bluuebunny/crossref_metadata_2025_split huggingface dataset:
Accelerated brain ageing and disability in multiple sclerosis
Authors: Cole JH , Raffel J , Friede T , Eshaghi A , Brownlee W , Chard D , De Stefano N , Enzinger C , Pirpamer L , Filippi M , Gasperini C , Rocca MA , Rovira A , Ruggieri S , Sastre-Garriga J , Stromillo ML , Uitdehaag BMJ , Vrenken H , Barkhof F , Nicholas R , Ciccarelli O ,   on behalf of the MAGNIMS study group
Published: March 2019

SummaryBackgroundBrain atrophy occurs in both normal ageing and in multiple sclerosis (MS), but it occurs at a faster rate in MS, where it is the major driver of disability progression. Here, we employed a neuroimaging biomarker of structural brain ageing to explore how MS influences the brain ageing process.MethodsIn a longitudinal, multi-centre sample of 3,565 MRI scans in 1,204 MS/clinically isolated syndrome (CIS) patients and 150 healthy controls (HCs) (mean follow-up time: patients 3⋅41 years, HCs 1⋅97 years) we measured ‘brain-predicted age’ using T1-weighted MRI. Brain-predicted age difference (brain-PAD) was calculated as the difference between the brain-predicted age and chronological age. Positive brain-PAD indicates a brain appears older than its chronological age. We compared brain-PAD between MS/CIS patients and HCs, and between disease subtypes. In patients, the relationship between brain-PAD and Expanded Disability Status Scale (EDSS) at study entry and over time was explored.FindingsAdjusted for age, sex, intracranial volume, cohort and scanner effects MS/CIS patients had markedly older-appearing brains than HCs (mean brain-PAD 11⋅8 years [95% CI 9⋅1—14⋅5] versus −0⋅01 [−3⋅0—3⋅0], p<0⋅0001). All MS subtypes had greater brain-PAD scores than HCs, with the oldest-appearing brains in secondary-progressive MS (mean brain-PAD 18⋅0 years [15⋅4—20⋅5], p<0⋅05). At baseline, higher brain-PAD was associated with a higher EDSS, longer time since diagnosis and a younger age at diagnosis. Brain-PAD at study entry significantly predicted time-to-EDSS progression (hazard ratio 1⋅02 [1⋅01—1⋅03], p<0⋅0001): for every 5 years of additional brain-PAD, the risk of progression increased by 14⋅2%.InterpretationMS increases brain ageing across all MS subtypes. An older-appearing brain at baseline was associated with more rapid disability progression, suggesting ‘brain-age’ could be an individualised prognostic biomarker from a single, cross-sectional assessment.FundingUK MS Society; National Institute for Health Research University College London Hospitals Biomedical Research Centre.
Evaluation of BMP-mediated patterning in a 3D mathematical model of the zebrafish blastula embryo
Authors: Li Linlin , Wang Xu , Mullins Mary C. , Umulis David M. 
Published: March 2019

AbstractBone Morphogenetic Proteins (BMPs) play an important role in dorsal-ventral (DV) patterning of the early zebrafish embryo. BMP signaling is regulated by a network of extracellular and intracellular factors that impact the range and signaling of BMP ligands. Recent advances in understanding the mechanism of pattern formation support a source-sink mechanism, however it is not clear how the source-sink mechanism shapes patterns in 3D, nor how sensitive the pattern is to biophysical rates and boundary conditions along both the anteroposterior (AP) and DV axes of the embryo. We propose a new three-dimensional growing Partial Differential Equation (PDE)-based model to simulate the BMP patterning process during the blastula stage. This model provides a starting point to elucidate how different mechanisms and components work together in 3D to create and maintain the BMP gradient in the embryo. We also show how the 3D model fits the BMP signaling gradient data at multiple time points along both axes. Furthermore, sensitivity analysis of the model suggests that the spatiotemporal patterns of Chordin and BMP ligand gene expression are dominant drivers of shape in 3D and more work is needed to quantify the spatiotemporal profiles of gene and protein expression to further refine the models.
A Long Timescale Stimulus History Effect in the Primary Visual Cortex
Authors: Kim Hyewon , Homann Jan , Tank David W. , Berry Michael J. 
Published: March 2019

AbstractResponses of neurons in the primary visual cortex (V1) are often understood as encoding the current visual stimulus. Yet, some studies indicate that temporal contingency effects exist in the responses of neurons in early sensory areas. We explored if the recent stimulus history would alter the response of V1 layer 2/3 pyramidal cells in head-fixed awake mice during presentation of sequences of complex images. The activity of individual neurons was sparse, such that either one or none of the images in the sequence typically yielded a strong response. We then substituted an image preceding this primary image in order to determine if responses to the primary image were affected. We found that the amplitude of the neuron’s response could be significantly altered by substitutions up to five images back from the primary image, even when the substituted image elicited virtually no response by itself. This stimulus history effect was heterogeneous across the population, with some cells showing facilitation and others suppression. For individual cells, the history effect was robust and reproducible across days. Our data show that responses of V1 neurons not only reflect the current stimulus but also encode, through their response amplitude, information about multiple images previously presented as far as 1000 msec in the past. This might enable V1 to retain information about the extended trajectory of past stimuli and perform complex temporal computations that are as of yet not appreciated.
Human Hepatocyte Nuclear Factor 4-α encodes isoforms with distinct transcriptional functions
Authors: Lambert Élie , Babeu Jean-Philippe , Simoneau Joël , Lévesque Dominique , Jolibois Émilie , Scott Michelle , Boudreau François , Boisvert François-Michel 
Published: March 2019

SUMMARYHNF4α is a nuclear receptor produced as 12 isoforms from two promoters by alternative splicing. In order to characterize the transcriptional capacities of all 12 HNF4α isoforms, stable lines expressing each isoform were generated. The entire transcriptome associated with each isoform was analyzed as well as their respective interacting proteome. Major differences were noted in the transcriptional function of these isoforms. The α1 and α2 isoforms were the most potent regulators of gene expression while the α3 isoform exhibited significantly reduced activity. The α4, α5 and α6 isoforms, which use an alternative first exon, were characterized for the first time, and showed a greatly reduced transcriptional potential with an inability to recognize the consensus response element of HNF4α. Several transcription factors and coregulators were identified as potential specific partners for certain HNF4α isoforms. An analysis integrating the vast amount of omics data enabled the identification of transcriptional regulatory mechanisms specific to certain HNF4α isoforms, hence demonstrating the importance of considering all isoforms given their seemingly diverse functions.
Syncrip/hnRNPQ is required for activity-induced Msp300/Nesprin-1 expression and new synapse formation
Authors: Titlow Josh , Robertson Francesca , Järvelin Aino , Ish-Horowicz David , Smith Carlas , Gratton Enrico , Davis Ilan 
Published: March 2019

AbstractMemory and learning involve activity-driven expression of proteins and cytoskeletal reorganisation at new synapses, often requiring post-transcriptional regulation a long distance from corresponding nuclei. A key factor expressed early in synapse formation is Msp300/Nesprin-1, which organises actin filaments around the new synapse. How Msp300 expression is regulated during synaptic plasticity is not yet known. Here, we show that the local translation of msp300 is promoted during activity-dependent plasticity by the conserved RNA binding protein Syncrip/hnRNP Q, which binds to msp300 transcripts and is essential for plasticity. Single molecule imaging shows that Syncrip is associated in vivo with msp300 mRNA in ribosome-rich particles. Elevated neural activity alters the dynamics of Syncrip RNP granules at the synapse, suggesting a change in particle composition or binding that facilitates translation. These results introduce Syncrip as an important early-acting activity-dependent translational regulator of a plasticity gene that is strongly associated with human ataxias.Syncrip regulates synaptic plasticity via msp300Titlow et al. find that Syncrip (hnRNPQ RNA binding protein) acts directly on msp300 to modulate activity-dependent synaptic plasticity. In vivo biophysical experiments reveal activity-dependent changes in RNP complex sizes compatible with an increase in translation at the synapse.
Optimal Individualized Combination Immunotherapy/Oncolytic Virotherapy Determined ThroughIn SilicoClinical Trials Improves Late Stage Melanoma Patient Outcomes
Authors: Cassidy Tyler , Craig Morgan 
Published: March 2019

AbstractOncolytic virothcrapics, including the modified herpes simplex virus talimogene laherparepvec (T-VEC), have shown great promise as potent instigators of anti-tumour immune effects. The OPTiM trial in particular demonstrated the superior anti-cancer effects of T-VEC as compared to more traditional immunotherapy treatment using exogenous administration of granulocyte-macrophage colony-stimulating factor (GM-CSF). Theoretically, a combined approach leveraging immunotherapies: like exogenous cytokine administration and oncolytic virotherapv would elicit an even greater immune response and improve patient outcomes, but given that their efficacy and safety must be tested in large clinical trials, combination therapeutic regimens have yet to be established. By adopting computational biology andin silicoclinical trial approaches, here we show significantly improved patient outcomes for individuals with late-stage melanoma by personalizing and optimizing combination oncolytic, virotherapv and GM-CSF therapy. Our results serve as a proof-of-concept, for interdisciplinary approaches to determining combination therapy, and suggest promising avenues of investigation towards tailored combination immunotherapy/oncolytic virotherapy.
The genomic diversification of clonally propagated grapevines
Authors: Vondras Amanda M. , Minio Andrea , Blanco-Ulate Barbara , Figueroa-Balderas Rosa , Penn Michael A. , Zhou Yongfeng , Seymour Danelle , Zhou Ye , Liang Dingren , Espinoza Lucero K. , Anderson Michael M. , Walker M. Andrew , Gaut Brandon , Cantu Dario 
Published: March 2019

AbstractVegetatively propagated clones accumulate somatic mutations. The purpose of this study was to better understand the consequences of clonal propagation and involved defining the nature of somatic mutations throughout the genome. Fifteen Zinfandel winegrape clone genomes were sequenced and compared to one another using a highly contiguous genome reference produced from one of the clones, Zinfandel 03.Though most heterozygous variants were shared, somatic mutations accumulated in individual and subsets of clones. Overall, heterozygous mutations were most frequent in intergenic space and more frequent in introns than exons. A significantly larger percentage of CpG, CHG, and CHH sites in repetitive intergenic space experienced transition mutations than genic and non-repetitive intergenic spaces, likely because of higher levels of methylation in the region and the increased likelihood of methylated cytosines to spontaneously deaminate. Of the minority of mutations that occurred in exons, larger proportions of these were putatively deleterious when they occurred in relatively few clones.These data support three major conclusions. First, repetitive intergenic space is a major driver of clone genome diversification. Second, clonal propagation is associated with the accumulation of putatively deleterious mutations. Third, the data suggest selection against deleterious variants in coding regions such that mutations are less frequent in coding than noncoding regions of the genome.
Indirect Readout of DNA Controls Filamentation and Activation of a Sequence-Specific Endonuclease
Authors: Polley Smarajit , Lyumkis Dmitry , Horton N. C. 
Published: March 2019

ABSTRACTFilament or run-on oligomer formation by enzymes is increasingly recognized as an important phenomenon with potentially unique regulatory properties and biological roles. SgrAI is an allosterically regulated type II restriction endonuclease that forms run-on oligomeric (ROO) filaments with enhanced DNA cleavage activity and altered sequence specificity. Here, we present the 3.5 Å cryo-electron microscopy structure of the ROO filament of SgrAI bound to a mimic of cleaved primary site DNA and Mg2+. Large conformational changes stabilize a second metal ion cofactor binding site within the catalytic pocket and facilitate assembling a higher-order enzyme form that is competent for rapid DNA cleavage. The structural changes illuminate the mechanistic origin of hyper-accelerated DNA cleavage activity within the filamentous SgrAI form. An analysis of the protein-DNA interface and the stacking of individual nucleotides reveals how indirect DNA readout within filamentous SgrAI enables recognition of substantially more nucleotide sequences than its low-activity form, thereby expanding DNA sequence specificity. Together, substrate DNA binding, indirect readout, and filamentation simultaneously enhance SgrAI’s catalytic activity and modulate substrate preference. This unusual enzyme mechanism may have evolved to perform the specialized functions of bacterial innate immunity in rapid defense against invading phage DNA without causing damage to the host DNA.
Stratification and prediction of drug synergy based on target functional similarity
Authors: Yang Mi , Menden Michael P. , Jaaks Patricia , Dry Jonathan , Garnett Mathew , Saez-Rodriguez Julio 
Published: March 2019

ABSTRACTTargeted mono-therapies in cancer are hampered by the ability of tumor cells to escape inhibition through rewiring or alternative pathways. Drug combination approaches can provide a means to overcome these resistance mechanisms. Effective use of combinations requires strategies to select combinations from the enormous space of combinations, and to stratify patients according to their likelihood to respond. We here introduce two complementary workflows: One prioritising experiments in high-throughput screens for drug synergy enrichment, and a consecutive workflow to predict hypothesis-driven synergy stratification. Both approaches only need data of efficacy of single drugs. They rely on the notion of target functional similarity between two target proteins. This notion reflects how similarly effective drugs are on different cancer cells as a function of cancer signaling pathways’ activities on those cells. Our synergy prediction workflow revealed that two drugs targeting either the same or functionally opposite pathways are more likely to be synergistic. This enables experimental prioritisation in high-throughput screens and supports the notion that synergy can be achieved by either redundant pathway inhibition or targeting independent compensatory mechanisms. We tested the synergy stratification workflow on seven target protein pairs (AKT/EGFR, AKT/MTOR, BCL2/MTOR, EGFR/MTOR, AKT/BCL2, AKT/ALK and AKT/PARP1, representing 29 combinations and predicted their synergies in 33 breast cancer cell lines (Pearson’s correlation r=0.27). Additionally, we experimentally validated predicted synergy of the BRAF/Insulin Receptor combination (Dabrafenib/BMS−754807) in 48 colorectal cancer cell lines (r=0.5). In conclusion, our synergy prediction workflow can support compound prioritization in large scale drug screenings, and our synergy stratification workflow can select where the efficacy of drugs already known for inducing synergy is higher.
A multi-omics digital research object for the genetics of sleep regulation
Authors: Jan Maxime , Gobet Nastassia , Diessler Shanaz , Franken Paul , Xenarios Ioannis 
Published: March 2019

AbstractMore and more researchers make use of multi-omics approaches to tackle complex cellular and organismal systems. It has become apparent that the potential for re-use and integrate data generated by different labs can enhance knowledge. However, a meaningful and efficient re-use of data generated by others is difficult to achieve without in depth understanding of how these datasets were assembled. We therefore designed and describe in detail a digital research object embedding data, documentation and analytics on mouse sleep regulation. The aim of this study was to bring together electrophysiological recordings, sleep-wake behavior, metabolomics, genetics, and gene regulatory data in a systems genetics model to investigate sleep regulation in the BXD panel of recombinant inbred lines. We here showcase both the advantages and limitations of providing such multi-modal data and analytics. The reproducibility of the results was tested by a bioinformatician not implicated in the original project and the robustness of results was assessed by re-annotating genetic and transcriptome data from the mm9 to the mm10 mouse genome assembly.
Effects of short-term resistance training and tapering on maximal strength, peak power, throwing ball velocity, and sprint performance in handball players
Authors: Hermassi Souhail , Ghaith Aloui , Schwesig René , Shephard Roy J. , Chelly Mohamed Souhaiel 
Published: March 2019

ABSTRACTThe purpose of this study was to assess the effect of short-term resistance training and two weeks of tapering on physical performances in handball players. Following a ten-week progressive resistance training program, subjects were divided between an experimental (n = 10) and a control group (n = 10). The experimental group completed a resistance training program, followed by a two-week period when the training intensity was tapered by 60%, while the control group maintained their typical pattern of training. Muscle power (force–velocity test and squat and counter-movement jump tests), sprinting ability (10m and 30m), ability to change direction (T-half test) and throwing velocity (a 3-step throw with a run, and a jump throw) were evaluated before training, at the end of training and after tapering. The experimental group showed significantly larger interaction effects for the 10-week training period (12/15, 80%), than for the following 2 weeks of tapering (10/15, 67%), with the largest gains being in 15 m sprint times (d=3.78) and maximal muscular strength in the snatch (d=3.48). Although the performance of the experimental group generally continued to increase over tapering, the mean effect size for the training period was markedly higher (d=1.92, range: 0.95-3.78) than that seen during tapering (d=1.02, range:−0.17-2.09). Nevertheless the ten weeks of progressive resistance training followed by two weeks of tapering was an effective overall tactic to increase muscle power, sprint performance and ball throwing velocity in handball players.
Genetic admixture patterns in Argentinian Patagonia
Authors: Parolin María Laura , Toscanini Ulises F , Velázquez Irina F , Llull Cintia , Berardi Gabriela L , Holley Alfredo , Tamburrini Camila , Avena Sergio , Carnese Francisco R , Lanata José L , Sánchez Carnero Noela , Arce Lucas F , Basso Néstor G , Pereira Rui , Gusmão Leonor 
Published: March 2019

AbstractAs for other Latin American populations, Argentinians are the result of the admixture amongst different continental groups, mainly from America and Europe, and to a lesser extent from Sub-Saharan Africa. However, it is known that the admixture processes did not occur homogeneously throughout the country. Therefore, considering the importance for anthropological, medical and forensic researches, this study aimed to investigate the population genetic structure of the Argentinian Patagonia, through the analysis of 46 ancestry informative markers, in 433 individuals from five different localities. Overall, in the Patagonian sample, the average individual ancestry was estimated as 35.8% Native American (95% CI: 32.2-39.4%), 62.1% European (58.5-65.7%) and 2.1% African (1.7-2.4%). Comparing the five localities studied, statistically significant differences were observed for the Native American and European contributions, but not for the African ancestry. The admixture results combined with the genealogical information revealed intra-regional variations that are consistent with the different geographic origin of the participants and their ancestors. As expected, a high European ancestry was observed for donors with four grandparents born in Europe (96.8%) or in the Central region of Argentina (85%). In contrast, the Native American ancestry increased when the four grandparents were born in the North (71%) or in the South (61.9%) regions of the country, or even in Chile (60.5%). In summary, our results showed that differences on continental ancestry contribution have different origins in each region in Patagonia, and even in each locality, highlighting the importance of knowing the origin of the participants and their ancestors for the correct interpretation and contextualization of the genetic information.
Disparate effects of antibiotic-induced microbiome change and enhanced fitness inDaphnia magna
Authors: Motiei Asa , Brindefalk Björn , Ogonowski Martin , El-Shehawy Rehab , Pastuszek Paulina , Ek Karin , Liewenborg Birgitta , Udekwu Klas , Gorokhova Elena 
Published: March 2019

AbstractIt is a common view that an organism’s microbiota has a profound influence on host fitness; however, supporting evidence is lacking in many organisms. We manipulated the gut microbiome ofDaphnia magnaby chronic exposure to different concentrations of the antibiotic Ciprofloxacin (0.01 – 1 mg L−1), and evaluated whether this affected the animals’ fitness and antioxidant capacity. In line with our expectations, antibiotic exposure altered the microbiome in a concentration-dependent manner. However, contrary to these expectations, the reduced diversity of gut bacteria was not associated with any fitness detriment. Moreover, the growth-related parameters correlated negatively with diversity indices; and, in the daphnids exposed to the lowest ciprofloxacin concentrations, the antioxidant capacity, growth, and fecundity were even higher than in control animals. These findings suggest that ciprofloxacin exerts direct stimulatory effects on growth and reproduction inDaphnia, while microbiome-mediated effects are of lesser importance. Thus, although microbiome profiling of Daphnia may be a sensitive tool to identify early effects of antibiotic exposure, disentangling direct and microbiome-mediated effects on host fitness is not straightforward.