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971.
Liver X receptors in cardiovascular and metabolic disease 总被引:5,自引:0,他引:5
Liver X receptors (LXRs) α and β are nuclear oxysterol receptors and metabolic sensors initially found to regulate cholesterol
metabolism and lipid biosynthesis. Recent studies have elucidated the importance of LXR in the development of cardiovascular
diseases and metabolic disorders. LXR agonists prevent development of atherosclerosis by modulation of metabolic as well as
inflammatory gene expression in rodent models. Moreover, LXR activation inhibits hepatic gluconeogenesis and lowers serum
glucose levels, indicating possible application of LXR activation in the treatment of diabetes mellitus. However, first-generation
LXR agonists elevate hepatic and serum trigylceride levels, making subtype-specific agonists and selective LXR modulators
rather than unselective LXR agonists a potential pharmacological strategy. This review summarizes the multiple physiological
and pathophysiological implications of LXRs and observations that identify LXRs as potential targets for therapeutic interventions
in human cardiovascular and metabolic disease.
Received 30 August 2005; received after revision 10 October 2005; accepted 4 November 2005 相似文献
972.
Human skin is permanently exposed to microorganisms, but rarely infected. One reason for this natural resistance might be
the existence of a ‘chemical barrier’ consisting in constitutively and inducibly produced antimicrobial peptides and proteins
(AMPs). Many of these AMPs can be induced in vitro by proinflammatory cytokines or bacteria. Apart from being expressed in vivo in inflammatory lesions, some AMPs are also focally expressed in skin in the absence of inflammation. This suggests that
non-inflammatory stimuli of endogenous and/or exogenous origin can also stimulate AMP synthesis without inflammation. Such
mediators might be ideal ‘immune stimulants’ to induce only the innate antimicrobial skin effector molecules without causing
inflammation.
Received 9 August 2005; received after revision 21 October 2005; accepted 16 November 2005 相似文献
973.
Genome-wide association is a promising approach to identify common genetic variants that predispose to human disease. Because of the high cost of genotyping hundreds of thousands of markers on thousands of subjects, genome-wide association studies often follow a staged design in which a proportion (pi(samples)) of the available samples are genotyped on a large number of markers in stage 1, and a proportion (pi(samples)) of these markers are later followed up by genotyping them on the remaining samples in stage 2. The standard strategy for analyzing such two-stage data is to view stage 2 as a replication study and focus on findings that reach statistical significance when stage 2 data are considered alone. We demonstrate that the alternative strategy of jointly analyzing the data from both stages almost always results in increased power to detect genetic association, despite the need to use more stringent significance levels, even when effect sizes differ between the two stages. We recommend joint analysis for all two-stage genome-wide association studies, especially when a relatively large proportion of the samples are genotyped in stage 1 (pi(samples) >or= 0.30), and a relatively large proportion of markers are selected for follow-up in stage 2 (pi(markers) >or= 0.01). 相似文献
974.
Gilbert SL Zhang L Forster ML Anderson JR Iwase T Soliven B Donahue LR Sweet HO Bronson RT Davisson MT Wollmann RL Lahn BT 《Nature genetics》2006,38(2):245-250
Hypertonia, which results from motor pathway defects in the central nervous system (CNS), is observed in numerous neurological conditions, including cerebral palsy, stroke, spinal cord injury, stiff-person syndrome, spastic paraplegia, dystonia and Parkinson disease. Mice with mutation in the hypertonic (hyrt) gene exhibit severe hypertonia as their primary symptom. Here we show that hyrt mutant mice have much lower levels of gamma-aminobutyric acid type A (GABA(A)) receptors in their CNS, particularly the lower motor neurons, than do wild-type mice, indicating that the hypertonicity of the mutants is likely to be caused by deficits in GABA-mediated motor neuron inhibition. We cloned the responsible gene, trafficking protein, kinesin binding 1 (Trak1), and showed that its protein product interacts with GABA(A) receptors. Our data implicate Trak1 as a crucial regulator of GABA(A) receptor homeostasis and underscore the importance of hyrt mice as a model for studying the molecular etiology of hypertonia associated with human neurological diseases. 相似文献
975.
976.
Skin barrier function and allergic risk 总被引:11,自引:0,他引:11
Hudson TJ 《Nature genetics》2006,38(4):399-400
977.
Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis 总被引:21,自引:0,他引:21
Palmer CN Irvine AD Terron-Kwiatkowski A Zhao Y Liao H Lee SP Goudie DR Sandilands A Campbell LE Smith FJ O'Regan GM Watson RM Cecil JE Bale SJ Compton JG DiGiovanna JJ Fleckman P Lewis-Jones S Arseculeratne G Sergeant A Munro CS El Houate B McElreavey K Halkjaer LB Bisgaard H Mukhopadhyay S McLean WH 《Nature genetics》2006,38(4):441-446
Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease. 相似文献
978.
Greenway MJ Andersen PM Russ C Ennis S Cashman S Donaghy C Patterson V Swingler R Kieran D Prehn J Morrison KE Green A Acharya KR Brown RH Hardiman O 《Nature genetics》2006,38(4):411-413
We recently identified angiogenin (ANG) as a candidate susceptibility gene for amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by adult-onset loss of motor neurons. We now report the finding of seven missense mutations in 15 individuals, of whom four had familial ALS and 11 apparently 'sporadic' ALS. Our findings provide further evidence that variations in hypoxia-inducible genes have an important role in motor neuron degeneration. 相似文献
979.
Gandhi TK Zhong J Mathivanan S Karthick L Chandrika KN Mohan SS Sharma S Pinkert S Nagaraju S Periaswamy B Mishra G Nandakumar K Shen B Deshpande N Nayak R Sarker M Boeke JD Parmigiani G Schultz J Bader JS Pandey A 《Nature genetics》2006,38(3):285-293
We present the first analysis of the human proteome with regard to interactions between proteins. We also compare the human interactome with the available interaction datasets from yeast (Saccharomyces cerevisiae), worm (Caenorhabditis elegans) and fly (Drosophila melanogaster). Of >70,000 binary interactions, only 42 were common to human, worm and fly, and only 16 were common to all four datasets. An additional 36 interactions were common to fly and worm but were not observed in humans, although a coimmunoprecipitation assay showed that 9 of the interactions do occur in humans. A re-examination of the connectivity of essential genes in yeast and humans indicated that the available data do not support the presumption that the number of interaction partners can accurately predict whether a gene is essential. Finally, we found that proteins encoded by genes mutated in inherited genetic disorders are likely to interact with proteins known to cause similar disorders, suggesting the existence of disease subnetworks. The human interaction map constructed from our analysis should facilitate an integrative systems biology approach to elucidating the cellular networks that contribute to health and disease states. 相似文献
980.