounting for 3.1% and 0.2% of the genome respectively. The hotspots and clusters are found to co-localize with different functional genomic features, as exemplified by the associations of hotspots of middle-size CNVs with histone-modification sites, work with balancing and positive selections to meet the need for diversity in immune proteins, and facilitate the development of sensory-perception and neuroactive ligand-receptor interaction pathways in the function-sparse late-replicating genomic sequences. Genetic variants of different lengths co-localize with retrotransposons of different ages on a ‘long-with-young’ and ‘short-with-all’ basis. Hotspots and clusters are highly associated with tumour suppressor genes and oncogenes (p< 10−10), and enriched with somatic tumour CNVs and the trait- and disease-associated SNPs identified by genome-wise association studies, exceeding tenfold enrichment in clusters comprising SNPs and extra-long CNVs.ConclusionsIn conclusion, the genetic-variant hotspots and clusters represent two-edged swords that spearhead both positive and negative genomic changes. Their strong associations with complex traits and diseases also open up a potential ‘Common Disease-Hotspot Variant’ approach to the missing heritability problem.
APP accumulates around dense-core amyloid plaques with presynaptic proteins in Alzheimer’s disease brain
Authors: Jordà-Siquier Tomàs , Petrel Melina , Kouskoff Vladimir , Cordelières Fabrice , Frykman Susanne , Müller Ulrike , Mulle Christophe , Barthet Gaël 
Published: October 2020

SummaryIn Alzheimer’s disease (AD), a central role is given to the extracellular deposition of Aβ peptides, remotely produced by the proteolysis of the amyloid precursor protein (APP). This contrasts with other neurodegenerative diseases which are characterized by the intraneuronal aggregation of full-length proteins such as huntingtin, α-synuclein or TDP-43. Importantly, the distribution of APP around amyloid plaques is poorly characterized. Here, we combined an extensive set of methodological and analytical tools to investigate neuropathological features of APP in the human AD hippocampus and in two mouse models of AD. We report that APP remarkably accumulates in the surrounding of dense-core amyloid plaques together with the secretases necessary to produce Aβ peptides. In addition, the Nter domain, but not the Cter domain of APP is enriched in the core of amyloid plaques uncovering a potential pathological role of the secreted APP-Nter in dense-core plaques. To investigate the subcellular compartment in which APP accumulates, we labelled neuritic and synaptic markers and report an enrichment in presynaptic proteins (Syt1, VAMP2) and phosphorylated-Tau. Ultrastructural analysis of APP accumulations reveals abundant multivesicular bodies containing presynaptic vesicles proteins and autophagosomal built-up of APP. Altogether, our data supports a role of presynaptic APP in AD pathology and highlights APP accumulations as a potential source of Aβ and Nter peptides to fuel amyloid plaques.
Phylogenetic analysis of the salinipostin γ-butyrolactone gene cluster uncovers new potential for bacterial signaling-molecule diversity
Authors: Creamer Kaitlin E. , Kudo Yuta , Moore Bradley S. , Jensen Paul R. 
Published: October 2020

AbstractBacteria communicate by small-molecule chemicals that facilitate intra- and inter-species interactions. These extracellular signaling molecules mediate diverse processes including virulence, bioluminescence, biofilm formation, motility, and specialized metabolism. The signaling molecules produced by members of the phylum Actinobacteria are generally comprised of γ-butyrolactones, γ-butenolides, and furans. The best known actinomycete γ-butyrolactone is A-factor, which triggers specialized metabolism and morphological differentiation in the genus Streptomyces. Salinipostins A-K are unique γ-butyrolactone molecules with rare phosphotriester moieties that were recently characterized from the marine actinomycete genus Salinispora. The production of these compounds has been linked to the 9-gene biosynthetic gene cluster spt. Critical to salinipostin assembly is the γ-butyrolactone synthase encoded by spt9. Here, we report the global distribution of spt9 among sequenced bacterial genomes, revealing a surprising diversity of gene homologs across 12 bacterial phyla, the majority of which are not known to produce γ-butyrolactones. Further analyses uncovered a large group of spt-like gene clusters outside of the genus Salinispora, suggesting the production of new salinipostin-like diversity. These gene clusters show evidence of horizontal transfer between many bacterial taxa and location specific homologous recombination exchange among Salinispora strains. The results suggest that γ-butyrolactone production may be more widespread than previously recognized. The identification of new γ-butyrolactone biosynthetic gene clusters is the first step towards understanding the regulatory roles of the encoded small molecules in Actinobacteria.ImportanceSignaling molecules orchestrate a wide variety of bacterial behaviors. Among Actinobacteria, γ-butyrolactones mediate morphological changes and regulate specialized metabolism. Despite their importance, few γ-butyrolactones have been linked to their cognate biosynthetic gene clusters. A new series of γ-butyrolactones called the salinipostins was recently identified from the marine actinomycete genus Salinispora and linked to the spt biosynthetic gene cluster. Here we report the detection of spt-like gene clusters in diverse bacterial families not known for the production of this class of compounds. This finding expands the taxonomic range of bacteria that may employ this class of compounds and provides opportunities to discover new compounds associated with chemical communication.
The molecular and metabolic program for adaptation of white adipocytes to cool physiologic temperatures
Authors: Mori Hiroyuki , Dugan Colleen E. , Nishii Akira , Benchamana Ameena , Li Ziru , Cadenhead Thomas S. , Das Arun K. , Evans Charles R. , Overmyer Katherine A. , Romanelli Steven M. , Peterson Sydney K. , Bagchi Devika P. , Corsa Callie A. , Hardij Julie , Learman Brian S. , El Azzouny Mahmoud , Inoki Ken , MacDougald Ormond A. 
Published: October 2020

ABSTRACTAlthough visceral adipocytes located within the body’s central core are maintained at ~37°C, adipocytes within bone marrow, subcutaneous, and dermal depots are found primarily within the peripheral shell, and generally exist at cooler temperatures. Responses of brown and beige/brite adipocytes to cold stress are well-studied; however, comparatively little is known about mechanisms by white adipocytes adapt to temperatures below 37°C. Here we report that adaptation of cultured adipocytes to 31°C, the temperature at which distal marrow adipose tissues and subcutaneous adipose tissues often reside, induces extensive changes in gene expression, increased anabolic and catabolic lipid metabolism, and elevated oxygen consumption with reduced reliance on glucose and preferential use of pyruvate, glutamine and fatty acids as energy sources. Cool temperatures up-regulate stearoyl-CoA desaturase-1 expression and monounsaturated lipid levels in cultured adipocytes and distal bone marrow adipose tissues, and stearoyl-CoA desaturase-1 activity is required for acquisition of maximal oxygen consumption at 31°C.
Improved diagnostic prediction of the pathogenicity of bloodstream isolates ofStaphylococcus epidermidis
Authors: VanAken Shannon M. , Newton Duane , VanEpps J. Scott 
Published: October 2020

ABSTRACTWith an estimated 440,000 active cases occurring each year, medical device associated infections pose a significant burden on the US healthcare system, costing about $9.8 billion in 2013.Staphylococcus epidermidisis the most common cause of these device-associated infections, which typically involve isolates that are multi-drug resistant and possess multiple virulence factors.S. epidermidisis also frequently a benign contaminant of otherwise sterile blood cultures. Therefore, tests that distinguish pathogenic from non-pathogenic isolates would improve the accuracy of diagnosis and prevent overuse/misuse of antibiotics. Attempts to use multi-locus sequence typing (MLST) with machine learning for this purpose had poor accuracy (~73%). In this study we sought to improve the diagnostic accuracy of predicting pathogenicity by focusing on phenotypic markers (i.e., antibiotic resistance, growth fitness in human plasma, and biofilm forming capacity) and the presence of specific virulence genes (i.e., mecA, ses1, andsdrF). Commensal isolates from healthy individuals (n=23), blood culture contaminants (n=21), and pathogenic isolates considered true bacteremia (n=54) were used. Multiple machine learning approaches were applied to characterize strains as pathogenicvsnon-pathogenic. The combination of phenotypic markers and virulence genes improved the diagnostic accuracy to 82.4% (sensitivity: 84.9% and specificity: 80.9%). Oxacillin resistance was the most important variable followed by growth rate in plasma. This work shows promise for the addition of phenotypic testing in clinical diagnostic applications.
Virus infections inVarroa destructor-resistant honeybees
Authors: Oddie Melissa A. Y. , Lanz Sandra , Dahle Bjørn , Yañez Orlando , Neumann Peter 
Published: October 2020

AbstractPopulations of European honeybee subspecies,Apis mellifera, have the ability to adapt naturally to the ectoparasitic mite,Varroa destructor. It is possible that a tolerance to mite-vectored viruses may contribute to colony survival. If this is the case, surviving populations should show lower virus titers and prevalence compared to susceptible populations. Here, we investigated the prevalence and titers of 10 viruses, some known to be associated withV. destructor, in adult workers and pupae as well as mites. Samples were collected from both a mite-surviving and mite-susceptible honeybee population in Norway. Surviving colonies had a lower prevalence of a key virus (DWV-A) associated withV. destructorin individual adult bees sampled, and generally lower titers of this virus in mite infested pupae and mites within the colonies when compared to sympatric, susceptible controls. However, these surviving colonies also displayed higher prevalence and titers of two viruses not associated withV. destructor(BQCV & LSV1). The results of this study therefore suggest that general tolerance to virus infections is unlikely to be a key mechanism for natural colony survival in Norway, but evidence may point to mite control as a predominant mechanism.
Remote testing of vitamin D levels across the UK MS population – a case control study
Authors: Vickaryous Nicola , Jitlal Mark , Jacobs Benjamin Meir , Middleton Rod , Chandran Siddharthan , MacDougall Niall John James , Giovannoni Gavin , Dobson Ruth 
Published: October 2020

AbstractObjectiveThe association between vitamin D deficiency and multiple sclerosis (MS) is well described. We set out to use remote sampling to ascertain vitamin D status and vitamin D supplementation in a cross-sectional study of people with MS across the UK.MethodsPeople with MS and matched controls were recruited from across the UK. 1768 people with MS enrolled in the study; remote sampling kits were distributed to a subgroup. Dried blood spots (DBS) were used to assess serum 25(OH)D in people with MS and controls.Results1768 MS participants completed the questionnaire; 388 MS participants and 309 controls provided biological samples. Serum 25(OH)D was higher in MS than controls (median 71nmol/L vs 49nmol/L). A higher proportion of MS participants than controls supplemented (72% vs 26%, p<0.001); people with MS supplemented at higher vD doses than controls (median 1600 vs 600 IU/day, p<0.001). People with MS who did not supplement had lower serum 25(OH)D levels than non-supplementing controls (median 38 nmol/L vs 44 nmol/L). Participants engaged well with remote sampling.ConclusionsThe UK MS population have higher serum 25(OH)D than controls, mainly as a result of vitamin D supplementation. Remote sampling is a feasible way of carrying out large studies.
Serotype has a significant impact on the virulence of 7th pandemicVibrio choleraeO1
Authors: Nordqvist Stefan L , Thorell Kaisa , Nilsson Frida , Löfstrand Madeleine , Hagelberg Arvid , Holmgren Jan , Lebens Michael R. 
Published: October 2020

AbstractOf over 200 different identifiedVibrio choleraeserogroups only the O1 serogroup is consistently associated with endemic and epidemic cholera disease. The O1 serogroup has two serologically distinguishable variants, the Ogawa and Inaba serotypes, which differ only by a methyl group present on the terminal sugar of the Ogawa O-antigen but absent from Inaba strains. This methylation is catalyzed by a methyltransferase encoded by thewbeTgene, which in Inaba strains is disrupted by mutation. It is currently thought that there is little difference between the two serotypes. However, here we show, using isogenic pairs of O1 El TorV. cholerae, that Inaba strains show significantly different patterns of gene expression and are significantly less able than the corresponding Ogawa strains to cause cholera in an infant mouse infection model. Our results suggest that changes in gene expression resulting from the loss of thewbeTgene lead to reduced virulence and possibly also reduced survival fitness outside the human host.Author SummaryThe bacteriumVibrio choleraecauses the pandemic diarrheal disease cholera. Despite many identified serotypes ofV. choleraeonly one, O1, causes pandemic cholera. The O1 serotype of pandemicV. choleraehas two distinguishable variants (called Ogawa and Inaba) long considered to be clinically and epidemiologically equivalent. Cholera outbreaks consist only of one the two variants at any time. In general, Ogawa strains cause the majority of outbreaks with relatively short-lived Inaba outbreaks occurring sporadically. We have suggested earlier that Inaba outbreaks occur during periods of environmental selective pressure against the Ogawa serotype. We demonstrate here that the two variants are not clinically equivalent. The Ogawa serotype is better able to respond to infection in an animal model by up regulating the expression of virulence genes essential for disease development. We suggest that this phenomenon is the result of wider ranging differences in gene expression resulting from the mutation that converts Ogawa into Inaba strains, and may help to explain the dominance of the Ogawa serotype in nature.
Easy identification of insertion sequence mobilization events in related bacterial strains with ISCompare
Authors: Mogro E.G. , Ambrosis N. , Lozano M.J. 
Published: October 2020

AbstractMotivationBacterial genomes are composed by a core and an accessory genome. The first composed of housekeeping and essential genes, while the second is composed, in its majority, of mobile genetic elements, including transposable elements (TEs). Insertion sequences (ISs), the smallest TEs, have an important role in genome evolution, and contribute to bacterial genome plasticity and adaptability. ISs can spread in a genome, presenting different locations in nearly related strains, and producing phenotypic variations. Few tools are available which can identify differentially located ISs (DLIS) on assembled genomes.ResultsWe developed ISCompare to profile IS mobilization events in related bacterial strains using complete or draft genome assemblies. ISCompare was validated using artificial genomes with simulated random IS insertions and real sequences, achieving the same or better results than other available tools, with the advantage that ISCompare can analyse multiple ISs at the same time and outputs a list of candidate DLIS. We think that ISCompare provides an easy and straightforward approach to look for differentially located ISs on bacterial genomes.Availability and implementationISCompare was implemented in python3 and its source code is freely available for download athttps://github.com/maurijlozano/ISCompare.Supplementary informationSupplementary data are available athttps://github.com/maurijlozano/ISCompare.
Lateralized functional responses in the cortex arise from the dynamic interactions in the structural connectome
Authors: Kumar Neeraj , Jaiswal Amit Kumar , Roy Dipanjan , Banerjee Arpan 
Published: October 2020

AbstractStructure-function relationships are fundamental to studies of neural systems, yet the mechanistic underpinnings of how structural networks shape hemispheric lateralization remain elusive. For instance, the asymmetric neuroanatomic embedding of primary auditory cortices was shown when connectivity with all other brain areas were considered. Concomitantly, functional lateralization e.g., left hemispheric dominance of speech processing and right hemispheric dominance of music perception, is widely acknowledged. The present article provides a parsimonious mechanistic explanation based on computational modelling and empirical recordings to demonstrate emergence of hemispheric lateralization of brain function. For validation of the model, empirical EEG recordings of auditory steady state responses (ASSR) were undertaken, and empirical findings suggest right hemispheric dominance at the level of cortical sources in binaural and monaural hearing conditions. Subsequently, we demonstrate the entrainment and phase of oscillations in connected brain regions based on a neurodynamic model constrained by empirically derived structural connectivity matrix from diffusion data. For relevance, we have taken into consideration time-delays in neural communication stemming from fibre distances and neuronal coupling arising from fibre densities. Based on relevant network parameters, we could demonstrate the emergence of right hemispheric dominance of ASSR in binaural and monaural hearing conditions when auditory cortical areas were chosen as triggers of entrained phase oscillators. Furthermore, we discovered emergence of left-lateralized functional response when bilateral Broca’s area replaced auditory areas as triggers. Hence, a single unified mechanism based on entrainment of phase oscillators in a large-scale brain network could explain both emergence of right and left hemispheric laterality.Significance statementThe origin of hemispheric specialization of sensory processing is a fundamental question in neuroscience. For instance, speech and language are predominantly processed in the left hemispheric regions, while the right hemisphere is specialized for processing rhythmic, tonal, and melodic stimuli. Identification of the network mechanisms that give rise to such functional lateralization from structural constraints remains elusive. In the present study, we simulate neural activity observed during human EEG recordings of auditory steady-state responses from a biophysically realistic large-scale model constrained by underlying structural connectivity. Subsequently, we demonstrate how hemispheric lateralization of brain responses to sensory stimuli emerge from the time-delayed interactions among whole-brain neuronal ensembles.
The Theory and Practice of the viral dose in neutralization assay: insights on SARS-CoV-2 “doublethink” effect
Authors: Manenti Alessandro , Molesti Eleonora , Maggetti Marta , Torelli Alessandro , Lapini Giulia , Montomoli Emanuele 
Published: October 2020

AbstractDue to the global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is an urgent need for reliable high-throughput serological assays in order to evaluate the immunological responses against SARS-COV-2 virus and to enable population screening, as well as vaccines and drug’s efficacy testing. Several serological assays for SARS-CoV-2 are now becoming available in the market. However, it has also become extremely important to have well-established assays with desirable high sensitivity and specificity. To date, the micro-neutralization (MN) assay, is currently considered the gold-standard being capable of evaluating and detecting, functional neutralizing antibodies (nAbs). Several protocols exist for microneutralization assays which vary in several steps of the protocol: cell seeding conditions, number of cells seeded, virus amount used in the infection step, virus-serum-cells incubation period etc. These potential differences account for a high degree of variability and inconsistency of the results and using a harmonized protocol for the micro-neutralization assay could potentially solve this.Given this situation, the main aim of our study was to carry out SARS-CoV-2 wild type virus MN assay in order to investigate which optimal tissue culture infective dose 50 (TCID50) infective dose in use is the most adequate choice for implementation in terms of reproducibility, standardization possibilities and comparability of results. Therefore, we assessed the MN by using two different viral infective doses: a standard dose of 100 TCID50/well and a lower dose of 25 TCID50/well. The results obtained, yielded by MN on using the lower infective dose (25 TCID50), were in line with those obtained with the standard infective dose; in some cases, however, we detected a titre that was one or two dilution steps higher, which maintained all negative samples negative. This suggesting that the lower dose can potentially have a positive impact on the detection and estimation of neutralizing antibodies present in a given sample, showing higher sensitivity but similar specificity and therefore, it would require a more accurate assessment and cross-laboratories standardisation especially when MN is employed as serological assay of choice for pre-clinical and clinical studies.
Photochemical probe identification of the small-molecule binding site in a mammalian membrane-boundO-acyltransferase
Authors: Lanyon-Hogg Thomas , Ritzefeld Markus , Zhang Leran , Pogranyi Balazs , Mondal Milon , Sefer Lea , Johnston Callum D. , Coupland Claire E. , Andrei Sebastian A. , Newington Joshua , Magee Anthony I. , Siebold Christian , Tate Edward W. 
Published: October 2020

AbstractThe mammalian membrane-boundO-acyltransferase (MBOAT) superfamily is involved in biological processes including growth, development and appetite sensing. MBOATs are attractive drug targets in cancer and obesity; however, information on the binding site and molecular mechanisms underlying small-molecule inhibition is elusive. This study reports development of a photochemical probe to interrogate the small-molecule binding site in the human MBOAT Hedgehog acyltransferase (HHAT) based on HHAT inhibitor RUSKI-201. Structure-activity relationship investigation identified the improved enantiomeric inhibitorIMP-1575, which is the most potent HHAT inhibitor reported to-date, and guided rational design of a photocrosslinking probe that maintained HHAT-inhibitory potency. Photocrosslinking and proteomic sequencing of HHAT delivered identification of the first small-molecule binding site in a mammalian MBOAT. Topology and homology data suggested a potential mechanism for HHAT inhibition which was confirmed via kinetic analysis. Our results provide an optimal HHAT inhibitorIMP-1575(Ki= 38 nM) and a strategy for mapping of interaction sites in MBOATs.