bluuebunny/crossref_metadata_2025_split huggingface dataset:
Growth hormone transgenesis disrupts immune function in muscle of coho salmon (Oncorhynchus kisutch) impacting cross-talk with growth systems
Authors: Alzaid Abdullah , Kim Jin-Hyoung , Devlin Robert H. , Martin Samuel A.M. , Macqueen Daniel J. 
Published: October 2017

ABSTRACTThe suppression of growth during infection should facilitate resource allocation towards effective immune function. Work supporting this hypothesis has been recently reported in teleosts, demonstrating immune-responsive regulation of the insulin-like growth factor (IGF) system - a key endocrine growth pathway that acts downstream of growth hormone (GH). Skeletal muscle is the main target for growth and energetic storage in fish, yet little is known about how growth is regulated in this tissue during an immune response. We addressed this knowledge gap by characterizing muscle immune responses in size-matched coho salmon (Oncorhynchus kisutch) achieving different growth rates. We compared a wild-type strain with two GH transgenic groups achieving either maximal or highly-suppressed growth – an experimental design that separates GH’s direct effects from its influence on growth rate. Fish were sampled 30h post-injection with PBS (control) or mimics of bacterial (peptidoglycan) or viral (Poly:IC) infection. We quantified the mRNA level expression of genes from the GH, GH receptor (GHR), IGF hormone, IGF1 receptor (IGF-1R) and IGF binding protein (IGFBP) families, along with marker genes for muscle growth and host defence genes involved in inflammatory or antiviral responses. We provide strong evidence for dampened immunity in the GH transgenics compared to wild-type animals. Strikingly, the muscle of GH transgenics achieving rapid growth showed no detectable antiviral response, coupled with evidence of a constitutive inflammatory state. GH and IGF system gene expression was also strongly altered by GH transgenesis and fast growth, both for baseline expression levels and responses to immune stimulation. Overall, our findings demonstrate that GH transgenesis disrupts normal immune function and growth-immune cross-talk in muscle, with implications for the health and welfare of farmed salmon.
The relationship between spatial configuration and functional connectivity of brain regions
Authors: Bijsterbosch Janine D. , Woolrich Mark W. , Glasser Matthew F. , Robinson Emma C. , Beckmann Christian F. , Van Essen David C. , Harrison Samuel J. , Smith Stephen M. 
Published: October 2017

AbstractBrain connectivity is often considered in terms of the communication between functionally distinct brain regions. Many studies have investigated the extent to which patterns of coupling strength between multiple neural populations relates to behavior. For example, studies have used "functional connectivity fingerprints" to characterise individuals' brain activity. Here, we investigate the extent to which the exact spatial arrangement of cortical regions interacts with measures of brain connectivity. We find that the shape and exact location of brain regions interact strongly with the modelling of brain connectivity, and present evidence that the spatial arrangement of functional regions is strongly predictive of non-imaging measures of behaviour and lifestyle. We believe that, in many cases, cross-subject variations in the spatial configuration of functional brain regions are being interpreted as changes in functional connectivity. Therefore, a better understanding of these effects is important when interpreting the relationship between functional imaging data and cognitive traits.
DNA lesions proximity modulates damage tolerance pathways inEscherichia coli
Authors: Chrabaszcz Élodie , Laureti Luisa , Pagès Vincent 
Published: October 2017

ABSTRACTThe genome of all organisms is constantly threatened by numerous agents that cause DNA damages. When the replication fork encounters an unrepaired DNA lesion, two DNA damage tolerance pathways are possible: error-prone translesion synthesis (TLS) that requires specialized DNA polymerases, and error-free Damage Avoidance (DA) that relies on homologous recombination. The balance between these two mechanisms is essential since it defines the level of mutagenesis during lesion bypass, allowing genetic variability and adaptation to the environment, but also introducing the risk of generating genome instability. Here we report that the mere proximity of replication-blocking lesions that arise inEscherichia coli’s genome during a genotoxic stress, leads to a strong increase in the use of the error-prone TLS. We show that this increase is caused by the local inhibition of homologous recombination due to the overlapping of single-stranded DNA regions generated downstream the lesions. This increase in TLS is independent of SOS activation, but its mutagenic effect is additive with the one of SOS. Hence, the combination of SOS induction and lesions proximity leads to a strong increase in TLS that becomes the main lesion tolerance pathway used by the cell during a genotoxic stress.
The evolution of the temporal program of genome replication
Authors: Agier Nicolas , Delmas Stéphane , Zhang Qing , Fleiss Aubin , Jaszczyszyn Yan , van Dijk Erwin , Thermes Claude , Weigt Martin , Cosentino-Lagomarsino Marco , Fischer Gilles 
Published: October 2017

AbstractComparative analyses of temporal programs of genome replication revealed either a nearly complete conservation between closely related species or a comprehensive reprogramming between distantly related species. Therefore, many important questions on the evolutionary remodeling of replication timing programs remain unanswered. To address this issue, we generated genome-wide replication timing profiles for ten yeast species from the genus Lachancea, covering a continuous evolutionary range from closely related to more divergent species. The comparative analysis of these profiles revealed that the replication program linearly evolves with increasing evolutionary divergence between these species. We found that the evolution of the timing program mainly results from a high evolutionary turnover rate of the cohort of active replication origins. We detected about one thousand evolutionary events of losses of active replication origins and gains of newborn origins since the species diverged from their last common ancestor about 80 million years ago. We show that the relocation of active replication origins is independent from synteny breakpoints, suggesting that chromosome rearrangements did not drive the evolution of the replication programs. Rather, origin gains and losses are linked both in space, along chromosomes, and in time, along the same branches of the phylogenetic tree. New origins continuously arise with on average low to medium firing efficiencies and increase in efficiency and earliness as they evolutionarily age. Yet, a subset of newborn origins emerges with high firing efficiency and origin losses occur concomitantly to their emergence and preferentially in their direct chromosomal vicinity. These key findings on the evolutionary birth, death and conservation of active replication origins provide the first description of how the temporal program of genome replication has evolved in eukaryotes.
Effects of Force Fields on the Conformational and Dynamic Properties of Amyloid β(1-40) Dimer Explored by Replica Exchange Molecular Dynamics Simulations
Authors: Watts Charles R. , Gregory Andrew , Frisbie Cole , Lovas Sándor 
Published: October 2017

AbstractAlzheimer’s disease is histologically marked by fibrils of Amyloid beta (Aβ) peptide within the extracellular matrix. Fibrils themselves are benign compared to the cytotoxicity of the oligomers and pre-fibrillary aggregates. The conformational space and structural ensembles of Aβ peptides and their oligomers in solution are inherently disordered and proven to be challenging to study. Optimum force field selection for molecular dynamics (MD) simulations and the biophysical relevance of results are still unknown. We compared the conformational space of the Aβ(1–40) dimers by 300 ns replica exchange MD simulations at physiological temperature (310 K) using: the AMBER-ff99sb-ILDN, AMBER-ff99sb*-ILDN, AMBER-ff99sb-NMR, and CHARMM22* force fields. Statistical comparisons of simulation results to experimental data and previously published simulations utilizing the CHARMM22* and CHARMM36 force fields were performed. All force fields yield sampled ensembles of conformations with collision cross sectional areas for the dimer that are statistically significantly larger than experimental results. All force fields, with the exception of AMBER-ff99sb-ILDN (8.8±6.4%) and CHARMM36 (2.7±4.2%), tend to overestimate the α-helical content compared to experimental CD (5.3±5.2%). Using the AMBER-ff99sb-NMR force field resulted in the greatest degree of variance (41.3±12.9%). Except for the AMBER-ff99sb-NMR force field, the others tended to under estimate the expected amount of β-sheet and over estimate the amount of turn/bend/random coil conformations. All force fields, with the exception AMBER-ff99sb-NMR, reproduce a theoretically expected β-sheet-turn-β-sheet conformational motif, however, only the CHARMM22* and CHARMM36 force fields yield results compatible with collapse of the central and C-terminal hydrophobic cores from residues 17-21 and 30-36. Although analyses of essential subspace sampling showed only minor variations between force fields, secondary structures of lowest energy conformers are different.
Gut microbiota has a widespread and modifiable effect on host gene regulation
Authors: Richards Allison L , Muehlbauer Amanda L , Alazizi Adnan , Burns Michael B , Findley Anthony , Messina Francesco , Gould Trevor J , Cascardo Camilla , Pique-Regi Roger , Blekhman Ran , Luca Francesca 
Published: October 2017

AbstractVariation in gut microbiome is associated with wellness and disease in humans, yet the molecular mechanisms by which this variation affects the host are not well understood. A likely mechanism is through changing gene regulation in interfacing host epithelial cells. Here, we treated colonic epithelial cells with live microbiota from five healthy individuals and quantified induced changes in transcriptional regulation and chromatin accessibility in host cells. We identified over 5,000 host genes that change expression, including 588 distinct associations between specific taxa and host genes. The taxa with the strongest influence on gene expression alter the response of genes associated with complex traits. Using ATAC-seq, we show that a subset of these changes in gene expression are likely the result of changes in host chromatin accessibility and transcription factor binding induced by exposure to gut microbiota. We then created a manipulated microbial community with titrated doses ofCollinsella, demonstrating that both natural and controlled microbiome composition leads to distinct, and predictable, gene expression profiles in host cells. Together, our results suggest that specific microbes play an important role in regulating expression of individual host genes involved in human complex traits. The ability to fine tune the expression of host genes by manipulating the microbiome suggests future therapeutic routes.
Summarizing Performance for Genome Scale Measurement of miRNA: Reference Samples and Metrics
Authors: Pine PS , Lund SP , Parsons JR , Vang LK , Mahabal AA , Cinquini L , Kelly SC , Kincaid H , Crichton DJ , Spira A , Liu G , Gower AC , Pass HI , Goparaju C , Dubinett SM , Krysan K , Stass SA , Kukuruga D , Van Keuren-Jensen K , Courtright-Lim A , Thompson KL , Rosenzweig BA , Sorbara L , Srivastava S , Salit ML 
Published: October 2017

ABSTRACTBackgroundThe potential utility of microRNA as biomarkers for early detection of cancer and other diseases is being investigated with genome-scale profiling of differentially expressed microRNA. Processes for measurement assurance are critical components of genome-scale measurements. Here, we evaluated the utility of a set of total RNA samples, designed with between-sample differences in the relative abundance of miRNAs, as process controls.ResultsThree pure total human RNA samples (brain, liver, and placenta) and two different mixtures of these components were evaluated as measurement assurance control samples on multiple measurement systems at multiple sites and over multiple rounds. In silico modeling of mixtures provided benchmark values for comparison with physical mixtures. Biomarker development laboratories using next-generation sequencing (NGS) or genome-scale hybridization assays participated in the study and returned data from the samples using their routine workflows. Multiplexed and single assay reverse-transcription PCR (RT-PCR) was used to confirm in silico predicted sample differences. Data visualizations and summary metrics for genome-scale miRNA profiling assessment were developed using this dataset, and a range of performance was observed. These metrics have been incorporated into an online data analysis pipeline and provide a convenient dashboard view of results from experiments following the described design. The website also serves as a repository for the accumulation of performance values providing new participants in the project an opportunity to learn what may be achievable with similar measurement processes.ConclusionsThe set of reference samples used in this study provides benchmark values suitable for assessing genome-scale miRNA profiling processes. Incorporation of these metrics into an online resource allows laboratories to periodically evaluate their performance and assess any changes introduced into their measurement process.
An evolutionary switch in the specificity of an endosomal CORVET tether underlies formation of regulated secretory vesicles in the ciliateTetrahymena thermophila
Authors: Sparvoli Daniela , Richardson Elisabeth , Osakada Hiroko , Lan Xun , Iwamoto Masaaki , Bowman Grant R. , Kontur Cassandra , Bourland William A. , Lynn Denis H. , Pritchard Jonathan K. , Haraguchi Tokuko , Dacks Joel B. , Turkewitz Aaron P. 
Published: October 2017

SummaryIn the endocytic pathway of animals, two related complexes, called CORVET (Class C Core Vacuole/Endosome Transport) and HOPS (Homotypic fusion and protein sorting), act as both tethers and fusion factors for early and late endosomes, respectively. Mutations in CORVET or HOPS lead to trafficking defects and contribute to human disease including immune dysfunction. HOPS and CORVET are conserved throughout eukaryotes but remarkably, in the ciliateTetrahymena thermophila,the HOPS-specific subunits are absent while CORVET-specific subunits have proliferated. VPS8 (Vacuolar Protein Sorting), a CORVET subunit, expanded to 6 paralogs inTetrahymena. This expansion correlated with loss of HOPS within a ciliate subgroup including the Oligohymenophorea, which containsTetrahymena. As uncovered via forward genetics, a singleVPS8paralog inTetrahymena(VPS8A) is required to synthesize prominent secretory granules called mucocysts. More specifically,∆vps8acells fail to deliver a subset of cargo proteins to developing mucocysts, instead accumulating that cargo in vesicles also bearing the mucocyst sorting receptor, Sor4p. Surprisingly, although this transport step relies on CORVET, it does not appear to involve early endosomes. Instead,Vps8aassociates with the late endosomal/lysosomal marker Rab7, indicating target specificity switching occurred in CORVET subunits during the evolution of ciliates. Mucocysts belong to a markedly diverse and understudied class of protist secretory organelles called extrusomes. Our results underscore that biogenesis of mucocysts depends on endolysosomal trafficking, revealing parallels with invasive organelles in apicomplexan parasites and suggesting that a wide array of secretory adaptations in protists, like in animals, depend on mechanisms related to lysosome biogenesis.AbbreviationsLRO(Lysosome-related organelle)HOPS(homotypic fusion and protein sorting complex)CORVET(Class C core Vacuole/Endosome Transport)VPS(vacuolar protein sorting)GRL(granule lattice)GRT(granule tip)Igr(Induced upon granule regeneration)SNARE(Soluble NSF attachment protein receptor)LECA(last eukaryotic common ancestor)
Computational Tools for the Identification and Interpretation of Sequence Motifs in Immunopeptidomes
Authors: Alvarez Bruno , Barra Carolina , Nielsen Morten , Andreatta Massimo 
Published: October 2017

AbstractRecent advances in proteomics and mass-spectrometry have widely expanded the detectable peptide repertoire presented by major histocompatibility complex (MHC) molecules on the cell surface, collectively known as the immunopeptidome. Finely characterizing the immunopeptidome brings about important basic insights into the mechanisms of antigen presentation, but can also reveal promising targets for vaccine development and cancer immunotherapy. In this report, we describe a number of practical and efficient approaches to analyze immunopeptidomics data, discussing the identification of meaningful sequence motifs in various scenarios and considering current limitations. We address the issue of filtering false hits and contaminants, and the problem of motif deconvolution in cell lines expressing multiple MHC alleles, both for the MHC class I and class II systems. Finally, we demonstrate how machine learning can be readily employed by non-expert users to generate accurate prediction models directly from mass-spectrometry eluted ligand data sets.
Prophylactic vaccination protects against the development of oxycodone self-administration
Authors: Nguyen Jacques D. , Hwang Candy S. , Grant Yanabel , Janda Kim D. , Taffe Michael A. 
Published: October 2017

AbstractAbuse of prescription opioids is a growing public health crisis in the United States, with drug overdose deaths increasing dramatically over the past 15 years. Few preclinical studies exist on the reinforcing effects of oxycodone or on the development of therapies for oxycodone abuse. This study was conducted to determine if immunopharmacotherapy directed against oxycodone would be capable of altering oxycodone-induced antinociception and intravenous self-administration. Male Wistar rats were administered a small-molecule immunoconjugate vaccine (Oxy-TT) or the control carrier protein, tetanus toxoid (TT), and trained to intravenously self-administer oxycodone (0.06 or 0.15 mg/kg/infusion). Brain oxycodone concentrations were 50% lower in Oxy-TT rats compared to TT rats 30 minutes after injection (1 mg/kg, s.c.) whereas plasma oxycodone was 15-fold higher from drug sequestration by circulating antibodies. Oxy-TT rats were also less sensitive to 1–2 mg/kg, s.c. oxycodone on a hot water nociception assay. Half of the Oxy-TT rats failed to acquire intravenous self-administration under the 0.06 mg/kg/infusion training dose. Oxycodone self-administration of Oxy-TT rats trained on 0.15 mg/kg/infusion was higher than controls; however under progressive ratio (PR) conditions the Oxy-TT rats decreased their oxycodone intake, unlike TT controls. These data demonstrate that active vaccination provides protection against the reinforcing effects of oxycodone. Anti-oxycodone vaccines may entirely prevent repeated use in some individuals who otherwise would become addicted. Vaccination may also reduce dependence in those who become addicted and therefore facilitate the effects of other therapeutic interventions which either increase the difficulty of drug use or incentivize other behaviors.
Effects of mRNA degradation and site-specific transcriptional pausing on protein expression noise
Authors: Kim Sangjin , Jacobs-Wagner Christine 
Published: October 2017

AbstractGenetically identical cells exhibit diverse phenotypes, even when experiencing the same environment. This phenomenon, in part, originates from cell-to-cell variability (noise) in protein expression. While various kinetic schemes of stochastic transcription initiation are known to affect gene expression noise, how post-transcription initiation events contribute to noise at the protein level remains incompletely understood. To address this question, we developed a stochastic simulation-based model of bacterial gene expression that integrates well-known dependencies between transcription initiation, transcription elongation dynamics, mRNA degradation and translation. We identified realistic conditions under which mRNA lifetime and transcriptional pauses modulate the protein expression noise initially introduced by the promoter architecture. For instance, we found that the short lifetime of bacterial mRNAs facilitates the production of protein bursts. Conversely, RNA polymerase (RNAP) pausing at specific sites during transcription elongation can attenuate protein bursts by fluidizing the RNAP traffic to the point of erasing the effect of a bursty promoter. Pause-prone sites, if located close to the promoter, can also affect noise indirectly by reducing both transcription and translation initiation due to RNAP and ribosome congestion. Our findings highlight how the interplay between transcription initiation, transcription elongation, translation and mRNA degradation shapes the distribution in protein numbers. They also have implications for our understanding of gene evolution and suggest combinatorial strategies for modulating phenotypic variability by genetic engineering.
RACIPE: A computational tool for Modeling Gene Regulatory Circuits using Randomization
Authors: Huang Bin , Jia Dongya , Feng Jingchen , Levine Herbert , Onuchic José N. , Lu Mingyang 
Published: October 2017

AbstractMotivationOne of the major challenges in traditional mathematical modeling of gene regulatory circuits is the insufficient knowledge of kinetic parameters. These parameters are often inferred from existing experimental data and/or educated guesses, which can be time-consuming and error-prone, especially for large networks.ResultsWe present a computational tool based on our newly developed method named random circuit perturbation (RACIPE), to explore the robust dynamical features of gene regulatory circuits without the requirement of detailed kinetic parameters. RACIPE generates an ensemble of circuit models with distinct random parameters and uniquely identifies robust dynamical properties by statistical analysis. Here, we discuss software implementation and illustrate the usage of RACIPE on coupled toggle-switch circuits and a published circuit of B-lymphopoiesis. We expect RACIPE to contribute to a more comprehensive and unbiased understanding of gene regulatory mechanisms.AvailabilityRACIPE is a free open source software distributed under (Apache 2.0) license and can be downloaded from GitHub (https://github.com/simonhb1990/RACIPE-1.0).ContactMingyang.Lu@jax.org, Herbert.Levine@rice.edu or jonuchic@rice.edu