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951.
Melum E Franke A Schramm C Weismüller TJ Gotthardt DN Offner FA Juran BD Laerdahl JK Labi V Björnsson E Weersma RK Henckaerts L Teufel A Rust C Ellinghaus E Balschun T Boberg KM Ellinghaus D Bergquist A Sauer P Ryu E Hov JR Wedemeyer J Lindkvist B Wittig M Porte RJ Holm K Gieger C Wichmann HE Stokkers P Ponsioen CY Runz H Stiehl A Wijmenga C Sterneck M Vermeire S Beuers U Villunger A Schrumpf E Lazaridis KN Manns MP Schreiber S Karlsen TH 《Nature genetics》2011,43(1):17-19
Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4-7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10?1? and P = 4.1 × 10??, respectively). 相似文献
952.
Lausch E Janecke A Bros M Trojandt S Alanay Y De Laet C Hübner CA Meinecke P Nishimura G Matsuo M Hirano Y Tenoutasse S Kiss A Rosa RF Unger SL Renella R Bonafé L Spranger J Unger S Zabel B Superti-Furga A 《Nature genetics》2011,43(2):132-137
Vertebral and metaphyseal dysplasia, spasticity with cerebral calcifications, and strong predisposition to autoimmune diseases are the hallmarks of the genetic disorder spondyloenchondrodysplasia. We mapped a locus in five consanguineous families to chromosome 19p13 and identified mutations in ACP5, which encodes tartrate-resistant phosphatase (TRAP), in 14 affected individuals and showed that these mutations abolish enzyme function in the serum and cells of affected individuals. Phosphorylated osteopontin, a protein involved in bone reabsorption and in immune regulation, accumulates in serum, urine and cells cultured from TRAP-deficient individuals. Case-derived dendritic cells exhibit an altered cytokine profile and are more potent than matched control cells in stimulating allogeneic T cell proliferation in mixed lymphocyte reactions. These findings shed new light on the role of osteopontin and its regulation by TRAP in the pathogenesis of common autoimmune disorders. 相似文献
953.
Franz Marxreiter Martin Regensburger Jürgen Winkler 《Cellular and molecular life sciences : CMLS》2013,70(3):459-473
Parkinson’s disease (PD), the second most common neurodegenerative disorder, affects 1–2 % of humans aged 60 years and older. The diagnosis of PD is based on motor symptoms such as bradykinesia, rigidity, tremor, and postural instability associated with the striatal dopaminergic deficit that is linked to neurodegenerative processes in the substantia nigra (SN). In the past, cellular replacement strategies have been evaluated for their potential to alleviate these symptoms. Adult neurogenesis, the generation of new neurons within two proliferative niches in the adult brain, is being intensively studied as one potential mode for cell-based therapies. The subventricular zone provides new neurons for the olfactory bulb functionally contributing to olfaction. The subgranular zone of the hippocampus produces new granule neurons for the dentate gyrus, required for memory formation and proper processing of anxiety provoking stimuli. Recent years have revealed that PD is associated with non-motor symptoms such as hyposmia, anhedonia, lack of novelty seeking behavior, depression, and anxiety that are not directly associated with neurodegenerative processes in the SN. This broad spectrum of non-motor symptoms may partly rely on proper olfactorial processing and hippocampal function. Therefore, it is conceivable that some non-motor deficits in PD are related to defective adult neurogenesis. Accordingly, in animal models and postmortem studies of PD, adult neurogenesis is severely affected, although the exact mechanisms and effects of these changes are not yet fully understood or are under debate due to conflicting results. Here, we review the current concepts related to the dynamic interplay between endogenous cellular plasticity and PD-associated pathology. 相似文献
954.
Valerie Le Fourn Sujin Park Insook Jang Katarina Gaplovska-Kysela Bruno Guhl Yangsin Lee Jin Won Cho Christian Zuber Jürgen Roth 《Cellular and molecular life sciences : CMLS》2013,70(11):1985-2002
Multisubunit protein complexes are assembled in the endoplasmic reticulum (ER). Existing pools of single subunits and assembly intermediates ensure the efficient and rapid formation of complete complexes. While being kinetically beneficial, surplus components must be eliminated to prevent potentially harmful accumulation in the ER. Surplus single chains are cleared by the ubiquitin–proteasome system. However, the fate of not secreted assembly intermediates of multisubunit proteins remains elusive. Here we show by high-resolution double-label confocal immunofluorescence and immunogold electron microscopy that naturally occurring surplus fibrinogen Aα–γ assembly intermediates in HepG2 cells are dislocated together with EDEM1 from the ER to the cytoplasm in ER-derived vesicles not corresponding to COPII-coated vesicles originating from the transitional ER. This route corresponds to the novel ER exit path we have previously identified for EDEM1 (Zuber et al. Proc Natl Acad Sci USA 104:4407–4412, 2007). In the cytoplasm, detergent-insoluble aggregates of fibrinogen Aα–γ dimers develop that are targeted by the selective autophagy cargo receptors p62/SQSTM1 and NBR1. These aggregates are degraded by selective autophagy as directly demonstrated by high-resolution microscopy as well as biochemical analysis and inhibition of autophagy by siRNA and kinase inhibitors. Our findings demonstrate that different pathways exist in parallel for ER-to-cytoplasm dislocation and subsequent proteolytic degradation of large luminal protein complexes and of surplus luminal single-chain proteins. This implies that ER-associated protein degradation (ERAD) has a broader function in ER proteostasis and is not limited to the elimination of misfolded glycoproteins. 相似文献
955.
Role of Nef in primate lentiviral immunopathogenesis 总被引:1,自引:0,他引:1
Kirchhoff F Schindler M Specht A Arhel N Münch J 《Cellular and molecular life sciences : CMLS》2008,65(17):2621-2636
More than a decade ago it was established that intact nef genes are critical for efficient viral persistence and greatly accelerate disease progression in SIVmac-infected rhesus macaques and in HIV-1-infected humans. Subsequent studies established a striking number of Nef functions that evidently contribute to the maintenance of high viral loads associated with the development of immunodeficiency in the 'evolutionary-recent' human and the experimental macaque hosts. Recent data show that many Nef activities are conserved across different lineages of HIV and SIV. However, some differences also exist. For example, Nef alleles from most SIVs that do not cause disease in their natural monkey hosts, but not those of HIV-1 and its simian precursors, down-modulate TCR-CD3 to suppress T cell activation and programmed death. This evolutionary loss of a specific Nef function may contribute to the high virulence of HIV-1 in humans. 相似文献
956.
Charles S. Peirce on Creative Metaphor: A Case Study on the Conveyor Belt Metaphor in Oceanography 总被引:1,自引:0,他引:1
Within Charles Sanders Peirce's semiotical theory, twodifferent kinds of creative metaphorical reasoning inscience can be identified. One of these, the buildingof remainder metaphors, is especially important forcreating new scientific models. We show that theconveyor belt metaphor provides an excellent examplefor Peirce's theory. The conveyor belt metaphor hasrecently been invented in order to describe theoceanic transport system. The paradigm of the oceanicconveyor belt strongly influenced the geosciencecommunity and the climate change discussion. Afteridentifying structures of metaphorical reasoning inscience (section 2), these structures are examined insection 3 for the conveyor belt metaphor in the fieldof oceanography. Finally, concluding remarks are givenin section 4. 相似文献
957.
The faculty of economics at today's Humboldt University in Berlin, as no other institution of economics, has witnessed three radical ruptures in its history: in 1933, National Socialism replaced the pluralism prevailing in the Weimar Republic by imposing a “German economics”; after WWII, GDR authorities replaced this NS regime by imposing a Marxist imperative, which after the fall of the wall was replaced by the Western standards of neoclassical economics. In reconstructing these three reforms, institutional history can serve as a context in which questions about the political nature of economic knowledge can be answered that remain speculative in a conceptual context. I thus present a natural experiment in the political epistemology of economics: How do economists respond to, resist, and stabilize, changing political regimes? How do economists renegotiate the autonomy of economic knowledge given changing demands as of its social task? Among others, I show that contrary to Robert Merton's old, but still widely held thesis in political epistemology—that the values of science are compatible only with democratic regimes—the totalitarian and authoritarian regimes created better conditions for methodological pluralism in economics than democratic society. 相似文献
958.
Ludwig Heesen Michael Peitz Laura Torres-Benito Irmgard Hölker Kristina Hupperich Kristina Dobrindt Johannes Jungverdorben Swetlana Ritzenhofen Beatrice Weykopf Daniela Eckert Seyyed Mohsen Hosseini-Barkooie Markus Storbeck Noemi Fusaki Renata Lonigro Raoul Heller Min Jeong Kye Oliver Brüstle Brunhilde Wirth 《Cellular and molecular life sciences : CMLS》2016,73(10):2089-2104
959.
960.
In this paper we propose a multiple feature approach for the normalization task which can map each disorder mention in the text to a unique unified medical language system (UMLS) concept unique identifier (CUI). We develop a two-step method to acquire a list of candidate CUIs and their associated preferred names using UMLS API and to choose the closest CUI by calculating the similarity between the input disorder mention and each candidate. The similarity calculation step is formulated as a classification problem and multiple features (string features, ranking features, similarity features, and contextual features) are used to normalize the disorder mentions. The results show that the multiple feature approach improves the accuracy of the normalization task from 32.99% to 67.08% compared with the MetaMap baseline. 相似文献