OBJECTIVETo investigate whether circulating levels of fibroblast growth factor 21 (FGF21), which previously has been shown to be elevated in obesity, could predict the development of type 2 diabetes in a 5.4-year, population-based, prospective study.RESEARCH DESIGN AND METHODSBaseline plasma FGF21 levels were measured using an enzyme-linked immunosorbent assay in 1,900 subjects from the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS). The prospective association of FGF21 with diabetes development over 5.4 years was analyzed using multiple logistic regression.RESULTSAt baseline, plasma levels of FGF21 increased progressively with worsening dysglycemia from normal glucose tolerance, through prediabetes, to diabetes (global trend, P < 0.001). Of 1,292 subjects without diabetes at baseline, a high baseline FGF21 level was a strong independent predictor for diabetes development (odds ratio 1.792; P < 0.01), together with waist circumference and fasting plasma glucose levels.CONCLUSIONSPlasma FGF21 levels were significantly increased in subjects with prediabetes and diabetes and predicted the development of diabetes in humans.

During meiosis, the Msh4-Msh5 complex is thought to stabilize single-end invasion intermediates that form during early stages of recombination and subsequently bind to Holliday junctions to facilitate crossover formation. To analyze Msh4-Msh5 function, we mutagenized 57 residues in Saccharomyces cerevisiae Msh4 and Msh5 that are either conserved across all Msh4/5 family members or are specific to Msh4 and Msh5. The Msh5 subunit appeared more sensitive to mutagenesis. We identified msh4 and msh5 threshold (msh4/5-t) mutants that showed wild-type spore viability and crossover interference but displayed, compared to wild-type, up to a two-fold decrease in crossing over on large and medium sized chromosomes (XV, VII, VIII). Crossing over on a small chromosome, however, approached wild-type levels. The msh4/5-t mutants also displayed synaptonemal complex assembly defects. A triple mutant containing a msh4/5-t allele and mutations that decreased meiotic double-strand break levels (spo11-HA) and crossover interference (pch2Δ) showed synergistic defects in spore viability. Together these results indicate that the baker's yeast meiotic cell does not require the ∼90 crossovers maintained by crossover homeostasis to form viable spores. They also show that Pch2-mediated crossover interference is important to maintain meiotic viability when crossovers become limiting.

Hypertension is a major risk factor of cardiovascular disease in China, and yet little is known about health-related quality of life (HRQOL) and its associations with demographic and social-economic characteristics in middle-aged patients with hypertension. A cross-sectional survey was undertaken in Chongqing, China, using a multistage stratified random sampling methodology. Data was collected on 1,224 eligible adults, aged between 45 and 53 years, including the Medical Outcomes Survey Short Form-36 to measure HRQOL. Hypertension was associated with poor state of physical functioning, role-physical, bodily pain, general health, vitality, and social function (p < 0.05 for all). In multivariable analyses, education level, job conditions, average monthly income, smoking status, sleep quality, perception of relationship with family, childhood breastfeeding history, and body mass index were associated with domains of SF36 among those with hypertension (p < 0.05 for all). Hypertensive respondents with high education, marital status, breastfeeding, higher incomes, good quality of sleep, positive relationship with family, and higher body mass index have better HRQOL in middle-aged people with hypertension. Those unemployed had a better state of general health and had a poorer state of social function. Nonsmokers had a poorer state of bodily pain than smokers. This study provides detailed information of the implications for health care providers to gain a more complete picture of their hypertension patients' health.

Sifuvirtide, a novel fusion inhibitor against human immunodeficiency virus type I (HIV-1), which is more potent than enfuvirtide (T20) in cell culture, is currently under clinical investigation for the treatment of HIV-1 infection. We now report that in vitro selection of HIV-1 variants resistant to sifuvirtide in the presence of increasing concentrations of sifuvirtide has led to several specific mutations in the gp41 region that had not been previously reported. Many of these substitutions were confined to the N-terminal heptad repeat region at positions 37, 38, 41, and 43, either singly or in combination. A downstream substitution at position 126 (N126K) in the Cterminal heptad repeat region was also found. Site-directed mutagenesis studies have further identified the critical amino acid substitutions and combinations thereof in conferring the resistant genotypes. Furthermore, the mutant viruses demonstrated variable degrees of cross-resistance to enfuvirtide, some of which are preferentially more resistant to sifuvirtide. Impaired infectivity was also found for many of the mutant viruses. Biophysical and structural analyses of the key substitutions have revealed several potential novel mechanisms against sifuvirtide. Our results may help to predict potential resistant patterns in vivo and facilitate the further clinical development and therapeutic utility of sifuvirtide.The envelope glycoprotein (Env) of HIV-1 is critical in mediating viral entry into the target cells, and it represents a major target for the development of novel antiretroviral therapeutics. The entry process starts with the binding of gp120 to a cellular receptor, CD4, and subsequently with a chemokine receptor, CCR5 or CXCR4, on the surface of the target cells (1). These interactions trigger a cascade of conformational changes that lead to the formation of a prehairpin intermediate of gp41 in which the hydrophobic N-terminal heptad repeat (NHR) 2 is exposed and allows the fusion peptides to insert into the target cell membrane (1, 2). This transient gp41 intermediate then refolds into a stabilized trimer of hairpins, also called the six-helix bundle (6-HB) structure, which brings the viral envelope and the target cell membrane into close proximity, thus facilitating the completion of the fusion process (1-4). Structure and function studies indicate that the 6-HB core consists of a parallel trimeric coiled-coil of NHR with the C-terminal heptad repeat (CHR) wrapped on the outside in an antiparallel fashion (5-7). Similar features have been found in the fusion-mediating subunits of other viruses with class I membrane fusion proteins (8 -17).Inhibitors capable of disrupting the entry process hold great promise for improved efficacy of clinical antiviral therapeutics. Several entry inhibitors have been developed, and two of these have been approved for clinical use, such as a peptide-based inhibitor enfuvirtide (T20) and a small molecule inhibitor Maraviroc against HIV-1 co-receptor CCR5 (18 -20). In addition, several other entry inhibitors ar...