Genetic factors regulating lung vasculature and immune cell functions associate with resistance to pneumococcal infection

Streptococcus pneumoniae is an important human pathogen responsible for high mortality and morbidity worldwide. The susceptibility to pneumococcal infections is controlled by as yet unknown genetic factors. To elucidate these factors could help to develop new medical treatments and tools to identify those most at risk. In recent years genome wide association studies (GWAS) in mice and humans have proved successful in identification of causal genes involved in many complex diseases for example diabetes, systemic lupus or cholesterol metabolism. In this study a GWAS approach was used to map genetic loci associated with susceptibility to pneumococcal infection in 26 inbred mouse strains. As a result four candidate QTLs were identified on chromosomes 7, 13, 18 and 19. Interestingly, the QTL on chromosome 7 was located within S. pneumoniae resistance QTL (Spir1) identified previously in a linkage study of BALB/cOlaHsd and CBA/CaOlaHsd F2 intercrosses. We showed that only a limited number of genes encoded within the QTLs carried phenotype-associated polymorphisms (22 genes out of several hundred located within the QTLs). These candidate genes are known to regulate TGFb signalling, smooth muscle and immune cells functions. Interestingly, our pulmonary histopathology and gene expression data demonstrated, lung vasculature plays an important role in resistance to pneumococcal infection. Therefore we concluded that the cumulative effect of these candidate genes on vasculature and immune cells functions as contributory factors in the observed differences in susceptibility to pneumococcal infection. We also propose that TGFbmediated regulation of fibroblast differentiation plays an important role in development of invasive pneumococcal disease.This work was supported by the European Union-funded Pneumopath Project HEALTH-F3-2009-222983. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer-reviewedPublisher Versio

Genetic background influences tumour development in heterozygous Men1 knockout mice

Multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder caused by MEN1 germline mutations, is characterised by parathyroid, pancreatic and pituitary tumours. MEN1 mutations also cause familial isolated primary hyperparathyroidism (FIHP), a milder condition causing hyperparathyroidism only. Identical mutations can cause either MEN1 or FIHP in different families, thereby implicating a role for genetic modifiers in altering phenotypic expression of tumours. We therefore investigated the effects of genetic background and potential for genetic modifiers on tumour development in adult Men1+/- mice, which develop tumours of the parathyroids, pancreatic islets, anterior pituitary, adrenal cortex and gonads, that had been backcrossed to generate C57BL/6 and 129S6/SvEv congenic strains. A total of 275 Men1+/- mice, aged 5–26 months were macroscopically studied, and this revealed that genetic background significantly influenced the development of pituitary, adrenal and ovarian tumours, which occurred in mice over 12 months of age and more frequently in C57BL/6 females, 129S6/SvEv males and 129S6/SvEv females, respectively. Moreover, pituitary and adrenal tumours developed earlier, in C57BL/6 males and 129S6/SvEv females, respectively, and pancreatic and testicular tumours developed earlier in 129S6/SvEv males. Furthermore, glucagon-positive staining pancreatic tumours occurred more frequently in 129S6/SvEv Men1+/- mice. Whole genome sequence analysis of 129S6/SvEv and C57BL/6 Men1+/- mice revealed >54,000 different variants in >300 genes. These included, Coq7, Dmpk, Ccne2, Kras, Wnt2b, Il3ra and Tnfrsf10a, and qRT-PCR analysis revealed that Kras was significantly higher in pituitaries of male 129S6/SvEv mice. Thus, our results demonstrate that Kras and other genes could represent possible genetic modifiers of Men1

Eosinophil microRNAs play a regulatory role in allergic diseases included in the atopic march

Background: The atopic march is defined by the increased prevalence of allergic diseases after atopic dermatitis onset. In fact, atopic dermatitis is believed to play an important role in allergen sensitization via the damaged skin barrier, leading to allergic diseases such as allergic asthma and allergic rhinitis. The eosinophil, a pro-inflammatory cell that contributes to epithelial damage, is one of the various cells recruited in the inflammatory reactions characterizing these diseases. Few studies were conducted on the transcriptome of this cell type and even less on their specific microRNA (miRNA) profile, which could modulate pathogenesis of allergic diseases and clinical manifestations post-transcriptionally. Actually, their implication in allergic diseases is not fully understood, but they are believed to play a role in inflammation-related patterns and epithelial cell proliferation. Methods: Next-generation sequencing was performed on RNA samples from eosinophils of individuals with atopic dermatitis, atopy, allergic rhinitis and asthma to obtain differential counts of primary miRNA (pri-miRNA); these were also analyzed for asthma-related phenotypes such as forced expiratory volume in one second (FEV1), immunoglobulin E (IgE) and provocative concentration of methacholine inducing a 20% fall in forced expiratory volume in 1 s (PC20) levels, as well as FEV1 to forced vital capacity (FEV1/FVC) ratio. Results: Eighteen miRNAs from eosinophils were identified to be significantly different between affected individuals and unaffected ones. Based on counts from these miRNAs, individuals were then clustered into groups using Ward’s method on Euclidian distances. Groups were found to be explained by asthma diagnosis, familial history of respiratory diseases and allergic rhinitis as well as neutrophil counts. Conclusions: The 18 differential miRNA counts for the studying phenotypes allow a better understanding of the epigenetic mechanisms underlying the development of the allergic diseases included in the atopic march

Early-life telomere length predicts lifespan and lifetime reproductive success in a wild bird

Poor conditions during early development can initiate trade-offs that favour current survival at the expense of somatic maintenance and subsequently, future reproduction. However, the mechanisms that link early and late life-history are largely unknown. Recently it has been suggested that telomeres, the nucleoprotein structures at the terminal end of chromosomes, could link early-life conditions to lifespan and fitness. In wild purple-crowned fairy-wrens, we combined measurements of nestling telomere length (TL) with detailed life-history data to investigate whether early-life TL predicts fitness prospects. Our study differs from previous studies in the completeness of our fitness estimates in a highly philopatric population. The association between TL and survival was age-dependent with early-life TL having a positive effect on lifespan only among individuals that survived their first year. Early-life TL was not associated with the probability or age of gaining a breeding position. Interestingly, early-life TL was positively related to breeding duration, contribution to population growth and lifetime reproductive success because of their association with lifespan. Thus, early-life TL, which reflects growth, accumulated early-life stress and inherited TL, predicted fitness in birds that reached adulthood but not noticeably among fledglings. These findings suggest that a lack of investment in somatic maintenance during development particularly affects late life performance. This study demonstrates that factors in early-life are related to fitness prospects through lifespan, and suggests that the study of telomeres may provide insight into the underlying physiological mechanisms linking early- and late-life performance and trade-offs across a lifetime.</p

Assessing attentional bias for alcohol-related cues using eye tracking in a virtual reality environment

peer reviewedSeveral experimental paradigms were developed to measure attentional biases towards alcohol-related cues. However, most of them are based on reaction times to two-dimensional stimuli displayed on a computer screen, such that their ecological validity has been questioned. To address this, we integrated an eye tracking system into a virtual reality headset (ET-VR) and measured attentional biases in a subclinical population of alcohol users. In this exploratory study, forty social drinkers were recruited and immersed in a virtual bar including alcohol-related stimuli. Attentional focus was assessed using dwell time and number of fixations for these alcohol-related stimuli as well as for neutral stimuli unrelated to alcohol consumption. The results show that the number of fixations and, to a lesser extent, the dwell time for alcohol- related cues were positively correlated with the drinking motivation of the participants. In contrast, no significant correlation was found for neutral stimuli. In conclusion, the present study shows that alcohol-induced attentional biases can be studied using an ET-VR device in a subclinical population of alcohol users.3. Good health and well-bein

Assessing attentional bias for alcohol-related cues using eye tracking in a virtual reality environment

peer reviewedSeveral experimental paradigms were developed to measure attentional biases towards alcohol-related cues. However, most of them are based on reaction times to two-dimensional stimuli displayed on a computer screen, such that their ecological validity has been questioned. To address this, we integrated an eye tracking system into a virtual reality headset (ET-VR) and measured attentional biases in a subclinical population of alcohol users. In this exploratory study, forty social drinkers were recruited and immersed in a virtual bar including alcohol-related stimuli. Attentional focus was assessed using dwell time and number of fixations for these alcohol-related stimuli as well as for neutral stimuli unrelated to alcohol consumption. The results show that the number of fixations and, to a lesser extent, the dwell time for alcohol- related cues were positively correlated with the drinking motivation of the participants. In contrast, no significant correlation was found for neutral stimuli. In conclusion, the present study shows that alcohol-induced attentional biases can be studied using an ET-VR device in a subclinical population of alcohol users.3. Good health and well-bein

Global profiling of alternative RNA splicing events provides insights into molecular differences between various types of hepatocellular carcinoma

Protein families encoded by transcripts that are differentially spliced in various types of HCC. Table S2. Bioinformatical prediction of functional changes caused by some of ASEs identified. Table S3. List of tumor suppressors for which AS is dysregulated in various types of HCC. Table S4. List of oncogenes for which AS is dysregulated in various types of HCC. Table S5. List of kinases for which AS is dysregulated in various types of HCC. Table S6. List of transcription factors for which AS is dysregulated in various types of HCC. Table S7. List of genes for which AS is dysregulated in all types of HCC. Table S8. List of genes uniquely dysregulated in HBV-associated HCC. Table S9. List of genes uniquely dysregulated in HCV-associated HCC. Table S10. List of genes uniquely dysregulated in HBV&HCV-associated HCC. Table S11. List of genes uniquely dysregulated in virus-free HCC. Figure S1. Characterization of splicing mysregulation in HCC. Figure S2. Characterization of ASEs that are modified in HBV- and HCV-associated HCC. Figure S3. AS modifications in transcripts encoded by kinases and transcriptions factores in HBV- and HCV-associated HCC. Figure S4. Global profiling of ASE modifications in both HBV&HCV-associated HCC and virus-free-associated HCC. Figure S5. RNA splicing factors in HCC. Figure S6. Modifications to AS of 96 transcripts in response to knockdown of splicing factors with specific siRNAs (PDF 6675 kb

Transposable elements are associated with the variable response to influenza infection

インフルエンザ重症度に関連する転移因子を特定: マルチオミクス解析で見えた「動く遺伝子」の新たな役割. 京都大学プレスリリース. 2023-05-11.A multiomics approach provides insights into flu severity. 京都大学プレスリリース. 2023-05-11.Influenza A virus (IAV) infections are frequent every year and result in a range of disease severity. Here, we wanted to explore the potential contribution of transposable elements (TEs) to the variable human immune response. Transcriptome profiling in monocyte-derived macrophages from 39 individuals following IAV infection revealed significant inter-individual variation in viral load post-infection. Using transposase-accessible chromatin using sequencing (ATAC-seq), we identified a set of TE families with either enhanced or reduced accessibility upon infection. Of the enhanced families, 15 showed high variability between individuals and had distinct epigenetic profiles. Motif analysis showed an association with known immune regulators (e.g., BATFs, FOSs/JUNs, IRFs, STATs, NFkBs, NFYs, and RELs) in stably enriched families and with other factors in variable families, including KRAB-ZNFs. We showed that TEs and host factors regulating TEs were predictive of viral load post-infection. Our findings shed light on the role TEs and KRAB-ZNFs may play in inter-individual variation in immunity

Children and Young People's Health Partnership (CYPHP) Evelina London model of care: protocol for an opportunistic cluster randomised controlled trial (cRCT) to assess child health outcomes, healthcare quality and health service use.

INTRODUCTION: Children and young people (CYP) in many high-income settings have poor healthcare outcomes, especially those with long-term conditions (LTCs). Emergency and outpatient hospital service use is increasing unsustainably. To address these problems, the Children and Young People's Health Partnership (CYPHP) has developed and is evaluating an integrated model of care as part of a health systems strengthening programme across two boroughs of London, UK that are characterised by mixed ethnic populations and varying levels of deprivation. The CYPHP Evelina London model of care comprises proactive case-finding and triage, specialist clinics and transformative education and training for professionals working with CYP. Services are delivered by multidisciplinary health teams with an emphasis on increased coordination across primary, community and hospital settings and integration of physical and mental healthcare that accounts for the CYP's social context. METHODS AND ANALYSIS: The phased roll out of the CYPHP Evelina London model allows an opportunistic population-based evaluation using a cluster randomised controlled trial design. Seventy general practices across two London boroughs, grouped into 23 clusters, were randomised to provide either the CYPHP model of care (n=11) or enhanced usual care (n=12).The evaluation will measure the impact of the CYPHP Evelina London model of care on child and parent health and well-being, healthcare quality and health service use up to 2 years postimplementation. A population-level evaluation will use routinely collected pseudonymised healthcare data to conduct a service-use analysis for all CYP registered with a participating general practice (n=~90 000) with the rate of non-elective admissions as the primary outcome. We will seek consent from a subset of this population, with specific conditions (target n=2138) to assess the impact on patient-reported outcomes using the Paediatric Quality of Life Inventory (PedsQL) and Warwick-Edinburgh Mental Well-Being Scale (WEBWMS) as, respectively, the child- and parent-related primary outcomes. ETHICS AND DISSEMINATION: Ethics approval obtained from South West-Cornwall & Plymouth Research Ethics Committee. Results will be submitted for publication in peer-reviewed journals. Findings will be generalisable to community-based models of care, especially in urban settings. Our process evaluation will identify barriers and enablers of implementation and delivery of care salient to the context and condition. TRIAL REGISTRATION NUMBER: NCT03461848; Pre-results