bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autophagosomes fuse to phagosomes and facilitate the degradation of apoptotic cells inCaenorhabditis elegans
Authors: Peña-Ramos Omar , Chiao Lucia , Liu Xianghua , Yu Xiaomeng , Yao Tianyou , He Henry , Zhou Zheng 
Published: July 2021

AbstractAutophagosomes are double-membrane intracellular vesicles that degrade protein aggregates, intracellular organelles, and other cellular components. During the development of the nematodeCaenorhabditis elegans, many somatic and germ cells undergo apoptosis. These cells are engulfed and degraded by their neighboring cells. We discovered a novel role of autophagosomes in facilitating the degradation of apoptotic cells using a real-time imaging technique. Specifically, the double-membrane autophagosomes in engulfing cells are recruited to the surfaces of phagosomes containing apoptotic cells and subsequently fuse to phagosomes, allowing the inner vesicle to enter the phagosomal lumen. Mutants defective in the production of autophagosomes display significant defects in the degradation of apoptotic cells, demonstrating the importance of autophagosomes to this process. The signaling pathway led by the phagocytic receptor CED-1, the adaptor protein CED-6, and the large GTPase dynamin (DYN-1) promotes the recruitment of autophagosomes to phagosomes. Moreover, the subsequent fusion of autophagosomes with phagosomes requires the functions of the small GTPase RAB-7 and the HOPS complex components. Further observations suggest that autophagosomes provide apoptotic cell-degradation activities in addition to and in parallel of lysosomes. Our findings reveal that, unlike the single-membrane,LC3-associatedphagocytosis (LAP) vesicles reported for mammalian phagocytes, the canonical double-membrane autophagosomes facilitate the clearance ofC. elegansapoptotic cells. These findings add autophagosomes to the collection of intracellular organelles that contribute to phagosome maturation, identify novel crosstalk between the autophagy and phagosome maturation pathways, and discover the upstream signaling molecules that initiate this crosstalk.
TIGAR-V2: Efficient TWAS Tool with Nonparametric Bayesian eQTL Weights of 49 Tissue Types from GTEx V8
Authors: Parrish Randy L. , Gibson Greg C. , Epstein Michael P. , Yang Jingjing 
Published: July 2021

AbstractStandard Transcriptome-Wide Association Study (TWAS) methods first train gene expression prediction models using reference transcriptomic data, and then test the association between the predicted genetically regulated gene expression and phenotype of interest. Most existing TWAS tools require cumbersome preparation of genotype input files and extra coding to enable parallel computation. To improve the efficiency of TWAS tools, we develop TIGAR-V2, which directly reads VCF files, enables parallel computation, and reduces up to 90% computation cost (mainly due to loading genotype data) compared to the original version. TIGAR-V2 can train gene expression imputation models using either nonparametric Bayesian Dirichlet Process Regression (DPR) or Elastic-Net (as used by PrediXcan), perform TWAS using either individual-level or summary-level GWAS data, and implements both burden and variance-component statistics for gene-based association tests. We trained gene expression prediction models by DPR for 49 tissues using GTEx V8 by TIGAR-V2 and illustrated the usefulness of these Bayesian cis-eQTL weights through TWAS of breast and ovarian cancer utilizing public GWAS summary statistics. We identified 88 and 37 risk genes respectively for breast and ovarian cancer, most of which are either known or near previously identified GWAS (~95%) or TWAS (~40%) risk genes and three novel independent TWAS risk genes with known functions in carcinogenesis. These findings suggest that TWAS can provide biological insight into the transcriptional regulation of complex diseases. TIGAR-V2 tool, trained Bayesian cis-eQTL weights, and LD information from GTEx V8 are publicly available, providing a useful resource for mapping risk genes of complex diseases.
GAIT-GM integrative cross-omics analyses reveal cholinergic defects in a C. elegans model of Parkinson’s disease
Authors: Mor Danielle E. , Huertas Francisco , Morse Alison M. , Kaletsky Rachel , Murphy Coleen T. , Kalia Vrinda , Miller Gary W. , Moskalenko Olexander , Conesa Ana , McIntyre Lauren M. 
Published: July 2021

AbstractBackgroundParkinson’s disease (PD) is a disabling neurodegenerative disorder in which multiple cell types, including dopaminergic and cholinergic neurons, are affected. The mechanisms of neurodegeneration in PD are unknown, limiting the development of therapies directed at disease-relevant molecular targets. C. elegans is a genetically tractable model system that can be used to disentangle disease mechanisms in complex diseases such as PD. Such mechanisms can be studied combining high-throughput molecular profiling technologies such as transcriptomics and metabolomics. However, the integrative analysis of multi-omics data in order to unravel disease mechanisms is a challenging task without advanced bioinformatics training. Galaxy, a widely-used resource for enabling bioinformatics analysis by the broad scientific community, has poor representation of multi-omics integration pipelines.ResultsWe present the integrative analysis of gene expression and metabolite levels of a C. elegans PD model using GAIT-GM, a new Galaxy tool for multi-omics data analysis. Using GAIT-GM, we discovered an association between branched-chain amino acid metabolism and cholinergic neurons in the C. elegans PD model. An independent follow-up experiment uncovered cholinergic neurodegeneration in the C. elegans model that is consistent with cholinergic cell loss observed in PD.ConclusionGAIT-GM is an easy to use Galaxy-based tool for generating novel testable hypotheses of disease mechanisms involving gene-metabolite relationships.
Mapping the vocal circuitry of Alston’s singing mouse with pseudorabies virus
Authors: Zheng Da-Jiang , Okobi Daniel E. , Shu Ryan , Agrawal Rania , Smith Samantha K. , Long Michael A. , Phelps Steven M. 
Published: July 2021

AbstractVocalizations, like many social displays, are often elaborate, rhythmically structured behaviors that are modulated by a complex combination of cues. Vocal motor patterns require close coordination of neural circuits governing the muscles of the larynx, jaw, and respiratory system. In the elaborate vocalization of Alston’s singing mouse (Scotinomys teguina), for example, each note of its rapid, frequency-modulated trill is accompanied by equally rapid modulation of breath and gape. To elucidate the neural circuitry underlying this behavior, we introduced the polysynaptic retrograde neuronal tracer pseudorabies virus (PRV) into the cricothyroid and digastricus muscles, which control frequency modulation and jaw opening respectively. Each virus singly labels ipsilateral motoneurons (nucleus ambiguous for cricothyroid, and motor trigeminal nucleus for digastricus). We find that the two isogenic viruses heavily and bilaterally co-label neurons in the gigantocellular reticular formation, a putative central pattern generator. The viruses also show strong co-labeling in compartments of the midbrain including the ventrolateral periaqueductal grey and the parabrachial nucleus, two structures strongly implicated in vocalizations. In the forebrain, regions important to social cognition and energy balance both exhibit extensive co-labeling. This includes the paraventricular and arcuate nuclei of the hypothalamus, the lateral hypothalamus, preoptic area, extended amygdala, central amygdala, and the bed nucleus of the stria terminalis. Finally, we find doubly labeled neurons in M1 motor cortex previously described as laryngeal, as well as in the prelimbic cortex, which indicate these cortical regions play a role in vocal production. Although we observe some novel patterns of double-labelling, the progress of both viruses is broadly consistent with vertebrate-general patterns of vocal circuitry, as well as with circuit models derived from primate literature.
The impact of whole genome duplications on the human gene regulatory networks
Authors: Mottes Francesco , Villa Chiara , Osella Matteo , Caselle Michele 
Published: July 2021

ABSTRACTThis work studies the effects of the two rounds of Whole Genome Duplication (WGD) at the origin of the vertebrate lineage on the architecture of the human gene regulatory networks. We integrate information on transcriptional regulation, miRNA regulation, and protein-protein interactions to comparatively analyse the role of WGD and Small Scale Duplications (SSD) in the structural properties of the resulting multilayer network. We show that complex network motifs, such as combinations of feed-forward loops and bifan arrays, deriving from WGD events are specifically enriched in the network. Pairs of WGD-derived proteins display a strong tendency to interact both with each other and with common partners and WGD-derived transcription factors play a prominent role in the retention of a strong regulatory redundancy. Combinatorial regulation and synergy between different regulatory layers are in general enhanced by duplication events, but the two types of duplications contribute in different ways. Overall, our findings suggest that the two WGD events played a substantial role in increasing the multi-layer complexity of the vertebrate regulatory network by enhancing its combinatorial organization, with potential consequences on its overall robustness and ability to perform high-level functions like signal integration and noise control.
Agonism and grooming behavior explain social status effects on physiology and gene regulation in rhesus macaques
Authors: Simons Noah D. , Michopoulos Vasiliki , Wilson Mark , Barreiro Luis B. , Tung Jenny 
Published: July 2021

ABSTRACTVariation in social status predicts molecular, physiological, and life history outcomes across a broad range of species, including our own. Experimental studies indicate that some of these relationships persist even when the physical environment is held constant. Here, we draw on data sets from one such study—experimental manipulation of dominance rank in captive female rhesus macaques—to investigate how social status shapes the lived experience of these animals to alter gene regulation, glucocorticoid physiology, and mitochondrial DNA phenotypes. We focus specifically on dominance rank-associated dimensions of the social environment, including both competitive and affiliative interactions. Our results show that simple summaries of rank-associated behavioral interactions are often better predictors of molecular and physiological outcomes than dominance rank itself. However, while measures of immune function are best explained by agonism rates, glucocorticoid-related phenotypes tend to be more closely linked to affiliative behavior. We conclude that dominance rank serves as a useful summary for investigating social environmental effects on downstream outcomes. Nevertheless, the behavioral interactions that define an individual’s daily experiences reveal the proximate drivers of social status-related differences, and are especially relevant for understanding why individuals who share the same social status sometimes appear physiologically distinct.
Allosteric control of Ubp6 and the proteasome via a bidirectional switch
Authors: Hung Ka Ying Sharon , Klumpe Sven , Eisele Markus R. , Elsasser Suzanne , Tian Geng , Sun Shuangwu , Moroco Jamie A. , Cheng Tat Cheung , Joshi Tapan , Seibel Timo , Van Dalen Duco , Feng Xin-Hua , Lu Ying , Ovaa Huib , Engen John R. , Lee Byung-Hoon , Rudack Till , Sakata Eri , Finley Daniel 
Published: July 2021

AbstractThe proteasome is the principal cellular protease, and recognizes target proteins that have been covalently marked by ubiquitin chains. The ubiquitin signal is subject to rapid editing at the proteasome, allowing it to reject substrates based on topological features of their attached ubiquitin chains. Editing is mediated by a key regulator of the proteasome, deubiquitinating enzyme Ubp6. The proteasome activates Ubp6, whereas Ubp6 inhibits the proteasome–both by deubiquitinating proteasome-bound ubiquitin conjugates, and through a noncatalytic effect that does not involve deubiquitination. We report mutants in both Ubp6 and proteasome subunit Rpt1 that abrogate Ubp6 activation. The Ubp6 mutations fall within its ILR element, defined here, which is conserved from yeast to mammals. The ILR is a component of the BL1 blocking loop, other parts of which obstruct ubiquitin access to the catalytic groove in free Ubp6. Rpt1 docking at the ILR opens the catalytic groove by rearranging not only BL1 but also a novel network of three directly interconnected active-site-blocking loops. Ubp6 activation and noncatalytic proteasome inhibition by Ubp6 are linked in that they were eliminated by the same Ubp6 and Rpt1 mutations. Ubp6 and ubiquitin together drive the proteasome into a unique conformational state associated with proteasome inhibition. Our results identify a multicomponent allosteric switch that exerts simultaneous control over the activity of both Ubp6 and the proteasome, and suggest that their active states are in general mutually exclusive. The findings lead to a new paradigm for allosteric control of deubiquitinating enzymes.
The interplay of RNA:DNA hybrid structure and G-quadruplexes determines the outcome of R-loop-replisome collisions
Authors: Kumar Charanya , Batra Sahil , Griffith Jack D. , Remus Dirk 
Published: July 2021

ABSTRACTR-loops are a major source of genome instability associated with transcription-induced replication stress. However, how R-loops inherently impact replication fork progression is not understood. Here, we characterize R-loop-replisome collisions using a fully reconstituted eukaryotic DNA replication system. We find that RNA:DNA hybrids and G-quadruplexes at both co-directional and head-on R-loops can impact fork progression by inducing fork stalling, uncoupling of leading strand synthesis from replisome progression, and nascent strand gaps. RNase H1 and Pif1 suppress replication defects by resolving RNA:DNA hybrids and G-quadruplexes, respectively. We also identify an intrinsic capacity of replisomes to maintain fork progression at certain R-loops by unwinding RNA:DNA hybrids, repriming leading strand synthesis downstream of G-quadruplexes, or utilizing R-loop transcripts to prime leading strand restart during co-directional R-loop-replisome collisions. Collectively, the data demonstrates that the outcome of R-loop-replisome collisions is modulated by R-loop structure, providing a mechanistic basis for the distinction of deleterious from non-deleterious R-loops.
Existence of positive solutions for p-Laplacian systems involving left and right fractional derivatives
Authors: Ramdane Samira , Guezane-Lakoud Assia 
Published: July 2021

PurposeThe paper deals with the existence of positive solutions for a coupled system of nonlinear fractional differential equations with p-Laplacian operator and involving both right Riemann–Liouville and left Caputo-type fractional derivatives. The existence results are obtained by the help of Guo–Krasnosel'skii fixed-point theorem on a cone in the sublinear case. In addition, an example is included to illustrate the main results.Design/methodology/approachFixed-point theorems.FindingsNo finding.Originality/valueThe obtained results are original.
Developing trauma-informed care: using psychodynamic concepts to help staff respond to the attachment needs of survivors of trauma
Authors: Rye Emma , Anderson Joanna , Pickard Max 
Published: July 2021

PurposeMany referrals to our mental health of learning disability service focus on concerns about behaviours that present risks to the referred person and to those around them, including support workers. If the referred person has good verbal ability, psychological therapy may be requested and offered, but the person may find it too difficult to engage for a number of reasons. Even when they do engage in therapy, the authors recognise the importance of helping staff better understand their attachment needs. This paper aims to demonstrate an innovative approach to helping staff provide Trauma-Informed Care (TIC).Design/methodology/approachThe authors developed a training programme for support workers using psychodynamic concepts, such as splitting, transference and counter-transference, to help them develop insight into the processes that get enacted during their work. In this paper the authors have generally used the term “care staff”, recognising that an important aspect of the role of those staff is to provide care within an attachment framework; as well as support to maximise independence.FindingsThe feedback from staff who have attended has been very positive, both at the time and later. Staff who have attended have talked to multidisciplinary colleagues about the impact their learning has had on their ability to work with service users who present great challenges, in the context of their trauma histories.Originality/valueThe importance of providing TIC is gaining traction across varied settings. The authors are in the process of developing both qualitative and quantitative research programmes to evaluate this approach to increasing TIC for adults with learning disabilities, reducing staff burn out and placement breakdown.
What next for end-point assessments?
Authors: Baker Denise , Robertshaw David 
Published: July 2021

PurposeThis paper reflects on changes to end-point assessment (EPA) brought about as a result of the COVID-19 pandemic and considers how proposed future change will impact on training providers and employers of health apprentices.Design/methodology/approachThe paper provides an analysis of apprenticeship policy, the role of EPA and consideration of assessment strategies used in higher education and health professions. Implications for policy, training providers and clinical practice are proposed.FindingsThese changes will bring the completion of EPA closer to education providers and allow them to take a more direct role within the process. Education providers will need to be issued with clear guidance to ensure regulatory compliance. The pedagogical value of EPA is questioned.Originality/valueTraining providers and policymakers will need to review their processes and guidance appropriately. This paper provides a summary of salient points needing consideration.
Determinants of alliance productivity and performance: evidence from the automobile industry
Authors: Rajan Rishabh , Dhir Sanjay , Sushil  
Published: July 2021

PurposeThis study aims to identify critical factors and examine their impact on alliance performance from an organizational learning point of view.Design/methodology/approachA modified total interpretive structural modeling (M-TISM) methodology was used in this study. The different paths/links in the developed M-TISM model were further validated by using the Mahindra-Ford alliance case study.FindingsIn this study, a total of seven critical factors were identified using an extensive literature review, and a hierarchical model was developed. Results show that prior alliance experience, inter-partner learning, knowledge transfer, absorptive capacity and knowledge internalization have a positive on the alliance productivity and performance. Furthermore, the findings indicate that prior alliance experience remains essential for alliance productivity and performance, while knowledge transfer and absorptive capacity can contribute to inter-partner learning and knowledge internalization in strategic alliances.Research limitations/implicationsThis study can help managers and policymakers to understand the identified critical factors from an organizational learning perspective and understand their impact on the alliance performance in a competitive environment. The managers should know that previous alliance experience, learning from partner firms, building an absorptive capacity, etc., are necessary to achieve superior alliance productivity and performance. For academicians, the M-TISM methodology used in this study can provide a mechanism to perform exploratory research and build a hierarchical model in different management research fields.Originality/valueThe study fills research gaps by identifying key factors, developing a hierarchical model, and examining their impact on the performance of strategic alliances in the Indian automotive industry.
No fault found: a systematic literature review and future research agenda
Authors: Singh Vipin Prakash , Ganguly Kunal , Samad Taab Ahmad 
Published: July 2021

PurposeNo fault found (NFF) in maintenance has been a frequently observed problem in industrial sectors, but very few academic contributions are devoted to reviewing and summarizing the related research. Considering the growing interest of academicians in NFF during the last decade, there is a critical need to examine theme evolution in this field, most influential authors, contemporary practices, research gaps and proposed solutions.Design/methodology/approachA portfolio of 169 articles published between 1982 and 2020 was collected from the Scopus database and was systematically analyzed using a two-tier method. First, the evolution, current state of literature and research clusters are identified using bibliometric techniques. Finally, the research clusters are studied to understand the literature's main themes and develop the future research agenda using content analysis.FindingsThe results indicate that publications on NFF are rising quickly in the last decade, especially after 2010. The previous NFF research primarily focuses on system design, fault diagnostics, reliability engineering, data management and human factors, but the criticality of economic and risk analysis has not been significantly represented.Research limitations/implicationsThe study resulted in developing an inclusive framework and identifying six research clusters that will help in granular understanding, benefit the researchers, practitioners and policy formulators in NFF.Originality/valueThis study examines the NFF's current research direction and calls for further research in integrating NFF economics on its stakeholders like manufacturers, supply chain, customers and risk analysis during the product life cycle.
Hindering talented employees’ internal mobility: managers’ territorial response to stress
Authors: Kraichy David , Walsh Megan M. 
Published: July 2021

PurposeIntegrating territoriality and the job demands-resources model, this study investigated tactics that managers use to hinder their talented employees’ internal job transfer attempts. This study proposed that managers’ psychological ownership of talent would relate to their use of persuasion and nurturing tactics, and that managers’ role overload and job social support would moderate these relationships.Design/methodology/approachThe data for this study was collected by administering two surveys approximately two weeks apart. A hundred and sixteen managers provided complete data for analysis.FindingsPsychological ownership of talent related to persuasion tactics but not nurturing tactics. When overload was higher and social support was lower, managers with higher psychological ownership reported using more persuasion tactics to hinder their talented employees’ internal mobility. This study did not find significant interactions for nurturing tactics.Practical implicationsInternal talent hindering can impede employee access to critical learning and growth opportunities, and employees who feel their mobility is restricted may be more inclined to turnover. Accordingly, managers who hinder internal mobility can negatively affect talented employees’ leadership development within an organization and the effectiveness of its succession plans.Originality/valueThis study demonstrates empirically that managers intentionally use tactics to hinder the internal transfers of their talented employees. This study identifies predictors and boundary conditions of hindering tactics, and this knowledge can help organizations address internal talent hindering.