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Emerging influenza viruses are a serious threat to human health because of their pandemic potential. A promising target for the development of novel anti-influenza therapeutics is the PA protein, whose endonuclease activity is essential for viral replication. Translation of viral mRNAs by the host ribosome requires mRNA capping for recognition and binding, and the necessary mRNA caps are cleaved or "snatched" from host pre-mRNAs by the PA endonuclease. The structure-based development of inhibitors that target PA endonuclease is now possible with the recent crystal structure of the PA catalytic domain. In this study, we sought to understand the molecular mechanism of inhibition by several compounds that are known or predicted to block endonuclease-dependent polymerase activity. Using an in vitro endonuclease activity assay, we show that these compounds block the enzymatic activity of the isolated PA endonuclease domain. Using X-ray crystallography, we show how these inhibitors coordinate the two-metal endonuclease active site and engage the active site residues. Two structures also reveal an induced-fit mode of inhibitor binding. The structures allow a molecular understanding of the structure-activity relationship of several known influenza inhibitors and the mechanism of drug resistance by a PA mutation. Taken together, our data reveal new strategies for structure-based design and optimization of PA endonuclease inhibitors.

Abstract The zebrafish has become an important model for cancer research. Several cancer models have been established by transgenic expression of human or mouse oncogenes in zebrafish. Since it is amenable to efficient transgenesis, zebrafish have immense potential to be used for studying interaction of oncogenes and pathways at the organismal level. Using the Gal4VP16-UAS binary transgenic expression approach, we established stable transgenic lines expressing an EGFP fusion protein of an activated zebrafish Smoothened (Smoa1-EGFP). Expression of the zebrafish Smoa1-EGFP itself did not lead to tumor formation either in founder fish or subsequent generations, however, co-expressing a constitutively active human AKT1 resulted in several tumor types, including spindle cell sarcoma, rhabdomyoma, ocular melanoma, astrocytoma, and myoxma. All tumor types showed GFP expression and increased Patched 1 levels, suggesting involvement of zebrafish Smoa1 in tumorigenesis. Immunofluorescence studies showed that tumors also expressed elevated levels of phosphorylated AKT, indicating activation of the PI3K-AKT pathway. These results suggest that co-activation of the hedgehog and AKT pathways promote tumorigenesis, and that the binary transgenic approach is a useful tool for studying interaction of oncogenes and oncogenic pathways in zebrafish.

The paper deals with basic approaches to monitoring of the currency risk. The purpose of the paper is to substantiate the theoretical and methodological foundations of the complex application of risk assessment methods to prevent the adoption of its excessive level, as well as instruments for monitoring the profitability of operations in the foreign exchange market, based on the calculation of the consolidated balanced index. It was determined that in the context of the volatility of the national currency the exposure of banks to currency risk increases significantly, it means that is, the magnitude of the consequences of its manifestation for most financial intermediaries increases. The authors of the paper consider the system of currency risk management as a set of goals, principles, functions, methods, tools and specific techniques of purposeful, continuous influence of the management system on the managed one for timely estimation and monitoring of currency risk in order to minimize it and achieve specified parameters of currency yields. In according to current management standards, implemented by leading financial institutions and international regulators, currency risk monitoring mechanisms must not only timely and effectively identify deviations from key risk targets, but also provide for the ability to identify unforeseen situations. It was proved that that the monitoring tools, policies and procedures have to meet a number of criteria, which are taken into account at the achievement of the main goals of the bank and increase its resistance to external shocks on the foreign exchange market. Taking into account the fact that the value of currency risk by the ES metric is included in the calculation of the consolidated balanced index, the change in the regulatory regimes is made on the basis of the projected deviations of the CEI from the target corridor, recorded at the initial stage in determining the level of risk exposure of the bank. Thus, the proposed balanced approach to forecasting involves the use, on the one hand, of statistically reliable quantitative analysis tools and, on the other hand, qualitative environmental change signals that aggregate the benefits of structural methods, while providing the flexibility and timeliness of managerial decision-making. The specification of currency risk management regimes should be tailored to the specific features of a particular bank and have a combinatorial nature that involves the integration of individual impulses by analysis tools, forecasting, time horizons and levels of management, as well as in terms of components of the CEI consolidated balance sheet and risk level of activity in the foreign exchange market. This approach allows for the flexibility of management systems and their adaptability to the external conditions of the bank, and the use of quality monitoring signals increases the speed of decision-making and elimination of deficiencies that can be inherent in econometric assessment tools.

To explore physical properties of Planck cold dust clumps, 674 of the pilot samples were observed at the 13.7 m telescope of Purple Mountain Observatory (PMO) in J = 1 - 0 transitions of CO, 13CO and C18O. HCO+, HCN and N2H+ emissions were also observed with PMO 13.7 m and IRAM 30 m telescopes. They are real cold and quiescent with mean Tk ~ 10 K and mean FWHM of 13CO (1-0) 1.27 km s-1. Column density ranges from 1020 to 1022 cm-2. Gas of the Planck clumps extends molecular space in the Milky Way. Turbulence dominates in cores. Filament structure is the majority and most of the cores are starless. Ten percent of the cores show asymmetric emission features including blue- and red- profiles. Planck clumps include different cold or low luminosity sources. Dense cores constitute an ideal sample for studying initial state of star formation while the diffuse clumps are suitable for investigating the formation of cores. [ABSTRACT FROM AUTHOR]

А brief analysis of formation of the galvanic production wastes in machine-building complex of the Republic of Belarus is given.

The article introduces various integration schemes for fabricating dual metal gate of complimentary metal oxide semiconductors (CMOS) field-effect transistors. Dual metal gate CMOS integration requires various wet etch processes. This integration is to separate varying metal gates within the transistors on the same wafer. Finally, such technological integration schemes should be established to remove totally the first metal gate without destructing the underlying gate dielectric.

Abstract: This study used polymerase chain reaction and direct sequencing methods to infer the relationship between population genetic structure of chukar partridge (Alectoris chukar) and environmental factors. A total of 491 nucleotides of mitochondrial DNA control region were sequenced from 78 chukar partridges in eight populations collected from the Longdong Loess Plateau in Northwestern China. Twenty-four variable sites defined 25 haplotypes. Statistically significant differences in haplotype frequencies were observed among all populations. Chukar partridge genetic diversity (S-, H- and N-values) decreased with decreasing latitude, altitude, variation coefficients of temperature and rainfall cline. However, genetic diversity increased with increasing longitude, rainfall and temperature. Temperature and rainfall were the determinant factors influencing the genetic structure of the chukar partridge in this plateau. In addition, the more stable the climate, the higher the genetic diversity observed. Natural selection may act to maintain the genetic structure of the chukar populations. [Copyright &y& Elsevier]

The aberrant expression of tissue factor (TF) in acute promyelocytic leukemia (APL) cells has been implicated in the pathogenesis of the APL coagulopathy. In this study, we found that in APL patients receiving ATRA or As2O3 treatment, the improvement in hypercoagulobility and hyperfibrinolysis paralleled the correction of plasma fibrinogen level and amelioration of bleeding symptoms. Notably, clinical improvement was also correlated to ATRA/As2O3-induced rapid decrease of membrane procoagulant activity (PCA) and TF contents of APL blasts. Consistent with the in vivo findings, the membrane PCA, TF antigen and its mRNA level within NB4 cells were rapidly down-regulated by 1 microM ATRA or As2O3, while 0.2 microg/ml DNR increased these TF parameters prior to its effect upon apoptosis induction. The down-regulation of TF mRNA by ATRA was partially de novo protein synthesis-dependent and at least partially attributed to a mechanism of destabilizing TF mRNA. On the other hand, in addition to its modulation on mRNA, As2O3 could also induce an accelerated TF protein turnover. These distinct effects were corroborated with the properties of these agents in causing the degradation of PML-RARalpha protein. All three therapeutic agents, however, enhanced the potential of NB4 cells to stimulate the expression of TF and PCA in endothelium. Taken together, our data suggest that the rapid and distinct regulation of TF on APL cells by these therapeutic agents might at least partially contribute to their effects on APL coagulopathy. [ABSTRACT FROM AUTHOR]

With a patterned transparent electrode and compressive-elastic gel material, a multi-input transparent touch screen, which detects touch location and touch force, has been realised. The input device of this touch screen is composed of a flexible upper single wall carbon nanotube electrode (SWCNT), a lower indium tin oxide electrode layer, and a silicone gel layer between two electrodes. When a touch force ranging from 0 N to 5 N was applied to the surface of the upper electrode film, the silicone gel was compressed to change the distance between the two electrodes, which resulted in a capacitance change ranging from 1.92 to 3.42pF. The SWCNT electrode on the polyethylene terephthalate showed sufficient flexibility and robustness for mechanical deformation. [ABSTRACT FROM AUTHOR]