183 research outputs found
In Search of Moslems in China: the Story of a Journey through Northwest China, April 30-July 2, 1936
Evolution of ecological specialization and venom of a predatory marine gastropod
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74591/1/j.1365-294X.2007.03627.x.pd
Primary and malignant cholangiocytes undergo CD40 mediated Fas dependent Apoptosis, but are insensitive to direct activation with exogenous fas ligand
Introduction
Cholangiocarcinoma is a rare malignancy of the biliary tract, the incidence of which is rising, but the pathogenesis of which remains uncertain. No common genetic defects have been described but it is accepted that chronic inflammation is an important contributing factor. We have shown that primary human cholangiocyte and hepatocyte survival is tightly regulated via co-operative interactions between two tumour necrosis family (TNF) receptor family members; CD40 and Fas (CD95). Functional deficiency of CD154, the ligand for CD40, leads to a failure of clearance of biliary tract infections and a predisposition to cholangiocarcinoma implying a direct link between TNF receptor-mediated apoptosis and the development of cholangiocarcinoma.
Aims
To determine whether malignant cholangiocytes display defects in CD40 mediated apoptosis. By comparing CD40 and Fas-mediated apoptosis and intracellular signalling in primary human cholangiocytes and three cholangiocyte cell lines.
Results
Primary cholangiocytes and cholangiocyte cell lines were relatively insensitive to direct Fas-mediated killing with exogenous FasL when compared with Jurkat cells, which readily underwent Fas-mediated apoptosis, but were extremely sensitive to CD154 stimulation. The sensitivity of cells to CD40 activation was similar in magnitude in both primary and malignant cells and was STAT-3 and AP-1 dependent in both.
Conclusions
1) Both primary and malignant cholangiocytes are relatively resistant to Fas–mediated killing but show exquisite sensitivity to CD154, suggesting that the CD40 pathway is intact and fully functional in both primary and malignant cholangiocytes 2) The relative insensitivity of cholangiocytes to Fas activation demonstrates the importance of CD40 augmentation of Fas dependent death in these cells. Agonistic therapies which target CD40 and associated intracellular signalling pathways may be effective in promoting apoptosis of malignant cholangiocytes
Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress
In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse
Biosynthetic Gene Cluster for the Cladoniamides, Bis-Indoles with a Rearranged Scaffold
The cladoniamides are bis-indole alkaloids isolated from Streptomyces uncialis, a lichen-associated actinomycete strain. The cladoniamides have an unusual, indenotryptoline structure rarely observed among bis-indole alkaloids. I report here the isolation, sequencing, and annotation of the cladoniamide biosynthetic gene cluster and compare it to the recently published gene cluster for BE-54017, a closely related indenotryptoline natural product. The cladoniamide gene cluster differs from the BE-54017 gene cluster in gene organization and in the absence of one N-methyltransferase gene but otherwise contains close homologs to all genes in the BE-54017 cluster. Both gene clusters encode enzymes needed for the construction of an indolocarbazole core, as well as flavin-dependent enzymes putatively involved in generating the indenotryptoline scaffold from an indolocarbazole. These two bis-indolic gene clusters exemplify the diversity of biosynthetic routes that begin from the oxidative dimerization of two molecules of l-tryptophan, highlight enzymes for further study, and provide new opportunities for combinatorial engineering
IL-17RA Signaling Amplifies Antibody-Induced Arthritis
Objective: To investigate the role of IL-17RA signaling in the effector phase of inflammatory arthritis using the K/BxN serumtransfer model. Methods: Wild-type and Il17ra 2/2 mice were injected with serum isolated from arthritic K/BxN mice and their clinical score was recorded daily. Mice were also harvested on days 12 and 21 and ankles were analyzed for cytokine and chemokine mRNA expression by qPCR on day 12 and for bone and cartilage erosions by histology on day 21, respectively. The induction of cytokine and chemokine expression levels by IL-17A in synovial-like fibroblasts was also analyzed using qPCR. Results: Il17ra 2/2 mice were partially protected from clinical signs of arthritis and had markedly fewer cartilage and bone erosions. The expression of several pro-inflammatory mediators, including the chemokines KC/CXCL1, MIP-2/CXCL2, LIX/ CXCL5 MIP-1c/CCL9, MCP-3/CCL7, MIP-3a/CCL20, the cytokines IL-1b, IL-6, RANKL and the matrix metalloproteinases MMP2, MMP3, and MMP13 were decreased in the ankles of Il17ra 2/2 mice compared to wild-type mice. Many of these proinflammatory genes attenuated in the ankles of Il17ra 2/2 mice were shown to be directly induced by IL-17A in synovial fibroblasts in vitro. Conclusions: IL-17RA signaling plays a role as an amplifier of the effector phase of inflammatory arthritis. This effect is likel
Design, rationale, and analysis plan for the Stand Up for Health trial in contact centres:a stepped wedge feasibility study
Cocaine Is Low on the Value Ladder of Rats: Possible Evidence for Resilience to Addiction
International audienceBACKGROUND:Assessing the relative value of cocaine and how it changes with chronic drug use represents a long-standing goal in addiction research. Surprisingly, recent experiments in rats--by far the most frequently used animal model in this field--suggest that the value of cocaine is lower than previously thought.METHODOLOGY/PRINCIPAL FINDINGS:Here we report a series of choice experiments that better define the relative position of cocaine on the value ladder of rats (i.e., preference rank-ordering of different rewards). Rats were allowed to choose either taking cocaine or drinking water sweetened with saccharin--a nondrug alternative that is not biologically essential. By systematically varying the cost and concentration of sweet water, we found that cocaine is low on the value ladder of the large majority of rats, near the lowest concentrations of sweet water. In addition, a retrospective analysis of all experiments over the past 5 years revealed that no matter how heavy was past cocaine use most rats readily give up cocaine use in favor of the nondrug alternative. Only a minority, fewer than 15% at the heaviest level of past cocaine use, continued to take cocaine, even when hungry and offered a natural sugar that could relieve their need of calories.CONCLUSIONS/SIGNIFICANCE:This pattern of results (cocaine abstinence in most rats; cocaine preference in few rats) maps well onto the epidemiology of human cocaine addiction and suggests that only a minority of rats would be vulnerable to cocaine addiction while the large majority would be resilient despite extensive drug use. Resilience to drug addiction has long been suspected in humans but could not be firmly established, mostly because it is difficult to control retrospectively for differences in drug self-exposure and/or availability in human drug users. This conclusion has important implications for preclinical research on the neurobiology of cocaine addiction and for future medication development
Stable Genetic Effects on Symptoms of Alcohol Abuse and Dependence from Adolescence into Early Adulthood
Relatively little is known about how genetic influences on alcohol abuse and dependence (AAD) change with age. We examined the change in influence of genetic and environmental factors which explain symptoms of AAD from adolescence into early adulthood. Symptoms of AAD were assessed using the four AAD screening questions of the CAGE inventory. Data were obtained up to six times by self-report questionnaires for 8,398 twins from the Netherlands Twin Register aged between 15 and 32 years. Longitudinal genetic simplex modeling was performed with Mx. Results showed that shared environmental influences were present for age 15–17 (57%) and age 18–20 (18%). Unique environmental influences gained importance over time, contributing 15% of the variance at age 15–17 and 48% at age 30–32. At younger ages, unique environmental influences were largely age-specific, while at later ages, age-specific influences became less important. Genetic influences on AAD symptoms over age could be accounted for by one factor, with the relative influence of this factor differing across ages. Genetic influences increased from 28% at age 15–17 to 58% at age 21–23 and remained high in magnitude thereafter. These results are in line with a developmentally stable hypothesis that predicts that a single set of genetic risk factors acts on symptoms of AAD from adolescence into young adulthood
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