bluuebunny/crossref_metadata_2025_split huggingface dataset:
Precision Methylome andin vivoMethylation Kinetics Characterization ofKlebsiella Pneumoniae
Authors: Fu Jing , Zhang Ju , Yang Li , Ding Nan , Yue Liya , Zhang Xiangli , Lu Dandan , Jia Xinmiao , Li Cuidan , Guo Chongye , Yin Zhe , Jiang Xiaoyuan , Zhao Yongliang , Chen Fei , Zhou Dongsheng 
Published: December 2020

AbstractKlebsiella pneumoniae(K. pneumonia) is an important pathogen that can cause severe hospital-/community-acquired infections. To panoramically analyzeK. pneumoniae’smethylation features, we completed the whole genome sequences of 14K. pneumoniaestrains covering various serotypes, multilocus-sequence typings (MLSTs), clonal groups (CG), viscosity/virulence and drug-resistances, and further characterized their methylomes using PacBio-SMRT and bisulfite technologies. We identified 15 methylation motifs (13 6mA and two 5mC motifs), among which eight were novel ones. Their corresponding MTases were further validated. Additionally, we analyzed the genomic distribution of GATC and CCWGG methylation motifs shared by all strains, and identified differential distributive patterns of some hemi/un-methylated GATC motifs tending to locate in the intergenic regions (IGRs). Specifically, we characterized thein vivomethylation kinetics at single-base resolution on a genome-wide scale by simulating the dynamic processes of replication-mediated passive demethylation and MTase-catalyzed re-methylation. The slower methylation-rates of the GATC motifs in the replication origins (oriC) and IGRs suggest an epigenetic mechanism implicated in the regulation of replication-initiation and transcription. Our findings illustrate the first comprehensive dynamic methylome map ofK. pneumoniaat single base resolution, and provide an efficient means and important reference for a better understanding of epigenetic regulation in bacteria.
Epigenetic alterations underlie airway macrophage differentiation and phenotype during lung fibrosis
Authors: McErlean Peter , Bell Christopher G. , Hewitt Richard J. , Busharat Zabreen , Ogger Patricia P. , Ghai Poonam , Albers Gesa , Kingston Shaun , Molyneaux Philip L. , Beck Stephan , Lloyd Clare M. , Maher Toby M. , Byrne Adam J 
Published: December 2020

AbstractAirway macrophages (AMs) are key regulators of the lung environment and are implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a fatal respiratory disease with no cure. However, the epigenetics of AMs development and function in IPF are limited. Here, we characterised the DNA-methylation (DNAm) profile of AMs from IPF (n=30) and healthy (n=14) donors. Our analysis revealed epigenetic heterogeneity was a key characteristic of IPF AMs. DNAm ‘clock’ analysis indicated epigenetic alterations in IPF-AMs was not associated with accelerated ageing. In differential DNAm analysis, we identified numerous differentially methylated positions (DMPs, n=11) and regions (DMRs, n=49) between healthy and IPF AMs respectively. DMPs and DMRs encompassed genes involved in lipid (LPCAT1) and glucose (PFKB3) metabolism and importantly, DNAm status was associated with disease severity in IPF. Collectively, our data identify that profound changes in the epigenome underpin the development and function of AMs in the IPF lung.
Optogenetic activation of the serotonergic neural circuit between the dorsal raphe nucleus and pre-Bötzinger complex contributes to inhibition of seizure-induced respiratory arrest in the DBA/1 mouse SUDEP model
Authors: Ma HaiXiang , Yu Qian , Shen Yue , Lian XiTing , Gu LeYuan , lu Han , Zhao HaiTing , Zeng Chang , Nagayasu Kazuki , Zhang HongHai 
Published: December 2020

AbstractSudden unexpected death in epilepsy (SUDEP) is the leading cause of death among epilepsy patients, occurring even more frequently in cases with anti-epileptic drug resistance. However, the underlying mechanism of SUDEP remains elusive. Our previous study demonstrated that enhancement of serotonin (5-HT) synthesis by intraperitoneal (IP) injection of 5-hydroxytryptophan (5-HTP) significantly reduced the incidence of seizure-induced respiratory arrest (S-IRA) in a DBA/1 mouse SUDEP model. Given that the 5-HT2A receptor (5-HT2AR) plays an important role in mediating the respiration system in the brain, we hypothesized that 5-HT2AR plays a key role in S-IRA and SUDEP. To test this hypothesis, we examined whether the decreased incidence of S-IRA evoked by either acoustic stimulation or pentylenetetrazole (PTZ) injection following 5-HTP administration will be blocked by treatment with ketanserin (KET), a selective antagonist of 5HT2AR, in the DBA/1 mouse SUDEP model. We observed that the reduction in S-IRA by 5-HTP was significantly reversed by IP or intracerebroventricular injection of KET. Considering the localization of 5-HT2AR in the pre-Bötzinger complex (PBC), which plays a key role in regulating respiratory rhythm, we next examined whether KET acts on 5-HT2AR in the PBC. To test this hypothesis, we activated the neural circuit between the dorsal raphe nucleus (DR) and PBC using optogenetics technology. We observed that stimulation of TPH2-ChETA-expressing neurons in the DR reduced the incidence of S-IRA evoked by PTZ, and this suppressant effect was significantly reversed by administration of KET in the bilateral PBC with no changes in electroencephalogram activity. The neural circuit between the DR and PBC was confirmed by injection of cholera toxin subunit B555 (CTB-555), a nerve tracer, in the DR or PBC separately. Calcium signaling evoked by PTZ within neurons of the PBC during seizures was significantly reduced by photostimulation of the DR. Taken together, our findings suggest that 5-HT2AR plays a critical role in regulating S-IRA and targeting the serotonergic neural circuit between the DR and PBC is a promising approach to preventing SUDEP.
The Role of Aquaporin-4 in Optic Nerve Head Astrocytes in Experimental Glaucoma
Authors: Kimball Elizabeth , Schaub Julie , Quillen Sarah , Keuthan Casey , Pease Mary Ellen , Korneva Arina , Quigley Harry 
Published: December 2020

AbstractPurposeTo study aquaporin channel expression in astrocytes of the mouse optic nerve (ON) and the response to IOP elevation in mice lacking aquaporin 4 (AQP4 null).MethodsC57BL/6 (B6) and AQP4 null mice were exposed to bead-induced IOP elevation for 3 days (3D-IOP), 1 and 6 weeks. Mouse ocular tissue sections were immunolabeled against aquaporins 1(AQP1), 4(AQP4), and 9(AQP9). Ocular tissue was imaged to identify normal AQP distribution, ON changes, and axon loss after IOP elevation. Ultrastructure examination, cell proliferation, gene expression & transport block was also analyzed.ResultsB6 mice presented abundant AQP4 in Müller cells, astrocytes of retina and myelinated ON (MON), but minimal expression in prelaminar and unmyelinated ON (UON). MON of AQP4 nulls had smaller ON area, smaller axon diameter, higher axon density, and larger proportionate axon area than B6 (all p≤0.05). Bead-injection led to comparable 3D-IOP elevation (p=0.42) and axonal transport blockade in both strains. In B6, AQP4 distribution was unchanged after 3D-IOP. At baseline, AQP1 and AQP9 were present in retina, but not in UON and this was unaffected after IOP elevation in both strains. In 3D-IOP mice, ON astrocytes and microglia proliferated, more in B6 than AQP4 null. After 6 week IOP elevation, axon loss occurred equally in the two mouse types (24.6%, AQP4 null vs. 23.3%, B6).ConclusionLack of AQP4 was neither protective nor detrimental to the effects of IOP elevation. The minimal presence of AQP4 in UON may be a vital aspect of the regionally specific phenotype of astrocytes in the mouse optic nerve head.
Ubiquitin-protein ligaseUbr5cooperates with Hedgehog signalling to promote skeletal tissue homeostasis
Authors: Mellis David , Staines Katherine A , Peluso Silvia , Georgiou Ioanna Ch. , Dora Natalie , Kubiak Malgorzata , Grillo Michela , Farquharson Colin , Kinsella Elaine , Thornburn Anna , Ralston Stuart H , Salter Donald M , Riobo-Del Galdo Natalia A , Hill Robert E , Ditzel Mark 
Published: December 2020

AbstractMammalian Hedgehog (HH) signalling pathway plays an essential role in tissue homeostasis and its deregulation is linked to rheumatological disorders. UBR5 is the mammalian homologue of the E3 ubiquitin-protein ligase Hyd, a negative regulator of the Hh-pathway inDrosophila.To investigate a possible role of UBR5 in regulation of the musculoskeletal system through modulation of mammalian HH signaling, we created a mouse model for specific loss ofUbr5function in limb bud mesenchyme. Our findings revealed a role for UBR5 in maintaining cartilage homeostasis and suppressing metaplasia.Ubr5loss of function resulted in progressive and dramatic articular cartilage degradation, enlarged, abnormally shaped sesamoid bones and extensive heterotopic tissue metaplasia linked to calcification of tendons and ossification of synovium. Genetic suppression of smoothened(Smo), a key mediator of HH signalling, dramatically enhanced theUbr5mutant phenotype. Analysis of HH signalling in both mouse and cell model systems revealed that loss ofUbr5stimulated canonical HH-signalling while also increasing PKA activity. In addition, human osteoarthritic samples revealed similar correlations betweenUBR5expression, canonical HH signalling and PKA activity markers. Our studies identified a crucial function for theUbr5gene in the maintenance of skeletal tissue homeostasis and an unexpected mode of regulation of the HH signalling pathway.Author SummaryUbiquitin ligases modify proteins post-translationally which is essential for a variety of cellular processes. UBR5 is an E3 ubiquitin ligase and inDrosophilais a regulator of Hedgehog signaling. In mammals, the Hedgehog (HH) signalling pathway, among many other roles, plays an essential role in tissue maintenance, a process called homeostasis. A murine genetic system was developed to specifically eliminate UBR5 function from embryonic limb tissue that subsequently forms bone and connective tissue (ligaments and tendons). This approach revealed that UBR5 operates as a potent suppressor of excessive growth of normal cartilage and bone and prevents formation of bone in ectopic sites in connective tissue near the knees and ankle joints. In contrast to abnormal growth, UBR5 inhibits degradation of the articular cartilage that cushions the knee joint leading to extensive exposure of underlying bone. Furthermore, Ubr5 interacts with smoothened, a component of the HH pathway, identifying UBR5 as a regulator of mammalian HH signaling in the postnatal musculoskeletal system. In summary, this work shows that UBR5 interacts with the HH pathway to regulate skeletal homeostasis in and around joints of the legs and identifies targets that may be harnessed for biomedical engineering and clinical applications.
BBLN-1 is essential for intermediate filament organization and apical membrane morphology
Authors: Remmelzwaal Sanne , Geisler Florian , Stucchi Riccardo , van der Horst Suzanne , Pasolli Milena , Kroll Jason R. , Jarosinska Olga D. , Akhmanova Anna , Richardson Christine A. , Altelaar Maarten , Leube Rudolf E. , Ramalho João J. , Boxem Mike 
Published: December 2020

AbstractEpithelial tubes are essential components of metazoan organ systems that control the flow of fluids and the exchange of materials between body compartments and the outside environment. The size and shape of the central lumen confer important characteristics to tubular organs and need to be carefully controlled. Here, we identify the small coiled-coil protein BBLN-1 as a regulator of lumen morphology in theC. elegansintestine. Loss of BBLN-1 causes the formation of bubble-shaped invaginations of the apical membrane into the cytoplasm of intestinal cells, and abnormal aggregation of the subapical intermediate filament (IF) network. BBLN-1 interacts with IF proteins and localizes to the IF network in an IF-dependent manner. The appearance of invaginations is a result of the abnormal IF aggregation, indicating a direct role for the IF network in maintaining lumen homeostasis. Finally, we identify bublin (BBLN) as the mammalian ortholog of BBLN-1. When expressed in theC. elegansintestine, bublin recapitulates the localization pattern of BBLN-1 and can compensate for the loss of BBLN-1. In mouse intestinal organoids, bublin localizes subapically, together with the IF protein keratin 8. Our results therefore may have implications for understanding the role of IFs in regulating epithelial tube morphology in mammals.SummaryWe identify BBLN-1 as an evolutionary conserved regulator of lumen morphology in theC. elegansintestine. Loss ofbbln-1causes intermediate filament network reorganization that induces severe apical morphology defects. We also identify bublin (BBLN) as the mammalian ortholog, which can compensate for the loss of BBLN-1 inC. elegans.
The role of sigma-1 receptor in organization of endoplasmic reticulum signaling microdomains
Authors: Zhemkov Vladimir , Ditlev Jonathon A. , Lee Wan-Ru , Liou Jen , Rosen Michael K. , Bezprozvanny Ilya 
Published: December 2020

SUMMARYSigma 1 receptor (S1R) is a 223 amino acid-long transmembrane endoplasmic reticulum (ER) protein. S1R modulates activity of multiple effector proteins but its signaling functions are poorly understood. We here test the hypothesis that biological activity of S1R in cells can be explained by its ability to interact with cholesterol and to form cholesterol-enriched microdomains in the ER. Using reduced reconstitution systems, we demonstrate direct effects of cholesterol on S1R clustering. We identify a novel cholesterol-binding motif in the transmembrane region of S1R and demonstrate its importance for S1R clustering. We demonstrate that S1R-induced membrane microdomains have increased local membrane thickness. Increased local cholesterol concentration and membrane thickness in these domains can modulate signaling of inositol-requiring enzyme 1α (IRE1α) in the ER. Further, S1R agonists cause reduction in S1R clusters, suggesting that biological activity of S1R agonists is linked to remodeling of ER membrane microdomains.
Structural Spine Plasticity in Olfaction: Memory and Forgetting, Enhanced vs. Reduced Discriminability after Learning
Authors: Meng John Hongyu , Riecke Hermann 
Published: December 2020

AbstractHow animals learn to discriminate between different sensory stimuli is an intriguing question. An important, common step towards discrimination is the enhancement of differences between the representations of relevant stimuli. This can be part of the learning process. In rodents, the olfac-tory bulb, which is known to contribute to this pattern separation, exhibits extensive structural synaptic plasticity even in adult animals: reciprocal connections between excitatory mitral cells and inhibitory granule cells are persistently formed and eliminated, correlated with mitral cell and granule cell activity. Here we present a Hebbian-type model for this plasticity. It captures the experimental observation that the same learning protocol that enhanced the discriminability of similar stimuli actually reduced that of dissimilar stimuli. The model predicts that the learned bulbar network structure is remembered across training with additional stimuli, unless the new stimuli interfere with the representations of previously learned ones.
Nuclear receptor NHR-49 promotes peroxisome proliferation to compensate for aldehyde dehydrogenase deficiency inC. elegans
Authors: Zeng Lidan , Li Xuesong , Preusch Christopher B. , He Gary J. , Xu Ningyi , Cheung Tom H. , Qu Jianan , Mak Ho Yi 
Published: December 2020

AbstractThe intracellular level of fatty aldehydes is tightly regulated to minimize the formation of toxic aldehyde adducts of cellular components. Accordingly, deficiency of a fatty aldehyde dehydrogenase FALDH causes the neurologic disorder Sjögren-Larsson syndrome (SLS) in humans. However, cellular responses to unresolved, elevated fatty aldehyde levels are poorly understood. Based on lipidomic and imaging analysis, we report that the loss of endoplasmic reticulum-, mitochondria- and peroxisomes-associated ALH-4, theC. elegansFALDH ortholog, increases fatty aldehyde levels and reduces fat storage. ALH-4 deficiency in the intestine, cell-nonautonomously induces NHR-49/NHR-79-dependent hypodermal peroxisome proliferation. This is accompanied by the upregulation of catalases and fatty acid catabolic enzymes, as indicated by RNA sequencing. Such a response is required to counteract ALH-4 deficiency sincealh-4; nhr-49double mutant animals are not viable. Our work reveals unexpected inter-tissue communication of fatty aldehyde levels, and suggests pharmacological modulation of peroxisome proliferation as a therapeutic strategy for SLS.
Leveraging auxiliary data from arbitrary distributions to boost GWAS discovery with Flexible cFDR
Authors: Hutchinson Anna , Reales Guillermo , Willis Thomas , Wallace Chris 
Published: December 2020

AbstractGenome-wide association studies (GWAS) have identified thousands of genetic variants that are associated with complex traits. However, a stringent significance threshold is required to identify robust genetic associations. Leveraging relevant auxiliary covariates has the potential to boost statistical power to exceed the significance threshold. Particularly, abundant pleiotropy and the non-random distribution of SNPs across various functional categories suggests that leveraging GWAS test statistics from related traits and/or functional genomic data may boost GWAS discovery. While type 1 error rate control has become standard in GWAS, control of the false discovery rate can be a more powerful approach. The conditional false discovery rate (cFDR) extends the standard FDR framework by conditioning on auxiliary data to call significant associations, but current implementations are restricted to auxiliary data satisfying specific parametric distributions, typically GWASp-values for related traits. We relax these distributional assumptions, enabling an extension of the cFDR framework that supports auxiliary covariates from arbitrary continuous distributions (“Flexible cFDR”). Our method can be applied iteratively, thereby supporting multi-dimensional covariate data. Through simulations we show that Flexible cFDR increases sensitivity whilst controlling FDR after one or several iterations. We further demonstrate its practical potential through application to an asthma GWAS, leveraging various functional genomic data to find additional genetic associations for asthma, which we validate in the larger, independent, UK Biobank data resource.Author summaryGenome-wide association studies (GWAS) detect regions of the human genome that are associated with various traits, including complex diseases, but the power to detect these genomic regions is currently limited by sample size. The conditional false discovery rate (cFDR) provides a tool to leverage one GWAS study to improve power in another. The motivation is that if two traits have some genetic correlation, then our interpretation of a low but not significantp-value for the trait of interest will differ depending on whether that SNP shows strong or absent evidence of association with the related trait. Here, we describe an extension to the cFDR framework, called “Flexible cFDR”, that controls the FDR and supports auxiliary data from arbitrary distributions, surpassing current implementations of cFDR which are restricted to leveraging GWASp-values from related traits. In practice, our method can be used to iteratively leverage various types of functional genomic data with GWAS data to increase power for GWAS discovery. We describe the use of Flexible cFDR to supplement data from a GWAS of asthma with auxiliary data from functional genomic experiments. We identify associations novel to the original GWAS and validate these discoveries with reference to a larger, more highly-powered GWAS of asthma.
Exploring Binary Relations for Ontology Extension and Improved Adaptation to Clinical Text
Authors: Slater Luke T , Hoehndorf Robert , Karwath Andreas , Gkoutos Georgios V 
Published: December 2020

AbstractBackgroundThe controlled domain vocabularies provided by ontologies make them an indispensable tool for text mining. Ontologies also include semantic features in the form of taxonomy and axioms, which make annotated entities in text corpora useful for semantic analysis. Extending those semantic features may improve performance for characterisation and analytic tasks. Ontology learning techniques have previously been explored for novel ontology construction from text, though most recent approaches have focused on literature, with applications in information retrieval or human interaction tasks. We hypothesise that extension of existing ontologies using information mined from clinical narrative text may help to adapt those ontologies such that they better characterise those texts, and lead to improved classification performance.ResultsWe develop and present a framework for identifying new classes in text corpora, which can be integrated into existing ontology hierarchies. To do this, we employ the Stanford Open Information Extraction algorithm and integrate its implementation into the Komenti semantic text mining framework. To identify whether our approach leads to better characterisation of text, we present a case study, using the method to learn an adaptation to the Disease Ontology using text associated with a sample of 1,000 patient visits from the MIMIC-III critical care database. We use the adapted ontology to annotate and classify shared first diagnosis on patient visits with semantic similarity, revealing an improved performance over use of the base Disease Ontology on the set of visits the ontology was constructed from. Moreover, we show that the adapted ontology also improved performance for the same task over two additional unseen samples of 1,000 and 2,500 patient visits.ConclusionsWe report a promising new method for ontology learning and extension from text. We demonstrate that we can successfully use the method to adapt an existing ontology to a textual dataset, improving its ability to characterise the dataset, and leading to improved analytic performance, even on unseen portions of the dataset.
Activity of epigenetic inhibitors againstBabesia divergens
Authors: Vanheer Leen N. , Kafsack Björn F.C. 
Published: December 2020

ABSTRACTBabesiosis in a tick-borne parasitic disease of humans and livestock, that has dramatically increased in frequency and geographical range over the past few decades. Infection of cattle often causes large economic losses, and human infection can be fatal in immunocompromised patients. Unlike for malaria, another disease caused by hemoprotozoan parasites, limited treatment options exist for Babesia infections. As epigenetic regulation is a promising target for new anti-parasitic drugs, we screened 324 epigenetic inhibitors againstBabesia divergensblood stages and identified 75 (23%) and 17 (5%) compounds that displayed ≥90% inhibition at 10 µM and 1 µM, respectively, including over a dozen compounds with activity in the low nanomolar range. We observed differential activity of some inhibitor classes againstBabesia divergensandPlasmodium falciparumparasites and identified pairs of compounds with a high difference in activity, despite a high similarity in chemical structure, highlighting new insights into the development of epigenetic inhibitors as anti-parasitic drugs.