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Cardiac phase-resolved T(2)* magnetic resonance imaging reveals differences between normal hearts and a humanized mouse model of hypertrophic cardiomyopathy
Get PDFBACKGROUND/OBJECTIVES: While T(2)* mapping effectively assesses cerebral blood oxygenation, its utility for capturing cardiac phase-dependent myocardial changes in hypertrophic cardiomyopathy (HCM) is underexplored. This study investigates T(2)* dynamics in an HCM mouse model, to validate T(2)* as a clinically relevant biomarker for improved HCM diagnosis and treatment monitoring. METHODS: A cardiac-specific Mybpc3 genetic mouse model, closely mirroring human HCM, was used with 12 young mice (6–11 weeks old), including both male and female wild-type (WT) and Mybpc3-KI (HCM) groups. The cardiac function was assessed using self-gated multi-slice 2D CINE imaging. To investigate myocardial T(2)* variations across the cardiac cycle, multi-gradient echo (MGE) imaging was employed. This approach used retrospective gating and continuous acquisition synchronization with pulse oximetry at 9.4 T small animal MRI. RESULTS: Mybpc3-KI mice demonstrated left-ventricular (LV) hypertrophy compared to WT (HCM = 50.08 ± 4.68 µm/g vs. WT = 45.80 ± 20.07 µm/g, p < 0.01) and reduced ejection fraction (HCM = 38.55 ± 5.39% vs. WT= 72.53 ± 3.95%, p < 0.01). Myocardial T(2)* was significantly elevated in HCM across all cardiac phases (HCM = 12.14 ± 1.54 ms vs. WT = 7.93 ± 1.57 ms, p = 0.002). Strong correlations were observed between myocardial T(2)* and LV mass (rho = 0.88, p = 0.03). CONCLUSIONS: T(2)* was elevated in HCM with increased LV mass, highlighting the potential of T(2)* MRI as a sensitive biomarker for distinguishing healthy mice from those with HCM and revealing possible myocardial abnormalities
PDE3A as therapeutic target for modulation of compartmentalised cyclic nucleotide-dependent signalling
Get PDFPhosphodiesterase 3A (PDE3A) hydrolyses cAMP, adjusting cAMP signalling pathways with temporal and spatial accuracy. Thereby, PDE3A contributes to the control of several cellular compartments, including the plasma membrane, the cytosol, the nucleus and the sarcoplasmic reticulum (SR). This ability allows it to regulate important cellular functions like contractility, metabolism, differentiation and proliferation. Dysregulated cAMP signalling causes or is associated with diseases. The therapeutic potential of PDE3A is, however, limited by the lack of specific modulators. Emerging approaches to targeting PDE3A centre on specifically addressing its catalytic domain or its cellular localisation. This review highlights the growing knowledge of PDE3A's functions in cellular signalling and therapeutic modalities, opening the door to more fully utilize its potential for the treatment of disease
Extensive folding variability between homologous chromosomes in mammalian cells
Get PDFGenetic variation and 3D chromatin structure have major roles in gene regulation. Due to challenges in mapping chromatin conformation with haplotype-specific resolution, the effects of genetic sequence variation on 3D genome structure and gene expression imbalance remain understudied. Here, we applied Genome Architecture Mapping (GAM) to a hybrid mouse embryonic stem cell (mESC) line with high density of single-nucleotide polymorphisms (SNPs). GAM resolved haplotype-specific 3D genome structures with high sensitivity, revealing extensive allelic differences in chromatin compartments, topologically associating domains (TADs), long-range enhancer–promoter contacts, and CTCF loops. Architectural differences often coincide with allele-specific differences in gene expression, and with Polycomb occupancy. We show that histone genes are expressed with allelic imbalance in mESCs, and are involved in haplotype-specific chromatin contacts marked by H3K27me3. Conditional knockouts of Polycomb enzymatic subunits, Ezh2 or Ring1, show that one-third of ASE genes, including histone genes, is regulated through Polycomb repression. Our work reveals highly distinct 3D folding structures between homologous chromosomes, and highlights their intricate connections with allelic gene expression
Molecular machineries shaping the mitochondrial inner membrane
No full textMitochondria display intricately shaped deep invaginations of the mitochondrial inner membrane (MIM) termed cristae. This peculiar membrane architecture is essential for diverse mitochondrial functions, such as oxidative phosphorylation or the biosynthesis of cellular building blocks. Conserved protein nano-machineries such as F(1)F(o)-ATP synthase oligomers and the mitochondrial contact site and cristae organizing system (MICOS) act as adaptable protein-lipid scaffolds controlling MIM biogenesis and its dynamic remodelling. Signal-dependent rearrangements of cristae architecture and MIM fusion events are governed by the dynamin-like GTPase optic atrophy 1 (OPA1). Recent groundbreaking structural insights into these nano-machineries have considerably advanced our understanding of the functional architecture of mitochondria. In this Review, we discuss how the MIM-shaping machineries cooperate to control cristae and crista junction dynamics, including MIM fusion, in response to cellular signalling pathways. We also explore how mutations affecting MIM-shaping machineries compromise mitochondrial functions
Contemporary practice and resource availability for genetic testing in paediatric hypertrophic cardiomyopathy
Get PDFSingle-cell RNA sequencing delineates renal anti-fibrotic mechanisms mediated by TRPC6 inhibition
Get PDFChronic kidney disease (CKD) is characterized by persistent inflammation and tubulointerstitial fibrosis leading to end-stage renal disease. Transient receptor potential canonical 6 (TRPC6) channel inhibition mitigates tubular injury and renal fibrosis in murine models of unilateral ureteral obstruction (UUO) and 2-month chronic post–ischemia-reperfusion injury (2m post-I/R). Through integrated analysis of single-cell-RNA-sequencing (scRNA-Seq) data from UUO mice treated with the selective TRPC6 inhibitor SH045, here the renoprotective cell composition and cell type-specific transcriptional programs are defined. We explored translational aspects by conducting an in-depth scRNA-Seq analysis of kidney samples from patients with CKD. These results reveal global transcriptional shifts with a dramatic diversification of inflammatory cells, endothelial cells and fibroblasts. Notably, a distinct subpopulation of novel endothelial cells is delineated, which is termed ECRIN, that regulate inflammatory networks implicating VEGF and GAS signaling pathways. The data also indicates that inhibition of TRPC6 channels triggers a Prnp transcription factor regulatory network, which contributes to the alleviation of renal fibrosis. The key findings are supported at the protein level by immunofluorescence and western blot analysis. We observed similar patterns in the chronic 2m postI/R injury model. These findings provide novel insights into the potential therapeutic benefits of TRPC6 inhibition in CKD
Co-option of an endogenous retrovirus (LTR7-HERVH) in early human embryogenesis: becoming useful and going unnoticed
Get PDFWhile it is straightforward to understand why most mutations affecting functional sequence are harmful, how genomic changes result in new beneficial traits is harder to understand. Domestication of transposable elements (TEs) is an important source of both new genes and new regulatory systems as, for their own propagation, TEs need to have transcription factor binding sites and functional products that predispose to their recruitment. But are such predispositions to gain-of-function sufficient? Here we consider the case of the endogenous retrovirus, HERVH. Knockdown data supports HERVH having roles in pluripotency, self-renewal and defence against transpositionally-active retroelements in the early human embryo. We clarify the pluripotent cell types associated with HERVH expression and, in the process, note a key unresolved issue, framed by the unwanted transcript hypothesis: how can some cell types have 2% of their transcripts being HERVH-derived but survive the multiplicity of cellular devices that suppress foreign transcripts, be this by transcriptional repression or post-transcriptional filtering? We note a common coupling between novelty generation and suppression evasion. For example, pluripotency-associated KLF4 binding is thought to compete with transcriptional suppressor binding. Similarly, HERVH has a strong splice site enabling efficient novel chimeric transcript formation, the resulting exon-intron junctions enabling evasion of the unwanted transcript filters that recognize low or absent intron presence. We conclude that to better understand domestication, a focus on predispositions to avoidance of unwanted transcripts filters, as well as predispositions to gain of functions, is necessary. The same insights will be valuable for transgene design (eg for gene therapy) and instructive of gain-of-function in tumours, as HERVH is known to be involved in onco-exaptation events
Glial fibrillary acidic protein astrocytopathy based on a two-center chinese cohort study
Get PDFOBJECTIVE: Glial fibrillary acidic protein astrocytopathy (GFAP-A) is a recently defined nosological form belonging to the class of autoimmune inflammatory disorders affecting the central nervous system (CNS). Here, we report the clinical and MRI characteristics, treatment, and prognosis of a GFAP-A cohort from two centers in China. METHODS: We retrospectively analyzed the data from 38 adult patients with positive GFAP antibodies and diagnosed as GFAP-A between June 2019 and September 2024. Clinical features, semiquantitative antibody test results, MRI features, treatment approaches, and prognosis were collected. RESULTS: Among the 38 patients, 24 were male, and the median age at disease onset was 49.5 years. The clinical phenotype included encephalomyelitis (28.9%), myelitis (23.7%), encephalitis (18.4%), meningoencephalomyelitis (18.4%), meningitis/spinal meningitis (7.9%), and peripheral neuropathy (2.6%). In enhanced MRI images, 4 (10.5%) of the patients showed enhancement of the cerebral meninges, 2 (5.3%) had enhancement of the ependyma, and 5 (13.2%) had enhancement of the spinal cord pia mater. 77.1% of the patients responded to the glucocorticoid treatment, while 65.8% had a monophasic course. Spearman correlation analysis showed that CSF-specific oligoclonal bands were significantly correlated with 1-year relapse (CI = 0.527, p = 0.003). INTERPRETATION: The clinical manifestations of GFAP-A are highly diverse, encompassing encephalitis, myelitis, and meningitis, including spinal meningitis. The enhancement of the spinal pia mater and ependyma on MRI was confirmed. Most patients exhibit a positive response to glucocorticoid therapy. The presence of CSF-specific oligoclonal bands could potentially serve as an indicator for predicting recurrence
Retinoic acid-induced 2 deficiency impairs genomic stability in breast cancer
Get PDFBACKGROUND: Genome instability is a fundamental feature and hallmark of cancer, associated with aggressiveness, drug resistance and poor prognosis. RAI2 was initially identified as a novel metastasis suppressor protein specifically associated with the presence of disseminated tumour cells in the bone marrow of breast cancer patients, but its molecular function is largely unknown. METHODS: We analysed the consequences of RAI2 depletion on gene expression and genomic stability in luminal breast cancer cell lines, performed cytotoxicity profiling using a library of pharmacologically active compounds, and characterized a potential function of the RAI2 protein in the DNA damage response. We performed in silico validation in different breast cancer datasets. RESULTS: Analysis of clinical samples revealed that in primary breast tumours, low RAI2 gene expression is significantly associated with genomically unstable tumours and poor prognosis. RAI2 depletion in breast cancer cell lines resulted in loss of mitotic fidelity characterized by prolonged mitosis with increased chromosome segregation errors and micronuclei formation. Drug screening revealed increased sensitivity of RAI2-depleted breast cancer cells to topoisomerase I and Aurora A inhibitors. We also found that genotoxic stress induces the RAI2 protein, which has an affinity for and colocalises with poly-(ADP-ribose). We validated the association of RAI2 gene expression with DNA repair capacity in clinical samples. CONCLUSIONS: Our findings support, for the first time, a functional role of RAI2 in the maintenance of genomic stability. Understanding the underlying the molecular mechanism could help to improve patient diagnosis and treatment