Molecular-modeling based design, synthesis, and activity of substituted piperidines as gamma-secretase inhibitors

Alzheimer's disease (AD) is a debilitating disease widely thought to be associated with the accumulation of beta amyloid (Abeta) in the brain. Inhibition of gamma-secretase, one of the enzymes responsible for Abeta production, may be a useful strategy for the treatment of AD. Described below is a series of gamma-secretase inhibitors designed from a scaffold identified by a ROCS [J. Comput. Chem.1996, 17, 1653] search of the corporate database.     

Postglacial colonization of the Tibetan plateau inferred from the matrilineal genetic structure of the endemic red-necked snow finch, Pyrgilauda ruficollis

Most phylogeographical studies of postglacial colonization focus on high latitude locations in the Northern Hemisphere. Here, we studied the phylogeographical structure of the red-necked snow finch Pyrgilauda ruficollis, an endemic species of the Tibetan plateau. We analysed 879 base pairs (bp) of the mitochondrial cytochrome b gene and 529 bp of the control region in 41 birds from four regional groups separated by mountain ranges. We detected 34 haplotypes, 31 of which occurred in a single individual and only three of which were shared among sampling sites within regional groups or among regional groups. Haplotype diversity was high (h = 0.94); nucleotide diversity was low (eth = 0.00415) and genetic differentiation was virtually non-existent. Analyses of mismatch distributions and geographically nested clades yielded results consistent with contiguous range expansion, and the expansion times were estimated as 0.07-0.19 million years ago (Ma). Our results suggest that P. ruficollis colonized the Tibetan plateau after the extensive glacial period (0.5-0.175 Ma), expanding from the eastern margin towards the inner plateau. Thus, in contrast to many of the post-glacial phylogeographical structures known at high latitudes, this colonization occurred without matrilineal population structuring. This might be due to the short glacial cycles typical of the Tibetan plateau, adaptation of P. ruficollis to cold conditions, or refugia and colonized habitat being semicontinuous and thus promoting population mixing.     

GABAergic disinhibition facilitates polysynaptic excitatory transmission in rat anterior cingulate cortex

Various studies implicate the anterior cingulate cortex (ACC) in processing pain. Combining whole-cell patch clamp recordings in rat ACC slices and a formalin-induced conditioned place avoidance (F-CPA) behavioral model, the present study was to address the effect of GABA(A) receptors on excitatory transmission to ACC layer V neurons and its possible functional significance related to pain. Removal of GABA(A) inhibition by bicuculline (10 microM) induced a novel long-lasting response in layer V neurons, which could be blocked by high divalent extracellular solution and was sensitive to relatively higher rate stimuli. Co-application of NMDA receptor antagonist APV (50 microM) and non-NMDA receptor antagonist DNQX (10 microM) completely blocked the responses. Enhancement of inhibition by intra-ACC microinjection of muscimol abolished the acquisition of F-CPA without affecting formalin-induced acute nociceptive responses. These results suggest that GABA(A) inhibition may be involved in pain-related aversion by modulating glutamate-mediated excitatory transmission in the ACC.     

Matrix metalloproteinase 11 depletion inhibits cell proliferation in gastric cancer cells

Our previous study has shown that matrix metalloproteinase 11 (MMP11) is highly expressed in tumor cell lines and primary tumor of gastric cancer (GC). In order to reveal the correlation between expression of MMP11 and biological features of GC cell, we have constructed the recombinant plasmids producing hairpin small interfering RNA (siRNA) to target MMP11 mRNA using a vector-based RNA interference technology. Stable transfection of recombinants into GC cell line BGC823 specifically depleted the mRNA and protein of MMP11 as demonstrated by RT-PCR and Western blotting analysis. The siRNA-treated cells exhibited significantly decreased growth ability compared with mock transfectants and parental BGC823 cells. Furthermore, colony formation of MMP11 deficient cells was dramatically inhibited in soft agar and tumorigenicity was reduced in nude mice, respectively. These results provide new insights into the function of MMP11 and suggest that MMP11 may play an important role in the control of cell proliferation and tumor development in GC.     

Two-dimensional Cu and first Pb coordination polymers based on a flexible 1,4-cyclohexanedicarboxylate ligand displaying different conformations and coordination modes

Two novel metal-organic hybrid coordination polymers {[Cu(bpo)(chdc)(H₂O)](H₂O)_0.5}_n (1) and [Pb(chdc)(H₂O)]_n (2) have been synthesized under different conditions and structurally characterized by single-crystal X-ray diffraction technique, where H₂chdc refers to a flexible 1,4-cyclohexanedicarboxylic acid ligand and bpo is 2,5-bis(4-pyridyl)-1,3,4-oxadiazole. Complex 1 has a two-dimensional (2-D) grid-like [11.28 × 13.63 Å²] framework in which the Cu^II centers are extended via bidentate bridging ligands bpo and e,e-trans-chdc along two directions, exhibiting large porous cavities. Coordination polymer 2 represents the first Pb^II complex of H₂chdc in which the larger Pb^II centers are connected by e,a-cis-chdc anions to afford a 2-D close-knit structure.     

Selecting cases from nuclear families for case-control association analysis

We examine the efficiency of a number of schemes to select cases from nuclear families for case-control association analysis using the Genetic Analysis Workshop 14 simulated dataset. We show that with this simulated dataset comparing all affected siblings with unrelated controls is considerably more powerful than all of the other approaches considered. We find that the test statistic is increased by almost 3-fold compared to the next best sampling schemes of selecting all affected sibs only from families with affected parents (AF aff), one affected sib with most evidence of allele-sharing from each family (SF), and all affected sibs from families with evidence for linkage (AF L). We consider accounting for biological relatedness of samples in the association analysis to maintain the correct type I error. We also discuss the relative efficiencies of increasing the ratio of unrelated cases to controls, methods to confirm associations and issues to consider when applying our conclusions to other complex disease datasets.     

Purification and characterization of a vaterite-inducing peptide, pelovaterin, from the eggshells of Pelodiscus sinensis (Chinese soft-shelled turtle)

Proteins play a crucial role in the biomineralization of hard tissues such as eggshells. We report here the purification, characterization, and in vitro mineralization studies of a peptide, pelovaterin, extracted from eggshells of a soft-shelled turtle. It is a glycine-rich peptide with 42 amino acid residues and three disulfide bonds. When tested in vitro, the peptide induced the formation of a metastable vaterite phase. The floret-shaped morphology formed at a lower concentration ( approximately 1 microM) was transformed into spherical particles at higher concentrations (>500 microM). The solution properties of the peptide are investigated by circular dichroism (CD), fluorescence emission spectroscopy, and dynamic light scattering (DLS) experiments. The conformation of pelovaterin changed from an unordered state at a low concentration to a beta-sheet structure at high concentrations. Fluorescence emission studies indicated that the quantum yield is significantly decreased at higher concentrations, accompanied by a blue shift in the emission maximum. At higher concentrations a red-edge excitation shift was observed, indicating the restricted mobility of the peptide. On the basis of these observations, we discuss the presence of a peptide concentration-dependent monomer-multimer equilibrium in solution and its role in controlling the nucleation, growth, and morphology of CaCO(3) crystals. This is the first peptide known to induce the nucleation and stabilization of the vaterite phase in solution.     

Modeling and simulation of the swelling behavior of pH-stimulus-responsive hydrogels

The modulation of the swelling ability of the hydrogel matrix by pH-stimulus enables the dynamic control of the swelling forces, thereby obtaining effective diffusivity and permeability of the solutes, or mechanical energy from the hydrogel. In this work, a chemo-electro-mechanical model describing hydrogel behavior, based on multi-field effects, is developed to simulate the swelling and shrinking of these fascinating bio-materials, and it is termed the multi-effect-coupling pH-stimulus (MECpH) model. This model accounts for the ionic fluxes within both the hydrogel and solution, the coupling between the electric field, ionic fluxes, and mechanical deformations of the hydrogel. The main contribution of this model is to incorporate the relationship between the concentrations of the ionized fixed-charge groups and the diffusive hydrogen ion, which follows a Langmuir isotherm, into the Poisson-Nernst-Planck system. To validate this MECpH model, one-dimensional steady-state simulations under varying pH solution are carried out via a meshless Hermite-Cloud methodology, and the numerical results are compared with available experimental data. It is shown that the presently developed MECpH model is accurate, efficient, and numerically stable.