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71.
Reductions in Heel Bone Quality Across Gestation Are Attenuated in Pregnant Adolescents With Higher Prepregnancy Weight and Greater Increases in PTH Across Gestation 下载免费PDF全文
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Zha S Sekiguchi J Brush JW Bassing CH Alt FW 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(27):9302-9306
Upon DNA damage, histone H2AX is phosphorylated by ataxia-telangiectasia mutated (ATM) and other phosphoinositide 3-kinase-related protein kinases. To elucidate further the potential overlapping and unique functions of ATM and H2AX, we asked whether they have synergistic functions in the development and maintenance of genomic stability by inactivating both genes in mouse germ line. Combined ATM/H2AX deficiency caused embryonic lethality and dramatic cellular genomic instability. Mechanistically, severe genomic instability in the double-deficient cells is associated with a requirement for H2AX to repair oxidative DNA damage resulting from ATM deficiency. We discuss these findings in the context of synergies between ATM and other repair factors. 相似文献
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Chromosome 15q25.1 genetic markers associated with level of response to alcohol in humans 总被引:1,自引:0,他引:1 下载免费PDF全文
Geoff Joslyn Gerry Brush Margaret Robertson Tom L. Smith Jelger Kalmijn Marc Schuckit Raymond L. White 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(51):20368-20373
As with other genetically complex common psychiatric and medical conditions, multiple genetic and environmental components contribute to alcohol use disorders (AUDs), which can confound attempts to identify genetic components. Intermediate phenotypes are often more closely correlated with underlying biology and have often proven invaluable in genetic studies. Level of response (LR) to alcohol is an intermediate phenotype for AUDs, and individuals with a low LR are at increased risk. A high rate of concurrent alcohol and nicotine use and dependence suggests that these conditions may share biochemical and genetic mechanisms. Genetic association studies indicate that a genetic locus, which includes the CHRNA5-CHRNA3-CHRNB4 gene cluster, plays a role in nicotine consumption and dependence. Genetic association with alcohol dependence was also recently shown. We show here that two of the markers from the nicotine studies also show an association (multiple testing corrected P < 0.025) with several LR phenotypes in a sample of 367 siblings. Additional markers in the region were analyzed and shown to be located in a 250-kb expanse of high linkage disequilibrium containing three additional genes. These findings indicate that LR intermediate phenotypes have utility in genetic approaches to AUDs and will prove valuable in the identification of other genetic loci conferring susceptibility to AUDs. 相似文献
74.
Michael J. Thrippleton Jehill Parikh Bridget A. Harris Steven J. Hammer Scott I. K. Semple Peter J. D. Andrews Joanna M. Wardlaw Ian Marshall 《NMR in biomedicine》2014,27(2):183-190
MRSI permits the non‐invasive mapping of brain temperature in vivo, but information regarding its reliability is lacking. We obtained MRSI data from 31 healthy male volunteers [age range, 22–40 years; mean ± standard deviation (SD), 30.5 ± 5.0 years]. Eleven subjects (age range, 23–40 years; mean ± SD, 30.5 ± 5.2 years) were invited to receive four point‐resolved spectroscopy MRSI scans on each of 3 days in both 1.5‐T (TR/TE = 1000/144 ms) and 3‐T (TR/TE = 1700/144 ms) clinical scanners; a further 20 subjects (age range, 22–40 years; mean ± SD, 30.5 ± 4.9 years) were scanned on a single occasion at 3 T. Data were fitted in the time domain to determine the water–N‐acetylaspartate chemical shift difference, from which the temperature was estimated. Temperature data were analysed using a linear mixed effects model to determine variance components and systematic temperature changes during the scanning sessions. To characterise the effects of instrumental drift on apparent MRSI brain temperature, a temperature‐controlled phantom was constructed and scanned on multiple occasions. Components of apparent in vivo temperature variability at 1.5 T/3 T caused by inter‐subject (0.18/0.17 °C), inter‐session (0.18/0.15 °C) and within‐session (0.36/0.14 °C) effects, as well as voxel‐to‐voxel variation (0.59/0.54 °C), were determined. There was a brain cooling effect during in vivo MRSI of 0.10 °C [95% confidence interval (CI): –0.110, –0.094 °C; p < 0.001] and 0.051 °C (95% CI: –0.054, –0.048 °C; p < 0.001) per scan at 1.5 T and 3 T, respectively, whereas phantom measurements revealed minimal drift in apparent MRSI temperature relative to fibre‐optic temperature measurements. The mean brain temperature at 3 T was weakly associated with aural (R = 0.55, p = 0.002) and oral (R = 0.62, p < 0.001) measurements of head temperature. In conclusion, the variability associated with MRSI brain temperature mapping was quantified. Repeatability was somewhat higher at 3 T than at 1.5 T, although subtle spatial and temporal variations in apparent temperature were demonstrated at both field strengths. Such data should assist in the efficient design of future clinical studies. © 2013 The Authors. NMR in Biomedicine published by John Wiley & Sons, Ltd. 相似文献
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Celestino-Soper PB Violante S Crawford EL Luo R Lionel AC Delaby E Cai G Sadikovic B Lee K Lo C Gao K Person RE Moss TJ German JR Huang N Shinawi M Treadwell-Deering D Szatmari P Roberts W Fernandez B Schroer RJ Stevenson RE Buxbaum JD Betancur C Scherer SW Sanders SJ Geschwind DH Sutcliffe JS Hurles ME Wanders RJ Shaw CA Leal SM Cook EH Goin-Kochel RP Vaz FM Beaudet AL 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(21):7974-7981
We recently reported a deletion of exon 2 of the trimethyllysine hydroxylase epsilon (TMLHE) gene in a proband with autism. TMLHE maps to the X chromosome and encodes the first enzyme in carnitine biosynthesis, 6-N-trimethyllysine dioxygenase. Deletion of exon 2 of TMLHE causes enzyme deficiency, resulting in increased substrate concentration (6-N-trimethyllysine) and decreased product levels (3-hydroxy-6-N-trimethyllysine and γ-butyrobetaine) in plasma and urine. TMLHE deficiency is common in control males (24 in 8,787 or 1 in 366) and was not significantly increased in frequency in probands from simplex autism families (9 in 2,904 or 1 in 323). However, it was 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 or 1 in 130; P = 0.023). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (metaanalysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2-4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism. 相似文献
79.
Zhao J Schloss PD Kalikin LM Carmody LA Foster BK Petrosino JF Cavalcoli JD VanDevanter DR Murray S Li JZ Young VB LiPuma JJ 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(15):5809-5814
The structure and dynamics of bacterial communities in the airways of persons with cystic fibrosis (CF) remain largely unknown. We characterized the bacterial communities in 126 sputum samples representing serial collections spanning 8-9 y from six age-matched male CF patients. Sputum DNA was analyzed by bar-coded pyrosequencing of the V3-V5 hypervariable region of the 16S rRNA gene, defining 662 operational taxonomic units (OTUs) from >633,000 sequences. Bacterial community diversity decreased significantly over time in patients with typically progressive lung disease but remained relatively stable in patients with a mild lung disease phenotype. Antibiotic use, rather than patient age or lung function, was the primary driver of decreasing diversity. Interpatient variability in community structure exceeded intrapatient variability in serial samples. Antibiotic treatment was associated with pronounced shifts in community structure, but communities showed both short- and long-term resilience after antibiotic perturbation. There was a positive correlation between OTU occurrence and relative abundance, with a small number of persistent OTUs accounting for the greatest abundance. Significant changes in community structure, diversity, or total bacterial density at the time of pulmonary exacerbation were not observed. Despite decreasing community diversity in patients with progressive disease, total bacterial density remained relatively stable over time. These findings show the critical relationship between airway bacterial community structure, disease stage, and clinical state at the time of sample collection. These features are the key parameters with which to assess the complex ecology of the CF airway. 相似文献
80.
John Pietzsch Henning Gruell Stylianos Bournazos Bridget M. Donovan Florian Klein Ron Diskin Michael S. Seaman Pamela J. Bjorkman Jeffrey V. Ravetch Alexander Ploss Michel C. Nussenzweig 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(39):15859-15864
Passive transfer of neutralizing antibodies against HIV-1 can prevent infection in macaques and seems to delay HIV-1 rebound in humans. Anti-HIV antibodies are therefore of great interest for vaccine design. However, the basis for their in vivo activity has been difficult to evaluate systematically because of a paucity of small animal models for HIV infection. Here we report a genetically humanized mouse model that incorporates a luciferase reporter for rapid quantitation of HIV entry. An antibody’s ability to block viral entry in this in vivo model is a function of its bioavailability, direct neutralizing activity, and effector functions.HIV-1 (HIV), the causative agent of AIDS, represents a formidable global challenge, with the development of an effective vaccine being of paramount importance (1–4). Rapid progress in this area has been hindered in part by lack of a widely available small animal model for HIV entry. Currently available animal models include nonhuman primates and immunodeficient humanized mice, neither of which is readily available or amenable to genetic modifications (5, 6).Some viral pathogens exhibit a narrow host range, one of those being HIV. HIV’s entry into target cells is mediated by binding of its trimeric envelope spike (gp160) to human CD4 (hCD4) (7) and subsequently to a coreceptor such as human CXCR4 (8) or human CCR5 (hCCR5) (9–11). hCCR5 is of particular interest because it seems to be the primary coreceptor used for transmission (12, 13), as evidenced by the finding that homozygous deletion in the CCR5 allele confers resistance against HIV-1 acquisition (14, 15) and can also lead to long-term control of HIV after stem cell transplantation (16). Finally, HeLa cells and other HIV-resistant cells, including mouse cells, support viral entry when they are engineered to express hCD4/hCCR5/hCXCR4 (17–19).Here, we describe a hCCR5- and hCD4-expressing luciferase reporter mouse that can be used to measure HIV pseudovirus entry and antibody-mediated protection against initial infection in vivo. 相似文献