bluuebunny/crossref_metadata_2025_split huggingface dataset:
Placental-expanded, mesenchymal cells improve muscle function following hip arthroplasty
Authors: Winkler Tobias , Perka Carsten , Roth Philipp von , Agres Alison N. , Plage Henning , Preininger Bernd , Pumberger Matthias , Geissler Sven , Hagai Esther Lukasiewicz , Ofir Racheli , Pinzur Lena , Eyal Eli , Stoltenburg-Didinger Gisela , Meisel Christian , Consentius Christine , Streitz Mathias , Reinke Petra , Duda Georg N. , Volk Hans-Dieter 
Published: April 2018

AbstractBackgroundNo regenerative approach has thus far been shown to be effective in skeletal muscle injuries, despite high frequency and associated functional deficits. We sought to address surgical trauma related muscle injuries using local intraoperative application of allogeneic placenta-derived, mesenchymal-like adherent cells (PLX-PAD), using hip arthroplasty as a standardized injury model, because of the high regenerative and immunomodulatory potency of this cell type.MethodsOur pilot phase I/IIa study was prospective, randomized, double blind and placebo-controlled. Twenty patients undergoing hip arthroplasty via a direct lateral approach were injected with 3.0×108or 1.5×108PLX-PAD or a placebo into the gluteus medius muscle.ResultsWe did not observe any relevant PLX-PAD-related adverse events at the 2-year follow-up. Improved gluteus medius strength was noted as early as week 6 in the treatment-groups. Surprisingly, until week 26 the low-dose outperformed the high-dose group and reached significantly improved strength compared to placebo, mirrored by an increase in muscle volume. Histology indicated accelerated healing after cell therapy. Biomarker studies revealed that low-dose treatment reduced the surgery-related immunological stress reaction more than high-dose. Signs of late-onset immune reactivity after high-dose treatment corresponded to reduced functional improvement.ConclusionAllogeneic PLX-PAD therapy improved strength and volume of injured skeletal muscle with a reasonable safety profile. Outcomes could be positively correlated with the modulation of early postoperative stress-related immunological reactions.Trial RegistrationClinicalTrials.gov(numberNCT01525667) and EudraCT (number 2011-003934-16)FundingThe study was funded by the Sponsor, Pluristem Therapeutics, the Israeli innovation authority and the German Federal Ministry of Education and Research.Conflict of interestT. Winkler, C. Perka and G.N. Duda are members of a clinical advisory board of Pluristem Ltd for future indications. T. Winkler, C. Perka, G.N. Duda, P. von Roth filed a patent together with Pluristem Ltd. E. Lukasiewicz Hagai, R. Ofir, L. Pinzur and E. Eyal are current or former employees of Pluristem Ltd. T. Winkler, P. Reinke and H.-D. Volk received in the past consulting fees from Pluristem Ltd. but not for this project.
Mendelian randomisation analysis of the effect of educational attainment and cognitive ability on smoking behaviour
Authors: Sanderson Eleanor , Smith George Davey , Bowden Jack , Munafò Marcus R. 
Published: April 2018

AbstractRecent analyses have shown educational attainment to be associated with a number of health outcomes. This association may, in part, be due to an effect of educational attainment on smoking behaviour. In this study we apply a multivariable Mendelian randomisation design to determine whether the effect of educational attainment on smoking behaviour could be due to educational attainment or general cognitive ability. We use individual data from the UK Biobank study (N = 120,050) and summary data from large GWAS studies of educational attainment, cognitive ability and smoking behaviour. Our results show that more years of education are associated with a reduced likelihood of smoking which is not due to an effect of general cognitive ability on smoking behaviour. Given the considerable physical harms associated with smoking, the effect of educational attainment on smoking is likely to contribute to the health inequalities associated with differences in educational attainment.
The effect of body mass index on smoking behaviour and nicotine metabolism: a Mendelian randomization study
Authors: Taylor Amy E. , Richmond Rebecca C. , Palviainen Teemu , Loukola Anu , Kaprio Jaakko , Relton Caroline , Smith George Davey , Munafò Marcus R. 
Published: April 2018

AbstractBackgroundGiven clear evidence that smoking lowers weight, it is possible that individuals with higher body mass index (BMI) smoke in order to lose or maintain their weight.Methods and FindingsWe undertook Mendelian randomization analyses using 97 genetic variants associated with BMI. We performed two sample Mendelian randomization analyses of the effects of BMI on smoking behaviour in UK Biobank (N=335,921) and the Tobacco and Genetics consortium genomewide association study (GWAS) (N≤74,035) respectively, and two sample Mendelian randomization analyses of the effects of BMI on cotinine levels (N≤4,548) and nicotine metabolite ratio (N≤1,518) in published GWAS, and smoking-related DNA methylation in the Avon Longitudinal Study of Parents and Children (N≤846).In inverse variance weighted Mendelian randomization analysis, there was evidence that higher BMI was causally associated with smoking initiation (OR for ever vs never smoking per one SD increase in BMI: 1.19, 95% CI: 1.11 to 1.27) and smoking heaviness (1.45 additional cigarettes smoked per day per SD increase in BMI, 95% CI: 1.03 to 1.86), but little evidence for a causal effect with smoking cessation. Results were broadly similar using pleiotropy robust methods (MR-Egger, median and weighted mode regression). These results were supported by evidence for a causal effect of BMI on DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) locus. There was no strong evidence that BMI was causally associated with cotinine, but suggestive evidence for a causal negative association with the nicotine metabolite ratio.ConclusionsThere is a causal bidirectional association between BMI and smoking, but the relationship is likely to be complex due to opposing effects on behaviour and metabolism. It may be useful to consider BMI
and smoking together when designing prevention strategies to minimise the effects of these risk factors on health outcomes.
Genomic and epidemiological monitoring of yellow fever virus transmission potential
Authors: N. R. Faria , M. U. G. Kraemer , S. C. Hill , J. Goes de Jesus , R. S. de Aguiar , F. C. M. Iani , J. Xavier , J. Quick , L. du Plessis , S. Dellicour , J. Thézé , R. D. O. Carvalho , G. Baele , C.-H. Wu , P. P. Silveira , M. B. Arruda , M. A. Pereira , G. C. Pereira , J. Lourenço , U. Obolski , L. Abade , T. I. Vasylyeva , M. Giovanetti , D. Yi , D.J. Weiss , G. R. W. Wint , F. M. Shearer , S. Funk , B. Nikolai , T. E. R. Adelino , M. A. A. Oliveira , M. V. F. Silva , L. Sacchetto , P. O. Figueiredo , I. M. Rezende , E. M. Mello , R. F. C. Said , D. A. Santos , M. L. Ferraz , M. G. Brito , L. F. Santana , M. T. Menezes , R. M. Brindeiro , A. Tanuri , F. C. P. dos Santos , M. S. Cunha , J. S. Nogueira , M. Rocco I. , A. C. da Costa , S. C. V. Komninakis , V. Azevedo , A. O. Chieppe , E. S. M. Araujo , M. C. L. Mendonça , C. C. dos Santos , C. D. dos Santos , A. M. Mares-Guia , R. M. R. Nogueira , P. C. Sequeira , R. G. Abreu , M. H. O. Garcia , R. V. Alves , A. L. Abreu , O. Okumoto , E. G. Kroon , C. F. C. de Albuquerque , K. Lewandowski , S. T. Pullan , M. Carroll , E. C. Sabino , R. P. Souza , M. A. Suchard , P. Lemey , G. S. Trindade , B. P. Drumond , A. M. B. Filippis , N. J. Loman , S. Cauchemez , L. C. J. Alcantara , O. G. Pybus 
Published: April 2018

AbstractThe yellow fever virus (YFV) epidemic that began in Dec 2016 in Brazil is the largest in decades. The recent discovery of YFV in BrazilianAedes sp.vectors highlights the urgent need to monitor the risk of re-establishment of domestic YFV transmission in the Americas. We use a suite of epidemiological, spatial and genomic approaches to characterize YFV transmission. We show that the age- and sex-distribution of human cases in Brazil is characteristic of sylvatic transmission. Analysis of YFV cases combined with genomes generated locally using a new protocol reveals an early phase of sylvatic YFV transmission restricted to Minas Gerais, followed in late 2016 by a rise in viral spillover to humans, and the southwards spatial expansion of the epidemic towards previously YFV-free areas. Our results establish a framework for monitoring YFV transmission in real-time, contributing to the global strategy of eliminating future yellow fever epidemics.
Community origins and regional differences highlight risk of plasmid-mediated fluoroquinolone resistant Enterobacteriaceae infections in children
Authors: Logan Latania K. , Medernach Rachel L. , Rispens Jared R. , Marshall Steven H. , Hujer Andrea M. , Domitrovic T. Nicholas , Rudin Susan D. , Zheng Xiaotian , Qureshi Nadia K. , Konda Sreenivas , Hayden Mary K. , Weinstein Robert A. , Bonomo Robert A. 
Published: April 2018

AbstractBackground:Fluoroquinolones (FQs) are uncommonly prescribed in children, yet pediatric multidrug-resistant (MDR)-Enterobacteriaceae (Ent) infections often reveal FQ resistance (FQR). We sought to define the molecular epidemiology of FQR and MDR-Ent in children.Methods:A case-control analysis of children with MDR-Ent infections at 3 Chicago hospitals was performed. Cases were children with third-generation-cephalosporin-resistant (3GCR) and/or carbapenem-resistant (CR)-Ent infections. PCR and DNA analysis assessed bla and plasmid-mediated FQR (PMFQR) genes. Controls were children with 3GC and carbapenem susceptible-Ent infections matched by age, source and hospital. We assessed clinical-epidemiologic predictors of PMFQR Ent infection.Results:Of 169 3GCR and/or CR Ent isolates from children (median age 4.8 years), 85 were FQR; 56 (66%) contained PMFQR genes. The predominant organism was E. coli and most common bla gene blaCTX-M-1 group. In FQR isolates, PMFQR gene mutations included aac6’1b-cr, oqxA/B, qepA, and qnrA/B/D/S in 83%, 15%, 13% and 11% of isolates, respectively. FQR E. coli was often associated with phylogroup B2, ST43/ST131. On multivariable analysis, PMFQR Ent infections occurred mostly in outpatients (OR 33.1) of non-black-white-Hispanic race (OR 6.5). Residents of Southwest Chicago were >5 times more likely to have PMFQR-Ent infections than those in the reference region, while residence in Central Chicago was associated with a 97% decreased risk. Other demographic, comorbidity, invasive-device, antibiotic use, or healthcare differences were not found.Conclusions:The strong association of infection with MDROs showing FQR with patient residence rather than with traditional risk factors suggests that the community environment is a major contributor to spread of these pathogens in children.
Tuning site-specific dynamics to drive allosteric activation in a pneumococcal zinc uptake regulator
Authors: Capdevila Daiana A. , Huerta Fidel , Edmonds Katherine A. , Le My T. , Wu Hongwei , Giedroc David P. 
Published: April 2018

AbstractMarR (multiple antibiotic resistance repressor) family proteins are bacterial repressors that regulate transcription in response to a wide range of chemical signals. Although specific features of MarR family function have been described, the role of atomic motions in MarRs remains unexplored thus limiting insights into the evolution of allostery in this ubiquitous family of repressors. Here, we provide the first experimental evidence that internal dynamics play a crucial functional role in MarR proteins. Streptococcus pneumoniae AdcR (adhesin-competence repressor) regulates ZnIIhomeostasis and ZnIIfunctions as an allosteric activator of DNA binding. ZnIIcoordination triggers a transition from independent domains to a more compact structure. We identify residues that impact allosteric activation on the basis of ZnII-induced perturbations of atomic motions over a wide range of timescales. These findings reconcile the distinct allosteric mechanisms proposed for other MarRs and highlight the importance of conformational dynamics in biological regulation.
Routine Determination of Ice Thickness for Cryo-EM Grids
Authors: Rice William J. , Cheng Anchi , Noble Alex J. , Eng Edward T. , Kim Laura Y. , Carragher Bridget , Potter Clinton S. 
Published: April 2018

AbstractRecent advances in instrumentation and automation have made cryo-EM a popular method for producing near-atomic resolution structures of a variety of proteins and complexes. Sample preparation is still a limiting factor in collecting high quality data. Thickness of the vitreous ice in which the particles are embedded is one of the many variables that need to be optimized for collection of the highest quality data. Here we present two methods, using either an energy filter or scattering outside the objective aperture, to measure ice thickness for potentially every image collected. Unlike geometrical or tomographic methods, these can be implemented directly in the single particle collection workflow without interrupting or significantly slowing down data collection. We describe the methods as implemented into the Leginon/Appion data collection workflow, along with some examples from test cases. Routine monitoring of ice thickness should prove helpful for optimizing sample preparation, data collection, and data processing.
The evolutionary traceability of proteins
Authors: Jain Arpit , von Haeseler Arndt , Ebersberger Ingo 
Published: April 2018

AbstractOrthologs document the evolution of genes and metabolic capacities encoded in extant and ancient genomes. Orthologous genes that are detected across the full diversity of contemporary life allow reconstructing the gene set of LUCA, the last universal common ancestor. These genes presumably represent the functional repertoire common to – and necessary for – all living organisms. Design of artificial life has the potential to test this. Recently, a minimal gene (MG) set for a self-replicating cell was determined experimentally, and a surprisingly high number of genes have unknown functions and are not represented in LUCA. However, as similarity between orthologs decays with time, it becomes insufficient to infer common ancestry, leaving ancient gene set reconstructions incomplete and distorted to an unknown extent. Here we introduce theevolutionary traceability, together with the softwareprotTrace, that quantifies, for each protein, the evolutionary distance beyond which the sensitivity of the ortholog search becomes limiting. We show that the LUCA set comprises only high-traceable proteins most of which have catalytic functions. We further show that proteins in the MG set lacking orthologs outside bacteria mostly have low traceability, leaving open whether their eukaryotic orthologs have just been overlooked. On the example of REC8, a protein essential for chromosome cohesion, we demonstrate how a traceability-informed adjustment of the search sensitivity identifies hitherto missed orthologs in the fast-evolving microsporidia. Taken together, the evolutionary traceability helps to differentiate between true absence and non-detection of orthologs, and thus improves our understanding about the evolutionary conservation of functional protein networks.
Phenomic selection: a low-cost and high-throughput method based on indirect predictions. Proof of concept on wheat and poplar
Authors: Rincent Renaud , Charpentier Jean-Paul , Faivre-Rampant Patricia , Paux Etienne , Gouis Jacques Le , Bastien Catherine , Segura Vincent 
Published: April 2018

ABSTRACTGenomic selection - the prediction of breeding values using DNA polymorphisms - is a disruptive method that has widely been adopted by animal and plant breeders to increase productivity. It was recently shown that other sources of molecular variations such as those resulting from transcripts or metabolites could be used to accurately predict complex traits. These endophenotypes have the advantage of capturing the expressed genotypes and consequently the complex regulatory networks that occur in the different layers between the genome and the phenotype. However, obtaining such omics data at very large scales, such as those typically experienced in breeding, remains challenging. As an alternative, we proposed using near-infrared spectroscopy (NIRS) as a high-throughput, low cost and non-destructive tool to indirectly capture endophenotypic variants and compute relationship matrices for predicting complex traits and coined this new approach “phenomic selection” (PS). We tested PS on two species of economic interest (Triticum aestivum L. and Populus nigra L.) using NIRS on various tissues (grains, leaves, wood). We showed that one could reach predictions as accurate as with molecular markers, for developmental, tolerance and productivity traits, even in environments radically different from the one in which NIRS were collected. Our work constitutes a proof of concept and provides new perspectives for the breeding community, as PS is theoretically applicable to any organism at low cost and does not require any molecular information.ARTICLE SUMMARYDespite its widely adopted interest in breeding, genomic selection - the prediction of breeding values using DNA polymorphisms - remains difficult to implement for many species because of genotyping costs. As an alternative or complement depending on the context, we propose “phenomic selection” (PS) as the use of low-cost and high-throughput phenotypic records to reconstruct similarities between genotypes and predict their performances. As a proof of concept of PS, we made use of near infrared spectroscopy applied to different tissues in poplar and wheat to predict various key traits and showed that PS could reach predictions as accurate as with molecular markers.
DNA local structure decreases mutation rates
Authors: Duan Chaorui , Huan Qing , Chen Xiaoshu , Wu Shaohuan , Carey Lucas B. , He Xionglei , Qian Wenfeng 
Published: April 2018

ABSTRACTBackgroundMutation rates vary across the genome. Whereas manytransfactors that influence mutation rates have been identified, as have specific sequence motifs at the 1-7 bp scale,ciselements remain poorly characterized. The lack of understanding why different sequences have different mutation rates hampers our ability to identify positive selection in evolution and to identify driver mutations in tumorigenesis.ResultsHere we show, using a combination of synthetic genes and sequencing of thousands of isolated yeast colonies, that intrinsic DNA curvature is the majorcisdeterminant of mutation rate. Mutation rate negatively correlates with DNA curvature within genes, and a 10% decrease in curvature results in a 70% increase in mutation rate. Consistently, both yeast cells and human tumors accumulate mutations in regions with small curvature. We further show that this effect is due to differences in the intrinsic mutation rate, likely due to differences in mutagen sensitivity, and not due to differences in the local activity of DNA repair.ConclusionsOur study establishes a framework in understanding thecisproperties of DNA sequence in modulating the local mutation rate and identifies a novel causal source of non-uniform mutation rates across the genome.
Pupil responses as indicators of value-based decision-making
Authors: Van Slooten Joanne C. , Jahfari Sara , Knapen Tomas , Theeuwes Jan 
Published: April 2018

AbstractPupil responses have been used to track cognitive processes during decision-making. Studies have shown that in these cases the pupil reflects the joint activation of many cortical and subcortical brain regions, also those traditionally implicated in value-based learning. However, how the pupil tracks value-based decisions and reinforcement learning is unknown. We combined a reinforcement learning task with a computational model to study pupil responses during value-based decisions, and decision evaluations. We found that the pupil closely tracks reinforcement learning both across trials and participants. Prior to choice, the pupil dilated as a function of trial-by-trial fluctuations in value beliefs. After feedback, early dilation scaled with value uncertainty, whereas later constriction scaled with reward prediction errors. Our computational approach systematically implicates the pupil in value-based decisions, and the subsequent processing of violated value beliefs, ttese dissociable influences provide an exciting possibility to non-invasively study ongoing reinforcement learning in the pupil.
Actin filaments regulate microtubule growth at the centrosome
Authors: Inoue Daisuke , Obino Dorian , Farina Francesca , Gaillard Jérémie , Guerin Christophe , Blanchoin Laurent , Lennon-Duménil Ana-Maria , Théry Manuel 
Published: April 2018

AbstractThe centrosome is the main microtubule-organizing centre. It also organizes a local network of actin filaments. However, the precise function of the actin network at the centrosome is not well understood. Here we show that increasing densities of actin filaments at the centrosome of lymphocytes were correlated with reduced amounts of microtubules. Furthermore, lymphocyte activation resulted in centrosomal-actin disassembly and an increase in microtubule number. To further investigate the direct crosstalk between actin and microtubules at the centrosome, we performed in vitro reconstitution assays based on (i) purified centrosomes and (ii) on the co-micropatterning of microtubule seeds and actin filaments. The two assays demonstrated that actin filaments perturb microtubule growth by steric hindrance. Finally, we showed that cell adhesion and spreading leads to lower densities of centrosomal actin thus resulting in higher microtubule growth. Hence we propose a novel mechanism by which the number of centrosomal microtubules is regulated by cell adhesion and actin-network architecture.
The relationship between transmission time and clustering methods inMycobacterium tuberculosisepidemiology
Authors: Meehan Conor J , Moris Pieter , Kohl Thomas A. , Pečerska Jūlija , Akter Suriya , Merker Matthias , Utpatel Christian , Beckert Patrick , Gehre Florian , Lempens Pauline , Stadler Tanja , Kaswa Michel K. , Kühnert Denise , Niemann Stefan , de Jong Bouke C 
Published: April 2018

AbstractBackgroundTracking recent transmission is a vital part of controlling widespread pathogens such asMycobacterium tuberculosis. Multiple methods with specific performance characteristics exist for detecting recent transmission chains, usually by clustering strains based on genotype similarities. With such a large variety of methods available, informed selection of an appropriate approach for determining transmissions within a given setting/time period is difficult.MethodsThis study combines whole genome sequence (WGS) data derived from 324 isolates collected 2005-2010 in Kinshasa, Democratic Republic of Congo (DRC), a high endemic setting, with phylodynamics to unveil the timing of transmission events posited by a variety of standard genotyping methods. Clustering data based on Spoligotyping, 24-loci MIRU-VNTR typing, WGS based SNP (Single Nucleotide Polymorphism) and core genome multi locus sequence typing (cgMLST) typing were evaluated.FindingsOur results suggest that clusters based on Spoligotyping could encompass transmission events that occurred over 70 years prior to sampling while 24-loci-MIRU-VNTR often represented two or more decades of transmission. Instead, WGS based genotyping applying low SNP or cgMLST allele thresholds allows for determination of recent transmission events in timespans of up to 10 years e.g. for a 5 SNP/allele cut-off.InterpretationWith the rapid uptake of WGS methods in surveillance and outbreak tracking, the findings obtained in this study can guide the selection of appropriate clustering methods for uncovering relevant transmission chains within a given time-period. For high resolution cluster analyses, WGS-SNP and cgMLST based analyses have similar clustering/timing characteristics even for data obtained from a high incidence setting.