Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis

Signalling pathways that control endothelial cell (EC) permeability, leukocyte adhesion and inflammation are pivotal for atherosclerosis initiation and progression. Here we demonstrate that the Sterile-20-like mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), which has been implicated in inflammation, is abundantly expressed in ECs and in atherosclerotic plaques from mice and humans. On the basis of endothelial-specific MAP4K4 gene silencing and gene ablation experiments in Apoe(-/-) mice, we show that MAP4K4 in ECs markedly promotes Western diet-induced aortic macrophage accumulation and atherosclerotic plaque development. Treatment of Apoe(-/-) and Ldlr(-/-) mice with a selective small-molecule MAP4K4 inhibitor also markedly reduces atherosclerotic lesion area. MAP4K4 silencing in cultured ECs attenuates cell surface adhesion molecule expression while reducing nuclear localization and activity of NFkappaB, which is critical for promoting EC activation and atherosclerosis. Taken together, these results reveal that MAP4K4 is a key signalling node that promotes immune cell recruitment in atherosclerosis

Lead-like Drugs: A Perspective

Lead-like drugs, or drugs below molecular weight 300, are an important and sometimes overlooked component of the current pharmacopeia and contemporary medicinal chemistry practice. To examine the recent state-of-the-art in lead-like drug discovery, we surveyed recent drug approvals from 2011 to 2017 and top 200 prescribed medications, as well as provide case studies on recently approved lead-like drugs. Many of these recent drugs are close analogs of previously known drugs or natural substrates, with a key focus of their medicinal chemistry optimization being the choice of a low molecular weight starting point and maintaining low molecular weight during the optimization. However, the identification of low molecular weight starting points may be limited by the availability of suitable low molecular weight screening sets. To increase the discovery rate of lead-like drugs, we suggest an increased focus on inclusion and prosecution of lead-like starting points in screening libraries

Development of nano-porous hydroxyapatite coated e-glass for potential bone-tissue engineering application: An in vitro approach

To reconstruct the defects caused by craniectomies autologous, bone grafting was usually used, but they failed most commonly due to bone resorption, infections and donor-site morbidity. In the present investigation, an effort has been made for the first time to check the feasibility and advantage of using hydroxyapatite (HAp) coated e-glass as component of bone implants. Sol-gel synthesized coatings were found to be purely hydroxyapatite from XRD with graded and interconnected pores all over the surface observable in TEM. The interconnected porous nature of ceramics are found to increase bioactivity by acting to up-regulate the process of osseointegration through enhanced nutrient transfer and induction of angiogenesis. From TEM studies and nano indentation studies, we have shown that pores were considered to be appropriate for nutrient supply without compromising the strength of sample while in contact with physiological fluid. After SBF immersion test, porous surface was found to be useful for nucleation of apatite crystals, hence increasing the feasibility and bioactivity of sample. However, our quasi-dynamic study showed less crystallization but had significant formation of apatite layer. Overall, the in vitro analyses show that HAp coated e-glass leads to significant improvement of implant properties in terms of biocompatibility, cell viability and proliferation, osteoinductivity and osteoconductivity. HAp coating of e-glass can potentially be utilized in fabricating durable and strong bioactive non-metallic implants and tissue engineering scaffolds

Levels in doubly odd

The band structures of the doubly odd 138Pr nucleus have been investigated using the 128Te(14N, 4n)138Pr reaction at a beam energy of 55-65 MeV. Altogether six distinct structures have been established, of which the lower part of the yrast band and two side bands were known from earlier works. The observed level properties of the members of the yrast band have been compared with theoretical calculations performed within the Particle Rotor Model (PRM) with axially symmetric core. The experimental branching ratios and B(M1)/B(E2) values when compared with the theoretical results of the PRM, suggest an oblate core

MAP4K4 Is a Threonine Kinase That Phosphorylates FARP1

Mitogen-activated protein kinase 4 (MAP4K4) regulates the MEK kinase cascade and is implicated in cytoskeletal rearrangement and migration; however, identifying MAP4K4 substrates has remained a challenge. To ascertain MAP4K4-dependent phosphorylation events, we combined phosphoproteomic studies of MAP4K4 inhibition with <i>in vitro</i> assessment of its kinase specificity. We identified 235 phosphosites affected by MAP4K4 inhibition in cells and found that pTP and pSP motifs were predominant among them. In contrast, <i>in vitro</i> assessment of kinase specificity showed that MAP4K4 favors a pTL motif. We showed that MAP4K4 directly phosphorylates and coimmunoprecipitates with FERM, RhoGEF, and pleckstrin domain-containing protein 1 (FARP1). MAP4K4 inhibition in SH-SY5Y cells increases neurite outgrowth, a process known to involve FARP1. As FARP1 and MAP4K4 both contribute to cytoskeletal rearrangement, the results suggest that MAP4K4 exerts some of its effects on the cytoskeleton via phosphorylation of FARP1

La forêt

Collection : RadiovisionRésumé : Recouvrant un cinquième du territoire français, la forêt est composée de différentes espèces d'arbre. Le chêne, arbre le plus noble et le plus précieux qui peut vivre jusqu'à 800 ans, le hêtre et encore l'épicéa en montagne. La manière de cultiver la forêt est à repenser depuis que le bois n'est plus utilisé comme combustible. (source : Réseau Canopé)Durée : 00:29:20Thème : Sciences de la natur