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131.
Chen Z Davies E Miller WS Shan S Valenzano KJ Kyle DJ 《Bioorganic & medicinal chemistry letters》2004,14(21):5275-5279
Small molecule mu agonists based on the 4-phenyl piperidine scaffold were designed and synthesized to further investigate the therapeutic potential of loperamide analogs. The resulting compounds show excellent agonistic activity towards the human mu receptor with interesting SAR trends within the series. 相似文献
132.
Peat AJ Boucheron JA Dickerson SH Garrido D Mills W Peckham J Preugschat F Smalley T Schweiker SL Wilson JR Wang TY Zhou HQ Thomson SA 《Bioorganic & medicinal chemistry letters》2004,14(9):2121-2125
A series of [1-aryl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]arylhydrazones were discovered as novel inhibitors glycogen synthase kinase-3 (GSK-3). Based on initial modeling a detailed SAR was constructed. Modification of the interior binding aryl ring (Ar(1)) determined this to be a tight binding region with little room for modification. As predicted from the model, a large variety of modifications could be incorporated into the hydrazone aryl ring. This work led to GSK-3 inhibitors in the low nano-molar range. 相似文献
133.
van Kerkhove W 《Journal of applied animal welfare science : JAAWS》2004,7(4):279-285
A popular perspective on the social behavior of dogs in multiple-dog households sees the dogs' behavior as reflecting the sociobiological laws of the rigidly structured dominance hierarchy that has been described for wolf packs. This view suggests that aggression problems among dogs are natural expressions of conflict that arise whenever dominance status is in contention. One recommended solution has been for the owner to endorse and enforce a particular dominance hierarchy because, on the wolf pack model, aggression is minimized when the structure of the hierarchy is clear, strong, and stable. This article questions the validity of this perspective on 2 principal grounds. First, because it does not seem to occur in the wild, this article suggests the strong dominance hierarchy that has been described for wolves may be a by-product of captivity. If true, it implies that social behavior—even in wolves—may be a product more of environmental circumstances and contingencies than an instinctive directive. Second, because feral dogs do not exhibit the classic wolf-pack structure, the validity of the canid, social dominance hierarchy again comes into question. This article suggests that behavioral learning theory offers another perspective regarding the behavior of dogs and wolves in the wild or in captivity and offers an effective intervention for aggression problems. 相似文献
134.
Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a) 总被引:9,自引:0,他引:9
Cellular senescence can be triggered by telomere shortening as well as a variety of stresses and signaling imbalances. We used multiparameter single-cell detection methods to investigate upstream signaling pathways and ensuing cell cycle checkpoint responses in human fibroblasts. Telomeric foci containing multiple DNA damage response factors were assembled in a subset of senescent cells and signaled through ATM to p53, upregulating p21 and causing G1 phase arrest. Inhibition of ATM expression or activity resulted in cell cycle reentry, indicating that stable arrest requires continuous signaling. ATR kinase appears to play a minor role in normal cells but in the absence of ATM elicited a delayed G2 phase arrest. These pathways do not affect expression of p16, which was upregulated in a telomere- and DNA damage-independent manner in a subset of cells. Distinct senescence programs can thus progress in parallel, resulting in mosaic cultures as well as individual cells responding to multiple signals. 相似文献
135.
136.
Dietary Ethanol Mediates Selection on Aldehyde Dehydrogenase Activity in Drosophila melanogaster 总被引:1,自引:0,他引:1
Fry JD Bahnck CM Mikucki M Phadnis N Slattery WC 《Integrative and comparative biology》2004,44(4):275-283
Ethanol is an important environmental variable for fruit-breedingDrosophila species, serving as a resource at low levels anda toxin at high levels. The first step of ethanol metabolism,the conversion of ethanol to acetaldehyde, is catalyzed primarilyby the enzyme alcohol dehydrogenase (ADH). The second step,the oxidation of acetaldehyde to acetate, has been a sourceof controversy, with some authors arguing that it is carriedout primarily by ADH itself, rather than a separate aldehydedehydrogenase (ALDH) as in mammals. We review recent evidencethat ALDH plays an important role in ethanol metabolism in Drosophila.In support of this view, we report that D. melanogaster populationsmaintained on ethanol-supplemented media evolved higher activityof ALDH, as well as of ADH. We have also tentatively identifiedthe structural gene responsible for the majority of ALDH activityin D. melanogaster. We hypothesize that variation in ALDH activitymay make an important contribution to the observed wide variationin ethanol tolerance within and among Drosophila species. 相似文献
137.
Marrero J González LJ Sánchez A Ayala M Paz-Lago D González W Fallarero A Castellanos-Serra L Coto O 《Proteomics》2004,4(5):1265-1279
Heavy metals are required as nutrients for essential functions in microorganisms. However, higher concentrations of these cations are generally toxic and may produce contrasting effects on living organisms. Enterobacter liquefaciens strain C-1, a bacterium isolated from the Moa mine in Cuba, is able to survive in the presence of high concentrations of heavy metals. The proteomes of Enterobacter liquefaciens strain C-1, grown under aerobic conditions in the presence and absence of Co (II) were compared using two-dimensional gel electrophoresis analysis in the isoelectric point range of 4-7 and the mass range of 15-120 kDa. Significant changes in the expression level (> two-fold) were detected for 13 spots: seven and six were up- and down-regulated, respectively. Because the genome of this bacterium is unknown, identification by peptide mass fingerprinting only succeeded in four cases and most of the cross-species identifications were supported by de novo sequencing of tryptic peptides followed by sequence alignment using the MS BLAST program. Twelve different proteins were identified, ten are involved in cellular antioxidant defence probably induced by the presence of Co (II). This is the first step towards understanding the role of proteins participating in the mechanism of resistance to heavy metals in this bacterium. 相似文献
138.
Calverley DC Varteresian T Brass E Tsao-Wei DD Groshen S Mack WJ Buchanan TA Hodis HN Schreiber AD 《Immunity & ageing : I & A》2004,1(1):4
BACKGROUND: Atherosclerosis lesions contain abundant immunoglobulins complexed with oxidized LDL (OxLDL) that are endocytosed by macrophages to form foam cells. While recent evidence supports a role for the macrophage scavenger receptor pathway in 75-90% of OxLDL uptake, in vitro evidence suggests another potential uptake pathway could involve autoantibody binding to IgG subclass-specific Fc receptors. OBJECTIVE AND METHODS: To address this mechanism from an in vivo standpoint, the objective of this study was to utilize flow cytometry to prospectively determine monocyte Fcgamma (FcR) I, II, and III receptor expression levels in patients with acute coronary syndrome (ACS, n = 48), diabetes mellitus (DM, n = 59), or neither (C, n = 88). RESULTS: Increased FcR I expression was found in the ACS versus DM groups [geometric mean, (95% CI) = 2.26 (2.07, 2.47) versus 1.83 (1.69, 1.98) (p < 0.001)] and versus C [1.90 (1.78, 2.03) (p = 0.005)]. Similar relationships were found with both the FcR II receptor [ACS mean = 4.57 (4.02, 5.19) versus DM 3.61 (3.22, 4.05) (p = 0.021) and versus C 3.86 (3.51, 4.24) (p = 0.09)] and FcR III receptor [ACS mean = 1.55 (1.44, 1.68) versus DM 1.36 (1.27, 1.46) (p = 0.038) and versus C 1.37 (1.30, 1.45) (p = 0.032)]. There was no difference between DM and C groups in FcR I, II or III expression. CONCLUSIONS: This in vivo data supports a possible second OxLDL-autoantibody macrophage uptake mechanism through an Fc receptor-mediated pathway and a potential relationship between atherosclerotic plaque macrophage FcR levels and ACS. 相似文献
139.
At the University of Pittsburgh School of Medicine, our experience with urethrolysis over the past several years offered a unique opportunity to assess outcomes after delayed time to urethrolysis. We observed a highly suggestive association between prolonged time to urethrolysis and a greater likelihood of persistent bladder dysfunction. If this observation is corroborated by other studies, it would be prudent to lower our threshold of clinical suspicion to detect bladder outlet obstruction. Videourodynamics testing can be invaluable for making the distinction between outlet obstruction versus de novo urge incontinence. Here, we briefly review the literature on urethrolysis and present the urethrolysis technique utilized at our institution. The article concludes with several challenging and controversial clinical judgment questions asked ofDr Leng by Dr Chancellor. 相似文献
140.
Bowen BW Bass AL Chow SM Bostrom M Bjorndal KA Bolten AB Okuyama T Bolker BM Epperly S Lacasella E Shaver D Dodd M Hopkins-Murphy SR Musick JA Swingle M Rankin-Baransky K Teas W Witzell WN Dutton PH 《Molecular ecology》2004,13(12):3797-3808
Juvenile loggerhead turtles (Caretta caretta) from West Atlantic nesting beaches occupy oceanic (pelagic) habitats in the eastern Atlantic and Mediterranean, whereas larger juvenile turtles occupy shallow (neritic) habitats along the continental coastline of North America. Hence the switch from oceanic to neritic stage can involve a trans-oceanic migration. Several researchers have suggested that at the end of the oceanic phase, juveniles are homing to feeding habitats in the vicinity of their natal rookery. To test the hypothesis of juvenile homing behaviour, we surveyed 10 juvenile feeding zones across the eastern USA with mitochondrial DNA control region sequences (N = 1437) and compared these samples to potential source (nesting) populations in the Atlantic Ocean and Mediterranean Sea (N = 465). The results indicated a shallow, but significant, population structure of neritic juveniles (PhiST = 0.0088, P = 0.016), and haplotype frequency differences were significantly correlated between coastal feeding populations and adjacent nesting populations (Mantel test R2 = 0.52, P = 0.001). Mixed stock analyses (using a Bayesian algorithm) indicated that juveniles occurred at elevated frequency in the vicinity of their natal rookery. Hence, all lines of evidence supported the hypothesis of juvenile homing in loggerhead turtles. While not as precise as the homing of breeding adults, this behaviour nonetheless places juvenile turtles in the vicinity of their natal nesting colonies. Some of the coastal hazards that affect declining nesting populations may also affect the next generation of turtles feeding in nearby habitats. 相似文献