Treatment outcomes of patients on Second-line Antiretroviral Therapy in resource-limited settings: A Systematic Review and Meta-Analysis

A growing proportion of patients on antiretroviral therapy in resource-limited settings have switched to second-line regimens. We carried out a systematic review in order to summarize reported rates and reasons for virological failure among people on second-line therapy in resource-limited settings

Key Role of Polyphosphoinositides in Dynamics of Fusogenic Nuclear Membrane Vesicles

The role of phosphoinositides has been thoroughly described in many signalling and membrane trafficking events but their function as modulators of membrane structure and dynamics in membrane fusion has not been investigated. We have reconstructed models that mimic the composition of nuclear envelope precursor membranes with naturally elevated amounts of phosphoinositides. These fusogenic membranes (membrane vesicle 1(MV1) and nuclear envelope remnants (NER) are critical for the assembly of the nuclear envelope. Phospholipids, cholesterol, and polyphosphoinositides, with polyunsaturated fatty acid chains that were identified in the natural nuclear membranes by lipid mass spectrometry, have been used to reconstruct complex model membranes mimicking nuclear envelope precursor membranes. Structural and dynamic events occurring in the membrane core and at the membrane surface were monitored by solid-state deuterium and phosphorus NMR. “MV1-like” (PC∶PI∶PIP∶PIP2, 30∶20∶18∶12, mol%) membranes that exhibited high levels of PtdIns, PtdInsP and PtdInsP2 had an unusually fluid membrane core (up to 20% increase, compared to membranes with low amounts of phosphoinositides to mimic the endoplasmic reticulum). “NER-like” (PC∶CH∶PI∶PIP∶PIP2, 28∶42∶16∶7∶7, mol%) membranes containing high amounts of both cholesterol and phosphoinositides exhibited liquid-ordered phase properties, but with markedly lower rigidity (10–15% decrease). Phosphoinositides are the first lipids reported to counterbalance the ordering effect of cholesterol. At the membrane surface, phosphoinositides control the orientation dynamics of other lipids in the model membranes, while remaining unchanged themselves. This is an important finding as it provides unprecedented mechanistic insight into the role of phosphoinositides in membrane dynamics. Biological implications of our findings and a model describing the roles of fusogenic membrane vesicles are proposed

Stretch-Activated Piezo1 Channel in Endothelial Cells Relaxes Mouse Intrapulmonary Arteries

In intrapulmonary artery (IPA), endothelial cells (EC) respond to mechanical stimuli by releasing vasoactive factors to set the vascular tone. Piezo1, a stretch-activated calcium permeable channel is a sensor of mechanical stress in EC. The present study was undertaken to investigate the implication of Piezo1 in the endothelium-dependent regulation of IPA tone and its potential involvement in pulmonary hypertension, the main disease of this circulation. IPA tone was quantified by means of a myograph in control Piezo1+/+ mouse and in mouse lacking endothelial Piezo1 (EC-Piezo1-/-). Endothelial intracellular calcium concentration ([Ca2+]i) and nitric oxide (NO) production were measured, in mouse or human EC, with fluo-4 and DAF-fm probes, respectively. Immunofluorescence labeling and patch-clamp experiments revealed the presence of Piezo1 channels in EC. Yoda1, a Piezo1 agonist, induced an endothelium-dependent relaxation that was significantly reduced in pulmonary arteries in EC-Piezo1-/- compared to Piezo1+/+ mouse. Yoda1 as well as mechanical stimulation (by osmotic stress) increased [Ca2+]i in mouse or human EC. Consequently, both stimuli increased the production of NO. NO and [Ca2+]i increases were reduced in EC from Piezo1-/- mouse or in the presence of Piezo1 inhibitors. Furthermore, deletion of Piezo1 increased alpha-adrenergic mediated contraction. Finally, in chronically hypoxic mice, a model of pulmonary hypertension, Piezo1 still mediated arterial relaxation and deletion of this channel did not impair the development of the disease. The present study thus demonstrates that endothelial Piezo1 contributes to intrapulmonary vascular relaxation by controlling endothelial [Ca2+]i and NO production and that this effect is still present in pulmonary hypertension

1-D-ice flow modelling at EPICA Dome C and Dome Fuji, East Antarctica

One-dimensional (1-D) ice flow models are used to construct the age scales at the Dome C and Dome Fuji drilling sites (East Antarctica). The poorly constrained glaciological parameters at each site are recovered by fitting independent age markers identified within each core. We reconstruct past accumulation rates, that are larger than those modelled using the classical vapour saturation pressure relationship during glacial periods by up to a factor 1.5. During the Early Holocene, changes in reconstructed accumulation are not linearly related to changes in ice isotopic composition. A simple model of past elevation changes is developed and shows an amplitude variation of 110–120 m at both sites. We suggest that there is basal melting at Dome C (0.56±0.19 mm/yr). The reconstructed velocity profile is highly non-linear at both sites, which suggests complex ice flow effects. This induces a non-linear thinning function in both drilling sites, which is also characterized by bumps corresponding to variations in ice thickness with time