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Gut microbiota and short-chain fatty acids in cardiometabolic HFpEF: mechanistic pathways and nutritional therapeutic perspectives
Full text linkHeart failure with preserved ejection fraction (HFpEF) accounts for more than half of the cases of HF worldwide. Among the different phenotypes, cardiometabolic HFpEF has the highest prevalence. Cumulative insults related to cardiometabolic comorbidities—obesity, hypertension and type 2 diabetes—create a milieu of metabolic derangements, low-grade systemic inflammation (i.e., metainflammation), endothelial dysfunction, and coronary microvascular disease. Emerging data indicate that the gut–heart axis is a potential amplifier of this process. Cardiometabolic comorbidities promote gut dysbiosis, loss of short-chain fatty acid (SCFA)-producing taxa, and disruption of the intestinal barrier, leading to endotoxemia and upregulation of pro-inflammatory pathways such as TLR4- and NLRP3-mediated signaling. Concomitantly, beneficial gut-derived metabolites (acetate, propionate, butyrate) decrease, while detrimental metabolites increase (e.g., TMAO), potentially fostering myocardial fibrosis, diastolic dysfunction, and adverse remodeling. SCFAs—acetate, propionate, and butyrate—may exert pleiotropic actions that directly target HFpEF pathophysiology: they may provide a CPT1-independent energy substrate to the failing myocardium, may improve lipid and glucose homeostasis via G protein-coupled receptors and AMPK activation, and may contribute to lower blood pressure and sympathetic tone, reinforce gut barrier integrity, and act as anti-inflammatory and epigenetic modulators through the inhibition of NF-κB, NLRP3, and histone deacetylases. This review summarizes current evidence linking gut microbiota dysfunction to cardiometabolic HFpEF, elucidates the mechanistic role of SCFAs, and discusses nutritional approaches aimed at enhancing their production and activity. Targeting gut–heart axis and SCFAs pathways may represent a biologically plausible and low-risk approach that could help attenuate inflammation and metabolic dysfunctions in patients with cardiometabolic HFpEF, offering novel potential therapeutic targets for their management
VERIDAH: solving enumeration anomaly aware vertebra labeling across imaging sequences
No full textThe human spine commonly consists of seven cervical, twelve thoracic, and five lumbar vertebrae. However, enumeration anomalies may result in individuals having eleven or thirteen thoracic vertebrae and four or six lumbar vertebrae. Although the identification of enumeration anomalies has potential clinical implications for chronic back pain and operation planning, the thoracolumbar junction is often poorly assessed and rarely described in clinical reports. Additionally, even though multiple deep-learning-based vertebra labeling algorithms exist, there is a lack of methods to automatically label enumeration anomalies. Our work closes that gap by introducing "Vertebra Identification with Anomaly Handling" (VERIDAH), a novel vertebra labeling algorithm based on multiple classification heads combined with a weighted vertebra sequence prediction algorithm. We show that our approach surpasses existing models on T2w TSE sagittal (98.30% vs. 94.24% of subjects with all vertebrae correctly labeled, p < 0.001) and CT imaging (99.18% vs. 77.26% of subjects with all vertebrae correctly labeled, p < 0.001) and works in arbitrary field-of-view images. VERIDAH correctly labeled the presence of thoracic enumeration anomalies in 87.80% and 96.30% of T2w and CT images, respectively, and lumbar enumeration anomalies in 94.48% and 97.22% for T2w and CT, respectively. Our code and models are available at: https://github.com/Hendrik-code/spineps
The HTT1a protein initiates HTT aggregation in a knock-in mouse model of Huntington's disease
Full text linkThe mutation that causes Huntington's disease is a CAG repeat expansion in exon 1 of the huntingtin gene (HTT) that leads to an abnormally long polyglutamine tract in the huntingtin protein (HTT). Mutant CAG repeats are unstable and increase in size in specific neurons and brain regions with age, a phenomenon that constitutes the first step in the pathogenesis of the disease. In the presence of an expanded CAG repeat, cryptic polyA sites in intron 1 of the HTT pre-mRNA can become activated leading to the polyadenylation of a prematurely terminated transcript, HTT1a. This encodes the HTT1a protein, which is known to be very aggregation-prone and highly pathogenic. Given that the longer the CAG repeat the more HTT1a is generated, could the production of HTT1a be the mechanism through which somatic CAG repeat expansion exerts its pathogenic consequences? Resolving this issue is very important for the design of therapeutic approaches to lower huntingtin levels. We have used a CRISPR-Cas9 approach to prevent the production of HTT1a in a knock-in mouse model of Huntington's disease. All potential cryptic polyA sites were deleted from Htt intron 1 in HdhQ150 mice and colonies were established that were heterozygous for the intron 1 deletion on a mutant allele (HdhQ150ΔI) and heterozygous for the deletion on a wild-type allele (WTΔI). The CAG repeat sizes in the HdhQ150 and HdhQ150ΔI colonies were well-matched at approximately 195 CAGs. As predicted, the deletion of the cryptic polyA sites from Htt intron 1 prevented the generation of the Htt1a transcript in the HdhQ150ΔI mice. However, very low levels of the HTT1a protein were detected, which resulted from a Htt readthrough product of exon 1 and exon 2, that had retained the deleted intron and terminated at a cryptic polyA site in intron 2. HdhQ150, HdhQ150ΔI, wild-type and WTΔI mice were studied until 17 months of age. Immunohistochemical and homogeneous time resolved fluorescence analysis showed that HTT aggregation in both HdhQ150 and HdhQ150ΔI brains contained HTT1a, but the dramatic decrease in soluble HTT1a levels in HdhQ150ΔI brains delayed the appearance of aggregated HTT1a by several months. Although this delay in aggregate pathology only partially reversed transcriptional dysregulation, the biomarkers NEFL and BRP39 (YKL40) remained at wild-type levels in HdhQ150ΔI mice at 17 months of age. These data demonstrate that the production of HTT1a initiates HTT aggregation and that it is important to target HTT1a in huntingtin-lowering therapeutic strategies
Complement inhibition for acute neuromyelitis optica spectrum disorder attacks: insights from an international case series
Full text linkBACKGROUND AND OBJECTIVES: Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune disease mainly driven by aquaporin-4 antibodies (AQP4-IgG). During an attack, AQP4-IgG activates the complement system, leading to astrocyte destruction, inflammation, neuronal damage, and thus devastating and often irreversible neurologic deficits. Terminal complement inhibitors such as eculizumab and ravulizumab effectively prevent relapses, yet their therapeutic potential in stopping ongoing complement-mediated injury during acute attacks remains insufficiently explored. METHODS: We conducted a multinational retrospective case series across NMOSD-specialized centers in 6 countries, analyzing 33 AQP4-IgG–positive patients (mean age: 48.1 years; 28 women) treated with component 5 (C5) inhibition during or shortly after acute relapse (mean 20.1 days from symptom onset; range 2–62). Eculizumab was used in 25 patients and ravulizumab in 8. Two additional patients were excluded because of delayed treatment initiation beyond 62 days. RESULTS: Lesion locations included myelitis (57.6%) and optic neuritis (30.3%). Expanded Disability Status Scale scores worsened from a pre-relapse median of 0 (interquartile range [IQR] 0–2) to a nadir of 6.5 (IQR 3.5–8), improving to 3.5 (IQR 3–6.5) at 1–3 months and 2.5 (IQR 2–6) at 6 months. All patients stabilized clinically; 20 continued C5 inhibition as attack-preventing therapy. Good, moderate, and poor/absent recovery were observed in 15, 11, and 7 patients, respectively. Earlier treatment was associated with better outcomes: treatment within 21 days yielded an odds ratio of 1.58 (95% CI 0.32–8.52) for good response. Plasma exchange was administered in 57.6% and was associated with higher overall response rates, but not with good response alone. DISCUSSION: These findings highlight the potential of complement inhibition as a treatment option for acute NMOSD attacks, particularly in patients with insufficient response to standard therapies. Given the absence of clinical worsening and the encouraging course observed in most of the patients, further investigation into the role of C5 inhibition in acute attack management is warranted. CLASSIFICATION OF EVIDENCE: This retrospective case series provides Class IV evidence that the C5 complement inhibitors eculizumab or ravulizumab may improve disability in patients with NMOSD when given during or shortly after acute relapse
Immunoglobulin G complexes from post-infectious ME/CFS, including post-COVID ME/CFS disrupt cellular energetics and alter inflammatory marker secretion
Full text linkBACKGROUND: Autoimmunity is a key clinical feature in both post-infectious Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Post-Acute Sequelae of COVID (PASC). Passive transfer of immunoglobulins from patients' sera into mice induces some clinical features of PASC. However, the physiological effects of immunoglobulins on cellular alterations remain elusive. In this study, we tested the potential effects of immunoglobulins from ME/CFS patients on endothelial cell dysfunction. METHODS: We have isolated immunoglobulins from 106 individuals, including ME/CFS (n = 39), PCS-CFS (n = 15), MS (n = 20) patients, and healthy controls (n = 41). Protein composition of the isolated immune complexes was studied using mass spectrometry. The effect of isolated immune complexes on mitochondria was evaluated using confocal microscopy and a Seahorse XFe96 Extracellular Flux Analyzer, and the impact on inflammatory cytokine secretion was studied using a multiplex bead-based assay. RESULTS: Here, we demonstrate that IgG isolated from post-infectious ME/CFS patients selectively induces mitochondrial fragmentation in human endothelial cells and alters cellular energetics. This effect is lost upon cleavage of IgG into its Fab and Fc fragments. The digested Fab fragment from ME/CFS alone was able to alter the cellular energetics, resembling the effect of intact IgG. IgG from post-infectious ME/CFS, including post-COVID ME/CFS patients, induced distinct but separate cytokine secretion profiles in healthy PBMCs. Proteomics analysis of IgG-bound immune complexes revealed significant changes in immune complexes from ME/CFS patients, affecting extracellular matrix organization, whereas those from post-COVID ME/CFS patients pointed to alterations in hemostasis and blood clot regulation. CONCLUSIONS: We demonstrate that IgGs from ME/CFS patients carry a chronic protective stress response that promotes mitochondrial adaptation via fragmentation, without altering mitochondrial ATP generation capacity in endothelial cells. Together, these results highlight a potential pathogenic role of IgG in post-infectious ME/CFS and point to novel therapeutic strategies targeting antibody-mediated metabolic dysregulation
Targeting mutual dependence of phosphatidylinositol-3-kinase α/δ and small ubiquitin-like modifier signaling in pancreatic cancer
Full text linkBACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal cancer, with a 5-year survival rate of <13%. Despite advances in diagnostics and treatments, the standard of care for PDAC remains inadequate, and most patients develop resistance to therapy. Targeted approaches, such as Kirsten rat sarcoma (KRAS) inhibition, have shown promise in preclinical models, although clinical application remains challenged by the rapid development of resistance. The phosphatidylinositol-3-kinase (PI3K) signaling pathway is critical for PDAC development and maintenance, yet pharmacologic targeting has failed to yield significant clinical benefits. METHODS: To investigate the relationship between the PI3K and small ubiquitin-like modifier (SUMO) pathways in PDAC, we used a comprehensive approach that included unbiased genome-wide clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats-associated protein 9 resistance screens, pharmacologic screens, transcriptomics, proteomics, and phosphoproteomics experiments. Genetic knockout models were applied to validate our findings. A novel molecularly targeted combination therapy was tested in preclinical mouse models. RESULTS: Using genetic and pharmacologic screenings, we discovered a mutual and targetable codependence between the PI3K and the SUMO pathways. Simultaneous inhibition of PIK3α and PIK3δ, combined with SUMO-activating E1 targeting, triggered synthetic lethality and cell death. In syngeneic orthotopic immune-competent PDAC models, this combination therapy reduced tumor growth and promoted immune cell infiltration and activity. CONCLUSIONS: Our study introduces a novel rational combination therapy in PDAC. Dual targeting of PI3Kα/δ and SUMO signaling bears potential for clinical translation
Gestational diabetes mellitus alters placental precursor mRNA splicing
No full textGestational diabetes mellitus (GDM) is defined as hyperglycemia first identified during pregnancy and can lead to adverse maternal and neonatal outcomes. The molecular mechanisms leading to these outcomes are currently poorly understood. While transcriptomics of GDM placentas has been previously studied, the effect on precursor mRNA splicing remains largely unknown. This study explores the impact of GDM on placental splicing and identifies its regulatory mechanisms. Using RNA sequencing data from Norwegian and Chinese cohorts, we uncovered thousands of differential splicing events. Pathway enrichment analysis revealed significant associations with metabolic and diabetes-related pathways. Splicing factor motif and cross-linking and immunoprecipitation sequencing analyses highlighted serine/arginine-rich splicing factor 10 (SRSF10) as a key regulator in this process, with its binding enriched at misspliced exons. Silencing SRSF10 in placental cells mirrored GDM-associated missplicing in key genes. These findings underscore splicing dysregulation as a critical process in GDM pathogenesis, suggesting that targeting SRSF10 could be a potential therapeutic approach to mitigate the deleterious effects of GDM
Bispecific BAFF-R/BCMA CAR T cells control growth of heterogeneous plasma cells in multiple myeloma
No full textMultiple myeloma treatment has experienced tremendous advances through chimeric antigen receptor (CAR) therapies directed to the B cell maturation antigen (BCMA), but remissions are usually transient. To mitigate the risk of BCMA immune escape, we aimed for a simultaneous targeting of BCMA together with the B cell-activating factor receptor (BAFF-R). Single-cell RNA sequencing discovered increased BAFF-R gene (TNFRSF13C) expression in relapsed and refractory multiple myeloma cases, and it emerged as prognostic marker for long-term complete responses. BAFF-R was expressed in plasma cells at earlier maturation stages compared with BCMA-positive plasma cell phenotypes. Bispecific BAFF-R/ BCMA CARs endowed T cells with cytolytic efficacy against multiple myeloma cell lines and primary multiple myeloma cells. In vivo, the dual CAR compensated for BCMA downregulation when BAFF-R was expressed, preventing the evolution of antigen escape mutants that drive resistance to CAR T cell therapy. Our study proposes BAFF-R as a complementary target antigen suitable to eliminate malignant plasma cells with less advanced differentiation, lack of BCMA, and occurrence in dismal prognosis patients
Assessing the robustness of an artificial intelligence segmentation model for quantitative cardiovascular magnetic resonance imaging across cardiac phenotypes
Full text linkPURPOSE: To introduce an artificial intelligence-based cardiovascular magnetic resonance segmentation algorithm (Nick) for automated quantification of function and parametric mapping across cardiac phenotypes reflecting clinical routine. METHODS: Nick was compared to manual gold standard (GS) segmentations in 359 multi-centre cases at 1.5T and 3T, consisting of 104 healthy individuals and 255 diseased patients with various cardiac phenotypes. Left and right ventricular (LV, RV) volumes and LV mass (LVM) were derived from short-axis segmentations. For parametric mapping, the LV myocardium was segmented to quantify T1 and T2 relaxation times. Statistical analysis comprised mean differences, correlation coefficients (R(2)), Bland-Altman analysis, tolerance range assessments, and paired boxplots. The number of slices and contours requiring manual correction was estimated based on slice-level differences. RESULTS: Nick demonstrated high agreement with the GS for LV and RV volume estimations (R(2)≥0.93) and LVM quantification (R(2)=0.86). For the ejection fractions, correlations were slightly lower (R(2)=0.85/0.72 for LV/RV) with small mean differences (+ 1.14%/-2.48% for LV/RV). T1 and T2 mapping values showed excellent agreement with manual reference values (R²≥0.92) and minimal biases (-1.64/0.14 ms for T1/T2). Nick underestimated LV volumes at end-diastole (-4.48 ml) and end-systole (-3.28 ml) as well as the RV end-diastolic volume (-5.14 ml) and stroke volume (-6.75 ml). Nonetheless, tolerance testing for mean deviations revealed clinically acceptable biases for all comparisons, and less than two slices per case required correction on average. CONCLUSION: Comparison to expert segmentations revealed robust performance of Nick in routine clinical cases with variable pathology, supporting its future integration into clinical workflows
CAR T cells as novel therapeutic strategy for multiple sclerosis and other neuroimmune disorders
Full text linkChimeric antigen receptor (CAR) T-cell therapy is rapidly emerging as a transformative approach for treating multiple sclerosis (MS) and other neuroimmune disorders such as neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and myasthenia gravis (MG), alongside several other rare neuroimmunological conditions currently being evaluated in compassionate-use or early-phase studies. These conditions are driven in part by autoreactive B cells that sustain chronic inflammation and progressive tissue damage. While current immunomodulatory therapies have improved clinical outcomes, they often require lifelong administration and fail to effectively eliminate compartmentalized inflammation within the central nervous system. Recent advances in CD19- and BCMA-directed CAR T-cell therapy, initially developed for hematologic malignancies, demonstrate the potential to achieve targeted, durable B-cell depletion and immune reprogramming in autoimmune diseases. Preclinical models and early-phase clinical trials have shown promising efficacy, including reduced relapse rates, stabilization of disability progression, and decreased autoantibody levels, alongside a favorable safety profile with lower rates of high-grade cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) compared to oncologic applications. This review synthesizes the current evidence supporting the use of CAR T-cell therapy in neuroinflammatory diseases and explores its potential to redefine treatment paradigms by shifting from chronic immunosuppression to long-term immune tolerance, creating a favorable environment for repair mechanisms. Realizing the full therapeutic promise of CAR T-cells in autoimmune neurology will require sustained research in heterogeneous populations and across disease spectrums