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121.
Cells counteract the adverse effects of chromosome breakage by activating the DNA damage response (DDR), which entails a coordinated series of events that regulate cell cycle progression and repair of DNA lesions. The packaging of genomic DNA into condensed, often inaccessible chromatin severely complicates efficient DNA damage repair in living cells. Recent studies implicate a large number of chromatin-modifying enzymes in the DDR, suggesting a stepwise model in which chromatin is continually reconfigured to accommodate the association and action of repair factors during the different stages of the DDR. Emerging evidence suggests that the histone ubiquitin ligases RNF8/RNF168 act in concert with ATP-dependent chromatin remodelling enzymes to orchestrate the signalling and repair of DNA lesions in specific chromatin topologies. 相似文献
122.
Canales E Carlson JS Appleby T Fenaux M Lee J Tian Y Tirunagari N Wong M Watkins WJ 《Bioorganic & medicinal chemistry letters》2012,22(13):4288-4292
The use of a tri-substituted acylhydrazine as an isostere of a tertiary amide was explored in a series of HCV NS5B thumb site II inhibitors. Direct replacement generated an analog with similar conformational and physicochemical properties. The series was extended to produce compounds with potent binding affinities and encouraging levels of cellular potency. 相似文献
123.
Background
It is known that people who suffer from depression are more likely to have other physical illnesses, but the extent of the association between depression and non-psychiatric hospitalisation episodes has never been researched in great depth. We therefore aimed to investigate whether depressed middle-aged and older people were more likely to be hospitalised for causes other than mental illnesses, and whether the outcomes for this group of people were less favourable.Methods & Findings
Hospital events from 1995 to 2006 were obtained from the Dutch National Medical Register and linked to participants of the Longitudinal Aging Study Amsterdam (LASA). Linkage was accomplished in 97% of the LASA sample by matching gender, year of birth and postal code. Depression was measured at each wave point of the LASA study using the Centre for Epidemiologic Studies Depression (CES-D). Hospital outcomes including admission, length of stay, readmission and death while in hospital were recorded at 6, 12 and 24 months intervals after each LASA interview. Generalised Estimating Equation models were also used to investigate potential confounders. After 12 months, 14% of depressed people were hospitalised compared to 10% of non-depressed individuals. There was a 2-fold increase in deaths while in hospital amongst the depressed (0.8% vs 0.4%), who also had longer total length of stay (2.6 days vs 1.4 days). Chronic illnesses and functional limitations had major attenuating effects, but depression was found to be an independent risk factor for length of stay after full adjustment (OR = 1.33, 95% CI: 1.22–1.46 after 12 months).Conclusions
Depression in middle and old age is associated with non-psychiatric hospitalisation, longer length of stay and higher mortality in clinical settings. Targeting of this high-risk group could reduce the financial, medical and social burden related to hospital admission. 相似文献124.
125.
In ADHD several EEG biomarkers have been described before, with relevance to treatment outcome to stimulant medication. This pilot-study aimed at personalizing neurofeedback treatment to these specific sub-groups to investigate if such an approach leads to improved clinical outcomes. Furthermore, pre- and post-treatment EEG and ERP changes were investigated in a sub-group to study the neurophysiological effects of neurofeedback. Twenty-one patients with ADHD were treated with QEEG-informed neurofeedback and post-treatment effects on inattention (ATT), hyperactivity/impulsivity (HI) and comorbid depressive symptoms were investigated. There was a significant improvement for both ATT, HI and comorbid depressive complaints after QEEG-informed neurofeedback. The effect size for ATT was 1.78 and for HI was 1.22. Furthermore, anterior individual alpha peak frequency (iAPF) demonstrated a strong relation to improvement on comorbid depressive complaints. Pre- and post-treatment effects for the SMR neurofeedback sub-group exhibited increased N200 and P300 amplitudes and decreased SMR EEG power post-treatment. This pilot study is the first study demonstrating that it is possible to select neurofeedback protocols based on individual EEG biomarkers and suggests this results in improved treatment outcome specifically for ATT, however these results should be replicated in further controlled studies. A slow anterior iAPF at baseline predicts poor treatment response on comorbid depressive complaints in line with studies in depression. The effects of SMR neurofeedback resulted in specific ERP and EEG changes. 相似文献
126.
127.
LJ Schurgers IA Joosen EM Laufer ML Chatrou M Herfs MH Winkens R Westenfeld V Veulemans T Krueger CM Shanahan W Jahnen-Dechent E Biessen J Narula C Vermeer L Hofstra CP Reutelingsperger 《PloS one》2012,7(8):e43229
Background
Vitamin K-antagonists (VKA) are treatment of choice and standard care for patients with venous thrombosis and thromboembolic risk. In experimental animal models as well as humans, VKA have been shown to promote medial elastocalcinosis. As vascular calcification is considered an independent risk factor for plaque instability, we here investigated the effect of VKA on coronary calcification in patients and on calcification of atherosclerotic plaques in the ApoE−/− model of atherosclerosis.Methodology/Principal Findings
A total of 266 patients (133 VKA users and 133 gender and Framingham Risk Score matched non-VKA users) underwent 64-slice MDCT to assess the degree of coronary artery disease (CAD). VKA-users developed significantly more calcified coronary plaques as compared to non-VKA users. ApoE−/− mice (10 weeks) received a Western type diet (WTD) for 12 weeks, after which mice were fed a WTD supplemented with vitamin K1 (VK1, 1.5 mg/g) or vitamin K1 and warfarin (VK1&W; 1.5 mg/g & 3.0 mg/g) for 1 or 4 weeks, after which mice were sacrificed. Warfarin significantly increased frequency and extent of vascular calcification. Also, plaque calcification comprised microcalcification of the intimal layer. Furthermore, warfarin treatment decreased plaque expression of calcification regulatory protein carboxylated matrix Gla-protein, increased apoptosis and, surprisingly outward plaque remodeling, without affecting overall plaque burden.Conclusions/Significance
VKA use is associated with coronary artery plaque calcification in patients with suspected CAD and causes changes in plaque morphology with features of plaque vulnerability in ApoE−/− mice. Our findings underscore the need for alternative anticoagulants that do not interfere with the vitamin K cycle. 相似文献128.
M Gloerich JP Ten Klooster MJ Vliem T Koorman FJ Zwartkruis H Clevers JL Bos 《Nature cell biology》2012,14(8):793-801
The microvillus brush border at the apex of the highly polarized enterocyte allows the regulated uptake of nutrients from the intestinal lumen. Here, we identify the small G protein Rap2A as a molecular link that couples the formation of microvilli directly to the preceding cell polarization. Establishment of apicobasal polarity, which can be triggered by the kinase LKB1 in single, isolated colon cells, results in enrichment of PtdIns(4,5)P(2) at the apical membrane. The subsequent recruitment of phospholipase D1 allows polarized accumulation of phosphatidic acid, which provides a local cue for successive signalling by the guanine nucleotide exchange factor PDZGEF, the small G protein Rap2A, its effector TNIK, the kinase MST4 and, ultimately, the actin-binding protein Ezrin. Thus, epithelial cell polarization is translated directly into the acquisition of brush borders through a small G protein signalling module whose action is positioned by a cortical lipid cue. 相似文献
129.
Parts L Hedman ÅK Keildson S Knights AJ Abreu-Goodger C van de Bunt M Guerra-Assunção JA Bartonicek N van Dongen S Mägi R Nisbet J Barrett A Rantalainen M Nica AC Quail MA Small KS Glass D Enright AJ Winn J;MuTHER Consortium Deloukas P Dermitzakis ET McCarthy MI Spector TD Durbin R Lindgren CM 《PLoS genetics》2012,8(5):e1002704
130.
Synthesis and evaluation of the quorum sensing inhibitory effect of substituted triazolyldihydrofuranones 总被引:1,自引:0,他引:1
Brackman G Risseeuw M Celen S Cos P Maes L Nelis HJ Van Calenbergh S Coenye T 《Bioorganic & medicinal chemistry》2012,20(15):4737-4743
Acylhomoserine lactone (AHL) analogues in which the amide function is replaced by a triazole group were synthesized and evaluated for their effect on quorum sensing (QS) and biofilm formation in Burkholderia cenocepacia and Pseudomonas aeruginosa. In addition, the influence of the length of the acyl-mimicking chain was investigated. The compounds showed selectivity between two different AHL QS systems. 3-(1H-1,2,3-Triazol-1-yl)dihydrofuran-2(3H)-ones, in which the 4-substituent best resembled the acyl chain of the native AHL molecule exhibited significant QS agonistic and antagonistic activities. Replacing this aliphatic substituent by a phenyl-containing moiety resulted in active inhibitors of QS. The most active compounds showed biofilm inhibitory as well as biofilm eradicating activities in both test organisms. 相似文献