Antiretroviral therapies

We describe an algorithm which enables us to search the conformational space of the side chains of a protein to identify the global minimum energy combination of side chain conformations as well as all other conformations within a specified energy cutoff of the global energy minimum. The program is used to explore the side chain conformational energy surface of a number of proteins, to investigate how this surface varies with the energy model used to describe the interactions within the system and the rotamer library. Enumeration of the rotamer combinations enables us to directly evaluate the partition function, and thus calculate the side chain contribution to the conformational entropy of the folded protein. An investigation of these conformations and the relationships between them shows that most of the conformations near to the global energy minimum arise from changes in side chain conformations that are essentially independent; very few result from a concerted change in conformation of two or more residues. Some of the limitations of the approach are discussed.     

Structural analysis of substrate binding by the molecular chaperone DnaK

DnaK and other members of the 70-kilodalton heat-shock protein (hsp70) family promote protein folding, interaction, and translocation, both constitutively and in response to stress, by binding to unfolded polypeptide segments. These proteins have two functional units: a substrate-binding portion binds the polypeptide, and an adenosine triphosphatase portion facilitates substrate exchange. The crystal structure of a peptide complex with the substrate-binding unit of DnaK has now been determined at 2.0 angstroms resolution. The structure consists of a beta-sandwich subdomain followed by alpha-helical segments. The peptide is bound to DnaK in an extended conformation through a channel defined by loops from the beta sandwich. An alpha-helical domain stabilizes the complex, but does not contact the peptide directly. This domain is rotated in the molecules of a second crystal lattice, which suggests a model of conformation-dependent substrate binding that features a latch mechanism for maintaining long lifetime complexes.     

Long-term inhalable particles and other air pollutants related to mortality in nonsmokers

Long-term ambient concentrations of inhalable particles less than 10 microm in diameter (PM10) (1973- 1992) and other air pollutants-total suspended sulfates, sulfur dioxide, ozone (O3), and nitrogen dioxide-were related to 1977-1992 mortality in a cohort of 6,338 nonsmoking California Seventh-day Adventists. In both sexes, PM10 showed a strong association with mortality for any mention of nonmalignant respiratory disease on the death certificate, adjusting for a wide range of potentially confounding factors, including occupational and indoor sources of air pollutants. The adjusted relative risk (RR) for this cause of death as associated with an interquartile range (IQR) difference of 43 d/yr when PM10 exceeded 100 microg/m3 was 1.18 (95% confidence interval [CI]: 1.02, 1.36). In males, PM10 showed a strong association with lung cancer deaths-RR for an IQR was 2.38 (95% CI: 1.42, 3.97). Ozone showed an even stronger association with lung cancer mortality for males with an RR of 4.19 (95% CI: 1.81, 9.69) for the IQR difference of 551 h/yr when O3 exceeded 100 parts per billion. Sulfur dioxide showed strong associations with lung cancer mortality for both sexes. Other pollutants showed weak or no association with mortality.     

In vitro gas production profiles and fermentation end‐products in processed peas,lupins and faba beans

BACKGROUND: An experiment was carried out to establish whether using a pre‐compacting device (expander) changes the contribution of dry matter (DM) and degradative behaviour of peas, lupins and faba beans over the different fractions (non‐washable fraction, NWF; insoluble washable fraction, ISWF; soluble washable fraction, SWF). Samples of the entire concentrate ingredients (WHO ingredients) and their different fractions (NWF, ISWF and SWF) were subjected to three processes (Retsch milling, R; expander treatment, E; expander‐pelleting, EP) and their fermentation characteristics were evaluated using an in vitro gas production technique. RESULTS: In peas and faba beans, both the E and EP processes increased the size of the NWF (P < 0.05) and decreased the size of the SWF compared with the R process. The maximum fractional rate of gas production in the first phase of fermentation was higher in the E and EP samples than in the R samples (P < 0.05). In lupins and faba beans the E and EP processes shifted the pattern of fermentation towards a more glucogenic fermentation, as represented by a lower non‐glucogenic to glucogenic ratio (NGR). Ammonia production (NH₃‐N) in the E and EP samples was significantly (P < 0.05) lower than that in the R samples. CONCLUSION: It is concluded that the E and EP processes provide a certain level of protection against ruminal breakdown to dietary protein and shift the pattern of fermentation towards a more glucogenic fermentation. Copyright © 2008 Society of Chemical Industry