bluuebunny/crossref_metadata_2025_split huggingface dataset:
Translating GWAS Findings Into Therapies For Depression And Anxiety Disorders: Drug Repositioning Using Gene-Set Analyses Reveals Enrichment Of Psychiatric Drug Classes
Authors: So Hon-Cheong , Lau Alexandria , Chau Carlos Kwan-Long , Wong Sze-Yung 
Published: May 2017

AbstractDepression and anxiety disorders are the first and sixth leading cause of disability worldwide according to latest reports from the World Health Organization. Despite their high prevalence and the significant disability resulted, there are limited advances in new drug development. On the other hand, the advent of genome-wide association studies (GWAS) has greatly improved our understanding of the genetic basis underlying psychiatric disorders.In this work we employed gene-set analyses of GWAS summary statistics for drug repositioning. We explored five related GWAS datasets, including two on major depressive disorder (MDD-PGC and MDD-CONVERGE, with the latter focusing on severe melancholic depression), one on anxiety disorders, and two on depressive symptoms and neuroticism in the population. We extracted gene-sets associated with each drug from DSigDB and examined their association with each GWAS phenotype. We also performed repositioning analyses on meta-analyzed GWAS data, integrating evidence from all related phenotypes.Importantly, we showed that the repositioning hits are generally enriched for known psychiatric medications or those considered in clinical trials, except for MDD-PGC. Enrichment was seen for antidepressants and anxiolytics but also for antipsychotics. We also revealed new candidates or drug classes for repositioning, some of which were supported by experimental or clinical studies. For example, the top repositioning hit using meta-analyzed p-values was fendiline, which was shown to produce antidepressant-like effects in mouse models by inhibition of acid sphingomyelinase and reducing ceramide levels. Taken together, our findings suggest that human genomic data such as GWAS are useful in guiding drug discoveries for depression and anxiety disorders.
Nucleotide-Driven Triple-State Remodeling of the AAA-ATPase Channel in the Activated Human 26S Proteasome
Authors: Zhu Yanan , Wang Wei Li , Yu Daqi , Ouyang Qi , Lu Ying , Mao Youdong 
Published: May 2017

SUMMARYThe proteasome is a sophisticated ATP-dependent molecular machine responsible for protein degradation in all eukaryotic cells. It remains elusive how conformational changes of the AAA-ATPase unfoldase in the regulatory particle (RP) control the gating of substrate-translocation channel to the proteolytic chamber of the core particle (CP). Here we report three alternative states of the ATP-γS-bound human proteasome, in which the CP gate is asymmetrically open, visualized by cryo-EM at near-atomic resolutions. Only four nucleotides are stably bound to the AAA-ATPase ring in the open-gate states. Concerted nucleotide exchange gives rise to a back-and-forth wobbling motion of the AAA-ATPase channel, coincident with remarkable transitions of their pore loops between the spiral staircase and saddle-shaped circle topologies. Gate opening in the CP is thus controlled with nucleotide-driven remodeling of the AAA-ATPase unfoldase. These findings demonstrate an elegant mechanism of allosteric coordination among sub-machines within the holoenzyme that is crucial for substrate translocation.
RGBM: Regularized Gradient Boosting Machines for the Identification of Transcriptional Regulators of Discrete Glioma Subtypes
Authors: Mall Raghvendra , Cerulo Luigi , Kunji Khalid , Bensmail Halima , Sabedot Thais S. , Noushmehr Houtan , Iavarone Antonio , Ceccarelli Michele 
Published: May 2017

AbstractThe transcription factors (TF) which regulate gene expressions are key determinants of cellular phenotypes. Reconstructing large-scale genome-wide networks which capture the influence of TFs on target genes are essential for understanding and accurate modelling of living cells. We propose RGBM: a gene regulatory network (GRN) inference algorithm, which can handle data from heterogeneous information sources including dynamic time-series, gene knockout, gene knockdown, DNA microarrays and RNA-Seq expression profiles. RGBM allows to use an a priori mechanistic of active biding network consisting of TFs and corresponding target genes. RGBM is evaluated on the DREAM challenge datasets where it surpasses the winners of the competitions and other established methods for two evaluation metrics by about 10-15%.We use RGBM to identify the main regulators of the molecular subtypes of brain tumors. Our analysis reveals the identity and corresponding biological activities of the master regulators driving transformation of the G-CIMP-high into the G-CIMP-low subtype of glioma and PA-like into LGm6-GBM, thus, providing a clue to the yet undetermined nature of the transcriptional events driving the evolution among these novel glioma subtypes.RGBM is available for download on CRAN athttps://cran.rproject.org/web/packages/RGBM/index.html
Modeling zero-inflated count data with glmmTMB
Authors: Brooks Mollie E. , Kristensen Kasper , van Benthem Koen J. , Magnusson Arni , Berg Casper W. , Nielsen Anders , Skaug Hans J. , Mächler Martin , Bolker Benjamin M. 
Published: May 2017

AbstractEcological phenomena are often measured in the form of count data. These data can be analyzed using generalized linear mixed models (GLMMs) when observations are correlated in ways that require random effects. However, count data are oftenzero-inflated, containing more zeros than would be expected from the standard error distributions used in GLMMs, e.g., parasite counts may be exactly zero for hosts with effective immune defenses but vary according to a negative binomial distribution for non-resistant hosts.We present a new R package,glmmTMB, that increases the range of models that can easily be fitted to count data using maximum likelihood estimation. The interface was developed to be familiar to users of thelme4R package, a common tool for fitting GLMMs. To maximize speed and flexibility, estimation is done using Template Model Builder (TMB), utilizing automatic differentiation to estimate model gradients and the Laplace approximation for handling random effects. We demonstrateglmmTMBand compare it to other available methods using two ecological case studies.In general,glmmTMBis more flexible than other packages available for estimating zero-inflated models via maximum likelihood estimation and is faster than packages that use Markov chain Monte Carlo sampling for estimation; it is also more flexible for zero-inflated modelling thanINLA, but speed comparisons vary with model and data structure. Our package can be used to fit GLMs and GLMMs with or without zero-inflation as well as hurdle models. By allowing ecologists to quickly estimate a wide variety of models using a single package,glmmTMBmakes it easier to find appropriate models and test hypotheses to describe ecological processes.
Distinct features of multivesicular body-lysosome fusion revealed by a new cell-free content-mixing assay
Authors: Karim Mahmoud Abdul , Samyn Dieter Ronny , Mattie Sevan , Brett Christopher Leonard 
Published: May 2017

ABSTRACTWhen marked for degradation, surface receptor and transporter proteins are internalized and delivered to endosomes where they are packaged into intralumenal vesicles (ILVs). Many rounds of ILV formation create multivesicular bodies (MVBs) that fuse with lysosomes exposing ILVs to hydrolases for catabolism. Despite being critical for protein degradation, the molecular underpinnings of MVB-lysosome fusion remain unclear, although machinery underlying other lysosome fusion events is implicated. But how then is specificity conferred? And how is MVB maturation and fusion coordinated for efficient protein degradation? To address these questions, we developed a cell-free MVB-lysosome fusion assay using S. cerevisiae as a model. After confirming that the Rab7 ortholog Ypt7 and the multisubunit tethering complex HOPS are required, we found that the Qa-SNARE Pep12 distinguishes this event from homotypic lysosome fusion. Mutations that impair MVB maturation block fusion by preventing Ypt7 activation, confirming that a Rab-cascade mechanism harmonizes MVB maturation with lysosome fusion.IMPACT STATEMENTEndocytosis culminates with multivesicular bodies (MVBs) fusing with lysosomes. But the molecular underpinnings of this event remain unclear. Here, using S. cerevisiae as a model, Karim et al. employ a new in vitro assay to show that MVB-lysosome fusion is driven by ESCRT-dependent Rab-GTPase activation and the syntaxin ortholog Pep12, distinguishing it from other lysosome membrane fusion events.
Dense Bicoid Hubs Accentuate Binding along the Morphogen Gradient
Authors: Mir Mustafa , Reimer Armando , Haines Jenna E. , Li Xiao-Yong , Stadler Michael , Garcia Hernan , Eisen Michael B. , Darzacq Xavier 
Published: May 2017

ABSTRACTMorphogen gradients direct the spatial patterning of developing embryos, however, the mechanisms by which these gradients are interpreted remain elusive. Here we performin vivosingle molecule imaging in earlyDrosophila melanogasterembryos of the transcription factor Bicoid that forms a gradient and initiates patterning along the anteroposterior axis. We observe that Bicoid binds to DNA with a rapid off-rate, such that its average occupancy at target loci is on-rate dependent, a property required for concentration-sensitive regulation. Surprisingly, we also observe abundant specific DNA binding in posterior nuclei, where Bicoid levels are vanishingly low. Live embryo imaging reveals spatiotemporal “hubs” of local high Bicoid concentration that are dependent on the ubiquitous maternal factor Zelda. We propose that localized modulation of transcription factor on-rates via clustering, provides a general mechanism to facilitate binding to low-affinity targets, and that this may be a prevalent feature directing other developmental transcription networks.
Shopping for kids’ luxury brands: young mothers’ identity quest in retail spaces
Authors: Silhouette-Dercourt Virginie , de Lassus Christel 
Published: May 2017

Purpose
The purpose of this paper is to focus on mothers as key influencers in luxury retailing contexts.

Design/methodology/approach
Using a semiotic interpretation of mothers’ discourses, the authors underline the identity motivations for purchasing luxury apparel for their pre-adolescent children.

Findings
The paper shows that when shopping for luxury brands for their pre-adolescent children, mothers manage discrepancies between their “real” and “idealised” selves as well as the pushes and pulls of being a mother and a woman.

Research limitations/implications
The findings point to possible future research on this topic, particularly with regard to investigating how luxury stores and retailers can adapt so as to satisfy mothers’ identity quest.

Practical implications
Managers of luxury brand retail spaces looking at the future of retailing could analyse their store environment in the light of these mothers’ identity-related motivations. As well as focussing on how children look, store layout and merchandising should provide different spaces for mothers’ identity expression, using new in-store digital technologies.

Originality/value
This study is one of the first to analyse luxury shopping for children taking the point of view of mothers. The paper underlines how young mothers build their new maternal identity and their projected relationship with their child through purchases of children’s luxury goods in specific retail environments.
Doing it for the kids: the role of sustainability in family consumption
Authors: Ritch Elaine L. , Brownlie Douglas 
Published: May 2017

Purpose
The purpose of this paper is to explore social dynamics around food and clothing provisioning for young families and how involvement in environmental concerns shapes those dynamics and presents challenges and opportunities to in terms of evolving consumer tastes. Through collecting and analysing narratives of mothering, the authors explore the influence of children on decision making in household provisioning; in particular, how their education into sustainable concepts through the European initiative of eco-schools impacts provisioning.

Design/methodology/approach
The exploratory research design specifically sought the demographic profile identified in extant literature as engaging with sustainability issues to explore how they were interpreted into familial consumption. This resulted in 28 unstructured interviews exploring a range of related topics with a group of highly educated working mothers with a profession.

Findings
The study finds that family consumption behaviour is mediated by relations towards environmental concerns and taste positions taken by both parents and children. It illustrates how care for children’s safety, social resilience and health and well-being is habitus informed as well as being the subject of wider institutional logics including educational interventions such as school eco-status and participation in mother and child activity groups. However, tensions arose surrounding the children’s socialisation with peers and space was provided to help the children self-actualise.

Research limitations/implications
The exploratory goal of the study limited the scope of its empirical work to a small group of participants sharing consumer characteristics and geographical location.

Practical implications
The research provides ideas for retailers, brands and marketers to better position their product offering as it relates to growing family concerns for ecological issues and sustainable consumption, as well as what motivates sustainable behaviours, from both the child and mothers perspective.

Social implications
The research identifies the immersion of sustainability into family households when there are no financial implications, influenced through campaigns, schools and society. This provides examples of what motivates sustainable behaviours for retailers and marketers to develop strategies that can be capitalised on.

Originality/value
The originality of the research emerges through examining how children influence sustainability within households and decision making, moving beyond health implications to educate children to be responsible consumers through play and authentic experiences.
Fulfilling employees’ psychological contracts: organizational socialization’s role
Authors: DeBode Jason D. , Mossholder Kevin W. , Walker Alan G. 
Published: May 2017

PurposeThe purpose of this paper is to examine the mediating role of psychological contract fulfillment in the relationship between socialization tactics and attachment-related outcomes (i.e. organizational commitment and person-organization fit).Design/methodology/approachData were obtained from online data collection services which allowed for a custom sample of new employees (n=326) from a variety of organizations and industries.FindingsPsychological contract fulfillment partially mediated the relationship between one socialization tactic (i.e. social) and attachment-related outcomes.Post hocanalyses offered support for a hierarchy of socialization tactics with respect to prediction of organization-relevant outcomes.Research limitations/implicationsResearchers and practitioners have long believed socialization plays an important role in creating successful new employees. However, researchers have yet to adequately examine the mechanisms facilitating these relationships. This study advances the socialization literature by highlighting one such mechanism – psychological contract fulfillment.Originality/valueThis study seeks to explore the “black box” of socialization. Specifically, whereas prior work has suggested one tactic (i.e. social) may be more important than others, this is among the few studies exploring a potential hierarchy of socialization tactics. The authors then discuss the implications of this hierarchy for future research.
The influence of servant leadership, trust in leader and thriving on employee creativity
Authors: Jaiswal Neeraj Kumar , Dhar Rajib Lochan 
Published: May 2017

PurposeThe purpose of this paper is to investigate how servant leadership, trust in leader and thriving drive employee creativity.Design/methodology/approachUsing a dyadic sample of 48 teams (each team comprising a supervisor and the subordinates under him), the authors investigated the role of servant leadership in predicting employee creativity, the mediating role of trust in leader and interactive role of thriving therein.FindingsFindings of the study revealed that servant leaders instilled trust within followers, which acted as a mediator in predicting creativity. Further, thriving was found to act as a moderator that influenced the relationship between trust in leader and employee creativity. Findings also indicated that thriving employees exhibited a greater degree of creative behavior when they trusted their leader.Research limitations/implicationsBased on these findings, the study draws the attention of managers toward the role of servant leadership, trust in leaders and thriving in promoting employee creativity.Originality/valueThis is one of the first studies to integrate servant leadership, trust in leader, thriving and creative behavior into a single theoretical model. The study further provides evidence to validate the proposed model in context of predicting employee creativity.
Measuring leader behaviour: evidence for a “big five” model of leadership
Authors: Langford Peter H. , Dougall Cameron B. , Parkes Louise P. 
Published: May 2017

Purpose
The purpose of this paper is to provide evidence for a “leadership big five”, a model of leadership behaviour integrating existing theories of leadership and conceptually aligned with the most established model of personality, the big five. Such a model provides researchers and practitioners with a common language to describe leadership behaviour in a field with a plethora of leadership models. The model also describes a wider range of leadership behaviour than other models of leadership, and presents dimensions that correlate with important organisational outcomes as demonstrated in this study.

Design/methodology/approach
In total, 1,186 employees completed the Voice Leadership 360, a survey designed to measure the leadership big five, collectively rating 193 managers from a range of different sectors and industries, using a 360-degree survey methodology.

Findings
Confirmatory factor analyses and internal reliability analyses provide evidence for 22 lower-order factors of leadership behaviour that aggregate into five higher-order factors of leadership aligned with the big five personality descriptors. Further evidence for the validity of the model is indicated by significant correlations between 360-degree survey ratings and raters’ judgements of leaders’ personality, and significant correlations between 360-degree survey ratings and both work unit engagement levels and manager reports of work unit performance.

Research limitations/implications
The cross-sectional design is the main limitation of the present study, limiting conclusions that changes in leadership behaviours will lead to changes in organisational outcomes. The primary research implications of this study include the support for an integrating model of leadership behaviour that aligns with a large body of psychological research, as well as the development of a survey that can be used for future exploration of the model.

Practical implications
Practitioners may use the results of the study to rethink how they develop competency frameworks and measure leadership behaviour in organisation development contexts. This broad model of leadership and the familiarity of its dimensions could increase the effectiveness of behaviour change interventions, and the presented survey provides a reliable and valid tool for 360-degree assessments.

Originality/value
The study provides evidence that leadership can be described in a structurally similar way to human personality. It presents a leadership model that consists of a broader range of leadership behaviours related to organisational outcomes compared with previous models of leadership.
Network ties and transactive memory systems: leadership as an enabler
Authors: Cabeza Pulles Dainelis , LLorens Montes Francisco Javier , Gutierrez-Gutierrrez Leopoldo 
Published: May 2017

PurposeThe purpose of this paper is to study the relationship between network ties (NT) and transactive memory systems (TMS), observed through three dimensions – specialization (TMSS), credibility (TMSCR), and coordination (TMSCO) – in the presence of leadership (LDR) as a moderating variable, in university research-and-development (R&D) groups.Design/methodology/approachThe data are composed of 257 university R&D groups. To confirm the hypotheses, the authors use multiple linear regression analysis with a moderating effect.FindingsThe conclusions show that the relationships between NT and two of the three dimensions of TMS (TMSCR and TMSCO) are significant when LDR is included as a moderating variable. Although the effect of TMSS is positive, it is not significant. Including the interaction element enables better explanation of two of the dimensions of TMS in the sector analyzed. Thus, LDR is perfectly applicable to the university R&D environment.Research limitations/implicationsThis research has several limitations that suggest further possibilities for empirical research. The limitations include the cross-sectional nature of the research and the judgment of a single manager as the basis of the perception analyzed for each group.Practical implicationsThe authors provide several implications for R&D practitioners. The results of this study could be validated in other universities in other geographic areas, enabling better generalization and applicability of the results. The results described may serve as a guide for group leaders of university R&D. This research helps us to see the importance of LDR in forming internal research networks that help researchers to perform common projects in order to obtain better results in the group. Thus, the groups provided better results to society.Originality/valueNo studies have tested the moderating effect of LDR in university R&D empirically. The results provide information to fill this gap and demonstrate the applicability of LDR as a key element in the organization, improvement, and cohesion of R&D groups.