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1.
Complement factor H binds malondialdehyde epitopes and protects from oxidative stress 总被引:2,自引:0,他引:2
Weismann D Hartvigsen K Lauer N Bennett KL Scholl HP Charbel Issa P Cano M Brandstätter H Tsimikas S Skerka C Superti-Furga G Handa JT Zipfel PF Witztum JL Binder CJ 《Nature》2011,478(7367):76-81
Oxidative stress and enhanced lipid peroxidation are linked to many chronic inflammatory diseases, including age-related macular degeneration (AMD). AMD is the leading cause of blindness in Western societies, but its aetiology remains largely unknown. Malondialdehyde (MDA) is a common lipid peroxidation product that accumulates in many pathophysiological processes, including AMD. Here we identify complement factor H (CFH) as a major MDA-binding protein that can block both the uptake of MDA-modified proteins by macrophages and MDA-induced proinflammatory effects in vivo in mice. The CFH polymorphism H402, which is strongly associated with AMD, markedly reduces the ability of CFH to bind MDA, indicating a causal link to disease aetiology. Our findings provide important mechanistic insights into innate immune responses to oxidative stress, which may be exploited in the prevention of and therapy for AMD and other chronic inflammatory diseases. 相似文献
2.
Nadine de Courtenay 《Studies in history and philosophy of science》2010,41(1):41-57
Two complementary debates of the turn of the nineteenth and twentieth century are examined here: the debate on the legitimacy of hypotheses in the natural sciences and the debate on intentionality and ‘representations without object’ in philosophy. Both are shown to rest on two core issues: the attitude of the subject and the mode of presentation chosen to display a domain of phenomena. An orientation other than the one which contributed to shape twentieth-century philosophy of science is explored through the analysis of the role given to assumptions in Boltzmann’s research strategy, where assumptions are contrasted to hypotheses, axioms, and principles, and in Meinong’s criticism of the privileged status attributed to representations in mental activities. Boltzmann’s computational style in mathematics and Meinong’s criticism of the confusion between representation and judgment give prominence to an indirect mode of presentation, adopted in a state of suspended belief which is characteristic of assumptions and which enables one to grasp objects that cannot be reached through direct representation or even analogies. The discussion shows how assumptions and the movement to fiction can be essential steps in the quest for objectivity. The conclusion restates the issues of the two debates in a contemporary perspective and shows how recent developments in philosophy of science and philosophy of language and mind can be brought together by arguing for a twofold conception of reference. 相似文献
3.
Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis 总被引:11,自引:0,他引:11
Hellemans J Preobrazhenska O Willaert A Debeer P Verdonk PC Costa T Janssens K Menten B Van Roy N Vermeulen SJ Savarirayan R Van Hul W Vanhoenacker F Huylebroeck D De Paepe A Naeyaert JM Vandesompele J Speleman F Verschueren K Coucke PJ Mortier GR 《Nature genetics》2004,36(11):1213-1218
Osteopoikilosis, Buschke-Ollendorff syndrome (BOS) and melorheostosis are disorders characterized by increased bone density. The occurrence of one or more of these phenotypes in the same individual or family suggests that these entities might be allelic. We collected data from three families in which affected individuals had osteopoikilosis with or without manifestations of BOS or melorheostosis. A genome-wide linkage analysis in these families, followed by the identification of a microdeletion in an unrelated individual with these diseases, allowed us to map the gene that is mutated in osteopoikilosis. All the affected individuals that we investigated were heterozygous with respect to a loss-of-function mutation in LEMD3 (also called MAN1), which encodes an inner nuclear membrane protein. A somatic mutation in the second allele of LEMD3 could not be identified in fibroblasts from affected skin of an individual with BOS and an individual with melorheostosis. XMAN1, the Xenopus laevis ortholog, antagonizes BMP signaling during embryogenesis. In this study, LEMD3 interacted with BMP and activin-TGFbeta receptor-activated Smads and antagonized both signaling pathways in human cells. 相似文献
4.
Vertebrate eggs awaiting fertilization are arrested at metaphase of meiosis II by a biochemical activity termed cytostatic factor (CSF). This activity inhibits the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase that triggers anaphase onset and mitotic/meiotic exit by targeting securin and M-phase cyclins for destruction. On fertilization a transient rise in free intracellular calcium causes release from CSF arrest and thus APC/C activation. Although it has previously been shown that calcium induces the release of APC/C from CSF inhibition through calmodulin-dependent protein kinase II (CaMKII), the relevant substrates of this kinase have not been identified. Recently, we characterized XErp1 (Emi2), an inhibitor of the APC/C and key component of CSF activity in Xenopus egg extract. Here we show that calcium-activated CaMKII triggers exit from meiosis II by sensitizing the APC/C inhibitor XErp1 for polo-like kinase 1 (Plx1)-dependent degradation. Phosphorylation of XErp1 by CaMKII leads to the recruitment of Plx1 that in turn triggers the destruction of XErp1 by phosphorylating a site known to serve as a phosphorylation-dependent degradation signal. These results provide a molecular explanation for how the fertilization-induced calcium increase triggers exit from meiosis II. 相似文献
5.
Illing PT Vivian JP Dudek NL Kostenko L Chen Z Bharadwaj M Miles JJ Kjer-Nielsen L Gras S Williamson NA Burrows SR Purcell AW Rossjohn J McCluskey J 《Nature》2012,486(7404):554-558
Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T?cells. HLA polymorphisms mostly map to the antigen-binding cleft, thereby diversifying the repertoire of self-derived and pathogen-derived peptide antigens selected by different HLA allotypes. A growing number of immunologically based drug reactions, including abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Stevens-Johnson syndrome (SJS), are associated with specific HLA alleles. However, little is known about the underlying mechanisms of these associations, including AHS, a prototypical HLA-associated drug reaction occurring exclusively in individuals with the common histocompatibility allele HLA-B*57:01, and with a relative risk of more than 1,000 (refs?6, 7). We show that unmodified abacavir binds non-covalently to HLA-B*57:01, lying across the bottom of the antigen-binding cleft and reaching into the F-pocket, where a carboxy-terminal tryptophan typically anchors peptides bound to HLA-B*57:01. Abacavir binds with exquisite specificity to HLA-B*57:01, changing the shape and chemistry of the antigen-binding cleft, thereby altering the repertoire of endogenous peptides that can bind HLA-B*57:01. In this way, abacavir guides the selection of new endogenous peptides, inducing a marked alteration in 'immunological self'. The resultant peptide-centric 'altered self' activates abacavir-specific T-cells, thereby driving polyclonal CD8 T-cell activation and a systemic reaction manifesting as AHS. We also show that carbamazepine, a widely used anti-epileptic drug associated with hypersensitivity reactions in HLA-B*15:02 individuals, binds to this allotype, producing alterations in the repertoire of presented self peptides. Our findings simultaneously highlight the importance of HLA polymorphism in the evolution of pharmacogenomics and provide a general mechanism for some of the growing number of HLA-linked hypersensitivities that involve small-molecule drugs. 相似文献
6.
COMPARISON OF TWO METHODS OF OPERATING THEATRE PLANNING: APPLICATION IN BELGIAN HOSPITAL 总被引:3,自引:0,他引:3
Sondes CHAABANE~ Nadine MESKENS~ Alain GUINET~ Marius LAURENT~ ~LAMIH laboratory Valenciennes University Valenciennes Cedex France ~MAAD Laboratory FUCAM Mons Belgium ~LIESP Laboratory INSA-Lyon France ~CHU de TIVOLI La Louvière Belgium 《系统科学与系统工程学报(英文版)》2008,17(2):171-186
Operating Theatre is the centre of the hospital management's efforts. It constitutes the most expensive sector with more than 10% of the intended operating budget of the hospital. To reduce the costs while maintaining a good quality of care, one of the solutions is to improve the existent planning and scheduling methods by improving the services and surgical specialty coordination or finding the best estimation of surgical case durations. The other solution is to construct an effective surgical case plan and schedule. The operating theatre planning and scheduling is the two important steps, which aim to make a surgical case programming with an objective of obtaining a realizable and efficient surgical case schedule. This paper focuses on the first step, the operating theatre planning problem. Two planning methods are introduced and compared. Real data of a Belgian university hospital "Tivoli" are used for the experiments. 相似文献
7.
Charlier C Coppieters W Rollin F Desmecht D Agerholm JS Cambisano N Carta E Dardano S Dive M Fasquelle C Frennet JC Hanset R Hubin X Jorgensen C Karim L Kent M Harvey K Pearce BR Simon P Tama N Nie H Vandeputte S Lien S Longeri M Fredholm M Harvey RJ Georges M 《Nature genetics》2008,40(4):449-454
The widespread use of elite sires by means of artificial insemination in livestock breeding leads to the frequent emergence of recessive genetic defects, which cause significant economic and animal welfare concerns. Here we show that the availability of genome-wide, high-density SNP panels, combined with the typical structure of livestock populations, markedly accelerates the positional identification of genes and mutations that cause inherited defects. We report the fine-scale mapping of five recessive disorders in cattle and the molecular basis for three of these: congenital muscular dystony (CMD) types 1 and 2 in Belgian Blue cattle and ichthyosis fetalis in Italian Chianina cattle. Identification of these causative mutations has an immediate translation into breeding practice, allowing marker assisted selection against the defects through avoidance of at-risk matings. 相似文献
8.
Long- and short-lived radioactive isotopes and their daughter products in meteorites are chronometers that can test models for Solar System formation. Differentiated meteorites come from parent bodies that were once molten and separated into metal cores and silicate mantles. Mineral ages for these meteorites, however, are typically younger than age constraints for planetesimal differentiation. Such young ages indicate that the energy required to melt their parent bodies could not have come from the most likely heat source-radioactive decay of short-lived nuclides ((26)Al and (60)Fe) injected from a nearby supernova-because these would have largely decayed by the time of melting. Here we report an age of 4.5662 +/- 0.0001 billion years (based on Pb-Pb dating) for basaltic angrites, which is only 1 Myr younger than the currently accepted minimum age of the Solar System and corresponds to a time when (26)Al and (60)Fe decay could have triggered planetesimal melting. Small (26)Mg excesses in bulk angrite samples confirm that (26)Al decay contributed to the melting of their parent body. These results indicate that the accretion of differentiated planetesimals pre-dated that of undifferentiated planetesimals, and reveals the minimum Solar System age to be 4.5695 +/- 0.0002 billion years. 相似文献
9.
Kévin Baranger Yannick Marchalant Amandine E. Bonnet Nadine Crouzin Alex Carrete Jean-Michel Paumier Nathalie A. Py Anne Bernard Charlotte Bauer Eliane Charrat Katrin Moschke Mothoharu Seiki Michel Vignes Stefan F. Lichtenthaler Frédéric Checler Michel Khrestchatisky Santiago Rivera 《Cellular and molecular life sciences : CMLS》2016,73(1):217-236
10.
Recent decline in the global land evapotranspiration trend due to limited moisture supply 总被引:31,自引:0,他引:31
Jung M Reichstein M Ciais P Seneviratne SI Sheffield J Goulden ML Bonan G Cescatti A Chen J de Jeu R Dolman AJ Eugster W Gerten D Gianelle D Gobron N Heinke J Kimball J Law BE Montagnani L Mu Q Mueller B Oleson K Papale D Richardson AD Roupsard O Running S Tomelleri E Viovy N Weber U Williams C Wood E Zaehle S Zhang K 《Nature》2010,467(7318):951-954
More than half of the solar energy absorbed by land surfaces is currently used to evaporate water. Climate change is expected to intensify the hydrological cycle and to alter evapotranspiration, with implications for ecosystem services and feedback to regional and global climate. Evapotranspiration changes may already be under way, but direct observational constraints are lacking at the global scale. Until such evidence is available, changes in the water cycle on land?a key diagnostic criterion of the effects of climate change and variability?remain uncertain. Here we provide a data-driven estimate of global land evapotranspiration from 1982 to 2008, compiled using a global monitoring network, meteorological and remote-sensing observations, and a machine-learning algorithm. In addition, we have assessed evapotranspiration variations over the same time period using an ensemble of process-based land-surface models. Our results suggest that global annual evapotranspiration increased on average by 7.1?±?1.0?millimetres per year per decade from 1982 to 1997. After that, coincident with the last major El Ni?o event in 1998, the global evapotranspiration increase seems to have ceased until 2008. This change was driven primarily by moisture limitation in the Southern Hemisphere, particularly Africa and Australia. In these regions, microwave satellite observations indicate that soil moisture decreased from 1998 to 2008. Hence, increasing soil-moisture limitations on evapotranspiration largely explain the recent decline of the global land-evapotranspiration trend. Whether the changing behaviour of evapotranspiration is representative of natural climate variability or reflects a more permanent reorganization of the land water cycle is a key question for earth system science. 相似文献