Molecular Structure of the Na,K-ATPase α4β1 Isoform in Its Ouabain-Bound Conformation.

Na,K-ATPase is the active ion transport system that maintains the electrochemical gradients for Na and K across the plasma membrane of most animal cells. Na,K-ATPase is constituted by the association of two major subunits, a catalytic α and a glycosylated β subunit, both of which exist as different isoforms (in mammals known as α1, α2, α3, α4, β1, β2 and β3). Na,K-ATPase α and β isoforms assemble in different combinations to produce various isozymes with tissue specific expression and distinct biochemical properties.

Utility of preoperative prophylactic antibiotics for preventing surgical site infections in children with infantile hypertrophic pyloric stenosis: a systematic review and meta-analysis.

Purpose: The aim of this study was to determine the utility of prophylactic antibiotics before pyloromyotomy for the prevention of Surgical Site Infections (SSI) among children with Infantile Hypertrophic Pyloric Stenosis (IHPS).

Methods: A systematic search of PubMed, Scopus, Embase, and Web of Science databases was performed to identify papers published till 30th July 2024. The main outcome of interest was the incidence of SSIs.

Modulation of Annexin-Induced Membrane Curvature by Cholesterol and the Anionic Lipid Headgroup during Plasma Membrane Repair.

Annexins (ANXAs), calcium-sensitive phospholipid-binding proteins, are pivotal for cellular membrane repair, which is crucial for eukaryotic cell survival under membrane stress. With their unique trimeric arrangements and crystalline arrays on the membrane surface, ANXA4 and ANXA5 induce membrane curvature and rapidly orchestrate plasma membrane resealing. However, the influence of cholesterol and anionic lipid headgroups on annexin-induced membrane curvature remains poorly understood at the molecular level.

Phospholamban inhibits the cardiac calcium pump by interrupting an allosteric activation pathway.

Phospholamban (PLB) is a transmembrane micropeptide that regulates the sarcoplasmic reticulum Ca-ATPase (SERCA) in cardiac muscle, but the physical mechanism of this regulation remains poorly understood. PLB reduces the Ca sensitivity of active SERCA, increasing the Ca concentration required for pump cycling. However, PLB does not decrease Ca binding to SERCA when ATP is absent, suggesting PLB does not inhibit SERCA Ca affinity.

Bending of a lipid membrane edge by annexin A5 trimers.

Plasma membrane damage occurs in healthy cells and more frequently in cancer cells where high growth rates and metastasis result in frequent membrane damage. The annexin family of proteins plays a key role in membrane repair. Annexins are recruited at the membrane injury site by Ca and repair the damaged membrane in concert with several other proteins.

Harnessing the medical undergraduate human resource for screening of sight-threatening diabetic retinopathy.

Purpose: To assess whether medical undergraduates can be trained to effectively screen diabetic retinopathy (DR) by statistical comparison with a retina specialist at a tertiary eye care center in India.

Methods: Three final-year undergraduate medical students, having completed ophthalmology department rotation, received training from a retina specialist for grading DR, following which they were asked to grade a set of 50 fundus photographs centered on the macula with a view of 50° as sight-threatening DR (STDR), diabetic macular edema, and grade of DR. Agreement among the undergraduates and retina specialist was determined with the help of Cohen's Kappa coefficient.

Sensing membrane voltage by reorientation of dipolar transmembrane peptides.

Membrane voltage plays a vital role in the behavior and functions of the lipid bilayer membrane. For instance, it regulates the exchange of molecules across the membrane through transmembrane proteins such as ion channels. In this paper, we study the membrane voltage-sensing mechanism, which entails the reorientation of α-helices with a change in the membrane voltage.

Specific protonation of acidic residues confers K selectivity to the gastric proton pump.

The gastric proton pump (H,K-ATPase) transports a proton into the stomach lumen for every K ion exchanged in the opposite direction. In the lumen-facing state of the pump (E2), the pump selectively binds K despite the presence of a 10-fold higher concentration of Na. The molecular basis for the ion selectivity of the pump is unknown.

ATP-Bound State of the Uncoupling Protein 1 (UCP1) from Molecular Simulations.

The uncoupling protein 1 (UCP1) dissipates the transmembrane (TM) proton gradient in the inner mitochondrial membrane (IMM) by leaking protons across the membrane and producing heat in the process. Such a nonshivering production of heat in the brown adipose tissue can combat obesity-related diseases. UCP1-associated proton leak is activated by free fatty acids and inhibited by purine nucleotides.

Drastic differences between the release kinetics of two highly related porphyrins in liposomal membranes: mTHPP and pTHPP.

Hypothesis: The release of hydrophobic compounds from liposomal membranes occurs by partitioning and is thus determined by the physicochemical properties (e.g. logP and water solubility) of the drug.

A case of eosinophilic granulomatous polyangiitis with concurrent central and peripheral nervous system involvement.

Eosinophilic granulomatous polyangiitis (EGPA) like other antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis has multisystemic involvement. It commonly manifests with prodromal pulmonary involvement as asthma, chronic sinusitis followed by systemic vasculitic complications associated with blood and tissue eosinophilia. Central nervous system manifestations at presentation are uncommon compared with peripheral nervous system involvement.

Engineering a membrane-binding protein to trimerize and induce high membrane curvature.

The annexins are a family of Ca-dependent peripheral membrane proteins. Several annexins are implicated in plasma membrane repair and are overexpressed in cancer cells. Annexin A4 (ANXA4) and annexin A5 (ANXA5) form trimers that induce high curvature on a membrane surface, a phenomenon deemed to accelerate membrane repair.

The molecular basis of the antidepressant action of the magic mushroom extract, psilocin.

Magic mushrooms, and their extract psilocybin, are well-known for their psychedelic properties and recreational use. Psilocin, the bio-active form of psilocybin, can potentially treat various psychiatric diseases. Psilocin putatively exerts its psychedelic effect as an agonist to the serotonin 2A receptor (5-HTR), which is also the receptor for the neurological hormone serotonin.

Interaction of psychedelic tryptamine derivatives with a lipid bilayer.

Naturally occurring psychedelics have been used for a long time as remedies or in religious ceremonies and recreational activities. Recent studies have proven the therapeutic potential of some psychedelic compounds to safely treat a wide range of diseases such as anxiety, depression, migraine, and addiction. It is hypothesized that psychedelic compounds like tryptamines can exert their effects by two possible mechanisms: binding to the transmembrane serotonin receptor and/or modifying the properties of the neuronal membrane that can alter the conformational equilibrium and desensitize receptors.

Interplay of membrane crosslinking and curvature induction by annexins.

Efficient plasma membrane repair (PMR) is required to repair damage sustained in the cellular life cycle. The annexin family of proteins, involved in PMR, are activated by Ca influx from extracellular media at the site of injury. Mechanistic studies of the annexins have been overwhelmingly performed using a single annexin, despite the recruitment of multiple annexins to membrane damage sites in living cells.

Molecular Mechanism of Hydrotropic Properties of GTP and ATP.

Hydrotropes are small amphiphilic compounds that increase the aqueous solubility of hydrophobic molecules. Recent evidence suggests that adenosine triphosphate (ATP), which is the primary energy carrier in cells, also assumes hydrotropic properties to prevent the aggregation of hydrophobic proteins, but the mechanism of hydrotropy is unknown. Here, we compare the hydrotropic behavior of all four biological nucleoside triphosphates (NTPs) using molecular dynamics (MD) simulations.

Structural Basis for Binding of Potassium-Competitive Acid Blockers to the Gastric Proton Pump.

As specific inhibitors of the gastric proton pump, responsible for gastric acidification, K-competitive acid blockers (P-CABs) have recently been utilized in the clinical treatment of gastric acid-related diseases in Asia. However, as these compounds have been developed based on phenotypic screening, their detailed binding poses are unknown. We show crystal and cryo-EM structures of the gastric proton pump in complex with four different P-CABs, tegoprazan, soraprazan, PF-03716556 and revaprazan, at resolutions reaching 2.

Magic mushroom extracts in lipid membranes.

The active hallucinogen of magic mushrooms, psilocin, is being repurposed to treat nicotine addiction and treatment-resistant depression. Psilocin belongs to the tryptamine class of psychedelic compounds which include the hormone serotonin. It is believed that psilocin exerts its effect by binding to the serotonin 5-HT receptor.

Long chain sphingomyelin depletes cholesterol from the cytoplasmic leaflet in asymmetric lipid membranes.

The transbilayer distribution of cholesterol (CHL) in complex asymmetric lipid membranes remains controversial, with contrasting investigations suggesting that there is more CHL either in the exoplasmic, outer leaflet (OL) or the cytoplasmic, inner leaflet (IL) depending on cell type or model, membrane composition, and method of investigation. Here, we launch systematic coarse-grained molecular dynamics simulations to investigate the impact of the sphingomyelin (SM) acyl chain length upon CHL distribution in asymmetric lipid membrane mixtures which account for the variation of the most abundant headgroups and acyl chain unsaturation in the two membrane leaflets. We find that there is always more CHL in the OL, but longer chain SM depletes more CHL from the IL than short chain SM in simple membrane mixtures containing SM and 16 : 0, 18 : 1 phospholipids.

Determinants of mortality and long-term outcome in children with refractory and super refractory status epilepticus.

Aim: To evaluate factors associated with progression of convulsive refractory status epilepticus(RSE) to super refractory status epilepticus(SRSE) and long term outcome in children.

Materials And Methods: In this open cohort study, data of children admitted with convulsive RSE from 2010 to 2018 was retrospectively analyzed. The outcome at two years was graded according to the Glasgow outcome scale(GOS).

An Intracellular Pathway Controlled by the N-terminus of the Pump Subunit Inhibits the Bacterial KdpFABC Ion Pump in High K Conditions.

The heterotetrameric bacterial KdpFABC transmembrane protein complex is an ion channel-pump hybrid that consumes ATP to import K against its transmembrane chemical potential gradient in low external K environments. The KdpB ion-pump subunit of KdpFABC is a P-type ATPase, and catalyses ATP hydrolysis. Under high external K conditions, K can diffuse into the cells through passive ion channels.

EnCurv: Simple Technique of Maintaining Global Membrane Curvature in Molecular Dynamics Simulations.

The EnCurv method for maintaining membrane curvature in molecular dynamics simulations is introduced. The method allows maintaining any desired curvature in a sector of lipid membrane bent in a single plane without adding any unphysical interactions into the system and without restrictions on lateral and transversal lipid diffusion and distribution. The current implementation is limited to the membranes curved in a single plane but generalization to arbitrary curvature and membrane topology is possible.

Cholesterol binding to the sterol-sensing region of Niemann Pick C1 protein confines dynamics of its N-terminal domain.

Lysosomal accumulation of cholesterol is a hallmark of Niemann Pick type C (NPC) disease caused by mutations primarily in the lysosomal membrane protein NPC1. NPC1 contains a transmembrane sterol-sensing domain (SSD), which is supposed to regulate protein activity upon cholesterol binding, but the mechanisms underlying this process are poorly understood. Using atomistic simulations, we show that in the absence of cholesterol in the SSD, the luminal domains of NPC1 are highly dynamic, resulting in the disengagement of the NTD from the rest of the protein.