One- and Two-Dimensional CP/MAS 13C NMR Analyses of Dynamics in Poly(2-hydroxypropyl ether of bisphenol-A) (FUNDAMENTAL MATERIAL PROPERTIES-Molecular Dynamic Characterisitics)

The dynamics of amorphous poly(2-hydroxypropyl ether of bisphenol-A) (PHR), quenched from the melt, has been investigated by one- and two-dimensional solid-state 13C NMR spectroscopy. CP/MAS 13C NMR spectra from .150 to 180 oC give two specific features: (1) below 23 oC, resonance lines for CH carbons of phenylene rings split into two lines; (2) linewidths of resonance lines become broad at 20 - 50 oC above the glass transition temperature. The feature (1) indicates that phenylene C-H carbons exist in chemically different two sites at low temperatures. These two sites are probably associated with OH … hydrogen bond formation. The coalescence of the resonance lines at elevated temperatures is caused by flip motion of phenylene rings, which corresponds to the relaxation for PHR. The correlation time of the flip motion is analyzed by the two-site exchange model, and is found to follow the Arrhenius equation. The apparent activation energy is 51 kJ mol-1 by assuming an inhomogeneous correlation time distribution described by a Kohlrausch-Williams-Watts (KWW) function with an exponent of 0.2. The feature (2) is caused by the so-called motional broadening, which is originated by enhanced segmental motions. This dynamics corresponds to the relaxation for PHR and can be described by William-Landel-Ferry (WLF) equation. Two-dimensional CP/MAS 13C exchange NMR experiments confirm the existence of flip angle distribution as well as the distribution of correlation times of phenylene ring flip motion with a KWW exponent of 0.2

SP7 Inhibits Osteoblast Differentiation at a Late Stage in Mice

RUNX2 and SP7 are essential transcription factors for osteoblast differentiation at an early stage. Although RUNX2 inhibits osteoblast differentiation at a late stage, the function of SP7 at the late stage of osteoblast differentiation is not fully elucidated. Thus, we pursued the function of SP7 in osteoblast differentiation. RUNX2 induced Sp7 expression in Runx2−/− calvarial cells. Adenoviral transfer of sh-Sp7 into primary osteoblasts reduced the expression of Alpl, Col1a1, and Bglap2 and mineralization, whereas that of Sp7 reduced Bglap2 expression and mineralization at a late stage of osteoblast differentiation. Sp7 transgenic mice under the control of 2.3 kb Col1a1 promoter showed osteopenia and woven-bone like structure in the cortical bone, which was thin and less mineralized, in a dose-dependent manner. Further, the number of processes in the osteoblasts and osteocytes was reduced. Although the osteoblast density was increased, the bone formation was reduced. The frequency of BrdU incorporation was increased in the osteoblastic cells, while the expression of Col1a1, Spp1, Ibsp, and Bglap2 was reduced. Further, the osteopenia in Sp7 or Runx2 transgenic mice was worsened in Sp7/Runx2 double transgenic mice and the expression of Col1a1 and Bglap2 was reduced. The expression of Sp7 and Runx2 was not increased in Runx2 and Sp7 transgenic mice, respectively. The expression of endogenous Sp7 was increased in Sp7 transgenic mice and Sp7-transduced cells; the introduction of Sp7 activated and sh-Sp7 inhibited Sp7 promoter; and ChIP assay showed the binding of endogenous SP7 in the proximal region of Sp7 promoter. These findings suggest that SP7 and RUNX2 inhibit osteoblast differentiation at a late stage in a manner independent of RUNX2 and SP7, respectively, and SP7 positively regulates its own promoter

Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets

Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index

Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ∼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488–47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10−13), ALDH2/MYL2 (rs671, P = 3.40 × 10−11; rs12229654, P = 4.56 × 10−9), ITIH4 (rs2535633, P = 1.77 × 10−10) and NT5C2 (rs11191580, P = 3.83 × 10−8) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10−8) and an additional 14 at P < 1.0 × 10−3 with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Synthesis of copper and zinc sulfide nanocrystals via thermolysis of the polymetallic thiolate cage

In this paper report on the synthesis of copper and zinc sulfide nanocrystals (NCs) via the formation of polymetallic thiolate cages. Cu2S NCs derived from Cu–dodecanethiol complex formed well-defined spherers, which were sufficiently monodisperse (with a size distribution of ~10% standard deviation of approximately 4.7 nm diameter on average) to generate ordered self-assemblies. An electron diffraction pattern and UV–vis spectrum of Cu2S NCs indicate that this process can provide pure β-chalcocite (Cu2S). Nearly monodisperse ZnS NCs with a size ranging from 3 to 7 nm were obtained by thermolysis of the S–Zn–dodecanethiol precursor. The electron diffraction pattern indicates that zinc sulfide NCs are either wurtzite or a mixture of wurtzite and zincblende. TEM observation and UV–vis spectra revealed that the growth rate of ZnS NCs depends strongly on the annealing temperature. UV–vis spectra of 3 nm ZnS NCs show sharp excitonic features and a large blue shift from the bulk material. The photoluminescence spectra exhibit a large red shift from the absorption band edges. These shifts could be attributed to recombination from the surface traps. The narrow size distribution of Cu2S and ZnS NCs led to the formation of ordered self-assemblies with various well-defined but nonclosed-packing