Lipid-dependent conformational landscape of the ErbB2 growth factor receptor dimers

Altered lipid metabolism has been linked to cancer development and progression. Several roles have been attributed to the increased saturation and length of lipid acyl tails observed in tumors, but its effect on signaling receptors is still emerging. In this work, we have analyzed the lipid dependence of the ErbB2 growth factor receptor dimerization that plays an important role in the pathogenesis of breast cancer. We have performed coarse-grain ensemble molecular dynamics simulations to comprehensively sample the ErbB2 monomer-dimer association. Our results indicate a dynamic dimer state with a complex conformational landscape that is modulated with increasing lipid tail length. We resolve the native N-terminal "active" and C-terminal "inactive" conformations in all membrane compositions. However, the relative population of the N-terminal and C-terminal conformers is dependent on length of the saturated lipid tails. In short-tail membranes, additional non-specific dimers are observed which are reduced or absent in long-tailed bilayers. Our results indicate that the relative population as well as the structure of the dimer state is modulated by membrane composition. We have correlated these differences to local perturbations of the membrane around the receptor. Our work is an important step in characterizing ErbB dimers in healthy and diseased states and emphasize the importance of sampling lipid dynamics in understanding receptor association

A systematic review of preclinical animal studies on fenofibrate’s potential role in type 1 diabetic micro-vascular complications

Fenofibrate is a peroxisome-proliferator-activator α agonist and it is a widely used drug for hyperlipidemia since its approval in 2004. So, in this review we are focusing on the effect of fenofibric acid’s mechanism to alleviate type 1 diabetic micro vascular complications like diabetic retinopathy, diabetic cardiomyopathy in animal models, since the drug is safe, efficacious and more economical when compared with the currently available treatment strategies for juvenile diabetic complications and also a profound observation is needed due to the rarity of research in these therapeutic areas. Important preclinical animal studies published from January 2001 to June 2020 were recognised from databases like PubMed and Cochrane central register of controlled trials. Reviewers screened the articles based on the selection criteria and risk of bias was determined using Systematic Review Centre for Laboratory animal Experimentation risk of bias tool for animal studies. Our literature search yielded a total of 5 studies and after pooling up the data from the 5 preclinical studies, we found that Fenofibrate have the efficacy to prevent type 1 diabetic complications, chiefly diabetic retinopathy and those mechanisms are dependent on peroxisome-proliferator-activator and fibroblast growth factor-21 pathways. Fenofibrate is a well safe and moreover, cost effective medication in preventing type 1 diabetic micro vascular complications especially diabetic retinopathy and also in maintaining the glucose homeostasis in apart from its anti-dyslipidemic effect

Thermodynamic and kinetic characterization of transmembrane helix association

The transient dimerization of transmembrane proteins is an important event in several cellular processes and computational methods are being increasingly used to quantify their underlying energetics. Here, we probe the thermodynamics and kinetics of a simple transmembrane dimer to understand membrane protein association. A multi-step framework has been developed in which the dimerization profiles are calculated from coarse-grain molecular dynamics simulations, followed by meso-scale simulations using parameters calculated from the coarse-grain model. The calculated value of ΔGassoc is approx. −20 kJ mol−1 and is consistent between three methods. Interestingly, the meso-scale stochastic model reveals low dimer percentages at physiologically-relevant concentrations, despite a favorable ΔGassoc. We identify generic driving forces arising from the protein backbone and lipid bilayer and complementary factors, such as protein density, that govern self-interactions in membranes. Our results provide an important contribution in understanding membrane protein organization and linking molecular, nano-scale computational studies to meso-scale experimental data

Evaluation of changes in benthic standing stock and polychaete community structure along the south eastern Arabian Sea shelf during the monsoon trawl-ban

The south eastern Arabian Sea is characterized by moderate coastal upwelling, high biological production and subsurface oxygen depletion during the southwest monsoon(June–September). Concurrently,a seasonal closure to trawling activities(15th June–31st July)is implemented here,as a sustainable ecosystem management practise. The effects of monsoon driven environmental changes and consequences of trawling cessation on macrofauna were assessed, based on surveys at 12 sites(30–200m)preceding and during different phases of the southwest monsoon. Macrofaunal density and biomass increased considerably towards the mid and late monsoon along the inner shelf(30–50 m)where trawling is in- tense, while no temporal changes were observed along the outer shelf(100–200m).Density increased four-folds at the 30m contour and three-folds at 50m, while biomass nearly doubled at both depths,reflecting a marked increase in density of polychaetes(61–87% of macrofauna). The disproportionate increase in faunal density and biomass along the inner shelf(30–50 m) was due to abundance of juvenile polychaetes and dominance of small-sized opportunists towards late monsoon(August–September).A concurrent hike in nominal species count of polychaetes was also observed in the study area. The increase in polychaete standing stock and high density of planktonic larvaed uring onset and peak monsoon, coupled with occurrence of juveniles as well as gamete-bearing adults in sediments,indicates that the southwest monsoon is a peak breeding season for the dominant polychaetes in the region. The trawl-ban during this period facilitates the recoupment of benthos by maximising spawning success and larval settlement, thereby enhancing overall ecosystem integrity