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Identification and characterization of alamandine-(1-5), a new component of the renin-angiotensin system
No full textBACKGROUND: The renin-angiotensin system comprises a biochemical cascade that hydrolyzes angiotensinogen into several different bioactive peptides, which can activate different receptors, promoting plenty of specific effects. This study aimed to evaluate the presence of the putative product of alamandine, the pentapeptide Ala-(1-5) (alamandine-[1-5]), in the circulation and its biological activity. METHODS: To accomplish this, we have used mass spectrometry (MALDI/TOF/TOF, LC-MS/MS) and several methodologies, including isolated blood vessels, isolated perfused hearts, isolated cardiomyocytes, blood pressure recording in freely moving normotensive and SHR, high-resolution echocardiography, central administration (ICV infusion and microinjection in the insular cortex), cell culture (endothelial cells and G-protein-coupled receptors-transfected CHO cells), and wild-type and Mas (Mas receptor proto-oncogene), MrgD (Mas-related G-protein-coupled receptor subtype D), or AT(2) (angiotensin II type 2) receptor-deficient mice. RESULTS: We show that Ala-(1-5) is present in the circulation of healthy humans and rodents and promotes many biological central and peripheral actions. A major role for ACE (angiotensin-converting enzyme) activity in the formation of Ala-(1-5) from alamandine in the circulation was observed using plasma samples from angiotensinogen-KO mice. Ala-(1-5) increases baroreflex sensitivity and produces a long-lasting (≈6 hours) antihypertensive effect in SHR, associated with a significant reduction in cardiac output. Additionally, Ala-(1-5) decreases inotropism in isolated perfused hearts and reduces contractility in cardiomyocytes. In CHO-transfected cells, Ala-(1-5) can bind and stimulate NO production through all receptors from the renin-angiotensin system protective arm (Mas, MrgD, and AT2 receptors). On the other hand, the Ala-(1-5) effects on cardiomyocytes and mouse aortic rings were abolished only by MrgD genetic deletion, but not by Mas or AT2 receptor knockout. CONCLUSIONS: Our data demonstrate that Ala-(1-5) is a newly identified peptide within the renin-angiotensin system, with strong blood pressure-lowering effects that vary in mechanisms of action among different tissues. Ala-(1-5) has distinct characteristics that differentiate it from the conventional renin-angiotensin system pathways responsible for reducing blood pressure
Genetic elements promote retention of extrachromosomal DNA in cancer cells
Full text linkExtrachromosomal DNA (ecDNA) is a prevalent and devastating form of oncogene amplification in cancer. Circular megabase-sized ecDNAs lack centromeres, stochastically segregate during cell division and persist over many generations. It has been more than 40 years since ecDNAs were first observed to hitchhike on mitotic chromosomes into daughter cell nuclei, but the mechanism underlying this process remains unclear. Here we identify a family of human genomic elements, termed retention elements, that tether episomes to mitotic chromosomes to increase ecDNA transmission to daughter cells. Using Retain-seq, a genome-scale assay that we developed, we reveal thousands of human retention elements that confer generational persistence to heterologous episomes. Retention elements comprise a select set of CpG-rich gene promoters and act additively. Live-cell imaging and chromosome conformation capture show that retention elements physically interact with mitotic chromosomes at regions that are mitotically bookmarked by transcription factors and chromatin proteins. This activity intermolecularly recapitulates promoter–enhancer interactions. Multiple retention elements are co-amplified with oncogenes on individual ecDNAs in human cancers and shape their sizes and structures. CpG-rich retention elements are focally hypomethylated. Targeted cytosine methylation abrogates retention activity and leads to ecDNA loss, which suggests that methylation-sensitive interactions modulate episomal DNA retention. These results highlight the DNA elements and regulatory logic of mitotic ecDNA retention. Amplifications of retention elements promote the maintenance of oncogenic ecDNA across generations of cancer cells, and reveal the principles of episome immortality intrinsic to the human genome
Fecal detection of calprotectin subunits links inflammatory bowel disease activity with chronicity of intestinal inflammation
Full text linkBACKGROUND & AIMS: Quantification of the human S100A8/ S100A9 tetrameric protein complex in stool, referred to as fecal calprotectin, is an extensively validated biomarker supporting the diagnosis and management of gastrointestinal diseases. Here, we studied the quaternary protein structures (termed configuration) of S100A8 and S100A9 and their biological function in inflammatory bowel diseases (IBD). METHODS: We dissected fecal S100A8 and S100A9 configurations in patients with IBD by size-exclusion chromatography coupled with tandem mass spectrometry and systematically defined human S100A8 and S100A9 homodimer functions compared with the calprotectin heterotetramer (CP) in the intestine of mice and in human epithelium and T cells. Moreover, we report a protein interaction network of fecal S100A8 and S100A9 in IBD. RESULTS: Stool from patients with active IBD contained abundant S100A8 and S100A9 dimers besides CP. Fecal S100A9 detection associated with clinical and endoscopic disease activity in IBD patients with low CP concentration. Oral exposure to human recombinant S100A8 and S100A9 homodimers, but not to CP, worsened intestinal inflammation in toxic and genetic mouse models. Functional profiling revealed that human S100A8 and S100A9 homodimers enhanced activation of cluster of differentiation 4(+) and 8(+) T cells, which promoted experimental colitis. In turn, genetic inactivation of S100a9 protected against experimental enteritis and colitis, and pharmacologic inhibition of S100A9 ameliorated chronic colitis. CONCLUSIONS: Collectively, this study links the detection of fecal S100A9 dimers with clinical and endoscopic disease activity in IBD and identifies inflammatory actions of S100A8 and S100A9 homodimers in the intestine. Our findings pave the way for novel diagnostic and therapeutic approaches in patients with inflammatory diseases of the intestine
The neuronal circuits and cellular encoding of thermosensation
No full textThe neural circuits processing thermal information play a key role in shaping somatosensory perception, regulating core body temperature and avoiding harm. The circuits underlying thermal perception are less understood than for other sensory systems, but recent research has shed light on the wiring, cellular encoding principles and their link to perception. While thermosensation was traditionally viewed as a slower, modulatory sense, it is now recognized as a fast and sensitive sensory system that exhibits complex features such as multisensory integration and sensory illusions. Here, we highlight recent progress in the understanding of innocuous thermal processing and perception and attempt to identify the principles of wiring of the thermal system and cellular encoding of temperature across mammals and insects. Intriguingly, while warm and cool reflect the same physical property, there are notable differences in their perception and encoding in the nervous system. We argue that the thermal system is an ideal model to advance our understanding of the neural mechanisms of sensory perception and sensory-guided behaviours
Metabo-epigenetic circuits of heart failure: chromatin-modifying enzymes as determinants of metabolic plasticity
Full text linkMetabolic adaptations are a functional requirement for the heart to accommodate its broad range of physiologic operating conditions. It is increasingly recognized that persistent and exaggerated metabolic alterations precede adverse cardiac remodeling leading to heart failure. These metabolic shifts are coupled with changes in cardiac gene expression, driven in part by chromatin-modifying enzymes, which have recently been identified as both sensors and transducers of metabolic stress and gene regulatory networks, respectively. This review synthesizes the latest evidence implicating chromatin-modifying enzymes as key regulators of metabolic reprogramming in the heart, providing a framework to understand how metabolic stressors are incorporated as epigenetic modifications that regulate cardiac gene expression. We propose a model of ‘metabo-epigenetic circuitry’ within which energy metabolic perturbations drive transcriptional and epigenetic changes that ultimately contribute to cardiac dysfunction. Although many nodes in these circuits remain unidentified, this viewpoint opens new avenues for investigating chromatin-modifying enzymes as therapeutic targets to halt the metabolic programs that promote heart failure
Autophagy-regulated mitochondrial inheritance controls early CD8(+) T cell fate commitment
Full text linkT cell immunity deteriorates with age, accompanied by a decline in autophagy and asymmetric cell division. Here we show that autophagy regulates mitochondrial inheritance in CD8(+) T cells. Using a mouse model that enables sequential tagging of mitochondria in mother and daughter cells, we demonstrate that autophagy-deficient T cells fail to clear premitotic old mitochondria and inherit them symmetrically. By contrast, autophagy-competent cells that partition mitochondria asymmetrically produce daughter cells with distinct fates: those retaining old mitochondria exhibit reduced memory potential, whereas those that have not inherited old mitochondria and exhibit higher mitochondrial turnover are long-lived and expand upon cognate-antigen challenge. Multiomics analyses suggest that early fate divergence is driven by distinct metabolic programmes, with one-carbon metabolism activated in cells retaining premitotic mitochondria. These findings advance our understanding of how T cell diversity is imprinted early during division and support the development of strategies to modulate T cell function
Highlights from the Susan Lindquist School on Proteostasis-EMBO|FEBS Lecture Course, 16-19 September, 2025, Espoo, Finland
No full textThe maintenance of protein homeostasis is a fundamental premise for the survival of all life. The synthesis, folding, localization, and degradation of thousands of proteins must be organized according to various conditions. To ensure such a stable and functional proteome, the proteostasis network evolved. Dedicated to this, the fourth School on Proteostasis, a co-funded EMBO|FEBS Lecture Course in memory of Susan Lindquist, took place in Espoo, Finland on 16-19 September 2025, with 59 early career researchers (PhD students or postdoctoral fellows), 18 leading scientists, and two editors attending and discussing the current state of the field. From basic principles to the latest therapeutic developments, this meeting provided a comprehensive overview of proteostasis. This report summarizes the lecture course and highlights selected presentations
ESC-Leitlinien zu Myokarditis und Perikarditis: erste gemeinsame europäische Leitlinie für Myokarditis und Perikarditis [ESC guidelines on myocarditis and pericarditis: first combined European guidelines for myocarditis and pericarditis]
Full text linkThe new guidelines for myocarditis and pericarditis from the European Society of Cardiology (ESC) are the first guidelines for myocarditis and for the first time they also combine the two entities. A key aspect is the introduction of the term inflammatory myopericardial syndrome (IMPS), an umbrella term that covers the spectrum of both diseases and enables uniform diagnostics and treatment but in particular draws attention to the fact that there are overlapping causes, diagnostic approaches and treatment options. Other major aspects relate to noninvasive diagnostics using multimodal imaging. There is a paradigm shift that enables the definitive diagnosis of myocarditis also using cardiovascular magnetic resonance imaging. An etiologically oriented treatment mostly requires an endomyocardial biopsy in pericardial effusion cytological work-up is instrumental. Furthermore, an intuitive risk stratification is introduced, which influences both the treatment and follow-up examinations and involves abandoning fixed waiting periods with respect to resuming sports and work. Diagnostic algorithms are based on the initial symptoms, such as chest pain, heart failure and arrhythmia and integrate the risk stratification into the treatment process. For pericarditis, innovative treatment approaches using interleukin‑1 antagonists are coming to the fore. Another focus is the consideration of genetic factors, which are particularly relevant in recurrent forms
Alpha-synuclein quantitative seed amplification assay predicts conversion to dementia
Full text linkINTRODUCTION: The alpha-synuclein seed amplification assay (SAA) has shown excellent performance in the detection of Lewy body pathology in cerebrospinal fluid (CSF). Lewy body pathology is prognostically relevant in patients at risk for dementia. Current assays only provide binary results, so there is a need to quantify the extent of pathology in living patients. METHODS: In addition to the "standard" SAA, we developed a quantitative SAA (qnSAA) and measured 432 CSF samples (216 baseline-follow-up pairs). RESULTS: qnSAA results correlated with cognitive performance. Seventy-five percent of participants with fast qnSAA kinetics converted to dementia in the observed interval. Overall, participants with fast qnSAA kinetics accounted for 27.3% of dementia converters in the entire cohort. DISCUSSION: Findings demonstrate promising properties of qnSAA measurements in a cohort of patients at risk for dementia. qnSAA results showed improved prognostic relevance and have potential to measure target engagement of therapies against Lewy body pathology
Takotsubo-Syndrom: Kann die Grundlagenwissenschaft helfen? [Takotsubo syndrome: can basic science help?]
Full text linkTakotsubo syndrome (TTS) is a stress-associated acute heart failure mimicking the clinical features of acute myocardial infarction. Elevated catecholamine levels appear to play a pivotal role in the pathogenesis. Despite rapid recovery of systolic left ventricular function in most cases the acute and/or long-term prognosis is often limited depending mostly on the clinical risk profile. A pathophysiology-oriented treatment does not yet exist due to the lack of evidence-based strategies; however, basic research has identified several possible mechanisms beyond a purely catecholamine hypothesis. This includes, for example, an apical beta-2-adrenoceptor mediated myocardial inhibition, a microvascular, mitochondrial or metabolic dysfunction as well as myocardial inflammation. In a translational approach, based on experimental data, the inhibition of the calcineurin signalling pathway as the driver of TTS is currently being investigated in the acute setting in a randomized double-blind phase II clinical study. This article, for example, discusses how basic science can contribute to the identification of important aspects of the pathophysiology and translation of causal treatment strategies