Genetic Determinants of Serum Calcification Propensity and Cardiovascular Outcomes in the General Population.

Background: Serum calciprotein particle maturation time (T), a measure of vascular calcification propensity, is associated with cardiovascular morbidity and mortality. We aimed to identify genetic loci associated with serum T and study their association with cardiovascular disease and mortality.

Methods: We performed a genome-wide association study of serum T in 2,739 individuals of European descent participating in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, followed by a two-sample Mendelian randomization (MR) study to examine causal effects of T on cardiovascular outcomes.

Progress in understanding the structural mechanism underlying prestin's electromotile activity.

Prestin (SLC26A5), a member of the SLC26 transporter family, is the molecular actuator that drives OHC electromotility (eM). A wealth of biophysical data indicates that eM is mediated by an area motor mechanism, in which prestin molecules act as elementary actuators by changing their area in the membrane in response to changes in membrane potential. The area changes of a large and densely packed population of prestin molecules sum up, resulting in macroscopic cellular movement.

Genetic Profiles of Ferroptosis in Malignant Brain Tumors and Off-Target Effects of Ferroptosis Induction.

Glioblastoma represents the most devastating form of human brain cancer, associated with a very poor survival rate of patients. Unfortunately, treatment options are currently limited and the gold standard pharmacological treatment with the chemotherapeutic drug temozolomide only slightly increases the survival rate. Experimental studies have shown that the efficiency of temozolomide can be improved by inducing ferroptosis - a recently discovered form of cell death, which is different from apoptosis, necrosis, or necroptosis and, which is characterized by lipid peroxidation and reactive oxygen species accumulation.

The Abl-interactor Abi suppresses the function of the BRAG2 GEF family member Schizo.

Guanine nucleotide exchange factors (GEF) of the BRAG subfamily activate small Arf GTPases, which are pivotal regulators of intracellular membrane traffic and actin dynamics. Consequently, BRAG proteins have been implicated to regulate the surface levels of adhesive and signaling receptors. However, not much is known about the mechanism leading to the regulation of these surface proteins.

Serum free sulfhydryl status associates with new-onset chronic kidney disease in the general population.

Background: Serum sulfhydryl groups (R-SH, free thiols) reliably reflect the systemic redox status in health and disease. As oxidation of R-SH occurs rapidly by reactive oxygen species (ROS), oxidative stress is accompanied by reduced levels of free thiols. Oxidative stress has been implicated in the pathophysiology of chronic kidney disease (CKD), in which redox imbalance may precede the onset of CKD.

Zinc Ameliorates the Osteogenic Effects of High Glucose in Vascular Smooth Muscle Cells.

In diabetic patients, medial vascular calcification is common and associated with increased cardiovascular mortality. Excessive glucose concentrations can activate the nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-kB) and trigger pro-calcific effects in vascular smooth muscle cells (VSMCs), which may actively augment vascular calcification. Zinc is able to mitigate phosphate-induced VSMC calcification.

Protective effects of spironolactone on vascular calcification in chronic kidney disease.

Background: Vascular calcification is common in chronic kidney disease (CKD) and associated with increased cardiovascular mortality. Aldosterone has been implicated as an augmenting factor in the progression of vascular calcification. The present study further explored putative beneficial effects of aldosterone inhibition by the mineralocorticoid receptor antagonist spironolactone on vascular calcification in CKD.

Association of Reading Performance in Geographic Atrophy Secondary to Age-Related Macular Degeneration With Visual Function and Structural Biomarkers.

Importance: As a disabling and frequent disease, geographic atrophy secondary to age-related macular degeneration (AMD) constitutes an important study subject. Emerging clinical trials require suitable end points. The characterization and validation of reading performance as a functional outcome parameter is warranted.

Increased β-adrenergic stimulation augments vascular smooth muscle cell calcification via PKA/CREB signalling.

In chronic kidney disease (CKD), hyperphosphatemia promotes medial vascular calcification, a process augmented by osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). VSMC function is regulated by sympathetic innervation, and these cells express α- and β-adrenergic receptors. The present study explored the effects of β2-adrenergic stimulation by isoproterenol on VSMC calcification.

GWAS meta-analysis followed by Mendelian randomization revealed potential control mechanisms for circulating α-Klotho levels.

The protein α-Klotho acts as transmembrane co-receptor for fibroblast growth factor 23 (FGF23) and is a key regulator of phosphate homeostasis. However, α-Klotho also exists in a circulating form, with pleiotropic, but incompletely understood functions and regulation. Therefore, we undertook a genome-wide association study (GWAS) meta-analysis followed by Mendelian randomization (MR) of circulating α-Klotho levels.

Transient Oxygen-Glucose Deprivation Causes Region- and Cell Type-Dependent Functional Deficits in the Mouse Hippocampus .

Neurons are highly vulnerable to conditions of hypoxia-ischemia (HI) such as stroke or transient ischemic attacks. Recovery of cognitive and behavioral functions requires re-emergence of coordinated network activity, which, in turn, relies on the well-orchestrated interaction of pyramidal cells (PYRs) and interneurons. We therefore modelled HI in the mouse hippocampus, a particularly vulnerable region showing marked loss of PYR and fast-spiking interneurons (FSIs) after hypoxic-ischemic insults.

Painful diabetic neuropathy leads to functional Ca3.2 expression and spontaneous activity in skin nociceptors of mice.

Painful diabetic neuropathy occurs in approximately 20% of diabetic patients with underlying pathomechanisms not fully understood. We evaluated the contribution of the Ca3.2 isoform of T-type calcium channel to hyperglycemia-induced changes in cutaneous sensory C-fiber functions and neuropeptide release employing the streptozotocin (STZ) diabetes model in congenic mouse strains including global knockouts (KOs).

HDAC Screening Identifies the HDAC Class I Inhibitor Romidepsin as a Promising Epigenetic Drug for Biliary Tract Cancer.

Inhibition of histone deacetylases (HDACs) is a promising anti-cancer approach. For biliary tract cancer (BTC), only limited therapeutic options are currently available. Therefore, we performed a comprehensive investigation of HDAC expression and pharmacological HDAC inhibition into a panel of eight established BTC cell lines.

Theta-gamma coupling during REM sleep depends on breathing rate.

Temporal coupling between theta and gamma oscillations is a hallmark activity pattern of several cortical networks and becomes especially prominent during REM sleep. In a parallel approach, nasal breathing has been recently shown to generate phase-entrained network oscillations which also modulate gamma. Both slow rhythms (theta and respiration-entrained oscillations) have been suggested to aid large-scale integration but they differ in frequency, display low coherence, and modulate different gamma sub-bands.

From Pinocytosis to Methuosis-Fluid Consumption as a Risk Factor for Cell Death.

The volumes of a cell [cell volume (CV)] and its organelles are adjusted by osmoregulatory processes. During pinocytosis, extracellular fluid volume equivalent to its CV is incorporated within an hour and membrane area equivalent to the cell's surface within 30 min. Since neither fluid uptake nor membrane consumption leads to swelling or shrinkage, cells must be equipped with potent volume regulatory mechanisms.

Plants have neither synapses nor a nervous system.

The alleged existence of so-called synapses or equivalent structures in plants provided the basis for the concept of Plant Neurobiology (Baluska et al., 2005; Brenner et al., 2006).

5-(Indol-2-yl)pyrazolo[3,4-]pyridines as a New Family of TASK-3 Channel Blockers: A Pharmacophore-Based Regioselective Synthesis.

TASK channels belong to the two-pore-domain potassium (K) channels subfamily. These channels modulate cellular excitability, input resistance, and response to synaptic stimulation. TASK-channel inhibition led to membrane depolarization.

Systematic Review on Optical Diagnosis of Early Gastrointestinal Neoplasia.

Background: Meticulous endoscopic characterization of gastrointestinal neoplasias (GN) is crucial to the clinical outcome. Hereby the indication and type of resection (endoscopically, en-bloc or piece-meal, or surgical resection) are determined. By means of established image-enhanced (IEE) and magnification endoscopy (ME) GN can be characterized in terms of malignancy and invasion depth.

Histone deacetylase 2-dependent ventricular electrical remodeling in a porcine model of early heart failure.

Aims: Heart failure (HF) is linked to electrical remodeling that promotes ventricular arrhythmias. Underlying molecular signaling is insufficiently understood, in particular concerning patients with early disease stages. Previous observations suggest a key role for epigenetic mechanisms in cardiac remodeling processes.

Axonal GABA stabilizes excitability in unmyelinated sensory axons secondary to NKCC1 activity.

Key Points: GABA depolarized sural nerve axons and increased the electrical excitability of C-fibres via GABA receptor. Axonal excitability responses to GABA increased monotonically with the rate of action potential firing. Action potential activity in unmyelinated C-fibres is coupled to Na-K-Cl cotransporter type 1 (NKCC1) loading of axonal chloride.

Further evidence for de novo variants in SYNCRIP as the cause of a neurodevelopmental disorder.

SYNCRIP encodes for the Synaptotagmin-binding cytoplasmic RNA-interacting protein, involved in RNA-binding and regulation of multiple cellular pathways. It has been proposed as a candidate gene for neurodevelopmental disorders (NDDs) with autism spectrum disorder (ASD), intellectual disability (ID), and epilepsy. We ascertained genetic, clinical, and neuroradiological data of three additional individuals with novel de novo SYNCRIP variants.

Expression of the α7 Nicotinic Acetylcholine Receptor Is Critically Required for the Antifibrotic Effect of PHA-543613 on Skin Fibrosis.

Introduction: Targeting the α7 nicotinic acetylcholine receptor (α7nAChR) has recently been suggested as a potential new treatment for fibrotic skin diseases. Here, we performed a genetic and pharmacologic approach to clarify the role of this receptor in the bleomycin (BLM) mouse model of skin fibrosis using α7nAChR KO mice.

Methods: We analyzed the expression of extracellular matrix (ECM) components in murine skin using quantitative RT-PCR, pepsin digestion/SDS-PAGE of proteins and performed hydroxyproline assays as well as histological/immunohistochemical staining of skin sections.