bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biomarkers for aging identified in cross-sectional studies tend to be non-causative
Authors: Nelson Paul G. , Promislow Daniel E. L. , Masel Joanna 
Published: May 2019

AbstractBiomarkers are important tools for diagnosis, prognosis, and identification of the causal factors of physiological conditions. Biomarkers are typically identified by correlating biological measurements with the status of a condition in a sample of subjects. Cross-sectional studies sample subjects at a single timepoint, while longitudinal studies follow a cohort through time. Identifying biomarkers of aging is subject to unique challenges. Individuals who age faster have intrinsically higher mortality rates and so are preferentially lost over time, in a phenomenon known as cohort selection. In this paper, we use simulations to show that cohort selection biases cross-sectional analysis away from identifying causal loci of aging, to the point where cross-sectional studies are less likely to identify loci that cause aging than if loci had been chosen at random. We go on to show this bias can be corrected by incorporating correlates of mortality identified from longitudinal studies, allowing cross sectional studies to effectively identify the causal factors of aging.
Pharmacodynamics of linezolid-plus-fosfomycin against vancomycin-susceptible and -resistant enterococci in vitro and in vivo of a Galleria mellonella larval infection model
Authors: Qi Caifen , Xu Shuangli , Wu Maomao , Zhu Shuo , Liu Yanyan , Huang Hong , Zhang Guijun , Li Jiabin , Huang Xiaohui 
Published: May 2019

AbstractObjectiveTo explore the in vitro and in vivo antibacterial activity of linezolid/fosfomycin combination against vancomycin-susceptible and -resistant enterococci (VSE and VRE), providing theoretical basis for the treatment of VRE.MethodsThe checkerboard method and time-kill curve study were used to evaluate the synergistic effect of linezolid combined with fosfomycin against VSE and VRE. The transmission electron microscopy (TEM) was employed to observe the bacterial cell morphology followed by each drug alone and in combination, elucidating the possible result of antibiotic combination therapy. The Galleria mellonella infection model was constructed to demonstrate the in vivo efficacy of linezolid plus fosfomycin for VSE and VRE infection.ResultsThe fractional inhibitory concentration index (FICI) values of all strains suggested that linezolid showed synergy or additivity in combination with fosfomycin against five of the six strains. Time-kill experiments demonstrated that the combination of linezolid-fosfomycin at 1×MIC or 2×MIC led to higher degree of bacterial killing without regrowth for all isolates tested than each monotherapy. TEM imaging showed that the combination treatment damaged the bacterial cell morphology more obviously than each drug alone. In the Galleria mellonella infection model, the enhanced survival rate of the combination treatment was revealed compared to linezolid monotherapy (P<0.05).ConclusionsOur data manifest that the combination of linezolid and fosfomycin may be a possible therapeutic regimen for VRE infection. The combination displays excellent bacterial killing and inhibits amplification of fosfomycin-resistant subpopulations.
Intraspecific diversity of fission yeast mitochondrial genomes
Authors: Tao Yu-Tian , Suo Fang , Tusso Sergio , Wang Yan-Kai , Huang Song , Wolf Jochen B. W. , Du Li-Lin 
Published: May 2019

ABSTRACTThe fission yeastSchizosaccharomyces pombeis an important model organism, but its natural diversity and evolutionary history remain under-studied. In particular, the population genomics of theS. pombemitochondrial genome (mitogenome) has not been thoroughly investigated. Here, we assembled the complete circular-mapping mitogenomes of 192S. pombeisolatesde novo, and found that these mitogenomes belong to 69 non-identical sequence types ranging from 17618 bp to 26910 bp in length. Using the assembled mitogenomes, we identified 20 errors in the reference mitogenome and discovered two previously unknown mitochondrial introns. Analysing sequence diversity of these 69 types of mitogenomes revealed two highly distinct clades, with only three mitogenomes exhibiting signs of inter-clade recombination. This diversity pattern suggests that currently availableS. pombeisolates descend from two long-separated ancestral lineages. This conclusion is corroborated by the diversity pattern of the recombination-repressedK-region located between donor mating-type locimat2andmat3in the nuclear genome. We estimated that the two ancestralS. pombelineages diverged about 31 million generations ago. These findings shed new light on the evolution ofS. pombeand the datasets generated in this study will facilitate future research on genome evolution.
Gene editing preserves visual function in a mouse model of retinal degeneration
Authors: Vagni Paola , Perlini Laura E. , Chenais Naïg A. L. , Marchetti Tommaso , Parrini Martina , Contestabile Andrea , Cancedda Laura , Ghezzi Diego 
Published: May 2019

AbstractInherited retinal dystrophies are a large and heterogeneous group of degenerative diseases caused by mutations in various genes. Given the favourable anatomical and immunological characteristics of the eye, gene therapy holds great potential for their treatment. We used a tailored CRISPR/Cas9-based gene editing system to prevent retinal photoreceptor death in the Rd10 mouse model of retinitis pigmentosa. We tested the gene editing toolin vitroand then usedin vivosubretinal electroporation to deliver it to one of the retinas of mouse pups at different stages of photoreceptor differentiation. Three months after gene editing, the treated eye exhibited a higher visual acuity compared to the untreated eye. Moreover, we observed preservation of light-evoked responses both in explanted retinas and in the visual cortex of treated animals. Our study validates a CRISPR/Cas9-based therapy as a valuable new approach for the treatment of retinitis pigmentosa caused by autosomal recessive loss-of-function point mutations.
Microbial metabolite fluxes in a model marine anoxic ecosystem
Authors: Louca Stilianos , Astor Yrene M. , Doebeli Michael , Taylor Gordon T. , Scranton Mary I. 
Published: May 2019

AbstractPermanently anoxic regions in the ocean are widespread, and exhibit unique microbial metabolic activity exerting substantial influence on global elemental cycles and climate. Reconstructing microbial metabolic activity rates in these regions has been challenging, due to the technical difficulty of direct rate measurements. In Cariaco Basin, which is the largest permanently anoxic marine basin and an important model system for geobiology, long-term monitoring has yielded time series for the concentrations of biologically important compounds; however the underlying metabolite fluxes remain poorly quantified. Here we present a computational approach for reconstructing vertical fluxes and in situ net production/consumption rates from chemical concentration data, based on a 1-dimensional time-dependent diffusive transport model that includes adaptive penalization of overfitting. We use this approach to estimate spatiotemporally resolved fluxes of oxygen, nitrate, hydrogen sulfide, ammonium, methane and phosphate within the sub-euphotic Cariaco Basin water column (depths 150–900 m, years 2001–2014), and to identify hotspots of microbial chemolithotrophic activity. Predictions of the fitted models are in excellent agreement with the data, and substantially expand our knowledge of the geobiology in Cariaco Basin. In particular, we find that the diffusivity, and consequently fluxes of major reductants such as hydrogen sulfide and methane, are about two orders of magnitude greater than previously estimated, thus resolving a long standing apparent conundrum between electron donor fluxes and measured dark carbon assimilation rates.
Computational and experimental analysis of the glycophosphatidylinositol-anchored proteome of the human parasitic nematodeBrugia malayi
Authors: Mersha Fana B. , Cortes Leslie K. , Luck Ashley N. , McClung Colleen M. , Ruse Cristian I. , Taron Christopher H. , Foster Jeremy M. 
Published: May 2019

AbstractFurther characterization of essential systems in the parasitic filarial nematodeBrugia malayiis needed to better understand its biology, its interaction with its hosts, and to identify critical components that can be exploited to develop novel treatments. The production of glycophosphatidylinositol-anchored proteins (GPI-APs) is essential in humans, yeast, and the nematodeCaenorhabditis elegans. In addition, GPI-APs perform many important roles for cells. In this study, we characterized theB. malayiGPI-anchored proteome using both computational and experimental approaches. We used bioinformatic strategies to show the presence or absence ofB. malayiGPI-AP biosynthetic pathway genes and to compile a putativeB. malayiGPI-AP proteome using available prediction programs. We verified thesein silicoanalyses using proteomics to identify GPI-AP candidates prepared from the surface of intact worms and from membrane enriched extracts. Our study represents the first description of the GPI-anchored proteome inB. malayiand lays the groundwork for further exploration of this essential protein modification as a target for novel anthelmintic therapeutic strategies.
MHC genotyping from rhesus macaque exome sequences
Authors: Caskey John R. , Wiseman Roger W. , Karl Julie A. , Baker David A. , Lee Taylor , Raveendran Muthuswamy , Harris R. Alan , Hu Jianhong , Muzny Donna M. , Rogers Jeffrey , O’Connor David H. 
Published: May 2019

AbstractIndian rhesus macaque major histocompatibility complex (MHC) variation can influence the outcomes of transplantation and infectious disease studies. Frequently, rhesus macaques are MHC genotyped to identify variants that could account for unexpected results. Since the MHC is only one region in the genome where variation could impact experimental outcomes, strategies for simultaneously profiling variation in the macaque MHC and the remainder of the protein coding genome would be useful. Here we introduce macaque exome sequence (MES) genotyping, in which MHC class I and class II genotypes are determined with high confidence using target-enrichment probes that are enriched for MHC sequences. For a cohort of 27 Indian rhesus macaques, we describe two methods for obtaining MHC genotypes from MES data and demonstrate that the MHC class I and class II genotyping results obtained with these methods are 98.1% and 98.7% concordant, respectively, with expected MHC genotypes. In contrast, conventional MHC genotyping results obtained by deep sequencing of short multiplex PCR amplicons were only 92.6% concordant with expectations for this cohort.
The transcriptional correlates of divergent electric organ discharges inParamormyropselectric fish
Authors: Losilla Mauricio , Gallant Jason R. 
Published: May 2019

AbstractBackgroundUnderstanding the genomic basis of phenotypic diversity can be greatly facilitated by examining adaptive radiations with hypervariable traits. In this study, we focus on a rapidly diverged species group of mormyrid electric fish in the genusParamormyrops, which are characterized by extensive phenotypic variation in electric organ discharges (EODs). The main components of EOD diversity are waveform duration, complexity and polarity. Using an RNA-sequencing based approach, we sought to identify gene expression correlates for each of these EOD waveform features by comparing 11 specimens ofParamormyropsthat exhibit variation in these features.ResultsPatterns of gene expression amongParamormyropsare highly correlated, and 3,274 genes (16%) were differentially expressed. Using our most restrictive criteria, we detected 71-144 differentially expressed genes correlated with each EOD feature, with little overlap between them. The predicted functions of several of these genes are related to extracellular matrix, cation homeostasis, lipid metabolism, and cytoskeletal and sarcomeric proteins. These genes are of significant interest given the known morphological differences between electric organs that underlie differences in the EOD waveform features studied.ConclusionsIn this study, we identified plausible candidate genes that may contribute to phenotypic differences in EOD waveforms among a rapidly diverged group of mormyrid electric fish. These genes may be important targets of selection in the evolution of species-specific differences in mate-recognition signals.
Intercellular Conduction Optimizes Arterial Network Function and Conserves Blood Flow Homeostasis during Cerebrovascular Challenges
Authors: Zechariah Anil , T. Tran Cam Ha , Hald Bjorn O. , Sandow Shaun L. , Sancho Maria , Fabris Sergio , Tuor Ursula I. , Gordon Grant R.J. , Welsh Donald G. 
Published: May 2019

AbstractCerebral arterial networks match blood flow delivery with neural activity. Neurovascular response begins with a stimulus and a focal change in vessel diameter, which by themselves is inconsequential to blood flow magnitude, until they spread and alter the contractile status of neighboring arterial segments. We sought to define the mechanisms underlying integrated vascular behavior and considered the role of intercellular electrical signalling in this phenomenon. Electron microscopic and histochemical analysis revealed the structural coupling of cerebrovascular cells and the expression of gap junctional subunits at the cell interfaces, enabling intercellular signaling among vascular cells. Indeed, robust vasomotor conduction was detected in human and mice cerebral arteries after focal vessel stimulation; a response attributed to endothelial gap junctional communication, as its genetic alteration attenuated this behavior. Conducted responses was observed to ascend from the penetrating arterioles, influencing the contractile status of cortical surface vessels, in a simulated model of cerebral arterial network. Ascending responses recognisedin vivoafter whisker stimulation, were significantly attenuated in mice with altered endothelial gap junctional signalling confirming that gap junctional communication drives integrated vessel responses. The diminishment in vascular communication also impaired the critical ability of the cerebral vasculature to maintain blood flow homeostasis and hence tissue viability, after stroke. Our findings establish the integral role of intercellular electrical signalling in transcribing focal stimuli into coordinated changes in cerebrovascular contractile activity and expose, a hitherto unknown mechanism for flow regulation after stroke.SignificanceNeurovascular responses are viewed as a one step process whereby stimuli derived from neural cells focally diffuse to a neighboring vessel, altering its contractile state. While focal changes in tone can subtly tune flow distribution, they can’t substantively change “perfusion magnitude” as vascular resistance is broadly distributed along the cerebral arterial tree. We report that nature overcomes this biophysical constraint by conducting electrical signals among coupled vascular cells, along vessels, and across branch points. Our quantitative exploration of intercellular conduction illustrates how network coordination optimizes blood flow delivery in support of brain function. Diminishing the ability of vascular cells to electrically communicate, mitigates the brain’s ability to regulate perfusion during functional hyperemia and after stroke, the latter advancing tissue injury.
Novel application method for mesenchymal stem cell therapy utilizing its attractant–responsive accumulation property
Authors: Ueda Nobuyuki , Atsuta Ikiru , Ayukawa Yasunori , Yamaza Takayoshi , Furuhashi Akihiro , Narimatsu Ikue , Matsuura Yuri , Kondo Ryosuke , Watanabe Yu , Zhang Xiaoxu , Koyano Kiyoshi 
Published: May 2019

AbstractObjectivesIt remains difficult to control the delivery of appropriate amounts of mesenchymal stem cell (MSC)-based cell therapies. To examine the ability of MSCs to accumulate at sites of damage and potential therapeutic benefit of providing continuous migration of MSCs to these sites, we observed the effect of MSCs administered in a collagen gel scaffold on healing of a tooth extraction site.Materials and MethodsMSCs isolated from the bone marrow of green fluorescent protein (GFP)-expressing donor mice were expanded for 3 weeks in three-dimensional (3-D) culture using a collagen gel scaffold, and evaluated to confirm the efficacy of the scaffold. Next, MSCs suspended in collagen gel were subcutaneously administered into the backs of mice. Two days later, extraction of the maxillary first molar was carried out. Numbers of MSCs in scaffolds, migration and accumulation around the extracted tooth cavity, extraction site healing, and presence of MSCs in vital organs were evaluated.ResultsMSCs cultured in the collagen gel scaffold maintained stemness for 2 weeks. After subcutaneous administration, numbers of MSCs in scaffolds slightly decreased over time, but cells survived for at least 2 weeks. After tooth extraction, GFP-expressing MSCs were confirmed in the surrounding mucosa of the extracted tooth cavity; in the scaffold group, numbers of MSCs increased over time and fewer were observed in lung tissue. Wound healing was enhanced by injection of MSCs via the tail vein or into the back compared with the untreated control group.ConclusionsDelivery in a collagen gel could maintain the characteristics of MSCs, which migrated to the damaged area and promoted wound healing without side effects occurring with conventional administration methods.
Changes of TLQP-21 in Response to Glucose Load
Authors: Corda Giulia , Noli Barbara , Manconi Barbara , Brancia Carla , Pellegrini Manuela , Naro Fabio , Ferri Gian-Luca , Cocco Cristina 
Published: May 2019

AbstractThe TLQP-21 peptide peripherally potentiates glucose-stimulated insulin secretion. The aim of this study was to investigate a possible endocrine mechanism through which TLQP-21 increases the insulin secretion. Using an antibody specific for the common N-terminal portion of the TLQP peptides, we studied pancreas and plasma of mice subjected to intraperitoneal glucose load, by immunohistochemistry and immunosorbent assay (ELISA), alone or coupled to High Performance Liquid Chromatography (HLPC). Mice underwent a period of starvation hence have received a glucose load, or saline, and were sacrificed 30 or 120 minutes later. In normal endocrine pancreas, the TLQP-antiserum stained either peripheral or central cells. Interestingly, 30 min after a glucose load, TLQP immunostaining was disappeared in pancreas and, when analysed by ELISA, the TLQP-levels started to increase in plasma reaching peak concentration at 120 min. (controls vs. 30 and 120 min.: p<0.05 and p<0.001, respectively). The analysis of plasma and pancreas extracts using HLPC coupled to ELISA demonstrated the presence of the TLQP-21, with statistically significant increase of this peptide in plasma at 120 min (vs. controls p<0.05) in agreement to the changes seen by measuring the totality of the TLQP peptides. In pancreas sections we found the presence of the C3a-R1, involved in insulin secretion, and previously identified as a TLQP-21 receptor. Hence, after a glucose load, TLQP-21, may be released by the pancreas into the plasma, returning to the pancreas in order to modulate the insulin secretion through the C3a-R1.
Mating strategy is determinant of Adenovirus prevalence in European bats
Authors: Rossetto Federica , Iglesias-Caballero Maria , Liedtke H. Christoph , Gomez-Mestre Ivan , Berciano Jose M. , Pérez-Suárez Gonzalo , de Paz Oscar , Echevarría Juan E. , Casas Inmaculada , Juste Javier 
Published: May 2019

AbstractAdenoviruses are double-strained DNA viruses found in a great number of vertebrates, including humans. In order to understand their transmission dynamics, it is crucial, even from a human health perspective, to investigate how host traits influence their prevalence. Bats are important reservoirs for Adenoviruses, and here we use the results of recent screenings in Western Europe to evaluate the association between characteristic traits of bat species and their probability of hosting Adenoviruses, taking into account their phylogenetic relationships. Across species, we found an important phylogenetic component in the presence of Adenoviruses and mating strategy as the most determinant factor conditioning the prevalence of Adenoviruses across bat species. Contrary to other more stable mating strategies (e.g. harems), swarming could hinder transmission of Adenoviruses since this strategy implies that contacts between individuals are too short. Alternatively, bat species with more promiscuous behavior may develop a stronger immune system. Outstandingly high prevalence of Adenoviruses was reported for the Iberian species Pipistrellus pygmaeus, P. kuhlii and Nyctalus lasiopterus and we found that in the latter, males were more likely to be infected by Adenoviruses than females, due to the immunosuppressing consequence of testosterone during the mating season. As a general trend across species, we found that the number of Adenoviruses positive individuals was different across localities and that the difference in prevalence between populations was correlated with their geographic distances (P. pygmaeus). These results increase our knowledge about the transmission mechanisms of Adenoviruses.Author SummaryAdenoviruses are DNA viruses with a wide range of vertebrate hosts, including humans, causing ocular, respiratory and gastrointestinal diseases. Here, we focus on the prevalence of Adenoviruses in bats, which are known to be natural reservoir of many viruses, using the results of recent screenings for prevalence of these viruses in 33 European bat species. Our aim is to find association between Adenoviruses prevalence and biological and behavioral host traits, considering the heterogeneity both between and within species in order to have a deeper understanding of mechanisms of viral transmission.Our results highlight the importance of mating strategy: bats species using swarming as mating strategy are less likely to be infected by Adenoviruses. Moreover, we found that locality of capture can explain a higher prevalence of Adenovirus within species. However, no general pattern has been found in the analysis at individual level, suggesting a strong species specificity and complex viral transmission dynamics.