bluuebunny/crossref_metadata_2025 huggingface dataset:
Stabilizing selection generates selection against introgressed DNA
Authors: Veller Carl , Simons Yuval
Published: August 2024

DNA introgressed from one population into another is often deleterious to the recipient population if the two populations have diverged genetically from one another. Previous explanations of this phenomenon have posited negative interactions between donor-population alleles and the recipient population’s genome or environment, or higher genetic load in the donor population. Here, we show that stabilizing selection on quantitative traits—even around the same optimal trait values in the two populations and when the populations are demographically identical—generates selection against the minor-parent ancestry in a population formed via unequal admixture of the two populations. We calculate the rate at which minor-parent ancestry is purged under this mechanism, both in the early generations after admixture and in the long term, and we verify these calculations with whole-genome simulations. Because of its ubiquity, stabilizing selection offers a general mechanism for the deleterious effect of introgressed ancestry.
Divergent Evolution in Bilateral Prostate Cancer: a Case Study
Authors: Haas Roni , Patel Yash , Liu Lydia Y. , Huang Rong Rong , Weiner Adam , Yamaguchi Takafumi N. , Agrawal Raag , Boutros Paul C. , Reiter Robert E.
Published: August 2024

Multifocal prostate cancer is a prevalent phenomenon, with most cases remaining uncharacterized from a genomic perspective. A patient presented with bilateral prostate cancer. On systematic biopsy, two indistinguishable clinicopathologic lesions were detected. Whole-genome sequencing displayed somatically unrelated tumours with distinct driver CNA regions, suggesting independent origins of the two tumors. We demonstrated that similar clinicopathologic multifocal tumours, which might be interpreted as clonal disease, can in fact represent independent cancers. Genetic prognostics can prevent mischaracterization of multifocal disease to enable optimal patient management.
Unveiling Genetic Associations: InvestigatingCLDN16, GRID2, NRG3,andCACNG4Gene Polymorphisms with Insulin Resistance Risk Among Normal BMI Individuals in the Indian Population
Authors: Thummala Sabitha , Khan Ghori Junaid Ahmed , Fathima Sarah , Saikia Katherine , Kruthi Nithya , Duraimani Shanti Lakshmi , Balamurali AR , Ranganathan Rahul
Published: August 2024

Studies estimate that India has about 65+ million diabetic patients with a substantial impending increase, making it the international ‘diabetes capital’. Diabetes Mellitus is a metabolic disorder which is signified by elevated blood sugar levels due to defects in insulin action, secretion or both. Insulin resistance (IR) or insulin resistance-linked obesity is also known to be a causing factor of Metabolic syndrome which is a combination of cardiovascular risk factors that include raised fasting plasma glucose, central obesity, hypertension, raised triglycerides, and reduced High-Density Lipoprotein (HDL) cholesterol. This study investigated the association between four single nucleotide polymorphisms (SNPs) in the selected genes - rs6801387 (CLDN16), rs72872727 (GRID2), rs1414756 (NRG3), and rs8065294 (CACNG4) and (IR) among a normal BMI Indian population. Through Chi-Square tests, we detected significant associations between SNP genotypes and (IR). Allele frequency analysis revealed higher frequencies of allele G (rs6801387) and T (rs72872727) among individuals with HOMA2-IR >2, while allele T (rs8065294) indicated decreased risk, emphasizing the relevance of genetic factors in metabolic disorders. The differences in clinical parameters such as fat mass, serum triglycerides and HbA1c between the cases and controls highlights the multifactorial nature of the condition. Inheritance model suggested the dominant inheritance for rs6801387 and rs72872727 and codominant inheritance for rs1414756 and rs806529, offering insights into genetic associations with IR. Despite the study’s moderate sample size,these genetic biomarkers exhibit strong susceptibility to the studied condition, showing the importance of exploring their functional significance and underlying biological mechanisms in future research endeavours.
Parent attitudes and behaviors associated with household food security among rural lower income families
Authors: Moore Amy M. , Savage Jennifer S. , Poulsen Melissa N. , Hosterman Jennifer Franceschelli , McCabe Carolyn F. , Bailey-Davis Lisa
Published: August 2024

Objective

To examine associations between Theory of Planned Behavior constructs related to parent engagement in health-promoting behaviors and food resource management with household food security status.

Methods

A cross-sectional secondary analysis of baseline data from 1622 parents enrolled in the ENCIRCLE study, a pragmatic cluster-randomized controlled trial to prevent obesity among preschool-aged children from rural lower-income families. Logistic regression models examined associations between parent engagement in health-promoting behaviors (attitude, subjective norm, perceived behavioral control) and food resource management (self-confidence, behaviors) with household food security status.

Results

Parents with greater perceived behavioral control (OR=1.44, CI:1.14-1.82) and food resource management self-confidence (OR=2.08, CI:1.80-2.41) had significantly higher odds of experiencing household food security in adjusted models.

Conclusions and Implications

Findings suggest that perceived behavioral control and food resource management self-confidence may help safeguard lower-income families. Health promotion efforts should target these factors to help parents engage in health-promoting behaviors during times of economic hardship.
Bronchoalveolar Lavage Single-Cell Transcriptomics Identifies Immune Cells Driving COVID-19 Severity in Patients
Authors: Asaba Clinton Njinju , Bitazar Razieh , Labonté Patrick Ndonyi , Bukong Terence Ndonyi
Published: August 2024

The continuous threats posed by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, including the emergence of potentially more infectious and deadly variants, necessitate ongoing studies to uncover novel and detailed mechanisms driving disease severity. Using single-cell transcriptomics, we conducted a secondary data analysis of bronchoalveolar lavage fluid (BALF) from COVID-19 patients of varying severities and healthy controls to comprehensively examine immune responses. We observed significant immune cell alterations correlating with disease severity. In severe cases, macrophages showed upregulation of pro-inflammatory genes TNFα and IL1β, contributing to severe inflammation and tissue damage. Neutrophils exhibited increased activation, marked by S100A8, CXCL8, and IL1β expression, with extended viability and reduced phagocytosis. Genes such as MCL1 and HIF1α supported extended viability, while MSR1 and MRC1 indicated reduced phagocytosis. Enhanced formation of neutrophil extracellular traps (NETs) and reduced clearance, indicated by NET-associated markers, were linked to thrombo-inflammation and organ damage. Both macrophages and neutrophils in severe cases showed impaired efferocytosis, indicated by decreased expression of MSR1 and TREM2 in macrophages and downregulation of FCGR3B in neutrophils, leading to the accumulation of apoptotic cells and exacerbating inflammation. Severe cases were characterized by M1 macrophages with high TNFα and IL1β, while milder cases had M2 macrophages with elevated PPARγ. Low-density neutrophils (LDNs) increased significantly in severe cases, showing higher CXCR4 and CD274 and lower FCGR3B compared to high-density neutrophils (HDNs). NK and T cells in severe cases demonstrated altered receptor and gene expression, with increased activation markers IFNγ and ISG15, suggesting a paradoxical state of activation and exhaustion. This imbalance suggests a potential mechanism for immune dysregulation and ineffective antiviral responses in severe COVID-19. This analysis highlights the critical role of dysregulated neutrophil, macrophage, NK, and T cell responses in severe COVID-19, identifying potential therapeutic targets and providing novel insights into the disease.
Australian medical research that considered sex as a biological variable: a meta-analysis
Authors: Ryan Janelle , Landen Shanie , Harley Vincent
Published: August 2024

Subjects in medical research have predominantly been male (1). Women experience 50-75% more adverse drug responses (2) resulting in withdrawn medications (3). While sex differences in metabolism, disease and treatment response are increasingly recognised, sex-informed medicine is lagging. In 2016, USAs National Institutes of Health (NIH) formulated the Sex as a Biological Variable policy (4), stating that grant recipients must consider sex in experimental design, planning, analysis and reporting of their findings. Australian data is lacking on the inclusion of both males and females as well as appropriate analysis of sex differences.

We analysed the 219 Medical Journal of Australia (MJA) research articles over 2019-2023 (Box 1). We tallied when; i) both males and females were included in the study, ii) sex differences were reported and/or considered, and iii) the analysis was appropriate to support sex-related claims.

We found that articles published in MJA are including males and females, however testing of sex differences is uncommon and appropriate statistical analysis is lacking. We hope that this article will bring attention to this fundamental issue and improve future efforts to investigate sex differences.
Protocol for a scoping review of theorised pathways between home energy decarbonisation and health and health inequalities
Authors: Ponce Hardy Vicki , Stevenson Amy , McCartney Gerry , Heppenstall Alison , Meier Petra
Published: August 2024

Introduction: Access to adequate energy in the home is necessary for a healthy and well life, however current energy use, particularly in high-income countries, is unsustainable. Decarbonisation of home energy can benefit climate mitigation and health but there is the potential to create new, or compound existing, inequalities in health if not implemented equitably. Mapping the theoretical causal pathways between home decarbonisation and health will contribute to further understanding of these mechanisms. Aims: Firstly, to identify theoretical pathways between decarbonisation of home energy and health and health inequalities in high-income countries, and secondly, to synthesise these into a putative causal evidence map. Inclusion criteria: All populations in high-income countries are included, as defined by the World Bank in 2023/24. Included concepts are decarbonisation of home energy, and health and health inequalities. Context for this review comprises of the inclusion of a clear theory linking the concepts. All study designs are included. Methods: This protocol is for a review of theories rather than of intervention effectiveness. Medline/OVID, Scopus, and EconLit will be searched, with no limitation on date. Relevant international policy websites will also be searched. The search is limited to papers in English. Citation tracing may identify further relevant papers. Abstracts and full texts will be screened using Rayyan. At least 10% will be double-screened, and the rest screened by one author, and included full texts will be screened until data saturation is reached. Study inclusion is based on consistency with the inclusion criteria, with some flexibility allowed due to the theoretical nature of this review. Data extracted from papers will be used to develop a diagrammatic map of pathways.
Health Data Nexus: An Open Data Platform for AI Research and Education in Medicine
Authors: Adams January , Cymerys Rafal , Szuster Karol , Hekman Daniel , Salo Zoryana , Solanki Rutvik , Mamdani Muhammad , Johnson Alistair , Ryniak Katarzyna , Pollard Tom , Rotenberg David , Haibe-Kains Benjamin
Published: August 2024

We outline the development of the Health Data Nexus, a data platform which enables data storage and access management with a cloud-based computational environment. We describe the importance of this secure platform in an evolving public sector research landscape that utilizes significant quantities of data, particularly clinical data acquired from health systems, as well as the importance of providing meaningful benefits for three targeted user groups: data providers, researchers, and educators. We then describe the implementation of governance practices, technical standards, and data security and privacy protections needed to build this platform, as well as example use-cases highlighting the strengths of the platform in facilitating dataset acquisition, novel research, and hosting educational courses, workshops, and datathons. Finally, we discuss the key principles that informed the platform’s development, highlighting the importance of flexible uses, collaborative development, and open-source science.
Benchmarking Vision Encoders for Survival Analysis using Histopathological Images
Authors: Nizami Asad , Halder Arita
Published: August 2024

Abstract

Cancer is a complex disease characterized by the uncontrolled growth of abnormal cells in the body but can be prevented and even cured when detected early. Advanced medical imaging has introduced Whole Slide Images (WSIs). When combined with deep learning techniques, it can be used to extract meaningful features. These features are useful for various tasks such as classification and segmentation. There have been numerous studies involving the use of WSIs for survival analysis. Hence, it is crucial to determine their effectiveness for specific use cases. In this paper, we compared three publicly available vision encoders-UNI, Phikon and ResNet18 which are trained on millions of histopathological images, to generate feature embedding for survival analysis. WSIs cannot be fed directly to a network due to their size. We have divided them into 256 × 256 pixels patches and used a vision encoder to get feature embeddings. These embeddings were passed into an aggregator function to get representation at the WSI level which was then passed to a Long Short Term Memory (LSTM) based risk prediction head for survival analysis. Using breast cancer data from The Cancer Genome Atlas Program (TCGA) and k-fold cross-validation, we demonstrated that transformer-based models are more effective in survival analysis and achieved better C-index on average than ResNet-based architecture. The code1for this study will be made available.
Treatment Efficacy of Theophylline in ADYC5 Dyskinesia: A Retrospective Case Series Study
Authors: Taenzler Dirk , Hause Frank , Merkenschlager Andreas , Sinz Andrea
Published: August 2024

Background

ADCY5-related dyskinesia is a rare disorder caused by mutations in the ADCY5 gene resulting in abnormal involuntary movements. Currently, there are no standardized guidelines to treat this condition.

Objectives

The aim of this study is to evaluate the efficacy of theophylline administration in improving symptoms and quality of life in patients with ADCY5-related dyskinesia.

Methods

A retrospective study was conducted involving 12 patients (aged 2-34 years) with ADCY5-related dyskinesia. Participants completed a questionnaire about theophylline administration, including dosage, improvement of symptoms, adverse effects, and changes in quality of life. Data were analyzed for reported efficacy and side effects.

Results

Theophylline administration demonstrated substantial efficacy, with 92% (11 out of 12) of patients reporting significant improvements in their movement disorders. The average improvement score was 7.0 (± 1.9) on a 10-point scale. Notable improvements included reductions in severity and frequency of episodes, improved gait, more independent mobility, psycho-social well-being, and quality of sleep. Adverse effects were reported by 6 patients, including dystonia, speech worsening, headaches, nausea, impaired sleep, and agitation.

Conclusions

Theophylline shows substantial promise as a treatment option for ADCY5-related dyskinesia, improving various aspects of patients’ quality of life and movement disorder symptoms. Further research is needed to optimize dosing, to understand long-term effects, and to explore combinational drug therapies. Despite the small cohort size and the retrospective nature of this study, the results support theophylline administration to decrease dyskinetic movements and enhance overall quality of life in patients.
‘We need to feel that the Government value our lives’: Examining Irish women’s experience of cervical screening services
Authors: McGregor Royanne , Foley Sarah
Published: August 2024

Cervical cancer is one of the top three cancers diagnosed in women globally. When women have access to a testing programme, abnormal cells can be detected to prevent the development of cancer. Research to date indicates that social and cultural barriers are the top two barriers in accessing cervical screening. In Ireland there may be a lack of trust in the National Cervical Screening programme due to previous mishandling of tests, and media coverage of the impacts of inaccurate screening results in Ireland. To understand impact of the health scandal on women’s trust in cervical screening in Ireland, nine Irish women ages between 25-65 were interviewed. Data was thematically analysed using a feminist perspective to centre the women’s voices in making sense of their appraisal and engagement with services. The data analysis resulted in four themes: Personal Reflections on Systemic Failure; Collective Concern and Blame; Decision Making Influencers and Rebuilding Knowledge and Trust. This analysis conveys distrust in the Irish Cervical Screening programme, feelings of anger, and a sense of neglect from the services. Irish women now place their trust in each other, the experience of their friends, families, their local GP. We discuss these finding to explore how Irish women have reinterpreted the narrative over the screening test in Ireland, and the potential to decrease concern around the topic by incorporating this experience into official narratives. This scandal heightened existing distrust and concern for the quality of women’s screening services, and therefore has global relevance which can be applied to screening services more generally.
Remarkable similarity in oxygen tolerance among taxonomically diverse marine taxa revealed through hierarchical analysis
Authors: Essington Timothy E. , Thorson James T. , Deutsch Curtis
Published: August 2024

Species’ ranges are shifting in response to increasing temperature and decreasing oxygen in coastal oceans. Forecasting these shifts is limited by information on physiological oxygen thresholds and how they depend on temperature. Here, we adopt an ecophysiological metric, the metabolic index, and estimate its parameters from data collected on marine taxa using phylogenetic trait imputation. The metabolic index is the ratio of temperature-dependent rates of oxygen supply to basal oxygen demands. By applying a hierarchical phylogenetic model to a data set of 74 marine taxa that accounts for both taxonomic distance (from Linnean classification) and biases related to lab methods, we find that the critical oxygen pressure at a reference body size and temperature is remarkably consistent across taxa, ranging 2.9 to 4.9 kPa. In comparison, the estimated effect of temperature on the critical oxygen pressure was more variable among taxa. These findings suggest that species-level differences in oxygen tolerance might be primarily related to differences in body size and preferred temperature. Further, this work provides data-informed distributions of parameters for species that lack experimental data to aid species distribution forecasting.
Modeling statin-induced myopathy with human iPSCs reveals that impaired proteostasis underlies the myotoxicity and is targetable for the prevention
Authors: Zhao Xiaolin , Ni Liyang , Kubo Miharu , Matsuto Mariko , Sakurai Hidetoshi , Shimizu Makoto , Takahashi Yu , Sato Ryuichiro , Yamauchi Yoshio
Published: August 2024

Statins, HMG-CoA reductase inhibitors, have been widely prescribed to lower circulating low-density lipoprotein cholesterol levels and reduce the risk of cardiovascular disease. Although statins are well tolerated, statin-associated muscle symptoms (SAMS) are the major adverse effect and cause statin intolerance. Therefore, understanding the molecular mechanisms of SAMS and identifying effective strategies for its prevention are of significant clinical importance; however, both remain unclear. Here we establish a model of statin-induced myopathy (SIM) with human induced pluripotent stem cell (hiPSC)-derived myocytes (iPSC-MCs) and investigate the effect of statins on protein homeostasis (proteostasis) that affects skeletal muscle wasting and myotoxicity. We show that treating hiPSC-MCs with statins induces atrophic phenotype and myotoxicity, establishing a hiPSC-based SIM model. We then examine whether statins impair the balance between protein synthesis and degradation. The results show that statins not only suppress protein synthesis but also promote protein degradation by upregulating the expression of the muscle-specific E3 ubiquitin ligase Atrogin-1 in a mevalonate pathway-dependent manner. Mechanistically, blocking the mevalonate pathway inactivates the protein kinase Akt, leading to the inhibition of mTORC1 and GSK3β but the activation of FOXO1. These changes explain the statin-induced impairment in proteostasis. Finally, we show that pharmacological blockage of FOXO1 prevents SIM in hiPSC-MCs, implicating FOXO1 as a key mediator of SIM. Taken together, this study suggests that the mevalonate pathway is critical for maintaining skeletal muscle proteostasis and identifies FOXO1 as a potential target for preventing SIM.
Tactile Mechanisms and Afferents Underlying the Rat Pup Transport Response
Authors: Ni Zheyi , Neifert Connor , Rosete Arturo , Albeely Abdalla M. , Yang Yu , Pratelli Marta , Brecht Michael , Clemens Ann M.
Published: August 2024

Juvenile rodents and other altricial mammals react with calming, immobility and folding up of feet to parental pickup, a set of behaviors referred to as transport response. Here we investigate sensory mechanisms underlying the rat transport response. Grasping rat pups in anterior neck positions evokes strong immobility and folding up of feet, whereas more posterior grasping positions have lesser effects on immobility and foot position. Transport responses are enhanced by slow (1Hz) and even more so by fast (4Hz) gentle shaking and translation of the pup, features consistent with parental transport. In response to lateral grasping, the forepaw below the grasping position points downwards and the forepaw lateral to the grasping position points upwards and medially. Such forepaw adjustments put the pup’s center of gravity below the grasping point, optimizing pup transportability along with folding up of feet and tail lifting. Tactile stimuli on the back, belly, tail, whisker, dorsal forepaws and dorsal hind-paws do not significantly affect the behaviour of anterior-neck-held pups. Instead, ground contact or paw stimulation consistent with ground contact disrupts transport responses. We identify afferents mediating the transport response by examining membrane labelling with FM1-43 following anterior neck grasping. We observe a dense innervation of the anterior neck skin region (∼30 terminals/ mm2). We also observed an age-related decrease of cytochrome oxidase reactivity in the rat somatosensory cortical neck representation, a possible correlate to the developmental decrease in the pup transport response. We conclude anterior neck grasping and loss of ground contact trigger calming and postural adjustments for parental transport in rat pups, responses putatively driven from the densely innervated anterior neck skin.
Preferential binding of human BRCA1 protein with open X-like conformation of Holliday junction, a homologous recombination intermediate
Authors: Kabir Sahil Hasan , K Vishnupriya , Pal Nibedita
Published: August 2024

BRCA1 is a complex tumor suppressor protein involved in multiple critical cellular processes, e.g., DNA double strand break repair, cell cycle checkpoint, etc. BRCA1 depleted cells are reported to have decreased homologous recombination (HR) and promote error-prone non-homologous end joining for DNA damage repair. Holliday junction (HJ) is an important intermediate of HR. Although BRCA1 is shown to have a very high affinity for HJ and recruits several proteins at the DNA damage site, the question remains what the binding mode of BRCA1 protein with an HJ is. Using single-molecule Fluorescence Correlation Spectroscopy (FCS) we have shown that BRCA1 prefers an open X-like conformation of HJ and has a lesser affinity for stacked HJ. Further, using molecular docking and all-atom molecular dynamics simulation, we show that mostly charged and polar amino acids in the DNA binding region of BRCA1 form complex with HJ. Interestingly, most of those amino acids are reported to be places for missense changes.
A coregulatory influence map of glioblastoma heterogeneity and plasticity - From cells in vitro to tumors and back again
Authors: Bernhard Chloe , Geles Konstantinos , Pawlak Geoffrey , Dhifli Wajdi , Dispot Aurelien , Dusol Jules , Kondratova Maria , Martin Sophie , Messe Melissa , Reita Damien , Tulasne David , Van Seuningen Isabelle , Entz-Werle Natacha , Ciafre Silvia-Anna , Dontenwill Monique , Elati Mohamed
Published: August 2024

We present GBM-cRegMap, an online resource providing a comprehensive coregulatory influence network perspective on glioblastoma (GBM) heterogeneity and plasticity. Using representation learning algorithms, we derived two components of this resource: GBM-CoRegNet, a highly specific coregulatory network of tumor cells, and GBM-CoRegMap, a unified network influence map based on 1612 tumors from 16 studies. As a widely applicable closed-loop system connecting cellular models and tumors, GBM-cRegMap will provide the GBM research community with an easy-to-use web tool (https://gbm.cregmap.com) that maps any existing or newly generated transcriptomic "query" data to a reference coregulatory network and a large-scale manifold of disease heterogeneity. Using GBM-cRegMap, we demonstrated the synergy between the two components by refining the molecular classification of GBM, identifying potential key regulators, and aligning the transcriptional profiles of tumors and in vitro models. Through the amalgamation of a vast dataset, we validated the proneural (PN)-mesenchymal (MES) axis and identified three subclasses of classical (CL) tumors: astrocyte-like (CL-A), epithelial basal-like (CL-B), and cilium-rich (CL-C). We revealed the CL-C subclass, an intermediate state demonstrating the plasticity of GBM cells along the PN-MES axis under chemotherapy. We identified key regulators, such as PAX8, and NKX2.5, involved in TMZ resistance. Notably, NKX2.5, more expressed in higher-grade gliomas, negatively impacts patient survival and regulates genes involved in glucose metabolism.
Air Pocket for a Non-Air-Breathing Fish: Developing Respirometry Methodology for the critically endangered Delta Smelt
Authors: Kwan Garfield Tsz , Mauduit Florian , Zillig Kenneth W. , Yanagitsuru Yuzo R. , Baird Sarah E. , Cocherell Dennis E. , Fangue Nann A.
Published: August 2024

Respirometry quantifies O2 consumption to estimate metabolic activity across stressor(s), and the resulting data is central for devising conservation strategies for fishes. Due to its rapid adoption and widespread utility, protocols have been established to foster quality control and increase consistency. However, the application of established respirometry protocols on the Delta Smelt (Hypomesus transpacificus) have been largely unsuccessful, with reports over the past 12 years documenting high mortality rates that can only be circumvented with very short measurement duration (~4 h). This prevents the measurement of standard metabolic rate (SMR) and critical O2 tension (Pcrit), and ultimately obstructed physiological research, management actions and conservation tools development. In this study, we detailed the anecdotal, behavioral and empirical evidence that culminated in successful measurements of Delta Smelt SMR and Pcrit at 10, 12, 15, 17 and 19 degrees C. We discovered the Delta Smelt is physotomous and requires frequent refilling of its air bladder to maintain buoyancy. Inspired by air-breathing fish respirometry, the inclusion of an air pocket within their chamber led to considerably more robust respirometry measurements compared to past attempts. The influence of fasting and time of day on O2 consumption were also examined. Altogether, this methodology paves the way for acquiring critical knowledge needed to inform Delta Smelt research and conservation (e.g. the development of metabolic index). The lessons learned may also have implications for other aspects of Delta Smelt conservation such as decreasing conservation aquaculture operating costs and improving survival during fish transport and supplementation.
The immunobiology of persistent intestinal infection byCampylobacter jejuniin the chicken
Authors: Gilroy Rachel , Wedley Amy , Jopson Sue , Hall Judith , Wigley Paul
Published: August 2024

Infection of the intestinal tract of the chicken withCampylobacter jejuniis frequently prolonged with limited immune clearance from the caeca, the main site of colonisation. Previously it has been shown early infection of broiler chickens leads to a pro-inflammatory response, followed by regulatory and Th17 responses along with adaptive Th1 and Th2 cytokine responses. Here we show that infection up to 28 days post challenge leads to prolonged expression of IL-4 and high titre IgM and IgY serum antibody responses toC. jeuni, along with increased levels of total IgA in the gut of infected birds. Whilst early pro-inflammatory cytokine and chemokine responses largely wane, expression of both IL-10 and IL-17A remain high in the colonised caeca or caecal tonsils. Based on this and previous studies we hypothesize that the nature of the immune response toC.jeuniinfection is one that allows persistence in the gut, but limits inflammation and invasive infection from the gut through maintaining the intestinal barrier and producing secretory antibody. This protects the birds from campylobacteriosis, but the persistence in the gut for the production lifetime of chickens remains an unsolved public health issue.
Cyclic Electromagnetic DNA Simulation (CEDS) can regulate the Functions of Different miRNAs and DNA Motifs: Protein Signaling Pathways in RAW 264.7 Cells detected by IP-HPLC Analysis
Authors: Kim Yeon Sook , Lee Suk Keun
Published: August 2024

Based on the hydrogen bonding magnetic resonance (HBMR) in double-stranded DNAs (dsDNAs) exhibiting unique base pair polarities, Cyclic Electromagnetic DNA Simulation (CEDS)1was designed to target nine miRNAs and four protein binding site sequences, which are known to have an anti-oncogenic or oncogenic role in cells. RAW 264.7 cells were cultured and treated with CEDS at 20-25 Gauss in a 5% CO2and 37℃ incubator for 20 min. Besides the cytological observation, the expressions of murine miRNAs and proteins were assessed by quantitative polymerase chain reaction (qPCR) and immunoprecipitation high-performance liquid chromatography (IP-HPLC) using 350 antisera, respectively. The results demonstrated that CEDS was found to increase the number of the corresponding mature and primary miRNAs and influenced the protein signaling in cells. For example, miR-34a-5p*-CEDS was able to downregulate 59 out of 43 target proteins (72.9%), and attenuated RAS-NFkB signaling axis, which subsequently led to the inactivation of proliferation-related signaling axis, protection-ER stress-survival signaling axis, telomere-glycolysis-fibrosis signaling axis, and FAS- and PARP-mediated apoptosis signaling axis. Conversely, miR-34a-5p*-CEDS activated the p53/Rb/E2F1-SHH/PTCH/GLI-Notch/Jagged proliferation signaling axis, epigenetic modification-RAS-p53 associated apoptosis signaling axis, and oncogenesis-senescence-innate immunity-chronic inflammation signaling axis. Among nine CEDS targeting mature miRNAs, miR-150-5p*-CEDSs exhibited a potent anti-oncogenic effect on RAW 264.7 cells, while miR-34a-5p*-, miR-181a-5p*-, miR-216a-5p*-, miR-365a-3p*-, and miR-655-3p*-CEDSs exhibited a dual effect, inducing both anti-oncogenic and oncogenic effects. Conversely, miR-155-5p*-CEDS appears to induce marked oncogenic effect, rather than anti-oncogenic effect. Among four CEDS targeting protein binding site sequences, p53 binding site sequence AGACATGCCT*-CEDS induced an oncogenic effect by upregulating proliferation, telomere, and oncogenesis signaling, while concomitantly inducing an anti-oncogenic effect by downregulating RAS and NFkB signaling and upregulating p53- and PARP-mediated apoptosis. Canonical E2Fs binding site sequence TTTC(C/G)CGC*-CEDS facilitated an oncogenic effect by enhancing RAS and NFkB signaling, resulting in the upregulation of proliferation, telomere, and senescence signaling. Consequently, it was found that CEDS using a miRNA or protein binding site sequence impacted the protein signaling in RAW 264.7 cells in a sequence-specific manner. It is therefore proposed that CEDS can target miRNAs and DNA motifs, influencing their hybridization and conformation, and subsequently regulate the protein signaling in the cells.
Monitoring DNA double strand break repair inSaccharomyces cerevisiaeat high throughput and high resolution
Authors: Ezra Yael Shalev , Saguy Alon , Levin Gaia , Weiss Lucien E. , Alalouf Onit , Shechtman Yoav
Published: August 2024

The yeast mating type switching process is used as a biological model system to study eukaryotic DNA double strand break (DSB) repair, a process of fundamental importance in health and disease. However, tools for tracking the mating type switching process in real-time in live cells are limited. We developed methods to follow and quantify mating type switching occurrence in real-time, at the single live cell level, applicable for detection of rare events and population heterogeneity. First, we show, using a fluorescent reporter in live cells, that switching probability in strains tagged by a fluorescent repressor-operator system (FROS) is reduced, not only due to the integration of operator repeats, but also due to the overexpressed fluorescent molecules in the nucleus. Next, by applying wavefront shaping to imaging flow cytometry, we collected 3D data in high throughput, and were able to differentiate between MATa and MATα conformation and to detect DNA dynamics during switching with unprecedented spatial and temporal resolutions. Using a strain with theMAT-stkmutation, which gives rise to inefficient HO endonuclease DSB activity, we discriminated between two consecutive distances between the HMLα and the MAT loci upon DNA damage. We suggest that initial nearing between the loci occurs for both single and double strand breaks, and further and closer proximity occurs for DSB only, leading to mating type switching. Our approach can be adapted to other biological systems to study DSB repair with high precision, throughput and sensitivity.
DEK-rRNA interactions regulate ribosome biogenesis and stress response
Authors: Xu Nengwei , Chen Kunqi , Prell Malte , Liang Pengtao , Yang Shuhuai , Guo Shengjie , Lu Yuli , Dorle Soham , Idaghdour Samia , Kappes Ferdinand
Published: August 2024

DNA/chromatin-based functions of the DEK oncogene, a unique nucleic acid-interacting factor in metazoans, have been widely investigated, yet its role in cellular RNA biology is under-studied. Herein we employed CLIP-seq alongside mutational, biochemical, and cellular approaches to gain deeper insights into the cellular DEK-RNA interplay. We confirm interaction of DEK with coding RNA, yet also report association with ribosomal RNA (rRNA) and thereby establishing a robust link between DEK and ribosome biology. Indeed, cells lacking DEK showed marked deficits in cytoplasmic ribosome quality and function. This phenotype was exclusively rescued by C-terminal DEK, harboring two RNA interaction domains, but not by an rRNA-binding deficient mutant. Mechanistically, we uncovered pleiotropic involvement of DEK in RNA polymerase I-mediated rRNA transcription and processing pathways. More specifically, we found direct interaction of DEK with RNA polymerase III-transcribed 5S rRNA and identified DEK as a regulator of the Impaired Ribosome Biogenesis Checkpoint (IRBC). Within this ribosomal stress pathway, DEK depletion results in free 5S RNP, triggering stabilization of p53 via inhibition of MDM2. In summary, our multilayer analysis revealed DEK as a potent cellular RNA binding protein and provides first evidence of DEK as a regulator of ribosome biogenesis and stress response via the 5S RNP-MDM2-p53 axis.
Complement activation at injury sites drives the phagocytosis of necrotic cell debris and resolution of liver injury
Authors: Vandendriessche Sofie , Mattos Matheus Silvério , Bialek Emilia Laura , Schuermans Sara , Proost Paul , Marques Pedro Elias
Published: August 2024

Cells die by necrosis due to excessive chemical or thermal stress, leading to plasma membrane rupture, release of intracellular components and severe inflammation. The clearance of necrotic cell debris is crucial for tissue recovery and injury resolution, however, the underlying mechanisms are still poorly understood, especially in vivo. This study examined the role of complement proteins in promoting clearance of necrotic cell debris by leukocytes and their influence on liver regeneration. We found that independently of the type of necrotic liver injury, either paracetamol (APAP) overdose or thermal injury, complement proteins C1q and (i)C3b were deposited specifically on necrotic lesions via the activation of the classical pathway. Importantly, C3 deficiency led to a significant accumulation of necrotic debris and impairment of liver recovery in mice, which was attributed to decreased phagocytosis of debris by recruited neutrophils in vivo. Monocytes and macrophages also took part in debris clearance, although the necessity of C3 and CD11b was dependent on the specific type of necrotic liver injury. Using human neutrophils, we showed that depletion of C1q or C3 caused a reduction in the volume of necrotic debris that is phagocytosed, indicating that complement promotes effective debris uptake by neutrophils in mice and humans. In summary, complement activation at injury sites is a pivotal event for necrotic debris clearance by phagocytes and determinant for efficient recovery from tissue injury.

Abstract Figure

Key points

The complement cascade is activated on necrotic cell debrisin vivovia the classical pathway

Deficiency in complement C3 impairs necrotic debris clearance and liver recovery after injury

Complement-mediated debris clearance is performed by neutrophils, monocytes and macrophages

Human neutrophils depend on complement opsonization to phagocytose necrotic cell debris efficiently
Estimating Ancestral States of Complex Characters: A Case Study on the Evolution of Feathers
Authors: Cockx Pierre , Benton Michael J. , Keating Joseph N.
Published: August 2024

Feathers are a key novelty underpinning the evolutionary success of birds, yet the origin of feathers remains poorly understood. Debates about feather evolution hinge upon whether filamentous integument has evolved once or multiple time independently on the lineage leading to modern birds. These contradictory results stem from subjective methodological differences in statistical ancestral state estimates. Here we conduct a comprehensive comparison of ancestral state estimation methodologies applied to stem-group birds, testing the role of outgroup inclusion, tree time scaling method, model choice and character coding strategy. Models are compared based on their Akaike Information Criteria (AIC), mutual information, as well as the uncertainty of marginal ancestral state estimates. Our results demonstrate that ancestral state estimates of stem-bird integument are strongly influenced by tree time scaling method, outgroup selection and model choice, while character coding strategy seems to have less effect on the ancestral estimates produced. We identify the best fitting models using AIC scores and a leave-one-out cross-validation approach (LOOCV). Our analyses broadly support the independent origin of filamentous integument in dinosaurs and pterosaurs and support a younger evolutionary origin of feathers than has been suggested previously. More generally, our study highlights that special care must be taken in selecting the outgroup, tree and model when conducting ASE analyses. With respect to model selection, our results suggest that considering a LOOCV approach, may yield more reliable results than simply comparing AIC scores when the analyses involve a limited number of taxa.
Enrichment analysis for spatial and single-cell metabolomics accounting for molecular ambiguity
Authors: Wadie Bishoy , Molenaar Martijn R , Vieira Lucas Maciel , Alexandrov Theodore
Published: August 2024

Imaging mass spectrometry (imaging MS) has advanced spatial and single-cell metabolomics, but the reliance on MS1 data complicates the accurate identification of molecular structures, not being able to resolve isomeric and isobar molecules. This prevents application of conventional methods for overrepresentation analysis (ORA) and metabolite set enrichment analysis (MSEA). To address this, we introduce S2IsoMEr R package and a web app for METASPACE, which uses bootstrapping to propagate isomeric/isobaric ambiguities into the enrichment analysis. We demonstrate S2IsoMEr for single-cell metabolomics and the METASPACE web app for spatial metabolomics.
Mammalian PIEZO channels rectify anionic currents
Authors: Wijerathne Tharaka D. , Bhatt Aashish , Jiang Wenjuan , Luo Yun Lyna , Lacroix Jerome J.
Published: August 2024

Under physiological conditions, mammalian PIEZO channels (PIEZO1 and PIEZO2) elicit transient currents mostly carried by monovalent and divalent cations. PIEZO1 is also known to permeate chloride ions, with a Cl-/ Na+permeability ratio of about 0.2. Yet, little is known about how anions permeate PIEZO channels. Here, by separately measuring sodium and chloride currents using non-permanent counter-ions, we show that both PIEZO1 and PIEZO2 rectify chloride currents outwardly, favoring entry of chloride ions at voltages above their reversal potential, whereas little to no rectification was observed for sodium currents. Interestingly, chloride currents elicited by 9K, an anion-selective PIEZO1 mutant harboring multiple positive residues along intracellular pore fenestrations, also rectify but in the inward direction. Molecular dynamics simulation indicate that the inward rectification of chloride currents in 9K correlates with the largely positive electrostatic potential at the intracellular pore entrance, suggesting that rectification can be tuned by pore polarity. These results demonstrate that the pore of mammalian PIEZO channels inherently rectifies chloride currents.

Statement of significance

Mechanosensitive PIEZO ion channels play many important roles across cells and tissues. Their open pore facilitates the flow of cations down their electrochemical gradients, eliciting sodium-driven membrane depolarization and calcium-dependent signaling under physiological conditions. Yet, these channels also permeate chloride ions. In this study, we show that the two mammalian PIEZO channel homologs preferentially permeate chloride ions into the cells at voltages more positive than the chloride reversal potential. Although PIEZOs permeate cations more effectively than chloride ions, the influx of chloride ions mediated by PIEZOs could participate in certain physiological processes.
PHIStruct: Improving phage-host interaction prediction at low sequence similarity settings using structure-aware protein embeddings
Authors: Gonzales Mark Edward M. , Ureta Jennifer C. , Shrestha Anish M.S.
Published: August 2024

Motivation

Recent computational approaches for predicting phage-host interaction have explored the use of sequence-only protein language models to produce embeddings of phage proteins without manual feature engineering. However, these embeddings do not directly capture protein structure information and structure-informed signals related to host specificity.

Result

We present PHIStruct, a multilayer perceptron that takes in structure-aware embeddings of receptor-binding proteins, generated via the structure-aware protein language model SaProt, and then predicts the host from among the ESKAPEE genera. Compared against recent tools, PHIStruct exhibits the best balance of precision and recall, with the highest and most stable F1 score across a wide range of confidence thresholds and sequence similarity settings. The margin in performance is most pronounced when the sequence similarity between the training and test sets drops below 40%, wherein, at a relatively high-confidence threshold of above 50%, PHIStruct presents a 7% to 9% increase in class-averaged F1 over machine learning tools that do not directly incorporate structure information, as well as a 5% to 6% increase over BLASTp.

Availability and Implementation

The data and source code for our experiments and analyses are available athttps://github.com/bioinfodlsu/PHIStruct.
Design and analysis of double-permanent-magnet enhanced hybrid stepping machine with tangential and radial magnetization
Authors: Chai Xiaobao , Liu Jinglin , Guan RuiZhi , Xiao Minglang
Published: August 2024

Purpose

To improve the output torque density of the machine and to be better suited for automation applications, this paper aims to propose a double-permanent-magnet enhanced hybrid stepping machine (DPMEHSM) with tangential and radial magnetization.

Design/methodology/approach

First, the structure of DPMEHSM is introduced and its operation principle is analyzed by describing the variation in stator poles versus time. Second, based on the similar electrical load and amount of PM, the size equations of the DPMEHSM are designed and the main parameters are presented. Third, the electromagnetic performances including the PM flux linkage distribution, magnetic density distribution, air-gap field, back electromotive force (back-EMF), detent torque, holding torque and output torque of DPMEHSM and stator-PM hybrid stepping machine (SPMHSM) are analyzed based on the finite element method.

Findings

The results show that the DPMEHSM has superiority in back-EMF, holding torque and output torque.

Originality/value

This paper proposes a DPMEHSM with tangential and radial magnetization to improve the output torque density.