DECIPHER: Improving Genetic Diagnosis Through Dynamic Integration of Genomic and Clinical Data.

DECIPHER (atabas of Genomi Varation and henotype in umans Using nsembl esources) shares candidate diagnostic variants and phenotypic data from patients with genetic disorders to facilitate research and improve the diagnosis, management, and therapy of rare diseases. The platform sits at the boundary between genomic research and the clinical community. DECIPHER aims to ensure that the most up-to-date data are made rapidly available within its interpretation interfaces to improve clinical care.

Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer.

The accumulation of senescent cells in the tumor microenvironment can drive tumorigenesis in a paracrine manner through the senescence-associated secretory phenotype (SASP). Using a new p16-FDR mouse line, we show that macrophages and endothelial cells are the predominant senescent cell types in murine KRAS-driven lung tumors. Through single cell transcriptomics, we identify a population of tumor-associated macrophages that express a unique array of pro-tumorigenic SASP factors and surface proteins and are also present in normal aged lungs.

Metabolomic and transcriptomic analyses of Fmo5-/- mice reveal roles for flavin-containing monooxygenase 5 (FMO5) in NRF2-mediated oxidative stress response, unfolded protein response, lipid homeostasis, and carbohydrate and one-carbon metabolism.

Flavin-containing monooxygenase 5 (FMO5) is a member of the FMO family of proteins, best known for their roles in the detoxification of foreign chemicals and, more recently, in endogenous metabolism. We have previously shown that Fmo5-/- mice display an age-related lean phenotype, with much reduced weight gain from 20 weeks of age. The phenotype is characterized by decreased fat deposition, lower plasma concentrations of glucose, insulin and cholesterol, higher glucose tolerance and insulin sensitivity, and resistance to diet-induced obesity.

The relationship between striatal dopamine and anterior cingulate glutamate in first episode psychosis changes with antipsychotic treatment.

The neuromodulator dopamine and excitatory neurotransmitter glutamate have both been implicated in the pathogenesis of psychosis, and dopamine antagonists remain the predominant treatment for psychotic disorders. To date no study has measured the effect of antipsychotics on both of these indices together, in the same population of people with psychosis. Striatal dopamine synthesis capacity (Ki) and anterior cingulate glutamate were measured using 18F-DOPA positron emission tomography and proton magnetic resonance spectroscopy respectively, before and after at least 5 weeks' naturalistic antipsychotic treatment in people with first episode psychosis (n = 18) and matched healthy controls (n = 20).

Dax1 modulates ERα-dependent hypothalamic estrogen sensing in female mice.

Coupling the release of pituitary hormones to the developmental stage of the oocyte is essential for female fertility. It requires estrogen to restrain kisspeptin (KISS1)-neuron pulsatility in the arcuate hypothalamic nucleus, while also exerting a surge-like effect on KISS1-neuron activity in the AVPV hypothalamic nucleus. However, a mechanistic basis for this region-specific effect has remained elusive.

Steps on the Path to Clinical Translation: A workshop by the British and Irish Chapter of the ISMRM.

The British and Irish Chapter of the International Society for Magnetic Resonance in Medicine (BIC-ISMRM) held a workshop entitled "Steps on the path to clinical translation" in Cardiff, UK, on 7th September 2022. The aim of the workshop was to promote discussion within the MR community about the problems and potential solutions for translating quantitative MR (qMR) imaging and spectroscopic biomarkers into clinical application and drug studies. Invited speakers presented the perspectives of radiologists, radiographers, clinical physicists, vendors, imaging Contract/Clinical Research Organizations (CROs), open science networks, metrologists, imaging networks, and those developing consensus methods.

Sleeve gastrectomy causes weight-loss independent improvements in hepatic steatosis.

Background And Aims: Sleeve gastrectomy (VSG) leads to improvement in hepatic steatosis, associated with weight loss. The aims of this study were to investigate whether VSG leads to weight-loss independent improvements in liver steatosis in mice with diet-induced obesity (DIO); and to metabolically and transcriptomically profile hepatic changes in mice undergoing VSG.

Methods: Mice with DIO were treated with VSG, sham surgery with subsequent food restriction to weight-match to the VSG group (Sham-WM), or sham surgery with return to unrestricted diet (Sham-Ad lib).

Neurophysiological and psychosocial mechanisms of fibromyalgia: A comprehensive review and call for an integrative model.

Research into the neurobiological and psychosocial mechanisms involved in fibromyalgia has progressed remarkably in recent years. Despite this, current accounts of fibromyalgia fail to capture the complex, dynamic, and mutual crosstalk between neurophysiological and psychosocial domains. We conducted a comprehensive review of the existing literature in order to: a) synthesize current knowledge on fibromyalgia; b) explore and highlight multi-level links and pathways between different systems; and c) build bridges connecting disparate perspectives.

Fission yeast obeys a linear size law under nutrient titration.

Steady-state cell size and geometry depend on growth conditions. Here, we use an experimental setup based on continuous culture and single-cell imaging to study how cell volume, length, width and surface-to-volume ratio vary across a range of growth conditions including nitrogen and carbon titration, the choice of nitrogen source, and translation inhibition. Overall, we find cell geometry is not fully determined by growth rate and depends on the specific mode of growth rate modulation.

The association between peripheral inflammation, brain glutamate and antipsychotic response in Schizophrenia: Data from the STRATA collaboration.

Glutamate and increased inflammation have been separately implicated in the pathophysiology of schizophrenia and the extent of clinical response to antipsychotic treatment. Despite the mechanistic links between pro-inflammatory and glutamatergic pathways, the relationships between peripheral inflammatory markers and brain glutamate in schizophrenia have not yet been investigated. In this study, we tested the hypothesis that peripheral levels of pro-inflammatory cytokines would be positively associated with brain glutamate levels in schizophrenia.

Characterisation of placental, fetal brain and maternal cardiac structure and function in pre-eclampsia using MRI.

Background: Pre-eclampsia is a multiorgan disease of pregnancy that has short- and long-term implications for the woman and fetus, whose immediate impact is poorly understood. We present a novel multi-system approach to MRI investigation of pre-eclampsia, with acquisition of maternal cardiac, placental, and fetal brain anatomical and functional imaging.

Methods: A prospective study was carried out recruiting pregnant women with pre-eclampsia, chronic hypertension, or no medical complications, and a non-pregnant female cohort.

Identification of an increased lifetime risk of major adverse cardiovascular events in UK Biobank participants with scoliosis.

Background: Structural changes caused by spinal curvature may impact the organs within the thoracic cage, including the heart. Cardiac abnormalities in patients with idiopathic scoliosis are often studied post-corrective surgery or secondary to diseases. To investigate cardiac structure, function and outcomes in participants with scoliosis, phenotype and imaging data of the UK Biobank (UKB) adult population cohort were analysed.

Attenuation of reverse transcriptase facilitates SAMHD1 restriction of HIV-1 in cycling cells.

Background: SAMHD1 is a deoxynucleotide triphosphohydrolase that restricts replication of HIV-1 in differentiated leucocytes. HIV-1 is not restricted in cycling cells and it has been proposed that this is due to phosphorylation of SAMHD1 at T592 in these cells inactivating the enzymatic activity. To distinguish between theories for how SAMHD1 restricts HIV-1 in differentiated but not cycling cells, we analysed the effects of substitutions at T592 on restriction and dNTP levels in both cycling and differentiated cells as well as tetramer stability and enzymatic activity in vitro.

Diet suppresses glioblastoma initiation in mice by maintaining quiescence of mutation-bearing neural stem cells.

Glioblastoma is thought to originate from neural stem cells (NSCs) of the subventricular zone that acquire genetic alterations. In the adult brain, NSCs are largely quiescent, suggesting that deregulation of quiescence maintenance may be a prerequisite for tumor initiation. Although inactivation of the tumor suppressor p53 is a frequent event in gliomagenesis, whether or how it affects quiescent NSCs (qNSCs) remains unclear.

The CDK7 inhibitor CT7001 (Samuraciclib) targets proliferation pathways to inhibit advanced prostate cancer.

Background: Current strategies to inhibit androgen receptor (AR) are circumvented in castration-resistant prostate cancer (CRPC). Cyclin-dependent kinase 7 (CDK7) promotes AR signalling, in addition to established roles in cell cycle and global transcription, providing a rationale for its therapeutic targeting in CRPC.

Methods: The antitumour activity of CT7001, an orally bioavailable CDK7 inhibitor, was investigated across CRPC models in vitro and in xenograft models in vivo.

Towards robust clinical genome interpretation: developing a consistent terminology to characterize disease-gene relationships - allelic requirement, inheritance modes and disease mechanisms.

Purpose: The terminology used for gene-disease curation and variant annotation to describe inheritance, allelic requirement, and both sequence and functional consequences of a variant is currently not standardized. There is considerable discrepancy in the literature and across clinical variant reporting in the derivation and application of terms. Here we standardize the terminology for the characterization of disease-gene relationships to facilitate harmonized global curation, and to support variant classification within the ACMG/AMP framework.

The dcGO Domain-Centric Ontology Database in 2023: New Website and Extended Annotations for Protein Structural Domains.

Protein structural domains have been less studied than full-length proteins in terms of ontology annotations. The dcGO database has filled this gap by providing mappings from protein domains to ontologies. The dcGO update in 2023 extends annotations for protein domains of multiple definitions (SCOP, Pfam, and InterPro) with commonly used ontologies that are categorised into functions, phenotypes, diseases, drugs, pathways, regulators, and hallmarks.

Predicting treatment resistance from first-episode psychosis using routinely collected clinical information.

Around a quarter of people who experience a first episode of psychosis (FEP) will develop treatment-resistant schizophrenia (TRS), but there are currently no established clinically useful methods to predict this from baseline. We aimed to explore the predictive potential for clozapine use as a proxy for TRS of routinely collected, objective biomedical predictors at FEP onset, and to externally validate the model in a separate clinical sample of people with FEP. We developed and externally validated a forced-entry logistic regression risk prediction Model fOr cloZApine tReaTment, or MOZART, to predict up to 8-year risk of clozapine use from FEP using routinely recorded information including age, sex, ethnicity, triglycerides, alkaline phosphatase levels, and lymphocyte counts.