bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic interactions drive heterogeneity in causal variant effect sizes for gene expression and complex traits
Authors: Patel Roshni A. , Musharoff Shaila A. , Spence Jeffrey P. , Pimentel Harold , Tcheandjieu Catherine , Mostafavi Hakhamanesh , Sinnott-Armstrong Nasa , Clarke Shoa L. , Smith Courtney J. ,   VA Million Veteran Program, Durda Peter P. , Taylor Kent D. , Tracy Russell , Liu Yongmei , Johnson Craig W. , Aguet Francois , Ardlie Kristin G. , Gabriel Stacey , Smith Josh , Nickerson Deborah A. , Rich Stephen S. , Rotter Jerome I. , Tsao Philip S. , Assimes Themistocles L. , Pritchard Jonathan K. 
Published: December 2021

AbstractDespite the growing number of genome-wide association studies (GWAS), it remains unclear to what extent gene-by-gene and gene-by-environment interactions influence complex traits in humans. The magnitude of genetic interactions in complex traits has been difficult to quantify because GWAS are generally underpowered to detect individual interactions of small effect. Here, we develop a method to test for genetic interactions that aggregates information across all trait-associated loci. Specifically, we test whether SNPs in regions of European ancestry shared between European American and admixed African American individuals have the same causal effect sizes. We hypothesize that in African Americans, the presence of genetic interactions will drive the causal effect sizes of SNPs in regions of European ancestry to be more similar to those of SNPs in regions of African ancestry. We apply our method to two traits: gene expression in 296 African Americans and 482 European Americans in the Multi-Ethnic Study of Atherosclerosis (MESA) and low-density lipoprotein cholesterol (LDL-C) in 74K African Americans and 296K European Americans in the Million Veteran Program (MVP). We find significant evidence for genetic interactions in our analysis of gene expression; for LDL-C, we observe a similar point estimate although this is not significant, likely due to lower statistical power. These results suggest that gene-by-gene or gene-by-environment interactions modify the effect sizes of causal variants in human complex traits.
Gap genes are involved in inviability in hybrids between Drosophila melanogaster and D. santomea
Authors: Chang Wenhan , Kreitman Martin , Matute Daniel R. 
Published: December 2021

ABSTRACTEvolved changes within species lead to the inevitable loss of viability in hybrids. Inviability is also a convenient phenotype to genetically map and validate functionally divergent genes and pathways differentiating closely related species. Here we identify the Drosophila melanogaster form of the highly conserved essential gap gene giant (gt) as a key genetic determinant of hybrid inviability in crosses with D. santomea. We show that the coding region of this allele in D. melanogaster/D. santomea hybrids is sufficient to cause embryonic inviability not seen in either pure species. Further genetic analysis indicates that tailless (tll), another gap gene, is also involved in the hybrid defects. giant and tll are both members of the gap gene network of transcription factors that participate in establishing anterior-posterior specification of the dipteran embryo, a highly conserved developmental process. Genes whose outputs in this process are functionally conserved nevertheless evolve over short timescales to cause inviability in hybrids.
The genetic origin and architecture of sex determination
Authors: De Tisham 
Published: December 2021

AbstractHere, I demonstrate that sex determination and sexual dimorphism across tree of life are deeply related to polyamine biochemistry in cells, especially to the synteny of genes: [SAT1-NR0B1], [SAT2-SHBG] and DMRT1. This synteny was found to be most distinct in mammals. Further, the common protein domain of SAT1 and SAT2 - PF00583 was shown to be present in the genome of the last universal common ancestor (LUCA). Protein domain-domain interaction analysis of LUCA’s genes suggests the possibility that LUCA had developed an immune defence against viruses. This domain-domain interaction analysis is the first scientific evidence indicating that viruses existed at least 3.5 billions years ago and probably co-existed with LUCA on early Hadean Earth.
Protein-protein interactions on membrane surfaces analysed using pull-downs with supported bilayers on silica beads
Authors: Andhare Devika S. , Khurana Himani , Pucadyil Thomas J. 
Published: December 2021

AbstractDiscovery-based proteomics workflows that identify novel interactors rely on immunoprecipitations or pull-downs with genetically-tagged bait proteins immobilized on appropriate matrices. But strategies to analyse protein interactions on a diffusible membrane surface combined with the practical ease of pull-downs remain unavailable. Such strategies are important to analyse protein complexes that mature in composition and stability because of diffusion-based encounter between participant proteins. Here, we describe a generic pull-down strategy to analyse such complexes using chelating lipid-containing supported bilayers formed on silica beads. These templates can display desired His-tagged bait proteins on a diffusible membrane surface. Using clathrin-mediated endocytosis as a paradigm, we find that the clathrin-binding adaptor protein epsin1 displayed as bait on these templates pulls down significantly higher amounts of clathrin from brain lysates than when immobilized on conventional matrices. Together, our results establish the potential of such templates as superior matrices for analysing protein-protein interactions and resultant complexes formed on membrane surfaces.
Healthy lifestyle, genetic risk, and incidence of cancer: A prospective cohort study of 13 cancer types
Authors: Byrne Stephanie , Boyle Terry , Ahmed Muktar , Lee Sang Hong , Benyamin Beben , Hyppönen Elina 
Published: December 2021

AbstractBackgroundGenetic and lifestyle factors are related to the risk of cancer, but it is unclear whether a healthy lifestyle can offset genetic risk. Our aim was to investigate this for 13 cancer types using data from the UK Biobank prospective cohort.MethodsIn 2006-2010, participants aged 37-73 years were assessed and followed until 2015-2019. Analyses were restricted to those of European ancestries with no history of malignant cancer (n=195,822). Polygenic risk scores (PRSs) were computed for 13 cancer types and these cancers combined (‘overall cancer’), and a healthy lifestyle score was calculated from current recommendations. Relationships with cancer incidence were examined using Cox regression, adjusting for relevant confounders. Interactions between HLI and PRSs were assessed.ResultsThere were 15,240 incident cancers during the 1,926,987 person-years of follow-up (median follow-up= 10.2 years). After adjusting for confounders, an unhealthy lifestyle was associated with a higher risk of overall cancer [lowest vs highest tertile hazard ratio (95% confidence interval) = 1.32(1.26, 1.37)] and eight cancer types. The greatest increased risks were seen for cancers of the lung [3.5(2.96,4.15)], bladder [2.03 (1.57, 2.64)], and pancreas [1.98 (1.54,2.55)]. Positive additive interactions were observed, suggesting a healthy lifestyle may partially offset genetic risk of colorectal, breast, and pancreatic cancers, and may completely offset genetic risk of lung and bladder cancers.ConclusionsA healthy lifestyle is beneficial for most cancers and may offset genetic risk of some cancers. These findings have important implications for those genetically predisposed to these cancers and population strategies for cancer prevention.
Clinical features of UK Biobank subjects carrying protein truncating variants in genes implicated in schizophrenia pathogenesis
Authors: Curtis David 
Published: December 2021

AbstractThe SCHEMA consortium has identified ten genes in which protein truncating variants (PTVs) confer substantial risk of schizophrenia. Exome-sequenced participants in the UK Biobank who carried PTVs in these genes were studied to determine to what extent they demonstrated features of schizophrenia or had neuropsychiatric impairment. Following automated quality control and visual inspection of reads, 251 subjects were identified as having well-supported PTVs in one of these genes. The frequency of PTVs in CACNA1G was higher than had been observed in SCHEMA cases, casting doubt on its role in schizophrenia pathogenesis, but otherwise rates were similar to those observed in SCHEMA controls. Numbers were too small to allow formal statistical analysis but in general carriers of PTVs did not appear to have high rates of psychiatric illness or reduced educational or occupational functioning. One subject with a PTV in SETD1A had a diagnosis of schizophrenia. one with a PTV in HERC1 had psychotic depression and two subjects seemed to have developmental disorders, one with a PTV in GRIN2A and one with a PTV in RBCC1. There seemed to be somewhat increased rates of affective disorders among carriers of PTVs in HERC1 and RB1CC1. Carriers of PTVs did not appear to have subclinical manifestations of schizophrenia. Although PTVs in these genes can substantially increase schizophrenia risk, their effect seems to be dichotomous and most carriers appear psychiatrically well.This research has been conducted using the UK Biobank Resource.
A phenotypic rescue approach identifies lineage regionalization defects in a mouse model of DiGeorge syndrome
Authors: Lania Gabriella , Franzese Monica , Noritaka Adachi , Bilio Marchesa , Russo Annalaura , D’Agostino Erika , Angelini Claudia , Kelly Robert G. , Baldini Antonio 
Published: December 2021

ABSTRACTTBX1 is a key regulator of pharyngeal apparatus (PhAp) development. Vitamin B12 treatment partially rescues aortic arch patterning defects of Tbx1+/- embryos. Here we show that it also improves cardiac outflow tract septation and branchiomeric muscle anomalies of Tbx1 hypomorphic mutants. At molecular level, the in vivo vB12 treatment let us to identify genes that were dysregulated by Tbx1 haploinsufficiency and rescued by treatment. We found that SLUG, encoded by the rescued gene Snai2, identified a population of mesodermal cells that was partially overlapping with but distinct from ISL1+ and TBX1+ populations. In addition, SLUG+ cells were mislocalized and had a greater tendency to aggregate in Tbx1+/- and Tbx1-/- embryos and vB12 treatment restore cellular distribution. Adjacent neural crest-derived mesenchymal cells, which do not express TBX1, were also affected, showing enhanced segregation from cardiopharyngeal mesodermal cells. We propose that TBX1 regulates cell distribution in core mesoderm and the arrangement of multiple lineages within the PhAp.
Positional motif analysis reveals the extent of specificity of protein-RNA interactions observed by CLIP
Authors: Kuret Klara , Amalietti Aram Gustav , Ule Jernej 
Published: December 2021

AbstractBackgroundCrosslinking and immunoprecipitation (CLIP) is a method used to identify in vivo RNA– protein binding sites on a transcriptome-wide scale. With the increasing amounts of available data for RNA-binding proteins (RBPs), it is important to understand to what degree the enriched motifs specify the RNA binding profiles of RBPs in cells.ResultsWe develop positionally-enriched k-mer analysis (PEKA), a computational tool for efficient analysis of enriched motifs from individual CLIP datasets, which minimises the impact of technical and regional genomic biases by internal data normalisation. We cross-validate PEKA with mCross, and show that background correction by size-matched input doesn’t generally improve the specificity of detected motifs. We identify motif classes with common enrichment patterns across eCLIP datasets and across RNA regions, while also observing variations in the specificity and the extent of motif enrichment across eCLIP datasets, between variant CLIP protocols, and between CLIP and in vitro binding data. Thereby we gain insights into the contributions of technical and regional genomic biases to the enriched motifs, and find how motif enrichment features relate to the domain composition and low-complexity regions (LCRs) of the studied proteins.ConclusionsOur study provides insights into the overall contributions of regional binding preferences, protein domains and LCRs to the specificity of protein-RNA interactions, and shows the value of cross-motif and cross-RBP comparison for data interpretation. Our results are presented for exploratory analysis via an online platform in an RBP-centric and motif-centric manner (https://imaps.goodwright.com/apps/peka/). PEKA is available from https://github.com/ulelab/peka.
Differential N-terminal processing of beta and gamma actin in vivo
Authors: Chen Li , Tang Hsin-Yao , Kashina Anna 
Published: December 2021

AbstractActin is one of the most essential and abundant intracellular proteins, playing an essential physiological role as the major constituent of the actin cytoskeleton. Two cytoplasmic actins, beta- and gamma-actin, are encoded by different genes, but their amino acid sequences differ only by four conservative substitutions at the N-terminus, making it very difficult to dissect their individual regulation in vivo. The majority of actins are N-terminally acetylated, following the removal of N-terminal Met. Here, we analyzed beta and gamma cytoplasmic actin N-termini in vivo and found that beta actin, unlike gamma actin, specifically undergoes sequential removal of N-terminal amino acid Asp residues. This processing affects ∼1-3% of beta actin in different cell types. We identified candidate enzymes capable of mediating this type of processing, and used CRISPR/Cas-9 to delete them, individually or together, in mammalian cell lines. This deletion abolishes most of the beta actin N-terminal processing and results in changes in F-actin levels, cell spreading, filopodia formation, and cell migration, suggesting that the beta actin processing mediated by these enzymes is physiologically important to beta actin function. We propose that selective N-terminal processing of beta actin by sequential removal of Asp contributes to differentiating the functions of non-muscle actin isoforms in vivo.
Direct Imaging and Identification of Proteoforms up to 70 kDa from Human Tissue
Authors: Su Pei , McGee John P. , Durbin Kenneth R. , Hollas Michael A. R. , Yang Manxi , Neumann Elizabeth K. , Allen Jamie L. , Drown Bryon S. , Butun Fatma Ayaloglu , Greer Joseph B. , Early Bryan P. , Fellers Ryan T. , Spraggins Jeffrey M. , Laskin Julia , Camarillo Jeannie M. , Kafader Jared O. , Kelleher Neil L. 
Published: December 2021

AbstractImaging of proteoforms in human tissues is hindered by low molecular specificity and limited proteome coverage. Here, we introduce proteoform imaging mass spectrometry (PiMS), which increases the size limit for proteoform detection and identification by 4-fold compared to reported methods, and reveals tissue localization of proteoforms at <80 μm spatial resolution. PiMS advances proteoform imaging by combining ambient nanospray desorption electrospray ionization (nano-DESI) with ion detection using individual ion mass spectrometry (I2MS). We demonstrate the first proteoform imaging of human kidney, identifying 169 of 400 proteoforms <70 kDa using top-down mass spectrometry and database lookup from the human proteoform atlas, including dozens of key enzymes in primary metabolism. PiMS images reveal distinct spatial localizations of proteoforms to both anatomical structures and cellular neighborhoods in the vasculature, medulla, and cortex regions of the human kidney. The benefits of PiMS are poised to increase proteome coverage for label-free protein imaging of tissues.TeaserNano-DESI combined with individual ion mass spectrometry generates images of proteoforms up to 70 kDa.
Combining accountability forms: transparency and “intelligent” accountability in a public service organization
Authors: O'Regan Brianna , King Robyn , Smith David 
Published: December 2021

PurposeThe paper's purpose is to consider the challenges, a public sector organization faces combining both transparency and “intelligent” forms of accountability (cf. Roberts, 2009).Design/methodology/approachThe authors conducted a case study of StatePol, a police service in an Australian state.FindingsThe data analysis revealed three themes. First, prior to 2013, transparency forms of accountability dominated, emphasizing crime statistics with the effect of reinforcing internal partitions and inhibiting collective action. Second, post-2013, a greater emphasis was placed on “intelligent” accountability with conversations around process and collective accountability at the operational level. Crime statistics were used less for operational-level accountability and more for attention-directing. Third, changing the emphasis from transparency to its combined use with “intelligent” accountability required strong leadership, clearly communicated strategy and middle-level managers with appropriate skills.Originality/valueThe authors identify a number of important factors in combining transparency and “intelligent” forms of accountability. The authors note the difficulties that fragmentation between forms of accountability and the somewhat amorphous nature of the accountability concept itself can cause. In doing so, the authors provide empirical evidence of the challenges changing from an emphasis on transparency, to combined use with an “intelligent” form of accountability.
Understanding the China miracle from the paradigm of realm economics
Authors: Chen Xiaodong 
Published: December 2021

PurposeThe core of the micro–macro paradigm of mainstream Western economics is the assumption that a rational economic man with complete freedom of economic behaviors living in a fully competitive, free-market economy pursues maximum personal benefits. The purpose of this paper is to show the reasons for failure of mainstream Western economics explaining the “mystery of China’s economic growth” and the necessity of understanding the mystery from the paradigm of realm economics.Design/methodology/approachThe system of socialism with Chinese characteristics led by the Communist Party of China (CPC) and the local governments that play a crucial role in the reform and opening-up has the realm attribute. It is necessary to develop a new paradigm for realm economic analysis and promote the creation of new economic globalization and international political and economic order.FindingsAccording to the fourth plenary session of the 19th CPC Central Committee, “Since the New China was founded 70 years ago, our Party has led our people to create the rarely-seen miracle of rapid economic development and miracle of long-term social stability”. The authors find that it is effective and necessary to explain the miracle of China’s economic growth from the paradigm of realm economics.Originality/valueAs proven by practice, the system of socialism with Chinese characteristics and the governance system of China are guided by Marxism, rooted in China with a deep Chinese cultural foundation, and sincerely supported by the people.
Solving the dilemma in supplier selection by the group of weight vector with kernel
Authors: Liu Sifeng , Liu Tao , Yuan Wenfeng , Yang Yingjie 
Published: December 2021

PurposeThe purpose of this paper is to solve the dilemma in the process of major selection decision-making.Design/methodology/approachFirstly, the group of weight vector with kernel has been defined. Then, the weighted comprehensive clustering coefficient vector was calculated based on the group of weight vector with kernel. Under the action of weighted comprehensive clustering coefficient vector, the information including in other components around component k and supporting object i to be classified into the k-th category has been gathered to component k. At last, a novel two-stage decision model based on the group of weight vector with kernel and the weighted comprehensive clustering coefficient vector is put forward to solve the dilemma in grey clustering evaluation. Then the overall evaluation conclusion can be consistent with the clustering result according to the rule of maximum value.FindingsA new way to solve the dilemma in the process of major selection decision-making has been found. People can obtain a consistent result with two-stage decision model at the case of dilemma. That is, the conclusion of the overall evaluation is consistent with the clustering result according to the rule of maximum value.Practical implicationsSeveral functional groups of weight vector with kernel have been put forward. The proposed model can solve the clustering dilemma effectively and produce consistent results. A practical application of decision problem to solve the dilemma in supplier evaluation and selection of a key component of large commercial aircraft C919 have been completed by the novel two-stage decision model.Originality/valueThe two-stage decision model, the group of weight vector with kernel and the weighted comprehensive clustering coefficient vector were presented in this paper firstly. People can solve the dilemma in grey clustering evaluation effectively by the novel two-stage decision model based on the group of weight vector with kernel and the weighted comprehensive clustering coefficient vector.
Do “inferior” jobs always suffer from a wage penalty? Evidence from temporary workers in Cambodia and Pakistan
Authors: Nguyen-Huu Thanh-Tam 
Published: December 2021

Purpose
This paper aims to investigate the wage gap between temporary and permanent workers in Pakistan and Cambodia.

Design/methodology/approach
Quantile regression estimator is likely to be the most relevant to the sample.

Findings
The estimates indicate the presence of a temporary employment wage penalty in Pakistan and contrarily a wage premium in Cambodia. Moreover, quantile regression estimates show that wage differentials could greatly vary across the wage distribution. The wage gap is wider at the bottom of the wage distribution in Pakistan, suggesting a sticky floor effect that the penalty of being in temporary jobs could be more severe for disadvantaged workers. By contrast, a glass ceilings effect is found in Cambodia, indicating that the wage premium is small at the bottom and becomes high at the top of the pay ladder.

Originality/value
Despite the rise of temporary jobs in the past several decades, the empirical evidence on wage differentials between temporary and permanent workers is extremely limited in developing Asian countries. This paper is the first research work that systematically examines the temporary-permanent wage gap in selected Asian countries, based on their National Labor Force Survey data.