bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring the Role of Plasma Lipids and Statins Interventions on Multiple Sclerosis Risk and Severity: A Mendelian Randomization Study
Authors: Almramhi Mona M. , Finan Chris , Storm Catherine S. , Schmidt Amand F. , Kia Demis A. , Coneys Rachel , Chopade Sandesh , Hingorani Aroon D. , Wood Nicholas W. 
Published: August 2022

AbstractBackgroundThere has been considerable interest in statins due to their pleiotropic effects beyond their lipid-lowering properties. Many of these pleiotropic effects are predominantly ascribed to their capacity to inhibit the isoprenylation of Rho small guanosine triphosphatases (Rho GTPases). We aimed to genetically investigate the role of lipids and statin interventions on multiple sclerosis (MS) risk and severity.MethodWe employed two-sample Mendelian randomization (MR) to: (1) investigate the causal role of lipids (high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG)) levels in MS risk and severity, (2) genetically mimic both cholesterol-dependent (via low-density lipoprotein cholesterol (LDL-C) and cholesterol biosynthesis pathway) and cholesterol-independent (via Rho GTPases) effects of statins on MS risk and MS severity.ResultsThe results of MR using the inverse variance weighted method show that lifelong higher HDL-C (OR 1.14 (95% CI 1.04 to1.26), p-value 7.94E-03) increase MS risk, but LDL-C and TG were not. MR results also show that genetically predicted RAC2 (OR 0.86 (95% CI 0.78 to 0.95), p-value 3.80E-03) is implicated causally in reducing MS risk. Furthermore, we found no evidence for the causal role of lipids and genetically mimicked statins on MS severity. There is no evidence of reverse causation between MS risk and lipids.ConclusionsEvidence from this study suggests that HDL-C is a risk factor for MS development. The MR findings suggest that RAC2 (a member of Rho GTPases) is a potent genetic modifier of MS risk. Since RAC2 has been reported to mediate some of the pleiotropic effects of statins, we suggest that statins reduce MS risk via a RAC2-related mechanism(s) (i.e., cholesterol-independent pathway).
A Role for the Fornix in Temporal Sequence Memory
Authors: Read Marie-Lucie , Umla-Runge Katja , Lawrence Andrew D. , Costigan Alison G. , Hsieh Liang-Tien , Chamberland Maxime , Ranganath Charan , Graham Kim S. 
Published: August 2022

AbstractConverging evidence from studies of human and nonhuman animals suggests that the hippocampus contributes to sequence learning by using temporal context to bind sequentially occurring items. The fornix is a white matter pathway containing the major input and output pathways of the hippocampus, including projections from medial septum, and to diencephalon, striatum, and prefrontal cortex. If the fornix meaningfully contributes to hippocampal function, then individual differences in fornix microstructure might predict sequence memory. Here, we tested this prediction by performing tractography in 51 healthy adults who had undertaken a sequence memory task. Microstructure properties of the fornix were compared with those of tracts connecting medial temporal lobe regions, but not predominantly the hippocampus: the Parahippocampal Cingulum bundle (PHC) (conveying retrosplenial projections to parahippocampal cortex) and the Inferior Longitudinal Fasciculus (ILF) (conveying occipital projections to perirhinal cortex). Using principal components analysis, we combined Diffusion Tensor Imaging and Neurite Orientation Dispersion and Density Imaging measures obtained from multi-shell diffusion MRI into two informative indices, the first (PC1) capturing axonal packing/myelin, the second (PC2) capturing microstructural complexity. We found a significant correlation between fornix PC2 and implicit reaction-time indices of sequence memory, indicating that greater fornix microstructural complexity is associated with better sequence memory. No such relationship was found with measures from the PHC and ILF. This study highlights the importance of the fornix in aiding memory for objects within a temporal context, potentially reflecting a role in mediating network communication within an extended hippocampal system.
Oncogenic EFNA4 amplification promotes lung adenocarcinoma lymph node metastasis
Authors: Zhao Xiangyu , Chen Yuxing , Sun Xiaoqin , He Zaoke , Wu Tao , Wu Chenxu , Chen Jing , Wang Jinyu , Diao Kaixuan , Liu Xue-Song 
Published: August 2022

AbstractLymph nodes metastases are common in patients with lung cancer. And those patients are often at a higher risk for death from lung tumor than those with tumor-free lymph nodes. So-matic DNA alterations are key drivers of cancer, and copy number alterations (CNAs) are a major type of DNA alteration that promotes lung cancer progression. Here, we performed genome-wide DNA copy number analysis, and identified a novel lung cancer metastasis related gene, EFNA4. EFNA4 genome locus was significantly amplified and EFNA4 mRNA expression was significantly up-regulated in lung cancer compared with normal lung tissue, and also in lung cancer with lymph node metastases compared with lung cancer without metastasis. EFNA4 encodes Ephrin A4, which is the ligand for Eph receptors. The function of EFNA4 in human lung cancer remains largely unknown. Through cell line experiments we showed that EFNA4 overexpression contributes to lung tumor cells growth, migration and adhesion. Conversely, EFNA4 knockdown or knockout led to the growth suppression of cells and tumor xenografts in mice. Lung cancer patients with EFNA4 over-expression have poor prognosis. Together, by elucidating a new layer of the role of EFNA4 in tumor proliferation and migration, our study demonstrates a better understanding of the function of the significantly amplified and overexpressed gene EFNA4 in lung tumor metastasis and suggests EFNA4 as a potential target in metastatic lung cancer therapy.Simple SummaryLymph nodes are likely to be the first stop for lung cancer metastasis. To further investigate the mechanism of lung cancer lymph node metastasis, we performed cancer genome analysis and found that EFNA4, a member of the ephrin (EPH) family, is amplified and up-regulated in lung tumor patients, especially in patients with lymph node metastases. In vitro and in vivo experiments show that overexpression of EFNA4 promotes lung tumor cell proliferation and migration, while knockdown or knockout of EFNA4 inhibits cell proliferation and migration. Altogether, our results suggest that the DNA amplification of EFNA4 genome locus could play an oncogenic function in promoting lung cancer lymph node metastasis.
Helicobacter chronic stage inflammation undergoes fluctuations that are altered in tlpA mutants
Authors: Johnson Kevin S. , Yang Christina , Carter J. Elliot , Worthington Atesh K. , Robinson Elektra K. , Lopez-Magaña Raymond , Salgado Frida , Arnold Isabelle , Ottemann Karen M. 
Published: August 2022

AbstractHelicobacter pylori colonizes half of the world’s population and is responsible for a significant disease burden by causing gastritis, peptic ulcers, and gastric cancer. The development of host inflammation drives these diseases, but there are still open questions in the field about how H. pylori controls this process. We characterized H. pylori inflammation using an eight month mouse infection time course and comparison of wild type and a previously identified mutant lacking the TlpA chemoreceptor that causes elevated inflammation. Our work shows that H. pylori chronic stage corpus inflammation undergoes surprising fluctuations, with changes in Th17 and eosinophil numbers. The H. pylori tlpA mutant changed the inflammation temporal characteristics, resulting in different inflammation from wild type at some time points. tlpA mutants have equivalent total and gland colonization at late stage infections. During early infection, in contrast, they show elevated gland and total colonization compared to WT. Our results suggest the chronic inflammation setting is dynamic, and may be influenced by colonization properties of early infection.ImportanceHelicobacter pylori established chronic infection in half of the world’s population. This infection initiates during childhood, and leads to later life gastric diseases including gastritis, peptic ulcers, and gastric cancer. These diseases are driven by host inflammation, with more severe inflammation leading to more severe disease. It is not fully understood how H. pylori controls inflammation. In this work, we used an H. pylori mouse infection model and characterized inflammation and colonization of wild-type H. pylori and a mutant that was known to cause elevated inflammation. We found that inflammation in the chronic stage undergoes surprising fluctuations, with related changes in Th17 numbers. H. pylori tlpA mutants caused offset inflammation dynamics, suggesting that H. pylori infection underlies this dynamism. Although there were not colonization dynamics at the time of inflammation fluctuations, there were differences between WT and tlpA mutant colonization at early time points. Our results suggest the chronic inflammation setting is more dynamic than previously thought and may be influenced by colonization properties of early infection.
Observations on Paleospecies Determination, With Additional Data on Tyrannosaurus Including Its Highly Divergent Species Specific Supraorbital Display Ornaments That Give T. rex a New and Unique Life Appearance
Authors: Paul Gregory S. 
Published: August 2022

AbstractIntrageneric dinosaur species have been being named for decades without either significant examination of the methods and standards used to do so, or widely publicized controversy over the results. The long standing assumption that all large known specimens of the iconic North American Tyrannosaurus consisted of just the one popular species T. rex was recently challenged with the first comprehensive test of the question. The result was the diagnosing and naming of two additional taxa, T. imperator and T. regina, based on a number of species levels characters regarding robustness and tooth proportions in the context of their stratigraphic distribution. In association a rare in-depth look was taken at the current state of naming vertebrate paleospecies, which it turns out are not highly rigorous because of inherent problems with the species concept and other matters. The results of the paper were severely criticized in in a manner never seen before for new dinosaur species even when based on less evidence. This study takes another look as the determination of paleospecies, and shows that many of the claims made in the criticisms regarding the Tyrannosaurus species work were inaccurate. New data on the proportions of strength bars in Tyrannosaurus skulls reinforces the basing of the three species in part on robustness factors, and allows all but one skull to be assigned to one of the species. These results allow the first detailed systematic examination of the supraorbital display bosses of the genus. They sort out as visually distinctive species specific ornaments based on both stratigraphic and taxonomic factors, strongly affirm that Tyrannosaurus was multispecific, and the species probably dimorphic. New skulls of T. rex show that the species sported – males probably -- striking display bosses not yet observed in other tyrannosaurids.
Annotation-free discovery of functional groups in microbial communities
Authors: Shan Xiaoyu , Goyal Akshit , Gregor Rachel , Cordero Otto X. 
Published: August 2022

AbstractRecent studies have shown that microbial communities are composed of groups of functionally cohesive taxa, whose abundance is more stable and better associated with metabolic fluxes than that of any individual taxon. However, identifying these functional groups in a manner that is independent from error-prone functional gene annotations remains a major open problem. Here, we develop a novel approach that identifies functional groups of taxa in an unsupervised manner, solely based on the patterns of statistical variation in species abundance and environmental parameters. We demonstrate the power of this approach on three distinct data sets. On data of replicate microcosm with heterotrophic soil bacteria, our unsupervised algorithm recovered experimentally validated functional groups that divide metabolic labor and remain stable despite large variation in species composition. When leveraged against the ocean microbiome data, our approach discovered a functional group that combines aerobic and anaerobic ammonia oxidizers, whose summed abundance tracks closely with nitrate concentrations in the water column. Finally, we show that our framework can enable the detection of species groups that are likely responsible for the production or consumption of metabolites abundant in animal gut microbiomes, serving as a hypothesis generating tool for mechanistic studies. Overall, this work advances our understanding of structure-function relationships in complex microbiomes and provides a powerful approach to discover functional groups in an objective and systematic manner.
Decoding the coupled decision-making of the epithelial-mesenchymal transition and metabolic reprogramming in cancer
Authors: Galbraith Madeline , Levine Herbert , Onuchic José N. , Jia Dongya 
Published: August 2022

AbstractCancer metastasis relies on an orchestration of multiple traits driven by different functional interacting modules including metabolism and epithelial-mesenchymal transition (EMT). Cancer cells can adjust their metabolism during metastasis by increasing oxidative phosphorylation without compromising glycolysis, acquiring a hybrid metabolic phenotype (W/O). Often required by metastasis, cancer cells engage EMT and can acquire a hybrid epithelial/mesenchymal (E/M) phenotype. Both the W/O and E/M states are associated with high metastatic potentials. Many regulatory links coupling metabolism and EMT have been identified, but how these two modules regulate each other remains largely unexplored. Here, we investigate the coupled decision-making networks of metabolism and EMT, and systematically analyzed the effect of their crosstalk. This crosstalk can exhibits synergistic or antagonistic effects on the acquisition and stability of different coupled metabolism-EMT states. Strikingly, the aggressive E/M-W/O state can be enabled and stabilized by the crosstalk irrespective of these hybrid states availability in individual metabolism or EMT modules. To acquire an E/M-W/O state, the W/O state emerges first, followed by the E/M state, suggesting metabolism can drive EMT. Our work emphasizes the mutual activation between metabolism and EMT, providing an important step towards understanding the multi-faceted nature of cancer metastasis.
An adhesion signaling axis involving Dystroglycan, β1-Integrin and Cas adaptor proteins regulates the establishment of the cortical glial scaffold
Authors: Wong Wenny , Estep Jason A. , Treptow Alyssa M. , Rajabli Niloofar , Jahncke Jennifer N. , Ubina Teresa , Wright Kevin M. , Riccomagno Martin M. 
Published: August 2022

AbstractThe mature mammalian cortex is composed of six architecturally and functionally distinct layers. Two key steps in the assembly of this layered structure are the initial establishment of the glial scaffold and the subsequent migration of post-mitotic neurons to their final position. These processes involve the precise and timely regulation of adhesion and detachment of neural cells from their substrates. Although much is known about the roles of adhesive substrates during neuronal migration and the formation of the glial scaffold, less is understood about how these signals are interpreted and integrated within these neural cells. Here, we providein vivoevidence that Cas proteins, a family of cytoplasmic adaptors, serve a functional and redundant role during cortical lamination.Castriple conditional knock-out (CasTcKO) mice display severe cortical phenotypes that feature cobblestone malformations. Molecular epistasis and genetic experiments suggest that Cas proteins act downstream of transmembrane Dystroglycan and β1-Integrin in a radial glial cell-autonomous manner. Overall, these data establish a new and essential role for Cas adaptor proteins during the formation of cortical circuits and reveal a signaling axis controlling cortical scaffold formation.
Subcellular spatially resolved gene neighborhood networks in single cells
Authors: Fang Zhou , Ford Adam J. , Hu Thomas , Zhang Nicholas , Mantalaris Athanasios , Coskun Ahmet F. 
Published: August 2022

AbstractMesenchymal stem cell (MSC)-based therapies have offered promising treatments against several disorders. However, the clinical efficacy and consistency remain underdeveloped. Single-cell and bulk molecular analyses have provided considerable heterogeneity of MSCs due to origin, expansion, and microenvironment. Image-based cellular omics methods elucidate ultimate variability in stem cell colonies, otherwise masked by bulk omics approaches. Here, we present a spatially resolved Gene Neighborhood Network (spaGNN) method to produce transcriptional density maps and analyze neighboring RNA distributions in single human MSCs and chondrocytes cultured on 2D collagen-coated substrates. This proposed strategy provides cell classification based on subcellular spatial features and gene neighborhood networks. Machine learning-based clustering of resultant data yields subcellular density classes of 20-plex biomarkers containing diverse transcript and protein features. The spaGNN reveals tissue-source-specific MSC transcription and spatial distribution characteristics. Multiplexed spaGNN analysis allows for rapid examination of spatially resolved subcellular features and activities in a broad range of cells used in pre-clinical and clinical research.
Multi-organ functions of yolk sac during human early development
Authors: Botting Rachel A , Goh Issac , Rose Antony , Webb Simone , Engelbert Justin , Gitton Yorick , Stephenson Emily , Quiroga Londoño Mariana , Mather Michael , Mende Nicole , Imaz-Rosshandler Ivan , Horsfall Dave , Basurto-Lozada Daniela , Chipampe Nana-Jane , Rook Victoria , Mazin Pavel , Vijayabaskar MS , Hannah Rebecca , Gambardella Laure , Green Kile , Ballereau Stephane , Inoue Megumi , Tuck Liz , Lorenzi Valentina , Kwakwa Kwasi , Alsinet Clara , Olabi Bayanne , Miah Mohi , Admane Chloe , Popescu Dorin-Mirel , Acres Meghan , Dixon David , Coulthard Rowen , Lisgo Steven , Henderson Deborah J , Dann Emma , Suo Chenqu , Kinston Sarah J , Park Jong-eun , Polanski Krzysztof , Van Dongen Stijn , Meyer Kerstin B , de Bruijn Marella , Palis James , Behjati Sam , Laurenti Elisa , Wilson Nicola K , Vento-Tormo Roser , Chédotal Alain , Bayraktar Omer , Roberts Irene , Jardine Laura , Göttgens Berthold , Teichmann Sarah A , Haniffa Muzlifah 
Published: August 2022

AbstractThe yolk sac (YS) represents an evolutionarily-conserved extraembryonic structure that ensures timely delivery of nutritional support and oxygen to the developing embryo. However, the YS remains ill-defined in humans. We therefore assemble a complete single cell 3D map of human YS from 3-8 post conception weeks by integrating multiomic protein and gene expression data. We reveal the YS as a site of primitive and definitive haematopoiesis including a YS-specific accelerated route to macrophage production, a source of nutritional/metabolic support and a regulator of oxygen-carrying capacity. We reconstruct the emergence of primitive haematopoietic stem and progenitor cells from YS hemogenic endothelium and their decline upon stromal support modulation as intraembryonic organs specialise to assume these functions. The YS therefore functions as ‘three organs in one’ revealing a multifaceted relay of vital organismal functions as pregnancy proceeds.One Sentence SummaryHuman yolk sac is a key staging post in a relay of vital organismal functions during human pregnancy.
SNP discovery by exome capture and resequencing in a pea genetic resource collection
Authors: Aubert G. , Kreplak J. , Leveugle M. , Duborjal H. , Klein A. , Boucherot K. , Vieille E. , Chabert-Martinello M. , Cruaud C. , Bourion V. , Lejeune-Hénaut I. , Pilet-Nayel M.L. , Bouchenak-Khelladi Y. , Francillonne N. , Tayeh N. , Pichon J.P. , Rivière N. , Burstin J. 
Published: August 2022

Background & SummaryIn addition to being the model plant used by Mendel1to establish genetic laws, pea (Pisum sativumL., 2n=14) is a major pulse crop cultivated in many temperate regions of the world. In order to face new challenges imposed particularly by global climate change and new regulations targeted at reducing chemical inputs, pea breeders have to take advantage of the genetic diversity present in thePisumgenepool to develop improved, resilient varieties. The aim of this study was to assess the genetic diversity of a pea germplasm collection and allow genome-wide association studies using this collection.To be able to perform genome-wide association approaches with high resolution, genotyping with a large set of genetic markers such as Single Nucleotide Polymorphism (SNP) markers well-spread over the genome is required. Rapid advances in second-generation sequencing technologies and the development of bioinformatic tools have revolutionized the access to and the characterization of available genetic diversity. High-density, high-throughput genotyping has been possible for a large number of species, including those with large and complex genomes2such as pea (2n=14) which genome size is estimated to be 4.45 Gb3. In this study, which is part of the PeaMUST project4, we used a target capture technology based on pea transcriptome sequences to generate exome-enriched genomic libraries that were further subjected to Illumina sequencing in paired-end mode. This methodology was chosen because whole-genome resequencing is relatively expensive for species with large genomes and because capturing genetic variations in repeated non-coding regions is difficult to achieve or to interpret5. Whole-exome sequencing represented an interesting alternative that focused on coding regions only6,7. Mapping the obtained reads on the reference pea genome sequence enabled the discovery of an abundant set of SNPs. The development of this resource is a crucial cornerstone in research and breeding projects towards boosting the improvement of pea production and quality.
Metabolomic-Genomic prediction drastically improves prediction accuracy of breeding values in crop breeding
Authors: Guo Xiangyu , Sarup Pernille , Jahoor Ahmed , Jensen Just , Christensen Ole Fredslund 
Published: August 2022

AbstractMetabolomics is intermediate stage between genotype and phenotype, and therefore useful for breeding. Objective was to investigate heritabilities and accuracies of genetic evaluation of malting quality (MQ) traits by integrating both genomic and metabolomic information. In total, 2,430 plots of 562 malting spring barley lines from three years and two locations were included. Five MQ traits were measured in wort produced from each plot. Metabolomic features used were 24,018 Nuclear Magnetic Resonance intensities measured on each wort sample. Methods for statistical analyses were genomic best linear unbiased prediction (GBLUP) and metabolomic-genomic best linear unbiased prediction (MGBLUP). Accuracies of predicted breeding values were compared using two cross-validation strategies: leave-one-year-out (LOYO) and leave-one-line-out (LOLO). Plot heritabilities ranged from 0.060 to 0.279 for GBLUP, and increased to range from 0.123 to 0.283 for MGBLUP. LOLO scheme yielded higher accuracies than LOYO scheme, and MGBLUP yielded higher accuracies than GBLUP regardless of cross-validation scheme.Author SummaryMetabolomics is intermediate stage between genotype and phenotype, and therefore useful for breeding. We carried out a study on 2,430 plots of 562 malting spring barley lines and 24,018 Nuclear Magnetic Resonance intensities measured on each wort sample, to investigate the prediction of breeding values of five malting quality traits by integrating genomic and metabolomic information using a metabolomics-genomic model. Results showed an increase in prediction accuracy for this model compared to a genomic model.