bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of acute TLR-7 agonist-induced hemorrhagic myocarditis in mice by refined multi-parametric quantitative cardiac MRI
Authors: Baxan Nicoleta , Papanikolaou Angelos , Salles-Crawley Isabelle , Lota Amrit , Chowdhury Rasheda , Dubois Olivier , Branca Jane , Hasham Muneer G. , Rosenthal Nadia , Prasad Sanjay K. , Zhao Lan , Harding Sian E. , Sattler Susanne 
Published: December 2018

AbstractBACKGROUNDHemorrhagic myocarditis is a potentially fatal complication of excessive levels of systemic inflammation. It has been reported in viral infection, but is also possible in systemic autoimmunity. Cardiac magnetic resonance (CMR) imaging is the current gold standard for non-invasive detection of suspected inflammatory damage to the heart and changes in T1 and T2 relaxation times are commonly used to detect edema associated with immune cell infiltration and fibrosis. These measurements also form the basis of the Lake Louise Criteria, which define a framework for the CMR-based diagnosis of myocarditis. However, they do not take into account the possibility of hemorrhage leading to tissue iron deposition which strongly influences T1 and T2 measurements and may complicate interpretation based on these two parameters only.METHODSSystemic inflammation was induced in CFN mice by application of the TLR-7 agonist Resiquimod. Histopathology was performed on heart sections to assess immune cell infiltration (Hematoxylin & Eosin), fibrosis (PicoSirius Red) and tissue iron deposition (Perl’s Prussian Blue). A multi-parametric cardiac MRI tissue mapping approach measuring T1, T2, and T2* relaxation times was established to non-invasively identify these parameters in this small rodent model.RESULTSResiquimod-treated mice developed severe thrombocytopenia and hemorrhagic myocarditis. We identified patches of cardiac hemorrhage based on the presence of two major MRI phenotypes. Increased T2 with normal T1 and T2* values correlated with infiltration/edema only, while decreased T1, T2, and T2* values identify areas with infiltration/edema in the presence of iron indicating hemorrhagic myocarditis.CONCLUSIONWe show that over-activation of the TLR-7 pathway by Resiquimod treatment of CFN mice induces an early immune response reminiscent of excessive systemic inflammation due to viral infection. This causes internal bleeding which manifests most prominently as severe hemorrhagic myocarditis. We optimized a comprehensive noninvasive in vivo MRI approach based on quantitative measurement of T1, T2 and T2* to demonstrate the presence of diffuse myocardial edema, infiltration and iron deposition without the need of contrast agent administration. We propose that adding quantitative T2* mapping to CMR protocols for detection of myocarditis will improve diagnostic sensitivity and interpretation of disease mechanisms.
RAISS: Robust and Accurate imputation from Summary Statistics
Authors: Julienne Hanna , Shi Huwenbo , Pasaniuc Bogdan , Aschard Hugues 
Published: December 2018

AbstractMotivationMulti-trait analyses using public summary statistics from genome-wide association studies (GWAS) are becoming increasingly popular. A constraint of multi-trait methods is that they require complete summary data for all traits. While methods for the imputation of summary statistics exist, they lack precision for genetic variants with small effect size. This is benign for univariate analyses where only variants with large effect size are selected a posteriori. However, it can lead to strong p-value inflation in multi-trait testing. Here we present a new approach that improve the existing imputation methods and reach a precision suitable for multi-trait analyses.ResultsWe fine-tuned parameters to obtain a very high accuracy imputation from summary statistics. We demonstrate this accuracy for small size-effect variants on real data of 28 GWAS. We implemented the resulting methodology in a python package specially designed to efficiently impute multiple GWAS in parallel.AvailabilityThe python package is available at: https://gitlab.pasteur.fr/statistical-genetics/raiss, its accompanying documentation is accessible here http://statistical-genetics.pages.pasteur.fr/raiss/.Contacthanna.julienne@pasteur.fr
A circuit of protein-protein regulatory interactions enables polarity establishment in a bacterium
Authors: Zhao Wei , Duvall Samuel W. , Kowallis Kimberly A. , Tomares Dylan T. , Petitjean Haley N. , Childers W. Seth 
Published: December 2018

AbstractAsymmetric cell division generates specialized daughter cells that play a variety of roles including tissue morphogenesis in eukaryotes and pathogenesis in bacteria. In the gram-negative bacteriumCaulobacter crescentus, asymmetric localization of two biochemically distinct signaling hubs at opposite cell poles provides the foundation for asymmetric cell division. Through a set of genetic, synthetic biology and biochemical approaches we have characterized the regulatory interactions between three scaffolding proteins. These studies have revealed that the scaffold protein PodJ functions as a central mediator for organizing the new cell signaling hub, including promoting bipolarization of the central developmental scaffold protein PopZ. In addition, we identified that the old pole scaffold SpmX serves as a negative regulator of PodJ subcellular accumulation. These two scaffold-scaffold regulatory interactions serve as the core of an integrated cell polarization circuit that is layered on top of the cell-cycle circuitry to coordinate cell differentiation and asymmetric cell division.
Direct capture of CRISPR guides enables scalable, multiplexed, and multi-omic Perturb-seq
Authors: Replogle Joseph M. , Xu Albert , Norman Thomas M. , Meer Elliott J. , Terry Jessica M. , Riordan Daniel , Srinivas Niranjan , Mikkelsen Tarjei S. , Weissman Jonathan S. , Adamson Britt 
Published: December 2018

AbstractPairing CRISPR-based genetic screens with single-cell transcriptional phenotypes (Perturb-seq) has advanced efforts to explore the function of mammalian genes and genetic networks. We present strategies for Perturb-seq that enable direct capture of CRISPR sgRNAs within 3’ or 5’ single-cell RNA-sequencing libraries using the 10x Genomics platform. This technology greatly expands the accessibility, scalability, and flexibility of Perturb-seq, specifically enabling use with programmed combinatorial perturbations and multiplexing with multi-omic measurements.
Thermosensitive alternative splicing senses and mediates temperature adaptation inDrosophila
Authors: Evantal Naveh , Anduaga Ane Martin , Bartok Osnat , Patop Ines Lucía , Weiss Ron , Kadener Sebastian 
Published: December 2018

SUMMARYCircadian rhythms are generated by the cyclic transcription, translation and degradation of clock genes, includingtimeless(tim). Currently, little is known about the mechanisms by which the circadian clock senses and adapts to temperature changes. Here we show that temperature dramatically changes the splicing pattern oftim. We found that at 18°C TIM protein levels are diminished due to the induction of two cold-specific splicing isoforms (tim-coldandtim-short&cold). At 29°C, another isoform,tim-Mediumis strongly upregulated. We found that this isoform switching mechanism allows flies to regulate the levels and activity of TIM by setting miRNA-dependent thresholds for expression as well as by expressing isoforms with specific functions. Flies in which the production oftim-short&coldis abrogated display altered patterns of locomotor activity and alteredtimexpression. Interestingly, the introns oftimcarry the information for the temperature sensitivity, suggesting thattimsplicingper seis the temperature sensor.
Mechanistic interpretation of non-coding variants helps discover transcriptional regulators of drug response
Authors: Xie Xiaoman , Hanson Casey , Sinha Saurabh 
Published: December 2018

ABSTRACTIdentification of functional non-coding variants (polymorphisms) and their mechanistic interpretation is a major challenge of modern genomics, especially for precision medicine. Transcription factor (TF) binding profiles and epigenomic landscapes in reference samples can help us functionally annotate the genome, but do not provide ready answers regarding the effects of non-coding variants. A promising computational approach is to build models that predict TF-DNA binding from sequence, and use such models to score a variant’s impact on TF binding strength. Here, we asked if this mechanistic approach to variant interpretation can be combined with information on genotype-phenotype associations to discover important transcription factors regulating phenotypic variation among individuals. We developed a statistical approach that integrates phenotype, genotype, gene expression, TF ChIP-seq and Hi-C chromatin interaction data to answer this question. Using drug sensitivity measured in lymphoblastoid cell lines as the phenotype of interest, we tested if the non-coding variants statistically linked to the phenotype are enriched for strong predicted impact on DNA-binding strength of a TF, and used this test to identify TFs regulating individual differences in the phenotype. Our method relies on a new method for predicting variant impact on TF-DNA binding, that uses a combination of biophysical modelling and machine learning. We report statistical and literature-based support for many of the TFs discovered here as regulators of drug response variation. We show that the use of mechanistically driven variant impact predictors can identify TF-drug associations that would otherwise be missed. We examined in depth the evidence underlying one reported association – that of the transcription factor ELF1 with the drug doxorubicin – and identified several genes that may mediate this regulatory relationship.
Hyocholic acid species and the risk of type 2 diabetes
Authors: Zheng Xiaojiao , Chen Tianlu , Jiang Runqiu , Zhao Aihua , Huang Fengjie , Zhang Yunjing , Han Xiaolong , Li Mengci , Wei Meilin , You Yijun , Wang Shouli , Ma Xiaojing , Bao Yuqian , Jiang Miao , Liu Jiajian , Zhao Qing , Ge Kun , Dong Bing , Li Defa , Liang Dandan , Lei Sha , Li Yitao , Lan Ke , Lu Aiping , Zhang Weituo , Wang Congrong , Yu Haoyong , Rajani Cynthia , Panee Jun , Xie Guoxiang , Jia Weiping , Jia Wei 
Published: December 2018

ABSTRACTHyocholic acid (HCA) and its derivatives are found in only trace amounts in human blood, but constitute approximately 76 % of the bile acid (BA) pool in the pig, a species known for its exceptional resistance to type 2 diabetes mellitus (T2DM). Here we show that HCA species play a crucial role in maintaining glucose homeostasis and preventing T2DM. We found that in two cohort studies (n=1,213), both obesity and diabetes were associated with lower serum concentrations of HCA species. Serum HCA levels in apparently healthy individuals (n=132) were found to be strong predictors for metabolic health 10 years later. Oral administration of HCA increased serum fasting GLP-1, to a greater extent than metformin, in healthy and diabetic mouse models. HCA upregulated GLP-1 secretion in intestinal enteroendocrine cells via simultaneously activating G-protein-coupled BA receptor, TGR5, and inhibiting farnesoid X receptor, a unique mechanism that is not found in other BA species.
Structural Basis for eIF2B Inhibition in Integrated Stress Response
Authors: Kashiwagi Kazuhiro , Yokoyama Takeshi , Nishimoto Madoka , Takahashi Mari , Sakamoto Ayako , Yonemochi Mayumi , Shirouzu Mikako , Ito Takuhiro 
Published: December 2018

AbstractA core event in the integrated stress response, an adaptive pathway common to all eukaryotic cells in response to various stress stimuli, is the phosphorylation of eukaryotic translation initiation factor 2 (eIF2). Normally, unphosphorylated eIF2 transfers methionylated initiator tRNA to the ribosome in a GTP-dependent manner. In contrast, phosphorylated eIF2 inhibits its specific guanine nucleotide exchange factor eIF2B, which leads to a deficiency of active eIF2 and resultant global translation repression. To unveil the mechanism by which the eIF2 phosphorylation status regulates the eIF2B nucleotide exchange activity, we determined cryo-electron microscopic and crystallographic structures of eIF2B in complex with unphosphorylated or phosphorylated eIF2. Intriguingly, the unphosphorylated and phosphorylated forms of eIF2 bind to eIF2B in completely different manners: the nucleotide exchange-active “productive” and nucleotide exchange-inactive “nonproductive” modes, respectively. The nonproductive-mode phosphorylated eIF2, extending from one of the two eIF2B “central cavities”, not only prevents nucleotide exchange on itself, but also sterically prevents unphosphorylated eIF2 from productively binding on the other central cavity of eIF2B, which explains how phosphorylated eIF2 inhibits eIF2B.One Sentence SummaryA drastic change in the binding mode of eIF2 to eIF2B induces translational control in stress.
Phosphorylation regulates auto-inhibition of kinesin KIF3A
Authors: Chen Kunning , Saw Wuan-Geok , Lama Dilraj , Verma Chandra , Grüber Gerhard , Koh Cheng-Gee 
Published: December 2018

ABSTRACTKinesin are molecular motors that move along the microtubules. They function to transport cargoes, vesicles and organelles to designated locations in the cells. KIF3A belongs to the Kinesin-2 family and forms a heterotrimeric complex with KIF3B and KAP3. We have earlier shown that the cargo trafficking activity of KIF3 motor can be regulated by CaMKII kinase and POPX2 phosphatase. In this study, we elucidated the mechanism of KIF3A regulation. We find that KIF3A adopts an auto-inhibited state through the interaction between the motor and tail domains. The motor-tail interaction also hinders the ATPase activity of the motor domain. We show that the phosphorylation status of serine-689/690 (mouse/human) at the C-terminal region of KIF3A is crucial for the motor-tail interaction. The motor domain does not interact well with the tail domain when serine-689 is phosphorylated by CaMKII or mutated to aspartic acid to mimic phosphorylation. Molecular dynamics simulations suggest that the non-phosphorylated tail domain folds into the hydrophobic pocket formed by the motor dimers. Phosphorylation of serine-689 results in conformational changes that leads to the relieve of auto-inhibition.
Navigating the structural landscape ofde novoα–helical bundles
Authors: Rhys Guto G. , Wood Christopher W. , Beesley Joseph L. , Zaccai Nathan R. , Burton Antony J. , Brady R. Leo , Thomson Andrew R. , Woolfson Derek N. 
Published: December 2018

ABSTRACTThe association of amphipathicαhelices in water leads to α-helical-bundle protein structures. However, the driving force for this—the hydrophobic effect—is not specific and does not define the number or the orientation of helices in the associated state. Rather, this is achieved through deeper sequence-to-structure relationships, which are increasingly being discerned. For example, for one structurally extreme but nevertheless ubiquitous class of bundle—the α-helical coiled coils—relationships have been established that discriminate between all-parallel dimers, trimers and tetramers. Association states above this are known, as are antiparallel and mixed arrangements of the helices. However, these alternative states are less-well understood. Here, we describe a synthetic-peptide system that switches between parallel hexamers and various up-down-up-down tetramers in response to single-amino-acid changes and solution conditions. The main accessible states of each peptide variant are characterized fully in solution and, in most cases, to high-resolution X-ray crystal structures. Analysis and inspection of these structures helps rationalize the different states formed. This navigation of the structural landscape of α-helical coiled coils above the dimers and trimers that dominate in nature has allowed us to design rationally a well-defined and hyperstable antiparallel coiled-coil tetramer (apCC-Tet). This robustde novoprotein provides another scaffold for further structural and functional designs in protein engineering and synthetic biology.
Dynamics of centriole amplification in centrosome-depleted brain multiciliated progenitors
Authors: Mercey Olivier , Jord Adel Al , Rostaing Philippe , Mahuzier Alexia , Fortoul Aurélien , Boudjema Amélie-Rose , Faucourt Marion , Spassky Nathalie , Meunier Alice 
Published: December 2018

AbstractCentrioles are essential microtubule-based organelles organizing cilia and centrosomes. Their mode of biogenesis is semi-conservative: each pre-existing centriole scaffolds the formation of a new one, a process coordinated with the cell cycle. By contrast, multiciliated progenitors with two centrosomal centrioles massively amplify centrioles to support the nucleation of hundred of motile cilia and transport vital fluids. This occurs through cell type-specific organelles called deuterosomes, composed of centrosome-related elements, and is regulated by the cell cycle machinery. Deuterosome-dependent centriole amplification was proposed for decades to occur de novo, i.e. independently from pre-existing centrioles. Challenging this hypothesis, we recently reported an accumulation of procentriole and deuterosome precursors at the centrosomal daughter centriole during centriole amplification in brain multiciliated cells. Here we further investigate the relationship between the centrosome and the dynamic of centriole amplification by (i) characterizing the centrosome behavior during the centriole amplification dynamics and (ii) assessing the dynamics of amplification in centrosome-depleted cells. Surprisingly, although our data strengthen the centrosomal origin of amplified centrioles, we show limited consequences in deuterosome/centriole number when we deplete centrosomal centrioles. Interestingly, in absence of centrosomal centrioles, procentrioles are still amplified sequentially from a single focal region, characterized by microtubule convergence and pericentriolar material (PCM) self-assembly. The relevance of deuterosome association with the daughter centriole as well as the role of the PCM in the focal and sequential genesis of centrioles in absence of centrosomal centrioles are discussed.
Mapping axon conduction delaysin vivofrom microstructural MRI
Authors: Drakesmith Mark , Jones Derek K 
Published: December 2018

AbstractThe conduction velocity (CV) of action potentials along axons is a key neurophysiological property central to neural communication. The ability to estimate CV in humansin vivofrom non-invasive MRI methods would therefore represent a significant advance in neuroscience. However, there are 2 major challenges that this paper aims to address: (1) much of the complexity of the neurophysiology of action potentials cannot be captured with currently available MRI techniques. Therefore, we seek to establish the variability in CV thatcanbe captured when predicting CV purely from parameters that can be estimated from MRI (axon diameter and g-ratio); and (2) errors inherent in existing MRI-based biophysical models of tissue will propagate through to estimates of CV, the extent to which is currently unknown.Issue (1) is investigated by performing a sensitivity analysis on a comprehensive model of axon electrophysiology and determining the relative sensitivity to various morphological and electrical parameters.The investigations suggest that 89.2 % of the variance in CV is accounted for by variation in AD and g-ratio. The observed dependency of CV on AD and g-ratio is well characterised by a previously reported model by Rushton.Issue (2) is investigated through simulation of diffusion and relaxometry MRI data for a range of axon morphologies, applying models of restricted diffusion and relaxation processes to derive estimates of axon volume fraction (AVF), AD and g-ratio and estimating CV from the derived parameters. The results show that errors in the AVF have the biggest detrimental impact on estimates of CV, particularly for sparse fibre populations (AVF<0.3). CV estimates are most accurate (below 5% error) where AVF is above 0.3, g-ratio is between 0.6 and 0.85 and AD is below 10 µm. Fortunately, these parameter bounds are typically satisfied by most myelinated axons.In conclusion, we demonstrate that accurate CV estimates can be inferred in axon populations across a range of configurations, except in some exceptional cases or where axonal density is low. As a proof of concept, for the first time, we generated anin vivomap of conduction velocity in the human corpus callosum with estimates consistent with values previously reported from invasive electrophysiology in primates.
Structural basis for the inhibition of translation through eIF2α phosphorylation
Authors: Gordiyenko Yuliya , Llácer José Luis , Ramakrishnan Venki 
Published: December 2018

AbstractOne of the responses to stress by eukaryotic cells is the down-regulation of protein synthesis by phosphorylation of translation initiation factor eIF2. Phosphorylation results in low availability of the eIF2 ternary complex (eIF2-GTP-tRNAi) by affecting its interaction with its GTP-GDP exchange factor eIF2B. We have determined the cryo-EM structure of eIF2B in complex with phosphorylated eIF2 at an overall resolution of 4.15 Å. Two eIF2 molecules bind opposite sides of an eIF2B hetero-decamer through eIF2α-D1, which contains the phosphorylated Ser51. eIF2α-D1 is mainly inserted between the N-terminal helix bundle domains of δ and α subunits of eIF2B. Phosphorylation of Ser51 enhances binding to eIF2B through direct interactions of phosphate groups with residues in eIF2Bα and indirectly by inducing contacts of eIF2α helix 58-63 with eIF2Bδ leading to a competition with Met-tRNAi.
Strong selective sweeps before 45,000BP displaced archaic admixture across the human X chromosome
Authors: Skov L. , Macià M.C. , Lucotte E. , Cavassim M.I.A. , Castellano D. , Mailund T. , Schierup M.H. , Munch K. 
Published: December 2018

AbstractThe X chromosome in non-African populations has less diversity and less Neanderthal introgression than expected. We analyzed X chromosome diversity across the globe and discovered seventeen chromosomal regions, where haplotypes of several hundred kilobases have recently reached high frequencies in non-African populations only. The selective sweeps must have occurred more than 45,000 years ago because the ancient Ust’-Ishim male also carries its expected proportion of these haplotypes. Surprisingly, the swept haplotypes are entirely devoid of Neanderthal introgression, which implies that a population without Neanderthal admixture contributed the swept haplotypes. It also implies that the sweeps must have happened after the main interbreeding event with Neanderthals about 55,000 BP. These swept haplotypes may thus be the only genetic remnants of an earlier out-of-Africa event.One Sentence SummaryAfter humans expanded out of Africa, the X chromosome experienced a burst of extreme natural selection that removed Neanderthal admixture.