Circadian transcriptional repressors REV-ERBα/β and E4BP4 regulate cardiac function.

Circadian rhythms are an endogenous timekeeping system with a period of approximately 24 h that regulate many aspects of body physiology to maintain organismal health. Dysregulation of circadian rhythmicity has been implicated in various human diseases like cancer as well as metabolic and cardiovascular disorders. Intrinsic, biological oscillations are regulated by the circadian clock, a molecular transcriptional/translational feedback loop that involves activators such as BMAL1 and CLOCK, and repressors such as REV-ERBα/β and E4BP4.

GPRC5B preserves a mature β-cell state in obesity by controlling MafA expression.

In vitro studies have implicated orphan receptor GPRC5B in β-cell survival, proliferation and insulin secretion, but its relevance for glucose homeostasis in vivo is largely unknown. Using tamoxifen-inducible, β-cell-specific GPRC5B knockout mice (Ins-G5b-KOs) we show here that loss of GPRC5B does not affect β-cell function in the lean state, but results in strongly reduced insulin secretion and disturbed glucose tolerance in mice subjected to high fat diet for 16 weeks. Flow cytometry and single-cell expression analyses in islets from obese mice show a reduced β-cell abundance and a less mature β-cell phenotype in Ins-G5b-KOs.

Loss of multiple micro-RNAs uncovers multi-level restructuring of gene regulation in rodents.

Background: The regulatory network that coordinates gene expression ultimately determines the phenotype of an organism. Micro-RNAs (miRNAs) are post-transcriptional regulators involved in key biological processes. Lineage-specific losses of multiple miRNA families are rare, and reported cases of multiple miRNA losses coincide with significant changes in gene regulation resulting in body plan modifications.

Differential expression of villin and advillin by neuroendocrine and tuft cells in the murine lower airways.

Previous studies identified a rare cell type in the mouse tracheal epithelium with immunoreactivity to the microvillus protein villin (Vil1), which persisted in mice lacking tuft cells due to deletion of the transcription factor Pou2f3. This study aimed to clarify the identity of this ill-defined cell type. Ultrastructurally, all cells with tightly packed microvilli observed in the tracheal epithelium of Pou2f3-mice contained basally located dense core vesicles, a characteristic feature of neuroendocrine cells (NEC).

Elevated hexosylceramides in Parkinson's disease cause gene upregulations in neurons mimicking responses to pathogens.

Parkinson's Disease (PD) is driven by pathological aggregates of alpha-synuclein (αSyn), whose formation is facilitated by impaired glycosphingolipid metabolism via acidic glucocerebrosidase (GCase). We investigated glucosylceramide (GlcCer) accumulation in human, mouse, and cellular PD models. Lipidomic analyses revealed elevated plasma GlcCer, especially GlcCer24:1, and a shift in phosphatidylcholine (PC) species in PD patients.

Calcific aortic valve disease augments vesicular microRNA-145-5p to regulate the calcification of valvular interstitial cells via cellular crosstalk.

Calcific aortic valve disease (CAVD) is one of the leading causes of cardiovascular death in the elderly population worldwide. MicroRNAs (miRNAs) are highly dysregulated in patients with CAVD undergoing surgical aortic valve replacement (SAVR). However, the miRNA-dependent mechanisms regulating inflammation and calcification or miRNA-mediated cell-cell crosstalk during the pathogenesis of CAVD remain poorly understood.

A 2-Decade Cardiac Magnetic Resonance Imaging Journey in Heritable Pulmonary Arterial Hypertension: Reversal With Sotatercept.

Background: Pulmonary arterial hypertension (PAH) is a progressive disease that leads to right heart failure.

Case Summary: We report on the long-term follow-up of a male patient diagnosed at the age of 26 years with heritable PAH. Over 2 decades, he underwent several targeted therapies and repeated multimodal assessments, including cardiac magnetic resonance imaging (CMR).

Hemodynamics and Phosphodiesterase-5 Inhibitor Treatment Associated with Survival in ILD-PH: A PVRI GoDeep Meta-Registry Analysis.

Background: Pulmonary hypertension (PH) in interstitial lung disease (ILD) lacks approved therapies. The PVRI GoDeep meta-registry collects real-world data of PH patients from international PH referral centers.

Methods: ILD-PH patients and relevant subgroups (IIP, IPF) were stratified by pulmonary vascular resistance (PVR).

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: results of the NEOMUN trial.

Background: The phase II NEOMUN trial was conducted to investigate the therapeutic effect of preoperative programmed death receptor-1 inhibitor pembrolizumab for treating non-small cell lung cancer (NSCLC). Herein, we report the final efficacy, safety, and long-term survival results.

Methods: Patients with resectable stage II/IIIA NSCLC were included.

Macrophage fatty acid metabolism under chronic hypoxia shapes γδ T cell recruitment via CCL22.

Hypoxia in solid tumors is associated with poor outcomes because of metabolic adaptations that support tumor cell survival and alter immune cell function. However, the metabolic and phenotypic adaptations of macrophages (MФs) to chronic hypoxia (CH) remain unclear. This study identifies impaired activity of the oxygen-dependent enzyme stearoyl-CoA desaturase 1 (SCD1) as a driver of altered fatty acid (FA) metabolism in MФs under CH.

Orphan receptor GPR153 facilitates vascular damage responses by modulating cAMP levels, YAP/TAZ signaling, and NF-κB activation.

Vascular cells express various G-protein-coupled receptors (GPCRs) with yet unknown function, among them orphan receptor GPR153. GPR153 was upregulated in smooth muscle cells (SMCs) in response to injury, and knockdown of GPR153 resulted in reduced proliferation and mildly altered differentiation in human SMCs. Mice with tamoxifen-inducible, SMC-specific GPR153 deficiency were partially protected against ligation-induced neointima formation, and their SMCs were characterized by reduced proliferation and dedifferentiation.

Transcriptional changes of the extracellular matrix in chronic thromboembolic pulmonary hypertension govern right ventricle remodeling and recovery.

Chronic thromboembolic pulmonary hypertension (CTEPH) leads to progressive right ventricular (RV) dysfunction. Pulmonary endarterectomy (PEA) is an established treatment for these patients; however, the molecular mechanisms underlying RV remodeling and recovery remain poorly understood. Here we show that RNA sequencing and histological analysis of RV free wall and septal biopsies from patients with CTEPH reveal extracellular matrix enrichment and cytoskeletal remodeling before PEA.

Adventitial Fibroblasts Release Interleukin 6 After Vascular Injury and Induce Smooth Muscle Cell Proliferation and Neointima Formation.

Background: Vascular restenosis resulting from neointima formation significantly limits the efficacy of percutaneous interventional therapies compared with bypass surgery. The adventitial layer is involved in neointima formation, but the detailed pathophysiological interplay of the different cell types in this process is still unclear.

Methods: We analyzed the correlation between adventitial and neointimal tissue size in human postmortem restenotic lesions after angioplasty.

Antagonizing CCR2 With Propagermanium Leads to Altered Distribution of Macrophage Subsets and Favorable Tissue Remodeling After Myocardial Infarction in Mice.

The aim of the present study was to investigate the inhibition of classically activated macrophages in myocardial infarction (MI) under the influence of the chemokine (C-C motif) receptor 2 (CCR2) antagonist propagermanium (PPG). Mice (C57BL/6; = 121) were subjected to occlusion of the left anterior descending artery and were randomized to the following groups: (a) MI with daily oral administration of 0.9% sodium chloride ("MI"), (b) MI with oral administration of 8 mg/kg PPG ("MI + PPG"), and (c) sham-operated mice served as control.

Rbpms2 prevents major cardiac defects in cardiomyocyte-specific Rbpms-deficient mice.

Cell-type-specific splicing depends on RNA-binding splicing factors. Several important splicing factors were identified in cardiomyocytes, including members of the RNA-binding proteins with multiple splicing (RBPMS) family, but their role during heart development has not been fully characterized. Here, we demonstrate that the function of RBPMS overlaps with the closely related paralog RBPMS2.

A genetic modifier links integrin α5 to the phenotypic variation in fibronectin 1a mutant zebrafish.

Phenotypic variation is often observed in individuals with the same mutation. However, the mechanisms that contribute to this variation remain largely unknown. Fibronectin mutants in both mouse and zebrafish fail to form a functional cardiovascular system, although the penetrance and expressivity of this phenotype vary depending on the genetic background.

Influence of canstatin on fibroblast-driven hypervascularisation in rheumatoid arthritis.

Objectives: Hypervascularisation is a dominant feature of the inflamed synovium in rheumatoid arthritis (RA). As RA synovial fibroblasts (RASFs) are key cells of synovial pathophysiology and are located adjacent to the aberrant endothelial cells (ECs), we hypothesised that this interaction might be responsible for the pathological hypervascularisation.

Methods: In the severe combined immunodeficiency (SCID) mouse model for RA, RASF-mediated helix-like vessel (HLV) formation was described and modulated by canstatin, an antiangiogenic collagen IV fragment that blocks the angiopoietin (ANGPT)/Tie2 pathway in EC.

Transcriptomic profiling of granuloma in patients with cardiac sarcoidosis.

Cardiac sarcoidosis (CS) is an inflammatory condition characterized by the accumulation and clustering of immune cells, primarily macrophages, leading to granuloma formation. Despite its clinical significance, CS remains relatively understudied, particularly concerning the molecular mechanisms driving fibrosis and disease progression. To explore potential therapeutic targets, we aimed to characterize the transcriptomic landscape of CS granulomas.

Enhancing allergy diagnosis: mass spectrometry as a complementary technique to the basophil activation test.

Accurate diagnostic tools for allergic conditions are essential for effective treatment. Traditional methods, such as skin prick tests (SPT) and specific IgE measurements are widely used, but they have limitations in sensitivity and specificity for certain allergens. While the Basophil Activation Test (BAT) offers improved specificity, particularly for allergens such as peanuts and sesame, its practicality and accessibility remain challenges.

SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging.

Sirtuin enzymes are deeply associated with senescence and aging. Sirtuin proteins are tightly regulated, but how their levels are governed during aging and how they elicit tissue-specific cellular changes are unclear. Here, we demonstrate that SIRT7 undergoes proteasomal degradation during senescence via targeting by the E3 ligase TRIP12.

Transcriptional adaptation: where mRNA decay meets genetic compensation.

Nonsense-mediated mRNA decay (NMD) is a translation-coupled quality control mechanism that safeguards cells against faulty transcripts that could lead to truncated and potentially harmful proteins. However, we posit that there is another side to NMD: it does not just clear away defective transcripts, it also triggers a form of genetic compensation known as transcriptional adaptation (TA). This recently discovered cellular response operates independently of protein loss.

A discovery platform for identification of host-induced bacterial biosensors from diverse sources.

Synthetic biology approaches such as whole-cell biosensing and 'sense-and-respond' therapeutics aim to enlist the vast sensing repertoire of gut microbes to drive cutting-edge clinical and research applications. However, well-characterised circuit components that sense health- and disease-relevant conditions within the gut remain limited. Here, we extend the flexibility and power of a biosensor screening platform using bacterial memory circuits.

The tumor suppressor FAT1 controls YAP/TAZ protein degradation and tumor cell proliferation through E3 ligase MIB2.

FAT1 is a tumor suppressor gene encoding the protocadherin FAT1, which has been found to be mutated in different types of human cancers with the highest frequency in head and neck squamous cell carcinoma (HNSCC). However, through which mechanisms mutations of FAT1 lead to tumor progression is incompletely understood. Here, we report that loss of FAT1 in various tumor cells, including HNSCC cells, resulted in increased protein levels of the transcriptional regulators YAP and TAZ.

Activation of expression marks newly forming myofibers and regulates muscle cell differentiation in adult zebrafish skeletal muscle repair.

Like mammals, zebrafish repair skeletal muscle through a multistep process that involves satellite cell activation, differentiation of progenitor cells into myocytes, their fusion into myotubes, followed by myotube maturation and myofiber hypertrophy. Coordination and timely regulation of these events are essential for functional muscle recovery. Here, we identify , a gene responsive to muscle stress, as a new player in the repair of adult zebrafish skeletal muscle and show its involvement in modulating molecular mechanisms behind myogenic cell differentiation.

PIEZO1 mediates periostin+ myofibroblast activation and pulmonary fibrosis in mice.

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease characterized by the excessive accumulation of activated myofibroblasts that deposit extracellular matrix (ECM) protein, leading to progressive scar formation and mechanical stress. However, the cellular origin and fate of myofibroblasts remain controversial, and the mechanisms by which myofibroblasts sense mechanical cues in the lung are unclear. Here, we report that periostin (Postn) is a reliable and distinctive marker for pulmonary myofibroblasts, while ablation of Postn+ myofibroblasts after injury ameliorated lung fibrosis.