bluuebunny/crossref_metadata_2025_split huggingface dataset:
From GWAS to signal validation: An approach for estimating genetic effects while preserving genomic context
Authors: Wolf Scott , Abhyankar Varada , Melo Diogo , Ayroles Julien F. , Pallares Luisa F. 
Published: March 2023

AbstractValidating associations between genotypic and phenotypic variation remains a challenge, despite advancements in association studies. Common approaches for signal validation rely on gene-level perturbations, such as loss-of-function mutations or RNAi, which test the effect of genetic modifications usually not observed in nature. CRISPR-based methods can validate associations at the SNP level, but have significant drawbacks, including resulting off-target effects and being both time-consuming and expensive. Both approaches usually modify the genome of a single genetic background, limiting the generalizability of experiments. To address these challenges, we present a simple, low-cost experimental scheme for validating genetic associations at the SNP level in outbred populations. The approach involves genotyping live outbred individuals at a focal SNP, crossing homozygous individuals with the same genotype at that locus, and contrasting phenotypes across resulting synthetic outbred populations. We tested this method inDrosophila melanogaster, measuring the longevity effects of a polymorphism at a naturally-segregating cis-eQTL for themidwaygene. Our results demonstrate the utility of this method in SNP-level validation of naturally occurring genetic variation regulating complex traits. This method provides a bridge between the statistical discovery of genotype-phenotype associations and their validation in the natural context of heterogeneous genomic contexts.
Structural basis for differential p19 targeting by IL-23 biologics
Authors: Daniele Stefano G. , Eldirany Sherif A. , Ho Minh , Bunick Christopher G. 
Published: March 2023

AbstractBackgroundIL-23 is central to the pathogenesis of psoriasis, and is structurally comprised of p19 and p40 subunits. “Targeted” IL-23 inhibitors risankizumab, tildrakizumab, and guselkumab differ mechanistically from ustekinumab because they bind p19, whereas ustekinumab binds p40; however, a knowledge gap exists regarding the structural composition of their epitopes and how these molecular properties relate to their clinical efficacy.ObjectivesTo characterize and differentiate the structural epitopes of the IL-23 inhibitors risankizumab, guselkumab, tildrakinumab, and ustekinumab, and correlate their molecular characteristics with clinical response in plaque psoriasis therapy.MethodsWe utilized epitope data derived from hydrogen-deuterium exchange studies for risankizumab, tildrakizumab, and guselkumab, and crystallographic data for ustekinumab to map drug epitope locations, hydrophobicity, and surface charge onto the IL-23 molecular surface (Protein Data Bank ID Code 3D87) using UCSF Chimera. PDBePISA was used to calculate solvent accessible surface area (SASA). Epitope composition was determined by classifying residues as acidic, basic, polar, or hydrophobic and calculating their contribution to epitope SASA. Linear regression and analysis of variance was performed.ResultsAll the p19-specific inhibitor epitopes differ in location and size, with risankizumab and guselkumab having large epitope surface areas (SA), and tildrakizumab and ustekinumab having smaller SA. The tildrakizumab epitope was mostly hydrophobic (56%), while guselkumab, risankizumab, and ustekinumab epitopes displayed >50% non-hydrophobic residues. Risankizumab and ustekinumab exhibited acidic surface charges, while tildrakizumab and guselkumab were net neutral. Each inhibitor binds an epitope with a unique size and composition, and with mostly distinct locations except for a 10-residue overlap region that lies outside of the IL-23 receptor epitope. We observed a strong correlation between epitope SA and PASI-90 rates (R2= 0.9969,p= 0.0016), as well as between epitope SA and KD(R2= 0.9772,p= 0.0115). In contrast, we found that total epitope hydrophobicity, polarity, and charge content do not correlate with clinical efficacy.ConclusionsStructural analysis of IL-23 inhibitor epitopes reveals strong association between epitope SA and early drug efficacy in plaque psoriasis therapy, exemplifying how molecular data can explain clinical observations, inform future innovation, and help clinicians in specific drug selection for patients.
Analysis of human GPER expression in normal tissues and select cancers using immunohistochemistry
Authors: Natale Christopher A. , Seykora John T. , Ridky Todd W 
Published: March 2023

AbstractGPER (G protein-coupled estrogen receptor) has been reported to play roles in several areas of physiology including cancer, metabolic disorders, and cardiovascular disease. However, the understanding of where this receptor is expressed in human tissue is limited due to limited available tools and methodologies that can reliably detect GPER protein. Recently, a highly specific monoclonal antibody against GPER (20H15L21) was developed and is suitable for immunohistochemistry. Using this antibody, we show that GPER protein expression varies markedly between normal human tissue, and also among cancer tissue. As GPER is an emerging therapeutic target for cancer and other diseases, this new understanding of GPER distribution will likely be helpful in design and interpretation of ongoing and future GPER research.
Evolutionary history of MEK1 illuminates the nature of cancer and RASopathy mutations
Authors: Andrianova Ekaterina P. , Marmion Robert A. , Shvartsman Stanislav Y. , Zhulin Igor B. 
Published: March 2023

AbstractMutations in signal transduction pathways lead to various diseases including cancers. MEK1 kinase, encoded by the humanMAP2K1gene, is one of the central components of the MAPK pathway and more than a hundred somatic mutations inMAP2K1gene were identified in various tumors. Germline mutations deregulating MEK1 also lead to congenital abnormalities, such as the Cardiofaciocutaneous Syndrome and Arteriovenous Malformation. Evaluating variants associated with a disease is a challenge and computational genomic approaches aid in this process. Establishing evolutionary history of a gene improves computational prediction of disease-causing mutations; however, the evolutionary history of MEK1 is not well understood. Here, by revealing a precise evolutionary history of MEK1 we construct a well-defined dataset of MEK1 metazoan orthologs, which provides sufficient depth to distinguish between conserved and variable amino acid positions. We used this dataset to match known and predicted disease-causing and benign mutations to evolutionary changes observed in corresponding amino acid positions. We found that all known and the vast majority of suspected disease-causing mutations are evolutionarily intolerable. We selected several MEK1 mutations that cannot be unambiguously assessed by automated variant prediction tools, but that are confidently identified as evolutionary intolerant and thus “damaging” by our approach, for experimental validation inDrosophila. In all cases, evolutionary intolerant variants caused increased mortality and severe defects in fruit fly embryos confirming their damaging nature predicted by out computational strategy. We anticipate that our analysis will serve as a blueprint to help evaluate known and novel missense variants in MEK1 and that our approach will contribute to improving automated tools for disease-associated variant interpretation.Significance StatementHigh-throughput genome sequencing has significantly improved diagnosis, management, and treatment of genetic diseases and cancers. However, in addition to its indisputable utility, genome sequencing produces many variants that cannot be easily interpreted – so called variants of uncertain significance (VUS). Various automated bioinformatics tools can help predicting functional consequences of VUS, but their accuracy is relatively low. Here, by tracing precise evolutionary history of each amino acid position in MEK1 kinase, mutations in which cause neurodegenerative diseases and cancer in humans, we can establish whether VUS seen in humans are evolutionarily tolerant. Using published data and newly performed experiments in an animal model, we show that evolutionarily tolerable variants in MEK1 are benign, whereas intolerable substitutions are damaging. Our approach will help in diagnostics of MEK1-associated diseases, it is generalizable to many other disease-associated genes, and it can help improving automated predictors.
Impaired potency of neutralizing antibodies against cell-cell fusion mediated by SARS-CoV-2
Authors: Wang Qian , Yeh Andre Yanchen , Guo Yicheng , Mohri Hiroshi , Yu Jian , Ho David D. , Liu Lihong 
Published: March 2023

AbstractThe SARS-CoV-2 Omicron subvariants have dominated the pandemic due to their high transmissibility and immune evasion conferred by the spike mutations. The Omicron subvariants can spread by cell-free virus infection and cell-cell fusion, the latter of which is more effective but has not been extensively investigated. In this study, we developed a simple and high-throughput assay that provides a rapid readout to quantify cell-cell fusion mediated by the SARS-CoV-2 spike proteins without using live or pseudotyped virus. This assay can be used to identify variants of concern and to screen for prophylactic and therapeutic agents. We further evaluated a panel of monoclonal antibodies (mAbs) and vaccinee sera against D614G and Omicron subvariants, finding that cell-cell fusion is substantially more resistant to mAb and serum inhibition than cell-free virus infection. Such results have important implications for the development of vaccines and antiviral antibody drugs against cell-cell fusion induced by SARS-CoV-2 spikes.
SARS-CoV-2 protein structure and sequence mutations: evolutionary analysis and effects on virus variants
Authors: Lomoio Ugo , Puccio Barbara , Tradigo Giuseppe , Guzzi Pietro Hiram , Veltri Pierangelo 
Published: March 2023

AbstractProteins sequence, structure, and function are related, so that any changes in the protein sequence may cause modifications in its structure and function. Thanks to the exponential growth of data availability, many studies have addressed different questions such as: (i) how structure evolves based on the sequence changes, (ii) how structure and function change over time. Computational experiments have contributed to the study of viral protein structures. For instance the Spike (S) protein has been investigated for its role in binding receptors and infection activity in COVID-19, hence the interest of scientific researchers in studying the effects of virus mutations due to sequence, structure and vaccination effects. Protein Contact Networks (PCNs) can be used for investigating protein structures to detect biological properties thorough network topology. We apply topological studies based on graph theory of the PCNs to compare the structural changes with sequence changes, and find that both node centrality and community extraction analysis play a relevant role in changes in protein stability and functionality caused by mutations. We compare the structural evolution to sequence changes and study mutations from a temporal perspective focusing on virus variants. We finally highlight a timeline correlation between Omicron variant identification and the vaccination campaign.
Subjective and objective indicators of neighbourhood safety and physical activity among UK adolescents
Authors: Fernandez Charlotte Constable , Patalay Praveetha , Vaughan Laura , Church David , Hamer Mark , Maddock Jane 
Published: March 2023

AbstractThe health benefits of regular physical activity in adolescence are well-documented. Many health-related behaviours and lifestyle choices are established in adolescence. The neighbourhood environment is a key setting for physical activity in adolescence and feeling unsafe in their neighbourhood may be a potential barrier to physical activity. This study aimed to examine associations between neighbourhood safety and physical activity using objective and subjective measures for both. Participants (n=10,913) came from the Millennium Cohort Study, a nationally representative UK longitudinal birth cohort. Results indicate that feeling unsafe in the neighbourhood, IMD crime and violent crime are barriers to physical activity participation in adolescents.
Identifying metabolic features of colorectal cancer liability using Mendelian randomization
Authors: Bull Caroline J. , Hazelwood Emma , Bell Joshua A. , Tan Vanessa Y. , Constantinescu Andrei-Emil , Borges Maria Carolina , Legge Danny N. , Burrows Kimberly , Huyghe Jeroen R. , Brenner Hermann , Castellví-Bel Sergi , Chan Andrew T , Kweon Sun-Seog , Marchand Loic Le , Li Li , Cheng Iona , Pai Rish K. , Figueiredo Jane C. , Murphy Neil , Gunter Marc J. , Timpson Nicholas J. , Vincent Emma E. 
Published: March 2023

AbstractBackgroundRecognizing the early signs of cancer risk is vital for informing prevention, early detection, and survival.MethodsTo investigate whether changes in circulating metabolites characterise the early stages of colorectal cancer (CRC) development, we examined associations between a genetic risk score (GRS) associated with CRC liability (72 single nucleotide polymorphisms) and 231 circulating metabolites measured by nuclear magnetic resonance spectroscopy in the Avon Longitudinal Study of Parents and Children (N=6,221). Linear regression models were applied to examine associations between genetic liability to colorectal cancer and circulating metabolites measured in the same individuals at age 8, 16, 18 and 25 years.ResultsThe GRS for CRC was associated with up to 28% of the circulating metabolites at FDR-P<0.05 across all time points, particularly with higher fatty acids and very-low- and low-density lipoprotein subclass lipids. Two-sample reverse Mendelian randomization (MR) analyses investigating CRC liability (52,775 cases, 45,940 controls) and metabolites measured in a random subset of UK Biobank participants (N=118,466, median age 58y) revealed broadly consistent effect estimates with the GRS analysis. In conventional (forward) MR analyses, genetically predicted polyunsaturated fatty acid concentrations were most strongly associated with higher CRC risk.ConclusionsThese analyses suggest that higher genetic liability to CRC can cause early alterations in systemic metabolism, and suggest that fatty acids may play an important role in CRC development.FundingThis work was supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, the Wellcome Trust, the Medical Research Council, Diabetes UK, the University of Bristol NIHR Biomedical Research Centre, and Cancer Research UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work used the computational facilities of the Advanced Computing Research Centre, University of Bristol -http://www.bristol.ac.uk/acrc/.
Approaches to improving mental health care for autistic people: a systematic review
Authors: Loizou Sofia , Pemovska Tamara , Stefanidou Theodora , Foye Una , Cooper Ruth , Kular Ariana , Greenburgh Anna , Baldwin Helen , Griffiths Jessica , Saunders Katherine R. K. , Barnett Phoebe , Minchin Matilda , Brady Gráinne , Ahmed Nafiso , Parker Jennie , Chipp Beverley , Olive Rachel Rowan , Jackson Robin , Timmerman Amanda , Sapiets Suzi , Driskell Eva , Parsons Bethany , Spain Debbie , Totsika Vaso , Mandy Will , Pender Richard , Clery Philippa , Trevillion Kylee , Lloyd-Evans Brynmor , Simpson Alan , Johnson Sonia 
Published: March 2023

AbstractBackgroundAutistic people have a high likelihood of developing mental health difficulties but a low chance of receiving effective mental health care. Therefore, there is a need to identify and examine strategies to improve mental health care for autistic people.AimsTo identify strategies that have been implemented to improve access, experiences of care and mental health outcomes for autistic adults and examine evidence on their acceptability, feasibility and effectiveness.MethodA co-produced systematic review was conducted. MEDLINE, PsycINFO, CINHAL, medRxiv and PsyArXiv were searched. We included all study designs reporting acceptability or feasibility outcomes and empirical quantitative study designs reporting effectiveness outcomes. Data were synthesised using a narrative approach.ResultsA total of 29 articles were identified. These included 16 studies of adapted mental health interventions, seven studies of service improvements and six studies of bespoke mental health interventions developed for autistic people. There was no conclusive evidence on effectiveness. However, most bespoke and adapted approaches appeared to be feasible and acceptable. Identified adaptations appeared to be acceptable and feasible, including increasing knowledge and detection of autism, providing environmental adjustments and communication accommodations, accommodating individual differences, and modifying the structure and content of interventions.ConclusionMany identified strategies are feasible and acceptable and can be readily implemented in services with the potential to make mental health care more suitable for autistic people, but important research gaps remain. Future research should address these and investigate a co-produced package of service improvement measures.
Species-specific metabolic reprogramming in human and mouse microglia during inflammatory pathway induction
Authors: Sabogal-Guaqueta Angelica Maria , Marmolejo-Garza Alejandro , Lima Marina Trombetta , Oun Asmaa , Hunneman Jasmijn , Chen Tingting , Koistinaho Jari , Lehtonen Sarka , Kortholt Arjan , Bakker Barbara M. , Eggen Bart J.L. , Boddeke Erik , Dolga Amalia 
Published: March 2023

AbstractMetabolic reprogramming is a hallmark of the immune cells in response to inflammatory stimuli. This metabolic process involves a switch from oxidative phosphorylation (OXPHOS) to glycolysis, or alterations in other metabolic pathways. However, most of the experimental findings have been acquired in murine immune cells and little is known about the metabolic reprogramming of human microglia. In this study, we investigated the transcriptomic and metabolic profiles of mouse and iPSC-derived human microglia challenged with the TLR4 agonist LPS. We found that both species displayed a metabolic shift and an overall increased glycolytic gene signature in response to LPS treatment. The metabolic reprogramming was characterized by the upregulation of hexokinases in mouse microglia and phosphofructokinases in human microglia. This study provides the first direct comparison of energy metabolism between mouse and human microglia, highlighting the species-specific pathways involved in immunometabolism and the importance of considering these differences in translational research.
Intrinsic motivations affecting millennial mobile impulsive shopping in emerging markets during the COVID-19 pandemic
Authors: Lavuri Rambabu , Kaur Jaspreet , Thaichon Park 
Published: March 2023

PurposeThis study examines intrinsic motivations and antecedents that affect millennial mobile impulsive shopping in markets with the technology acceptance model (TAM) during the COVID-19 pandemic.Design/methodology/approachThe study has been conducted by collecting data from 367 regular mobile shopping millennials, which was analyzed by structural equation modeling.FindingsThe findings reported that the perceived ease of use correlates positively with perceived usefulness. Similarly, perceived ease of use, usefulness, perceived utilitarian value and hedonic value significantly impacts shoppers' trust and attitude toward impulsive mobile shopping. Perceived trust was found to exhibit a positive association with mobile shopping. Finally, perceived usefulness, ease of use, utilitarian value, hedonic value, trust and attitude significantly positively impacted millennials' impulsive mobile shopping.Practical implicationsThis study's results will help e-retailers establish novel techniques and efforts to enhance market volume and build solid connections with mobile customers by ensuring secure purchase habits. The results would also help companies develop customer satisfaction-focused business strategies.Originality/valueThis study contributes to the body of literature by finding a significant impact of attitude, trust and shopping values on impulsive mobile shopping. These constructs have not been explored as factors impacting mobile impulsive shopping, especially when it comes to a pandemic.
Leadership development programmes: part of the solution or part of the problem of women’s under-representation in leadership?
Authors: Loumpourdi Maria 
Published: March 2023

Purpose
This paper aims to critically reflect on current leadership development programmes (LDPs) and their potential in addressing the issue of women’s under-representation in leadership positions. To this end, this paper queries the current processes through which employees are selected to participate in LDPs as well as how these programmes are designed.

Design/methodology/approach
Drawing on Martha Nussbaum’s capabilities approach, this conceptual paper draws attention to the pitfalls of current organisational practices aimed at women’s leadership development.

Findings
The introduction of gender quotas and the implementation of women-only LDPs are unlikely to address the persistent gender leadership gap. Instead, these practices are likely to intensify the negative effects of second-generation gender bias and perpetuate the issue of gender inequality and inequity in the workplace.

Originality/value
This paper critiques contemporary organisational practices aimed at women’s leadership development and suggests alternative practices which are more likely to respond to the issue of women’s under-representation in leadership positions.
How to handle gerontocracy
Authors: Canoy Marcel , Krabbe Yvonne , Koolman Xander 
Published: March 2023

PurposeThe article demonstrates the dangers of gerontocracy and offers solutions.Design/methodology/approachThe article combines desk research, literature review and economic analytical reasoning.FindingsGerontocracy in developed countries is a threat to financial, labour market and political sustainability of care for older people. Without actions today, the problem will become bigger every year, not least because of increased electoral weight of older people. This article proposes to handle gerontocracy in two ways. First is by using the potential of healthy retired people as volunteers, thereby mitigating the intergenerational solidarity challenges. Second is by taxing part of the windfall profits on the housing market, where older generation profited disproportionally.Originality/valueThe added value of the article is twofold. First, it signals a serious problem in affluent societies that is largely ignored, both in the academic world and in politics. Second, it offers original solutions that mitigate the problem.