bluuebunny/crossref_metadata_2025_split huggingface dataset:
Supplementation of OmniGen-AF improves the metabolic response to a glucose tolerance test in beef heifers1,2
Authors: Burdick Sanchez Nicole C , Carroll Jeffery A , Broadway Paul R , Schell Tyler H , Puntenney Steve B , McLean Derek J 
Published: August 2019

Abstract:
This study determined whether feeding the immunomodulating supplement, OmniGen-AF, to feedlot heifers would alter metabolic profiles to a glucose tolerance test. Heifer calves (n = 32; 217 ± 2 kg) were allocated into two treatment diets: 1) Control, fed a standard receiving ration, and 2) OmniGen, fed the Control diet supplemented with OmniGen at 4.54 g/45 kg BW/d. Heifers were fed for 42 d. On d 42, Heifers were processed through a working facility for placement of indwelling jugular catheters. After these procedures, heifers were moved into individual stanchions in an enclosed barn and all heifers were fed their treatment diets at 1400 h. All orts were removed at 2000 h to allow for a 12-h fast prior to first blood collection. The following day, heifers were administered 0.5 mL/kg BW of a 50% dextrose solution at 0900 h (0 min). Blood samples were collected for serum isolation at −60, −45, −30, −15, 0, 10, 20, 30, 45, 60, 90, 120, and 150 min relative to bolus dextrose infusion. Serum was stored at −80 oC until analyzed for cortisol, glucose, insulin, non-esterified fatty acid (NEFA) and urea N concentrations. There was a treatment × time interaction for post-challenge cortisol (P = 0.004) such that cortisol was greater in OmniGen heifers than Control heifers from 10- to 45- min post-infusion. Glucose concentrations increased post-infusion (P &lt; 0.01) and were reduced in OmniGen compared to Control heifers at 10-, 45-, and 90-min after challenge (treatment × time P &lt; 0.001). Similarly, there was a treatment × time interaction for post-challenge insulin concentrations (P = 0.04) such that insulin was greater in OmniGen-fed heifers than Control heifers from 10 to 30 min. In addition, there was a treatment × time interaction (P = 0.01) for NEFA concentrations such that concentrations were reduced in OmniGen-supplemented heifers from 10 to 30 min following administration of the dextrose bolus. Serum urea N concentrations were greater in Control heifers at 150 min compared to OmniGen-fed heifers (post-challenge treatment × time interaction: P &lt; 0.001). These data suggest that OmniGen-fed heifers were more responsive to changes in glucose, perhaps affecting the storage and/or redistribution of energy deposits and provide further evidence for altered metabolism in OmniGen-supplemented cattle. The differences observed may explain differences observed in the immune response in OmniGen-supplemented calves.
Metabolic Profiling of Aortic Stenosis and Hypertrophic Cardiomyopathy Identifies Mechanistic Contrasts in Substrate Utilisation
Authors: Pal Nikhil , Acharjee Animesh , Ament Zsuzsanna , Dent Tim , Yavari Arash , Mahmod Masliza , Ariga Rina , West James , Steeples Violetta , Cassar Mark , Howell Neil J. , Lockstone Helen , Elliott Kate , Yavari Parisa , Briggs William , Frenneaux Michael , Prendergast Bernard , Dwight Jeremy S , Kharbanda Rajesh , Watkins Hugh , Ashrafian Houman , Griffin Julian L 
Published: August 2019

ABSTRACTBackgroundAortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) are highly distinct disorders leading to left ventricular hypertrophy (LVH), but whether cardiac metabolism substantially differs between these in humans remains to be elucidated.MethodWe undertook a detailed invasive (aortic root and coronary sinus) metabolic profiling in patients with severe AS and HCM in comparison to non-LVH controls, to investigate cardiac fuel selection and metabolic remodelling. These patients were assessed under different physiological states (at rest and during stress induced by pacing). The identified changes in the metabolome were further validated by metabolomic and orthogonal transcriptomic analysis, in separately recruited patient cohorts.ResultsWe identified a highly discriminant metabolomic signature in severe AS characterised by striking accumulation of long-chain acylcarnitines, intermediates of long-chain transport and fatty acid metabolism, and validated this in a separate cohort. Mechanistically, we identify a down-regulation in the PPAR-α transcriptional network, including expression of genes regulating FAO.ConclusionsWe present a comprehensive analysis of changes in the metabolic pathways (transcriptome to metabolome) in severe AS, and its comparison to HCM. Our results demonstrate fundamental distinctions in substrate preference between AS and HCM, highlighting insufficient long-chain FAO, and the PPAR-α signalling network as a specific metabolic therapeutic target in AS.
Sex Differences in Maturation and Attrition of Adult Neurogenesis in the Hippocampus
Authors: Yagi Shunya , Splinter Jared E.J. , Tai Daria , Wong Sarah , Wen Yanhua , Galea Liisa A.M. 
Published: August 2019

ABSTRACTSex differences exist in the regulation of adult neurogenesis in the hippocampus in response to hormones and cognitive training. Here we investigated the trajectory and maturation rate of adult-born neurons in the dentate gyrus (DG) of male and female rats. Sprague-Dawley rats were perfused two hours, 24 hours, one, two or three weeks after BrdU injection, a DNA synthesis marker that labels dividing progenitor cells and their progeny. Adult-born neurons (BrdU/NeuN-ir) matured faster in males compared to females. Males had a greater density of neural stem cells (Sox2-ir) in the dorsal, but not in the ventral, DG and had higher levels of cell proliferation (Ki67-ir) than non-proestrous females. However, males showed a greater reduction in neurogenesis between one and two weeks after mitosis, whereas females showed similar levels of neurogenesis throughout the weeks. The faster maturation and greater attrition of new neurons in males compared to females suggests greater potential for neurogenesis to respond to external stimuli in males and emphasizes the importance of studying sex on adult hippocampal neurogenesis.Significance StatementPreviously studies examining the characteristics of adult-born neurons in the dentate gyrus have used almost exclusively male subjects. Researchers have assumed the two sexes have a similar maturation and attrition of new neurons in the dentate gyrus of adults. However, this study highlights notable sex differences in the attrition, maturation rate and potential of neurogenesis in the adult hippocampus that has significant implications for the field of neuroplasticity. These findings are important in understanding the relevance of sex differences in the regulation of neurogenesis in the hippocampus in response to stimuli or experience and may have consequences for our understanding of diseases that involve neurodegeneration of the hippocampus, particularly those that involve sex differences, such as Alzheimer’s disease and depression.
Comparative analysis of MOBQ4plasmids demonstrates that MOBQis acis-acting-enriched relaxase protein family
Authors: Garcillán-Barcia M. Pilar , Cuartas-Lanza Raquel , Cuevas Ana , de la Cruz Fernando 
Published: August 2019

ABSTRACTA group of small mobilizable plasmids is increasingly being reported in epidemiology surveys of enterobacteria. Some of them encode colicins, while others are cryptic. All of them encode a relaxase belonging to a previously non-described group of the MOBQclass, MOBQ4. While highly similar in their mobilization module, two families with unrelated replicons can be distinguished, MOBQ41and MOBQ42. Members of both groups were compatible between them and stably maintained inE. coli. MOBQ4plasmids were mobilized by conjugation. They contain two transfer genes,mobAcoding for the MOBQ4relaxase andmobC, which was non-essential but enhanced the plasmid mobilization frequency. The origin of transfer was located between these two divergently transcribedmobgenes. MPFIconjugative plasmids were the most efficient helpers for MOBQ4conjugative transmission. No interference in mobilization was observed when both MOBQ41and MOBQ42were present in the same donor cell. Remarkably, MOBQ4relaxases exhibited acis-acting preference for theiroriTs, a feature already observed in other MOBQplasmids. These findings indicate that MOBQ4plasmids can efficiently spread among enterobacteria aided by coresident IncI1, IncK and IncL/M plasmids, while ensuring their self-dissemination over highly-related elements.IMPORTANCEPlasmids are key vehicles of horizontal gene transfer and contribute greatly to bacterial genome plasticity. A group of plasmids, called mobilizable, is able to disseminate aided by helper conjugative plasmids. Here, we studied a group of phylogenetically-related mobilizable plasmids, MOBQ4, commonly found in clinically-relevant enterobacteria, uncovering the helper plasmids responsible for their dissemination. We found that the two plasmid species encompassed in the MOBQ4group can coexist and transfer orthogonally, despite origin-of-transfer cross-recognition by their relaxases. Specific discrimination among their highly similaroriTsequences is guaranteed by the preferentialcisactivity of the MOBQ4relaxases. Such strategy would be biologically relevant in a scenario of co-residence of non-divergent elements to favor self-dissemination.
Three dimensional nanoscopy of whole cells and tissues within situpoint spread function retrieval
Authors: Xu Fan , Ma Donghan , MacPherson Kathryn P. , Liu Sheng , Bu Ye , Wang Yu , Bi Cheng , Kwok Tim , Yin Peng , Calve Sarah , Landreth Gary E. , Huang Fang 
Published: August 2019

ABSTRACTSingle-molecule localization microscopy is a powerful tool in visualizing organelle structures, interactions, and protein functions in biological research. However, whole-cell and tissue specimens challenge the achievable resolution and depth of nanoscopy methods. As imaging depth increases, photons emitted by fluorescent probes, the sole source of molecular positions, were scattered and aberrated, resulting in image artifacts and rapidly deteriorating resolution. We propose a method to allow constructing the in situ 3D response of single emitters directly from single-molecule dataset and therefore allow pin-pointing single-molecule locations with limit-achieving precision and uncompromised fidelity through whole cells and tissues. This advancement expands the routine applicability of super-resolution imaging from selected cellular targets near coverslips to intra- and extra-cellular targets deep inside tissues. We demonstrate this across a range of cellular-tissue architectures from mitochondrial networks, microtubules, and nuclear pores in 2D and 3D cultures, amyloid-β plaques in mouse brains to developing cartilage in mouse forelimbs.
A ClyA nanopore tweezer for analysis of functional states of protein-ligand interactions
Authors: Li Xin , Lee Kuohao , Chen Jianhan , Chen Min 
Published: August 2019

AbstractConformational changes of proteins are essential to their functions. Yet it remains challenging to measure the amplitudes and timescales of protein motions. Here we show that the ClyA nanopore can be used as a molecular tweezer to trap a single maltose-binding protein (MBP) within its lumen, which allows conformation changes to be monitored as electrical current fluctuations in real time. The current measurements revealed three distinct ligand-bound states for MBP in the presence of reducing saccharides. Our biochemical and kinetic analysis reveal that these three states represented MBP bound to different isomers of reducing sugars. These findings shed light on the mechanism of substrate recognition by MBP and illustrate that the nanopore tweezer is a powerful, label-free, single-molecule approach for studying protein conformational dynamics under functional conditions.
Mapping RNA splicing variations in clinically-accessible and non-accessible tissues to facilitate Mendelian disease diagnosis using RNA-seq
Authors: Aicher Joseph K , Jewell Paul , Vaquero-Garcia Jorge , Barash Yoseph , Bhoj Elizabeth J 
Published: August 2019

AbstractPurposeRNA-seq is a promising approach to improve diagnoses by detecting pathogenic aberrations in RNA splicing that are missed by DNA sequencing. RNA-seq is typically performed on clinically-accessible tissues (CATs) from blood and skin. RNA tissue-specificity makes it difficult to identify aberrations in relevant but non-accessible tissues (non-CATs). We determined how RNA-seq from CATs represent splicing in and across genes and non-CATs.MethodsWe quantified RNA splicing in 801 RNA-seq samples from 56 different adult and fetal tissues from GTEx and ArrayExpress. We identified genes and splicing events in each non-CAT and determined when RNA-seq in each CAT would inadequately represent them. We developed an online resource, MAJIQ-CAT, for exploring our analysis for specific genes and tissues.ResultsIn non-CATs, 39.7% of genes have splicing that is inadequately represented by at least one CAT. 6.2% of genes have splicing inadequately represented by all CATs. A majority (52.8%) of inadequately represented genes are lowly expressed in CATs (TPM < 1), but 6.2% are inadequately represented despite being well expressed (TPM > 10).ConclusionMany splicing events in non-CATs are inadequately evaluated using RNA-seq from CATs. MAJIQ-CAT allows users to explore which accessible tissues, if any, best represent splicing in genes and tissues of interest.
Globally Harmonized Carbon Storage Data
Authors: Johnson Justin Andrew 
Published: August 2019

AbstractThis paper presents methods and results that combine multiple carbon storage and above-ground biomass datasets using a simple decision tree approach. The resulting dataset combines the positive attributes of the multiple input datasets in order to have global, high-resolution extent while utilizing the best statistical methods where possible. Visual inspection shows very different spatial configurations of carbon storage between the results and the input data, suggesting that combination of methods can improve estimates. The summation of the decision tree result was 336.55 petagrams while the summation of a dataset based on the IPCC Tier 1 method was 502.38 petagrams (49.27% higher than the results from the decision tree).
WikiMedMap: Expanding the Phenotyping Mapping Toolbox Using Wikipedia
Authors: Sulieman Lina , Wu Patrick , Denny Joshua C. , Bastarache Lisa 
Published: August 2019

AbstractResearchers utilizing phenotypic data from diverse sources require matching of phenotypes to standard clinical vocabularies. Mapping phenotypes to vocabulary can be difficult, as existing tools are often incomplete, can be difficult to access, and can be cumbersome to use, especially for non-experts. We created WikiMedMap as a simple tool that leverages Wikipedia and maps phenotype strings to standard clinical vocabularies. We assessed WikiMedMap by mapping phenotype strings from questionnaires in the UK Biobank and from Mendelian diseases in Online Mendelian Inheritance in Man (OMIM) database to eight vocabularies: International Classification of Diseases, Ninth Revision (ICD-9), ICD-10, ICD-O, Medical Subject Headings (MeSH), OMIM, Disease Database, and MedlinePlus. WikiMedMap outperformed conventional mapping tools in finding potential matches for phenotype strings. We envision WikiMedMap as a technique that complements existing and established tools to map strings to clinical vocabularies that usually do not coexist in one source.
TheUrfold: Structural Similarity Just above the Superfold Level?
Authors: Mura Cameron , Veretnik Stella , Bourne Philip E. 
Published: August 2019

OverviewWe suspect that there is a level of granularity of protein structure intermediate between the classical levels of ‘architecture’ and ‘topology’, as reflected in such phenomena as extensive 3D structural similarity above the level of (super)folds. Here, we examine this notion of architectural identity despite topological variability, starting with a concept that we call the ‘Urfold’. We believe that this model could offer a new conceptual approach for protein structural analysis and classification: indeed, the Urfold concept may help reconcile various phenomena that have been frequently recognized or debated for years, such as the precise meaning of ‘significant’ structural overlap and the degree of continuity of fold space. More broadly, the role of structural similarity in sequence/structure/function evolution has been studied via many models over the years; the Urfold may help synthesize these models into a generalized, consistent framework, by addressing a conceptual gap that we believe exists between the architecture and topology levels of structural classification schemes.
MECP2 duplication causes aberrant GABA pathways, circuits and behaviors in transgenic monkeys: neural mappings to patients with autism
Authors: Cai Dan-Chao , Wang Zhiwei , Bo Tingting , Yan Shengyao , Liu Yilin , Liu Zhaowen , Zeljic Kristina , Chen Xiaoyu , Zhan Yafeng , Xu Xiu , Du Yasong , Wang Yingwei , Cang Jing , Wang Guang-Zhong , Zhang Jie , Sun Qiang , Qiu Zilong , Ge Shengjin , Ye Zheng , Wang Zheng 
Published: August 2019

AbstractMECP2 gain- and loss-of-function in genetically-engineered monkeys demonstrably recapitulate typical phenotypes in patients, yet where MECP2 mutation affects the monkey brain and whether/how it relates to autism pathology remains unknown. Using expression profiles of 13,888 genes in 182 macaque neocortical samples, we first show that MECP2 coexpressed genes are enriched in GABA-related signaling pathways. We then perform analyses on multiple phenotypic levels including locomotive and cognitive behavior, resting-state electroencephalography and fMRI in MECP2 overexpressed and wild-type macaque monkeys. Behaviorally, transgenic monkeys exhibit hyperactive and repetitive locomotion, greater separation anxiety response, and less flexibility in rule switching. Moreover, decreased neural synchronization at beta frequency (12-30 Hz) is associated with greater locomotion after peer separation. Further analysis of fMRI-derived connectomics reveals widespread hyper- and hypo-connectivity, where hyper-connectivity prominently involving prefrontal and cingulate networks accounts for deficits in cognitive flexibility. To map MECP2-related aberrant circuits of monkeys to the pathological circuits of autistic patients, individuals in a large public neuroimaging database of autism were clustered using community detection on functional connectivity patterns. In a stratified cohort of 49 autisms and 72 controls, the dysfunctional connectivity profile particularly in prefrontal and temporal networks is highly correlated with that of transgenic monkeys, as is further responsible for the severity of social communicative deficits in patients. Through establishing a circuit-based construct link between transgenic animal models and stratified clinical patients, the present findings with explicable biological causes are potentially amenable to translation for accurate diagnosis and evaluation of future treatments in autism-related disorders.One sentence summaryWe identify shared circuit-level abnormalities between MECP2 transgenic monkeys and a stratified subgroup of human autism, and demonstrate the translational need of a multimodal approach to capture multifaceted effects triggered by a single genetic event in a genetically-engineered primate model.
Widespread transcriptional responses to the thermal stresses are prewired in human 3D genome
Authors: Li Xiaoli , Xu Bingxiang , Li Xiao , Wang Danyang , An Ziyang , Jia Yan , Niu Jing , Gao Juntao , Zhang Michael Q , Li Feifei , Zhang Zhihua 
Published: August 2019

AbstractTemperature changes is one of the most common environmental stress that consequences with massive phenotypic responses for almost all the life forms. The dysregulation of heat shock (HS) response genes had been found associated with various severe diseases, including cancer. Although the HS response has been well studied in animal cells, it remains elusive whether or not the cells response to cold shock (CS) similarly. Here, we comprehensively compared the changes of gene expression, epigenetic marks (H3K4me3 and H3K27ac), binding of genome architecture proteins (CTCF, SMC3 and Pol II) and chromatin conformation after HS and CS in human cells. Widespread expression change was observed after both HS and CS. Remarkably, we identified distinguished characters in those thermal stress responded genes at nearly all levels of chromatin architecture,i.e, the compartment, topological associated domain, chromatin loops and transcription elongation regulators, in the normal condition. However, the global chromatin architecture remains largely stable after both CS and HS. Interestingly, the thermal stresses responded genes are prone to spatial clustering even before the temperature changes. Our data suggested that the transcriptional response to the thermal stresses maybe independent to the changes of the high-level chromatin architecture, e.g., compartments and TAD, while it may be more dependent on the precondition of the chromatin and epigenetic settings at the normal condition.
Structural insights into the molecular mechanisms of the Mycobacterium evolvability factor Mfd
Authors: Putta Sivasankar , Prabha Swayam , Bhat Vinayak , Fox Gavin C. , Walsh Martin A. , Rao Desirazu N. , Nagaraja Valakunja , Natesh Ramanathan 
Published: August 2019

ABSTRACTMfd is a highly conserved ATP dependent DNA translocase that mediates the role of Transcription-Coupled-DNA-Repair(TCR) in bacteria. The molecular mechanisms and conformational remodelling that occurs in Mfd upon ATP binding, hydrolysis, and DNA translocation are poorly defined. Here we report a series of crystal and electron microscopy(EM) structures of Mfd from Mycobacterium tuberculosis (MtbMfd) and Mycobacterium smegmatis Mfd, solved in both the apo and nucleotide-bound states. The structures reveal the mechanism of nucleotide-binding, which lead to the remodeling of the Walker A motif at the catalytic pocket, inducing a flip-flop action of the hinge and flexible linker regions. Specifically, nucleotide binding unlocks the Translocation in RecG motif of the D6-domain to induce a ratchet-like motion. Functional studies of MtbMfd-RNAP complexes show that MtbMfd rescues stalled Transcription Elongation Complexes. We also report negative-stain and cryo-EM single particle reconstructions of MtbMfd higher order oligomer, that reveal an unexpected dodecameric assembly state. Given that Mfd accelerates the evolution of antimicrobial resistance(AMR), our results establish a framework for the design of new “anti-evolution” therapeutics to counter AMR.