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61.
Analysis of human transcriptomes 总被引:47,自引:0,他引:47
62.
Han MH Hwang SI Roy DB Lundgren DH Price JV Ousman SS Fernald GH Gerlitz B Robinson WH Baranzini SE Grinnell BW Raine CS Sobel RA Han DK Steinman L 《Nature》2008,451(7182):1076-1081
Understanding the neuropathology of multiple sclerosis (MS) is essential for improved therapies. Therefore, identification of targets specific to pathological types of MS may have therapeutic benefits. Here we identify, by laser-capture microdissection and proteomics, proteins unique to three major types of MS lesions: acute plaque, chronic active plaque and chronic plaque. Comparative proteomic profiles identified tissue factor and protein C inhibitor within chronic active plaque samples, suggesting dysregulation of molecules associated with coagulation. In vivo administration of hirudin or recombinant activated protein C reduced disease severity in experimental autoimmune encephalomyelitis and suppressed Th1 and Th17 cytokines in astrocytes and immune cells. Administration of mutant forms of recombinant activated protein C showed that both its anticoagulant and its signalling functions were essential for optimal amelioration of experimental autoimmune encephalomyelitis. A proteomic approach illuminated potential therapeutic targets selective for specific pathological stages of MS and implicated participation of the coagulation cascade. 相似文献
63.
For predicting forward default probabilities of firms, the discrete‐time forward hazard model (DFHM) is proposed. We derive maximum likelihood estimates for the parameters in DFHM. To improve its predictive power in practice, we also consider an extension of DFHM by replacing its constant coefficients of firm‐specific predictors with smooth functions of macroeconomic variables. The resulting model is called the discrete‐time varying‐coefficient forward hazard model (DVFHM). Through local maximum likelihood analysis, DVFHM is shown to be a reliable and flexible model for forward default prediction. We use real panel datasets to illustrate these two models. Using an expanding rolling window approach, our empirical results confirm that DVFHM has better and more robust out‐of‐sample performance on forward default prediction than DFHM, in the sense of yielding more accurate predicted numbers of defaults and predicted survival times. Thus DVFHM is a useful alternative for studying forward default losses in portfolios. Copyright © 2013 John Wiley & Sons, Ltd. 相似文献
64.
Youngjin Hwang 《Journal of forecasting》2017,36(5):581-596
The specification choices of vector autoregressions (VARs) in forecasting are often not straightforward, as they are complicated by various factors. To deal with model uncertainty and better utilize multiple VARs, this paper adopts the dynamic model averaging/selection (DMA/DMS) algorithm, in which forecasting models are updated and switch over time in a Bayesian manner. In an empirical application to a pool of Bayesian VAR (BVAR) models whose specifications include level and difference, along with differing lag lengths, we demonstrate that specification‐switching VARs are flexible and powerful forecast tools that yield good performance. In particular, they beat the overall best BVAR in most cases and are comparable to or better than the individual best models (for each combination of variable, forecast horizon, and evaluation metrics) for medium‐ and long‐horizon forecasts. We also examine several extensions in which forecast model pools consist of additional individual models in partial differences as well as all level/difference models, and/or time variations in VAR innovations are allowed, and discuss the potential advantages and disadvantages of such specification choices. Copyright © 2016 John Wiley & Sons, Ltd. 相似文献
65.
66.
Stein JL Medland SE Vasquez AA Hibar DP Senstad RE Winkler AM Toro R Appel K Bartecek R Bergmann Ø Bernard M Brown AA Cannon DM Chakravarty MM Christoforou A Domin M Grimm O Hollinshead M Holmes AJ Homuth G Hottenga JJ Langan C Lopez LM Hansell NK Hwang KS Kim S Laje G Lee PH Liu X Loth E Lourdusamy A Mattingsdal M Mohnke S Maniega SM Nho K Nugent AC O'Brien C Papmeyer M Pütz B Ramasamy A Rasmussen J Rijpkema M Risacher SL Roddey JC Rose EJ Ryten M Shen L Sprooten E Strengman E Teumer A 《Nature genetics》2012,44(5):552-561
Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)). 相似文献
67.
Eun Seong Hwang Gyesoon Yoon Hyun Tae Kang 《Cellular and molecular life sciences : CMLS》2009,66(15):2503-2524
Various intracellular organelles, such as lysosomes, mitochondria, nuclei, and cytoskeletons, change during replicative senescence,
but the utility of these changes as general markers of senescence and their significance with respect to functional alterations
have not been comprehensively reviewed. Furthermore, the relevance of these alterations to cellular and functional changes
in aging animals is poorly understood. In this paper, we review the studies that report these senescence-associated changes
in various aging cells and their underlying mechanisms. Changes associated with lysosomes and mitochondria are found not only
in cells undergoing replicative or induced senescence but also in postmitotic cells isolated from aged organisms. In contrast,
other changes occur mainly in cells undergoing in vitro senescence. Comparison of age-related changes and their underlying
mechanisms in in vitro senescent cells and aged postmitotic cells would reveal the relevance of replicative senescence to
the physiological processes occurring in postmitotic cells as individuals age. 相似文献
68.
The protein kinase A-regulated cardiac Cl- channel resembles the cystic fibrosis transmembrane conductance regulator. 总被引:12,自引:0,他引:12
Stimulation of beta-adrenoceptors in cardiac ventricular myocytes activates a strong chloride ion conductance as a result of phosphorylation by cyclic AMP-dependent protein kinase (PKA). This Cl- conductance, which is time- and voltage-independent, counters the tendency of the simultaneously enhanced Ca2+ channel current to prolong the ventricular action potential. Using inside-out giant patches excised from guinea-pig myocytes, we show here that phosphorylation by the PKA catalytic subunit plus Mg-ATP elicits discrete Cl- channel currents. In almost symmetrical Cl- solutions (approximately 150 mM), unitary current amplitude scales with membrane potential, and reverses sign near 0 mV, to yield a single channel conductance of approximately 12 pS. Opening of the phosphorylated channels requires hydrolysable nucleoside triphosphate, indicating that phosphorylation by PKA is necessary, but not sufficient, for channel activation. The properties of these PKA-regulated cardiac Cl- channels are very similar, if not identical, to those of the cystic fibrosis transmembrane conductance regulator (CFTR), the epithelial cell Cl- channel whose regulation is defective in patients with cystic fibrosis. The full cardiological impact of these Cl- channels and of their possible malfunction in patients with cystic fibrosis remains to be determined. 相似文献
69.
In Young Hwang Hui Ling Lee James Guoxian Huang Yvonne Yijuan Lim Wen Shan Yew Yung Seng Lee Matthew Wook Chang 《Cellular and molecular life sciences : CMLS》2018,75(15):2719-2733
Lack of pathogen specificity in antimicrobial therapy causes non-discriminant microbial cell killing that disrupts the microflora present. As a result, potentially helpful microbial cells are killed along with the pathogen, altering the biodiversity and dynamic interactions within the population. Moreover, the unwarranted exposure of antibiotics to microbes increases the likelihood of developing resistance and perpetuates the emergence of multidrug resistance. Synthetic biology offers an alternative solution where specificity can be conferred to reduce the non-specific, non-targeted activity of currently available antibiotics, and instead provides targeted therapy against specific pathogens and minimising collateral damage to the host’s inherent microbiota. With a greater understanding of the microbiome and the available genetic engineering tools for microbial cells, it is possible to devise antimicrobial strategies for novel antimicrobial therapy that are able to precisely and selectively remove infectious pathogens. Herein, we review the strategies developed by unlocking some of the natural mechanisms used by the microbes and how these may be utilised in targeted antimicrobial therapy, with the promise of reducing the current global bane of multidrug antimicrobial resistance. 相似文献
70.
Differential use of an in-frame translation initiation codon regulates human mu opioid receptor (OPRM1) 总被引:1,自引:1,他引:0
Kyu Young Song Hack Sun Choi Cheol Kyu Hwang Chun Sung Kim Ping-Yee Law Li-Na Wei Horace H. Loh 《Cellular and molecular life sciences : CMLS》2009,66(17):2933-2942
The pharmacological effects of morphine and morphine-like drugs are mediated primarily through the μ opioid receptor. Here
we show that differential use of an in-frame translational start codon in the 5′-untranslated region of the OPRM1 generates
different translational products in vivo and in vitro. The 5′-end of the OPRM1 gene is necessary for initiating the alternate
form and for subsequent degradation of the protein. Initiation of OPRM1 at the upstream site decreases the initiation at the
main AUG site. However, alternative initiation of the long form of OPRM1 produces a protein with a short half-life, resulting
from degradation mediated by the ubiquitin–proteasome pathway. Reporter and degradation assays showed that mutations of this
long form at the second and third lysines reduce ubiquitin-dependent proteasome degradation, stabilizing the protein. The
data suggest that MOP expression is controlled in part by initiation of the long form of MOP at the alternate site. 相似文献