Fused thiazolyl alkynes as potent mGlu5 receptor positive allosteric modulators

A new series of potent fused thiazole mGlu₅ receptor positive allosteric modulators (PAMs) (10, 11 and 27–31) are disclosed and details of the SAR and optimization are described. Optimization of alkynyl thiazole 9 (Lu AF11205) led to the identification of potent fused thiazole analogs 10b, 27a, 28j and 31d. In general, substituted cycloalkyl, aryl and heteroaryl carboxamides, and carbamate analogs are mGlu₅ PAMs, whereas smaller alkyl carboxamide, sulfonamide and sulfamide analogs tend to be mGlu₅ negative allosteric modulators (NAMs).     

The effect of pH on the lability of lead and cadmium sorbed on humic acid particles

Abstract

Sorption of lead(II) or cadmium(II) ions on humic acid particles (at pH 3.5) yields surface complexes which are sparingly soluble in the pH 3.55 region. Interaction of these species with acetic acid or dilute nitric acid released ASV labile metal species (mainly hydrated metal ion). When the pH was adjusted between 4 and 7, increasing amounts of the metal humate species (and humic acid substrate) dissolved and low levels of ASV labile species were detected. Overnight interaction with an excess of acetate ions (0.01 M) led to higher lability values (attributed to acetate/humate ligand exchange). The percentage of labile metal ion detected in acetate solutions varied with the amount of metal ion initially sorbed (range 100 to 500 mmol g^?1). With the lower loadings, the ASV labile levels peaked in the pH 6–7 region (at around 12% of total sorbed cadmium, and 4% of total lead). In alkaline solutions, the percentage of labile Cd fell to about half of the peak value, but with Pb, lability values increased at pH > 8, due possibly to the formation of hydroxy complex species. The ASV lability of the Cd and Pb humates, and their 24 hour lability values (determined using a transfer to cation exchanger technique) has been compared with the behaviour of Cu and Zn humates (using similar conditions).     

Determination of nitrite in lake sediments

Abstract

An evaluation of nitrite determination in marine lake sediments has shown that spectrophotometric measurements can be in error due to light scattering by colloidal (<0.2 μm) matter in extract solutions and incomplete nitrite recovery. The scatter error can be minimised by using uncoloured extract in the reference beam but precision at low levels remains poor (RSD 25 to 100%). Recovery tests on ‘spiked’ sediment indicated that optimum retrieval (～85%) occurred with 30 minute mixing with 0.2 M NH₄Cl, using a sediment to extractant ratio of 1:30. To counter this variable, calibration based on standard addition to sample suspensions is recommended. Modified procedure proposed is suitable for measuring up to 10 μg g^?1 of nitrite N; the lake sediments tested contained <100 ng g^?1     

Influence of spectral wavelength and N:P ratio on the cell cycle of Synechococcus strain CSIRNIO1 isolated from the central Eastern Arabian Sea

The novel phycoerythrin-containing Synechococcus strain CSIRNIO1 belonging to phylogenetic clade II was isolated from the coastal Arabian Sea. Chromophore characteristics of this isolate revealed the presence of phycoerythrin I (PEI), which allows it to utilize green light efficiently. The DNA distribution data indicate a bimodal slow growth model synchronized with the light/dark cycle. The duration of the cell cycle was regulated by spectral wavelength and nutrient concentration. Nitrate and phosphate enrichment shortened G1 phase duration when cells were exposed to equal doses of photosynthetically usable radiation (PUR) of different spectral wavelengths. G2 phase duration was influenced by spectral quality and phosphate concentration. S phase duration was not affected by the spectral wavelength. However, a shorter doubling time corresponding to shortened G1 and S phases was observed under nitrate enrichment. Phosphate enrichment resulted in shortening of all three phases (G1, S and G2). More efficient utilization of green and red light than blue light regulated the duration of the cell cycle as well as the doubling time, suggesting spectral selectivity in this strain. The effects of spectral wavelengths under varying nutrient concentrations will determine the proliferation of Synechococcus and its adaptation to different environmental conditions.     

Interactions between cadherin-11 and platelet-derived growth factor receptor-alpha signaling link cell adhesion and proliferation

Cadherins are homophilic cell-to-cell adhesion molecules that help cells respond to environmental changes. Newly formed cadherin junctions are associated with increased cell phosphorylation, but the pathways driving this signaling response are largely unknown. Since cadherins have no intrinsic signaling activity, this phosphorylation must occur through interactions with other signaling molecules. We previously reported that cadherin-11 engagement activates joint synovial fibroblasts, promoting inflammatory and degradative pathways important in rheumatoid arthritis (RA) pathogenesis. Our objective in this study was to discover interacting partners that mediate cadherin-11 signaling. Protein array screening showed that cadherin-11 extracellular binding domains linked to an Fc domain (cad11Fc) induced platelet-derived growth factor (PDGFR)-α phosphorylation in synovial fibroblasts and glioblastoma cells. PDGFRs are growth factor receptor tyrosine kinases that promote cell proliferation, survival, and migration in mesodermally derived cells. Increased PDGFR activity is implicated in RA pathology and associates with poor prognosis in several cancers, including sarcoma and glioblastoma. PDGFRα activation by cadherin-11 signaling promoted fibroblast proliferation, a signaling pathway independent from cadherin-11-stimulated IL-6 or matrix metalloproteinase (MMP)-3 release. PDGFRα phosphorylation mediated most of the cad11Fc-induced phosphatidyl-3-kinase (PI3K)/Akt activation, but only part of the mitogen-activated protein kinase (MAPK) response. PDGFRα-dependent signaling did not require cell cadherin-11 expression. Rather, cad11Fc immunoprecipitated PDGFRα, indicating a direct interaction between cadherin-11 and PDGFRα extracellular domains. This study is the first to report an interaction between cadherin-11 and PDGFRα and adds to our growing understanding that cadherin-growth factor receptor interactions help balance the interplay between tissue growth and adhesion.