Synthesis of Pyrazolo[3,4-d]pyrimidine Derivatives and Evaluation of their Src Kinase Inhibitory Activities

A series of pyrazolo[3,4-d]pyrimidine derivatives was synthesized and evaluated for the Src kinase inhibitory activities. Compound 6e and 10c exhibited inhibition of Src kinase with an IC50 value of 5.6 and 5.1 μM, respectively. Hydroxamate derivative 15a was found to be a metal-mediated inhibitor for human Csk with an IC50 value of 2.0 μM showing 56-fold selectivity over Src kinase inhibition

Topological structure vulnerability assessment of Shanghai Urban Metro Networks

ABSTRACT Topological structure vulnerability assessment approach for Urban Metro Networks (UMNS) was proposed in order to decrease the impact caused by incidents. Failure scale of stations and sections random failure and target attacks was evaluated. The results show that UMNS is more vulnerable to target attacks on stations than random failure on stations. But UMNS is less vulnerable to target attacks on sections than random failure on sections. Additionally, UMNS is more vulnerable to station failure than sections. It could be concluded as more resources should be put on big transfer stations in UMNS operation management to avoid large scale impacts. The proposed methodology is not intended to predict the occurrence of events but rather to be used a management tool. Results from the evaluation are valuable elements in planning UMNS. They can be used for network planning, further detailed hazard studies, deciding on the arrangement of emergency resources

Lentviral-mediated RNAi to inhibit target gene expression of the porcine integrin αv subunit, the FMDV receptor, and against FMDV infection in PK-15 cells

<p>Abstract</p> <p>Background</p> <p>shRNA targeting the integrin αv subunit, which is the foot-and-mouth disease virus (FMDV) receptor, plays a key role in virus attachment to susceptible cells. We constructed a RNAi lentiviral vector, iαv pLenti6/BLOCK -iT™, which expressed siRNA targeting the FMDV receptor, the porcine integrin αv subunit, on PK-15 cells. We also produced a lentiviral stock, established an iαv-PK-15 cell line, evaluated the gene silencing efficiency of mRNA using real-time qRT-PCR, integrand αv expression by indirect immunofluorescence assay (IIF) and cell enzyme linked immunosorbent assays (cell ELISA), and investigated the in vivo inhibitory effect of shRNA on FMDV replication in PK-15 cells.</p> <p>Results</p> <p>Our results indicated successful establishment of the iαv U6 RNAi entry vector and the iαv pLenti6/BLOCK -iT expression vector. The functional titer of obtained virus was 1.0 × 10⁶TU/mL. To compare with the control and mock group, the iαv-PK-15 group αv mRNA expression rate in group was reduced by 89.5%, whilst IIF and cell ELISA clearly indicated suppression in the experimental group. Thus, iαv-PK-15 cells could reduce virus growth by more than three-fold and there was a > 99% reduction in virus titer when cells were challenged with 10²TCID₅₀of FMDV.</p> <p>Conclusions</p> <p>Iαv-PK-15 cells were demonstrated as a cell model for anti-FMDV potency testing, and this study suggests that shRNA could be a viable therapeutic approach for controlling the severity of FMD infection and spread.</p

(Diethyl ether){1-[2-(1-methyl-1H-imidazol-2-yl-κN 3)-1,1-diphenyl­ethyl]-(1,2,3,3a,7a-η)-inden­yl}lithium(I)

In the title compound, [Li(C27H23N2)(C4H10O)], the Li atom possesses a nearly planar trigonal coordination environment (assuming the cyclo­penta­dienyl ring of the indenyl group occupies one coordination place). The diethyl ether ligand adopts a nearly planar W-type conformation

Molecular catalysis that transpires only when the complex is heterogenized: Studies of a hydrogenase complex surface-tethered on polycrystalline and (1 1 1)-faceted gold by EC, PM-FT-IRRAS, HREELS, XPS and STM

The proton-reduction catalytic activity of two di-iron hydrogenase complexes, [(μ-S_(2)C_(3)H_6)[Fe(CO)_3][Fe(CO)_(2)(PPh_3)] (1) and (μ-S_(2)C_(3)H_6)[Fe(CO)_3][Fe(CO)2(PPh2{(CH2)2SH})] (2), was investigated at polycrystalline and (1 1 1)-faceted Au electrodes in nonaqueous electrolyte. Compound (2) was irreversibly tethered to the surface through the single bondSH group; (1) was present only in the unadsorbed (dissolved) state. No enhancement of the proton reduction reaction was observed with the homogeneous complex. Pronounced catalysis was exhibited by the heterogenized (surface-attached) material. Neither increase nor decrease in activity was observed when unadsorbed complex (2) was added to the solution of the heterogenized catalyst. The conclusion from these observations, that no catalysis transpires unless the subject molecular complex is tethered to the electrode surface, is totally unexpected; it runs counter to conventional wisdom that an untethered homogeneous electrocatalyst, especially one that requires a particular entatic (partially rotated) configuration to complete its function, would invariably perform better than its surface-immobilized counterpart. The heterogenized complex, present at rather low coverages due to its sizable adsorbed-molecule cross section, was further investigated by polarization-modulation Fourier transform infrared reflection absorption spectroscopy (PM-FT-IRRAS), high-resolution electron-energy loss spectroscopy (HREELS), X-ray photoelectron spectroscopy (XPS) and scanning tunneling microscopy (STM). The electrochemistry (EC) and STM results indicated that the catalytic activity of the immobilized complex is a function of its surface coverage but not of its spatial configuration; the catalytic sites are accessible regardless of the particular arrangement of the pendant active site with respect to the surface. The surface-immobilized complex suffered a non-negligible loss in catalytic activity after the ex situ experiments, perhaps due to (partial) decarbonylation

Maternal ambient air pollution exposure with spatial-temporal variations and preterm birth risk assessment during 2013-2017 in Zhejiang Province, China.

Preterm birth (PTB) can give rise to significant neonatal morbidity and mortality, as well as children's long-term health defects. Many studies have illustrated the associations between ambient air pollution exposure during gestational periods and PTB risks, but most of them only focused on one single air pollutant, such as PM2.5. In this population-based environmental-epidemiology study, we recruited 6275 pregnant mothers in Zhejiang Province, China, and evaluated their gestational exposures to various air pollutants during 2013-2017. Time-to-event logistic regressions were performed to estimate risk associations after adjusting all confounders, and Quasi-AQI model and PCA-GLM analysis were applied to resolve the collinearity issues in multi-pollutant regression models. It was found that gestational exposure to ambient air pollutants was significantly associated with the occurrence of PTB, and SO2 was the largest contributor with a proportion of 29.4%. Three new variables, prime factor (a combination of PM2.5, PM10, SO2, and NO2), carbon factor (CO), and ozone factor (O3), were generated by PCA integration, contributing 63.4%, 17.1%, and 19.5% to PTB risks, respectively. The first and third trimester was the most crucial exposure window, suggesting the pregnant mothers better to avoid severe air pollution exposures during these sensitive periods

Synthesis and evaluation of phosphopeptides containing iminodiacetate groups as binding ligands of the Src SH2 domain

Phosphopeptide pTyr-Glu-Glu-Ile (pYEEI) has been introduced as an optimal Src SH2 domain ligand. Peptides, Ac-K(IDA)pYEEIEK(IDA) (1), Ac-KpYEEIEK (2), Ac-K(IDA)pYEEIEK (3), and Ac-KpYEEIEK(IDA) (4), containing 0–2 iminodiacetate (IDA) groups at the N- and C-terminal lysine residues were synthesized and evaluated as the Src SH2 domain binding ligands. Fluorescence polarization assays showed that peptide 1 had a higher binding affinity (Kd = 0.6 μM) to the Src SH2 domain when compared with Ac-pYEEI (Kd = 1.7 μM), an optimal Src SH2 domain ligand, and peptides 2–4 (Kd = 2.9–52.7 μM). The binding affinity of peptide 1 to the SH2 domain was reduced by more than 2-fold (Kd = 1.6 μM) upon addition of Ni2+ (300 μM), possibly due to modest structural effect of Ni2+ on the protein as shown by circular dichroism experimental results. The binding affinity of 1 was restored in the presence of EDTA (300 μM) (Kd = 0.79 μM). These studies suggest that peptides containing IDA groups may be used for designing novel SH2 domain binding ligands. [Refer to PDF for graphical abstract

Synthesis and Evaluation of Tripodal Peptide Analogues for Cellular Delivery of Phosphopeptides

Tripodal peptide analogues were designed on the basis of the phosphotyrosine binding pocket of the Src SH2 domain and assayed for their ability to bind to fluorescein-labeled phosphopeptides. Fluorescence polarization assays showed that a number of amphipathic linear peptide analogues (LPAs), such as LPA4, bind to fluorescein-labeled GpYEEI (F-GpYEEI). LPA4 was evaluated for potential application in cellular delivery of phosphopeptides. Fluorescence microimaging cellular uptake studies with fluorescein-attached LPA4 (F-LPA4) alone or with the mixture of LPA4 and F-GpYEEI in BT-20 cells showed dramatic increase of the fluorescence intensity in cytosol of cells, indicating that LPA4 can function as a delivery tool of F-GpYEEI across the cell membrane. Fluorescent flow cytometry studies showed the cellular uptake of F-LPA4 in an energy-independent pathway and confirmed the cellular uptake of F-GpYEEI in the presence of LPA4. These studies suggest that amphipathic tripodal peptide analogues, such as LPA4, can be used for cellular delivery of phosphopeptides