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121.
Death effector domains (DEDs) are protein–protein interaction domains initially identified in proteins such as FADD, FLIP and caspase-8 involved in regulating apoptosis. Subsequently, these proteins have been shown to have important roles in regulating other forms of cell death, including necroptosis, and in regulating other important cellular processes, including autophagy and inflammation. Moreover, these proteins also have prominent roles in innate and adaptive immunity and during embryonic development. In this article, we review the various roles of DED-containing proteins and discuss recent developments in our understanding of DED complex formation and regulation. We also briefly discuss opportunities to therapeutically target DED complex formation in diseases such as cancer. 相似文献
122.
Visual opsins bind 11-cis retinal at an orthosteric site to form rhodopsins but increasing evidence suggests that at least some are capable of binding an additional retinoid(s) at a separate, allosteric site(s). Microspectrophotometric measurements on isolated, dark-adapted, salamander photoreceptors indicated that the truncated retinal analog, β-ionone, partitioned into the membranes of green-sensitive rods; however, in blue-sensitive rod outer segments, there was an enhanced uptake of four or more β-ionones per rhodopsin. X-ray crystallography revealed binding of one β-ionone to bovine green-sensitive rod rhodopsin. Cocrystallization only succeeded with extremely high concentrations of β-ionone and binding did not alter the structure of rhodopsin from the inactive state. Salamander green-sensitive rod rhodopsin is also expected to bind β-ionone at sufficiently high concentrations because the binding site is present on its surface. Therefore, both blue- and green-sensitive rod rhodopsins have at least one allosteric binding site for retinoid, but β-ionone binds to the latter type of rhodopsin with low affinity and low efficacy. 相似文献
123.
Kevin N. Couper Tom Barnes Julius C. R. Hafalla Valery Combes Bernhard Ryffel Thomas Secher Georges E. Grau Eleanor M. Riley J. Brian de Souza 《PLoS pathogens》2010,6(1)
There is considerable debate as to the nature of the primary parasite-derived moieties that activate innate pro-inflammatory responses during malaria infection. Microparticles (MPs), which are produced by numerous cell types following vesiculation of the cellular membrane as a consequence of cell death or immune-activation, exert strong pro-inflammatory activity in other disease states. Here we demonstrate that MPs, derived from the plasma of malaria infected mice, but not naive mice, induce potent activation of macrophages in vitro as measured by CD40 up-regulation and TNF production. In vitro, these MPs induced significantly higher levels of macrophage activation than intact infected red blood cells. Immunofluorescence staining revealed that MPs contained significant amounts of parasite material indicating that they are derived primarily from infected red blood cells rather than platelets or endothelial cells. MP driven macrophage activation was completely abolished in the absence of MyD88 and TLR-4 signalling. Similar levels of immunogenic MPs were produced in WT and in TNF−/−, IFN-γ−/−, IL-12−/− and RAG-1−/− malaria-infected mice, but were not produced in mice injected with LPS, showing that inflammation is not required for the production of MPs during malaria infection. This study therefore establishes parasitized red blood cell-derived MPs as a major inducer of systemic inflammation during malaria infection, raising important questions about their role in severe disease and in the generation of adaptive immune responses. 相似文献
124.
Diagnosis of alpha 1-antitrypsin deficiency by enzymatic amplification of human genomic DNA and direct sequencing of polymerase chain reaction products. 总被引:3,自引:8,他引:3
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C R Newton N Kalsheker A Graham S Powell A Gammack J Riley A F Markham 《Nucleic acids research》1988,16(17):8233-8243
We have compared sequencing of cloned "polymerase chain reaction" (PCR) products and the direct sequencing of PCR products in the examination of individuals from six families affected with alpha 1-antitrypsin (AAT) deficiency. In families where paternity was in question we confirmed consanguinity by DNA fingerprinting using a panel of locus-specific minisatellite probes. We demonstrate that direct sequencing of PCR amplification products is the method of choice for the absolutely specific diagnosis of AAT deficiency and can distinguish normals, heterozygotes and homozygotes in a single, rapid and facile assay. Furthermore, we demonstrate the reproducibility of the PCR and a rapid DNA isolation procedure. We have also shown that two loci can be simultaneously amplified and that the PCR product from each locus can be independently examined by direct DNA sequencing. 相似文献
125.
Bradley B. Olwin Kirstin Arthur Kevin Hannon Patrick Hein Zhaohui Zhou Michael E. Zuber Arthur J. Kudla Aidan McFall Alan C. Rapraeger Bruce Riley Gyrgyi Szebenyi John F. Fallon 《Molecular reproduction and development》1994,39(1):90-101
Fibroblast growth factors (FGFs) are a family of nine proteins that bind to three distinct types of cell surface molecules: (i) FGF receptor tyrosine kinases (FGFR-1 through FGFR-4); (ii) a cysteine-rich FGF receptor (CFR); and (iii) heparan sulfate proteoglycans (HSPGs). Signaling by FGFs requires participation of at least two of these receptors: the FGFRs and HSPGs form a signaling complex. The length and sulfation pattern of the heparan sulfate chain determines both the activity of the signaling complex and, in part, the ligand specificity for FGFR-1. Thus, the heparan sulfate proteoglycans are likely to play an essential role in signaling. We have recently identified a role for FGF in limb bud development in vivo. In the chick limb bud, ectopic expression of the 18 kDa form of FGF-2 or FGF-2 fused to an artificial signal peptide at its amino terminus causes skeletal duplications. These data, and the observations that FGF-2 is localized to the subjacent mesoderm and the apical ectodermal ridge in the early developing limb, suggest that FGF-2 plays an important role in limb outgrowth. We propose that FGF-2 is an apical ectodermal ridgederived factor that participates in limb outgrowth and patterning. © 1994 Wiley-Liss, Inc. 相似文献
126.
This review promotes the value of isolated hepatocytes in modern Drug Discovery programmes and outlines how increased understanding, particularly in the area of in vitro-in vivo extrapolation (IVIVE), has led to more widespread use. The importance of in vitro metabolic intrinsic clearance data for predicting in vivo clearance has been acknowledged for several years and the greater utility of hepatocytes, compared with hepatic microsomes and liver slices, for this application is discussed. The application of hepatocytes in predicting drug-drug interactions (DDIs) resulting from reversible and irreversible (time-dependent) inhibition is relatively novel but affords the potential to study both phase I and phase II processes together with any impact of drug efflux and/or uptake (cellular accumulation). Progress in this area is reviewed along with current opinions on the comparative use of primary hepatocytes and higher throughput reporter gene-based systems for studying cytochrome P450 (CYP) induction. The appreciation of the role of transporter proteins in drug disposition continues to evolve. The study of hepatic uptake using isolated hepatocytes and the interplay between drug transport and metabolism with respect to both clearance and DDIs and subsequent IVIVE is also considered. 相似文献
127.
A 3.5 genome equivalent multi access YAC library: construction, characterisation, screening and storage. 总被引:16,自引:11,他引:16
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The construction of a yeast artificial chromosome (YAC) primary gridded library of 35,000 clones from human lymphoblastoid (48,XXXX) cell line DNA is described. The average YAC size is approximately 350kb representing a greater than 3.5 times coverage of the genome. The library is stored at -70 degrees C as gridded clones on nylon filters impregnated with 20% glycerol and as glycerol suspensions of individual clones in microtitre plates providing a prolonged multi-user potential. To date we have used 14 single copy probes to screen this library by colony hybridisation as well as PCR and have isolated between 1 and 5 YAC clones for every probe. 相似文献
128.
Luminal testicular factors are known to be important for the regulation of the epididymal epithelium. The present study was undertaken to test the hypothesis that complete deprivation of luminal factors by efferent duct ligation (EDL) would induce apoptosis in the epididymal epithelium, as does removal of trophic factors from other cell types. Additionally, experiments were performed to determine whether the apoptosis detected was p53 dependent or independent. Apoptosis detection was by terminal deoxynucleotidyl‐mediated deoxyuridine triphosphate‐biotin nick‐end labeling and by DNA fragmentation studies. EDL caused loss of testicular luminal contribution in zone 1A of the rat epididymis (proximal initial segment) within 6 hr and induced epithelial apoptosis within 12 hr of the efferent duct obstruction. The wave of apoptosis in zone 1A was completed by three days after EDL and was followed by a much smaller wave in zone 1B which peaked three days after EDL. Significant apoptosis was not detected in any epididymal region distal to the initial segment for periods as long as 15 days after EDL. p53, a key apoptotic‐pathway molecule in many tissues and conditions was tested by immunohistochemical and Western blot techniques and was not upregulated in the initial segment epithelium within the time cells were undergoing apoptosis and well before the wave of apoptosis was complete. It was concluded that epithelial apoptosis in the initial segment of the rat epididymis is induced by deprivation of luminal testicular factors, is localized to the proximal and middle initial segment, and is p53 independent. Mol. Reprod. Dev. 53:188–197, 1999. © 1999 Wiley‐Liss, Inc. 相似文献
129.
Reti NG Lappas M Huppertz B Riley C Wlodek ME Henschke P Permezel M Rice GE 《Cell and tissue research》2007,328(3):607-616
Ex situ culture of human gestational tissues has been routinely used as a model to investigate tissue function. The objective of
this study was to determine the effect of varying oxygen concentrations on human term placental explants over a 24-h time
period. Specifically, the effect of incubating placental explants in oxygen concentrations of 8%, 21% or 95% on tissue viability,
metabolism and cell death was measured by assessing glucose consumption, lactate production, release of lactate dehydrogenase,
parathyroid hormone-related protein (PTHrP), tumour necrosis factor-alpha (TNF-α) and 8-isoprostane, immunoreactivity for
cleaved-caspase-9 and immunohistochemistry for the caspase-3-cleaved cytokeratin-18 neoepitope, M30. Exposure to higher oxygen
concentrations significantly increased the rates of glucose consumption and lactate production. Apoptosis was significantly
increased under conditions of higher oxygen as evidenced by increased M30 in placental explant sections. Similarly, hyperoxia
significantly increased the releases of PTHrP, TNF-α and 8-isoprostane. Thus, incubation of placental explants with oxygen
concentrations of 95% and, to a lesser extent, 21% oxygen was associated with the modulation of multiple cellular response
pathways including those associated with tissue viability and cell death. These data are consistent with the hypothesis that
hyperoxia activates pathways and mechanisms involved in cellular metabolism, necrosis and apoptosis, thereby shifting the
balance from a steady state towards cell death. 相似文献
130.
Albani Alessandro De Liberato Claudio Wahid Isra Berrilli Federica Riley Erin Phelps Cardeti Giusy Ngakan Putu Oka Carosi Monica 《International journal of primatology》2019,40(6):671-686
International Journal of Primatology - Information on parasite biodiversity and abundance can improve our understanding of parasitic infections on endangered wildlife, as parasites can affect host... 相似文献