bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age as Moderator of the Relationship Between Self-efficacy and Effort in Occupational Teams
Authors: Gärtner Laura U A , Hertel Guido 
Published: January 2020

Abstract
Demographic changes increase the age range in occupational teams, which has potential consequences for collaboration not only at the team level (age diversity) but also at the individual level regarding how much effort workers expend. By integrating a life span perspective into theories on effort expenditure in teams, we assumed that workers’ chronological age moderates the relationship between task-specific self-efficacy beliefs and effort expenditure in organizational teamwork. More specifically, we assumed that task-specific self-efficacy beliefs are more strongly related with effort for older as compared with younger team members. Hypotheses were tested in 2 online studies (N = 209 and 271 workers, respectively) using the event reconstruction method. Participants were instructed to reexperience specific work events from the last few days (Study 1: 2 teamwork events; Study 2: 1 teamwork event and 1 working-alone event) and to indicate their self-efficacy and effort expenditure in each event. Results of both studies showed the expected age moderation of the self-efficacy–effort link in team settings, whereas no such moderation was observed in working-alone settings in Study 2. Finally, Study 2 also showed a stronger age moderation effect in unfamiliar as compared with familiar tasks.
Developing the Evidence-Grading Tools and Process for the Complex Attention-Deficit/Hyperactivity Disorder Guideline
Authors: Chan Eugenia , Froehlich Tanya E. , Barbaresi William J. , Fogler Jason 
Published: January 2020

ABSTRACT:
Clinical practice guidelines (CPGs) rely on a robust assessment of the quality of evidence supporting guideline recommendations. For the Society for Developmental and Behavioral Pediatrics (SDBP) CPG for the Assessment and Treatment of Children and Adolescents with Complex Attention-Deficit Hyperactivity Disorder (ADHD), the nature of the evidence and resource constraints led the guideline panel to develop an innovative, yet rigorous, approach to evidence grading. This study will (1) describe the challenges of evidence grading for the SDBP Complex ADHD Guideline; (2) discuss the rationale, process, and tools developed to conduct evidence grading; and (3) report on the experiences and readiness of the volunteer reviewers with diverse background in research methodology to conduct evidence grading. This evidence review process may serve as an example of approaches that can be used by other groups tasked with evaluating the evidence in support of new CPGs.
Summary-data-based mendelian randomisation reveals druggable targets for multiple sclerosis
Authors: Jacobs Benjamin Meir , Taylor Thomas , Awad Amine , Baker David , Giovanonni Gavin , Noyce Alastair , Dobson Ruth 
Published: January 2020

AbstractBackgroundMultiple Sclerosis (MS) is a complex autoimmune disease caused by a combination of genetic and environmental factors. Translation of Genome-Wide Association Study (GWAS) findings in MS into therapeutics and effective preventive strategies has been limited to date.MethodsWe used Summary Data-Based Mendelian Randomisation (SMR) to synthesise findings from public expression quantitative trait locus (eQTL; eQTLgen and CAGE), methylation quantitative trait locus (mQTL; Lothian Birth Cohort and Brisbane Systems Genetics Study), and MS GWAS datasets (International Multiple Sclerosis Genetics Consortium). By correlating the effects of methylation on MS (M-2-MS), methylation on expression (M-2-E), and expression on MS susceptibility (E-2-MS), we prioritise genetic loci with strong evidence of causally influencing MS susceptibility. We overlay these findings onto a list of ‘druggable’ genes, i.e. genes which are currently, or could theoretically, be targeted by therapeutic compounds. We use GeNets and STRING to identify protein-protein interactions and druggable pathways enriched in our results. We extend these findings to a model of Epstein-Barr Virus-infected B cells, Lymphoblastoid Cell Lines (LCLs). We conducted a systematic review of prioritised genes using the Open Targets platform to identify completed and planned trials targeted prioritised genes in MS and related disease areas.ResultsExpression of 45 genes in peripheral was strongly associated with MS susceptibility (False discovery rate 0.05). Of these 45 genes, 20 encode a protein which is currently targeted by an existing therapeutic compound. These genes were enriched for Gene Ontology terms pertaining to immune system function and leukocyte signalling. We refined this prioritised gene list by restricting to loci where CpG site methylation was associated with MS susceptibility (M-2-MS), with gene expression (M-2-E), and where expression was associated with MS susceptibility (E-2-MS). This approach yielded a list of 15 prioritised druggable target genes for which there was evidence of a causal pathway linking methylation, expression, and MS. Five of these 15 genes are targeted by existing drugs (CD40, ERBB2, VEGFB, MERTK, and PARP1), and three were replicated in a smaller eQTL dataset (CD40, MERTK, and PARP1). In LCLs, SMR prioritised 7 druggable gene targets, of which only one was priortised by the multi-omic approach in peripheral blood (FCRL3). Systematic review of Open Targets revealed multiple early-phase trials targeting 13/20 prioritised genes in disorders related to MS.ConclusionsWe use public datasets and SMR to identify a list of prioritised druggable genetic targets in Multiple Sclerosis. We hope our findings could be translated into effective repurposing of existing drugs to provide novel therapies for MS and, potentially, provide a platform for developing preventive therapies.
Single-color Fluorescence Lifetime Cross-Correlation Spectroscopyin vivo
Authors: Štefl M. , Herbst K. , Rübsam M. , Benda A. , Knop M. 
Published: January 2020

ABSTRACTThe ability to quantify protein concentrations and to measure protein interactionsin vivois key information needed for the understanding of complex processes inside cells, but the acquisition of such information from living cells is still demanding. Fluorescence based methods like two-color fluorescence cross-correlation spectroscopy can provide this information but measurement precision is hampered by various sources of errors caused by instrumental or optical limitations such as imperfect overlap of detection volumes or detector cross-talk. Furthermore, the nature and properties of used fluorescent proteins or fluorescent dyes, such as labeling efficiency, fluorescent protein maturation, photo-stability, bleaching and fluorescence brightness can have an impact.Here we take advantage of lifetime differences as a mean to discriminate fluorescent proteins with similar spectral properties and to use them for single-color fluorescence lifetime cross-correlation spectroscopy (sc-FLCCS). By using only one excitation and one detection wavelength, this setup avoids all sources of errors resulting from chromatic aberrations and detector cross-talk. To establish sc-FLCCS we first engineered and tested multiple GFP-like fluorescent proteins for their suitability. This identified a novel GFP variant termed slmGFP (short lifetime monomeric GFP) with the so-far shortest lifetime. Monte-Carlo simulations were employed to explore the suitability of different combinations of GFP variants. Two GFPs, Envy and slmGFP were predicted to constitute the best performing couple for sc-FLCCS measurements. We demonstrated application of this GFP pair for measuring protein interactions between the proteasome and interacting proteins and for measuring protein interactions between three partners when combined with a red florescent protein. Together, our findings establish sc-FLCCS as a valid alternative for conventional dual-color(dc)-FCCS measurements.STATEMENT OF SIGNIFICANCEThe quantification of protein concentrations and protein-protein interactionsin vivois a crucial information needed for the understanding of complex processes inside cells. Determination of such information is unfortunately still challenging. Fluorescence-based method like fluorescence cross-correlation spectroscopy (FCCS) is the only method which provides this informationin vivoand almost in the real time, however it suffers from limitations caused by experimental setup and biological origin of fluorescent proteins. We present single-color fluorescence lifetime cross-correlation spectroscopy as an alternative to FCCS, which uses the information of fluorescence lifetime to overcome some of these limitations. We challenged the method and determined its advantages and limitations and demonstrated the applicability of the method on the proteins of yeast proteasome.
Tumor Neoantigenicity Assessment with CSiN Score Incorporates Clonality and Immunogenicity to Predict Immunotherapy Outcomes
Authors: Lu Tianshi , Wang Shidan , Xu Lin , Zhou Qinbo , Singla Nirmish , Gao Jianjun , Manna Subrata , Pop Laurentiu , Xie Zhiqun , Chen Mingyi , Luke Jason J. , Brugarolas James , Hannan Raquibul , Wang Tao 
Published: January 2020

AbstractLack of responsiveness to checkpoint inhibitors is a central problem in the modern era of cancer immunotherapy. Tumor neoantigens are critical mediators of host immune response and immunotherapy treatment efficacy. Current studies of neoantigens almost entirely focus on total neoantigen load, which simplistically treats all neoantigens equally. Besides, neoantigen loads have been linked with treatment response and prognosis only in some studies, but not others. We developed a Cauchy-Schwarz index of Neoantigens (CSiN) score to characterize the degree of concentration of immunogenic neoantigens in truncal mutations. Unlike simple neoantigen loads, CSiN incorporates the effect of both clonality and MHC-binding affinity of neoantigens when characterizing patient neoantigen profiles. By exploiting the clinical responses in 501 treated patients (mostly by checkpoint inhibitors) and the overall survival of 1,978 baseline patients, we showed that CSiN scores predict treatment response to checkpoint inhibitors and prognosis in melanoma, lung cancer, and kidney cancer patients. CSiN substantially outperforms prior genetics-based prediction methods of responsiveness. Overall, our work fulfilled an important gap in current research involving neoantigens.One Sentence SummaryThe quality of tumor neoantigens predicts response to immunotherapy
One cell, one drop, one click: hybrid microfluidic mammalian single-cell isolation
Authors: Samlali Kenza , Ahmadi Fatemeh , Quach Angela B.V. , Soffer Guy , Shih Steve C.C. 
Published: January 2020

AbstractThe process of generating a stable knockout cell line is a complex process that can take several months to complete. In this work, we introduce a microfluidic method that is capable of isolating single cells, selecting successful edited clones, and expansion of these isoclones. Using a hybrid microfluidics method, droplets in channels can be individually addressed using a co-planar electrode system. In our hybrid microfluidic device, we show that we can trap single cells and subsequently encapsulate them on demand into pL-sized droplets. Furthermore, individual cells inside the droplet can be released from the traps or merged with other droplets by simply applying an electric potential to the electrodes that is actuated through a user interface. We use this high precision control to sort and to recover single isoclones to establish monoclonal cell lines, which is demonstrated with a heterozygous NCI-H1299 lung squamous cell population resulting from loss-of-function eGFP and RAF1 gene knock-out transfections.
Measurement Reliability for Individual Differences in Multilayer Network Dynamics: Cautions and Considerations
Authors: Yang Zhen , Telesford Qawi K. , Franco Alexandre R. , Lim Ryan , Gu Shi , Xu Ting , Ai Lei , Castellanos Francisco X. , Yan Chao-Gan , Colcombe Stan , Milham Michael P. 
Published: January 2020

AbstractMultilayer network models have been proposed as an effective means of capturing the dynamic configuration of distributed neural circuits and quantitatively describing how communities vary over time. Beyond general insights into brain function, a growing number of studies have begun to employ these methods for the study of individual differences. However, test-retest reliabilities for multilayer network measures have yet to be fully quantified or optimized, potentially limiting their utility for individual difference studies. Here, we systematically evaluated the impact of multilayer community detection algorithms, selection of network parameters, scan duration, and task condition on test-retest reliabilities of multilayer network measures (i.e., flexibility, integration, and recruitment). A key finding was that the default method used for community detection by the popular generalized Louvain algorithm can generate erroneous results. Although available, an updated algorithm addressing this issue is yet to be broadly adopted in the neuroimaging literature. Beyond the algorithm, the present work identified parameter selection as a key determinant of test-retest reliability; however, optimization of these parameters and expected reliabilities appeared to be dataset-specific. Once parameters were optimized, consistent with findings from the static functional connectivity literature, scan duration was a much stronger determinant of reliability than scan condition. When the parameters were optimized and scan duration was sufficient, both passive (i.e., resting state, Inscapes, and movie) and active (i.e., flanker) tasks were reliable, although reliability in the movie watching condition was significantly higher than in the other three tasks. The minimal data requirement for achieving reliable measures for the movie watching condition was 20 min, and 30 min for the other three tasks. Our results caution the field against the use of default parameters without optimization based on the specific datasets to be employed - a process likely to be limited for most due to the lack of test-retest samples to enable parameter optimization.HighlightsDynamic network reliability is highly dependent on many methodological decisionsThe default multilayer community detection algorithm generates erroneous resultsReliability-optimized intra-/inter-layer coupling parameters are dataset-dependentScan duration is a much stronger determinant of reliability than scan conditionMovies are the most reliable condition, requiring at least 20 min of data
Pharmacological depletion of microglia prevents vascular cognitive impairment in Ang II-induced hypertension
Authors: Kerkhofs Danielle , van Hagen Britt T. , Milanova Irina V. , Schell Kimberly J. , van Essen Helma , Wijnands Erwin , Goossens Pieter , Blankesteijn W. Matthijs , Unger Thomas , Prickaerts Jos , Biessen Erik A. , van Oostenbrugge Robert J. , Foulquier Sebastien 
Published: January 2020

AbstractRationale:Hypertension is a major risk factor for cerebral small vessel disease, the most prevalent cause of vascular cognitive impairment. As we have shown, hypertension induced by a prolonged Ang II infusion is associated with increased permeability of the blood-brain barrier (BBB) and chronic activation of microglia. In this study we therefore aim to determine the contribution of microglia to hypertension-induced cognitive impairment in an experimental hypertension model by a pharmacological depletion approach.Methods:For this study, adultCx3Cr1gfp/wtxThy1yfp/0reporter mice were infused for 12 weeks with Angiotensin II or saline and subgroups were treated with PLX5622, a highly selective CSF-1R inhibitor. Systolic blood pressure (SBP) was measured via tail-cuff. Short- and long-term spatial memory were assessed during an Object Location task and a Morris Water Maze task (MWM). At the end of the study, microglia depletion efficacy and BBB leakages were assessed using flow cytometry and immunohistochemistry.Results:SBP, heart weight and carotid pulsatility were increased by Ang II and were not affected by PLX5622. Short-term memory was significantly impaired in Ang II hypertensive mice, but not in Ang II mice treated with PLX5622. Histological and flow cytometry analyses revealed almost complete ablation of microglia upon CSF1R inhibition, while brain resident perivascular macrophages, were reduced by 60%. Number and size of BBB leakages were increased in Ang II hypertensive mice, but not altered by PLX5622 treatment.Conclusion:Our results show that depletion of microglia, and less so PVMs, by CSF1R inhibition prevents short-term memory impairment in Ang II induced hypertensive mice. This novel finding supports the critical role of brain immune cells, and most in particular microglia, in the pathogenesis of hypertension-related cognitive impairment.
Aphid feeding induces the relaxation of epigenetic control and the associated regulation of the defense response inArabidopsis
Authors: Annacondia Maria Luz , Markovic Dimitrije , Reig-Valiente Juan Luis , Scaltsoyiannes Vassilis , Pieterse Corné M.J. , Ninkovic Velemir , Slotkin R. Keith , Martinez German 
Published: January 2020

ABSTRACTEnvironmentally induced changes in the epigenome help individuals to quickly adapt to fluctuations in the conditions of their habitats. Here we explored those changes inArabidopsis thalianaplants subjected to multiple biotic and abiotic stresses, and identified transposable element (TE) activation in plants infested with the green peach aphid,Myzus persicae. We performed a genome-wide analysis of DNA methylation, mRNA expression, mRNA degradation and small RNA accumulation. Our results demonstrate that aphid feeding induces loss of methylation of hundreds of loci, mainly TEs. This loss of methylation has the potential to regulate gene expression and we found evidence that it is involved in the control of key plant immunity genes. Accordingly, we find that mutant plants deficient in epigenetic silencing show increased resistance toM.persicaeinfestation. Collectively, our results show that changes in DNA methylation play a significant role in the regulation of the plant transcriptional response and induction of defense response against aphid feeding.
A biomimetic five-module chimeric antigen receptor (5MCAR) designed to target and eliminate antigen-specific T cells
Authors: Kobayashi Shio , Thelin Martin A. , Parrish Heather L. , Deshpande Neha R. , Lee Mark S. , Karimzadeh Alborz , Niewczas Monika A. , Serwold Thomas , Kuhns Michael S. 
Published: January 2020

AbstractT cells express clonotypic T cell receptors (TCRs) that recognize peptide antigens in the context of class I or II MHC molecules (pMHCI/II). These receptor modules associate with three signaling modules (CD3γε, δε, and ζζ), and work in concert with a coreceptor module (either CD8 or CD4), to drive T cell activation in response to pMHCI/II. Here we describe a first generation biomimetic 5-module chimeric antigen receptor (5MCAR). We show that: (i) chimeric receptor modules built with the ectodomains of pMHCII assemble with CD3 signaling modules into complexes that redirect cytotoxic T lymphocyte (CTL) specificity and function in response to the clonotypic TCRs of pMHCII-specific CD4+T cells; and, (ii) surrogate coreceptor modules enhance the function of these complexes. Furthermore, we demonstrate that adoptively transferred5MCAR-CTLs can mitigate type I diabetes by targeting autoimmune CD4+T cells in NOD mice. This work provides a framework for the construction of biomimetic5MCARs that can be used as tools to study the impact of particular antigen-specific T cells in immune responses, and may hold potential for ameliorating diseases mediated by pathogenic T cells.
Involuntary orienting and conflict resolution during auditory attention: The role of ventral and dorsal streams
Authors: Stewart Hannah J , Shen Dawei , Sham Nasim , Alain Claude 
Published: January 2020

AbstractSelective attention to sound object features such as pitch and location is associated with enhanced brain activity in ventral and dorsal streams, respectively. We examined the role of these pathways in involuntary orienting and conflict resolution using functional magnetic resonance imaging (fMRI). Participants were presented with two tones that may share, or not, the same non-spatial (frequency) or spatial (location) auditory features. In separate blocks of trials, participants were asked to attend to sound frequency or sound location and ignore the change in the task-irrelevant feature. In both attend-frequency and attend-location tasks, response times were slower when the task-irrelevant feature changed than when it stayed the same (involuntary orienting). This behavioural cost coincided with enhanced activity in the prefrontal cortex and superior temporal gyrus (STG). Conflict resolution was examined by comparing situations where the change in stimulus features was congruent (both features changed) and incongruent (only one feature changed). Participants were slower and less accurate for incongruent than congruent sound features. This congruency effect was associated with enhanced activity in the prefrontal cortex, and was greater in the right STG and medial frontal cortex during the attend-location than during the attend-frequency task. Together, these findings do not support a strict division of ‘labour’ into ventral and dorsal streams, but rather suggest interactions between these pathways in situations involving changes in task-irrelevant sound feature and conflict resolution. These findings also validate the Test of Attention in Listening task by revealing distinct neural correlates for involuntary orienting and conflict resolution.
AUTS2 Governs Cerebellar Development, Purkinje Cell Maturation, Motor Function and Social Communication
Authors: Yamashiro Kunihiko , Hori Kei , Lai Esther S.K. , Aoki Ryo , Shimaoka Kazumi , Egusa Saki F. , Sakamoto Asami , Abe Manabu , Sakimura Kenji , Watanabe Takaki , Uesaka Naofumi , Kano Masanobu , Hoshino Mikio 
Published: January 2020

SummaryAutism susceptibility candidate 2(AUTS2), a risk gene for autism spectrum disorders (ASDs), is implicated in telencephalon development. Because AUTS2 is also expressed in the cerebellum where defects have been linked to ASDs, we investigated AUTS2 functions in the cerebellum. AUTS2 is specifically localized in Purkinje cells (PCs) and Golgi cells during postnatal development.Auts2conditional knockout (cKO) mice exhibited smaller and deformed cerebella containing immature-shaped PCs with reduced expression ofCacna1a.Auts2cKO and knock-down experiments implicated AUTS2 participation in elimination and translocation of climbing fiber synapses, and restriction of parallel fiber synapse numbers.Auts2cKO mice exhibited behavioral impairments in motor learning and vocal communications. BecauseCacna1ais known to regulate synapse development in PCs, it suggests that AUTS2 is required for PC maturation to elicit normal development of PC synapses and thus the impairment ofAUTS2may cause cerebellar dysfunction related to psychiatric illnesses such as ASDs.