Nicotinamide is an inhibitor of SIRT1 in vitro,but can be a stimulator in cells

Nicotinamide (NAM), a form of vitamin B₃, plays essential roles in cell physiology through facilitating NAD⁺ redox homeostasis and providing NAD⁺ as a substrate to a class of enzymes that catalyze non-redox reactions. These non-redox enzymes include the sirtuin family proteins which deacetylate target proteins while cleaving NAD⁺ to yield NAM. Since the finding that NAM exerts feedback inhibition to the sirtuin reactions, NAM has been widely used as an inhibitor in the studies where SIRT1, a key member of sirtuins, may have a role in certain cell physiology. However, once administered to cells, NAM is rapidly converted to NAD⁺ and, therefore, the cellular concentration of NAM decreases rapidly while that of NAD⁺ increases. The result would be an inhibition of SIRT1 for a limited duration, followed by an increase in the activity. This possibility raises a concern on the validity of the interpretation of the results in the studies that use NAM as a SIRT1 inhibitor. To understand better the effects of cellular administration of NAM, we reviewed published literature in which treatment with NAM was used to inhibit SIRT1 and found that the expected inhibitory effect of NAM was either unreliable or muted in many cases. In addition, studies demonstrated NAM administration stimulates SIRT1 activity and improves the functions of cells and organs. To determine if NAM administration can generate conditions in cells and tissues that are stimulatory to SIRT1, the changes in the cellular levels of NAM and NAD⁺ reported in the literature were examined and the factors that are involved in the availability of NAD⁺ to SIRT1 were evaluated. We conclude that NAM treatment can hypothetically be stimulatory to SIRT1.     

Clathrin self-assembly is mediated by a tandemly repeated superhelix.

Clathrin is a triskelion-shaped cytoplasmic protein that polymerizes into a polyhedral lattice on intracellular membranes to form protein-coated membrane vesicles. Lattice formation induces the sorting of membrane proteins during endocytosis and organelle biogenesis by interacting with membrane-associated adaptor molecules. The clathrin triskelion is a trimer of heavy-chain subunits (1,675 residues), each binding a single light-chain subunit, in the hub domain (residues 1,074-1,675). Light chains negatively modulate polymerization so that intracellular clathrin assembly is adaptor-dependent. Here we report the atomic structure, to 2.6 A resolution, of hub residues 1,210-1,516 involved in mediating spontaneous clathrin heavy-chain polymerization and light-chain association. The hub fragment folds into an elongated coil of alpha-helices, and alignment analyses reveal a 145-residue motif that is repeated seven times along the filamentous leg and appears in other proteins involved in vacuolar protein sorting. The resulting model provides a three-dimensional framework for understanding clathrin heavy-chain self-assembly, light-chain binding and trimerization.     

Effect of silica forms in rice husk ash on the properties of concrete

The strength and durability properties of concrete with or without three types of rice husk ash (RHA), namely, amorphous, partial crystalline, and crystalline RHA, were investigates. The three types of RHA were added into concrete at a 20% replacement level. Consequently, the pozzolanic reactivity of amorphous RHA was higher than that of partial crystalline and crystalline RHA. Concrete added with amorphous RHA showed excellent characteristics in its mechanical and durability properties. The results showed that the higher the amount of crystalline silica in RHA, the lower the concrete resistivity value became. When compared with each other, concretes with 20% of the cement replaced with these types of RHA achieved similar ultrasonic pulse velocity values, but all were lower than that of the control concrete. The incorporation of these kinds of RHA significantly reduced chloride penetration. The results not only encourage the use of amorphous materials, they also support the application of crystalline or partial crystalline RHA as mineral and pozzolanic admixtures for cement.     

Atomic-scale imaging of nanoengineered oxygen vacancy profiles in SrTiO3

At the heart of modern oxide chemistry lies the recognition that beneficial (as well as deleterious) materials properties can be obtained by deliberate deviations of oxygen atom occupancy from the ideal stoichiometry. Conversely, the capability to control and confine oxygen vacancies will be important to realize the full potential of perovskite ferroelectric materials, varistors and field-effect devices. In transition metal oxides, oxygen vacancies are generally electron donors, and in strontium titanate (SrTiO3) thin films, oxygen vacancies (unlike impurity dopants) are particularly important because they tend to retain high carrier mobilities, even at high carrier densities. Here we report the successful fabrication, using a pulsed laser deposition technique, of SrTiO3 superlattice films with oxygen doping profiles that exhibit subnanometre abruptness. We profile the vacancy concentrations on an atomic scale using annular-dark-field electron microscopy and core-level spectroscopy, and demonstrate absolute detection sensitivities of one to four oxygen vacancies. Our findings open a pathway to the microscopic study of individual vacancies and their clustering, not only in oxides, but in crystalline materials more generally.     

Caenorhabditis elegans early embryogenesis and vulval morphogenesis require chondroitin biosynthesis

Defects in glycosaminoglycan biosynthesis disrupt animal development and can cause human disease. So far much of the focus on glycosaminoglycans has been on heparan sulphate. Mutations in eight squashed vulva (sqv) genes in Caenorhabditis elegans cause defects in cytokinesis during embryogenesis and in vulval morphogenesis during postembryonic development. Seven of the eight sqv genes have been shown to control the biosynthesis of the glycosaminoglycans chondroitin and heparan sulphate. Here we present the molecular identification and characterization of the eighth gene, sqv-5. This gene encodes a bifunctional glycosyltransferase that is probably localized to the Golgi apparatus and is responsible for the biosynthesis of chondroitin but not heparan sulphate. Our findings show that chondroitin is crucial for both cytokinesis and morphogenesis during C. elegans development.     

Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase.

Nitric oxide is a messenger molecule, mediating the effect of endothelium-derived relaxing factor in blood vessels and the cytotoxic actions of macrophages, and playing a part in neuronal communication in the brain. Cloning of a complementary DNA for brain nitric oxide synthase reveals recognition sites for NADPH, FAD, flavin mononucleotide and calmodulin as well as phosphorylation sites, indicating that the synthase is regulated by many different factors. The only known mammalian enzyme with close homology is cytochrome P-450 reductase.     

自由端刚性加强的悬臂正锥壳的渐近解法

给出自由端刚性加强的悬臂正锥壳在非对称载荷作用下的第二次渐近解法的步骤，且以根部为简支或固定端情况为例，得到在法向载荷Ｚ的作用下全部内力及位移表达式。     

Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans

The efficacy and safety of biological molecules in cancer therapy, such as peptides and small interfering RNAs (siRNAs), could be markedly increased if high concentrations could be achieved and amplified selectively in tumour tissues versus normal tissues after intravenous administration. This has not been achievable so far in humans. We hypothesized that a poxvirus, which evolved for blood-borne systemic spread in mammals, could be engineered for cancer-selective replication and used as a vehicle for the intravenous delivery and expression of transgenes in tumours. JX-594 is an oncolytic poxvirus engineered for replication, transgene expression and amplification in cancer cells harbouring activation of the epidermal growth factor receptor (EGFR)/Ras pathway, followed by cell lysis and anticancer immunity. Here we show in a clinical trial that JX-594 selectively infects, replicates and expresses transgene products in cancer tissue after intravenous infusion, in a dose-related fashion. Normal tissues were not affected clinically. This platform technology opens up the possibility of multifunctional products that selectively express high concentrations of several complementary therapeutic and imaging molecules in metastatic solid tumours in humans.