Design and Structure-Based Study of New Potential FKBP12 Inhibitors

AbstractBased on the structure of FKBP12 complexed with FK506 or rapamycin, with computer-aided design, two neurotrophic ligands, (3R)-4-(p-Toluenesulfonyl)-1,4-thiazane-3-carboxylic acid-L-Leucine ethyl ester and (3R)-4-(p-Toluenesulfonyl)-1,4-thiazane-3-carboxylic acid-L-phenylalanine benzyl ester, were designed and synthesized. Fluorescence experiments were used to detect the binding affinity between FKBP12 and these two ligands. Complex structures of FKBP12 with these two ligands were obtained by x-ray crystallography. In comparing FKBP12-rapamycin complex and FKBP12-FK506 complex as well as FKBP12-GPI-1046 solution structure with these new complexes, significant volume and surface area effects and obvious contact changes were detected which are expected to cause their different binding energies—showing these two novel ligands will become more effective neuron regeneration drugs than GPI-1046, which is currently undergoing phase II clinical trail as a neurotrophic drug. Analysis of volume and surface area effects also gives a new clue for structure-based drug design

Body Mass Index and Diabetes in Asia: A Cross-Sectional Pooled Analysis of 900,000 Individuals in the Asia Cohort Consortium

10.1371/journal.pone.0019930PLoS ONE66

Serological survey of human serum samples for the presence of antibodies against AIV H5N1.

<p>Serological survey of human serum samples for the presence of antibodies against AIV H5N1.</p

Investigation of Avian Influenza Infections in Wild Birds, Poultry and Humans in Eastern Dongting Lake, China

<div><p>We investigated avian influenza infections in wild birds, poultry, and humans at Eastern Dongting Lake, China. We analyzed 6,621 environmental samples, including fresh fecal and water samples, from wild birds and domestic ducks that were collected from the Eastern Dongting Lake area from November 2011 to April 2012. We also conducted two cross-sectional serological studies in November 2011 and April 2012, with 1,050 serum samples collected from people exposed to wild birds and/or domestic ducks. Environmental samples were tested for the presence of avian influenza virus (AIV) using quantitative PCR assays and virus isolation techniques. Hemagglutination inhibition assays were used to detect antibodies against AIV H5N1, and microneutralization assays were used to confirm these results. Among the environmental samples from wild birds and domestic ducks, AIV prevalence was 5.19 and 5.32%, respectively. We isolated 39 and 5 AIVs from the fecal samples of wild birds and domestic ducks, respectively. Our analysis indicated 12 subtypes of AIV were present, suggesting that wild birds in the Eastern Dongting Lake area carried a diverse array of AIVs with low pathogenicity. We were unable to detect any antibodies against AIV H5N1 in humans, suggesting that human infection with H5N1 was rare in this region.</p></div

Maternal glycemia during pregnancy and offspring abdominal adiposity measured by MRI in the neonatal period and preschool years: The Growing Up in Singapore Towards healthy Outcomes (GUSTO) prospective mother-offspring birth cohort study

10.1093/ajcn/nqaa055AMERICAN JOURNAL OF CLINICAL NUTRITION112139-47AJCNAGUSTO (Growing up towards Healthy Outcomes)GUSTO (Growing up towards Healthy Outcomes

Sample collection sites around the Eastern Dongting Lake area.

<p>(A) Hunan Province. Dongting Lake is located to the north of Hunan Province (black circle). (B) Dongting Lake. The black circles indicate sample collection areas. Junshan district (green). Yueyang county (yellow) surrounding the Eastern Dongting Lake area. Villages where environmental samples from duck farms are shown in red.</p

Prevalence of AIV in samples collected from wild birds and domestic ducks.

<p>*P<0.001 between fecal and water samples among wild birds.</p><p>**P = 0.54 between fecal and water samples among domestic ducks.</p

Time distribution of AIV prevalence in wild birds and domestic ducks.

<p>Time distribution of AIV prevalence in wild birds and domestic ducks.</p

Monthly distribution for AIV isolation.

<p>‘P’ indicates virus isolated from the feces of domestic ducks. ‘W’ indicates virus isolated from the feces of wild birds.</p

Detection of AIVs in samples collected from wild birds and domestic ducks.

<p>Detection of AIVs in samples collected from wild birds and domestic ducks.</p