Explore the vast range of titles available.

The human microbiome is a complex and dynamic system that plays important roles in human health and disease. However, there remain limitations and theoretical gaps in our current understanding of the intricate relationship between microbes and humans. In this narrative review, we integrate the knowledge and insights from various fields, including anatomy, physiology, immunology, histology, genetics, and evolution, to propose a systematic framework. It introduces key concepts such as the ‘innate and adaptive genomes’, which enhance genetic and evolutionary comprehension of the human genome. The ‘germ-free syndrome’ challenges the traditional ‘microbes as pathogens’ view, advocating for the necessity of microbes for health. The ‘slave tissue’ concept underscores the symbiotic intricacies between human tissues and their microbial counterparts, highlighting the dynamic health implications of microbial interactions. ‘Acquired microbial immunity’ positions the microbiome as an adjunct to human immune systems, providing a rationale for probiotic therapies and prudent antibiotic use. The ‘homeostatic reprogramming hypothesis’ integrates the microbiome into the internal environment theory, potentially explaining the change in homeostatic indicators post-industrialization. The ‘cell-microbe co-ecology model’ elucidates the symbiotic regulation affecting cellular balance, while the ‘meta-host model’ broadens the host definition to include symbiotic microbes. The ‘health-illness conversion model’ encapsulates the innate and adaptive genomes’ interplay and dysbiosis patterns. The aim here is to provide a more focused and coherent understanding of microbiome and highlight future research avenues that could lead to a more effective and efficient healthcare system.

Trillions of microbes in the human intestinal tract, including bacteria, viruses, fungi, and protozoa, are collectively referred to as the gut microbiome. Recent technological developments have led to a significant increase in our understanding of the human microbiome. It has been discovered that the microbiome affects both health and the progression of diseases, including cancer and heart disease. Several studies have indicated that the gut microbiota may serve as a potential target in cancer therapy modulation, by enhancing the effectiveness of chemotherapy and/or immunotherapy. Moreover, altered microbiome composition has been linked to the long-term effects of cancer therapy; for example, the deleterious effects of chemotherapy on microbial diversity can, in turn, lead to acute dysbiosis and serious gastrointestinal toxicity. Specifically, the relationship between the microbiome and cardiac diseases in cancer patients following therapy is poorly understood. In this article, we provide a summary of the role of the microbiome in cancer treatment, while also speculating on a potential connection between treatment-related microbial changes and cardiotoxicity. Through a brief review of the literature, we further explore which bacterial families or genera were differentially affected in cancer treatment and cardiac disease. A deeper understanding of the link between the gut microbiome and cardiotoxicity caused by cancer treatment may help lower the risk of this critical and potentially fatal side effect.

Adeno-associated virus (AAV) forms the basis for several commercial gene therapy products and for countless gene transfer vectors derived from natural or synthetic viral isolates that are under intense preclinical evaluation. Here, we report a versatile pipeline that enables the direct side-by-side comparison of pre-selected AAV capsids in high-throughput and in the same animal, by combining DNA/RNA barcoding with multiplexed next-generation sequencing. For validation, we create three independent libraries comprising 183 different AAV variants including widely used benchmarks and screened them in all major tissues in adult mice. Thereby, we discover a peptide-displaying AAV9 mutant called AAVMYO that exhibits superior efficiency and specificity in the musculature including skeletal muscle, heart and diaphragm following peripheral delivery, and that holds great potential for muscle gene therapy. Our comprehensive methodology is compatible with any capsids, targets and species, and will thus facilitate and accelerate the stratification of optimal AAV vectors for human gene therapy. Adeno-associated virus is the basis of many gene therapies and gene transfer vectors. Here the authors report a pipeline to enable side-by-side comparison of pre-selected capsids in a high throughput manner.

Two-pore-domain potassium (K2P-) channels conduct outward K+ currents that maintain the resting membrane potential and modulate action potential repolarization. Members of the K2P channel family are widely expressed among different human cell types and organs where they were shown to regulate important physiological processes. Their functional activity is controlled by a broad variety of different stimuli, like pH level, temperature, and mechanical stress but also by the presence of lipids or pharmacological agents. In patients suffering from cardiovascular diseases, alterations in K2P-channel expression and function have been observed, suggesting functional significance and a potential therapeutic role of these ion channels. For example, upregulation of atrial specific K2P3.1 (TASK-1) currents in atrial fibrillation (AF) patients was shown to contribute to atrial action potential duration shortening, a key feature of AF-associated atrial electrical remodelling. Therefore, targeting K2P3.1 (TASK-1) channels might constitute an intriguing strategy for AF treatment. Further, mechanoactive K2P2.1 (TREK-1) currents have been implicated in the development of cardiac hypertrophy, cardiac fibrosis and heart failure. Cardiovascular expression of other K2P channels has been described, functional evidence in cardiac tissue however remains sparse. In the present review, expression, function, and regulation of cardiovascular K2P channels are summarized and compared among different species. Remodelling patterns, observed in disease models are discussed and compared to findings from clinical patients to assess the therapeutic potential of K2P channels.

The molecular mechanisms that regulate embryogenesis and cardiac development are calibrated by multiple signal transduction pathways within or between different cell lineages via autocrine or paracrine mechanisms of action. The heart is the first functional organ to form during development, which highlights the importance of this organ in later stages of growth. Knowledge of the regulatory mechanisms underlying cardiac development and adult cardiac homeostasis paves the way for discovering therapeutic possibilities for cardiac disease treatment. Serum response factor (SRF) is a major transcription factor that controls both embryonic and adult cardiac development. SRF expression is needed through the duration of development, from the first mesodermal cell in a developing embryo to the last cell damaged by infarction in the myocardium. Precise regulation of SRF expression is critical for mesoderm formation and cardiac crescent formation in the embryo, and altered SRF levels lead to cardiomyopathies in the adult heart, suggesting the vital role played by SRF in cardiac development and disease. This review provides a detailed overview of SRF and its partners in their various functions and discusses the future scope and possible therapeutic potential of SRF in the cardiovascular system.

Hypertrophic cardiomyopathy is the most-common form of monogenically inherited heart disease, and is associated with a high incidence of sudden cardiac death in young patients. The authors review the genetic mutations known to cause the disease, discuss potential pathological mechanisms that might lead to the clinical phenotype, and consider the implications for targeted therapies. Hypertrophic cardiomyopathy (HCM) is the most-common monogenically inherited form of heart disease, characterized by thickening of the left ventricular wall, contractile dysfunction, and potentially fatal arrhythmias. HCM is also the most-common cause of sudden cardiac death in individuals younger than 35 years of age. Much progress has been made in the elucidation of the genetic basis of HCM, resulting in the identification of more than 900 individual mutations in over 20 genes. Interestingly, most of these genes encode sarcomeric proteins, such as myosin-7 (also known as cardiac muscle β-myosin heavy chain; MYH7 ), cardiac myosin-binding protein C ( MYBPC3 ), and cardiac muscle troponin T ( TNNT2 ). However, the molecular events that ultimately lead to the clinical phenotype of HCM are still unclear. We discuss several potential pathways, which include altered calcium cycling and sarcomeric calcium sensitivity, increased fibrosis, disturbed biomechanical stress sensing, and impaired cardiac energy homeostasis. An improved understanding of the pathological mechanisms involved will result in greater specificity and success of therapies for patients with HCM. Key Points Hypertrophic cardiomyopathy (HCM) is the most-common form of monogenic heart disease, affecting up to 0.2% of the population The clinical course of HCM is remarkably variable, ranging from lifelong, asymptomatic, mutation-carrier status to early sudden cardiac death in adolescents During the past 2 decades, much progress has been made in unraveling the genetic basis of HCM; disease-causing mutations have been identified in over 20 genes, mostly encoding sarcomeric proteins The molecular mechanisms of HCM are unclear; potential pathways include altered calcium cycling and sarcomeric calcium sensitivity, increased fibrosis, disturbed biomechanical stress sensing, and impaired cardiac energy homeostasis An improved understanding of the pathological mechanisms involved in HCM should increase the specificity and efficacy of therapy for this condition

Amino acid auxotrophies are prevalent among bacteria. They can govern ecological dynamics in microbial communities and indicate metabolic cross-feeding interactions among coexisting genotypes. Despite the ecological importance of auxotrophies, their distribution and impact on the diversity and function of the human gut microbiome remain poorly understood. This study performed the first systematic analysis of the distribution of amino acid auxotrophies in the human gut microbiome using a combined metabolomic, metagenomic, and metabolic modeling approach. Results showed that amino acid auxotrophies are ubiquitous in the colon microbiome, with tryptophan auxotrophy being the most common. Auxotrophy frequencies were higher for those amino acids that are also essential to the human host. Moreover, a higher overall abundance of auxotrophies was associated with greater microbiome diversity and stability, and the distribution of auxotrophs was found to be related to the human host’s metabolome, including trimethylamine oxide, small aromatic acids, and secondary bile acids. Thus, our results suggest that amino acid auxotrophies are important factors contributing to microbiome ecology and host-microbiome metabolic interactions.

Over the past decades, there has been tremendous progress in understanding genetic alterations that can result in different phenotypes of human cardiomyopathies. More than a thousand mutations in various genes have been identified, indicating that distinct genetic alterations, or combinations of genetic alterations, can cause either hypertrophic (HCM), dilated (DCM), restrictive (RCM), or arrhythmogenic cardiomyopathies (ARVC). Translation of these results from “bench to bedside” can potentially group affected patients according to their molecular etiology and identify subclinical individuals at high risk for developing cardiomyopathy or patients with overt phenotypes at high risk for cardiac deterioration or sudden cardiac death. These advances provide not only mechanistic insights into the earliest manifestations of cardiomyopathy, but such efforts also hold the promise that mutation-specific pathophysiology might result in novel “personalized” therapeutic possibilities. Recently, the FLNC gene encoding the sarcomeric protein filamin C has gained special interest since FLNC mutations were found in several distinct and possibly overlapping cardiomyopathy phenotypes. Specifically, mutations in FLNC were initially only linked to myofibrillar myopathy (MFM), but are now increasingly found in various forms of human cardiomyopathy. FLNC thereby represents another example for the complex genetic and phenotypic continuum of these diseases.

Guidelines of the European Society of Cardiology recommend a clinical risk assessment for patients with atrial fibrillation (AF). However, scores such as the CHA2DS2-VASc score show only a modest performance for prediction of adverse endpoints. This retrospective single-center all-comer study uses data from the Heidelberg Registry of Atrial Fibrillation of 9,995 patients with non-valvular AF presenting to the emergency department (ED) of the University Hospital of Heidelberg from June 2009 until March 2020. Per CHA2DS2-VASc, risk was classified as low (0 point in men, ≤ 1 point in females), intermediate, or high (≥2 points in men and ≥3 points in females). The predictive performance of the CHA2DS2-VASc score, with and without highly sensitive cardiac troponin T (hs-cTnT), was evaluated for a composite endpoint comprising stroke, myocardial infarction (MI) or all-cause mortality. Performance of the CHA2DS2-VASc score for the prediction of the composite endpoint was poor Area under the curve (AUC): 0.648 (95%CI: 0.638-0.657) particularly in patients at intermediate-risk AUC: 0.542 (95%CI: 0.508-0.575). Adding hs-cTnT improved discrimination substantially in intermediate-risk patients (AUC: 0.778, 95% CI: 0.748-0.805). Notably, no events occurred in intermediate-risk patients with undetectable hs-cTnT (<5 ng/L). In patients with AF at intermediate thromboembolic risk, the addition of hs-cTnT to the CHA₂DS₂-VASc score enhances prediction of adverse cardiovascular outcomes. Hs-cTnT may help identify patients who could benefit from anticoagulation, while also identifying a low-risk subgroup unlikely to experience events.

The inflammatory response after myocardial infarction (MI) is a precisely regulated process that greatly affects subsequent remodeling. Here, we show that basophil granulocytes infiltrated infarcted murine hearts, with a peak occurring between days 3 and 7. Antibody-mediated and genetic depletion of basophils deteriorated cardiac function and resulted in enhanced scar thinning after MI. Mechanistically, we found that basophil depletion was associated with a shift from reparative Ly6Clo macrophages toward increased numbers of inflammatory Ly6Chi monocytes in the infarcted myocardium. Restoration of basophils in basophil-deficient mice by adoptive transfer reversed this proinflammatory phenotype. Cellular alterations in the absence of basophils were accompanied by lower cardiac levels of IL-4 and IL-13, two major cytokines secreted by basophils. Mice with basophil-specific IL-4/IL-13 deficiency exhibited a similarly altered myeloid response with an increased fraction of Ly6Chi monocytes and aggravated cardiac function after MI. In contrast, IL-4 induction in basophils via administration of the glycoprotein IPSE/α-1 led to improved post-MI healing. These results in mice were corroborated by the finding that initially low counts of blood basophils in patients with acute MI were associated with a worse cardiac outcome after 1 year, characterized by a larger scar size. In conclusion, we show that basophils promoted tissue repair after MI by increasing cardiac IL-4 and IL-13 levels.