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Skeletal muscle contracts or relaxes to maintain the body position and locomotion. For the contraction and relaxation of skeletal muscle, Ca2+ in the cytosol of skeletal muscle fibers acts as a switch to turn on and off a series of contractile proteins. The cytosolic Ca2+ level in skeletal muscle fibers is governed mainly by movement of Ca2+ between the cytosol and the sarcoplasmic reticulum (SR). Store-operated Ca2+ entry (SOCE), a Ca2+ entryway from the extracellular space to the cytosol, has gained a significant amount of attention from muscle physiologists...

Electrical pacemaker activity generates phasic contractions and motility patterns such as segmentation and peristalsis in the gastrointestinal tract. Pacemaker currents are generated in interstitial cells of Cajal (ICC), which release Ca2+ from intracellular stores that stimulates Ca2+ -activated Cl- channels (CaCCs) in the plasma membrane. Thus, Ca2+ stores must be maintained to sustain pacemaker activity. Store-operated Ca2+ entry (SOCE) facilitates the refilling of Ca2+ stores by a mechanism dependent upon interactions between STIM and Orai proteins...

The pulmonary arteries are exquisitely responsive to oxygen changes. They rapidly and proportionally contract as arterial PO2 decrease, and they relax as arterial PO2 is re-established. The hypoxic pulmonary vasoconstriction (HPV) is intrinsic since it does not require neural or endocrine factors, as evidenced in isolated vessels. On the other hand, pulmonary arteries also respond to sustained hypoxia with structural and functional remodeling, involving growth of smooth muscle medial layer and later recruitment of adventitial fibroblasts, secreted mitogens from endothelium and changes in the response to vasoconstrictor and vasodilator stimuli...

Pulmonary arterial hypertension (PAH), which is characterized by an elevation of pulmonary arterial resistance, leads to a lethal right heart failure. It is an urgent issue to clarify the pathogenesis of PAH-induced right heart failure. The present study aimed to elucidate the characteristics of cardiac fibroblasts (CFs) isolated from hypertrophied right ventricles of monocrotaline (MCT)-induced PAH model rats. CFs were isolated from the right ventricles of MCT-injected rats (MCT-CFs) and saline-injected control rats (CONT-CFs)...

The pore forming Ca2+ release activated Ca2+ channel (CRAC) isoforms ORAI1-3 and their regulators STIM1,2 accomplish store operated Ca2+ entry (SOCE). Activation of SOCE may lead to cytosolic Ca2+ oscillations, which in turn support cell proliferation and cell survival. ORAI/STIM and thus SOCE are upregulated by the serum and glucocorticoid inducible kinase SGK1, a kinase under powerful genomic regulation and activated by phosphorylation via the phosphoinositol-3-phosphate pathway. SGK1 enhances ORAI1 abundance partially by phosphorylation of Nedd4-2, an ubiquitin ligase priming the channel protein for degradation...

BACKGROUND: Offset analgesia (OA) is a disproportionally large decrease in the pain perception in response to a small decrease in the stimulation intensity. Traditionally, heat stimulation has been used to evoke OA. The aim of this study was to investigate if OA could be evoked by electrical stimulation. METHODS: Healthy volunteers (N=24) underwent two OA experimental sessions consisting of heat stimuli intensities of 48-49-48°C (traditional OA-paradigm) and electrical stimuli at 150-180-150% of the electrical pain perception (EPP) threshold...

Transcranial direct current stimulation (tDCS) has been shown to enhance cognitive performance on a variety of tasks. It is hypothesized that tDCS enhances performance by affecting task related cortical excitability changes in networks underlying or connected to the site of stimulation facilitating long term potentiation. However, many recent studies have called into question the reliability and efficacy of tDCS to induce modulatory changes in brain activity. In this study, our goal is to investigate the individual differences in tDCS induced modulatory effects on brain activity related to the degree of enhancement in performance, providing insight into this lack of reliability...

Background and objective: Upregulated T-cell immunoglobulin and mucin domain containing molecule-3 (Tim-3) in hepatitis B virus (HBV)-specific CD8+ T-cells contributes to CD8+ T-cell exhaustion during chronic HBV infection. The membrane-bound Tim-3 can be cleaved from the cell surface by sheddase, yielding soluble Tim-3 (sTim-3). This study investigated serum sTim-3 levels in patients with chronic HBV infection of various liver diseases. Methods: Serum sTim-3 levels were quantitatively determined in 288 patients with chronic HBV infection of various liver diseases...

The Chloride Channel Accessory (CLCA) protein family was first characterized as regulators of calcium-activated chloride channel (CaCC) currents (ICaCC), but the mechanism has not been fully established. We hypothesized that CLCAs might regulate ICaCC by modulating intracellular calcium levels. In cells stably expressing human CLCA2 or vector, we found by calcium imaging that CLCA2 moderately enhanced intracellular-store release but dramatically increased store-operated entry of calcium upon cytosolic depletion...

BACKGROUND: This study was aimed to investigate whether stimulating catheters for continuous lumbar plexus block reduce local anesthetic consumption after hip arthroplasty if compared with traditional non-stimulating catheters. METHODS: Seventy-two ASA I-III, 18-82 year-old, undergoing primary hip replacement (THA) for osteoarthritis with spinal anesthesia were randomized into two groups: Stim group (stimulating catheter, n=36) and Nonstim group (non-stimulating catheter, n=36)...

Inositol 1,4,5 trisphosphate (IP3 ) signaling plays a crucial role in a wide range of eukaryotic processes. In Plasmodium falciparum, IP3 elicits Ca2+ release from intracellular Ca2+ stores, even though no IP3 receptor homolog has been identified to date. The human host hormone melatonin plays a key role in entraining the P. falciparum life cycle in the intraerythrocytic stages, apparently through an IP3 -dependent Ca2+ signal. The melatonin-induced cytosolic Ca2+ ([Ca2+ ]cyt ) increase and malaria cell cycle can be blocked by the IP3 receptor blocker 2-aminoethyl diphenylborinate (2-APB)...

The KRAS GTPase plays a fundamental role in transducing signals from plasma membrane growth factor receptors to downstream signalling pathways controlling cell proliferation, survival and migration. Activating KRAS mutations are found in 20% of all cancers and in up to 40% of colorectal cancers, where they contribute to dysregulation of cell processes underlying oncogenic transformation. Multiple KRAS-regulated cell functions are also influenced by changes in intracellular Ca2+ levels that are concurrently modified by receptor signalling pathways...

RNA presents intringuing roles in many cellular processes and its versatility underpins many different applications in synthetic biology. Nonetheless, RNA origami as a method for nanofabrication is not yet fully explored and the majority of RNA nanostructures are based on natural pre-folded RNA. Here we describe a biologically inert and uniquely addressable RNA origami scaffold that self-assembles into a nanoribbon by seven staple strands. An algorithm is applied to generate a synthetic De Bruijn scaffold sequence that is characterized by the lack of biologically active sites and repetitions larger than a predetermined design parameter...

Store-operated calcium entry (SOCE), an important mechanism of Ca2+ signaling in a wide range of cell types, is mediated by stromal interaction molecule (STIM), which senses the depletion of endoplasmic reticulum Ca2+ stores and binds and activates Orai channels in the plasma membrane. This inside-out mechanism of Ca2+ signaling raises an interesting question about the evolution of SOCE: How did these two proteins existing in different cellular compartments evolve to interact with each other? We investigated the gating mechanism of Caenorhabditis elegans Orai channels...

Stromal interaction molecule (STIM)-1 and -2 are multi-domain, single-pass transmembrane proteins involved in sensing changes in compartmentalized calcium (Ca2+ ) levels and transducing this cellular signal to Orai1 channel proteins. Our understanding of the molecular mechanisms underlying STIM signaling has been dramatically improved through available X-ray crystal and solution NMR structures. This high-resolution structural data has revealed that intricate intramolecular and intermolecular protein-protein interactions are involved in converting STIMs from the quiescent to activation-competent states...

GRAM domain proteins were reported as novel ER-PM tethers defining specific membrane contact sites (MCS) subdomains. GRAMD2a pre-marks the sites occupied by STIM1 at MCS and its ablation impairs STIM1 translocation, but not store-operated Ca2+ entry. We discuss these apparently counterintuitive findings in the context of STIM/ORAI signaling at MCS.

OBJECTIVE: Application of therapeutic mild hypothermia in patients after resuscitation, often accompanied by myocardial infarction, cardiogenic shock, and systemic inflammation may impact on cardiac rhythm. We therefore tested susceptibility to atrial arrhythmias during hyperthermia (HT, 40.5°C), normothermia (NT, 38.0°C), and mild hypothermia (MH, 33.0°C). METHODS: Nine healthy, anesthetized closed-chest landrace pigs were instrumented with a quadripolar stimulation catheter in the high right atrium and a decapolar catheter in the coronary sinus...

Astronauts exposed to microgravity face sensorimotor challenges affecting balance control when readapting to Earth's gravity upon return from spaceflight. Small amounts of electrical noise applied to the vestibular system have been shown to improve balance control during standing and walking under discordant sensory conditions in healthy subjects, likely by enhancing information transfer through the phenomenon of stochastic resonance. The purpose of this study was to test the hypothesis that imperceptible levels of stochastic vestibular stimulation (SVS) could improve short-term adaptation to a locomotor task in a novel sensory discordant environment...

In both excitable and non-excitable cells, calcium (Ca2+ ) signals are maintained by a highly integrated process involving store-operated Ca2+ entry (SOCE), namely the opening of plasma membrane (PM) Ca2+ channels following the release of Ca2+ from intracellular stores. Upon depletion of Ca2+ store, the stromal interaction molecule (STIM) senses Ca2+ level reduction and migrates from endoplasmic reticulum (ER)-like sites to the PM where it activates the channel proteins Orai and/or the transient receptor potential channels (TRPC) prompting Ca2+ refilling...

The transmembrane docking of endoplasmic reticulum (ER) Ca2+ -sensing STIM proteins with plasma membrane (PM) Orai Ca2+ channels is a critical but poorly understood step in Ca2+ signal generation. STIM1 protein dimers unfold to expose a discrete STIM-Orai activating region (SOAR1) that tethers and activates Orai1 channels within discrete ER-PM junctions. We reveal that each monomer within the SOAR dimer interacts independently with single Orai1 subunits to mediate cross-linking between Orai1 channels. Superresolution imaging and mobility measured by fluorescence recovery after photobleaching reveal that SOAR dimer cross-linking leads to substantial Orai1 channel clustering, resulting in increased efficacy and cooperativity of Orai1 channel function...