HIV-1 Envelope Conformation,Allostery, and Dynamics

The HIV-1 envelope glycoprotein (Env) mediates host cell fusion and is the primary target for HIV-1 vaccine design. The Env undergoes a series of functionally important conformational rearrangements upon engagement of its host cell receptor, CD4. As the sole target for broadly neutralizing antibodies, our understanding of these transitions plays a critical role in vaccine immunogen design. Here, we review available experimental data interrogating the HIV-1 Env conformation and detail computational efforts aimed at delineating the series of conformational changes connecting these rearrangements. These studies have provided a structural mapping of prefusion closed, open, and transition intermediate structures, the allosteric elements controlling rearrangements, and state-to-state transition dynamics. The combination of these investigations and innovations in molecular modeling set the stage for advanced studies examining rearrangements at greater spatial and temporal resolution.     

Impact of a high-density grid catheter on long-term outcomes for structural heart disease ventricular tachycardia ablation

Journal of Interventional Cardiac Electrophysiology - Substrate mapping has highlighted the importance of targeting diastolic conduction channels and late potentials during ventricular tachycardia...     

Psoas and paraspinous muscle index as a predictor of mortality in African American men with type 2 diabetes mellitus

Aim

Recent studies revealed a correlation between skeletal muscle mass index and density with longevity; these studies largely evaluated appendicular skeletal muscles in older Caucasians. This retrospective cohort study assessed the association between axial skeletal muscles size and density with survival in African Americans with type 2 diabetes mellitus.

The Cretaceous superchron geodynamo: observations near the tangent cylinder

If relationships exist between the frequency of geomagnetic reversals and the morphology, secular variation, and intensity of Earth's magnetic field, they should be best expressed during superchrons, intervals tens of millions of years long lacking reversals. Here we report paleomagnetic and paleointensity data from lavas of the Cretaceous Normal Polarity Superchron that formed at high latitudes near the tangent cylinder that surrounds the solid inner core. The time-averaged field recorded by these lavas is remarkably strong and stable. When combined with global results available from lower latitudes, these data define a time-averaged field that is overwhelmingly dominated by the axial dipole (octupole components are insignificant). These observations suggest that the basic features of the geomagnetic field are intrinsically related. Superchrons may reflect times when the nature of core-mantle boundary heat flux allows the geodynamo to operate at peak efficiency.     

Combined infection of Norwalk-like virus and verotoxin-producing bacteria associated with a gastroenteritis outbreak

Detection of multiple pathogens, particularly a combination of viruses and bacteria, is infrequently documented in outbreaks of gastroenteritis. This paper reports the presence of Norwalk-like virus (NLV) and enterohaemorrhagic verotoxin-producing Escherichia coli in one individual, and NLV and verotoxin-producing Aeromonas sobria in another individual, both part of a large gastroenteritis outbreak. The causes of gastroenteritis in such outbreaks may be more complex than previously thought.     

Atherogenic mononuclear cell recruitment is facilitated by oxidized lipoprotein-induced endothelial junctional adhesion molecule-A redistribution

Background

Junctional adhesion molecule (JAM-) A is a transmembrane protein expressed in many cell types and maintains junctional integrity in endothelial cells. Upon inflammatory stimulation, JAM-A relocates to the apical surface and might thereby facilitate the recruitment of leukocytes.

Objective

Although inflammatory JAM-A redistribution is an established process, further effort is required to understand its exact role in the transmigration of mononuclear cells, particularly under atherogenic conditions.

Methods

By the use of RNA interference and genetic deletion, the role of JAM-A in the transmigration of T cells and monocytes through aortic endothelial cells was investigated. JAM-A–localization and subsequent mononuclear cell rolling, adhesion and transmigration were explored during endothelial inflammation, induced by oxidized LDL or cytokines.

Results

RNA interference or genetic deletion of JAM-A in aortic endothelial cells resulted in a decreased transmigration of mononuclear cells. Treatment of the endothelial cells with oxLDL resulted in an increase of both permeability and apical JAM-A presentation, as shown by bead adhesion and confocal microscopy experiments. Redistribution of JAM-A resulted in an increased leukocyte adhesion and transmigration, which could be inhibited with antibodies against JAM-A or by lovastatin-treatment, but not with the peroxisome proliferator activated receptor gamma-agonist pioglitazone.

Conclusions

This study demonstrates that redistribution of JAM-A in endothelial cells after stimulation with pro-atherogenic oxidized lipoproteins results in increased transmigration of mononuclear cells. This inflammatory dispersal of JAM-A could be counteracted with statins, revealing a novel aspect of their mechanism of action.