Large-scale genome-wide association studies in East Asians identify new genetic loci influencing metabolic traits

To identify the genetic bases for nine metabolic traits, we conducted a meta-analysis combining Korean genome-wide association results from the KARE project (n = 8,842) and the HEXA shared control study (n = 3,703). We verified the associations of the loci selected from the discovery meta-analysis in the replication stage (30,395 individuals from the BioBank Japan genome-wide association study and individuals comprising the Health2 and Shanghai Jiao Tong University Diabetes cohorts). We identified ten genome-wide significant signals newly associated with traits from an overall meta-analysis. The most compelling associations involved 12q24.11 (near MYL2) and 12q24.13 (in C12orf51) for high-density lipoprotein cholesterol, 2p21 (near SIX2-SIX3) for fasting plasma glucose, 19q13.33 (in RPS11) and 6q22.33 (in RSPO3) for renal traits, and 12q24.11 (near MYL2), 12q24.13 (in C12orf51 and near OAS1), 4q31.22 (in ZNF827) and 7q11.23 (near TBL2-BCL7B) for hepatic traits. These findings highlight previously unknown biological pathways for metabolic traits investigated in this study.     

Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules

Phosphodiesterases (PDEs) are a superfamily of enzymes that degrade the intracellular second messengers cyclic AMP and cyclic GMP. As essential regulators of cyclic nucleotide signalling with diverse physiological functions, PDEs are drug targets for the treatment of various diseases, including heart failure, depression, asthma, inflammation and erectile dysfunction. Of the 12 PDE gene families, cGMP-specific PDE5 carries out the principal cGMP-hydrolysing activity in human corpus cavernosum tissue. It is well known as the target of sildenafil citrate (Viagra) and other similar drugs for the treatment of erectile dysfunction. Despite the pressing need to develop selective PDE inhibitors as therapeutic drugs, only the cAMP-specific PDE4 structures are currently available. Here we present the three-dimensional structures of the catalytic domain (residues 537-860) of human PDE5 complexed with the three drug molecules sildenafil, tadalafil (Cialis) and vardenafil (Levitra). These structures will provide opportunities to design potent and selective PDE inhibitors with improved pharmacological profiles.     

Pathogenic bacteria attach to human fibronectin through a tandem beta-zipper

Staphylococcus aureus and Streptococcus pyogenes, two important human pathogens, target host fibronectin (Fn) in their adhesion to and invasion of host cells. Fibronectin-binding proteins (FnBPs), anchored in the bacterial cell wall, have multiple Fn-binding repeats in an unfolded region of the protein. The bacterium-binding site in the amino-terminal domain (1-5F1) of Fn contains five sequential Fn type 1 (F1) modules. Here we show the structure of a streptococcal (S. dysgalactiae) FnBP peptide (B3) in complex with the module pair 1F12F1. This identifies 1F1- and 2F1-binding motifs in B3 that form additional antiparallel beta-strands on sequential F1 modules-the first example of a tandem beta-zipper. Sequence analyses of larger regions of FnBPs from S. pyogenes and S. aureus reveal a repeating pattern of F1-binding motifs that match the pattern of F1 modules in 1-5F1 of Fn. In the process of Fn-mediated invasion of host cells, therefore, the bacterial proteins seem to exploit the modular structure of Fn by forming extended tandem beta-zippers. This work is a vital step forward in explaining the full mechanism of the integrin-dependent FnBP-mediated invasion of host cells.     

Synthesis and Characterization of Fluorene-based Polymers Containing Electron-withdrawing Thiazolo Thiazole Unit

1 Results Low bandgap polymers can be used for pure red light emitting materials or solar cell materials.To make low bandgap polymers,we designed conjugated polymers with alternating sequences of the appropriate donor/acceptor units in the main chain.3-hexyl thiophene was used as a electron donating unit.For the electron accepting unit,we selected thiazolothiazole and bithiazole units having electron withdrawing property.Polyfluorene(PF) is the preferred conjugated polymer in light-emitting applications...     

黄河沉积物中REE制约与示踪意义再认识

根据黄河不同地区的20个沉积物全岩样、酸溶相和酸不溶相中的稀土元素(REE)组成分析,并与1999年的研究比较,揭示出黄河沉积物REE组成主要受流域黄土源岩控制,而粒度、化学风化和人类活动等因素影响较弱.磷酸盐和Fe-Mn氧化物是形成酸溶相中的中稀土富集主要因素;而重矿物则明显影响了全岩和酸不溶残渣态REE分异特征.在世界大河中黄河沉积物REE组成非常独特,直接反映了我国上陆壳和陆表沉积物的组成特征,也可以用做标准化物质,用来对比研究世界其他河流的REE分异特征.     

Synthesis and Field-effect Transistor Behavior of New Oligo-selenophene Derivatives

1 Results In recent years,interests in organic semiconductor have increased due to the applications in optoelectronic devices such as organic light-emitting diodes (OLEDs)[1],field-effect transistors (FETs)[2],and photovoltaic devices[3]. These organic electronics have several advantages over conventional inorganic electronics including facile processability,chemical tunability,compatibility with plastic substrates,and low cost to fabricate. Selenophene-based molecules show good π-conjugating electron o...     

Effects of mistletoe (Viscum album L.) extracts on cultured tumor cells

Summary Bacterially fermented mistletoe preparations (BFMP) were tested on rat hepatoma tissue culture (HTC) cells and human leukemia Molt 4 cells. A dose-dependent inhibition of the growth rate of the cells was observed. For both cell lines, cytostatic concentrations, expressed in weight of fresh plant, were 0.5 mg/ml culture medium for oak BFMP and 1 mg/ml for apple tree BFMP. However, the action of the two preparations was markedly different on each cell line. Non-viable HTC cells were not stained by trypan blue while non-viable Molt 4 cells were fully colored by this reagent. A lysis of cellular membranes of HTC cells was observed by electron microscopy. Furthermore, oak BFMP inhibited the growth of virus transformed 3T3-SV40 cells more than that of non-transformed 3T3 cells. In contrast to BFMP, non-fermented extracts and a purified mistletoe lectin showed a greater inhibition of the growth of Molt 4 cells than of HTC cells. Samples withdrawn at different times during fermentation gradually lost their inhibitory effect on the growth of Molt 4 cells while their action on HTC cells increased up to the 4th day of fermentation. These results are discussed in relation to the cytotoxic substances of mistletoe already characterized.The bacterially fermented mistletoe preparations, named BFMP in the text, were obtained from the Hiscia Institute, CH-4144 Arlesheim, Switzerland, under the name of Iscador. For oak BFMP, mistletoe was fromQuercus petraea Liebl. andQuercus robur L.; for apple tree BFMP fromMalus domestica Borkh.     

Intracerebroventricular angiotensin II increases arterial blood pressure in rhesus monkeys by stimulation of pituitary hormones and the sympathetic nervous system

Summary Intracerebroventricular injections of angiotensin II in anesthetized rhesus monkeys increase systemic blood pressure and heart rate. These effects are accompanied by an increase in plasma ADH, cortisol, adrenaline and noradrenaline. Angiotensin II may participate in central mechanisms of blood pressure regulation by its stimulatory effect on the sympathetic nervous system, on ADH and on ACTH release in primates.