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951.
F Allagnat D Cunha F Moore J M Vanderwinden D L Eizirik A K Cardozo 《Cell death and differentiation》2011,18(2):328-337
Pancreatic β-cell apoptosis is a key feature of diabetes mellitus and the mitochondrial pathway of apoptosis is a major mediator of β-cell death. We presently evaluated the role of the myeloid cell leukemia sequence 1 (Mcl-1), an antiapoptotic protein of the Bcl-2 family, in β-cells following exposure to well-defined β-cell death effectors, for example, pro-inflammatory cytokines, palmitate and chemical endoplasmic reticulum (ER) stressors. All cytotoxic stresses rapidly and preferentially decreased Mcl-1 protein expression as compared with the late effect observed on the other antiapoptotic proteins, Bcl-2 and Bcl-xL. This was due to ER stress-mediated inhibition of translation through eIF2α phosphorylation for palmitate and ER stressors and through the combined action of translation inhibition and JNK activation for cytokines. Knocking down Mcl-1 using small interference RNAs increased apoptosis and caspase-3 cleavage induced by cytokines, palmitate or thapsigargin, whereas Mcl-1 overexpression partly prevented Bax translocation to the mitochondria, cytochrome c release, caspase-3 cleavage and apoptosis induced by the β-cell death effectors. Altogether, our data suggest that Mcl-1 downregulation is a crucial event leading to β-cell apoptosis and provide new insights into the mechanisms linking ER stress and the mitochondrial intrinsic pathway of apoptosis. Mcl-1 is therefore an attractive target for the design of new strategies in the treatment of diabetes. 相似文献
952.
Chin CD Laksanasopin T Cheung YK Steinmiller D Linder V Parsa H Wang J Moore H Rouse R Umviligihozo G Karita E Mwambarangwe L Braunstein SL van de Wijgert J Sahabo R Justman JE El-Sadr W Sia SK 《Nature medicine》2011,17(8):1015-1019
One of the great challenges in science and engineering today is to develop technologies to improve the health of people in the poorest regions of the world. Here we integrated new procedures for manufacturing, fluid handling and signal detection in microfluidics into a single, easy-to-use point-of-care (POC) assay that faithfully replicates all steps of ELISA, at a lower total material cost. We performed this 'mChip' assay in Rwanda on hundreds of locally collected human samples. The chip had excellent performance in the diagnosis of HIV using only 1 μl of unprocessed whole blood and an ability to simultaneously diagnose HIV and syphilis with sensitivities and specificities that rival those of reference benchtop assays. Unlike most current rapid tests, the mChip test does not require user interpretation of the signal. Overall, we demonstrate an integrated strategy for miniaturizing complex laboratory assays using microfluidics and nanoparticles to enable POC diagnostics and early detection of infectious diseases in remote settings. 相似文献
953.
Stuchell-Brereton MD Siglin A Li J Moore JK Ahmed S Williams JC Cooper JA 《Molecular biology of the cell》2011,22(15):2690-2701
Cytoplasmic dynein is a large multisubunit complex involved in retrograde transport and the positioning of various organelles. Dynein light chain (LC) subunits are conserved across species; however, the molecular contribution of LCs to dynein function remains controversial. One model suggests that LCs act as cargo-binding scaffolds. Alternatively, LCs are proposed to stabilize the intermediate chains (ICs) of the dynein complex. To examine the role of LCs in dynein function, we used Saccharomyces cerevisiae, in which the sole function of dynein is to position the spindle during mitosis. We report that the LC8 homologue, Dyn2, localizes with the dynein complex at microtubule ends and interacts directly with the yeast IC, Pac11. We identify two Dyn2-binding sites in Pac11 that exert differential effects on Dyn2-binding and dynein function. Mutations disrupting Dyn2 elicit a partial loss-of-dynein phenotype and impair the recruitment of the dynein activator complex, dynactin. Together these results indicate that the dynein-based function of Dyn2 is via its interaction with the dynein IC and that this interaction is important for the interaction of dynein and dynactin. In addition, these data provide the first direct evidence that LC occupancy in the dynein motor complex is important for function. 相似文献
954.
Larvae of the ground beetle genus Eustra Schmidt-Goebel are described and illustrated for the first time and some biological notes are reported. One specimen of an unknown Eustra species was collected while excavating a nest of the ant Pachycondyla javana Mayr, in Taiwan, which is the first report of a paussine associated with a member of the ant subfamily Ponerinae. Several larvae and adults of a second species, Eustra chinensis Bänninger, were collected in Shanghai under bark with no association with ants. First instar larvae of the latter species were also reared in the lab. The occurrence of larvae of the genus Eustra both inside and outside ant nests, together with a report of adults collected inside a nest in Taiwan, suggests that members of this genus may be facultative predators or facultative symbionts of ants, an attribute that has never been reported for this genus. The larvae of Eustra show several unique features, including a peculiar bidentate mandibular apex, an extremely long galea, one of two tarsal claws greatly reduced, abdominal setae (including those of terminal disk) elongate and clavate at apex, urogomphi wide and flattened, and inflated sensilla S-I. Larvae were studied by both optical and scanning electron microscopy, their morphological features are compared with those of other described Paussinae larvae, and their potential phylogenetic and functional significance are discussed. 相似文献
955.
Moore V Kanu A Byron O Campbell G Danson MJ Hough DW Crennell SJ 《Extremophiles : life under extreme conditions》2011,15(3):327-336
Using citrate synthase from the hyperthermophile Pyrococcus furiosus (PfCS) as our test molecule, we show through guanidine hydrochloride-induced unfolding that the dimer separates into folded,
but inactive, monomers before individual subunit unfolding takes place. Given that forces across the dimer interface are vital
for thermostability, a robust computational method was derived that uses the University of Houston Brownian Dynamics (UHBD)
program to calculate both the hydrophobic and electrostatic contribution to the dimerisation energy at 100°C. The results
from computational and experimental determination of the lowered stability of interface mutants were correlated, being both
of the same order of magnitude and placing the mutant proteins in the same order of stability. This computational method,
optimised for hyperthermophilic molecules and tested in the laboratory, after further testing on other examples, could be
of widespread use in the prediction of thermostabilising mutations in other oligomeric proteins for which dissociation is
the first step in unfolding. 相似文献
956.
Firn J Moore JL MacDougall AS Borer ET Seabloom EW HilleRisLambers J Harpole WS Cleland EE Brown CS Knops JM Prober SM Pyke DA Farrell KA Bakker JD O'Halloran LR Adler PB Collins SL D'Antonio CM Crawley MJ Wolkovich EM La Pierre KJ Melbourne BA Hautier Y Morgan JW Leakey AD Kay A McCulley R Davies KF Stevens CJ Chu CJ Holl KD Klein JA Fay PA Hagenah N Kirkman KP Buckley YM 《Ecology letters》2011,14(3):274-281
Many ecosystems worldwide are dominated by introduced plant species, leading to loss of biodiversity and ecosystem function. A common but rarely tested assumption is that these plants are more abundant in introduced vs. native communities, because ecological or evolutionary-based shifts in populations underlie invasion success. Here, data for 26 herbaceous species at 39 sites, within eight countries, revealed that species abundances were similar at native (home) and introduced (away) sites - grass species were generally abundant home and away, while forbs were low in abundance, but more abundant at home. Sites with six or more of these species had similar community abundance hierarchies, suggesting that suites of introduced species are assembling similarly on different continents. Overall, we found that substantial changes to populations are not necessarily a pre-condition for invasion success and that increases in species abundance are unusual. Instead, abundance at home predicts abundance away, a potentially useful additional criterion for biosecurity programmes. 相似文献
957.
Prion diseases are neurodegenerative disorders associated with the accumulation of an abnormal isoform of the mammalian prion protein (PrP). Fourier transform infrared spectroscopy (FTIR) has previously been used to show that the conformation of aggregated, infectious PrP (PrP(Sc) ) varies between prion strains and these unique conformations may determine strain-specific disease phenotypes. However, the relative amounts of α-helix, β-sheet and other secondary structures have not always been consistent between studies, suggesting that other proteins might be confounding the analysis of PrP(Sc) secondary structure. We have used FTIR and LC-MS/MS to analyze enriched PrP(Sc) from mouse and hamster prion strains both before and after the removal of protein contaminants that commonly co-purify with PrP(Sc) . Our data show that non-PrP proteins do contribute to absorbances that have been associated with α-helical, loop, turn and β-sheet structures attributed to PrP(Sc) . The major contaminant, the α-helical protein ferritin, absorbs strongly at 1652 cm(-1) in the FTIR spectrum associated with PrP(Sc) . However, even the removal of more than 99% of the ferritin from PrP(Sc) did not completely abolish absorbance at 1652 cm(-1) . Our results show that contaminating proteins alter the FTIR spectrum attributed to PrP(Sc) and suggest that the α-helical, loop/turn and β-sheet secondary structure that remains following their removal are derived from PrP(Sc) itself. 相似文献
958.
目的:分析以肠道外症状为首发表现的结肠癌临床特征,旨在提高结肠癌诊治水平。方法:收集我院1994年1月至2008年1月间以肠道外症状为首发表现的结肠癌47例,对其临床特点进行回顾性分析。结果:47例以肠道外症状为首发表现的结肠癌中位发病年龄为65岁;贫血症状多见,占78.7%(37/47),长期低热3例,肝转移瘤4例,肺转移瘤2例,皮肌炎1例;肿瘤多发生于右半结肠,占74.5%(35/47);病理类型:乳头状腺癌为主,占61.7%(29/47);Dukes分期:B期占44.7%(21/47),C期占42.6%(20/47);结肠镜是重要诊断方法,结肠镜与钡灌肠有互补优势;手术是主要治疗手段,综合治疗可延长患者生存期。结论:以肠道外症状为首发表现的结肠癌以贫血多见,病变多位于右半结肠,结肠镜是主要确诊方法,以手术为主的综合治疗可改善患者预后。 相似文献
959.
960.
Comhair SA Gaston BM Ricci KS Hammel J Dweik RA Teague WG Meyers D Ampleford EJ Bleecker ER Busse WW Calhoun WJ Castro M Chung KF Curran-Everett D Israel E Jarjour WN Moore W Peters SP Wenzel S Hazen SL Erzurum SC;National Heart Lung Blood Institute Severe Asthma Research Program 《PloS one》2011,6(5):e18574