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991.
Price AL Patel NH 《Journal of experimental zoology. Part B. Molecular and developmental evolution》2008,310(1):24-40
The evolution of mesoderm was important for the development of complex body plans as well as key organ systems. Genetic and molecular studies in the fruitfly, Drosophila melanogaster, have provided the majority of information concerning mesoderm development in arthropods. In Drosophila, twist is necessary for the specification and correct morphogenesis of mesoderm and myocyte enhancing factor 2 (mef2) is involved downstream of twist to activate muscle differentiation. In Drosophila, mesoderm is defined by positional cues in the blastoderm embryo, while in another arthropod group, the amphipod crustaceans, cell lineage plays a greater role in defining the mesoderm. It is not known how different mechanistic strategies such as positional information vs. cell-lineage-dependent development affect the timing and use of gene networks. Here we describe the development of the mesoderm in a malacostracan crustacean, Parhyale hawaiensis, and characterize the expression of Parhyale twist and mef2 orthologues. In Parhyale, the mesoderm of the post-mandibular segments arises mainly through the asymmetric division of mesoteloblasts as the germband elongates. Ph-twist expression is seen in a subset of segmental mesoderm during germband development, but not during early cleavages when the specific mesodermal cell lineages first arise. ph-mef2 expression starts after the segmental mesoderm begins to proliferate and persists in developing musculature. While the association of these genes with mesoderm differentiation appears to be conserved across the animal kingdom, the timing of expression and relationship with different mechanisms of mesoderm development may give us greater insight into the ancestral use of these genes during mesoderm differentiation. 相似文献
992.
To begin to understand the interplay between autophagy and the hypersensitive response (HR), a type of programmed cell death (PCD) induced during plant innate immunity, we generated ATG6 antisense plants in the genetically tractable Arabidopsis thaliana system. AtATG6 antisense (AtATG6-AS) plants senesce early and are sensitive to nutrient starvation, suggestive of impairment of autophagic function in these plants. Additionally, these plants exhibited multiple developmental abnormalities, a phenomenon not observed in other AtATG mutants. AtATG6-AS plants produced fewer Monodansylcadaverine (MDC) and LysoTracker (LT) stained-autolysosomes in response to carbon and nitrogen starvation indicating that AtATG6 plays a role in the autophagic pathway in Arabidopsis. Interestingly, the level of AtATG6 mRNA in wild type Col-0 Arabidopsis plants is increased during the early phase of virulent and avirulent Pseudomonas syringae pv tomato (Pst) DC3000 infection suggesting that AtATG6 plays an important role during pathogen infection. In AtATG6-AS plants, HR-PCD induced upon infection with avirulent Pst DC3000 carrying the AvrRpm1 effector protein is not able to be contained at the infection site and spreads into uninfected tissue. Additionally, the disease-associated cell death induced by the infection of virulent Pst DC3000 bacteria is also partially misregulated in AtATG6-AS plants. Therefore, the AtATG6 antisense plants characterized here provide an excellent genetic model system to elucidate the molecular mechanisms by which autophagy regulates pathogen-induced cell death. 相似文献
993.
Kumar Srivastava B Soni R Patel JZ Jha S Shedage SA Gandhi N Sairam KV Pawar V Sadhwani N Mitra P Jain MR Patel PR 《Bioorganic & medicinal chemistry letters》2008,18(14):3882-3886
Facile synthesis of biaryl pyrazole sulfonamide derivative of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide (SR141716, 1) and an investigation of the effect of replacement of the –CO group in the compound 1 by the –SO2 group in the aminopiperidine region is reported. Primary ex-vivo pharmacological testing and in vitro screening of sulfonamide derivative 2 showed the loss of CB1 receptor antagonism. 相似文献
994.
Chang CT Patel P Kang N Lawson JA Song WL Powell WS FitzGerald GA Rokach J 《Bioorganic & medicinal chemistry letters》2008,18(20):5523-5527
The stereospecific synthesis of two all-syn-EPA-derived isoprostanes (iPs), 5-epi-8,12-iso-iPF(3alpha)-VI 17 and 8,12-iso-iPF(3alpha)-VI 18, has been accomplished. These two synthetic probes have been used to discover and identify their presence in human urine. The eventual quantitative measurement of these two iPs may be a valuable index of oxidative stress in people with eicosapentaenoic acid- (EPA) and docosahexaenoic acid- (DHA) enriched phospholipids. 相似文献
995.
Liang GB Qian X Biftu T Singh S Gao YD Scapin G Patel S Leiting B Patel R Wu J Zhang X Thornberry NA Weber AE 《Bioorganic & medicinal chemistry letters》2008,18(13):3706-3710
Probing with tool molecules, and by modeling and X-ray crystallography the binding modes of two structurally distinct series of DPP-4 inhibitors led to the discovery of a rare aromatic fluorine H-bond and the spatial requirement for better biaryl binding in the DPP-4 enzyme active site. These newly found binding elements were successfully incorporated into novel DPP-4 inhibitors. 相似文献
996.
Ruebsam F Webber SE Tran MT Tran CV Murphy DE Zhao J Dragovich PS Kim SH Li LS Zhou Y Han Q Kissinger CR Showalter RE Lardy M Shah AM Tsan M Patel R Lebrun LA Kamran R Sergeeva MV Bartkowski DM Nolan TG Norris DA Kirkovsky L 《Bioorganic & medicinal chemistry letters》2008,18(12):3616-3621
Pyrrolo[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Structure-based design led to the discovery of compound 3 k, which displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; EC(50) (1b)=12 nM) as well as good stability towards human liver microsomes (HLM t(1/2)>60 min). 相似文献
997.
Ellis DA Blazel JK Webber SE Tran CV Dragovich PS Sun Z Ruebsam F McGuire HM Xiang AX Zhao J Li LS Zhou Y Han Q Kissinger CR Showalter RE Lardy M Shah AM Tsan M Patel R LeBrun LA Kamran R Bartkowski DM Nolan TG Norris DA Sergeeva MV Kirkovsky L 《Bioorganic & medicinal chemistry letters》2008,18(16):4628-4632
4-(1,1-Dioxo-1,4-dihydro-1lambda(6)-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyridazin-3-one analogs were discovered as a novel class of inhibitors of HCV NS5B polymerase. Structure-based design led to the identification of compound 3a that displayed potent inhibitory activities in biochemical and replicon assays (1b IC(50)<10 nM; 1b EC(50)=1.1 nM) as well as good stability toward human liver microsomes (HLM t(1/2)>60 min). 相似文献
998.
Biphenyl amide p38 kinase inhibitors 3: Improvement of cellular and in vivo activity 总被引:1,自引:0,他引:1
Angell R Aston NM Bamborough P Buckton JB Cockerill S deBoeck SJ Edwards CD Holmes DS Jones KL Laine DI Patel S Smee PA Smith KJ Somers DO Walker AL 《Bioorganic & medicinal chemistry letters》2008,18(15):4428-4432
The biphenyl amides (BPAs) are a novel series of p38α MAP kinase inhibitor. The optimisation of the series to give compounds that are potent in an in vivo disease model is discussed. SAR is presented and rationalised with reference to the crystallographic binding mode. 相似文献
999.
Patel SD Habeski WM Min H Zhang J Roof R Snyder B Bora G Campbell B Li C Hidayetoglu D Johnson DS Chaudhry A Charlton ME Kablaoui NM 《Bioorganic & medicinal chemistry letters》2008,18(20):5689-5693
The discovery of the CNS-penetrant and selective alpha(2C) adrenergic receptor antagonist N-{2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-[1,4]diazepan-1-yl]-ethyl}-2-phenoxy-nicotinamide, 13 is described. Structure-activity studies demonstrate the structural requirements for binding affinity, functional activity, and selectivity over other alpha(2)-AR subtypes. 相似文献
1000.
Ellsworth BA Meng W Patel M Girotra RN Wu G Sher PM Hagan DL Obermeier MT Humphreys WG Robertson JG Wang A Han S Waldron TL Morgan NN Whaley JM Washburn WN 《Bioorganic & medicinal chemistry letters》2008,18(17):4770-4773
Inhibition of sodium-dependent glucose transporter 2 (SGLT2), the transporter that is responsible for renal re-uptake of glucose, leads to glucosuria in animals. SGLT-mediated glucosuria provides a mechanism to shed excess plasma glucose to ameliorate diabetes-related hyperglycemia and associated complications. The current study demonstrates that the proper relationship of a 4′-substituted benzyl group to a β-1C-phenylglucoside is important for potent and selective SGLT2 inhibition. The lead C-arylglucoside (7a) demonstrates superior metabolic stability to its O-arylglucoside counterpart (4) and it promotes glucosuria when administered in vivo. 相似文献