Aldosterone signaling through transient receptor potential melastatin 7 cation channel (TRPM7) and its α-kinase domain

We demonstrated a role for the Mg2 + transporter TRPM7, a bifunctional protein with channel and α-kinase domains, in aldosterone signaling. Molecular mechanisms underlying this are elusive. Here we investigated the function of TRPM7 and its α-kinase domain on Mg2 + and pro-inflammatory signaling by aldosterone. Kidney cells (HEK-293) expressing wild-type human TRPM7 (WThTRPM7) or constructs in which the α-kinase domain was deleted (ΔKinase) or rendered inactive with a point mutation in the ATP binding site of the α-kinase domain (K1648R) were studied. Aldosterone rapidly increased [Mg2 +]i and stimulated NADPH oxidase-derived generation of reactive oxygen species (ROS) in WT hTRPM7 and TRPM7 kinase dead mutant cells. Translocation of annexin-1 and calpain-II and spectrin cleavage (calpain target) were increased by aldosterone in WT hTRPM7 cells but not in α-kinase-deficient cells. Aldosterone stimulated phosphorylation of MAP kinases and increased expression of pro-inflammatory mediators ICAM-1, Cox-2 and PAI-1 in Δkinase and K1648R cells, effects that were inhibited by eplerenone (mineralocorticoid receptor (MR) blocker). 2-APB, a TRPM7 channel inhibitor, abrogated aldosterone-induced Mg2 + responses in WT hTRPM7 and mutant cells. In 2-APB-treated ΔKinase and K1648R cells, aldosterone-stimulated inflammatory responses were unchanged. These data indicate that aldosterone stimulates Mg2 + influx and ROS production in a TRPM7-sensitive, kinase-insensitive manner, whereas activation of annexin-1 requires the TRPM7 kinase domain. Moreover TRPM7 α-kinase modulates inflammatory signaling by aldosterone in a TRPM7 channel/Mg2 +-independent manner. Our findings identify novel mechanisms for non-genomic actions of aldosterone involving differential signaling through MR-activated TRPM7 channel and α-kinase

Types and Prevalence of Coexisting Spine Lesions on Whole Spine Sagittal MR Images in Surgical Degenerative Spinal Diseases

∙The authors have no financial conflicts of interest. Purpose: We investigated types and prevalence of coexisting lesions found on whole spine sagittal T2-weighted images (WSST2I) acquired from magnetic resonance imaging (MRI) and evaluated their clinical significance in surgical degenerative spinal diseases. Materials and Methods: Coexisting spinal lesions were investigated using WSST2I from 306 consecutive patients with surgical degenerative spinal diseases. Severity of coexisting lesions was classified into four grades (0-3). Lesions of grade 2 and 3 were defined as “meaningful coexisting spine lesions ” (MCSL). Degenerative spinal diseases were classified into three pathologies: simple disc herniation, degenerative spinal stenosis, and ligament ossification disease. The relationships between MCSL, gender, age, and primary spine lesions were analyzed. Results: MCSL were found in 95 patients: a prevalence of 31.1%. Five out of 95 MCSL were surgically managed. The most common types of MCSL were disc herniation with 13.1 % prevalence, followed b

Protein–protein HADDocking using exclusively pseudocontact shifts

In order to enhance the structure determination process of macromolecular assemblies by NMR, we have implemented long-range pseudocontact shift (PCS) restraints into the data-driven protein docking package HADDOCK. We demonstrate the efficiency of the method on a synthetic, yet realistic case based on the lanthanide-labeled N-terminal ε domain of the E. coli DNA polymerase III (ε186) in complex with the HOT domain. Docking from the bound form of the two partners is swiftly executed (interface RMSDs < 1 Å) even with addition of very large amount of noise, while the conformational changes of the free form still present some challenges (interface RMSDs in a 3.1–3.9 Å range for the ten lowest energy complexes). Finally, using exclusively PCS as experimental information, we determine the structure of ε186 in complex with the HOT-homologue θ subunit of the E. coli DNA polymerase III

FIRE-2 Simulations: Physics versus Numerics in Galaxy Formation

The Feedback In Realistic Environments (FIRE) project explores feedback in cosmological galaxy formation simulations. Previous FIRE simulations used an identical source code (“FIRE-1”) for consistency. Motivated by the development of more accurate numerics – including hydrodynamic solvers, gravitational softening, and supernova coupling algorithms – and exploration of new physics (e.g. magnetic fields), we introduce “FIRE-2”, an updated numerical implementation of FIRE physics for the GIZMO code. We run a suite of simulations and compare against FIRE-1: overall, FIRE-2 improvements do not qualitatively change galaxy-scale properties. We pursue an extensive study of numerics versus physics. Details of the star-formation algorithm, cooling physics, and chemistry have weak effects, provided that we include metal-line cooling and star formation occurs at higher-than-mean densities. We present new resolution criteria for high-resolution galaxy simulations. Most galaxy-scale properties are robust to numerics we test, provided: (1) Toomre masses are resolved; (2) feedback coupling ensures conservation, and (3) individual supernovae are time-resolved. Stellar masses and profiles are most robust to resolution, followed by metal abundances and morphologies, followed by properties of winds and circum-galactic media (CGM). Central (∼kpc) mass concentrations in massive (>L*) galaxies are sensitive to numerics (via trapping/recycling of winds in hot halos). Multiple feedback mechanisms play key roles: supernovae regulate stellar masses/winds; stellar mass-loss fuels late star formation; radiative feedback suppresses accretion onto dwarfs and instantaneous star formation in disks. We provide all initial conditions and numerical algorithms used

Accuracy and repeatability of wrist joint angles in boxing using an electromagnetic tracking system

© 2019, The Author(s). The hand-wrist region is reported as the most common injury site in boxing. Boxers are at risk due to the amount of wrist motions when impacting training equipment or their opponents, yet we know relatively little about these motions. This paper describes a new method for quantifying wrist motion in boxing using an electromagnetic tracking system. Surrogate testing procedure utilising a polyamide hand and forearm shape, and in vivo testing procedure utilising 29 elite boxers, were used to assess the accuracy and repeatability of the system. 2D kinematic analysis was used to calculate wrist angles using photogrammetry, whilst the data from the electromagnetic tracking system was processed with visual 3D software. The electromagnetic tracking system agreed with the video-based system (paired t tests) in both the surrogate ( 0.9). In the punch testing, for both repeated jab and hook shots, the electromagnetic tracking system showed good reliability (ICCs > 0.8) and substantial reliability (ICCs > 0.6) for flexion–extension and radial-ulnar deviation angles, respectively. The results indicate that wrist kinematics during punching activities can be measured using an electromagnetic tracking system

Computational Approach to Dendritic Spine Taxonomy and Shape Transition Analysis

The common approach in morphological analysis of dendritic spines of mammalian neuronal cells is to categorize spines into subpopulations based on whether they are stubby, mushroom, thin, or filopodia shaped. The corresponding cellular models of synaptic plasticity, long-term potentiation, and long-term depression associate the synaptic strength with either spine enlargement or spine shrinkage. Although a variety of automatic spine segmentation and feature extraction methods were developed recently, no approaches allowing for an automatic and unbiased distinction between dendritic spine subpopulations and detailed computational models of spine behavior exist. We propose an automatic and statistically based method for the unsupervised construction of spine shape taxonomy based on arbitrary features. The taxonomy is then utilized in the newly introduced computational model of behavior, which relies on transitions between shapes. Models of different populations are compared using supplied bootstrap-based statistical tests. We compared two populations of spines at two time points. The first population was stimulated with long-term potentiation, and the other in the resting state was used as a control. The comparison of shape transition characteristics allowed us to identify the differences between population behaviors. Although some extreme changes were observed in the stimulated population, statistically significant differences were found only when whole models were compared. The source code of our software is freely available for non-commercial use1

Schwannoma-like pleomorphic adenoma of the parotid

Pleomorphic adenoma is the most common benign salivary gland tumour. It can occur in any salivary gland, but is most frequently found in the parotid gland. Chondroid metaplasia is a frequent finding in pleomorphic adenoma. Other forms of metaplasia have been described, but are encountered less frequently. We report a rare case of unusual pleomorphic adenoma of the parotid gland with schwannoma-like feature