Orai1 deficiency leads to heart failure and skeletal myopathy in zebrafish.

Mutations in the store-operated Ca²⁺ entry pore protein ORAI1 have been reported to cause myopathies in human patients but the mechanism involved is not known. Cardiomyocytes express ORAI1 but its role in heart function is also unknown. Using reverse genetics in zebrafish, we demonstrated that inactivation of the highly conserved zebrafish orthologue of ORAI1 resulted in severe heart failure, reduced ventricular systolic function, bradycardia and skeletal muscle weakness. Electron microscopy of Orai1-deficient myocytes revealed progressive skeletal muscle instability with loss of myofiber integrity and ultrastructural abnormalities of the z-disc in both skeletal and cardiac muscle. Isolated Orai1-deficient cardiomyocytes showed loss of the calcineurin-associated protein calsarcin from the z-discs. Furthermore, we found mechanosignal transduction was affected in Orai1-depleted hearts, indicating an essential role for ORAI1 in establishing the cardiac signaling transduction machinery at the z-disc. Our findings identify ORAI1 as an important regulator of cardiac and skeletal muscle function and provide evidence linking ORAI1-mediated calcium signaling to sarcomere integrity and cardiomyocyte function

S100A1: A Regulator of Striated Muscle Sarcoplasmic Reticulum Ca2+ Handling, Sarcomeric, and Mitochondrial Function

Calcium (Ca2+) signaling plays a key role in a wide range of physiological functions including control of cardiac and skeletal muscle performance. To assure a precise coordination of both temporally and spatially transduction of intracellular Ca2+ oscillations to downstream signaling networks and target operations, Ca2+ cycling regulation in muscle tissue is conducted by a plethora of diverse molecules. Ca2+ S100A1 is a member of the Ca2+-binding S100 protein family and represents the most abundant S100 isoform in cardiac and skeletal muscle. Early studies revealed distinct expression patterns of S100A1 in healthy and diseased cardiac tissue from animal models and humans. Further elaborate investigations uncovered S100A1 protein as a basic requirement for striated muscle Ca2+ handling integrity. S100A1 is a critical regulator of cardiomyocyte Ca2+ cycling and contractile performance. S100A1-mediated inotropy unfolds independent and on top of βAR-stimulated contractility with unchanged βAR downstream signaling. S100A1 has further been detected at different sites within the cardiac sarcomere indicating potential roles in myofilament function. More recently, a study reported a mitochondrial location of S100A1 in cardiomyocytes. Additionally, normalizing the level of S100A1 protein by means of viral cardiac gene transfer in animal heart failure models resulted in a disrupted progression towards cardiac failure and enhanced survival. This brief review is confined to the physiological and pathophysiological relevance of S100A1 in cardiac and skeletal muscle Ca2+ handling with a particular focus on its potential as a molecular target for future therapeutic interventions

Increased proinflammatory endothelial response to S100A8/A9 after preactivation through advanced glycation end products

BACKGROUND: Atherosclerosis is an inflammatory disease in which a perpetuated activation of NFkappaB via the RAGE (receptor for advanced glycation end products)-MAPK signalling pathway may play an important pathogenetic role. As recently S100 proteins have been identified as ligands of RAGE, we sought to determine the effects of the proinflammatory heterodimer of S100A8/S100A9 on the RAGE-NFkappaB mediated induction of proinflammatory gene expression. METHODS: Human umbilical vein endothelial cells (HUVEC) were preincubated for 72 h with AGE-albumin or unmodified albumin for control, whereas AGE-albumin induction resulted in an upregulation of RAGE. Following this preactivation, cells were stimulated for 48 h with heterodimeric human recombinant S100A8/S100A9. RESULTS: Heterodimeric S100A8/S100A9 enhanced secretion of IL-6, ICAM-1, VCAM-1 and MCP1 in AGE-albumin pretreated HUVEC in a dose dependent manner. These effects could not be detected after stimulation with the homodimeric proteins S100A8, S100A9, S100A1 and S100B. The effects of heterodimeric S100A8/S100A9 were reduced by inhibition of the MAP-kinase pathways ERK1/2 and p38 by PD 98059 and SB 203580, respectively. CONCLUSION: The heterodimeric S100A8/S100A9 might therefore play a hitherto unknown role in triggering atherosclerosis in diabetes and renal failure, pathophysiological entities associated with a high AGE burden. Thus, blocking heterodimeric S100A8/S100A9 might represent a novel therapeutic modality in treating atherosclerosis

As Far as the Eye Can See: Relationship between Psychopathic Traits and Pupil Response to Affective Stimuli

Psychopathic individuals show a range of affective processing deficits, typically associated with the interpersonal/affective component of psychopathy. However, previous research has been inconsistent as to whether psychopathy, within both offender and community populations, is associated with deficient autonomic responses to the simple presentation of affective stimuli. Changes in pupil diameter occur in response to emotionally arousing stimuli and can be used as an objective indicator of physiological reactivity to emotion. This study used pupillometry to explore whether psychopathic traits within a community sample were associated with hypo-responsivity to the affective content of stimuli. Pupil activity was recorded for 102 adult (52 female) community participants in response to affective (both negative and positive affect) and affectively neutral stimuli, that included images of scenes, static facial expressions, dynamic facial expressions and sound-clips. Psychopathic traits were measured using the Triarchic Psychopathy Measure. Pupil diameter was larger in response to negative stimuli, but comparable pupil size was demonstrated across pleasant and neutral stimuli. A linear relationship between subjective arousal and pupil diameter was found in response to sound-clips, but was not evident in response to scenes. Contrary to predictions, psychopathy was unrelated to emotional modulation of pupil diameter across all stimuli. The findings were the same when participant gender was considered. This suggests that psychopathy within a community sample is not associated with autonomic hypo-responsivity to affective stimuli, and this effect is discussed in relation to later defensive/appetitive mobilisation deficits

Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.</p

Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits

S100A1: A Multifaceted Therapeutic Target in Cardiovascular Disease

Cardiovascular disease is the leading cause of death worldwide, showing a dramatically growing prevalence. It is still associated with a poor clinical prognosis, indicating insufficient long-term treatment success of currently available therapeutic strategies. Investigations of the pathomechanisms underlying cardiovascular disorders uncovered the Ca2+ binding protein S100A1 as a critical regulator of both cardiac performance and vascular biology. In cardiomyocytes, S100A1 was found to interact with both the sarcoplasmic reticulum ATPase (SERCA2a) and the ryanodine receptor 2 (RyR2), resulting in substantially improved Ca2+ handling and contractile performance. Additionally, S100A1 has been described to target the cardiac sarcomere and mitochondria, leading to reduced pre-contractile passive tension as well as enhanced oxidative energy generation. In endothelial cells, molecular analyses revealed a stimulatory effect of S100A1 on endothelial NO production by increasing endothelial nitric oxide synthase activity. Emphasizing the pathophysiological relevance of S100A1, myocardial infarction in S100A1 knockout mice resulted in accelerated transition towards heart failure and excessive mortality in comparison with wild-type controls. Mice lacking S100A1 furthermore displayed significantly elevated blood pressure values with abrogated responsiveness to bradykinin. On the other hand, numerous studies in small and large animal heart failure models showed that S100A1 overexpression results in reversed maladaptive myocardial remodeling, long-term rescue of contractile performance, and superior survival in response to myocardial infarction, indicating the potential of S100A1-based therapeutic interventions. In summary, elaborate basic and translational research established S100A1 as a multifaceted therapeutic target in cardiovascular disease, providing a promising novel therapeutic strategy to future cardiologists

The impact of donor and recipient common clinical and genetic variation on estimated glomerular filtration rate in a European renal transplant population

Genetic variation across the HLA is known to influence renal‐transplant outcome. However, the impact of genetic variation beyond the HLA is less clear. We tested the association of common genetic variation and clinical characteristics, from both the donor and recipient, with post‐transplant eGFR at different time‐points, out to 5‐years post‐transplantation. We conducted GWAS meta‐analyses across 10,844 donors and recipients from five European ancestry cohorts. We also analysed the impact of polygenic risk scores (PRS), calculated using genetic variants associated with non‐transplant eGFR, on post‐transplant eGFR. PRS calculated using the recipient genotype alone, as well as combined donor and recipient genotypes were significantly associated with eGFR at 1‐year post‐transplant. 32% of the variability in eGFR at 1‐year post‐transplant was explained by our model containing clinical covariates (including weights for death/graft‐failure), principal components and combined donor‐recipient PRS, with 0.3% contributed by the PRS. No individual genetic variant was significantly associated with eGFR post‐transplant in the GWAS. This is the first study to examine PRS, composed of variants that impact kidney function in the general population, in a post‐transplant context. Despite PRS being a significant predictor of eGFR post‐transplant, the effect size of common genetic factors is limited compared to clinical variables

Long-term survival of cancer patients compared to heart failure and stroke: A systematic review

<p>Abstract</p> <p>Background</p> <p>Cancer, heart failure and stroke are among the most common causes of death worldwide. Investigation of the prognostic impact of each disease is important, especially for a better understanding of competing risks. Aim of this study is to provide an overview of long term survival of cancer, heart failure and stroke patients based on the results of large population- and hospital-based studies.</p> <p>Methods</p> <p>Records for our study were identified by searches of Medline via Pubmed. We focused on observed and relative age- and sex-adjusted 5-year survival rates for cancer in general and for the four most common malignancies in developed countries, i.e. lung, breast, prostate and colorectal cancer, as well as for heart failure and stroke.</p> <p>Results</p> <p>Twenty studies were identified and included for analysis. Five-year observed survival was about 43% for all cancer entities, 40-68% for stroke and 26-52% for heart failure. Five-year age and sex adjusted relative survival was 50-57% for all cancer entities, about 50% for stroke and about 62% for heart failure. In regard to the four most common malignancies in developed countries 5-year relative survival was 12-18% for lung cancer, 73-89% for breast cancer, 50-99% for prostate cancer and about 43-63% for colorectal cancer. Trend analysis revealed a survival improvement over the last decades.</p> <p>Conclusions</p> <p>The results indicate that long term survival and prognosis of cancer is not necessarily worse than that of heart failure and stroke. However, a comparison of the prognostic impact of the different diseases is limited, corroborating the necessity for further systematic investigation of competing risks.</p