bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cultivating problems for the future: Integration supports for resettled and spontaneous refugees in Ireland
Authors: Arnold Samantha , Quinn Emma , Gusciute Egle , Kinlen Louise 
Published: April 2019

Abstract
In this article, we look firstly at trends in arrivals of spontaneous refugees and resettled refugees in Ireland and the integration supports available to this group as outlined in national-level policy. We discuss the similarities between spontaneous and resettled refugee groups in Ireland and argue that integration needs in the longer term are similar; both groups of refugees require integration supports tailored to their specific needs. We discuss these needs in this article. We suggest that the current approach to provide only targeted supports to resettled refugees is somewhat paradoxical, in that one group of beneficiaries appears privileged in the provision of integration services and supports over the other group, despite similar needs. This article comes at a time when Ireland has opted-in to the European Union Recast Reception Conditions Directive, which provides asylum seekers the right to work under certain conditions. The article explores the impact of recent policy and legislative reforms on the integration prospects of spontaneous refugees in particular. It also looks to the future and discusses challenges under the current system and the increasing asylum application processing backlog.
Purging of highly deleterious mutations through severe bottlenecks in Alpine ibex
Authors: Grossen Christine , Guillaume Frederic , Keller Lukas F. , Croll Daniel 
Published: April 2019

AbstractHuman activity caused dramatic population declines in many wild species. The resulting bottlenecks have a profound impact on the genetic makeup of a species with unknown consequences for health. A key genetic factor for species survival is the evolution of deleterious mutation load, but how bottleneck strength and mutation load interact lacks empirical evidence. Here, we take advantage of the exceptionally well-characterized population bottlenecks of the once nearly extinct Alpine ibex. The species survived one of the most dramatic bottlenecks known for successfully restored species. We analyze 60 complete genomes of six ibex species and the domestic goat. We show that historic bottlenecks rather than the current conservation status predict levels of genome-wide variation. By retracing the recolonization of the Alps by Alpine ibex, we find genomic evidence of concurrent purging of highly deleterious mutations but accumulation of mildly deleterious mutations. This demonstrates how human-induced severe bottlenecks caused both relaxed selection and purging, thus reshaping the landscape of deleterious mutation load. Our findings also highlight that even populations of ~1000 individuals can accumulate mildly deleterious mutations. Hence, conservation efforts should focus on preventing population declines below such levels to ensure long-term survival of species.
Inhibition of Lipin lipid phosphatase hyperactivity rescues TorsinA neurological disease
Authors: Cascalho Ana , Foroozandeh Joyce , Hennebel Lise , Klein Christine , Rous Stef , Gonzalez Beatriz Dominguez , Pisani Antonio , Meringolo Maria , Gallego Sandra F. , Verstreken Patrik , Seibler Philip , Goodchild Rose E. 
Published: April 2019

AbstractTOR1A/TorsinA mutations cause poorly explained neurological diseases. A dominantly inherited mutation causes isolated dystonia, while biallelic mutations cause a recessive infant-onset syndrome with cases of lethality. Here we report an unexpected connection between lipid metabolism and these diseases. Lipin phosphatidic acid phosphatase activity was abnormally regulated in TorsinA dystonia patient cells, and in the brains of three different TorsinA disease model mice. Lipin activity was causative to symptoms given that loweringLipin1 in vivostrongly intervened against lethality in disease mice. Furthermore, Lipin hyperactivity caused cell deathin vitro, andLipin1deficiency suppressed neurodegenerationin vivo. In addition, it protected the striatal cholinergic interneurons that are implicated in TorsinA movement disorders, and concomitantly suppressed abnormal motor behaviors of TorsinA mice. These data establish the central role of Lipin lipid enzyme hyperactivity in TorsinA disease and show that Lipin inhibition is a therapeutic target for these incurable conditions.One Sentence SummaryLipin inhibition rescues TorsinA neurological disease
Effect of heritable symbionts on maternally-derived embryo transcripts
Authors: Mateos Mariana , Silva Nadisha O. , Ramirez Paulino , Higareda-Alvear Victor M. , Aramayo Rodolfo , Erickson James W. 
Published: April 2019

AbstractMaternally-transmitted endosymbiotic bacteria are ubiquitous in insects. Among other influential phenotypes, many heritable symbionts of arthropods are notorious for manipulating host reproduction through one of four reproductive syndromes, which are generally exerted during early developmental stages of the host: male feminization; parthenogenesis induction; male killing; and cytoplasmic incompatibility (CI). Major advances have been achieved in understanding mechanisms and identifying symbiont factors involved in reproductive manipulation, particularly male killing and cytoplasmic incompatibility. Nonetheless, whether cytoplasmically-transmitted bacteria influence the maternally-loaded components of the egg or early embryo has not been examined. In the present study, we investigated whether heritable endosymbionts that cause different reproductive phenotypes in Drosophila melanogaster influence the mRNA transcriptome of early embryos. We used mRNA-seq to evaluate differential expression in Drosophila embryos lacking endosymbionts (control) to those harbouring the male-killing Spiroplasma poulsonii strain MSRO-Br, the CI-inducing Wolbachia strain wMel, or Spiroplasma poulsonii strain Hyd1; a strain that lacks a reproductive phenotype and is naturally associated with Drosophila hydei. We found no consistent evidence of influence of symbiont on mRNA composition of early embryos, suggesting that the reproductive manipulation mechanism does not involve alteration of maternally-loaded transcripts. In addition, we capitalized on several available mRNA-seq datasets derived from Spiroplasma-infected Drosophila melanogaster embryos, to search for signals of depurination of rRNA, consistent with the activity of Ribosome Inactivating Proteins (RIPs) encoded by Spiroplasma poulsonii. We found small but statistically significant signals of depurination of Drosophila rRNA in the Spiroplasma treatments (both strains), but not in the symbiont-free control or Wolbachia treatment, consistent with the action of RIPs. The depurination signal was slightly stronger in the treatment with the male-killing strain. This result supports a recent report that RIP-induced damage contributes to male embryo death.
Cyclin B3 is dispensable for mouse spermatogenesis
Authors: Karasu Mehmet E. , Keeney Scott 
Published: April 2019

AbstractCyclins, as regulatory partners of cyclin-dependent kinases (CDKs), control the switch-like cell cycle transitions that orchestrate orderly duplication and segregation of genomes. Compared to mitosis, relatively little is known about how cyclin-CDK complexes control meiosis, the specialized cell division that generates gametes for sexual production. Mouse cyclin B3 was previously shown to have expression restricted to the beginning of meiosis, making it a candidate to regulate meiotic events. Indeed, female mice lacking cyclin B3 are sterile because oocytes arrest at the metaphase-to-anaphase transition of meiosis I. However, whether cyclin B3 functions during spermatogenesis was untested. Here, we found that males lacking cyclin B3 are fertile and show no detectable defects in spermatogenesis based on histological analysis of seminiferous tubules. Cytological analysis further showed no detectable defects in homologous chromosome synapsis or meiotic progression, and suggested that recombination is initiated and completed efficiently. Moreover, absence of cyclin B3 did not exacerbate previously described meiotic defects in mutants deficient for cyclin E2, suggesting a lack of redundancy between these cyclins. Thus, unlike in females, cyclin B3 is not essential for meiosis in males despite its prominent meiosis-specific expression.
A single K+-binding site in the crystal structure of the gastric proton pump
Authors: Yamamoto Kenta , Dubey Vikas , Irie Katsumasa , Nakanishi Hanayo , Khandelia Himanshu , Fujiyoshi Yoshinori , Abe Kazuhiro 
Published: April 2019

AbstractThe gastric proton pump (H+,K+-ATPase), a P-type ATPase responsible for gastric acidification, mediates electro-neutral exchange of H+and K+coupled with ATP hydrolysis, but with an as yet undetermined transport stoichiometry. Here we show crystal structures at a resolution of 2.5 Å of the pump in the E2-P transition state, in which the counter-transporting cation is occluded. We found a single K+bound to the cation-binding site of H+,K+-ATPase, indicating an exchange of 1H+/1K+per hydrolysis of one ATP molecule. This fulfils the energy requirement for the generation of a six pH unit gradient across the membrane. The structural basis of K+recognition is resolved, supported by molecular dynamics simulations, and this establishes how H+,K+-ATPase overcomes the energetic challenge to generate an H+gradient of more than a million-fold – the highest cation gradient known in any mammalian tissue – across the membrane.
Pro-Resolving Mediator Profiles And 5-Lipoxygenase Activity In Cerebrospinal Fluid Correlate with Disease Severity and Outcome in Adults with Tuberculous Meningitis
Authors: Colas Romain A. , Nhat Le Thanh Hoang , Thuong Nguyen Thuy Thuong , Cifuentes Esteban Alberto Gomez , Ly Lucy , Thanh Hai Hoang , Phu Nguyen Hoan , Mai Nguyen Thi Hoang , Thwaites Guy E. , Dalli Jesmond 
Published: April 2019

AbstractTuberculous meningitis (TBM) is the most lethal form of tuberculosis infection, characterized by a dysregulated immune response that frequently leads to neurological injury and death despite the best available treatment. The mechanisms driving the inflammatory response in TBM are not well understood. To gain insights into these mechanisms we used a lipid mediator profiling approach to investigate the regulation of a novel group of host protective mediators, termed specialized pro-resolving mediators (SPM), in the cerebrospinal fluid (CSF) of adults with TBM enrolled into a randomised placebo-controlled trial of adjunctive aspirin treatment. We found distinct lipid mediator profiles with increasing disease severity, changes that were linked with an upregulation of inflammatory eicosanoids in patients with severe TBM and a decrease in the production of a number of 5-lipoxygenase (ALOX5)-derived SPM. CSF pro-resolving mediator concentrations were also associated with 80-day survival. In survivors, we found a significant increase in pro-resolving mediator concentrations, including the ALOX5-derived resolvin (Rv)T2, RvT4 and 15-epi-Lipoxin (LX)B4, compared to those who died. Aspirin administration increased the ratio of pro-resolving to pro-inflammatory mediators decreasing the concentrations of the prothrombic mediator TxA2, changes that were linked with early reductions in brain infarcts and deaths. Together, these findings identify a CSF SPM signature that is associated with disease severity and 80-day mortality in TBM. Furthermore, the therapeutic manipulation of the ratio between pro-resolving mediators and pro-inflammatory/thrombogenic mediators in the CSF, by aspirin for example, offers a novel treatment strategy to reduce the morbidity and mortality caused by TBM.Authors SummaryInfections of the brain and the meninges byMycobacterium tuberculosis(M. tb) lead to severe inflammation and are associated with poor outcomes. The mechanisms leading to this disease remain poorly defined. Herein, we investigated howM. tbinfection regulates the concentrations of specialized pro-resolving mediators that are central in controlling the body’s ability to clear infections. In these investigations, we found that disease survival was linked with increased concentrations of a number of these protective molecules including resolvins and lipoxins. Treatment ofM. tb-infected patients with aspirin decreased the production of the immunosuppressive and thrombogenic mediator thromboxane A2improving the balance between protective and inflammatory molecules. Of note, these changes were linked with reduced disease severity and improved survival. Therefore, the present findings suggest a previously unappreciated role for pro-resolving mediators in TBM pathogenesis.
A symbiont phage protein aids in eukaryote immune evasion
Authors: Jahn M.T. , Arkhipova K. , Markert S.M. , Stigloher C. , Lachnit T. , Pita L. , Kupczok A. , Ribes M. , Stengel S.T. , Rosenstiel P. , Dutilh B.E. , Hentschel U. 
Published: April 2019

AbstractPhages are increasingly recognized as important members of host associated microbial communities. While recent studies have revealed vast genomic diversity in the virosphere, the new frontier is to understand how newly discovered phages may affect higher order processes, such as in the context of host-microbe interactions. Here, we aim to understand the tripartite interplay between phages, bacterial symbionts and marine sponges. In a viromics approach, we discover 491 novel viral clusters and show that sponges, as filter-feeding organisms, are distinct viral niches. By using a nested sampling design, we show that each sponge individual of the four species investigated harbours its own unique virome, regardless of the tissue investigated. We further discover a novel, symbiont phage-encoded ankyrin domain-containing protein which appears to be widely spread in phages of many host-associated contexts including human. The ankyrin protein (ANKp) modulates the eukaryotic immune response against bacteria as confirmed in macrophage infection assays. We predict that the role of ANKp in nature is to facilitate co-existence in the tripartite interplay between phages, symbionts and sponges and possibly in many other host-microbe associations.
Image processing approaches to enhance perivascular space visibility and quantification using MRI
Authors: Sepehrband Farshid , Barisano Giuseppe , Sheikh-Bahaei Nasim , Cabeen Ryan P , Choupan Jeiran , Law Meng , Toga Arthur W. 
Published: April 2019

AbstractImaging the perivascular spaces (PVS), also known as Virchow-Robin space, has significant clinical value, but there remains a need for neuroimaging techniques to improve mapping and quantification of the PVS. Current technique for PVS evaluation is a scoring system based on visual reading of visible PVS in regions of interest, and often limited to large caliber PVS. Enhancing the visibility of the PVS could support medical diagnosis and enable novel neuroscientific investigations. Increasing the MRI resolution is one approach to enhance the visibility of PVS but is limited by acquisition time and physical constraints. Alternatively, image processing approaches can be utilized to improve the contrast ratio between PVS and surrounding tissue. Here we combine T1- and T2-weighted images to enhance PVS contrast, intensifying the visibility of PVS. The Enhanced PVS Contrast (EPC) was achieved by combining T1- and T2-weighted images that were adaptively filtered to remove non-structured high-frequency spatial noise. EPC was evaluated on healthy young adults by presenting them to two expert readers and also through automated quantification. We found that EPC improves the conspicuity of the PVS and aid resolving a larger number of PVS. We also present a highly reliable automated PVS quantification approach, which was optimized using expert readings.
Reward motivation increases univariate activity but has limited effect on coding of task-relevant information across the frontoparietal cortex
Authors: Shashidhara Sneha , Erez Yaara 
Published: April 2019

AbstractSelection and integration of information based on current goals is fundamental for goal-directed behavior. Reward motivation has been shown to improve behavioral performance, yet the neural mechanisms that link motivation and control processes, and in particular its effect on context-dependent information processing, remain unclear. We used functional magnetic resonance imaging (fMRI) in 24 human volunteers (13 females) to test whether reward motivation enhances the coding of task-relevant information across the frontoparietal cortex, as would be predicted based on previous experimental evidence and theoretical accounts. In a cued target detection task, participants detected whether an object from a cued visual category was present in a subsequent display. The combination of the cue and the object visual category determined the behavioral status of the objects. To manipulate reward motivation, half of all trials offered the possibility of a monetary reward. We observed an increase with reward in overall univariate activity across the frontoparietal control network when the cue and subsequent object were presented. Multivariate pattern analysis (MVPA) showed that behavioral status information for the objects was conveyed across the network. However, in contrast to our prediction, reward did not increase the discrimination between behavioral status conditions in the stimulus epoch of a trial when object information was processed depending on a current context. In the high-level general-object visual region, the lateral occipital complex, the representation of behavioral status was driven by visual differences and was not modulated by reward. Our study provides useful evidence for the limited effects of reward motivation on task-related neural representations and highlights the necessity to unravel the diverse forms and extent of these effects.
MLKS2 is an ARM domain and F-actin-associated KASH protein that functions in stomatal complex development and meiotic chromosome segregation
Authors: Gumber Hardeep K. , McKenna Joseph F. , Tolmie Andrea F. , Jalovec Alexis M. , Kartick Andre C. , Graumann Katja , Bass Hank W. 
Published: April 2019

AbstractThe linker of nucleoskeleton and cytoskeleton (LINC) complex is an essential multi-protein structure spanning the eukaryotic nuclear envelope. The LINC complex functions to maintain nuclear architecture, positioning, and mobility, along with specialized functions in meiotic prophase and chromosome segregation. Members of the LINC complex were recently identified in maize, an important scientific and agricultural grass species. Here we characterizedMaize LINC KASH AtSINE-like2,MLKS2, which encodes a highly conserved SINE-group plant KASH protein with characteristic N-terminal armadillo repeats (ARM). Using a heterologous expression system, we showed that actively expressed GFP-MLKS2 is targeted to the nuclear periphery and colocalizes with F-actin and the endoplasmic reticulum, but not microtubules in the cell cortex. Expression of GFP-MLKS2, but not GFP-MLKS2ΔARM, resulted in nuclear anchoring. Genetic analysis of transposon-insertion mutations,mlks2-1andmlks2-2, showed that the mutant phenotypes were pleiotropic, affecting root hair nuclear morphology, stomatal complex development, multiple aspects of meiosis, and pollen viability. In male meiosis, the mutants showed defects for bouquet-stage telomere clustering, nuclear repositioning, perinuclear actin accumulation, dispersal of late prophase bivalents, and meiotic chromosome segregation. These findings support a model in which the nucleus is connected to cytoskeletal F-actin through the ARM-domain, predicted alpha solenoid structure of MLKS2. Functional conservation of MLKS2 was demonstrated through genetic rescue of the misshapen nuclear phenotype of an Arabidopsis (triple-WIP) KASH mutant. This study establishes a role for the SINE-type KASH proteins in affecting the dynamic nuclear phenomena required for normal plant growth and fertility.
Rapid characterisation of hERG channel kinetics I: using an automated high-throughput system
Authors: Lei Chon Lok , Clerx Michael , Gavaghan David J. , Polonchuk Liudmila , Mirams Gary R. , Wang Ken 
Published: April 2019

ABSTRACTPredicting how pharmaceuticals may affect heart rhythm is a crucial step in drug-development, and requires a deep understanding of a compound’s action on ion channels.In vitrohERG-channel current recordings are an important step in evaluating the pro-arrhythmic potential of small molecules, and are now routinely performed using automated high-throughput patch clamp platforms. These machines can execute traditional voltage clamp protocols aimed at specific gating processes, but the array of protocols needed to fully characterise a current is typically too long to be applied in a single cell. Shorter high-information protocols have recently been introduced which have this capability, but they are not typically compatible with high-throughput platforms. We present a new high-information 15 s protocol to characterise hERG (Kv11.1) kinetics, suitable for both manual and high-throughput systems. We demonstrate its use on the Nanion SyncroPatch 384PE, a 384 well automated patch clamp platform, by applying it to CHO cells stably expressing hERG1a. From these recordings we construct 124 cell-specific variants/parameterisations of a hERG model at 25 °C. A further 8 independent protocols are run in each cell, and are used to validate the model predictions. We then combine the experimental recordings using a hierarchical Bayesian model, which we use to quantify the uncertainty in the model parameters, and their variability from cell to cell, which we use to suggest reasons for the variability. This study demonstrates a robust method to measure and quantify uncertainty, and shows that it is possible and practical to use high-throughput systems to capture full hERG channel kinetics quantitatively and rapidly.Statement of SignificanceWe present a method for high-throughput characterisation of hERG potassium channel kinetics, via fitting a mathematical model to results of over one hundred single cell patch clamp measurements collected simultaneously on an automated voltage clamp platform. The automated patch clamp data are used to parameterise a mathematical ion channel model fully, opening a new era of automated and rapid development of mathematical models from quick and cheap experiments. The method also allows ample data for independent validation of the models and enables us to study experimental variability and propose its origins. In future the method can be applied to characterise changes to hERG currents in different conditions, for instance at different temperatures (see Part II of the study) or under mutations or the action of pharmaceuticals; and should be easily adapted to study many other currents.