bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integration of phased Hi-C and molecular phenotype data to study genetic and epigenetic effects on chromatin looping
Authors: Greenwald William W. , Li He , Benaglio Paola , Jakubosky David , Matsui Hiroko , Schmitt Anthony , Selvaraj Siddarth , D’Antonio Matteo , D’Antonio-Chronowska Agnieszka , Smith Erin N. , Frazer Kelly A. 
Published: June 2018

SummaryWhile genetic variation at chromatin loops is relevant for human disease, the relationships between loop strength, genetics, gene expression, and epigenetics are unclear. Here, we quantitatively interrogate this relationship using Hi-C and molecular phenotype data across cell types and haplotypes. We find that chromatin loops consistently form across multiple cell types and quantitatively vary in strength, instead of exclusively forming within only one cell type. We show that large haplotype loop imbalance is primarily associated with imprinting and copy number variation, rather than genetically driven traits such as allele-specific expression. Finally, across cell types and haplotypes, we show that subtle changes in chromatin loop strength are associated with large differences in other molecular phenotypes, with a 2-fold change in looping corresponding to a 100-fold change in gene expression. Our study suggests that regulatory genetic variation could mediate its effects on gene expression through subtle modification of chromatin loop strength.
Emergence and rapid global dissemination of CTX-M-15-associated Klebsiella pneumoniae strain ST307
Authors: Wyres Kelly L. , Hawkey Jane , Hetland Marit A.K. , Fostervold Aasmund , Wick Ryan R. , Judd Louise M. , Hamidian Mohammad , Howden Benjamin P. , Löhr Iren H. , Holt Kathryn E. 
Published: June 2018

AbstractRecent reports indicate the emergence of a new carbapenemase producing Klebsiella pneumoniae clone, ST307. Here we show that ST307 emerged in the mid-1990s (nearly 20 years prior to its first report), is already globally distributed and is intimately associated with a conserved plasmid harbouring the blaCTX-M-15 extended-spectrum beta-lactamase (ESBL) gene plus other antimicrobial resistance determinants. Our findings support the need for enhanced surveillance of this widespread ESBL clone in which carbapenem resistance is now emerging.
CRISPR delivery particles for developing therapeutic strategies in metabolic disease
Authors: Shen Yuefei , Cohen Jessica L. , Nicoloro Sarah M. , Kelly Mark , Yenilmez Batuhan , Henriques Felipe , Tsagkaraki Emmanouela , Edwards Yvonne J.K. , Hu Xiaodi , Friedline Randall H. , Kim Jason K. , Czech Michael P. 
Published: June 2018

ABSTRACTRNA-guided engineered nucleases derived from a prokaryotic adaptive immune system known as CRISPR-Cas represent a promising platform for gene deletion and editing. As a therapeutic approach, direct delivery of Cas9 protein and guide RNA could circumvent the safety problems associated with plasmid delivery and therefore represents an attractive tool for genome engineering. Gene deletion or editing in adipose tissue to enhance its energy expenditure, fat oxidation and secretion of bioactive factors through a “browning” process presents a potential therapeutic strategy to alleviate metabolic disease. Here, we developed novel CRISPR delivery particles, denoted CriPs, composed of nano-size complexes of Cas9 protein and single guide (sg)RNA, coated with an amphipathic peptide called Endo-Porter that mediates entry into cells. Efficient CRISPR-Cas9 mediated gene deletion of ectopically expressed Green fluorescent protein (GFP) by CriPs was achieved in multiple cell types including a macrophage cell line, primary macrophages and primary pre-adipocytes. Significant GFP loss was also observed in peritoneal exudate cells with minimum systemic toxicity in GFP expressing mice following intraperitoneal injection of CriPs containing sgRNA targeting Gfp. Furthermore, the disruption of the Nrip1 gene in white adipocytes by CriPs enhanced adipocyte “browning” with a marked increase of UCP1 expression. Deletion of Nrip1 by CriPs did not produce detectable off-target effects. Thus CriPs represent a novel CRISPR delivery system for Cas9 and sgRNA that is effective for ablating targeted gene products in cultured cells and in vivo, and provide a potential therapeutic strategy for metabolic disease.
Drosophila melanogasterinfected withWolbachiastrainwMelCS prefer cooler temperatures
Authors: Arnold Pieter A. , Levin Samantha C. , Stevanovic Aleksej L. , Johnson Karyn N. 
Published: June 2018

AbstractTemperature plays a fundamental role in the dynamics of host-pathogen interactions.Wolbachiais an endosymbiotic bacteria that infects about 40% of arthropod species, which can affect host behaviour and reproduction. Yet, the effect ofWolbachiaon host thermoregulatory behaviour is largely unknown, despite its use in disease vector control programs in thermally variable environments.Here, we used a thermal gradient to test whetherDrosophila melanogasterinfected withWolbachiastrainwMelCS exhibit different temperature preferences (Tp) to uninfected flies.We found thatWolbachia-infected flies preferred a cooler mean temperature (Tp= 25.06±0.25°C) than uninfected flies (Tp= 25.78±0.24°C).This finding suggests thatWolbachia-infected hosts might seek out cooler microclimates to reduce exposure to and lessen the consequences of high temperatures. This finding has generated hypotheses that will be fruitful in areas of research for exploring the mechanisms by which the change inTpoccurs in this complex and significant host-pathogen-environment interaction.
Logical design of oral glucose ingestion pattern minimizing blood glucose in humans
Authors: Fujii Masashi , Murakami Yohei , Karasawa Yasuaki , Sumitomo Yohei , Fujita Suguru , Koyama Masanori , Uda Shinsuke , Kubota Hiroyuki , Inoue Hiroshi , Konishi Katsumi , Oba Shigeyuki , Ishii Shin , Kuroda Shinya 
Published: June 2018

SUMMARYExcessive increase in blood glucose level after eating increases the risk of macroangiopathy, and a method for not increasing the postprandial blood glucose level is desired. However, a logical design method of the dietary ingestion pattern controlling the postprandial blood glucose 2 level has not yet been established. We constructed a mathematical model of blood glucose control by oral glucose ingestion in 3 healthy human subjects, used the model to predict an optimal glucose ingestion pattern, and showed that the optimal ingestion pattern minimized the peak value of blood glucose level. Subjects orally ingested 3 doses of glucose by bolus or over 2 hours, and blood glucose, insulin, C-peptide and incretins were measured for 4 hours. We constructed an ordinary differential equation model that reproduced the time course data of the blood glucose and blood hormone levels. Using the model, we predicted that intermittent ingestion 30 minutes apart was the optimal glucose ingestion patterns that minimized the peak value of blood glucose level. We confirmed with subjects that this intermittent pattern decreased the peak value of blood glucose level. This approach could be applied to design optimal dietary ingestion patterns.In BriefAs a forward problem, we measured blood glucose and hormones in three human subjects after oral glucose ingestion and constructed a mathematical model of blood glucose control. As an inverse problem, we used the model to predict the optimal oral glucose ingestion pattern that minimized the peak value of blood glucose level, and validated the pattern with the subjects.HighlightsModeling blood glucose concentrations predicts an intermittent ingestion pattern is optimalHuman validation shows ingestion at 30-minute intervals limits peak blood glucoseWe provide a strategy to design optimal dietary ingestion patterns
TGF-βRII knock-down promotes tumor growth and chemoresistance to gemcitabine of pancreatic cancer cells via phosphorylation of STAT3
Authors: Drubay Vincent , Skrypek Nicolas , Cordiez Lucie , Vasseur Romain , Schulz Céline , Boukrout Nihad , Duchêne Bélinda , Coppin Lucie , Seuningen Isabelle Van , Jonckheere Nicolas 
Published: June 2018

AbstractPancreatic adenocarcinoma (PDAC) is one of the most deadly cancers in the western countries because of a lack of early diagnostic markers and efficient therapeutics. At the time of diagnosis, more than 80% of patients have metastasis or locally advanced cancer and are therefore not eligible for surgical resection. Pancreatic cancer cell also harbour a high resistance to chemotherapeutic drugs such as gemcitabine that is one of the main palliative treatment for PDAC.TGF-β possesses both tumor-suppressive and oncogenic activities in pancreatic cancer. TGF-β signalling pathway plays complex role during carcinogenesis by initially inhibiting epithelial growth and later promoting the progression of advanced tumors and thus emerged as tumor suppressor pathway. TGF-β binds to its receptor TGF-βRII and activates different pathways: canonical pathway involving the Smad proteins and alternative pathways such as MAPKs. Smad4 is mutated in 50-80% of PDAC. Mutations of TGF-βRII also occurs (5-10%). In order to decipher the role of TGF-β in carcinogenesis and chemoresistance, we decided to characterize the knocking down of TGF-βRII that is the first actor of TGF-β signalling. We developed pancreatic cancer cell lines stably invalidated for TGF-βRII and studied the impact on biological properties of pancreatic cancer cells both in vitro and in vivo. We show that TGF-βRII silencing alters tumor growth and migration as well as resistance to. TGF-βRII silencing also leads to S727 STAT3 and S-63 c-Jun phosphorylation, decrease of MRP3 and increase of MRP4 ABC transporter expression and induction of a partial EMT phenotype.In the future, the better understanding TGF-β signaling pathways and underlying cellular mechanisms in chemoresistance to gemcitabine may bring new therapeutic tools to clinicians.
Nucleoporin 133 deficiency leads to glomerular damage in zebrafish
Authors: Cosentino Chiara Cianciolo , Berto Alessandro , Hari Michelle , Loffing Johannes , Neuhauss Stephan C. F. , Doye Valérie 
Published: June 2018

AbstractAlthough structural nuclear pore proteins (nucleoporins) are seemingly required in every cell type to assemble a functional nuclear transport machinery, mutations or deregulation of a subset of them have been associated with specific human hereditary diseases. In particular, previous genetic studies of patients with nephrotic syndrome identified mutations inNup107that impaired the expression or the localization of its direct partner at nuclear pores, Nup133. In the present study, we characterized the zebrafishnup133orthologous gene and its expression pattern during larval development. Morpholino-mediated gene knockdown revealed that Nup133 depletion in zebrafish larvae leads to the formation of kidney cysts, a phenotype that can be rescued by co-injection of wild type mRNA. Analysis of different markers for tubular and glomerular development shows that the overall kidney development is not affected bynup133knockdown. On the other hand, we demonstrate thatnup133is essential for the organization and functional integrity of the pronephric glomerular filtration barrier, as its downregulation results in proteinuria and moderate foot process effacement, mimicking some of the abnormalities typically featured by patients with nephrotic syndrome. These data indicate thatnup133is a new gene required for proper glomerular structure and function in zebrafish.
Inter-trial effects in visual pop-out search: Factorial comparison of Bayesian updating models
Authors: Allenmark Fredrik , Müller Hermann J. , Shi Zhuanghua 
Published: June 2018

AbstractMany previous studies on visual search have reported inter-trial effects, that is, observers respond faster when some target property, such as a defining feature or dimension, or the response associated with the target repeats versus changes across consecutive trial episodes. However, what processes drive these inter-trial effects is still controversial. Here, we investigated this question using a combination of Bayesian modeling of belief updating and evidence accumulation modeling in perceptual decision-making. In three visual singleton (‘pop-out’) search experiments, we explored how the probability of the response-critical states of the search display (e.g., target presence/absence) and the repetition/switch of the target-defining dimension (color/ orientation) affect reaction time distributions. The results replicated the mean reaction time (RT) inter-trial and dimension repetition/switch effects that have been reported in previous studies. Going beyond this, to uncover the underlying mechanisms, we used the Drift-Diffusion Model (DDM) and the Linear Approach to Threshold with Ergodic Rate (LATER) model to explain the RT distributions in terms of decision bias (starting point) and information processing speed (evidence accumulation rate). We further investigated how these different aspects of the decision-making process are affected by different properties of stimulus history, giving rise to dissociable inter-trial effects. We approached this question by (i) combining each perceptual decision making model (DDM or LATER) with different updating models, each specifying a plausible rule for updating of either the starting point or the rate, based on stimulus history, and (ii) comparing every possible combination of trial-wise updating mechanism and perceptual decision model in a factorial model comparison. Consistently across experiments, we found that the (recent) history of the response-critical property influences the initial decision bias, while repetition/switch of the target-defining dimension affects the accumulation rate, likely reflecting an implicit ‘top-down’ modulation process. This provides strong evidence of a disassociation between response- and dimension-based inter-trial effects.
Functional properties of CD8+ T cells under lymphopenic conditions
Authors: Silaeva Yu. Yu. , Kalinina A. A. , Khromykh L. M. , Kazansky D. B. 
Published: June 2018

AbstractA peripheral pool of T lymphocytes consists of several functionally distinct populations of CD8+ T cells. One of the major surface markers that allow to define different populations of T cells are CD44 and CD62L. Expression profile of these markers depends on the functional status of T lymphocyte. Naive CD8+ T cells express CD62L and do not express CD44 (CD62LhiCD44lo), clones of T cells activated during the primary immune response lose CD62L and express CD44 (CD62LloCD44hi). Central memory CD8+ T cells express both CD44 and CD62L (CD44hiCD62Lhi). However expression of activation markers not always correlate with an antigen experience of T cell. It is known, that in lymphopenic conditions peripheral T cells undergo homeostatic proliferation and acquire the memory like surface phenotype CD44hiCD62Lhi, but data about functional activity of these cells remain controversial. We studied relationship between surface expression of the markers CD44 and CD62L and functional properties of CD8+ T cells under lymphopenic conditions. We proved that surface expression of CD44 in not the only condition for T lymphocyte to acquire the functional properties of memory T-cells. It means that identification of CD8 + T-memory cells based solely on an expression profile of surface markers is not completely correct and requires confirmation by functional tests. Moreover, results of our research may become of practical importance for blood transfusion and bone marrow transplantation.
Options for calibrating CERES-maize genotype specific parameters under data-scarce environments
Authors: Adnan A.A , Diels J. , Jibrin J.M. , Kamara A.Y. , Craufurd P. , Mohammed I. B. , Tonnang Z.E.H. 
Published: June 2018

AbstractMost crop simulation models require the use of Genotype Specific Parameters (GSPs) which provide the Genotype component of G×E×M interactions. Estimation of GSPs is the most difficult aspect of most modelling exercises because it requires expensive and time-consuming field experiments. GSPs could also be estimated using multi-year and multi locational data from breeder evaluation experiments. This research was set up with the following objectives: i) to determine GSPs of 10 newly released maize varieties for the Nigerian Savannas using data from both calibration experiments and by using existing data from breeder varietal evaluation trials; ii) to compare the accuracy of the GSPs generated using experimental and breeder data; and iii) to evaluate CERES-Maize model to simulate grain and tissue nitrogen contents. For experimental evaluation, 8 different experiments were conducted during the rainy and dry seasons of 2016 across the Nigerian Savanna. Breeder evaluation data was also collected for 2 years and 7 locations. The calibrated GSPs were evaluated using data from a 4 year experiment conducted under varying nitrogen rates (0, 60 and 120kg N ha−1). For the model calibration using experimental data, calculated model efficiency (EF) values ranged between 0.86-0.92 and coefficient of determination (d-index) between 0.92-0.98. Calibration of time-series data produced nRMSE below 7% while all prediction deviations were below 10% of the mean. For breeder experiments, EF (0.52-0.81) and d-index (0.46-0.83) ranges were lower. Prediction deviations were below 17% of the means for all measured variables. Model evaluation using both experimental and breeder trials resulted in good agreement (low RMSE, high EF and d-index values) between observed and simulated grain yields, and tissue and grain nitrogen contents. We conclude that higher calibration accuracy of CERES-Maize model is achieved from detailed experiments. If unavailable, data from breeder experimental trials collected from many locations and planting dates can be used with lower but acceptable accuracy.
β-Blocker inhibits myocardial infarction-induced brown adipose tissue D2 activation and maintains a low thyroid hormone state in rats
Authors: Seara Fernando A. C. , Araujo Iracema G. , Império Güínever E. , Marassi Michelle P. , Silva Alba C. M. , Mecawi André S. , Reis Luis C. , Olivares Emerson L. 
Published: June 2018

AbstractConsidering the recognized role of thyroid hormones on the cardiovascular system during health and disease, we hypothesized that type 2 deiodinase (D2) activity, the main activation pathway of thyroxine (T4)-to-triiodothyronine (T3), could be an important site to modulate thyroid hormone status, which would then constitute a possible target for β-adrenergic blocking agents in a myocardial infarction (MI) model induced by left coronary occlusion in rats. Despite a sustained and dramatic fall in serum T4 concentrations (60-70%), the serum T3 concentration fell only transiently in the first week post-infarction (53%) and returned to control levels at 8 and 12 weeks after surgery compared to Sham group (P<0.05). Brown adipose tissue (BAT) D2 activity (fmoles T4/min.mg ptn) was dramatically increased by approximately 77% in the 8th week and approximately 100% in the 12th week in the MI group compared to that of the Sham group (P<0.05). Beta-blocker treatment (propranolol given in the drinking water, 0.5 g/L) maintained a low T3 state in MI animals, dampening both BAT D2 activity (44% reduction) and serum T3 (66% reduction in serum T3) compared to that of the non-treated MI group 12 weeks after surgery (P<0.05). Propranolol improved cardiac function (assessed by echocardiogram) in MI group compared to MI-non treated one by 40 and 57 % 1 and 12 weeks after treatment respectively (P<0.05). Our data suggest that the beta-adrenergic pathway may contribute to BAT D2 hyperactivity and T3 normalization after MI in rats. Propranolol treatment maintains low T3 state and improves cardiac function additionally.
Yeast Ded1 promotes 48S translation pre-initiation complex assembly in an mRNA-specific and eIF4F-dependent manner
Authors: Gupta Neha , Lorsch Jon R. , Hinnebusch Alan G. 
Published: June 2018

SummaryDEAD-box RNA helicase Dedl is thought to resolve secondary structures in mRNA 5′-untranslated regions (5′-UTRs) that impede 48S preinitiation complex (PIC) formation at the initiation codon. We reconstituted Ded1 acceleration of 48S PIC assembly on native mRNAs in a pure system, and recapitulated increased Ded1-dependence of mRNAs that are Ded1-hyperdependent in vivo. Stem-loop (SL) structures in 5′-UTRs of native and synthetic mRNAs increased the Ded1 requirement to overcome their intrinsically low rates of 48S PIC recruitment. Ded1 acceleration of 48S assembly was greater in the presence of eIF4F, and domains mediating one or more Ded1 interactions with eIF4G or helicase eIF4A were required for efficient recruitment of all mRNAs; however, the relative importance of particular Ded1 and eIF4G domains were distinct for each mRNA. Our results account for the Ded1 hyper-dependence of mRNAs with structure-prone 5′-UTRs, and implicate an eIF4E·eIF4G·eIF4A·Ded1 complex in accelerating 48S PIC assembly on native mRNAs.
Ensemble Feature Selection and Meta-Analysis of Cancer miRNA Biomarkers
Authors: Alejandro Lopez-Rincon , Marlet Martinez-Archundia , Gustavo Ulises Martinez-Ruiz , Alberto Tonda 
Published: June 2018

AbstractThe role of microRNAs (miRNAs) in cellular processes captured the attention of many researchers, since their dysregulation is shown to affect the cancer disease landscape by sustaining proliferative signaling, evading program cell death, and inhibiting growth suppressors. Thus, miRNAs have been considered important diagnostic and prognostic biomarkers for several types of tumors. Machine learning algorithms have proven to be able to exploit the information contained in thousands of miRNAs to accurately predict and classify cancer types. Nevertheless, extracting the most relevant miRNA expressions is fundamental to allow human experts to validate and make sense of the results obtained by automatic algorithms. We propose a novel feature selection approach, able to identify the most important miRNAs for tumor classification, based on consensus on feature relevance from high-accuracy classifiers of different typologies. The proposed methodology is tested on a real-world dataset featuring 8,129 patients, 29 different types of tumors, and 1,046 miRNAs per patient, taken from The Cancer Genome Atlas (TCGA) database. A new miRNA signature is suggested, containing the 100 most important oncogenic miRNAs identified by the presented approach. Such a signature is proved to be sufficient to identify all 29 types of cancer considered in the study, with results nearly identical to those obtained using all 1,046 features in the original dataset. Subsequently, a meta-analysis of the medical literature is performed to find references to the most important biomarkers extracted by the methodology. Besides known oncomarkers, 15 new miRNAs previously not ranked as important biomarkers for diagnosis and prognosis in cancer pathologies are uncovered. Such miRNAs, considered relevant by the machine learning algorithms, but still relatively unexplored by specialized literature, could provide further insights in the biology of cancer.