Illuminating the functional and structural repertoire of human TBC/RABGAPs.

The Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins (TBC/RABGAPs) are characterized by the presence of highly conserved TBC domains and act as negative regulators of RABs. The importance of TBC/RABGAPs in the regulation of specific intracellular trafficking routes is now emerging, as is their role in different diseases. Importantly, TBC/RABGAPs act as key regulatory nodes, integrating signalling between RABs and other small GTPases and ensuring the appropriate retrieval, transport and delivery of different intracellular vesicles.

IL-6 Trans-signaling Controls Liver Regeneration After Partial Hepatectomy.

Interleukin-6 (IL-6) is critically involved in liver regeneration after partial hepatectomy (PHX). Previous reports suggest that IL-6 trans-signaling through the soluble IL-6/IL-6R complex is involved in this process. However, the long-term contribution of IL-6 trans-signaling for liver regeneration after PHX is unknown. PHX-induced generation of the soluble IL-6R by ADAM (a disintegrin and metallo) proteases enables IL-6 trans-signaling, in which IL-6 forms an agonistic complex with the soluble IL-6 receptor (sIL-6R) to activate all cells expressing the signal-transducing receptor chain glycoprotein 130 (gp130). In contrast, without activation of ADAM proteases, IL-6 in complex with membrane-bound IL-6R and gp130 activates classic signaling. Here, we describe the generation of IL-6 trans-signaling mice, which exhibit boosted IL-6 trans-signaling and abrogated classic signaling by genetic conversion of all membrane-bound IL-6R into sIL-6R proteins phenocopying hyperactivation of ADAM-mediated shedding of IL-6R as single substrate. Importantly, although IL-6R deficient mice were strongly affected by PHX, survival and regeneration of IL-6 trans-signaling mice was indistinguishable from control mice, demonstrating that IL-6 trans-signaling fully compensates for disabled classic signaling in liver regeneration after PHX. Moreover, we monitored the long-term consequences of global IL-6 signaling inhibition versus IL-6 trans-signaling selective blockade after PHX by IL-6 monoclonal antibodies and soluble glycoprotein 130 as fragment crystallizable fusion, respectively. Both global IL-6 blockade and selective inhibition of IL-6 trans-signaling results in a strong decrease of overall survival after PHX, accompanied by decreased signal transducer and activator of transcription 3 phosphorylation and proliferation of hepatocytes. Mechanistically, IL-6 trans-signaling induces hepatocyte growth factor production by hepatic stellate cells. Conclusion: IL-6 trans-signaling, but not classic signaling, controls liver regeneration following PHX.

Finding acceptable parameter regions of stochastic Hill functions for multisite phosphorylation mechanism.

Multisite phosphorylation plays an important role in regulating switch-like protein activity and has been used widely in mathematical models. With the development of new experimental techniques and more molecular data, molecular phosphorylation processes emerge in many systems with increasing complexity and sizes. These developments call for simple yet valid stochastic models to describe various multisite phosphorylation processes, especially in large and complex biochemical networks. To reduce model complexity, this work aims at simplifying the multisite phosphorylation mechanism by a stochastic Hill function model. Furthermore, this work optimizes regions of parameter space to match simulation results from the stochastic Hill function with the distributive multisite phosphorylation process. While traditional parameter optimization methods have been focusing on finding the best parameter vector, in most circumstances, modelers would like to find a set of parameter vectors that generate similar system dynamics and results. This paper proposes a general α-ß-γ rule to return an acceptable parameter region of the stochastic Hill function based on a quasi-Newton stochastic optimization algorithm. Different objective functions are investigated characterizing different features of the simulation-based empirical data, among which the approximate maximum log-likelihood method is recommended for general applications. Numerical results demonstrate that with an appropriate parameter vector value, the stochastic Hill function model depicts the multisite phosphorylation process well except the initial (transient) period.

Influence of resistance training and herbal supplementation on plasma apelin and metabolic syndrome risk factors in postmenopausal women.

Purpose ­: Menopause is a normal condition that all women experience as they age. The aim of this study was to assess the effects of circuit resistance exercise training with Zataria multiflora (Avishan-e-Shirazi) dietary supplementation on plasma apelin, glucose, insulin, insulin sensitivity and insulin resistance. Methods ­: Ninety-six volunteer postmenopausal women were allocated into 8 groups. Resistance training consisted of 12 stations had been done for 8 weeks. Blood samples were collected at pre- and -post intervention. Results ­: Circuit RT increases apelin and decreases both insulin and blood glucose, whereas Zataria multiflora has no independent effect on apelin but does decrease blood glucose and is likely to be in some means synergistic with circuit RT effects. Conclusion ­: These results suggest that circuit resistance training augments plasma apelin and decreases both insulin and blood glucose. However, Zataria multiflora has no independent effect on apelin but does decrease blood glucose which is likely to be to some extent synergistic with training effects.

Objectif ­: La ménopause est une situation physiologique qui affecte toutes les femmes autour de la cinquantaine. Le but de cette étude était d'évaluer les effets d'un entraînement en résistance de type « circuit training ¼ avec supplémentation orale en Zataria multiflora (Avishan-e-Shirazi) sur l'apeline plasmatique, le glucose, l'insuline, la sensibilité à l'insuline et la résistance à l'insuline. Méthodologie ­: Quatre-vingt quatre femmes postménopausées bénévoles ont été réparties en 8 groupes. L'entraînement en circuit training comprenait 12 séances sur 8 semaines. Des échantillons sanguins ont été prélevés avant et après intervention. Résultats ­: Le circuit training augmente l'apeline et diminue à la fois l'insuline et la glycémie, alors que Zataria multiflora n'a pas d'effet indépendant sur l'apeline, mais diminue la glycémie et est semble synergique des effets du circuit training. Conclusion ­: Ces résultats suggèrent que le circuit training augmente l'apeline plasmatique et diminue insuline et glucose dans le sang. Cependant, Zataria multiflora n'a pas d'effet indépendant sur l'apeline mais fait diminuer la glycémie, ce qui est susceptible d'être dans une certaine mesure synergique avec les effets de l'entraînement.

The balance of interleukin (IL)-6, IL-6·soluble IL-6 receptor (sIL-6R), and IL-6·sIL-6R·sgp130 complexes allows simultaneous classic and trans-signaling.

Interleukin (IL-)6 is the major pro-inflammatory cytokine within the IL-6 family. IL-6 signals via glycoprotein 130 (gp130) and the membrane-bound or soluble IL-6 receptor (IL-6R), referred to as classic or trans-signaling, respectively. Whereas inflammation triggers IL-6 expression, eventually rising to nanogram/ml serum levels, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130) are constitutively present in the upper nanogram/ml range. Calculations based on intermolecular affinities have suggested that systemic IL-6 is immediately trapped in IL-6·sIL-6R and IL-6·sIL-6R·sgp130 complexes, indicating that sIL-6R and sgp130 constitute a buffer system that increases the serum half-life of IL-6 or restricts systemic IL-6 signaling. However, this scenario has not been experimentally validated. Here, we quantified IL-6·sIL-6R and IL-6·sIL-6R·sgp130 complexes over a wide concentration range. The amounts of IL-6 used in this study reflect concentrations found during active inflammatory events. Our results indicated that most IL-6 is free and not complexed with sIL-6R or sgp130, indicating that the level of endogenous sgp130 in the bloodstream is not sufficient to block IL-6 trans-signaling via sIL-6R. Importantly, addition of the single-domain antibody VHH6, which specifically stabilizes IL-6·sIL-6R complexes but did not bind to IL-6 or sIL-6R alone, drove free IL-6 into IL-6·sIL-6R complexes and boosted trans-signaling but not classic signaling, demonstrating that endogenous sIL-6R has at least the potential to form complexes with IL-6. Our findings indicate that even though high concentrations of sIL-6R and sgp130 are present in human serum, the relative ratio of free IL-6 to IL-6·sIL-6R allows for simultaneous classic and trans-signaling.

Micromechanical modeling of rate-dependent behavior of Connective tissues.

In this paper, a constitutive and micromechanical model for prediction of rate-dependent behavior of connective tissues (CTs) is presented. Connective tissues are considered as nonlinear viscoelastic material. The rate-dependent behavior of CTs is incorporated into model using the well-known quasi-linear viscoelasticity (QLV) theory. A planar wavy representative volume element (RVE) is considered based on the tissue microstructure histological evidences. The presented model parameters are identified based on the available experiments in the literature. The presented constitutive model introduced to ABAQUS by means of UMAT subroutine. Results show that, monotonic uniaxial test predictions of the presented model at different strain rates for rat tail tendon (RTT) and human patellar tendon (HPT) are in good agreement with experimental data. Results of incremental stress-relaxation test are also presented to investigate both instantaneous and viscoelastic behavior of connective tissues.

Specific mosaic KRAS mutations affecting codon 146 cause oculoectodermal syndrome and encephalocraniocutaneous lipomatosis.

Oculoectodermal syndrome (OES) and encephalocraniocutaneous lipomatosis (ECCL) are rare disorders that share many common features, such as epibulbar dermoids, aplasia cutis congenita, pigmentary changes following Blaschko lines, bony tumor-like lesions, and others. About 20 cases with OES and more than 50 patients with ECCL have been reported. Both diseases were proposed to represent mosaic disorders, but only very recently whole-genome sequencing has led to the identification of somatic KRAS mutations, p.Leu19Phe and p.Gly13Asp, in affected tissue from two individuals with OES. Here we report the results of molecular genetic studies in three patients with OES and one with ECCL. In all four cases, Sanger sequencing of the KRAS gene in DNA from lesional tissue detected mutations affecting codon 146 (p.Ala146Val, p.Ala146Thr) at variable levels of mosaicism. Our findings thus corroborate the evidence of OES being a mosaic RASopathy and confirm the common etiology of OES and ECCL. KRAS codon 146 mutations, as well as the previously reported OES-associated alterations, are known oncogenic KRAS mutations with distinct functional consequences. Considering the phenotype and genotype spectrum of mosaic RASopathies, these findings suggest that the wide phenotypic variability does not only depend on the tissue distribution but also on the specific genotype.

The relationship between playing computer or video games with mental health and social relationships among students in guidance schools, Kermanshah.

Computer or video games are a popular recreational activity and playing them may constitute a large part of leisure time. This cross-sectional study aimed to evaluate the relationship between playing computer or video games with mental health and social relationships among students in guidance schools in Kermanshah, Islamic Republic of Iran, in 2012. Our total sample was 573 students and our tool was the General Health Questionnaire (GHQ-28) and social relationships questionnaires. Survey respondents reported spending an average of 71.07 (SD 72.1) min/day on computer or video games. There was a significant relationship between time spent playing games and general mental health (P < 0.04) and depression (P < 0.03). There was also a significant difference between playing and not playing computer or video games with social relationships and their subscales, including trans-local relationships (P < 0.0001) and association relationships (P < 0.01) among all participants. There was also a significant relationship between social relationships and time spent playing games (P < 0.02) and its dimensions, except for family relationships.

Numerical simulation of nanoneedle-cell membrane collision: minimum magnetic force and initial kinetic energy for penetration.

Aims and objectives: This research aims to develop a kinetic model that accurately captures the dynamics of nanoparticle impact and penetration into cell membranes, specifically in magnetically-driven drug delivery. The primary objective is to determine the minimum initial kinetic energy and constant external magnetic force necessary for successful penetration of the cell membrane.Model Development: Built upon our previous research on quasi-static nanoneedle penetration, the current model development is based on continuum mechanics. The modeling approach incorporates a finite element method and explicit dynamic solver to accurately represent the rapid dynamics involved in the phenomenon. Within the model, the cell is modeled as an isotropic elastic shell with a hemiellipsoidal geometry and a thickness of 200 nm, reflecting the properties of the lipid membrane and actin cortex. The surrounding cytoplasm is treated as a fluid-like Eulerian body.Scenarios and Results: This study explores three distinct scenarios to investigate the penetration of nanoneedles into cell membranes. Firstly, we examine two scenarios in which the particles are solely subjected to either a constant external force or an initial velocity. Secondly, we explore a scenario that considers the combined effects of both parameters simultaneously. In each scenario, we analyze the critical values required to induce membrane puncture and present comprehensive diagrams illustrating the results.Findings and significance: The findings of this research provide valuable insights into the mechanics of nanoneedle penetration into cell membranes and offer guidelines for optimizing magnetically-driven drug delivery systems, supporting the design of efficient and targeted drug delivery strategies.

Experimental and numerical investigation of waterjet interaction with liver in connection with surgical technique.

Hepatectomy, or liver resection, is a process by which through surgery part or all of the liver is removed. In this operation, less bleeding, negligible damage and fast removal are the most important requirements. Surgery through waterjet is one of the most efficient techniques which is widely used in hepatectomy. Some clinical studies are conducted to investigate waterjet method in liver resection. In the present study interaction of waterjet with liver during the process of the surgery is investigated in terms of mechanical engineering. For this purpose, a system of waterjet is designed to consider the interaction of waterjet with liver at different nozzle diameter and velocities. For validation, SPH-FEM model is used to analyze waterjet interaction with hyperelastic liver. In this model, liver cutting is simulated using element deletion defined by a subroutine code based on maximum principal strain criterion. Depth of cut along with degraded volume are measured experimentally and compared with simulated method. Results show that good agreement exists between experimental and simulation finding. By comparing depth of cut in the experimental and simulation results, it can be seen that liver behavior changes from brittle to ductile by increasing waterjet velocity during the experimental tests. For the simulation, maximum principal strain threshold is set to be between 0.1 and 0.4. However, the best agreement between experimental and simulation results exists at maximum principal strain threshold equal to 0.2. The findings can help surgeons to find the best working range of waterjet device and the most efficient operation.