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131.
Mohamed A. Helal Amar G. Chittiboyina Mitchell A. Avery 《Bioorganic & medicinal chemistry letters》2019,29(24):126741
MCH receptor is a G protein-coupled receptor with two subtypes R1 and R2. Many studies have demonstrated the role of MCH-R1 in feeding and energy homeostasis. It has been proven that oral administration of small molecule MCH-R1 antagonists significantly reduces food intake and causes a dose-dependent weight loss. In this study, two ligand-based pharmacophores were developed and validated based on recently published MCH-R1 antagonists with diverse structures. Successful pharmacophores had one hydrogen bond acceptor, one positive ionizable, one ring aromatic and two or three hydrophobic groups. These 3D-QSAR models were used for virtual screening of the ZINC chemical database resulting in the identification of nine compounds with more than 50% displacement of radiolabeled MCH at a 20 μM concentration. Moreover, four of these compounds showed antagonistic activities in Aequorin functional assay, including MH-3 which is the first MCH-R1 antagonist based on a diazaspiro[4.5]decane scaffold. The most active compounds were also docked into our previously published MCH-R1 homology model to gain insights into their binding determinants. These compounds could represent a viable starting scaffold for the design of potent MCH-R1 antagonists with improved pharmacokinetic properties as an effective treatment for obesity. 相似文献
132.
Snipe Gallinago gallinago breeding on lowland wet grasslands in England have undergone widespread and dramatic declines in abundance and distribution since at least the 1970s. There are many potential drivers of the decline but reductions in habitat quality, driven by land management, are often proposed as a contributing factor in the historical declines of breeding waders. Breeding snipe are now restricted to a few key places such as nature reserves and environmentally sensitive areas where management for breeding waders is implemented. On average, populations have continued to decline, even in these key areas, though population trends vary from a decline of 98% to an increase of 61% between the early 1990s and 2006. We examined the relationship between regional variation in snipe population trends and soil conditions, other habitat features and land management. Snipe were more likely to persist in fields where the soil conditions were wet and soft. Fields are wetter and softer now than in the early 1990s and management influenced these conditions. Soil softness increased with decreasing grazing pressure and increasing surface flooding. Soil moisture increased with surface flooding and was higher in organic soils. Changes in field condition were consistent with decreases in grazing pressure and increases in surface flooding. In spite of habitat condition being altered in a way that should have been beneficial to snipe, the numbers have continued to decline. Thus, it is unlikely that the measures of habitat condition examined here have been the driver of the decline and other factors must be involved. Research efforts should now focus on alternative explanations of the decline, for example, changes in other key aspects of habitat quality such as prey abundance, or changes in snipe productivity or mortality. 相似文献
133.
SUM1, an Apparent Positive Regulator of the Cryptic Mating-Type Loci in SACCHAROMYCES CEREVISIAE 总被引:6,自引:2,他引:4
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Amar J. S. Klar Satya N. Kakar John M. Ivy James B. Hicks George P. Livi Lisa M. Miglio 《Genetics》1985,111(4):745-758
The mating-type information residing at the HML and HMR loci in Saccharomyces cerevisiae is kept unexpressed by the action of at least four MAR (or SIR) loci. To determine possible interactions between the MAR/SIR gene products and to find new regulatory loci, we sought extragenic suppressors of the mar1-1 mutation. A strain with the genotype HMLa MAT alpha HMRa mar1-1 is unable to mate because of the simultaneous expression of a and alpha information. A mutant of this strain was isolated that exhibits an alpha phenotype and, therefore, presumably fails to express the HML and HMR loci. We designate the new locus SUM1 (suppressor of mar). The mutation is recessive, centromere unlinked and does not correspond to the MAT, HML, HMR, SIR1, MAR1, MAR2 (SIR3) or SIR4 loci. The sum1 mutation affects expression of both a and alpha information at the HM loci. Suppression by sum1-1 is neither allele specific nor locus specific as it suppresses a deletion mutation of the MAR1 locus and mutations in SIR3 and SIR4. The sum1-1 mutation has no discernible phenotype in a Mar+ strain. We propose that the MAR/SIR gene products negatively regulate the SUM1 locus, the gene product of which is necessary for expression of the HM loci. 相似文献
134.
Distribution pattern and levels of nitrogenase (EC 1.7.99.2) and glutamine synthetase (GS, EC 6.3.1.2) were studied in N2-, NO3? and NH4+ grown Anabaena cylindrica (CCAP 1403/2a) using immunogold electron microscopy. In N2- and NO3? grown cultures, heterocysts were formed and nitrogenase activity was present. The nitrogenase antigen appeared within the heterocysts only and showed an even distribution. The level of nitrogenase protein in the heterocysts was identical with both nitrogen sources. In NO3? grown cells the 30% reduction in the nitrogenase activity was due to a corresponding decrease in the heterocyst frequency and not to a repressed nitrogenase synthesis. In NH4? grown cells, the nitrogenase activity was almost zero and new heterocysts were formed to a very low extent. The heterocysts found showed practically no nitrogenase protein throughout the cytoplasm, although some label occurred at the periphery of the heterocyst. This demonstrates that heterocyst differentiation and nitrogenase expression are not necessarily correlated and that while NH4+ caused repression of both heterocyst and nitrogenase synthesis, NO3? caused inhibition of heterocyst differentiation only. The glutamine synthetase protein label was found throughout the vegetative cells and the heterocysts of all three cultures. The relative level of the GS antigen varied in the heterocysts depending on the nitrogen source, whereas the GS level was similar in all vegetative cells. In N2- and NO3+ grown cells, where nitrogenase was expressed, the GS level was ca 100% higher in the heterocysts compared to vegetative cells. In NH4+ grown cells, where nitrogenase was repressed, the GS level was similar in the two cell types. The enhanced level of GS expressed in heterocysts of N2 and NO3? grown cultures apparently is related to nitrogenase expression and has a role in assimilation of N2derived ammonia. 相似文献
135.
Stabilized non-complementing diploids (Ncd) from fused protoplast products of B. subtilis 总被引:5,自引:0,他引:5
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Non-complementing diploids (Ncd) displaying the parental phenotype can be selected from polyethylene glycol (PEG)-treated fused polyauxotrophic protoplasts of Bacillus subtilis. These bacteria carry the two parental genomes, but only one of them is phenotypically expressed, the other being replicated but not expressed. Cellular cloning and DNA-DNA in situ hybridization led to the discovery of non-complementing diploid cells which at first sight could have been considered as parental haploids. The new class of stabilized Ncd (10(-7) segregants) can be obtained either directly after the primary fusion event or from segregating Ncd after further growth. The totally inactive chromosome of a stable Ncd can be activated after PEG-induced self fusion. DNA-mediated transformation studies using crude stable Ncd lysates as DNA donors show low frequencies for the genetic markers from the 'silent' chromosome. Contrary to the unstable Ncd situation, however, these frequencies remain low even with purified donor DNA. The differences in the transformation properties of the non-expressed markers are correlated to Ncd clone stability. These facts suggest that chromosome inactivation in PEG-induced fusion involves at least a two-stage process. The first would be reversible and the second irreversible, thus preserving the inactive chromosome state. 相似文献
136.
137.
Six kava analogues of the structural type 3-oxocyclohex-1-en-1-yl benzoates (and corresponding benzamides) were synthesized and evaluated for their affect on periodontal deconstruction in collagen anti-body primed oral gavage model of periodontitis. The compounds were prepared through an acylation or amidation of the enolizable cyclic 1,3-diketone. We have learned that three of the analogues are responsible for the reduction of inflammatory cell counts within soft tissue. These novel kava-like molecules where the lactone is replaced by an α,β-unsaturated ketone show promise in the prevention and treatment of inflammation and alveolar bone loss associated with periodontitis. 相似文献
138.
Medicinal plants described in the Indian “Ayurvedic” literature viz. Tulsi (Ocimum sanctum), Gulvel (Tinospora cardifolia), bitter Neem (Azadirachta indica), Kanher (Nerium Åndicum), Vekhand (Acorus calamus), and Peacock's feather (ash) were analyzed for minor and trace elements by instrumental neutron activation analysis. The samples and the standards from the National Institute of Standards and Technology, USA and IAEA, Vienna were irradiated for 5 min, 1 h, 5 h, and 10 h with thermal neutrons at a flux of 1012–1013 n cm?2s?1 in APSARA and CIRUS reactor at BARC Bombay. High resolution γ ray spectrometry was performed using a 45 cm3 HPGe detector and a 4096 MCA system. Concentrations of 13 elements were determined. Zinc, manganese, and sodium were significantly higher in Tulsi leaves while zinc is higher in Neem leaves. Peacock's feathers were found to be rich in manganese, iron, copper, and zinc. A high concentration of mercury was also found in the peacock's feather ash. The therapeutic significance in restoring ionic balance is discussed. 相似文献
139.
A novel effect of the inhibition of the decomposition of amino acids to carbonates on addition of imidazole (HIm) to a reacting system containing equimolar amounts of copper and zinc metal powders, an amino acid [glycine (Hgly), aspartic acid (H2Asp) or glycylglycine (H2gg)] (1:1:2) and excess hydrogen peroxide (H2O2) resulting in formation of a mixed metal mixed ligand peroxo complex compound was observed, because in the absence of imidazole the corresponding reaction system yields only a mixed metal peroxo carbonate. For the resulting complex compounds, the homogeneity, i.e. [Cu(Zn)(O2
2–)(Gly)2(HIm)(H2O)], [Cu(Zn)(O2
2–)(Asp)(HIm)(H2O)2] or [Cu(Zn)2(O2
2–)2(gg)(HIm)(H2O)4], molecular formula, presence of peroxo group and coordination environment were established by combined physicochemical evidence from elemental and thermogravimetric analysis in air and argon atmospheres, electron spin resonance and electronic and IR spectral data. It is noteworthy to mention that the corresponding carboxylic acids of the above-mentioned amino acids, i.e. acetic and succinic acids, either do not decompose to carbonates in the absence of imidazole or form novel homogeneous peroxo mixed metal mixed ligand complex compounds as described above in the presence of imidazole. This suggests an important and significant mutual influence (in vitro) of biologically active chromophores like peroxo ions, imidazole and amino groups in the above-mentioned chemical reactions containing bioactive metals such as copper and zinc. 相似文献
140.