bluuebunny/crossref_metadata_2025_split huggingface dataset:
Need for high-resolution Genetic Analysis in iPSC: Results and Lessons from the ForIPS Consortium Authors
Authors: Popp Bernt , Krumbiegel Mandy , Grosch Janina , Sommer Annika , Uebe Steffen , Kohl Zacharias , Plötz Sonja , Farrell Michaela , Trautmann Udo , Kraus Cornelia , Ekici Arif B. , Asadollahi Reza , Regensburger Martin , Günther Katharina , Rauch Anita , Edenhofer Frank , Winkler Jürgen , Winner Beate , Reis André 
Published: July 2018

ABSTRACTGenetic integrity of induced pluripotent stem cells (iPSCs) is essential for their validity as disease models and for potential therapeutic use. We describe the comprehensive analysis in the ForIPS consortium: an iPSC collection from donors with neurological diseases and healthy controls. Characterization included pluripotency confirmation, fingerprinting, conventional and molecular karyotyping in all lines. In the majority, somatic copy number variants (CNVs) were identified. A subset with available matched donor DNA was selected for comparative exome sequencing. We identified single nucleotide variants (SNVs) at different allelic frequencies in each clone with high variability in mutational load. Low frequencies of variants in parental fibroblasts highlight the importance of germline samples. Somatic variant number was independent from reprogramming, cell type and passage. Comparison with disease genes and prediction scores suggest biological relevance for some variants. We show that high-throughput sequencing has value beyond SNV detection and the requirement to individually evaluate each clone.
RNA-Seq and Protein Mass Spectrometry in Microdissected Kidney Tubules Reveal Signaling Processes that Initiate Lithium-Induced Diabetes Insipidus
Authors: Sung Chih-Chien , Chen Lihe , Limbutara Kavee , Jung Hyun Jun , Gilmer Gabrielle G. , Yang Chin-Rang , Khositseth Sookkasem , Lin Shih-Hua , Chou Chung-Lin , Knepper Mark A. 
Published: July 2018

ABSTRACT1Lithium salts, used for treatment of bipolar disorder, frequently induce nephrogenic diabetes insipidus (NDI), limiting therapeutic success. NDI is associated with loss of expression of the molecular water channel, aquaporin-2, in the renal collecting duct (CD). Here, we use the methods of systems biology in a well-established rat model of lithium-induced NDI to identify signaling pathways activated at the onset of polyuria. Using single-tubule RNA-Seq, full transcriptomes were determined in microdissected cortical CDs of rats 72 hrs after initiation of lithium chloride (LiCl) administration (vs. time-controls without LiCl). Transcriptome-wide changes in mRNA abundances were mapped to gene sets associated with curated canonical signaling pathways, showing evidence for activation of NF-κB signaling with induction of genes coding for multiple chemokines as well as most components of the Major Histocompatibility Complex (MHC) Class I antigen-presenting complex. Administration of antiinflammatory doses of dexamethasone to LiCl-treated rats countered the loss of aquaporin-2 protein. RNA-Seq also confirmed prior evidence of a shift from quiescence into the cell cycle with arrest. Time course studies demonstrated an early (12 hrs) increase in multiple immediate early genes including several transcription factors. Protein mass spectrometry in microdissected cortical CDs provided corroborative evidence but also identified decreased abundance of several anti-oxidant proteins. Integration of new data with prior data about lithium effects at a molecular level leads to a signaling model in which lithium increases ERK activation leading to induction of NF-κB signaling and an inflammatory-like response that represses Aqp2 gene transcription.
Explaining Visual Cortex Phenomena using Recursive Cortical Network
Authors: Lavin Alexander , Guntupalli J. Swaroop , Lázaro-Gredilla Miguel , Lehrach Wolfgang , George Dileep 
Published: July 2018

AbstractThe connectivity and information pathways of visual cortex are well studied, as are observed physiological phenomena, yet a cohesive model for explaining visual cortex processes remains an open problem. For a comprehensive understanding, we need to build models of the visual cortex that are capable of robust real-world performance, while also being able to explain psychophysical and physiological observations. To this end, we demonstrate how the Recursive Cortical Network (George et al., 2017) can be used as a computational model to reproduce and explain subjective contours, neon color spreading, occlusion vs. deletion, and the border-ownership competition phenomena observed in the visual cortex.
Tensor decomposition–based unsupervised feature extraction for integrated analysis of TCGA data on microRNA expression and promoter methylation of genes in ovarian cancer
Authors: Taguchi Y-h. , Ng Ka-Lok 
Published: July 2018

AbstractIntegrated analysis of epigenetic profiles is important but difficult. Tensor decomposition–based unsupervised feature extraction was applied here to data on microRNA (miRNA) expression and promoter methylation of genes in ovarian cancer. It selected seven miRNAs and 241 genes by expression levels and promoter methylation degrees, respectively, such that they showed differences between eight normal ovarian tissue samples and 569 tumor samples. The expression levels of the seven miRNAs and the degrees of promoter methylation of the 241 genes also correlated significantly. Conventional Student’sttest–based feature selection failed to identify miRNAs and genes that have the above properties. On the other hand, biological evaluation of the seven identified miRNAs and 241 identified genes suggests that they are strongly related to cancer as expected.
A practical guide to linking brain-wide gene expression and neuroimaging data
Authors: Arnatkevičiūtė Aurina , Fulcher Ben D. , Fornito Alex 
Published: July 2018

AbstractThe recent availability of comprehensive, brain-wide gene expression atlases such as the Allen Human Brain Atlas (AHBA) has opened new opportunities for understanding how spatial variations on the molecular scale relate to the macroscopic neuroimaging phenotypes. A rapidly growing body of literature is demonstrating relationships between gene expression and diverse properties of brain structure and function, but approaches for combining expression atlas data with neuroimaging are highly inconsistent, with substantial variations in how the expression data are processed. The degree to which these methodological variations affect findings is unclear. Here, we outline a seven-step analysis pipeline for relating brain-wide transcriptomic and neuroimaging data and compare how different processing choices influence the resulting data. We suggest that studies using AHBA should work towards a unified data processing pipeline to ensure consistent and reproducible results in this burgeoning field.
Oncogenic effects of germline mutations in lysosomal storage disease genes
Authors: Shin Junghoon , Kim Daeyoon , Kim Hyung-Lae , Choi Murim , Korbel Jan O. , Yoon Sung-Soo , Koh Youngil ,   on behalf of the PCAWG Germline Cancer Genome Working Group and the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
Published: July 2018

AbstractClinical observations have indicated that patients with Gaucher disease or Fabry disease are at increased risk of cancer. However, a systematic evaluation of the oncogenic effects of causal mutations of lysosomal storage diseases (LSDs) has been lacking. Here we report a comprehensive association analysis between potentially pathogenic germline mutations in LSD genes and cancer interrogating genomic (or exomic) variant datasets derived from the Pan-Cancer Analysis of Whole Genomes project (case cohort), the 1000 Genomes project (primary control cohort), and the Exome Aggregation Consortium that does not include The Cancer Genome Atlas subset (validation control cohort). We show that potentially pathogenic variants (PPVs) in 42 LSD genes are significantly enriched in cancer patients in a histology-dependent manner, cancer risk is higher in individuals with a greater number of PPVs, and cancer develops earlier in PPV carriers. Analysis of tumor genomic and transcriptomic data from the pancreatic adenocarcinoma cohort revealed potential mechanisms that might be involved in the oncogenic contribution of PPVs. Our findings extend the mechanistic understanding of inherited cancer susceptibility and highlight the promise of harnessing available therapeutic strategies to restore lysosomal function for personalized cancer prevention.
Mitochondrial acetyl-CoA reversibly regulates locus-specific histone acetylation and gene expression
Authors: Lozoya Oswaldo A. , Wang Tianyuan , Grenet Dagoberto , Wolfgang Taylor C. , Sobhany Mack , da Silva Douglas Ganini , Riadi Gonzalo , Chandel Navdeep , Woychik Richard P. , Santos Janine H. 
Published: July 2018

AbstractThe impact of mitochondria in epigenetics is emerging but our understanding of this relationship and its impact on gene expression remain incomplete. We previously showed that acute mitochondrial DNA (mtDNA) loss leads to histone hypoacetylation. It remains to be defined if these changes are maintained when mitochondrial dysfunction is chronic and, importantly, if they are sufficient to alter gene expression. To fill these gaps, we here studied both a progressive and a chronic model of mtDNA depletion using biochemical, pharmacological, genomics and genetic assays. We show that histones are hypoacetylated in both models. We link these effects to decreased histone acetyltransferase (HAT) activity independent of changes in ATP citrate lyase function, which can be reversibly modulated by altering specifically the mitochondrial pool of acetyl-CoA. Also, we determined that these changes regulate locus-specific gene expression and physiological outcomes, including the production of prostaglandins. These results may be relevant to the pathophysiology of mtDNA depletion syndromes and to understanding the effects of environmental agents, such as AZT or antibiotics, that lead to physical or functional mtDNA loss.
Phosphatidylinositol 4,5-Bisphosphate (PIP2) Regulates KCNQ3 K+ Channels through Multiple Sites of Action
Authors: Choveau Frank S. , La Rosa Victor De , Bierbower Sonya M. , Hernandez Ciria C. , Shapiro Mark S. 
Published: July 2018

AbstractPhosphatidylinositol 4,5-bisphosphate (PIP2) regulates the function of many ion channels, including M-type (KCNQ1-5, Kv7) K+ channels; however the molecular mechanisms involved in this regulation remain unclear. To identify the sites of action on KCNQ3 channels, we used as our baseline the A315T pore mutant (KCNQ3T) that increases channel currents without modifying the apparent affinity of PIP2 and performed extensive mutagenesis in regions that have been suggested to be involved in PIP2 interactions among the KCNQ family. Using the zebrafish (Danio rerio) voltage-sensitive phosphatase to deplete PIP2 as a probe for apparent affinity of the channels, we found that PIP2 modulates KCNQ channel function through four different domains. 1) the A-B helix linker that we previously identified as important for both KCNQ2 and KCNQ3, 2) the junction between S6 and the A helix (S6Jx), 3) the S2-S3 linker and 4) the S4-S5 linker. We found that PIP2 interactions within these domains were not coupled to the voltage dependence of activation. Extensive homology modeling and docking simulations between the wild-type or mutant KCNQ3 channels and PIP2, correlated with the experimental data. Our results indicate that PIP2 modulates KCNQ3 channel function by interacting synergistically with a minimum of four cytoplasmic domains.
Live tracking of inter-organ communication by endogenous exosomes in vivo
Authors: Verweij Frederik J , Revenu Celine , Arras Guillaume , Dingli Florent , Loew Damarys , Follain Gautier , Allio Guillaume , Goetz Jacky G. , Herbomel Philippe , Bene Filippo Del , Raposo Graça , van Niel Guillaume 
Published: July 2018

SUMMARYExtracellular vesicles (EVs) are released by most cell types but the definitive demonstration of their functional relevance remains challenging due to the lack of appropriate model organisms. Here we developed anin vivomodel to study EV physiology by expressing CD63-pHluorin in zebrafish embryos. A combination of microscopy techniques and proteomic analysis allowed us to study the biogenesis, composition, transfer, uptake and fate of individual endogenous EVsin vivo. We identified an exosome population released in a syntenin-dependent manner from the Yolk Syncytial Layer into the blood circulation. These exosomes were specifically captured, endocytosed and degraded by patrolling macrophages and endothelial cells in the Caudal Vein Plexus (CVP) in a scavenger receptor and dynamin-dependent manner. Interference with exosome secretion affected CVP growth, supporting their trophic role. Altogether, our work provides a unique model to track in vivo inter-organ communication by endogenous exosomes at individual vesicle level and high spatio-temporal accuracy.Highlights- Single endogenous EVs can be live-visualized in the whole embryo with CD63-pHluorin- In the YSL, syntenin regulates exosome release into the blood for their propagation- YSL exosomes reach the tail to be taken up by macrophages and endothelial cells- Uptake is scavenger receptor and dynamin-dependent and provides trophic supportBlurbWe propose zebrafish embryos expressing a fluorescent reporter for exosomes as a relevant model organism to live-track production, journey and fate of individual extracellular vesicles in vivo. Our model allows investigation of the composition of EVs and the molecular mechanisms controlling their biogenesis and fate and functions in receiving cells.
Damage-induced reactive oxygen species enable zebrafish tail regeneration by repositioning of Hedgehog expressing cells
Authors: Romero Maria Montserrat Garcia , McCathie Gareth , Jankun Philip , Roehl Henry Hamilton 
Published: July 2018

AbstractAquatic vertebrates have a remarkable ability to regenerate limbs and tails after amputation. Previous studies indicate that reactive oxygen species (ROS) signaling initiates regeneration, but the mechanism by which this takes place is poorly understood. Developmental signalling pathways have been shown to have pro-regenerative roles in many systems. However, whether these are playing roles that are specific to regeneration, or are simply recapitulating their developmental functions is unclear. We have analysed zebrafish larval tail regeneration and find evidence that ROS released upon wounding cause repositioning of notochord cells to the damage site. These cells secrete Hedgehog ligands which are required for regeneration. Hedgehog signalling is not required for normal tail development suggesting that it has a regeneration specific role. Our results provide a model for how ROS initiate tail regeneration, and indicate that developmental signaling pathways can play regenerative functions that are not directly related to their developmental roles.
Pannexin-1 mediated ATP release in adipocytes is sensitive to glucose and insulin and modulates lipolysis and macrophage migration
Authors: Tozzi Marco , Hansen Jacob B. , Novak Ivana 
Published: July 2018

One-sentence summaryInsulin inhibits ATP release in adipocytesAbstractExtracellular ATP signaling is involved in many physiological and pathophysiological processes, and purinergic receptors are targets for drug therapy in several diseases, including obesity and diabetes. Adipose tissue has crucial functions in lipid and glucose metabolism and adipocytes express purinergic receptors. However, the sources of extracellular ATP in adipose tissue are not yet characterized.Here, we show that upon adrenergic stimulation white adipocytes release ATP through the pannexin-1 pore that is regulated by a cAMP-PKA dependent pathway. The ATP release correlates with increased cell metabolism, and extracellular ATP induces Ca2+ signaling and lipolysis in adipocytes and promotes macrophages migration. Most importantly, ATP release is markedly inhibited by insulin, and thereby auto/paracrine purinergic signaling in adipose tissue would be attenuated. Furthermore, we define the signaling pathway for insulin regulated ATP release.Our findings reveal the insulin-pannexin-1-purinergic signaling cross-talk in adipose tissue and we propose that deregulation of this signaling may underlie adipose tissue inflammation and type-2 diabetes.
Natural selection onTMPRSS6associated with the blunted erythropoiesis and improved blood viscosity in Tibetan Pigs
Authors: Kong Xiaoyan , Dong Xinxing , Yang Shuli , Qian Jinhua , Yang Jianfa , Jiang Qiang , Li Xingrun , Wang Bo , Yan Dawei , Lu Shaoxiong , Mao Huaming , Gou Xiao 
Published: July 2018

AbstractTibetan pigs, indigenous to Tibetan plateau, are well adapted to hypoxia. So far, there have been not any definitively described genes and functional sites responsible for hypoxia adaptation for the Tibetan pig. Here we conducted resequencing of the nearly entire genomic region (40.1 kb) of the candidate geneTMPRSS6(Transmembrane protease, serine 6) associated with hemoglobin concentration (HGB) and red blood cell count (RBC) in 40 domestic pigs and 40 wild boars from five altitudes along the Tea-horse ancient road and identified 708 SNPs, in addition to an indel (CGTG/----) in the intron 10. Both the CGTG deletion frequency and the pairwise r2linkage disequilibrium showed an increase with elevated altitudes in 838 domestic pigs from five altitudes, suggesting thatTMPRSS6has been under Darwinian positive selection. As the conserved core sequence of hypoxia-response elements (HREs), the deletion of CGTG in Tibetan pigs decreased the expression levels ofTMPRSS6mRNA and protein in the liver revealed by real-time quantitative PCR and western blot, respectively. To explore whether reducedTMPRSS6expression level could improve blood viscosity, the relationship between CGTG indel and hematologic and hemorheologic parameters in 482 domestic pigs from continuous altitudes was detected and dissected a genetic effect on reducing HGB by 13.25g/L in Gongbo’gyamda Tibetan pigs and decreasing MCV by 4.79 fl in Diqing Tibetan pigs. In conclusion, the CGTG deletion ofTMPRSS6resulted in lower HGB and smaller MCV, thereby blunting erythropoiesis and improving blood viscosity as well as erythrocyte deformability.
How do citizens perceive farm animal welfare conditions in Brazil?
Authors: de Queiroz Ricardo Guimarães , de Faria Domingues Carla Heloisa , Canozzi Maria Eugênia Andrighetto , Garcia Rodrigo Garófallo , Ruviaro Clandio Favarini , Barcellos Júlio Otávio Jardim , Borges João Augusto Rossi 
Published: July 2018

AbstractThe aim of this study is to understand the perceptions of Brazilian citizens about the actual conditions of farm animal welfare in the poultry, beef, and dairy supply chains. To reach this aim, an online survey was conducted. The analysis was based on descriptive statistics and three logistic regressions models. Results of descriptive statistics showed that citizens in Brazil had mostly negative perceptions about the actual conditions of animal welfare in the poultry, beef, and dairy supply chains. Results of the logistic regression models showed that in the poultry and dairy supply chains, citizens with background in agricultural/veterinary sciences, and citizens who reported a higher level of knowledge about these supply chains, were more likely to perceive as bad the actual conditions of farm animal welfare. In the poultry supply chain, citizens who reported previous contact with poultry farms were also more likely to perceive as bad the actual condition of farm animal welfare. In addition, the perception that farmers are mainly focused on the economic aspect of farming and less on animal welfare, the perception that animals do not have a good quality of life while housed on farms, and the perception that animals are not adequately transported and slaughtered, negatively impact on perceptions about the actual conditions of farm animal welfare in the three supply chains. We concluded that a protocol aimed to improve citizens’ perceptions about the actual conditions of farm animal welfare should focus in all phases of the supply chains.
The tumor suppressor p53 promotes carcinoma invasion and collective cellular migration
Authors: He Shijie , Carman Christopher V. , Lee Jung Hyun , Lan Bo , Koehler Stephan , Atia Lior , Park Chan Young , Kim Jae Hun , Mitchel Jennifer A. , Park Jin-Ah , Butler James P. , Lee Sam W. , Fredberg Jeffrey J. 
Published: July 2018

SummaryLoss of function of the tumor suppressor p53 is generally thought to increase cell motility and invasiveness. Using 2-D confluent and 3-D spheroidal cell motility assays with bladder carcinoma cells and colorectal carcinoma cells, we report, to the contrary, that loss of p53 can decrease cell motility and invasion.AbstractFor migration of the single cell studied in isolation, loss of function of the tumor suppressor p53 is thought to increase cell motility. Here by contrast we used the 2-D confluent cell layer and the 3-D multicellular spheroid to investigate how p53 impacts dissemination and invasion of cellular collectives. We used two human carcinoma cell lines, the bladder carcinoma EJ and the colorectal carcinoma HCT116. We began by replicating single cell invasion in the traditional Boyden chamber assay, and found that the number of invading cells increased with loss of p53, as expected. In the confluent 2-D cell layer, however, for both EJ and HCT, speeds and effective diffusion coefficients for the p53 null types compared to their p53 expressing counterparts were significantly smaller. Compared to p53 expressers, p53 null cells exhibited more organized cortical actin rings together with reduced front-rear cell polarity. Furthermore, loss of p53 caused cells to exert smaller traction forces upon their substrates, and reduced formation of cryptic lamellipodia. In a 3-D collagen matrix, p53 consistently promoted invasion of the multicellular spheroids into surrounding matrix. Together, these results show that p53 expression in these carcinoma model systems increases collective cellular migration and invasion. As such, these studies point to paradoxical contributions of p53 in single cell versus collective cellular migration.