Direct effects of dominant winds on residence and travel times in the wide and open lacustrine embayment: Vidy Bay (Lake Geneva, Switzerland)

Numerical simulations were carried out to determine the residence (or flushing) time of water in Vidy Bay (north shore of Lake Geneva) for different meteorological conditions. A hydrodynamic model (Delft3D-FLOW) was applied to simulate the flow field in the embayment during 2010 and January 2011. Using these results, particle tracking was applied to estimate transport of wastewater effluent discharged into the embayment. The model predictions compared well with published field measurements of dissolved species (as given by electrical conductivity profiles) within the wastewater. The pelagic boundary of the embayment was defined by the largest within-bay gyre. Based on this definition, particle tracking was used to quantify the residence time under dominant wind conditions. Similarly, particle tracking was used to determine the travel time (i.e., time to exit the embayment) for each of Vidy Bay's three inflows (stream, stormwater and wastewater effluent). Although the wind field over the lake is variable, current patterns in the embayment can be simulated using the hydrodynamic model forced by a spatially uniform wind field. For a given wind speed, the main factor influencing residence and travel times is the wind angle. The presence of gyres leads to high mean residence times with large variability. As the wind direction becomes more aligned with the shoreline (i.e., with increasing westerly or easterly components), longshore currents dominate. These disrupt gyre formation and markedly reduce the mean and variability of embayment residence time. The numerical model was utilized to assess the potential for plume movement (in plan) from above the wastewater effluent outfall towards one of Lausanne's drinking water intakes. In the most direct pathway, westward longshore currents can move water from the embayment to the water column above the intake location

Alzheimer's disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production

Pathological amino-acid substitutions in the amyloid precursor protein (APP) and chemical gamma-secretase modulators affect the processing of APP by the gamma-secretase complex and the production of the amyloid-beta peptide A beta 42, the accumulation of which is considered causative of Alzheimer's disease. Here we demonstrate that mutations in the transmembrane domain of APP causing aggressive early-onset familial Alzheimer's disease affect both gamma- and epsilon-cleavage sites, by raising the A beta 42/40 ratio and inhibiting the production of AICD50-99, one of the two physiological APP intracellular domains (ICDs). This is in sharp contrast to gamma- secretase modulators, which shift A beta 42 production towards the shorter A beta 38, but unequivocally spare the epsilon-site and APP- and Notch-ICDs production. Molecular simulations suggest that familial Alzheimer's disease mutations modulate the flexibility of the APP transmembrane domain and the presentation of its gamma- site, modifying at the same time, the solvation of the epsilon-site

Anti-infectives in Drug Delivery-Overcoming the Gram-Negative Bacterial Cell Envelope.

Infectious diseases are becoming a major menace to the state of health worldwide, with difficulties in effective treatment especially of nosocomial infections caused by Gram-negative bacteria being increasingly reported. Inadequate permeation of anti-infectives into or across the Gram-negative bacterial cell envelope, due to its intrinsic barrier function as well as barrier enhancement mediated by resistance mechanisms, can be identified as one of the major reasons for insufficient therapeutic effects. Several in vitro, in silico, and in cellulo models are currently employed to increase the knowledge of anti-infective transport processes into or across the bacterial cell envelope; however, all such models exhibit drawbacks or have limitations with respect to the information they are able to provide. Thus, new approaches which allow for more comprehensive characterization of anti-infective permeation processes (and as such, would be usable as screening methods in early drug discovery and development) are desperately needed. Furthermore, delivery methods or technologies capable of enhancing anti-infective permeation into or across the bacterial cell envelope are required. In this respect, particle-based carrier systems have already been shown to provide the opportunity to overcome compound-related difficulties and allow for targeted delivery. In addition, formulations combining efflux pump inhibitors or antimicrobial peptides with anti-infectives show promise in the restoration of antibiotic activity in resistant bacterial strains. Despite considerable progress in this field however, the design of carriers to specifically enhance transport across the bacterial envelope or to target difficult-to-treat (e.g., intracellular) infections remains an urgently needed area of improvement. What follows is a summary and evaluation of the state of the art of both bacterial permeation models and advanced anti-infective formulation strategies, together with an outlook for future directions in these fields

Structural rearrangements maintain the Glycan Shield of an HIV-1 envelope trimer after the loss of a glycan

The HIV-1 envelope (Env) glycoprotein is the primary target of the humoral immune response and a critical vaccine candidate. However, Env is densely glycosylated and thereby substantially protected from neutralisation. Importantly, glycan N301 shields V3 loop and CD4 binding site epitopes from neutralising antibodies. Here, we use molecular dynamics techniques to evaluate the structural rearrangements that maintain the protective qualities of the glycan shield after the loss of glycan N301. We examined a naturally occurring subtype C isolate and its N301A mutant; the mutant not only remained protected against neutralising antibodies targeting underlying epitopes, but also exhibited an increased resistance to the VRC01 class of broadly neutralising antibodies. Analysis of this mutant revealed several glycans that were responsible, independently or through synergy, for the neutralisation resistance of the mutant. These data provide detailed insight into the glycan shield’s ability to compensate for the loss of a glycan, as well as the cascade of glycan movements on a protomer, starting at the point mutation, that affects the integrity of an antibody epitope located at the edge of the diminishing effect. These results present key, previously overlooked, considerations for HIV-1 Env glycan research and related vaccine studies.IS