bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reclassification of SLC22 Transporters: Analysis of OAT, OCT, OCTN, and other Family Members Reveals 8 Functional Subgroups
Authors: Engelhart Darcy , Granados Jeffry C. , Shi Da , Saier Milton , Baker Michael , Abagyan Ruben , Nigam Sanjay K. 
Published: December 2019

AbstractAmong transporters, the SLC22 family is emerging as a central hub of endogenous physiology. The family consists of organic anion transporters (OATs), organic cation transporters (OCTs) and zwitterion transporters (OCTNs). Despite being known as “drug” transporters, these multi-specific, oligo-specific, and relatively mono-specific transporters facilitate the movement of metabolites and key signaling molecules. An in-depth reanalysis supports a reassignment of these proteins into eight functional subgroups with four new subgroups arising from the previously defined OAT subclade. These OAT subgroups are: OATS1 (SLC22A6, SLC22A8, and SLC22A20), OATS2 (SLC22A7), OATS3 (SLC22A11, SLC22A12, and Slc22a22), and OATS4 (SLC22A9, SLC22A10, SLC22A24, and SLC22A25). We propose merging the OCTN (SLC22A4, SLC22A5, and Slc22a21) and OCT-related (SLC22A15 and SLC22A16) subclades into the OCTN/OCTN-related subgroup. Functional support for the eight subgroups comes from network analysis of data from GWAS, in vivo models, and in vitro assays. These data emphasize shared substrate specificity of SLC22 transporters for characteristic metabolites such as prostaglandins, uric acid, carnitine, creatinine, and estrone sulfate. Some important subgroup associations include: OATS1 with metabolites, signaling molecules, uremic toxins and odorants, OATS2 with cyclic nucleotides, OATS3 with uric acid, OATS4 with conjugated sex hormones, particularly etiocholanolone glucuronide, OCT with monoamine neurotransmitters, and OCTN/OCTN-related with ergothioneine and carnitine derivatives. The OAT-like and OAT-related subgroups remain understudied and therefore do not have assigned functionality. Relatedness within subgroups is supported by multiple sequence alignments, evolutionarily conserved protein motifs, genomic localization, and tissue expression. We also highlight low level sequence similarity of SLC22 members with other non-transport proteins. Our data suggest that the SLC22 family can work among itself, as well as with other transporters and enzymes, to optimize levels of numerous metabolites and signaling molecules, as proposed by the Remote Sensing and Signaling Theory.
Donor specific transcriptomic analysis of Alzheimer’s disease associated hypometabolism highlights a unique donor, microglia, and ribosomal proteins
Authors: Patel Sejal , Howard Derek , Man Alana , Schwartz Deborah , Jee Joelle , Felsky Daniel , Pausova Zdenka , Paus Tomas , French Leon 
Published: December 2019

AbstractAlzheimer’s disease (AD) starts decades before clinical symptoms appear. Low glucose utilization in regions of the cerebral cortex marks early AD and is clinically useful. To identify these regions, we conducted a voxel-wise meta-analysis of positron emission tomography studies that compared AD patients with healthy controls. This meta-analysis included 27 studies that assayed glucose utilization in 915 AD patients and 715 healthy controls. The resulting map marks hypometabolism in the posterior cingulate, middle frontal, angular gyrus, middle and inferior temporal regions. Using the Allen Human Brain Atlas, we identified genes with expression patterns associated with this hypometabolism pattern in the cerebral cortex. Of the six brains in the Atlas, one demonstrated a strong spatial association with the hypometabolism pattern. Previous neuropathological assessment of this brain from a 39-year-old male noted a neurofibrillary tangle in the entorhinal cortex. Using the transcriptomic data, we estimate lower proportions of neurons and more microglia in the hypometabolic regions when compared with the other five brains. Within this single brain, signal recognition particle (SRP)-dependent cotranslational protein targeting genes, which primarily encode cytosolic ribosome proteins, are highly expressed in the hypometabolic regions. Analyses of human and mouse data show that expression of these genes progressively increases across AD-associated states of microglial activation. In addition, genes involved in cell killing, chronic inflammation, ubiquitination, tRNA aminoacylation, and vacuole sorting are associated with the hypometabolism map. These genes suggest disruption of the protein life cycle and neuroimmune activation. Taken together, our molecular characterization of cortical hypometabolism reveals a molecular link to AD associated hypometabolism that may be relevant to preclinical stages.
Epigenetics of skeletal muscle-associated genes in theASB, LRRC, TMEM, andOSBPLgene families
Authors: Ehrlich Kenneth C. , Lacey Michelle , Ehrlich Melanie 
Published: December 2019

AbstractMuch remains to be discovered about the intersection of tissue-specific transcription control and the epigenetics of skeletal muscle (SkM), a very complex and dynamic organ. From four gene families,ASB, LRRC, TMEM, andOSBPL, we chose 21 genes that are preferentially expressed in human SkM relative to 52 other tissue types and analyzed relationships between their tissue-specific epigenetics and expression. We also compared their genetics, proteomics, and descriptions in the literature. For this study, we identified genes with little or no previous descriptions of SkM functionality (ASB4, ASB8, ASB10, ASB12, ASB16, LRRC14B, LRRC20, LRRC30, TMEM52, TMEM233, OSBPL6/ORP6, andOSBPL11/ORP11) and included genes whose SkM functions had been previously addressed (ASB2, ASB5, ASB11, ASB15, LRRC2, LRRC38, LRRC39, TMEM38A/TRIC-A, andTMEM38B/TRIC-B). Among the transcription-related SkM epigenetic features that we identified were super-enhancers, promoter DNA hypomethylation, lengthening of constitutive low-methylated promoter regions, and SkM-related enhancers for one gene embedded in a neighboring gene (e.g.,ASB8-PFKM, LRRC39-DBT, andLRRC14B-PLEKHG4Bgene-pairs). In addition, highly or lowly co-expressed long non-coding RNA (lncRNA) genes probably regulate several of these genes. Our findings give insights into tissue-specific epigenetic patterns and functionality of related genes in a gene family and can elucidate normal and disease-related regulation of gene expression in SkM.
Excess extracellular K+causes inner hair cell ribbon synapse degeneration
Authors: Zhao Hong-Bo , Zhu Yan , Liu Li-Man 
Published: December 2019

AbstractInner hair cell (IHC) ribbon synapses are the first synapse in the auditory system and can be degenerated by noise and aging, thereby leading to hidden hearing loss (HHL) and other hearing disorders. However, the mechanism underlying this cochlear synaptopathy remains unclear. Here, we report that elevation of extracellular K+, which is a consequence of noise exposure, could cause IHC ribbon synapse degeneration and swelling. Like intensity dependence in noise-induced cochlear synaptopathy, the K+-induced degeneration was dose-dependent, and could be attenuated by BK channel blockers. However, application of glutamate receptor (GluR) agonists caused ribbon swelling but not degeneration. In addition, consistent with synaptopathy in HHL, both K+and noise exposure only caused IHC but not outer hair cell ribbon synapse degeneration. These data reveal that K+excitotoxicity can degenerate IHC ribbon synapses in HHL, and suggest that BK channel may be a potential target for prevention and treatment of HHL.
The Innate Immune Toll-Like Receptor-2 modulates the Depressogenic and Anorexiolytic Neuroinflammatory Response in Obstructive Sleep Apnoea
Authors: Polsek Dora , Cash Diana , Veronese Mattia , Ilic Katarina , Wood Tobias C. , Milosevic Milan , Kalanj-Bognar Svjetlana , Morrell Mary J. , Williams Steve C.R. , Gajovic Srecko , Leschziner Guy D. , Mitrecic Dinko , Rosenzweig Ivana 
Published: December 2019

ABSTRACTBackgroundThe neurological mechanisms of the disease process of obstructive sleep apnea, the second most frequent sleep disorder, remain unclear whilst its links with several major neuropsychiatric disorders, such as depression, anxiety and even Alzheimer’s disorder, are increasingly recognised. A radical theory, that inflammation in the brain may underlie certain phenotypes of many of these disorders, has been proposed, and the microglial TLR2 system may serve as an important crossroad at the borderlands of several pathogenesis. This study undertook to investigate whether a neuroinflammatory response occurs under conditions of OSA, and whether it might be related to a modulated response due to TLR2 functionality in an established rodent model of OSA.MethodsThe effects of three weeks’ exposure to chronic intermittent hypoxia were monitored in mice with or without functional TLR2 (C57BL/6-Tyrc-Brd-Tg(Tlr2-luc/gfp)Kri/Gaj; TLR2−/−, C57BL/6-Tlr2tm1Kir), that were investigated by multimodalin vivoandex vivoimaging, combining magnetic resonance and bioluminescence imaging and a variety of functional tests.ResultsAn acute neuroinflammatory response was demonstrated following the three days in the basal forebrain of mice, and more chronically in other parts of the frontal cortex. Adaptive changes in specific neurocircuitry were demonstrated, with significant links to agitated (mal)adaptive behaviour under episodes of stress, and an increased ability to gain weight.ConclusionsOur results suggest that microglial activation and an innate immune response might be the missing link underlying the pathogenesis of well known structural, psychologic and metabolic changes experienced by some patients with OSA.
Different salicylic and jasmonic acids imbalances are involved in the oxidative stress-mediated cell death, induced by fumonisin B1 in maize seedlings with contrasting resistance toFusarium verticillioidesear rot in the field
Authors: Otaiza-González Santiago N. , Mary Verónica S. , Arias Silvina L. , Bertrand Lidwina , Velez Pilar A. , Rodriguez María G. , Rubinstein Héctor R. , Theumer Martín G. 
Published: December 2019

ABSTRACTBackground and aimFungal and plant secondary metabolites modulate the plant-pathogen interactions. However, the participation of fumonisins in theFusarium verticillioides-maize pathosystem is unclear. In this work was studied the cell death, and the reactive oxygen species (ROS) - phytohormone imbalance interplay underlying the phytotoxicity of fumonisin B1 (FB1) in maize germplasms with contrasting resistance toFusariumear rot in the field.MethodsResistant (RH) and susceptible hybrid (SH) maize seedlings, grown from uninoculated seeds irrigated with FB1 (1 and 20 ppm), were harvested at 7, 14 and 21 days after planting, and were examined for electrolyte leakage (aerial parts); and for oxidative stress biomarkers (aerial parts and roots). The phytohormone (salicylic and jasmonic acids) imbalance interplay underlying the FB1-induced cell death were further explored in seedlings exposed 24 h to the mycotoxin (1 ppm) in hydroponics.ResultsCell death increased in RH and SH watered with 1 and 20 ppm of mycotoxin, respectively. Both toxin concentrations were pro-oxidant, and the major perturbations were found in roots. An Integrated Biomarker Response index was calculated suggesting that phytotoxicity occurs in a redox context more efficiently controlled by RH.ConclusionThe pre-treatment with the antioxidant ascorbic acid led to the conclusion that cell death in RH was related to a salicylic acid increase mediated by ROS. Nevertheless, FB1 induced two different phytohormonal regulatory mechanisms mediated by oxidative stress in both maize hybrids.
Molecular dynamics simulation of local structural models of PrPScreveals how codon 129 polymorphism affects propagation of PrPSc
Authors: Otaki Hiroki , Taguchi Yuzuru , Nishida Noriyuki 
Published: December 2019

AbstractPrions are unconventional pathogen without nucleotide genome and their pathogenic properties are defined by the primary structure and the conformation of the constituent abnormal isoform (PrPSc) of prion protein (PrP). A polymorphic codon 129 of human PrP that is valine (V129) or methionine (M129) is particularly influential on properties of PrPSc, affecting transmission efficiencies and clinicopathological features. However, how the single residue is so influential has not been elucidated because the detailed structures of PrPSchave not been determined yet due to its incompatibility with high-resolution structural analysis. Previously we created an in-register parallel β-sheet local structural model of human PrPScencompassing residues 107 to 143 that seemed more compatible with V129 than M129, based on knowledge from α-synuclein amyloids and an NMR-based model of the amyloid of Y145Stop mutant of PrP in the literature. Here, we created an M129-compatible local structural model of PrPSc. Severe destabilization of the model by G127V mutation was consistent with the protective effects of V127 polymorphism of human PrP against prions. It was highly sensitive to the length of the hydrophobic side chain of codon 129 and replacement of M129 with leucine or valine destabilized the structures. Interestingly, the U-shaped β-arch which comprises M129 flexibly changed hydrophobic interaction networks inside the β-arch depending on the interactions with the surrounding structures, whereas the previous model with V129 maintained the similar network patterns irrespective of the surroundings. The differences between the two models may explain influences of the codon 129 polymorphism on transmissions and properties of human prions.
Clamping, bending, and twisting inter-domain motions in the misfold-recognising portion of UDP-glucose:glycoprotein glucosyl-transferase
Authors: Modenutti Carlos P. , Blanco Capurro Juan I. , Ibba Roberta , Vasiljević Snežana , Hensen Mario , Alonzi Dominic S. , Chandran Anu V. , Hill Johan C. , Rushton Jonathan , Kumar Abhinav , Rubichi Simone , Lia Andrea , Tax Gábor , Marti Lucia , Santino Angelo , Martí Marcelo A. , Zitzmann Nicole , Roversi Pietro 
Published: December 2019

SummaryUDP-glucose:glycoprotein glucosyltransferase (UGGT) is the only known glycoprotein folding quality control checkpoint in the eukaryotic glycoprotein secretory pathway. When the enzyme detects a misfolded glycoprotein in the Endoplasmic Reticulum (ER), it dispatches it for ER retention by re-glucosylating it on one of its N-linked glycans. Recent crystal structures of a fungal UGGT have suggested the enzyme is conformationally mobile. Here, a negative stain electron microscopy reconstruction of UGGT in complex with a monoclonal antibody confirms that the misfold-sensing N-terminal portion of UGGT and its C-terminal catalytic domain are tightly associated. Molecular Dynamics (MD) simulations capture UGGT in so far unobserved conformational states, giving new insights into the molecule’s flexibility. Principal component analysis of the MD trajectories affords a description of UGGT’s overall inter-domain motions, highlighting three types of inter-domain movements: bending, twisting and clamping. These inter-domain motions modify the accessible surface area of the enzyme’s central saddle, likely enabling the protein to recognize and re-glucosylate substrates of different sizes and shapes, and/or re-glucosylate N-linked glycans situated at variable distances from the site of misfold. We propose to name “Parodi limit” the maximum distance between a site of misfolding on a UGGT glycoprotein substrate and an N-linked glycan that monomeric UGGT can re-glucosylate on the same glycoprotein. MD simulations estimate the Parodi limit to be around 60-70 Å. Re-glucosylation assays using UGGT deletion mutants suggest that the TRXL2 domain is necessary for activity against urea-misfolded bovine thyroglobulin. Taken together, our findings support a “one-size-fits-all adjustable spanner” substrate recognition model, with a crucial role for the TRXL2 domain in the recruitment of misfolded substrates to the enzyme’s active site.
Identifying groups of people with similar sociobehavioural characteristics in Malawi to inform HIV interventions: a Latent Class Analysis
Authors: Merzouki Aziza , Styles Amanda , Estill Janne , Baranczuk Zofia , Petrie Karen , Keiser Olivia 
Published: December 2019

AbstractBackgroundWithin many sub-Saharan African countries including Malawi, HIV prevalence varies widely between regions. This variability may be related to the distribution of population groups with specific sociobehavioural characteristics that influence the transmission of HIV and the uptake of prevention. In this study, we intended to identify groups of people in Malawi with similar risk profiles.MethodsWe used data from the Demographic and Health Survey in Malawi from 2016, and stratified the analysis by sex. We considered demographic, socio-behavioural and HIV-related variables. Using Latent Class Analysis (LCA), we identified clusters of people sharing common sociobehavioural characteristics. The optimal number of clusters was selected based on the Bayesian information criterion. We compared the proportions of individuals belonging to the different clusters across the three regions and 28 districts of Malawi.ResultsWe found nine clusters of women and six clusters of men. Most women in the clusters with highest risk of being HIV infected were living in female-headed households and were formerly married or in a union. Among men, older men had the highest risk of being HIV infected, followed by young (20-25) single men. Generally, low HIV testing uptake correlated with lower risk of having HIV. However, rural adolescent girls had a low probability of being tested (48.7%) despite a relatively high HIV prevalence. Urban districts and Southern region had a higher percentage of high-prevalence and less tested clusters of individuals than other areas.ConclusionsLCA is an efficient method to find clusters of people sharing common HIV risk profiles, identify particularly vulnerable population groups, and plan targeted interventions focusing on these groups. Tailored support, prevention and HIV testing programmes should focus particularly on female household heads, adolescent girls living in rural areas, older married men, and young men who have never been married.FundingThe project was funded by the Swiss National Science Foundation (grant no 163878).
Zebrafish embryonic tissue differentiation is marked by concurrent cell cycle dynamic and gene promoter regulatory changes
Authors: Wragg Joseph W , Roos Leonie , Vucenovic Dunja , Cvetesic Nevena , Lenhard Boris , Müller Ferenc 
Published: December 2019

AbstractThe core promoter, a stretch of DNA surrounding the transcription start site (TSS) is a major integration point for regulatory signals controlling gene transcription. The process of cell differentiation is accompanied by a marked divergence in transcriptional repertoire between cells of different fates, accompanied by changes in cellular behaviour, in particular their proliferative activity. Investigation of divergent core promoter architectures suggest distinct regulatory networks act on the core promoter, modulating cell behavior through transcriptional profile changes, which ultimately drives key transitions in cellular behaviour during embryonic development. The role that promoter-associated gene regulatory networks play in development associated transitions in cell cycle dynamics (e.g. during differentiation) however, is poorly understood. In this study we demonstrate in a developingin vivomodel, how core promoter variations play a key role in defining transcriptional output in cells transitioning from a proliferative to cell-lineage specifying phenotype. The FUCCI transgenic system, differentially marks cells in G1 and S/G2/M phases of the cell cycle and can therefore be used to separate rapidly and slowly cycling cellsin vivo, by virtue of the cell cycle stage they primarily inhabit. Longitudinal assessment of cell proliferation rate during zebrafish embryo development, using this system, revealed a spatial and lineage-specific separation in cell cycling behaviour across post-gastrulation embryos. In order to investigate the role differential promoter usage plays in this process, cap analysis of gene expression (CAGE) was performed on fluorescent associated cell sorted (FACS) FUCCI zebrafish embryos going through somitogenesis, separating cells in accordance with the rate of their cell cycling. This analysis revealed a dramatic increase in lineage and tissue-specific gene expression, concurrent with a slowing of their cell cycling. Core promoters associated with rapidly cycling cells, showed broad distribution of transcription start site usage, featuring positionally constrained CCAAT-box, while slowly cycling cells favoured sharp TSS usage coupled with canonical TATA-box utilisation and enrichment of Sp1 binding sites. These results demonstrate the regulatory role of core promoters in cell cycle-dependent transcription regulation, during somitogenesis stages of embryo development.
Growth factor-mediated coupling between lineage size and cell fate choice underlies robustness of mammalian development
Authors: Saiz Néstor , Mora-Bitria Laura , Rahman Shahadat , George Hannah , Herder Jeremy P , García-Ojalvo Jordi , Hadjantonakis Anna-Katerina 
Published: December 2019

SummaryPrecise control and maintenance of the size of cell populations is fundamental for organismal development and homeostasis. The three cell types that comprise the mammalian blastocyst-stage embryo are generated in precise proportions and over a short time, suggesting a size control mechanism ensures a reproducible outcome. Guided by experimental observations, we developed a minimal mathematical model that shows growth factor signaling is sufficient to guarantee this robustness. The model anticipates, without additional parameter fitting, the response of the embryo to perturbations in its lineage composition. We experimentally added lineage-restricted cells to the epiblast bothin vivoandin silico, which resulted in a shift of the fate of progenitors away from the supernumerary cell type, while eliminating cells using laser ablation biased the specification of progenitors towards the targeted cell type. Finally, we show that FGF4 couples cell fate decisions to lineage composition through changes in local concentration of the growth factor. Our results provide a basis for the regulative abilities of the mammalian embryo and reveal how, in a self-organizing system, individual cell fate decisions are coordinated at the population level to robustly generate tissues in the right proportions.
Integrative transcriptome imputation reveals tissue-specific and shared biological mechanisms mediating susceptibility to complex traits
Authors: Zhang Wen , Voloudakis Georgios , Rajagopal Veera M. , Reahead Ben , Dudley Joel T. , Schadt Eric E. , Björkegren Johan L.M. , Kim Yungil , Fullard John F. , Hoffman Gabriel E. , Roussos Panos 
Published: December 2019

AbstractTranscriptome-wide association studies integrate gene expression data with common risk variation to identify gene-trait associations. By incorporating epigenome data to estimate the functional importance of genetic variation on gene expression, we improve the accuracy of transcriptome prediction and the power to detect significant expression-trait associations. Joint analysis of 14 large-scale transcriptome datasets and 58 traits identify 13,724 significant expression-trait associations that converge to biological processes and relevant phenotypes in human and mouse phenotype databases. We perform drug repurposing analysis and identify known and novel compounds that mimic or reverse trait-specific changes. We identify genes that exhibit agonistic pleiotropy for genetically correlated traits that converge on shared biological pathways and elucidate distinct processes in disease etiopathogenesis. Overall, this comprehensive analysis provides insight into the specificity and convergence of gene expression on susceptibility to complex traits.