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101.
Asagoshi K Lehmann W Braithwaite EK Santana-Santos L Prasad R Freedman JH Van Houten B Wilson SH 《Nucleic acids research》2012,40(2):670-681
The base excision DNA repair (BER) pathway known to occur in Caenorhabditis elegans has not been well characterized. Even less is known about the DNA polymerase (pol) requirement for the gap-filling step during BER. We now report on characterization of in vitro uracil-DNA initiated BER in C. elegans. The results revealed single-nucleotide (SN) gap-filling DNA polymerase activity and complete BER. The gap-filling polymerase activity was not due to a DNA polymerase β (pol β) homolog, or to another X-family polymerase, since computer-based sequence analyses of the C. elegans genome failed to show a match for a pol β-like gene or other X-family polymerases. Activity gel analysis confirmed the absence of pol β in the C. elegans extract. BER gap-filling polymerase activity was partially inhibited by both dideoxynucleotide and aphidicolin. The results are consistent with a combination of both replicative polymerase(s) and lesion bypass/BER polymerase pol θ contributing to the BER gap-filling synthesis. Involvement of pol θ was confirmed in experiments with extract from pol θ null animals. The presence of the SN BER in C. elegans is supported by these results, despite the absence of a pol β-like enzyme or other X-family polymerase. 相似文献
102.
Chen HK Liu Z Meyer-Franke A Brodbeck J Miranda RD McGuire JG Pleiss MA Ji ZS Balestra ME Walker DW Xu Q Jeong DE Budamagunta MS Voss JC Freedman SB Weisgraber KH Huang Y Mahley RW 《The Journal of biological chemistry》2012,287(8):5253-5266
Apolipoprotein E4 (apoE4), the major genetic risk factor for late onset Alzheimer disease, assumes a pathological conformation, intramolecular domain interaction. ApoE4 domain interaction mediates the detrimental effects of apoE4, including decreased mitochondrial cytochrome c oxidase subunit 1 levels, reduced mitochondrial motility, and reduced neurite outgrowth in vitro. Mutant apoE4 (apoE4-R61T) lacks domain interaction, behaves like apoE3, and does not cause detrimental effects. To identify small molecules that inhibit domain interaction (i.e. structure correctors) and reverse the apoE4 detrimental effects, we established a high throughput cell-based FRET primary assay that determines apoE4 domain interaction and secondary cell- and function-based assays. Screening a ChemBridge library with the FRET assay identified CB9032258 (a phthalazinone derivative), which inhibits domain interaction in neuronal cells. In secondary functional assays, CB9032258 restored mitochondrial cytochrome c oxidase subunit 1 levels and rescued impairments of mitochondrial motility and neurite outgrowth in apoE4-expressing neuronal cells. These benefits were apoE4-specific and dose-dependent. Modifying CB9032258 yielded well defined structure-activity relationships and more active compounds with enhanced potencies in the FRET assay (IC(50) of 23 and 116 nm, respectively). These compounds efficiently restored functional activities of apoE4-expressing cells in secondary assays. An EPR binding assay showed that the apoE4 structure correction resulted from direct interaction of a phthalazinone. With these data, a six-feature pharmacophore model was constructed for future drug design. Our results serve as a proof of concept that pharmacological intervention with apoE4 structure correctors negates apoE4 detrimental effects in neuronal cells and could be further developed as an Alzheimer disease therapeutic. 相似文献
103.
Lessard CJ Adrianto I Ice JA Wiley GB Kelly JA Glenn SB Adler AJ Li H Rasmussen A Williams AH Ziegler J Comeau ME Marion M Wakeland BE Liang C Ramos PS Grundahl KM Gallant CJ Alarcón-Riquelme ME Alarcón GS Anaya JM Bae SC Boackle SA Brown EE Chang DM Cho SK Criswell LA Edberg JC Freedman BI Gilkeson GS Jacob CO James JA Kamen DL Kimberly RP Kim JH Martin J Merrill JT Niewold TB Park SY Petri MA Pons-Estel BA Ramsey-Goldman R Reveille JD Scofield RH Song YW Stevens AM Tsao BP Vila LM Vyse TJ 《American journal of human genetics》2012,90(4):648-660
Systemic lupus erythematosus (SLE) is a chronic heterogeneous autoimmune disorder characterized by the loss of tolerance to self-antigens and dysregulated interferon responses. The etiology of SLE is complex, involving both heritable and environmental factors. Candidate-gene studies and genome-wide association (GWA) scans have been successful in identifying new loci that contribute to disease susceptibility; however, much of the heritable risk has yet to be identified. In this study, we sought to replicate 1,580 variants showing suggestive association with SLE in a previously published GWA scan of European Americans; we tested a multiethnic population consisting of 7,998 SLE cases and 7,492 controls of European, African American, Asian, Hispanic, Gullah, and Amerindian ancestry to find association with the disease. Several genes relevant to immunological pathways showed association with SLE. Three loci exceeded the genome-wide significance threshold: interferon regulatory factor 8 (IRF8; rs11644034; pmeta-Euro = 2.08 × 10−10), transmembrane protein 39A (TMEM39A; rs1132200; pmeta-all = 8.62 × 10−9), and 17q21 (rs1453560; pmeta-all = 3.48 × 10−10) between IKAROS family of zinc finger 3 (AIOLOS; IKZF3) and zona pellucida binding protein 2 (ZPBP2). Fine mapping, resequencing, imputation, and haplotype analysis of IRF8 indicated that three independent effects tagged by rs8046526, rs450443, and rs4843869, respectively, were required for risk in individuals of European ancestry. Eleven additional replicated effects (5 × 10−8 < pmeta-Euro < 9.99 × 10−5) were observed with CFHR1, CADM2, LOC730109/IL12A, LPP, LOC63920, SLU7, ADAMTSL1, C10orf64, OR8D4, FAM19A2, and STXBP6. The results of this study increase the number of confirmed SLE risk loci and identify others warranting further investigation. 相似文献
104.
David S. Freedman John C. Thornton F. Xavier Pi‐Sunyer Steven B. Heymsfield Jack Wang Richard N. Pierson Jr Heidi M. Blanck Dympna Gallagher 《Obesity (Silver Spring, Md.)》2012,20(12):2438-2444
Based on cross‐sectional analyses, it was suggested that hip circumference divided by height1.5 ?18 (the body adiposity index (BAI)), could directly estimate percent body fat without the need for further correction for sex or age. We compared the prediction of percent body fat, as assessed by dual‐energy X‐ray absorptiometry (PBFDXA), by BAI, BMI, and circumference (waist and hip) measurements among 1,151 adults who had a total body scan by DXA and circumference measurements from 1993 through 2005. After accounting for sex, we found that PBFDXA was related similarly to BAI, BMI, waist circumference, and hip circumference. In general, BAI underestimated PBFDXA among men (2.5%) and overestimated PBFDXA among women (4%), but the magnitudes of these biases varied with the level of body fatness. The addition of covariates and quadratic terms for the body size measures in regression models substantially improved the prediction of PBFDXA, but none of the models based on BAI could more accurately predict PBFDXA than could those based on BMI or circumferences. We conclude that the use of BAI as an indicator of adiposity is likely to produce biased estimates of percent body fat, with the errors varying by sex and level of body fatness. Although regression models that account for the nonlinear association, as well as the influence of sex, age, and race, can yield more accurate estimates of PBFDXA, estimates based on BAI are not more accurate than those based on BMI, waist circumference, or hip circumference. 相似文献
105.
106.
Vitseva OI Tanriverdi K Tchkonia TT Kirkland JL McDonnell ME Apovian CM Freedman J Gokce N 《Obesity (Silver Spring, Md.)》2008,16(5):932-937
Objective: Inflammatory activity in fat tissue has recently been implicated in mechanisms of insulin resistance and obesity‐related metabolic dysfunction. Toll‐like receptors (TLRs) play a key role in innate immune responses and recent studies implicate the TLR pathway in mechanisms of inflammation and atherosclerosis. The aim of this study was to examine differential TLR expression and function in human adipose tissue. Methods and Procedures: We biopsied subcutaneous abdominal fat from 16 obese subjects (age 39 ± 11 years, BMI 49 ± 14 kg/m2) and characterized TLR expression using quantitative real‐time PCR and confocal immunofluorescence imaging. In tissue culture, we stimulated isolated human adipocytes with Pam3CSK4 and lipopolysaccharide (LPS) (TLR2 and TLR4 agonists, respectively) and quantified TLR activity, interleukin‐6 (IL‐6) and tumor necrosis factor‐α (TNF‐α) production, and nuclear factor‐κB (NF‐κB) p65 nuclear activation using real‐time PCR, enzyme‐linked immunosorbent assay (ELISA), and immunofluorescence. Results: TLR1, 2, and 4 protein colocalized with adiponectin in human adipocytes with TLR4 exhibiting the highest immunohistochemical expression. Using real‐time PCR, we confirmed higher level of gene expression for TLR4 as compared to other members of the TLR family (TLR1, 2, 7, 8) in human adipose depots (P < 0.001). In tissue culture, adipocyte TLR2/TLR4 mRNA expression and protein increased significantly following Pam3CSK4 and LPS (P < 0.001). TLR2/TLR4 stimulation was associated with NF‐κB p65 nuclear translocation and proinflammatory cytokine production. Discussion: The findings demonstrate that TLRs are inducible in adipose tissue and linked with downstream NF‐κB activation and cytokine release. Adipose stores may play a dynamic role in the regulation of inflammation and innate immunity in human subjects via modulation of the TLR/NF‐κB regulatory pathway. 相似文献
107.
108.
The most massive teleost, the ocean sunfish(Mola mola), is an order of magnitude smaller than the largest cartilaginous fish,the whale shark (Rhincodon typus), and issignificantly smaller than several other extantelasmobranch species. Possible reasons for this discrepancy in maximum size include:anatomical, physiological, ecological, and life-history/ontogenetic constraints. Weexamined life-history traits and growth ratesas the most likely constraints on maximum teleostsize. For pelagic fishes there appear to be two life-history strategies: producing few,large, live young or many, tiny eggs. We propose that this dichotomy is an evolutionaryvestige of the freshwater origins of teleosts, and is the basis of the limitation onmaximal body size in teleosts. 相似文献
109.
Susan J. Middaugh Jennifer A. Haythornthwaite Bruce Thompson Robin Hill Kathleen M. Brown Robert R. Freedman Virginia Attanasio Rolf G. Jacob Michael Scheier Edwin A. Smith 《Applied psychophysiology and biofeedback》2001,26(4):251-278
The Raynaud's Treatment Study (RTS) compared temperature biofeedback training and a behavioral control procedure (frontalis EMG biofeedback) with nifedipine-XL and a medication placebo for treatment of primary Raynaud's phenomenon (RP) in a large (N = 313) multicenter trial. The present study describes the RTS biofeedback protocols and presents data on the acquisition of digital skin temperature and frontalis EMG responses in the RTS. The findings point to substantial problems with acquisition of physiological self-regulation skills in the RTS. Only 34.6% of the Temperature Biofeedback group (N = 81) and 55.4% of the EMG Biofeedback group (N = 74) successfully learned the desired physiological response. In contrast, 67.4% of a Normal Temperature Biofeedback group (N = 46) learned hand warming. Multivariate analysis found that coping strategies, anxiety, gender, and clinic site predicted acquisition of hand-warming skills whereas variables related to RP disease severity did not. Physiological data showed vasoconstriction in response to the onset of biofeedback and also found that performance in the initial sessions was critical for successful acquisition. These findings indicate that attention to the emotional and cognitive aspects of biofeedback training, and a degree of success in the initial biofeedback sessions, are important for acquisition. 相似文献
110.