Kv7.4 (KCNQ4) voltage-gated potassium channels control excitability in the inner ear and the central auditory pathway. Mutations in Kv7.4 channels result in inherited progressive deafness in humans. Calmodulin (CaM) is crucial for regulating Kv7 channels, but how CaM affects Kv7 activity has remained unclear. Here, based on electrophysiological recordings, we report that the third EF hand (EF3) of CaM controls the calcium-dependent regulation of Kv7.4 activation and that the S2-S3 loop of Kv7.4 is essential for the regulation mediated by CaM. Overexpression of the mutant CaM1234, which loses the calcium binding ability of all four EF hands, facilitates Kv7.4 activation by accelerating activation kinetics and shifting the voltage dependence of activation leftwards. The single mutant CaM3, which loses the calcium binding ability of the EF3, phenocopies facilitating effects of CaM1234 on Kv7.4 activation. Kv7.4 channels co-expressed with wild-type (WT) CaM show inhibited activation when intracellular calcium levels increase, while Kv7.4 channels co-expressed with CaM1234 or CaM3 are insensitive to calcium. Mutations C156A, C157A, C158V, R159, and R161A, which are located within the Kv7.4 S2-S3 loop, dramatically facilitate activation of Kv7.4 channels co-expressed with WT CaM but have no effect on activation of Kv7.4 channels co-expressed with CaM3, indicating that these five mutations decrease the inhibitory effect of Ca2+/CaM. The double mutation C156A/R159A decreases Ca2+/CaM binding and completely abolishes CaM-mediated calcium-dependent regulation of Kv7.4 activation. Taken together, our results provide mechanistic insights into CaM regulation of Kv7.4 activation and highlight the crucial role of the Kv7.4 S2-S3 loop in CaM regulation.Acute respiratory distress syndrome (ARDS) represents an acute diffuse inflammation of the lungs triggered by different causes, uniformly leading to a noncardiogenic pulmonary edema with inhomogeneous densities in lung X-ray and lung CT scan and acute hypoxemia. Edema formation results in „heavy” lungs, inducing loss of compliance and the need to spend more energy to „move” the lungs. Consequently, an ARDS patient, as long as the patient is breathing spontaneously, has an increased respiratory drive to ensure adequate oxygenation and CO2 removal. One would expect that, once the blood gases get back to „physiological” values, the respiratory drive would normalize and the breathing effort return to its initial status. However, in many ARDS patients, this is not the case; their respiratory drive appears to be upregulated and fully or at least partially detached from the blood gas status. Strikingly, similar alteration of the respiratory drive can be seen in patients suffering from SARS, especially SARS-Covid-19. We hypothesize that alterations of the renin-angiotensin-system (RAS) related to the pathophysiology of ARDS and SARS are involved in this dysregulation of chemosensitive control of breathing.Sarcopenic obesity is associated with several negative health outcomes. However, the prevalence of this condition – and the relationship to physical performance parameters – varies across definitions. The aim of this cross-sectional investigation was to describe the prevalence of sarcopenic obesity using different published definitions and their relationship with handgrip strength and walking speed in older Canadian adults. Individuals aged 65+ in the Canadian Longitudinal Study on Aging (n = 11,803; 49.6% male, 50.4% female) were included. Body composition was measured using dual X-ray absorptiometry. Sarcopenic obesity was defined using 29 definitions. Low handgrip strength was identified as less then 27 kg in males and less then 16 kg in females and poor physical performance was defined as gait speed ≤ 0.8 m/s. The prevalence of sarcopenic obesity ranged from 0.1 to 85.3% in males, and from 0 to 80.4% in females. Sarcopenic obesity was frequently associated with low handgrip strength (p less then 0.05) in both males (14/17 definitions, 82.4%) and females (21/29 definitions, 72.4%). In very few definitions, sarcopenic obesity was associated with slow gait speed (males 1/17 definitions [6.7%]; females 2/29 [6.9%]). In conclusion, the prevalence of sarcopenic obesity varied greatly according to definitions and sarcopenic obesity was frequently associated with low handgrip strength.Aging imposes a barrier for tissue regeneration. In the heart, aging leads to a severe rearrangement of the cardiac structure and function and to a subsequent increased risk of heart failure. An intricate network of distinct pathways contributes to age-related alterations during healthy heart aging and account for a higher susceptibility of heart disease. Our understanding of the systemic aging process has already led to the design of anti-aging strategies or to the adoption of protective interventions. Nevertheless, our understanding of the molecular determinants operating during cardiac aging or repair remains limited. Here, we will summarize the molecular and physiological alterations that occur during aging of the heart, highlighting the potential role for long non-coding RNAs (lncRNAs) as novel and valuable targets in cardiac regeneration/repair.This study investigated the relationship of body fat and fitness measures in schoolchild handball players. Twenty-eight young male handball players from handball first youth league volunteered for the present investigation (age 10.9 ± 0.72 years; body mass 54.8 ± 22.9 kg; height 1.48 ± 0.10 m; body fat 27.6 ± 9.23%). Measures included the Yo-Yo Intermittent Recovery Test level 1 (Yo-Yo IR1), jumping ability [squat and counter-movement jumps (SJ, CMJ)], and sprint tests (10 m, 15 m). Anthropometry was assessed by body mass, body mass index (BMI), and fat percentage (%BF). The power of the upper limb was measured as the total distance thrown overhead using a 2 kg medicine ball. Intrarater reliability for all parameters showed a coefficient of variation (CV) below 10% and an intraclass correlation coefficient (ICC) above 0.75. All ICC were excellent (ICC ≥ 0.96). Reliability as shown by the CV differed between 1.0 (sprint 15 m) and 5.6 (sprint 10 m). With the exception of medicine ball throw, we found significansical fitness. Decrease in% body fat could be considered both as a training and nutritional target to enhance and optimize sport performance-related outcomes.Genes communicate with each other through different regulatory effects, which lead to the emergence of complex network structures in cells, and such structures are expected to be different for normal and cancerous cells. To study these differences, we have investigated the Gene Regulatory Network (GRN) of cells as inferred from RNA-sequencing data. The GRN is a signed weighted network corresponding to the inductive or inhibitory interactions. Here we focus on a particular of motifs in the GRN, the triangles, which are imbalanced if the number of negative interactions is odd. By studying the stability of imbalanced triangles in the GRN, we show that the network of cancerous cells has fewer imbalanced triangles compared to normal cells. Moreover, in the normal cells, imbalanced triangles are isolated from the main part of the network, while such motifs are part of the network’s giant component in cancerous cells. Our result demonstrates that due to genes’ collective behavior the structure of the complex networks is different in cancerous cells from those in normal ones.Intracranial aneurysm (IA) is vascular enlargement occurred on the wall of cerebral vessels and can result in fatal subarachnoid hemorrhage when ruptured. Recent studies have supported the important role of long non-coding RNAs (lncRNAs) in IA treatment. This study identified functional significance of lncRNA myocardial infarction associated transcript (MIAT) in IA. Myocardial infarction associated transcript and ectodermal-neural cortex 1 (ENC1) expression was detected by reverse transcription quantitative polymerase chain reaction. Cell counting kit 8 assay flow cytometry were conducted to detect cell viability and apoptosis of endothelial cells in IA. The interaction among MIAT, ENC1, and myelocytomatosis oncogene (MYC) was analyzed by RNA pull down, RNA immunoprecipitation assay, chromatin immunoprecipitation assay, and dual luciferase reporter assay. Intracranial aneurysm was induced by ligating the left carotid artery and the bilateral posterior branch of the renal artery in rats for studying the role of MIAT and ENC1 in vivo. Myocardial infarction associated transcript and ENC1 were upregulated in IA. Endothelial cells in IA presented a decreased cell viability and an increased apoptotic rate. Myocardial infarction associated transcript could regulate the expression of ENC1, and MYC could bind to the promoter region of ENC1. High expression of MIAT increased endothelial cell apoptosis and vascular endothelial injury, while MIAT knockdown was identified to reduce the risk of IA both in vitro and in vivo through regulating ENC1. To sum up, MIAT silencing is preventive for IA occurrence by decreasing the MYC-mediated ENC1 expression, which represents a novel therapeutic target for IA.Mitochondrial enzymes involved in energy transformation are organized into multiprotein complexes that channel the reaction intermediates for efficient ATP production. Three of the mammalian urea cycle enzymes N-acetylglutamate synthase (NAGS), carbamylphosphate synthetase 1 (CPS1), and ornithine transcarbamylase (OTC) reside in the mitochondria. Urea cycle is required to convert ammonia into urea and protect the brain from ammonia toxicity. Urea cycle intermediates are tightly channeled in and out of mitochondria, indicating that efficient activity of these enzymes relies upon their coordinated interaction with each other, perhaps in a cluster. This view is supported by mutations in surface residues of the urea cycle proteins that impair ureagenesis in the patients, but do not affect protein stability or catalytic activity. We find the NAGS, CPS1, and OTC proteins in liver mitochondria can associate with the inner mitochondrial membrane (IMM) and can be co-immunoprecipitated. Our in-silico analysis of vertebrate NAGS proteins, the least abundant of the urea cycle enzymes, identified a protein-protein interaction region present only in the mammalian NAGS protein-„variable segment,” which mediates the interaction of NAGS with CPS1. Use of super resolution microscopy showed that NAGS, CPS1 and OTC are organized into clusters in the hepatocyte mitochondria. These results indicate that mitochondrial urea cycle proteins cluster, instead of functioning either independently or in a rigid multienzyme complex.Background Endurance athletes are prone to bradyarrhythmias, which in the long-term may underscore the increased incidence of pacemaker implantation reported in this population. Our previous work in rodent models has shown training-induced sinus bradycardia to be due to microRNA (miR)-mediated transcriptional remodeling of the HCN4 channel, leading to a reduction of the „funny” (If) current in the sinoatrial node (SAN). Objective To test if genetic ablation of G-protein-gated inwardly rectifying potassium channel, also known as I KACh channels prevents sinus bradycardia induced by intensive exercise training in mice. Methods Control wild-type (WT) and mice lacking GIRK4 (Girk4-/-), an integral subunit of I KACh were assigned to trained or sedentary groups. Mice in the trained group underwent 1-h exercise swimming twice a day for 28 days, 7 days per week. We performed electrocardiogram recordings and echocardiography in both groups at baseline, during and after the training period. At training cessation, mice were euthanized and SAN tissues were isolated for patch clamp recordings in isolated SAN cells and molecular profiling by quantitative PCR (qPCR) and western blotting.