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981.
982.
Nurulain T. Zaveri Faming Jiang Cris Olsen Willma E. Polgar Lawrence Toll 《Bioorganic & medicinal chemistry letters》2013,23(11):3308-3313
The nociceptin receptor (NOP) and its endogenous agonist, nociceptin/orphanin FQ (N/OFQ), members of the opioid receptor and peptide families respectively, modulate the pharmacological effects of classical opioids, particularly opioid-induced reward and nociception. We hypothesized that compounds containing both NOP and opioid receptor activity in a single molecule may have useful pharmacological profiles as non-addicting analgesics or as drug abuse medications. We report here our forays into the structure–activity relationships for discovering ‘bifunctional’ NOP–mu opioid receptor (MOP) ligands, starting from our NOP-selective scaffolds. This initial SAR suggests pharmacophoric elements that may be modified to modulate/increase opioid affinity, while maintaining high affinity for the NOP receptor, to result in potent bifunctional small-molecule NOP/MOP ligands. 相似文献
983.
984.
Harvesting may lead to evolutionary changes in life histories on a contemporary time scale, changes that could be maladaptive
in natural contexts. However, our understanding of the strength and direction of harvest-induced selection versus natural
selection is still limited, partly due to the difficulty of tracking the fate of individuals in the wild. Here, we present
direct estimates of harvest mortality, natural mortality and site fidelity of coastal Atlantic cod (Gadus morhua) from the Norwegian Skagerrak coast. Furthermore, we present standardised selection differentials for fish body size. Estimates
are obtained from acoustic telemetry, where we continuously monitored fish (n = 60) within a semi-sheltered area using a network of 25 listening stations. To obtain additional information about harvested
cod, all fish (body size: 30–66 cm) were also tagged with traditional T-bar tags with a printed reward of 500 NOK (60 E).
We estimate that 75% of the fish died within the study area during 1 year. Fishing mortality was markedly higher than natural
mortality. Together, recreational fishers and commercial fishers caught at least 50% of the tagged fish during 1 year. Standardised
selection differentials showed that fisheries targeted larger fish (i.e. favoured the survival of smaller fish), while natural
selection favoured the survival of larger fish. Albeit on a small scale, we provide empirical evidence that harvesting can
have a dominant influence on the fitness landscape experienced by a marine fish such as the Atlantic cod. We suggest that
no-take marine reserves may help to counter evolutionary impacts of harvesting in the ocean. 相似文献
985.
Quantitative trait loci for clinical mastitis on chromosomes 2, 6, 14 and 20 in Norwegian Red cattle 总被引:3,自引:0,他引:3
Sodeland M Kent MP Olsen HG Opsal MA Svendsen M Sehested E Hayes BJ Lien S 《Animal genetics》2011,42(5):457-465
Mastitis is the most frequent and costly disease in dairy production and solutions leading to a reduction in the incidence of mastitis are highly demanded. Here a genome-wide association study was performed to identify polymorphisms affecting susceptibility to mastitis. Genotypes for 17 349 SNPs distributed across the 29 bovine autosomal chromosomes from a total of 2589 sires with 1 389 776 daughters with records on clinical mastitis were included in the analysis. Records of occurrence of clinical mastitis were divided into seven time periods in the first three lactations in order to identify quantitative trait loci affecting mastitis susceptibility in particular phases of lactation. The most convincing results from the association mapping were followed up and validated by a combined linkage disequilibrium and linkage analysis. The study revealed quantitative trait loci affecting occurrence of clinical mastitis in the periparturient period on chromosomes 2, 6 and 20 and a quantitative trait locus affecting occurrence of clinical mastitis in late lactation on chromosome 14. None of the quantitative trait loci for clinical mastitis detected in the study seemed to affect lactation average of somatic cell score. The SNPs highly associated with clinical mastitis lie near both the gene encoding interleukin 8 on chromosome 6 and the genes encoding the two interleukin 8 receptors on chromosome 2. 相似文献
986.
987.
Ugleholdt R Pedersen J Bassi MR Füchtbauer EM Jørgensen SM Kissow HL Nytofte N Poulsen SS Rosenkilde MM Seino Y Thams P Holst PJ Holst JJ 《The Journal of biological chemistry》2011,286(52):44632-44645
The glucose-dependent insulinotropic polypeptide receptor (GIPr) has been implicated in high fat diet-induced obesity and is proposed as an anti-obesity target despite an uncertainty regarding the mechanism of action. To independently investigate the contribution of the insulinotropic effects and the direct effects on adipose tissue, we generated transgenic mice with targeted expression of the human GIPr to white adipose tissue or beta-cells, respectively. These mice were then cross-bred with the GIPr knock-out strain. The central findings of the study are that mice with GIPr expression targeted to adipose tissue have a similar high fat diet -induced body weight gain as control mice, significantly greater than the weight gain in mice with a general ablation of the receptor. Surprisingly, this difference was due to an increase in total lean body mass rather than a gain in total fat mass that was similar between the groups. In contrast, glucose-dependent insulinotropic polypeptide-mediated insulin secretion does not seem to be important for regulation of body weight after high fat feeding. The study supports a role of the adipocyte GIPr in nutrient-dependent regulation of body weight and lean mass, but it does not support a direct and independent role for the adipocyte or beta-cell GIPr in promoting adipogenesis. 相似文献
988.
989.
Mosenden R Singh P Cornez I Heglind M Ruppelt A Moutschen M Enerbäck S Rahmouni S Taskén K 《Journal of immunology (Baltimore, Md. : 1950)》2011,186(9):5119-5130
Type I protein kinase A (PKA) is targeted to the TCR-proximal signaling machinery by the A-kinase anchoring protein ezrin and negatively regulates T cell immune function through activation of the C-terminal Src kinase. RI anchoring disruptor (RIAD) is a high-affinity competitor peptide that specifically displaces type I PKA from A-kinase anchoring proteins. In this study, we disrupted type I PKA anchoring in peripheral T cells by expressing a soluble ezrin fragment with RIAD inserted in place of the endogenous A-kinase binding domain under the lck distal promoter in mice. Peripheral T cells from mice expressing the RIAD fusion protein (RIAD-transgenic mice) displayed augmented basal and TCR-activated signaling, enhanced T cell responsiveness assessed as IL-2 secretion, and reduced sensitivity to PGE(2)- and cAMP-mediated inhibition of T cell function. Hyperactivation of the cAMP-type I PKA pathway is involved in the T cell dysfunction of HIV infection, as well as murine AIDS, a disease model induced by infection of C57BL/6 mice with LP-BM5, a mixture of attenuated murine leukemia viruses. LP-BM5-infected RIAD-transgenic mice resist progression of murine AIDS and have improved viral control. This underscores the cAMP-type I PKA pathway in T cells as a putative target for therapeutic intervention in immunodeficiency diseases. 相似文献
990.
Jørgensen S Eskildsen M Fugger K Hansen L Larsen MS Kousholt AN Syljuåsen RG Trelle MB Jensen ON Helin K Sørensen CS 《The Journal of cell biology》2011,192(1):43-54
The eukaryotic cell cycle is regulated by multiple ubiquitin-mediated events, such as the timely destruction of cyclins and replication licensing factors. The histone H4 methyltransferase SET8 (Pr-Set7) is required for chromosome compaction in mitosis and for maintenance of genome integrity. In this study, we show that SET8 is targeted for degradation during S phase by the CRL4(CDT2) ubiquitin ligase in a proliferating cell nuclear antigen (PCNA)-dependent manner. SET8 degradation requires a conserved degron responsible for its interaction with PCNA and recruitment to chromatin where ubiquitylation occurs. Efficient degradation of SET8 at the onset of S phase is required for the regulation of chromatin compaction status and cell cycle progression. Moreover, the turnover of SET8 is accelerated after ultraviolet irradiation dependent on the CRL4(CDT2) ubiquitin ligase and PCNA. Removal of SET8 supports the modulation of chromatin structure after DNA damage. These results demonstrate a novel regulatory mechanism, linking for the first time the ubiquitin-proteasome system with rapid degradation of a histone methyltransferase to control cell proliferation. 相似文献