bluuebunny/crossref_metadata_2025_split huggingface dataset:
Left hemispheric deficit in the sustained neuromagnetic response to periodic click trains in children with ASD
Authors: Stroganova T.A. , Komarov K.S , Goiaeva D.E. , Obukhova T.S. , Ovsiannikova T.M. , Prokofyev A.O. , Orekhova E.V. 
Published: July 2020

AbstractDeficits in perception and production of vocal pitch are often observed in people with autism spectrum disorders (ASD), but the neural basis of these abnormalities is unknown. In magnetoencephalogram (MEG), spectrally complex periodic sounds trigger two continuous neural responses – the Auditory Steady State Response (ASSR) and the Sustained Field (SF). It has been shown that the SF in neuro-typical individuals is associated with low-level analysis of pitch in the ‘pitch processing center’ of the Heschl’s gyrus. Therefore, this auditory response may reflect vocal pitch processing abnormalities in ASD. The SF, however, has never been studied in people with these disorders. We used MEG and individual brain models to investigate the ASSR and SF evoked by monaural 40 Hz click trains in 7-13-year-old boys with ASD (N=35) and neuro-typical (NT) boys (N=35). In agreement with the previous research in adults, the cortical sources of the SF in children were located in the left and the right Heschl’s gyri, anterolateral to those of the ASSR. In both groups, the SF and ASSR dominated in the right hemisphere and were higher contralaterally to the stimulated ear. The ASSR increased with age in both NT and ASD children and did not differ between the groups. The SF was moderately decreased in both hemispheres and was markedly delayed and displaced in the left hemisphere in boys with ASD. The SF delay in participants with ASD was present irrespective of their intelligence level and severity of autism symptoms. We suggest that the selective left-hemispheric SF abnormalities in children with ASD reflect a low-level deficiency in pitch processing that may contribute to their difficulties with perception and production of linguistic prosody.
The ecogenomics of dsDNA bacteriophages in feces of stabled and feral horses
Authors: Babenko V. V. , Millard A. , Kulikov E. E. , Spasskaya N.N. , Letarova M. A. , Konanov D. N. , Belalov I. Sh. , Letarov A.V. 
Published: July 2020

AbstractThe viromes of the mammalian lower gut were shown to be heavily dominated by bacteriophages; however, only for humans were the composition and intervariability of the bacteriophage communities studied in depth. Here we present an ecogenomics survey of dsDNA bacteriophage diversity in the feces of horses (Equus caballus), comparing two groups of stabled horses, and a further group of feral horses that were isolated on an island. Our results indicate that the dsDNA viromes of the horse feces feature higher richness than in human viromes, with more even distribution of genotypes. No over-represented phage genotypes, such as CrAssphage-related viruses found in humans, were identified. Additionally, many bacteriophage genus-level clusters were found to be present in all three geographically isolated populations. The diversity of the horse intestinal bacteriophages is severely undersampled, and so consequently only a minor fraction of the phage contigs could be linked with the bacteriophage genomes. Our study indicates that bacteriophage ecological parameters in the intestinal ecosystems in horses and humans differ significantly, leading them to shape their corresponding viromes in different ways. Therefore, the diversity and structure of the intestinal virome in different animal species needs to be experimentally studied.Short abstract (needed in some journals as eLife)The viromes of the mammalian gut were shown to be heavily dominated by bacteriophages; however, only for humans were the composition and intervariability of the bacteriophage communities studied in depth. Here we present an ecogenomics survey of dsDNA bacteriophage diversity in the feces of horses (Equus caballus), comparing stabled horses, and feral horses that were isolated on an island. The viromes equine fecal viromes feature higher richness than in human viromes, with more even distribution of genotypes. No over-represented phage genotypes were identified. Additionally, many bacteriophage genus-level clusters were found to be present in geographically isolated populations. Only a minor fraction of the phage contigs could be linked with the bacteriophage genomes. Our study indicates that bacteriophage ecological parameters in the intestinal ecosystems in horses and humans differ significantly, leading them to shape their corresponding viromes in different ways.Importance. (needed for mBio)The study presents the first in depth analysis of the composition and variability of the gut dsDNA bacteriophage community in the mammalian species, other than humans. The study demonstrates that the bacteriophage ecology in the gut is substantially different in different animal species. The results also indicate that the genetic diversity of the equine intestinal bacteriophages is immense and almost totally unexplored by the moment.
A two-phase model of skin epidermal stratification: lessons from centrosomes
Authors: Damen Mareike , Wirtz Lisa , Soroka Ekaterina , Khatif Houda , Kukat Christian , Simons Benjamin D. , Bazzi Hisham 
Published: July 2020

AbstractThe development of complex stratified epithelial barriers in mammals is initiated from single-layered epithelia. How stratification is initiated and fueled are still open questions. Previous studies on skin epidermal stratification suggested a central role for perpendicular/asymmetric cell division orientation of the basal keratinocyte progenitors. Here, we use centrosomes, that organize the mitotic spindle, to test whether cell division orientation and stratification are linked. Genetically ablating centrosomes from the developing epidermis led to the activation of the p53-, 53BP1- and USP28-dependent mitotic surveillance pathway causing a thinner epidermis and hair follicle arrest. The centrosome/p53-double mutant keratinocyte progenitors significantly altered their division orientation in the later stages without majorly affecting epidermal differentiation. Together with time-lapse imaging and tissue growth dynamics measurements, the data suggested that the first and major phase of epidermal stratification is boosted by high proliferation rates of the basal and suprabasal transit-amplifying cells as well as cell delamination, whereas the second phase maybe uncoupled from the division orientation of the basal progenitors. The data provide insights for tissue homeostasis and hyperproliferative diseases that may recapitulate developmental programs.
Inhibition of the neuromuscular acetylcholine receptor with atracurium activates FOXO/DAF-16-induced longevity
Authors: McIntyre Rebecca L. , Denis Simone W. , Kamble Rashmi , Petr Michael , Schomakers Bauke V. , Jongejan Aldo , Scheibye-Knudsen Morten , Houtkooper Riekelt H. , Janssens Georges E. 
Published: July 2020

AbstractTranscriptome-based drug screening is emerging as a powerful tool to identify geroprotective compounds to intervene in age-related disease. We hypothesized that, by mimicking the transcriptional signature of the highly conserved longevity intervention ofFOXO3(daf-16in worms) overexpression, we could identify and repurpose compounds with similar downstream effects to increase longevity. Ourin silicoscreen, utilizing the LINCS transcriptome database of genetic and compound interventions, identified several FDA-approved compounds that activate FOXO downstream targets in mammalian cells. These included the neuromuscular blocker atracurium, which also robustly extends both lifespan and healthspan inC. elegans. This longevity is dependent on bothdaf-16signaling and inhibition of the neuromuscular acetylcholine receptor. Other neuromuscular blockers tubocurarine and pancuronium caused similar healthspan benefits. We demonstrate nuclear localization of DAF-16 upon atracurium treatment, and, using RNAseq transcriptomics, identify activation of DAF-16 downstream effectors. Together, these data demonstrate the capacity to mimic genetic lifespan interventions with drugs, and in doing so, reveal that the neuromuscular acetylcholine receptor regulates the highly conserved FOXO/DAF-16 longevity pathway.
A quantitative analysis of the interplay of environment, neighborhood and cell state in 3D spheroids
Authors: Zanotelli Vito RT , Leutenegger Matthias , Lun Xiao-Kang , Georgi Fanny , de Souza Natalie , Bodenmiller Bernd 
Published: July 2020

1AbstractCells react to their microenvironment by integrating external stimuli into phenotypic decisions via an intracellular signaling network. Even cells with deregulated signaling can adapt to their environment. To analyze the interplay of environment, neighborhood, and cell state on phenotypic variability, we developed an experimental approach that enables multiplexed mass cytometric imaging to analyze up to 240 pooled spheroid microtissues. This system allowed us to quantify the contributions of environment, neighborhood, and intracellular state to phenotypic variability in spheroid cells. A linear model explained on average more than half of the variability of 34 markers across four cell lines and six growth conditions. We found that the contributions of cell-intrinsic and environmental factors are hierarchically interdependent. By overexpression of 51 signaling protein constructs in subsets of cells, we identified proteins that have cell-intrinsic and extrinsic effects, exemplifying how cell states depend on the cellular neighborhood in spheroid culture. Our study deconvolves factors influencing cellular phenotype in a 3D tissue and provides a scalable experimental system, analytical principles, and rich multiplexed imaging datasets for future studies.
Population Genomics Reveals Molecular Determinants of Specialization to Tomato in the Polyphagous Fungal PathogenBotrytis cinereain France
Authors: Mercier Alex , Simon Adeline , Lapalu Nicolas , Giraud Tatiana , Bardin Marc , Walker Anne-Sophie , Viaud Muriel , Gladieux Pierre 
Published: July 2020

AbstractMany fungal plant pathogens encompass multiple populations specialized on different plant species. Understanding the factors underlying pathogen adaptation to their hosts is a major challenge of evolutionary microbiology, and it should help preventing the emergence of new specialized pathogens on novel hosts. Previous studies have shown that French populations of the grey mould pathogenBotrytis cinereaparasitizing tomato and grapevine are differentiated from each other, and have higher aggressiveness on their host-of-origin than on other hosts, indicating some degree of host specialization in this polyphagous pathogen. Here, we aimed at identifying the genomic features underlying the specialization ofB. cinereapopulations to tomato and grapevine. Based on whole genome sequences of 32 isolates, we confirmed the subdivision ofB. cinereapathogens into two genetic clusters on grapevine and another, single cluster on tomato. Levels of genetic variation in the different clusters were similar, suggesting that the tomato-specific cluster has not recently emerged following a bottleneck. Using genome scans for selective sweeps and divergent selection, tests of positive selection based on polymorphism and divergence at synonymous and non-synonymous sites and analyses of presence/absence variation, we identified several candidate genes that represent possible determinants of host specialization in the tomato-associated population. This work deepens our understanding of the genomic changes underlying the specialization of fungal pathogen populations.
Expression, subcellular localization, and phosphorylation of MK5 in adult cardiac ventricular fibroblasts
Authors: Sahadevan Pramod , Nawaito Sherin A. , Trépanier Joëlle , Benamar Sabrina , Sahmi Fatiha , Theberge-Julien Gabriel , Villeneuve Louis R. , Gaestel Matthias , Tardif Jean-Claude , Allen Bruce G. 
Published: July 2020

AbstractMAP kinase-activated protein kinase-5 (MK5) plays an important role in cardiac fibroblast function. Although p38 MAPK and atypical MAPKs and ERK3 and ERK4 have been identified as activators of MK5, the kinases that activate MK5 remain controversial. Here we examined the expression, subcellular distribution, and regulation of MK5 in cardiac ventricular myofibroblasts and myocytes. The copy numbers for MK5 and ERK4 mRNA were comparable in myocytes and myofibroblasts, whereas that of ERK3 was much higher in myofibroblasts. Interestingly, MK5 and ERK3 immunoreactivity was detected in myofibroblasts but not myocytes whereas ERK4 immunoreactivity was detected in myocytes: treating in myocytes with a proteasome inhibitor or hypertrophic agonists failed to rescue MK5 immunoreactivity. In myofibroblasts, MK5 and ERK3 immunoreactivity was predominantly nuclear and cytosolic, respectively. In serum-starved cardiac myofibroblasts, phosphothreonine-182 MK5 (pT182-MK5) immunoreactivity was predominantly nuclear but increased in intensity and relocated to the cytoplasm in response to serum, sorbitol, angiotensin II, TGFβ, or H2O2and this was prevented by inhibition of p38α/β. Phos-tag SDS-PAGE revealed multiple slower migrating bands of MK5 immunoreactivity, indicating phosphorylation of MK5 at multiple sites. Phos-tag PAGE also revealed MK5 phosphorylation was increased with fibroblast activation and in hearts exposed to a chronic increase in afterload. MK5 and ERK3 co-immunoprecipitated and proximity ligation assays revealed ERK3 and MK5 in close proximity in myofibroblast cytoplasmic compartment. Furthermore, p38α/βinhibition decreased the abundance of MK5 immunoreactivity in ERK3 immunoprecipitates. Finally, deleting MK5 did not reduce the abundance of ERK3 immunoreactivity. These observations suggest that p38αand/or p38βare the primary mediators of T182-MK5 phosphorylation and hence MK5 activation in cardiac myofibroblasts.
The developmental and genetic architecture of the sexually selected male ornament of swordtails
Authors: Schartl Manfred , Kneitz Susanne , Ormanns Jenny , Schmidt Cornelia , Anderson Jennifer L , Amores Angel , Catchen Julian , Wilson Catherine , Geiger Dietmar , Du Kang , Garcia-Olazábal Mateo , Sudaram Sudha , Winkler Christoph , Hedrich Rainer , Warren Wesley C , Walter Ronald , Meyer Axel , Postlethwait John H 
Published: July 2020

AbstractSexual selection results in sex-specific characters like the conspicuously pigmented extension of the ventral tip of the caudal fin - the “sword” - in males of several species of Xiphophorus fishes. To uncover the genetic architecture underlying sword formation and to identify genes that are associated with its development, we characterized the sword transcriptional profile and combined it with genetic mapping approaches. Results showed that the male ornament of swordtails develops from a sexually non-dimorphic prepattern of transcription factors in the caudal fin. Among genes that constitute the exclusive sword transcriptome only two are located in the genomic region associated with this trait; the chaperone, fkbp9, and the potassium channel, kcnh8 that in addition to its neural function performs a role known to affect fin growth. This indicates that during evolution of swordtails a brain gene has been recruited for an additional function in establishing a male ornament.
What the Phage: A scalable workflow for the identification and analysis of phage sequences
Authors: Marquet Mike , Hölzer Martin , Pletz Mathias W. , Viehweger Adrian , Makarewicz Oliwia , Ehricht Ralf , Brandt Christian 
Published: July 2020

AbstractPhages are among the most abundant and diverse biological entities on earth. Phage prediction from sequence data is a crucial first step to understanding their impact on the environment. A variety of bacteriophage prediction tools have been developed over the years. They differ in algorithmic approach, results, and ease of use. We, therefore, developed “What the Phage” (WtP), an easy-to-use and parallel multitool approach for phage prediction combined with an annotation and classification downstream strategy, thus, supporting the user’s decision-making process by summarizing the results of the different prediction tools in charts and tables. WtP is reproducible and scales to thousands of datasets through a workflow manager (Nextflow). WtP is freely available under a GPL-3.0 license (https://github.com/replikation/What_the_Phage).
The YtrBCDEF ABC transporter is involved in the control of social activities inBacillus subtilis
Authors: Benda Martin , Schulz Lisa , Rismondo Jeanine , Stülke Jörg 
Published: July 2020

AbstractBacillus subtilisdevelops genetic competence for the uptake of foreign DNA when cells enter the stationary phase and a high cell density is reached. These signals are integrated by the competence transcription factor ComK which is subject to transcriptional, post-transcriptional and post-translational regulation. Many proteins are involved in the development of competence, both to control ComK activity and to mediate DNA uptake. However, the precise function they play in competence development is often unknown. In this study, we have tested whether proteins required for genetic transformation play a role in the activation of ComK or rather downstream of competence gene expression. While these possibilities could be distinguished for most of the tested factors, two proteins (PNPase and the transcription factor YtrA) are required both for full ComK activity and for the downstream processes of DNA uptake and integration. Further analyses of the role of the transcription factor YtrA for the competence development revealed that the constitutive expression of the YtrBCDEF ABC transporter in theytrAmutant causes the loss of genetic competence. Moreover, constitutive expression of this ABC transporter also interferes with biofilm formation. Since theytrGABCDEFoperon is induced by cell wall-targeting antibiotics, we tested the cell wall properties upon overexpression of the ABC transporter and observed an increased thickness of the cell wall. The composition and properties of the cell wall are important for competence development and biofilm formation, suggesting that the increased cell wall thickness as a result of YtrBCDEF overexpression causes the observed phenotypes.
Crystal structure and molecular dynamics of human POLDIP2, a multifaceted adaptor protein in metabolism and genome stability
Authors: Kulik Anastasija A. , Maruszczak Klaudia K. , Thomas Dana C. , Nabi Naomi L. A. , Carr Martin , Bingham Richard J. , Cooper Christopher D. O. 
Published: July 2020

AbstractPolymerase δ-interacting protein 2 (POLDIP2, PDIP38) is a multifaceted, ‘moonlighting’ protein, involved in binding protein partners from many different cellular processes, including mitochondrial metabolism, DNA replication and repair, and reactive oxygen species generation. POLDIP2 is found in multiple cellular compartments, potentially shuttled depending on its role. How POLDIP2 binds to and coordinates many different proteins is currently unknown. Towards this goal, we present the crystal structure of the ‘mitochondrial’ fragment of POLDIP2 to 2.8 Å. POLDIP2 exhibited a compact two-domain β-strand-rich globular structure, confirmed by circular dichroism and small angle X-ray scattering approaches. POLDIP2 comprised canonical DUF525 (ApaG) and YccV-like domains, but with the conserved domain linker packed tightly, resulting in an ‘extended’ YccV module. A central channel through POLDIP2 was observed which we hypothesise could influence structural changes potentially mediated by redox conditions, following observation of a modified cysteine residue in the channel. Unstructured regions were rebuilt byab initiomodelling to generate a model of full length POLDIP2. Molecular dynamics simulations revealed a highly dynamic N-terminal region tethered to the YccV-domain by an extended linker, potentially facilitating interactions with distal binding partners. Finally we build models of POLDIP2 interacting in complex with two of its partners in genome stability, PrimPol and PCNA. These indicate that dynamic flexibility of the POLDIP2 N-terminal and loop regions are critical to mediate protein-protein interactions.
Epigenomic characterization of latent HIV infection identifies latency regulating transcription factors
Authors: Jefferys Stuart R , Burgos Sam , Peterson Jackson J , Selitsky Sara R , Turner Anne-Marie , James Lindsey I , Margolis David M , Parker Joel , Browne Edward P 
Published: July 2020

SummaryTranscriptional silencing of HIV generates a reservoir of latently infected cells, but the mechanisms that lead to this outcome are not well understood. We characterized a primary cell model of HIV latency, and observed that latency is a stable, heritable viral state that is rapidly reestablished after stimulation. Using Assay of Transposon-Accessible Chromatin sequencing (ATACseq) we found that latently infected cells exhibit reduced proviral accessibility, elevated activity of Forkead and Kruppel-like factor transcription factors (TFs), and reduced activity of AP-1, RUNX and GATA TFs. Latency reversing agents caused distinct patterns of chromatin reopening across the provirus. Furthermore, depletion of a chromatin domain insulator, CTCF inhibited HIV latency, identifying this factor as playing a key role in the initiation or enforcement of latency. These data indicate that HIV latency develops preferentially in cells with a distinct pattern of TF activity that promotes a closed proviral structure and inhibits viral gene expression.
Heterogeneous genetic basis of age at maturity in salmonid fishes
Authors: Waters Charles D. , Clemento Anthony , Aykanat Tutku , Garza John Carlos , Naish Kerry A. , Narum Shawn , Primmer Craig R. 
Published: July 2020

AbstractUnderstanding the genetic basis of repeated evolution of the same phenotype across taxa is a fundamental aim in evolutionary biology and has applications to conservation and management. However, the extent to which interspecific life-history trait polymorphisms share evolutionary pathways remains under-explored. We address this gap by studying the genetic basis of a key life-history trait, age at maturity, in four species of Pacific salmon (genus Oncorhynchus) that exhibit intra- and interspecific variation in this trait – Chinook Salmon, Coho Salmon, Sockeye Salmon, and Steelhead Trout. We tested for associations in all four species between age at maturity and two genome regions, six6 and vgll3, that are strongly associated with the same trait in Atlantic Salmon (Salmo salar). We also conducted a genome-wide association analysis in Steelhead to assess whether additional regions were associated with this trait. We found the genetic basis of age at maturity to be heterogeneous across salmonid species. Significant associations between six6 and age at maturity were observed in two of the four species, Sockeye and Steelhead, with the association in Steelhead being particularly strong in both sexes (p = 4.46×10−9 after adjusting for genomic inflation). However, no significant associations were detected between age at maturity and the vgll3 genome region in any of the species, despite its strong association with the same trait in Atlantic Salmon. We discuss possible explanations for the heterogeneous nature of the genetic architecture of this key life-history trait, as well as the implications of our findings for conservation and management.