Identification of common genetic variants in KCNQ family genes associated with gastric cancer survival in a Chinese population.

KCNQ family genes ( KCNQ1-5), encoding voltage-gated K + (Kv) channels, have been revealed to have potential pathophysiological roles in cancers. However, the associations between genetic variants located in KCNQ family genes and gastric cancer survival remain unclear. A large-scale cohort comprising 1,135 Chinese gastric cancer patients was enrolled to identify genetic variants in KCNQ family genes associated with overall survival (OS). Based on the survival evaluation of all five members, KCNQ1 was selected for subsequent genetic analysis. Cox regression models and stepwise Cox regression models were conducted to evaluate survival-related genetic variants. We found that KCNQ1 rs10832417 was associated with increased OS in gastric cancer patients (adjusted hazard ratio (HR) = 0.84, 95% confidence interval (CI): 0.72-0.98, P = 0.023). Subsequently, a nomogram was generated to support the prognostic capacity and clinical translation of rs10832417 variants. The rs10832417 T allele was predicted to increase the minimum free energy (MFE) of the secondary structure. Furthermore, we observed that gastric cancer patients with downregulation of KCNQ1 had poor survival in multiple public datasets. The present study found that KCNQ1 rs10832417 could serve as an independent prognostic predictor of gastric cancer, yielding novel insight into the progression and survival of gastric cancer.

Exploring the Pathophysiology of ATP-Dependent Potassium Channels in Insulin Resistance.

Ionic channels are present in eucaryotic plasma and intracellular membranes. They coordinate and control several functions. Potassium channels belong to the most diverse family of ionic channels that includes ATP-dependent potassium (KATP) channels in the potassium rectifier channel subfamily. These channels were initially described in heart muscle and then in other tissues such as pancreatic, skeletal muscle, brain, and vascular and non-vascular smooth muscle tissues. In pancreatic beta cells, KATP channels are primarily responsible for maintaining the membrane potential and for depolarization-mediated insulin release, and their decreased density and activity may be related to insulin resistance. KATP channels' relationship with insulin resistance is beginning to be explored in extra-pancreatic beta tissues like the skeletal muscle, where KATP channels are involved in insulin-dependent glucose recapture and their activation may lead to insulin resistance. In adipose tissues, KATP channels containing Kir6.2 protein subunits could be related to the increase in free fatty acids and insulin resistance; therefore, pathological processes that promote prolonged adipocyte KATP channel inhibition might lead to obesity due to insulin resistance. In the central nervous system, KATP channel activation can regulate peripheric glycemia and lead to brain insulin resistance, an early peripheral alteration that can lead to the development of pathologies such as obesity and Type 2 Diabetes Mellitus (T2DM). In this review, we aim to discuss the characteristics of KATP channels, their relationship with clinical disorders, and their mechanisms and potential associations with peripheral and central insulin resistance.

Mechanisms of infantile epileptic spasms syndrome: What have we learned from animal models?

The devastating developmental and epileptic encephalopathy of infantile epileptic spasms syndrome (IESS) has numerous causes, including, but not limited to, brain injury, metabolic, and genetic conditions. Given the stereotyped electrophysiologic, age-dependent, and clinical findings, there likely exists one or more final common pathways in the development of IESS. The identity of this final common pathway is unknown, but it may represent a novel therapeutic target for infantile spasms. Previous research on IESS has focused largely on identifying the neuroanatomic substrate using specialized neuroimaging techniques and cerebrospinal fluid analysis in human patients. Over the past three decades, several animal models of IESS were created with an aim to interrogate the underlying pathogenesis of IESS, to identify novel therapeutic targets, and to test various treatments. Each of these models have been successful at recapitulating multiple aspects of the human IESS condition. These animal models have implicated several different molecular pathways in the development of infantile spasms. In this review we outline the progress that has been made thus far using these animal models and discuss future directions to help researchers identify novel treatments for drug-resistant IESS.

Frameworked Electrolytes: A Pathway Towards Solid Future of Batteries.

All-solid-state batteries (ASSBs) represent a highly promising next-generation energy storage technology owing to their inherently high safety, device reliability, and potential for achieving high energy density in the post-ara of lithium-ion batteries, and therefore extensive searches are ongoing for ideal solid-state electrolytes (SSEs). Though promising, there is still a huge barrier that limits the large-scale applications of ASSBs, where there are a couple of bottleneck technical issues. In this perspective, a novel category of electrolytes known as frameworked electrolytes (FEs) are examined, where the solid frameworks are intentionally designed to contain 3D ionic channels at sub-nano scales, rendering them macroscopically solid. The distinctive structural design of FEs gives rise to not only high ionic conductivity but also desirable interfaces with electrode solids. This is achieved through the presence of sub-nano channels within the framework, which exhibit significantly different ion diffusion behavior due to the confinement effect. This perspective offers a compelling insight into the potential of FEs in the pursuit of ASSBs, where FEs offer an exciting opportunity to overcome the limitations of traditional solid-state electrolytes and propel the development of ASSBs as the holy grail of energy storage technology.

Predictions from a mathematical approach to model ionic signaling for rapid responses of Sertoli cells exhibit similarities to pharmacological approaches.

Sertoli cells are essential for the male reproduction system as they provide morphological support and nutrients for germ cells to guarantee ongoing spermatogenesis. The aim of this work was to predict the electrical properties at the plasma membrane that trigger Sertoli cell rapid responses by involving ionic channels. The rapid responses of Sertoli cells in culture were monitored using patch clamp electrical measurement and compared to data obtained using pharmacological tools (from intact seminiferous tubules). A mathematical model was used to define the roles of potassium channels and the ATP-dependent Na+/K+pump in these responses. Mathematical data verification was also performed to determine the resting and hormonal stimulated membrane potentials of Sertoli cells in the intact seminiferous tubules and of Sertoli cells in culture (patch clamp measurements). The prediction of these data based on mathematical modeling demonstrated, for the first time, the involvement of potassium channels and the activation of Na+/K+pump in the hyperpolarization of Sertoli cells and their consequent rapid responses. Moreover, the mathematical analysis showing the involvement of ionic balance in the rapid responses of these cells to hormones, such as follicle-stimulating hormone, is consistent with previous reports obtained using pharmacological techniques in Sertoli cells. Thus, the validation of such data is reliable and represents a first step in the proposition for a mathematical model to predict rapid responses of Sertoli cells to hormonal stimuli.

Adenosinergic System and Neuroendocrine Syncope: What Is the Link?

Although very common, the precise mechanisms that explain the symptomatology of neuroendocrine syncope (NES) remain poorly understood. This disease, which can be very incapacitating, manifests itself as a drop in blood pressure secondary to vasodilation and/or extreme slowing of heart rate. As studies continue, the involvement of the adenosinergic system is becoming increasingly evident. Adenosine, which is an ATP derivative, may be involved in a large number of cases. Adenosine acts on G protein-coupled receptors with seven transmembrane domains. A1 and A2A adenosine receptor dysfunction seem to be particularly implicated since the activation leads to severe bradycardia or vasodilation, respectively, two cardinal symptoms of NES. This mini-review aims to shed light on the links between dysfunction of the adenosinergic system and NHS. In particular, signal transduction pathways through the modulation of cAMP production and ion channels in relation to effects on the cardiovascular system are addressed. A better understanding of these mechanisms could guide the pharmacological development of new therapeutic approaches.

Electrophilic Agonists Modulate the Transient Receptor Potential Ankyrin-1 Channels Mediated by Insulin and Glucagon-like Peptide-1 Secretion for Glucose Homeostasis.

This pre-clinical study investigated the transient receptor potential ankyrin-1 (TRPA1) channels on modulating targets for glucose homeostasis using agonists: the electrophilic agonists, cinnamaldehyde (CIN) and allyl isothiocyanate (AITC), and the non-electrophilic agonist, carvacrol (CRV). A glucose tolerance test was performed on rats. CIN and AITC (5, 10 and 20 mg/kg) or CRV (25, 100, 300, and 600 mg/kg) were administered intraperitoneally (i.p.), and glycemia was measured. In the intestine, Glucagon-like peptide-1 (GLP-1) and disaccharidase activity were evaluated (in vivo and in vitro, respectively). Furthermore, in vivo and in vitro insulin secretion was determined. Islets were used to measure insulin secretion and calcium influx. CIN and AITC improved glucose tolerance and increased insulin secretion in vivo and in vitro. CRV was unable to reduce glycemia. Electrophilic agonists, CIN and AITC, inhibited disaccharidases and acted as secretagogues in the intestine by inducing GLP-1 release in vivo and in vitro and contributed to insulin secretion and glycemia. The effect of CIN on calcium influx in pancreatic islets (insulin secretion) involves voltage-dependent calcium channels and calcium from stores. TRPA1 triggers calcium influx and potentiates intracellular calcium release to induce insulin secretion, suggesting that electrophilic agonists mediate this signaling transduction for the control of glycemia.

Protein-Mediated Electroporation in a Cardiac Voltage-Sensing Domain Due to an nsPEF Stimulus.

This study takes a step in understanding the physiological implications of the nanosecond pulsed electric field (nsPEF) by integrating molecular dynamics simulations and machine learning techniques. nsPEF, a state-of-the-art technology, uses high-voltage electric field pulses with a nanosecond duration to modulate cellular activity. This investigation reveals a relatively new and underexplored phenomenon: protein-mediated electroporation. Our research focused on the voltage-sensing domain (VSD) of the NaV1.5 sodium cardiac channel in response to nsPEF stimulation. We scrutinized the VSD structures that form pores and thereby contribute to the physical chemistry that governs the defibrillation effect of nsPEF. To do so, we conducted a comprehensive analysis involving the clustering of 142 replicas simulated for 50 ns under nsPEF stimuli. We subsequently pinpointed the representative structures of each cluster and computed the free energy between them. We find that the selected VSD of NaV1.5 forms pores under nsPEF stimulation, but in a way that significant differs from the traditional VSD opening. This study not only extends our understanding of nsPEF and its interaction with protein channels but also adds a new effect to further study.

Spacer-Engineered Ionic Channels in Covalent Organic Framework Membranes toward Ultrafast Proton Transport.

Side-chain engineering of covalent organic frameworks as advanced ion conductors is a critical issue to be explored. Herein, ionic covalent organic framework membranes (iCOFMs) with spacer-engineered ionic channel are de novo designed and prepared. The ionic channels are decorated with side chains comprising spacers having different carbon chain lengths and the -SO3 H groups at the end. Attributed to the synergistic contribution from the spacers and the -SO3 H groups, the iCOFM with moderate-length spacer exhibit the highest through-plane proton conductivity of 889 mS cm-1 at 90 °C.

Patch Clamp: The First Four Decades of a Technique That Revolutionized Electrophysiology and Beyond.

Forty years ago, the introduction of a new electrophysiological technique, the patch clamp, revolutionized the fields of Cellular Physiology and Biophysics, providing for the first time the possibility of describing the behavior of a single protein, an ion-permeable channel of the cell plasma membrane, in its physiological environment. The new approach was actually much more potent and versatile than initially envisaged, and it has evolved into several different modalities that have radically changed our knowledge of how cells (not only the classical "electrically excitable "ones, such as nerves and muscles) use electrical signaling to modulate and organize their activity. This review aims at telling the history of the background from which the new technique evolved and at analyzing some of its more recent developments.