bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Impact of Occupational Stigma on Gig Workers' Workplace Well-being
Authors: Liu Beini , Guo Yuehua , Fu Yaoyao 
Published: June 2022

Objective
In this article, the influence of occupational stigma on workplace well-being of platform-based food-delivery workers is examined. The mediation effect of work-contingent self-esteem and the moderating effect of job control are also assessed.

Methods
Questionnaire data from 362 platform-based food-delivery workers were gathered at three time points, and multiple regression analyses were used to test each hypothesis.

Results
Occupational stigma reduces workplace well-being of platform-based food-delivery workers, and this relationship is mediated by work-contingent self-esteem. Job control exerts a negative moderating effect on the relationship between occupational stigma and platform-based food-delivery workers' work-contingent self-esteem.

Conclusions
Strategies for reducing occupational stigma should be prioritized to increase workplace well-being in gig workers. Giving them more control over their work will likely alleviate the detrimental effect of occupational stigma on work-contingent self-esteem.
The phers R package: using phenotype risk scores based on electronic health records to study Mendelian disease and rare genetic variants
Authors: Aref Layla , Bastarache Lisa , Hughey Jacob J. 
Published: June 2022

AbstractElectronic health record (EHR) data linked to DNA biobanks are a valuable resource for understanding the phenotypic effects of human genetic variation. We previously developed the phenotype risk score (PheRS) as an approach to quantify the extent to which a patient’s clinical features resemble a given Mendelian disease. Using PheRS, we have uncovered novel associations between Mendelian diseaselike phenotypes and rare genetic variants, and identified patients who may have undiagnosed Mendelian disease. Although the PheRS approach is conceptually simple, it involves multiple mapping steps and was previously only available as custom scripts, limiting the approach’s usability. Thus, we developed the phers R package, a complete and user-friendly set of functions and maps for performing a PheRS-based analysis on linked clinical and genetic data. The package includes up-to-date maps between EHR-based phenotypes (i.e., ICD codes and phecodes), human phenotype ontology (HPO) terms, and Mendelian diseases. Starting with occurrences of ICD codes, the package enables the user to calculate phenotype risk scores, validate the scores using case-control analyses, and perform genetic association analyses. By increasing PheRS’s transparency and usability, the phers R package will help improve our understanding of the relationships between rare genetic variants and clinically meaningful human phenotypes.AvailabilityThe phers R package is free and open-source, and available on CRAN and at https://phers.hugheylab.org.Contactjakejhughey@gmail.comSupplementary informationSupplementary data are available at Bioinformatics online.
MLL3 regulates the CDKN2A tumor suppressor locus in liver cancer
Authors: Soto-Feliciano Yadira M. , Zhu Changyu , Morris John P. , Huang Chun-Hao , Koche Richard P. , Ho Yu-jui , Banito Ana , Chen Chun-Wei , Shroff Aditya , Tian Sha , Livshits Geulah , Chen Chi-Chao , Fennell Myles , Armstrong Scott A. , Allis C. David , Tschaharganeh Darjus F. , Lowe Scott W. 
Published: June 2022

ABSTRACTMutations in genes encoding components of chromatin modifying and remodeling complexes are among the most frequently observed somatic events in human cancers. For example, missense and nonsense mutations targeting the mixed lineage leukemia family member 3 (MLL3/KMT2C) histone methyltransferase occur in a range of solid tumors and heterozygous deletions encompassing MLL3 occur in a subset of aggressive leukemias. Although MLL3 loss can promote tumorigenesis in mice, the molecular targets and biological processes by which MLL3 suppresses tumorigenesis remain poorly characterized. Here we combined genetic, epigenomic, and animal modeling approaches to demonstrate that one of the mechanisms by which MLL3 links chromatin remodeling to tumor suppression is by co-activating the Cdkn2a tumor suppressor locus. Disruption of Mll3 cooperates with Myc overexpression in the development of murine hepatocellular carcinoma (HCC), in which MLL3 binding to the Cdkn2a locus is blunted, resulting in reduced H3K4 methylation and low expression levels of the locus-encoded genes, Ink4a and Arf. Conversely, elevated MLL3 expression increases its binding to the CDKN2A locus and co-activates gene transcription. Endogenous Mll3 restoration reverses these chromatin and transcriptional effects and triggers Ink4a/Arf-dependent apoptosis. Underscoring the human relevance of this epistasis, we found that genomic alterations in MLL3 and CDKN2A display mutual exclusivity in human HCC samples. These results collectively point to a new mechanism for disrupting CDKN2A activity during cancer development and, in doing so, link MLL3 to an established tumor suppressor network.
Exploring the alternative conformation of a known protein structure based on contact map prediction
Authors: Li Jiaxuan , Wang Lei , Zhu Zefeng , Song Chen 
Published: June 2022

AbstractThe rapid development of deep learning-based methods has considerably advanced the field of protein structure prediction. The accuracy of predicting the 3D structures of simple proteins is comparable to that of experimentally determined structures, providing broad possibilities for structure-based biological studies. Another critical question is whether and how multistate structures can be predicted from a given protein sequence. In this study, analysis of multiple two-state proteins demonstrated that deep learning-based contact map predictions contain structural information on both states, which suggests that it is probably appropriate to change the target of deep learningbased protein structure prediction from one specific structure to multiple likely structures. Furthermore, by combining deep learning- and physics-based computational methods, we developed a protocol for exploring alternative conformations from a known structure of a given protein, by which we successfully approached the holo-state conformation of a leucine-binding protein from its apo-state structure.
Evolution of dispersal and the maintenance of fragmented metapopulations
Authors: Finand Basile , Monnin Thibaud , Loeuille Nicolas 
Published: June 2022

ABSTRACTBecause it affects dispersal risk and modifies competition levels, habitat fragmentation directly constrains dispersal evolution. When dispersal is traded-off against competitive ability, increased fragmentation is often expected to select higher dispersal. Such evolutionary effects could favor the maintenance of the metapopulation by fostering spatial rescue effects. Using an evolutionary model, we first investigate how dispersal evolves in a metapopulation when fragmentation and aggregation of this fragmentation are fixed. Our results suggest that high fragmentation indeed selects for dispersal increase, but this effect is largely reduced in aggregated landscapes, to the point of being nonexistent at the highest aggregation levels. Contrasted dispersal strategies coexist at high fragmentation levels and with no or low aggregation. We then simulate time-varying fragmentation scenarios to investigate the conditions under which evolutionary rescue of the metapopulation happens. Faster evolution of dispersal favors the persistence of the metapopulation, but this effect is very reduced in aggregated landscapes. Overall, our results highlight how the speed of evolution of dispersal and the structuration of the fragmentation will largely constrain metapopulation survival in changing environments.
Subtype-specific single β1 integrin mechanics for activation, mechanotransduction and cytoskeleton remodeling
Authors: Jo Myung Hyun , Li Jing , Jaumouillé Valentin , Hao Yuxin , Coppola Jessica , Yan Jiabin , Waterman Clare M. , Springer Timothy A. , Ha Taekjip 
Published: June 2022

AbstractAlthough integrins are known to be mechano-sensitive and to possess many subtypes that have distinct physiological roles, single molecule studies of force exertion have thus far been limited to RGD-binding integrins. Here, we show that integrin α4β1 and RGD-binding integrins (αVβ1 and α5β1) require markedly different tension thresholds to support cell spreading. Furthermore, actin assembled downstream of α4β1 forms cross-linked networks in circularly spread cells, is in rapid retrograde flow, and exerts low forces from actin polymerization. In contrast, actin assembled downstream of αVβ1 forms stress fibers linking focal adhesions in elongated cells, is in slow retrograde flow, and matures to exert high forces (>54-pN) via myosin II. Conformational activation of both integrins occurs below 12-pN, suggesting that post-activation subtype-specific cytoskeletal remodeling imposes the higher threshold for spreading on RGD substrates. Multiple layers of single integrin mechanics for activation, mechanotransduction and cytoskeleton remodeling revealed here may underlie subtype-dependence of diverse processes such as somite formation and durotaxis.
Spatial structure alters the site frequency spectrum produced by hitchhiking
Authors: Min Jiseon , Gupta Misha , Desai Michael M. , Weissman Daniel B. 
Published: June 2022

ABSTRACTThe reduction of genetic diversity due to genetic hitchhiking is widely used to find past selective sweeps from sequencing data, but very little is known about how spatial structure affects hitchhiking. We use mathematical modeling and simulations to find the unfolded site frequency spectrum (SFS) left by hitchhiking in the genomic region of a sweep in a population occupying a one-dimensional range. For such populations, sweeps spread as Fisher waves, rather than logistically. We find that this leaves a characteristic three-part SFS at loci very close to the swept locus. Very low frequencies are dominated by recent mutations that occurred after the sweep and are unaffected by hitchhiking. At moderately low frequencies, there is a transition zone primarily composed of alleles that briefly “surfed” on the wave of the sweep before falling out of the wavefront, leaving a spectrum close to that expected in well-mixed populations. However, for moderate-to-high frequencies, there is a distinctive scaling regime of the SFS produced by alleles that drifted to fixation in the wavefront and then were carried throughout the population. For loci slightly farther away from the swept locus on the genome, recombination is much more effective at restoring diversity in one-dimensional populations than it is in well-mixed ones. We find that these signatures of space can be strong even in apparently well-mixed populations with negligible spatial genetic differentiation, suggesting that spatial structure may frequently distort the signatures of hitchhiking in natural populations.
Shared functional specialization in transformer-based language models and the human brain
Authors: Kumar Sreejan , Sumers Theodore R. , Yamakoshi Takateru , Goldstein Ariel , Hasson Uri , Norman Kenneth A. , Griffiths Thomas L. , Hawkins Robert D. , Nastase Samuel A. 
Published: June 2022

AbstractHumans use complex linguistic structures to transmit ideas to one another. The brain is thought to deploy specialized computations to process these structures. Recently, a new class of artificial neural networks based on the Transformer architecture has revolutionized the field of language modeling, attracting attention from neuroscientists seeking to understand the neurobiology of languagein silico. Transformers integrate information across words via multiple layers of structured circuit computations, forming increasingly contextualized representations of linguistic content. Prior work has focused on the internal representations (the “embeddings”) generated by these circuits. In this paper, we instead analyze the circuit computations directly: we deconstruct these computations into functionally-specialized “transformations” to provide a complementary window onto linguistic computations in the human brain. Using functional MRI data acquired while participants listened to naturalistic spoken stories, we first verify that the transformations account for considerable variance in brain activity across the cortical language network. We then demonstrate that the emergent syntactic computations performed by individual, functionally-specialized “attention heads” differentially predict brain activity in specific cortical regions. These heads fall along gradients corresponding to different layers, contextual distances, and syntactic dependencies in a low-dimensional cortical space. Our findings indicate that large language models and the cortical language network may converge on similar trends of functional specialization for processing natural language.
CaMKIIα promoter-controlled circuit manipulations target both pyramidal cells and inhibitory interneurons in cortical networks
Authors: Veres Judit M. , Andrasi Tibor , Nagy-Pal Petra , Hajos Norbert 
Published: June 2022

AbstractA key assumption in studies of cortical functions is that excitatory principal neurons, but not inhibitory cells express calcium/calmodulin-dependent protein kinase II subunit α (CaMKIIα) resulting in a widespread use of CaMKIIα promoter-driven protein expression for principal cell manipulation and monitoring their activities. Using neuroanatomical and electrophysiological methods we demonstrate that in addition to pyramidal neurons, multiple types of cortical GABAegic cells are targeted by adeno-associated viral vector (AAV) carrying the CaMKIIα-Channelrhodopsin 2-mCherry construct. We show that the reporter protein, mCherry can visualize a large fraction of different interneuron types, including parvalbumin (PV), somatostatin (SST), neuronal nitric oxide synthase (nNOS) and neuropeptide Y (NPY)-containing GABAergic cells, which altogether cover around 50% of the whole inhibitory cell population in cortical structures. Importantly, the expression of the excitatory opsin Channelrhodopsin 2 in the interneurons effectively drive spiking of infected GABAergic cells even if the detectability of reporter proteins is ambiguous. Thus, our results challenge the use of CaMKIIα promoter-driven protein expression as a selective tool in targeting cortical glutamatergic neurons using viral vectors.
Necessity of integrated genomic analysis to establish a designed knock-in mouse from CRISPR-Cas9-induced mutants
Authors: Yoshida Masahide , Saito Tomoko , Takayanagi Yuki , Totsuka Yoshikazu , Onaka Tatsushi 
Published: June 2022

AbstractThe CRISPR-Cas9 method for generation of knock-in mutations in a rodent embryo yields many F0 generation candidates that may have the designed mutations. Genetic mutations must be confirmed using genomic DNA with a mixture of designed and unexpected mutations. In our study for establishing Prlhr-Venus knock-in reporter mice, we found that genomic rearrangements near the targeted knock-in allele, tandem multicopy at a target allele locus and mosaic genotype of two different knock-in alleles occurred in addition to the designed knock-in mutation in the F0 generation. Conventional PCR and genomic sequencing were not able to detect mosaicism or discriminate between the designed one-copy knock-in mutant and a multicopy-inserted mutant. However, by using a combination of Southern blotting and the next-generation sequencing-based RAISING method, these mutants were successfully detected in the F0 generation. In F1 and F2 generations, droplet digital PCR analysis contributed to establishment of the strain, although a multicopy was falsely detected as one copy by the analysis in the F0 generation. We emphasize that the combination of these five methods allowed us to select promising F0 generations and establish the designed strain and that focusing only on positive evidence of knock-in can lead to erroneous selection of undesirable strains.
Rapid presynaptic maturation in naturally regenerating axons
Authors: Browne Lorcan P. , Crespo Andres , Grubb Matthew S. 
Published: June 2022

AbstractSuccessful neuronal regeneration requires the re-establishment of synaptic connectivity. Crucial to this process is the reconstitution of presynaptic machinery responsible for controlling neurotransmitter release. In the mammalian adult CNS post-injury regeneration is usually only possible after extensive experimental intervention, and it is unknown how presynaptic function is re-established, let alone how it might be optimised to promote functional recovery. Here we addressed these questions by studying presynaptic maturation during a regenerative process that occurs entirely naturally. After toxin-induced injury, olfactory sensory neurons in the adult mouse olfactory epithelium can regenerate fully, sending axons to the brain to re-establish synaptic contact with postsynaptic partners in the olfactory bulb. Using electrophysiological recordings in acute slices, we found that after initial re-contact, functional connectivity in this system was rapidly established. Moreover, re-connecting presynaptic terminals had almost mature functional properties, including high release probability and a strong capacity for presynaptic inhibition. Release probability then matured quickly, rendering re-established terminals functionally indistinguishable from controls just one week after initial contact. These data show that successful synaptic regeneration in the adult mammalian brain is not quite a ‘plug-and-play’ process; instead, almost-mature presynaptic terminals undergo a rapid phase of functional maturation to re-integrate into established target networks.
Loss of the protein disrupted in schizophrenia 1 (DISC1) impairs cardiac resistance against ischemia
Authors: Marwarha Gurdeep , Pinho Maria J. , Scrimgeour Nathan R , Slagsvold Katrine Hordnes , Wahba Alexander , Røsbjørgen Ragnhild E , Enguita Francisco J. , Yang Kun , Ishizuka Koko , Casas Carlos Andrés Acosta , Pettersen Kristine , Bjørkøy Geir , Sawa Akira , Høydal Morten A 
Published: June 2022

AbstractTreatable targets that hinder heart failure development following myocardial infarction remain limited. Through an unbiased transcriptional regulation study for ischemic heart disease, we identified the protein disrupted in schizophrenia 1 (DISC1), which has been almost solely characterized in the brain. Here, we show that loss of DISC1 is a major driver of heart disease and ischemic damage. Silencing of DISC1 sensitizes human cardiomyocyte cell lines to hypoxia, whereas DISC1 overexpression is cardioprotective. Mechanistically, we provide evidence that reduced DISC1 protein levels interrupt multiple signaling processes vital for cardiomyocyte survival whereas overexpression of DISC1 enhances pro survival signalling. The present study has implications for understanding scenarios where cardiomyocytes are unable to increase the levels of DISC1 during ischemia, e.g., in individuals with DISC1 genetic defects. Indeed, patients with severe mental illness display 20 years earlier mortality, with IHD as the greatest cause of death. The present study can thus shed light on this long-term enigma in epidemiology. Furthermore, the promising data showing activation of pro survival signalling processes with DISC1 overexpression opens new directions towards potential treatment strategies of patients suffering from ischemic heart disease.
Genome-wide subcellular protein localisation in the flagellate parasite Trypanosoma brucei
Authors: Billington Karen , Halliday Clare , Madden Ross , Dyer Philip , Carrington Mark , Vaughan Sue , Hertz-Fowler Christiane , Dean Samuel , Sunter Jack Daniel , Wheeler Richard John , Gull Keith 
Published: June 2022

AbstractTrypanosoma brucei is a prototypical trypanosomatid, an important group of human, animal and plant unicellular parasites. Understanding their complex cell architecture and life cycle is hindered since, as with most eukaryotic microbes, ∼50% of the proteins encoded in the genome have completely unknown function. Using fluorescence microscopy and cell lines expressing endogenously tagged proteins we mapped the subcellular localisation of 89% of the proteome, giving clues to function, defining the lineage-specific organelle adaptations for obligate parasitism and mapping the ultra-conserved cellular architecture of eukaryotes. This includes the single flagellum, vital for morphogenesis and pathology: the first comprehensive cartographic analysis of the flagellum in any organism. To demonstrate the power of this resource, we identify novel specialisation of organelle molecular composition through the cell cycle and in specialised subdomains. This is a transformative resource, important for hypothesis generation for both eukaryotic evolutionary molecular cell biology and fundamental parasite cell biology.
Heritability and host genomic determinants of switchgrass root-associated microbiota in field sites spanning its natural range
Authors: Edwards Joseph A , Saran Usha Bishnoi , Bonnette Jason , MacQueen Alice , Yin Jun , Nguyen Tu uyen , Schmutz Jeremy , Grimwood Jane , Pennacchio Len A. , Daum Chris , del Rio Tijana Glavina , Fritschi Felix B. , Lowry David B. , Juenger Thomas E. 
Published: June 2022

ABSTRACTA fundamental goal in plant microbiome research is to determine the relative impacts of host and environmental effects on root microbiota composition, particularly how host genotype impacts bacterial community composition. Most studies characterizing the effect of plant genotype on root microbiota undersample host genetic diversity and grow plants outside of their native ranges, making the associations between host and microbes difficult to interpret. Here we characterized the root microbiota of a large population of switchgrass, a North American native C4 bioenergy crop, in three field locations spanning its native range. Our data, composed of >2000 samples, suggest field location is the primary determinant of microbiome composition; however, substantial heritable variation is widespread across bacterial taxa, especially those in the Sphingomonadaceae family. Despite diverse compositions, we find that relatively few highly prevalent bacterial taxa make up the majority of the switchgrass root microbiota, a large fraction of which is shared across sites. Local genotypes preferentially recruit / filter for local microbes, supporting the idea of affinity between local plants and their microbiota. Using genome-wide association, we identified loci impacting the abundance of >400 microbial strains and found an enrichment of genes involved in immune responses, signaling pathways, and secondary metabolism. We found loci associated with over half of the core microbiota (i.e. microbes in >80% of samples) regardless of field location. Finally, we show a genetic relationship between a basal plant immunity pathway and relative abundances of root microbiota. This study brings us closer to harnessing and manipulating beneficial microbial associations via host genetics.