Permeable Channels Research Articles

A New Algorithm Model Based on Extended Kalman Filter for Predicting Inter-Well Connectivity

Given that more and more oil reservoirs are reaching the high water cut stage during water flooding, the construction of an advanced algorithmic model for identifying inter-well connectivity is crucial to improve oil recovery and extend the oilfield service life cycle. This study proposes a state variable-based dynamic capacitance (SV-DC) model that integrates artificial intelligence techniques with dynamic data and geological features to more accurately identify inter-well connectivity and its evolution. A comprehensive sensitivity analysis was performed on single-well pairs and multi-well groups regarding the permeability amplitude, the width of the high permeable channel, change, and lasting period of injection pressure. In addition, the production performance of multi-well groups, especially the development of ineffective circulation channels and their effects on reservoir development, are studied in-depth. The results show that higher permeability, wider permeable channels, and longer injection pressure maintenance can significantly enhance inter-well connectivity coefficients and reduce time-lag coefficients. Inter-well connectivity in multi-well systems is significantly affected by well-group configuration and inter-well interference effects. Based on the simulation results, the evaluation index of ineffective circulation channels is proposed and applied to dozens of well groups. These identified ineffective circulation channel changing patterns provide an important basis for optimizing oil fields’ injection and production strategies through data-driven insights and contribute to improving oil recovery. The integration of artificial intelligence enhances the ability to analyze complex datasets, allowing for more precise adjustments in field operations. This paper’s research ideas and findings can be confidently extended to other engineering scenarios, such as geothermal development and carbon dioxide storage, where AI-based models can further refine and optimize resource management and operational strategies.

Three‐Dimensional VTe2/MXene/CNT Ternary Architectures for the Development of High Performance Microsupercapacitors

AbstractRapid advancements in portable electronics have created a demand for ultrathin power sources. Microsupercapacitors (MSCs) are becoming a competitive and advantageous option for these applications. It is widely recognized that to develop MSCs with exceptional performance, electrode materials having two‐dimensonal (2D) permeable channels, structural scaffolds with high‐conductivity and large surface area are suitable. Vanadium ditelluride (VTe2) stands out as an ideal material platform in this context. Its unique combination of metallic properties and exfoliative characteristics‐stemming from the conducting Te–V–Te layers held together by weak van der Waals interlayer interactions‐ renders it highly promising for high‐performance MSCs. This study is the first to report that the restacking issues and electrochemical performance of VTe2 can be successfully avoided by the simultaneous incorporation of MXene and CNT to form a ternary hybrid. Here, a laser‐induced graphene (LIG)‐based MSC utilizing VTe2/MXene/CNT as the active electrode material is fabricated. This MSC achieve fabrications an outstanding maximum energy density of 6.84 µWh cm−2 and a power density of 304.7 µW cm−2. This significant achievement demonstrates the potential of this LIG‐based MSC to advance the design of high‐performance micro‐energy storage devices.

Investigation of comparative entropy in different nanofluids inspired by solar radiations and unsteady effects: Model analysis for permeable channel

Entropy analysis in nano as well as conventional fluids is of paramount interest and highly affected by the active physical quantities. The research provides comprehensive comparative entropy performance of multiple nanofluids in the view of model quantities. The physical model considered in the presence of solar radiations, dissipation energy and magnetic field. The multiple fluids squeezed in a channel formed by two horizontal sheets with upper non-stationary surface. The entropy modeling performed using similarity variables for transient flow and governing laws. The numerical approach (RK method coupled with shooting scheme) is used for entropy results which obtained for ternary, hybrid, nano and base fluids. It is found that entropy optimized in ternary nanofluid while hybrid, nano and common fluids caused reduction in it. Dissipation effects (Ec=0.1,0.3,0.5,0.7) increases the entropy while significant reduction is observed for Ω1=0.1,0.2,0.3,0.4. The solar radiations in the range of Rd=1.0 to Rd=7.0 contributes effectively to improve entropy phenomena in both inward and outward plate movement. Thus, the system can be maintained at low entropy by strengthening the effects of Ω1 and optimum entropy is subject to Eckert number, α=0.1,0.2,0.3,0.4, radiations (Rd=1.0,3.0,5.0,7.0) for S>0.0 and S<0.0, respectively.

Canonical Transient Receptor Potential (TRPC) Channels in Cardiovascular Pathology and their Modulators.

Ion channels play a crucial role in various aspects of cardiac function, such as regulating rhythm and contractility. As a result, they serve as key targets for therapeutic interventions in cardiovascular diseases. Cell function is substantially influenced by the concentration of free cytosolic calcium (Ca2+) and the voltage across the plasma membrane. These characteristics are known to be regulated by Ca2+-permeable non-selective cationic channels, although our knowledge of these channels is still inadequate. The transient receptor potential (TRP) superfamily comprises of many non-selective cation channels with diverse Ca2+ permeability. Canonical or classical TRP (TRPC) channels are a subgroup of the TRP superfamily that are expressed ubiquitously in mammalian cells. TRPC channels are multidimensional signalling protein complexes that play essential roles in a variety of physiological and pathological processes in humans, including cancer, neurological disorders, cardiovascular diseases, and others. The objective of this article is to focus on the role that TRPC channels play in the cardiovascular system. The role of TRPC channels will be deeply discussed in cardiovascular pathology. Together, a critical element in developing novel treatments that target TRPC channels is comprehending the molecular mechanisms and regulatory pathways of TRPC channels in related cardiovascular diseases and conditions.

Altered Expression of Thyroid- and Calcium Ion Channels-Related Genes in Rat Testes by Short-Term Exposure to Commercial Herbicides Paraquat or 2,4-D.

Exposure to pesticides such as paraquat and 2,4-dichlorophenoxyacetic acid (2,4-D) has been linked to harmful health effects, including alterations in male reproduction. Both herbicides are widely used in developing countries and have been associated with reproductive alterations, such as disruption of spermatogenesis and steroidogenesis. The thyroid axis and Ca2+-permeable ion channels play a key role in these processes, and their disruption can lead to reproductive issues and even infertility. This study evaluated the short-term effects of exposure to commercial herbicides based on paraquat and 2,4-D on gene expression in rat testes. At the molecular level, exposure to paraquat increased the expression of the thyroid hormone transporters monocarboxylate transporter 8 (Mct8) and organic anion-transporting polypeptide 1C1 (Oatp1c1) and the thyroid receptor alpha (TRα), suggesting a possible endocrine disruption. However, it did not alter the expression of the sperm-associated cation channels (CatSper1-2) or vanilloid receptor-related osmotically activated channel (Trpv4) related to sperm motility. In contrast, exposure to 2,4-D reduced the expression of the Mct10 transporter, Dio2 deiodinase, and CatSper1, which could affect both the availability of T3 in testicular cells and sperm quality, consistent with previous studies. However, 2,4-D did not affect the expression of CatSper2 or Trpv4. Deregulation of gene expression could explain the alterations in male reproductive processes reported by exposure to paraquat and 2,4-D. These thyroid hormone-related genes can serve as molecular biomarkers to assess endocrine disruption due to exposure to these herbicides, aiding in evaluating the health risks of pesticides.

Plumbagin, a novel TRPV2 inhibitor, ameliorates microglia activation and brain injury in a middle cerebral artery occlusion/reperfusion mouse model.

Transient receptor potential vanilloid 2 (TRPV2) is a Ca2+-permeable non-selective cation channel. Despite the significant roles of TRPV2 in immunological response, cancer progression and cardiac development, pharmacological probes of TRPV2 remain to be identified. We aimed to discover TRPV2 inhibitors and to elucidate their molecular mechanism of action. Fluorescence-based Ca2+ assay in HEK-293 cells expressing murine TRPV2 was used to identify plumbagin as a novel TRPV2 inhibitor. Patch-clamp, in silico docking and site-directed mutagenesis were applied to investigate the molecular mechanisms critical for plumbagin interaction. ELISA and qPCR were used to assess nitric oxide release and mRNA levels of inflammatory mediators, respectively. si-RNA interference was used to knock down TRPV2 expression, which was validated by western blotting. Neurological and histological analyses were used to examine brain injury of mice following middle cerebral artery occlusion/reperfusion (MCAO/R). Plumbagin is a potent TRPV2 negative allosteric modulator with an IC50 value of 0.85 μM, exhibiting >14-fold selectivity over TRPV1, TRPV3 and TRPV4. Plumbagin suppresses TRPV2 activity by decreasing the channel open probability without affecting the unitary conductance. Moreover, plumbagin binds to an extracellular pocket formed by the pore helix and flexible loop between transmembrane helices S5 and S6 of TRPV2. Plumbagin effectively suppresses LPS-induced inflammation of BV-2 microglia and ameliorates brain injury of MCAO/R mice. Plumbagin is a novel pharmacological probe to study TRPV2 pathophysiology. TRPV2 is a novel molecular target for the treatment of neuroinflammation and ischemic stroke.

The Ca2+-activated Cl- channel TMEM16B shapes the response time course of olfactory sensory neurons.

Mammalian olfactory sensory neurons (OSNs) generate an odorant-induced response by sequentially activating two ion channels, which are in their ciliary membranes. First, a cationic, Ca2+-permeable cyclic nucleotide-gated channel is opened following odorant stimulation via a G protein-coupled transduction cascade and an ensuing rise in cAMP. Second, the increase in ciliary Ca2+ opens the excitatory Ca2+-activated Cl- channel TMEM16B, which carries most of the odorant-induced receptor current. While the role of TMEM16B in amplifying the response has been well established, it is less understood how this secondary ion channel contributes to response kinetics and action potential generation during single as well as repeated stimulation and, on the other hand, which response properties the cyclic nucleotide-gated (CNG) channel determines. We first demonstrate that basic membrane properties such as input resistance, resting potential and voltage-gated currents remained unchanged in OSNs that lack TMEM16B. The CNG channel predominantly determines the response delay and adaptation during odorant exposure, while the absence of the Cl- channels shortens both the time the response requires to reach its maximum and the time to terminate after odorant stimulation. This faster response termination in Tmem16b knockout OSNs allows them, somewhat counterintuitively despite the large reduction in receptor current, to fire action potentials more reliably when stimulated repeatedly in rapid succession, a phenomenon that occurs both in isolated OSNs and in OSNs within epithelial slices. Thus, while the two olfactory ion channels act in concert to generate the overall response, each one controls specific aspects of the odorant-induced response. KEY POINTS: Mammalian olfactory sensory neurons (OSNs) generate odorant-induced responses by activating two ion channels sequentially in their ciliary membranes: a Na+, Ca2⁺-permeable cyclic nucleotide-gated (CNG) channel and the Ca2⁺-activated Cl⁻ channel TMEM16B. The CNG channel controls response delay and adaptation during odorant exposure, while TMEM16B amplifies the response and influences the time required for the response to reach its peak and terminate. OSNs lacking TMEM16B display faster response termination, allowing them to fire action potentials more reliably during rapid repeated stimulation. The CNG and TMEM16B channels have distinct and complementary roles in shaping the kinetics and reliability of odorant-induced responses in OSNs.

A New model of gas-water two-phase seepage based on Newton's law of motion

The pore throat size, structure distribution, and lithology of porous media in gas reservoirs are varied, and the gas-water two-phase seepage law is complex, making it difficult to describe the seepage model. Newton's law of motion is a basic law of motion in classical mechanics, and its application in gas-water two-phase seepage modeling is an innovative practice of classical mechanics in seepage mechanics systems. Based on Newton's three laws of motion, a gas-water two-phase seepage model was established from the force analysis of fluid, and the relationship between velocity and pressure difference, pipe radius, water film thickness, viscosity, etc. was derived under the condition that the model reached a stable state, i.e., force balance. The relationship is referred to as the steady-state model. Subsequently. the equivalent permeability representation model was derived based on the steady-state model to calculate the permeability of rock samples with different channel distribution characteristics. The results were consistent with the measured values, and there is a good correspondence between channel distribution characteristics and permeability. The relative permeability calculation method was established based on the steady-state model and capillary pressure curve. The obtained relative permeability curve aligned with the two-phase seepage law and coincides with the relative permeability curve obtained by Poiseuille's law. Finally, a new productivity equation was derived based on the steady-state model, and the Inflow Performance Relationship (IPR) curve calculated by the gas well example was consistent with the traditional equation. The research results were based on the force analysis of fluid in porous media and fundamentally explored the law of fluid flow. The derived seepage model can be used to calculate reservoir permeability, the gas-water relative permeability curve, and gas well productivity analysis and to effectively guide gas reservoir development. The study was a successful application of the basic theory of mechanics in gas-water two-phase seepage in gas reservoirs.

Impact of magnetic field on tangent hyperbolic liquid flow through a permeable channel with heat transfer: Application to dialyzer

Impact of magnetic field on tangent hyperbolic liquid flow through a permeable channel with heat transfer: Application to dialyzer

The effect of plant alkaloid Chelidonin with fullerene C60 carbon nanoparticles on the permeability of hERG potassium channels

The effect of plant alkaloid Chelidonin with fullerene C60 carbon nanoparticles on the permeability of hERG potassium channels

PERIODIC FOAMING DURING SELECTIVE ISOLATION OF HIGHLY PERMEABLE CHANNELS OF POROUS MEDIUM

Selective isolation of watered interlayers by forming barriers formed by highly viscous gels or insoluble precipitates does not always lead to the desired results. Field experience confirms that at some distance from the formed barrier, the filtration flow restores its configuration and the water injected into the formation again moves through highly permeable channels. An increase in the efficiency of flow deflection can be achieved by creating not a single barrier, but a whole sequence of alternating deep-penetrating insulating barriers, separated from each other by a certain distance in highly permeable pores. The paper presents the results of studies of quasi-periodic foaming in order to control mobility under conditions of selective isolation of water in pore channels of high permeability. Foaming occurs due to the in-bulk reaction between concentrated aqueous solutions of gas-generating and gas-generating solutions. Flow pattern of injected aqueous solutions of foaming reagents along current tubes is investigated. The task is to determine the space-time distribution of reagents in given zones of the porous medium. The problem of establishing the correlation between the spatial distribution of the gas formation zone and the dynamics of the gas formation process over time on the one hand, as well as the concentration of reactants, the diffusion rate (mutual diffusion), the gas generation rate and the probability of nucleation on the other hand was solved. The degree of flow blockage in highly permeable zones of the formation depends on the rate of in-situ foam generation and the simulation consists in the fact that it is similar to the law of filtration with a limiting gradient. The paper discusses the process of quasi-periodic gas formation during the movement of mixing solutions in porous media. In stationary filtration in a homogeneous porous medium, the process is described by the proposed system of equations. A system of equations is proposed that describes the movement of a liquid taking into account adsorption of reagents, diffusion and dynamics of the foaming reaction. The results obtained can serve as the basis for developing a method for controlling the water cut of porous media during waterflooding of oil formations. This, in turn, leads to the leveling of the displacement front and an increase in the completeness of coverage.

Combined mechanistic and machine learning method for construction of oil reservoir permeability map consistent with well test measurements

We introduce a novel method for estimating the spatial distribution of absolute permeability in oil reservoirs, consistent with well logging and well test measurements. The primary objective is to create a permeability map, incorporating the well test interpretation results and achieving hydrodynamic similarity to the actual permeability distribution around each well. This enhancement aims to improve the accuracy of reservoir modeling outcomes in reproducing real data. We utilize Nadaraya-Watson kernel regression to parameterize the two-dimensional spatial distribution of rock permeability. The kernel regression parameters are optimized by minimizing the discrepancies between actual and predicted values of permeability at well locations, the integral permeability of the reservoir domain around each well, and skin factors. This inverse optimization problem is addressed by repeatedly solving forward problems, where an artificial neural network (ANN) predicts the integral permeability of the formation surrounding a well and skin factor. The ANN is trained on a physics-based dataset generated through a synthetic well test procedure, which includes the numerical modeling of the bottomhole pressure decline curve in a reservoir simulator and its interpretation using a semi-analytical reservoir model. The proposed method is tested on the “Egg Model”, a synthetic reservoir with significant heterogeneity due to highly permeable channels. The permeability map created by our approach demonstrates hydrodynamic similarity to the original map. Numerical reservoir simulations, corresponding to the constructed and original permeability maps, yield comparable pore pressure and water saturation distributions at the end of the simulation period. Additionally, we observe a notable match in flow rates and total volumes of produced oil, water, and injected water between simulations. The developed approach outperforms kriging in terms of numerical reservoir modeling outcomes. This research advances existing geostatistical interpolation techniques by fusing well logging and well test data to build the reservoir permeability map through an optimization framework coupled with machine learning. Unlike traditional variogram-based geostatistical simulation algorithms, our method provides a permeability distribution that is hydrodynamically similar to the actual one, enhancing initial guess in the history matching process. The novel incorporation of well test interpretation results into the permeability map represents a significant improvement over existing methods, offering an innovative approach that can benefit the petroleum industry. We also provide recommendations for further development of the proposed algorithm to account for geological realism.

Building predictive Markov models of ion channel permeation from molecular dynamics simulations

Molecular dynamics (MD) simulation of biological processes has always been a challenging task due to the long timescales of the processes involved and the large amount of output data to handle. Markov state models (MSMs) have been introduced as a powerful tool in this area of research, as they provide a mechanistically comprehensible synthesis of the large amount of MD data and, at the same time, can be used to rapidly estimate experimental properties of biological processes. Herein, we propose a method for building MSMs of ion channel permeation from MD trajectories, which directly evaluates the current flowing through the channel from the model’s transition matrix (T), which is crucial for comparing simulations and experimental data. This is achieved by including in the model a flux matrix that summarizes information on the charge moving across the channel between each pair of states of the MSM and can be used in conjunction with T to predict the ion current. A procedure to drastically reduce the number of states in the MSM while preserving the estimated ion current is also proposed. Applying the method to the KcsA channel returned an MSM with five states with significant equilibrium occupancy, capable of accurately reproducing the single-channel ion current from microsecond MD trajectories.

Characterization of human aquaporin ion channels in a yeast expression system as a tool for novel ion channel discovery.

Aquaporin (AQP) channels found in all domains of life are transmembrane proteins which mediate passive transport of water, glycerol, signaling molecules, metabolites, and charged solutes. Discovery of new classes of ion-conducting AQP channels has been slow, likely reflecting time- and labor-intensive methods required for traditional electrophysiology. Work here defines a sensitive mass-throughput system for detecting AQP ion channels, identified by rescue of cell growth in the K+-transport-defective yeast strain CY162 following genetic complementation with heterologously expressed cation-permeable channels, using the well characterized human AQP1 channel for proof of concept. Results showed AQP1 conferred transmembrane permeability to cations which rescued survival in CY162 yeast. Comprehensive testing showed that growth response properties fully recapitulated AQP1 pharmacological agonist and antagonist profiles for activation, inhibition, dose-dependence, and structure-function relationships, demonstrating validity of the yeast screening tool for AQP channel identification and drug discovery efforts. This method also provided new information on divalent cation blockers of AQP1, pH sensitivity of antagonists, and ion permeability of human AQP6. Site-directed mutagenesis of AQP1 channel regulatory domains confirmed that yeast growth rescue was mediated by the introduced channels. Optical monitoring with a lithium-sensitive photoswitchable probe in living cells independently demonstrated monovalent cation permeability of AQP1 channels in yeast plasma membrane. Ion channel properties of AQP1 expressed in yeast were consistent with those of AQP1 expressed in Xenopus laevis oocyte and K+-transport defective Escherichia coli. Outcomes here establish a powerful new approach for efficient screening of phylogenetically diverse AQPs for yet untested functions as cation channels.

Heat and mass transfer of ternary nanofluid in permeable vertical channel sandwiched between nanofluid zones with Soret and Dufour effects using sensitivity analysis

Heat and mass transfer of ternary nanofluid in permeable vertical channel sandwiched between nanofluid zones with Soret and Dufour effects using sensitivity analysis

Purinergic control of apical ion conductance by luminal ATP in rat colonic epithelium

ATP, released e.g. after cell damage or during inflammation, can alter ion transport across the intestinal mucosa via stimulation of purinergic receptors in the basolateral as well as in the apical membrane of epithelial cells. When ATP acts from the serosal side, it induces an increase in short-circuit current (Isc) via Cl− secretion across the colonic epithelium. In contrast, mucosal ATP or its derivative, BzATP, predominantly stimulating ionotropic P2X4 and P2X7 receptors, evoke an increase in Isc, which could not be explained by Cl− secretion. The underlying ion currents after stimulation of apical purinergic receptors in rat distal colon are still unclear and were investigated in the present study.Ussing chamber experiments revealed that the Isc induced by mucosal ATP was dependent on the presence of mucosal Ca2+ and inhibited by the K+ channel blocker, Ba2+, indicating the involvement of Ca2+-dependent K+ channels. Blockade of the transepithelial Isc by lanthanides (La3+, Gd3+) suggests that Ca2+ enters the epithelium via nonselective cation channels. Experiments with basolaterally depolarized epithelia confirmed the activation of apical lanthanide-sensitive Na+- and Ca2+-permeable cation channels by ATP. Putative candidates might be TRP channels, from which several subtypes were detected in colonic tissue in RT-PCR experiments. In addition, the activation of an apical Cl− conductance was observed when suitable Cl− concentration gradients were applied. Consequently, mucosal ATP, acting as ‘danger signal’, stimulates cation and anion channels in the apical membrane to induce a secretory response as part of the local defence mechanism in the intestinal epithelium.

Cadmium stress alleviates lipid accumulation caused by chiral penthiopyrad through regulating endoplasmic reticulum stress and mitochondrial dysfunction in zebrafish liver

The coexistence of cadmium (Cd) can potentiate (synergism) or reduce (antagonism) the pesticide effects on organisms, which may change with chiral pesticide enantiomers. Previous studies have reported the toxic effects of chiral penthiopyrad on lipid metabolism in zebrafish (Danio rerio) liver. The Cd effects and toxic mechanism on lipid accumulation were investigated from the perspective of endoplasmic reticulum (ER) stress and mitochondrial dysfunction. The coexistence of Cd increased the concentrations of penthiopyrad and its metabolites in zebrafish. Penthiopyrad exposure exhibited significant effects on lipid metabolism and mitochondrial function-related indicators, which were verified by lipid droplets and mitochondrial damage in subcellular structures. Moreover, penthiopyrad activated the genes of ER unfolded protein reaction (UPR) and Ca2+ permeable channels, and S-penthiopyrad exhibited more serious effects on ER stress with ER hyperplasia than R-penthiopyrad. As a mitochondrial uncoupler, the coexistence of Cd could decrease lipid accumulation by alleviating ER stress and mitochondrial dysfunction, and these effects were the most significant for R-penthiopyrad. There were antagonistic effects between Cd and penthiopyrad, which could reduce the damage caused by penthiopyrad in zebrafish, thus increasing the bioaccumulation of penthiopyrad in zebrafish. These findings highlighted the importance and necessity of evaluating the ecological risks of metal-chiral pesticide mixtures.

Role of Piezo1 in Terminal Density Reversal of Red Blood Cells.

Density reversal of senescent red blood cells has been known for a long time, yet the identity of the candidate ion transporter(s) causing the senescent cells to swell is still elusive. While performing fractionation of RBCs from healthy individuals in Percoll density gradient and characterization of the separated fractions, we identified a subpopulation of cells in low-density fraction (1.02% ± 0.47) showing signs of senescence such as loss of membrane surface area associated with a reduction in band 3 protein abundance, and Phosphatidylserine (PS) exposure to the outer membrane. In addition, we found that these cells are overloaded with Na+ and Ca2+. Using a combination of blockers and activators of ion pumps and channels, we revealed reduced activity of Plasma membrane Ca2+ ATPase and an increase in Ca2+ and Na+ leaks through ion channels in senescent-like cells. Our data revealed that Ca2+ overload in these cells is a result of reduced PMCA activity and facilitated Ca2+ uptake via a hyperactive Piezo1 channel. However, we could not exclude the contribution of other Ca2+-permeable ion channels in this scenario. In addition, we found, as a universal mechanism, that an increase in intracellular Ca2+ reduced the initially high selectivity of Piezo1 channel for Ca2+ and allowed higher Na+ uptake, Na+ accumulation, and swelling.

Astroglial CD38 impairs hippocampal synaptic plasticity after global cerebral ischemia

Cardiac arrest-induced global cerebral ischemia (GCI) results in profound cognitive impairment in survivors. Our prior work demonstrated persistent disruption of long-term potentiation (LTP) in hippocampal CA1 neurons, correlating with learning and memory deficits in a rodent model of cardiac arrest/cardiopulmonary resuscitation (CA/CPR). Delayed inhibition of the Ca2+-permeable TRPM2 ion channel restored LTP post-CA/CPR, yet the mechanisms upstream of TRPM2 activation remain elusive. This study investigates CD38 as a potential regulator of TRPM2, highlighting a novel target to reverse hippocampal synaptic plasticity deficits after ischemia. We observe elevated levels of CD38 in activated astrocytes in the CA1 region of the hippocampus 7 days following CA/CPR in both male and female mice. Delayed inhibition of CD38 reverses hippocampal synaptic plasticity impairments at subacute timepoints after CA/CPR, phenocopying TRPM2 restoration of LTP. Our previous findings demonstrated that TRPM2 inhibition reverses the CA/CPR-induced enhancement of GABAA receptor (GABAAR) clustering, which contribute to ongoing LTP deficits. We, therefore, assessed the effect of CD38 on GABAergic inhibitory potentiation and find that inhibition of CD38 reverses GABAAR clustering in a TRPM2-dependent manner. In this study, we identify astroglial CD38 as a potential target and upstream regulator of the TRPM2 channel, offering a promising approach to restore hippocampal synaptic plasticity impairments following GCI through modulation of GABAergic signaling.

Orai1 and Orai3 act through distinct signalling axes to promote stemness and tumorigenicity of breast cancer stem cells

BackgroundOne of major challenges in breast tumor therapy is the existence of breast cancer stem cells (BCSCs). BCSCs are a small subpopulation of tumor cells that exhibit characteristics of stem cells. BCSCs are responsible for progression, recurrence, chemoresistance and metastasis of breast cancer. Ca2+ signalling plays an important role in diverse processes in cancer development. However, the role of Ca2+ signalling in BCSCs is still poorly understood.MethodsA highly effective 3D soft fibrin gel system was used to enrich BCSC-like cells from ER+ breast cancer lines MCF7 and MDA-MB-415. We then investigated the role of two Ca2+-permeable ion channels Orai1 and Orai3 in the growth and stemness of BCSC-like cells in vitro, and tumorigenicity in female NOD/SCID mice in vivo.ResultsOrai1 RNA silencing and pharmacological inhibition reduced the growth of BCSC-like cells in tumor spheroids, decreased the expression levels of BCSC markers, and reduced the growth of tumor xenografts in NOD/SCID mice. Orai3 RNA silencing also had similar inhibitory effect on the growth and stemness of BCSC-like cells in vitro, and tumor xenograft growth in vivo. Mechanistically, Orai1 and SPCA2 mediate store-operated Ca2+ entry. Knockdown of Orai1 or SPCA2 inhibited glycolysis pathway, whereas knockdown of Orai3 or STIM1 had no effect on glycolysis.ConclusionWe found that Orai1 interacts with SPCA2 to mediate store-independent Ca2+ entry, subsequently promoting the growth and tumorigenicity of BCSC-like cells via glycolysis pathway. In contrast, Orai3 and STIM1 mediate store-operated Ca2+ entry, promoting the growth and tumorigenicity of BCSC-like cells via a glycolysis-independent pathway. Together, our study uncovered a well-orchestrated mechanism through which two Ca2+ entry pathways act through distinct signalling axes to finely control the growth and tumorigenicity of BCSCs.