Giant regular polyhedra from calixarene carboxylates and uranyl

Self-assembly of large multi-component systems is a common strategy for the bottom-up construction of discrete, well-defined, nanoscopic-sized cages. Icosahedral or pseudospherical viral capsids, built up from hundreds of identical proteins, constitute typical examples of the complexity attained by biological self-assembly. Chemical versions of the so-called 5 Platonic regular or 13 Archimedean semi-regular polyhedra are usually assembled combining molecular platforms with metals with commensurate coordination spheres. Here we report novel, self-assembled cages, using the conical-shaped carboxylic acid derivatives of calix[4]arene and calix[5]arene as ligands, and the uranyl cation UO22+ as a metallic counterpart, which coordinates with three carboxylates at the equatorial plane, giving rise to hexagonal bipyramidal architectures. As a result, octahedral and icosahedral anionic metallocages of nanoscopic dimensions are formed with an unusually small number of components

Generation of neutralizing antibodies and divergence of SIVmac239 in cynomolgus macaques following short-term early antiretroviral therapy.

Neutralizing antibodies (NAb) able to react to heterologous viruses are generated during natural HIV-1 infection in some individuals. Further knowledge is required in order to understand the factors contributing to induction of cross-reactive NAb responses. Here a well-established model of experimental pathogenic infection in cynomolgus macaques, which reproduces long-lasting HIV-1 infection, was used to study the NAb response as well as the viral evolution of the highly neutralization-resistant SIVmac239. Twelve animals were infected intravenously with SIVmac239. Antiretroviral therapy (ART) was initiated ten days post-inoculation and administered daily for four months. Viral load, CD4(+) T-cell counts, total IgG levels, and breadth as well as strength of NAb in plasma were compared simultaneously over 14 months. In addition, envs from plasma samples were sequenced at three time points in all animals in order to assess viral evolution. We report here that seven of the 12 animals controlled viremia to below 10(4) copies/ml of plasma after discontinuation of ART and that this control was associated with a low level of evolutionary divergence. Macaques that controlled viral load developed broader NAb responses early on. Furthermore, escape mutations, such as V67M and R751G, were identified in virus sequenced from all animals with uncontrolled viremia. Bayesian estimation of ancestral population genetic diversity (PGD) showed an increase in this value in non-controlling or transient-controlling animals during the first 5.5 months of infection, in contrast to virus-controlling animals. Similarly, non- or transient controllers displayed more positively-selected amino-acid substitutions. An early increase in PGD, resulting in the generation of positively-selected amino-acid substitutions, greater divergence and relative high viral load after ART withdrawal, may have contributed to the generation of potent NAb in several animals after SIVmac239 infection. However, early broad NAb responses correlated with relatively preserved CD4(+) T-cell numbers, low viral load and limited viral divergence

Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies.

CAPRISA, 2014.Antibodies capable of neutralizing HIV-1 often target variable regions 1 and 2 (V1V2) of the HIV-1 envelope, but the mechanism of their elicitation has been unclear. Here we define the developmental pathway by which such antibodies are generated and acquire the requisite molecular characteristics for neutralization. Twelve somatically related neutralizing antibodies (CAP256-VRC26.01-12) were isolated from donor CAP256 (from the Centre for the AIDS Programme of Research in South Africa (CAPRISA)); each antibody contained the protruding tyrosine-sulphated, anionic antigen-binding loop (complementarity-determining region (CDR) H3) characteristic of this category of antibodies. Their unmutated ancestor emerged between weeks 30-38 post-infection with a 35-residue CDR H3, and neutralized the virus that superinfected this individual 15 weeks after initial infection. Improved neutralization breadth and potency occurred by week 59 with modest affinity maturation, and was preceded by extensive diversification of the virus population. HIV-1 V1V2-directed neutralizing antibodies can thus develop relatively rapidly through initial selection of B cells with a long CDR H3, and limited subsequent somatic hypermutation. These data provide important insights relevant to HIV-1 vaccine development

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Ecology of Juvenile Salmon in Shallow Tidal Freshwater Habitats in the Vicinity of the Sandy River Delta, Lower Columbia River, 2008 Annual Report.

The tidal freshwater monitoring (TFM) project reported herein is part of the research, monitoring, and evaluation effort developed by the Action Agencies (Bonneville Power Administration, the U.S. Army Corps of Engineers [USACE], and the U.S. Bureau of Reclamation) in response to obligations arising from the Endangered Species Act (ESA) as a result of operation of the Federal Columbia River Power System. The project is being performed under the auspices of the Northwest Power and Conservation Council's Columbia Basin Fish and Wildlife Program (Project No. 2005-001-00). The research is a collaborative effort among the Pacific Northwest National Laboratory, the Oregon Department of Fish and Wildlife, the National Marine Fisheries Service, and the University of Washington. The overarching goal of the TFM project is to bridge the gap in knowledge between tidal freshwater habitats and the early life history attributes of migrating salmon. The research questions include: In what types of habitats within the tidal freshwater area of the Columbia River are juvenile salmon found, when are they present, and under what environmental conditions? What is the ecological contribution of shallow (0-5 m) tidal freshwater habitats to the recovery of ESA-listed salmon in the Columbia River basin? Field data collection for the TFM project commenced in June 2007 and since then has continued monthly at six to nine sites in the vicinity of the Sandy River delta (river kilometer 192-208). While this report includes summary data spanning the 19-month period of study from June 2007 through December 2008, it highlights sampling conducted during calendar year 2008. Detailed data for calendar year 2007 were reported previously. The 2008 research objectives were as follows: (1) Characterize the vegetation composition and percent cover, conventional water quality, water surface elevation, substrate composition, bathymetry, and beach slope at the study sites within the vicinity of the Sandy River delta. (2) Characterize the fish community and juvenile salmon migration, including species composition, length-frequency distribution, density (number/m{sup 2}), and temporal and spatial distributions in the vicinity of the Sandy River delta in the lower Columbia River and estuary (LCRE). (3) Determine the stock of origin for juvenile Chinook salmon (Oncorhynchus tshawytscha) captured at sampling sites through genetic identification. (4) Characterize the diets of juvenile Chinook and coho (O. kisutch) salmon captured within the study area. (5) Estimate run timing, residence times, and migration pathways for acoustic-tagged fish in the study area. (6) Conduct a baseline evaluation of the potential restoration to reconnect the old Sandy River channel with the delta. (7) Apply fish density data to initiate a design for a juvenile salmon monitoring program for beach habitats within the tidal freshwater segment of the LCRE (river kilometer 56-234)

On the Origin of Asymmetric Interactions between Permeant Anions and the Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Pore

Single channel and macroscopic current recording was used to investigate block of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(−) channel pore by the permeant anion [Formula: see text]. Block was 1–2 orders of magnitude stronger when [Formula: see text] was added to the intracellular versus the extracellular solution, depending on membrane potential. A point mutation within the pore, T-338A, strongly decreased the asymmetry of block, by weakening block by intracellular [Formula: see text] and at the same time strengthening block by external [Formula: see text]. Block of T-338A, but not wild-type, was strongest at the current reversal potential and weakened by either depolarization or hyperpolarization. In contrast to these effects, the T-338A mutation had no impact on block by the impermeant [Formula: see text] ion. We suggest that the CFTR pore has at least two anion binding sites at which [Formula: see text] and [Formula: see text] block Cl(−) permeation. The T-338A mutation decreases a barrier for [Formula: see text] movement between different sites, leading to significant changes in its blocking action. Our finding that apparent blocker binding affinity can be altered by mutagenesis of a residue which does not contribute to a blocker binding site has important implications for interpreting the effects of mutagenesis on channel blocker effects