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Find video protocols related to scientific articles indexed in Pubmed.
The association of the vanin-1 N131S variant with blood pressure is mediated by endoplasmic reticulum-associated degradation and loss of function.
PLoS Genet.
PUBLISHED: 09-01-2014
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High blood pressure (BP) is the most common cardiovascular risk factor worldwide and a major contributor to heart disease and stroke. We previously discovered a BP-associated missense SNP (single nucleotide polymorphism)-rs2272996-in the gene encoding vanin-1, a glycosylphosphatidylinositol (GPI)-anchored membrane pantetheinase. In the present study, we first replicated the association of rs2272996 and BP traits with a total sample size of nearly 30,000 individuals from the Continental Origins and Genetic Epidemiology Network (COGENT) of African Americans (P=0.01). This association was further validated using patient plasma samples; we observed that the N131S mutation is associated with significantly lower plasma vanin-1 protein levels. We observed that the N131S vanin-1 is subjected to rapid endoplasmic reticulum-associated degradation (ERAD) as the underlying mechanism for its reduction. Using HEK293 cells stably expressing vanin-1 variants, we showed that N131S vanin-1 was degraded significantly faster than wild type (WT) vanin-1. Consequently, there were only minimal quantities of variant vanin-1 present on the plasma membrane and greatly reduced pantetheinase activity. Application of MG-132, a proteasome inhibitor, resulted in accumulation of ubiquitinated variant protein. A further experiment demonstrated that atenolol and diltiazem, two current drugs for treating hypertension, reduce the vanin-1 protein level. Our study provides strong biological evidence for the association of the identified SNP with BP and suggests that vanin-1 misfolding and degradation are the underlying molecular mechanism.
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Co-infection with HPV types from the same species provides natural cross-protection from progression to cervical cancer.
Infect. Agents Cancer
PUBLISHED: 08-12-2014
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The worldwide administration of bivalent and quadrivalent HPV vaccines has resulted in cross-protection against non-vaccine HPV types. Infection with multiple HPV types may offer similar cross-protection in the natural setting. We hypothesized that infections with two or more HPV types from the same species, and independently, infections with two or more HPV types from different species, associate with protection from high-grade lesions.
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Recognition and repair of chemically heterogeneous structures at DNA ends.
Environ. Mol. Mutagen.
PUBLISHED: 08-11-2014
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Exposure to environmental toxicants and stressors, radiation, pharmaceutical drugs, inflammation, cellular respiration, and routine DNA metabolism all lead to the production of cytotoxic DNA strand breaks. Akin to splintered wood, DNA breaks are not "clean." Rather, DNA breaks typically lack DNA 5'-phosphate and 3'-hydroxyl moieties required for DNA synthesis and DNA ligation. Failure to resolve damage at DNA ends can lead to abnormal DNA replication and repair, and is associated with genomic instability, mutagenesis, neurological disease, ageing and carcinogenesis. An array of chemically heterogeneous DNA termini arises from spontaneously generated DNA single-strand and double-strand breaks (SSBs and DSBs), and also from normal and/or inappropriate DNA metabolism by DNA polymerases, DNA ligases and topoisomerases. As a front line of defense to these genotoxic insults, eukaryotic cells have accrued an arsenal of enzymatic first responders that bind and protect damaged DNA termini, and enzymatically tailor DNA ends for DNA repair synthesis and ligation. These nucleic acid transactions employ direct damage reversal enzymes including Aprataxin (APTX), Polynucleotide kinase phosphatase (PNK), the tyrosyl DNA phosphodiesterases (TDP1 and TDP2), the Ku70/80 complex and DNA polymerase ? (POL?). Nucleolytic processing enzymes such as the MRE11/RAD50/NBS1/CtIP complex, Flap endonuclease (FEN1) and the apurinic endonucleases (APE1 and APE2) also act in the chemical "cleansing" of DNA breaks to prevent genomic instability and disease, and promote progression of DNA- and RNA-DNA damage response (DDR and RDDR) pathways. Here, we provide an overview of cellular first responders dedicated to the detection and repair of abnormal DNA termini. Environ. Mol. Mutagen., 2014. © 2014 Wiley Periodicals, Inc.
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Genetic variation in the peroxisome proliferator-activated receptor (PPAR) and peroxisome proliferator-activated receptor gamma co-activator 1 (PGC1) gene families and type 2 diabetes.
Ann. Hum. Genet.
PUBLISHED: 08-02-2014
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We used a two-stage study design to evaluate whether variations in the peroxisome proliferator-activated receptors (PPAR) and the PPAR gamma co-activator 1 (PGC1) gene families (PPARA, PPARG, PPARD, PPARGC1A, and PPARGC1B) are associated with type 2 diabetes (T2D) risk. Stage I used data from a genome-wide association study (GWAS) from Shanghai, China (1019 T2D cases and 1709 controls) and from a meta-analysis of data from the Asian Genetic Epidemiology Network for T2D (AGEN-T2D). Criteria for selection of single nucleotide polymorphisms (SNPs) for stage II were: (1) P < 0.05 in single marker analysis in Shanghai GWAS and P < 0.05 in the meta-analysis or (2) P < 10(-3) in the meta-analysis alone and (3) minor allele frequency ? 0.10. Nine SNPs from the PGC1 family were assessed in stage II (an independent set of middle-aged men and women from Shanghai with 1700 T2D cases and 1647 controls). One SNP in PPARGC1B, rs251464, was replicated in stage II (OR = 0.87; 95% CI: 0.77-0.99). Gene-body mass index (BMI) and gene-exercise interactions and T2D risk were evaluated in a combined dataset (Shanghai GWAS and stage II data: 2719 cases and 3356 controls). One SNP in PPARGC1A, rs12640088, had a significant interaction with BMI. No interactions between the PPARGC1B gene and BMI or exercise were observed.
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ANZUP - a new co-operative cancer trials group in genito-urinary oncology.
BJU Int.
PUBLISHED: 07-28-2014
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Shomik Sengupta reports grants from Cancer Australia, during the conduct of the study; and is unremunerated deputy-chair of the bladder cancer subcommittee of the ANZUP Cancer Trials Group Ltd. Peter Grimison reports grants from Cancer Australia, during the conduct of the study; and is unremunerated Chair of the Germ Cell Subcommittee of the ANZUP Cancer Trials Group Ltd. Dickon Hayne reports grants from Cancer Australia, during the conduct of the study; and is unremunerated chair of the bladder cancer subcommittee of the ANZUP Cancer Trials Group Ltd. Scott Williams is unremunerated chair of the prostate cancer subcommittee the ANZUP Cancer Trials Group Ltd. Suzanne Chambers is unremunerated chair of the Quality of Life and Supportive Care Subcommittee of the ANZUP Cancer Trials Group Ltd. Paul DeSouza is unremunerated Chair of the Translational and Correlative Research Subcommittee of the ANZUP Cancer Trials Group Ltd. Martin Stockler reports reports grants from Cancer Australia, during the conduct of the study; Margaret McJannett is an employee of the ANZUP Cancer Trials Group Ltd. Guy Toner reports grants from Cancer Australia, during the conduct of the study; and is unremunerated Deputy-Chair of the Board of ANZUP Cancer Trials Group Ltd Ian Davis reports grants from Cancer Australia, during the conduct of the study; and is unremunerated Chair of the Board of ANZUP Cancer Trials Group Ltd.
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Admixture mapping identifies a locus at 15q21.2-22.3 associated with keloid formation in African Americans.
Hum. Genet.
PUBLISHED: 07-07-2014
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Keloids are benign dermal tumors that occur ~20 times more often in African versus Caucasian descent individuals. While most keloids occur sporadically, a genetic predisposition is supported by both familial aggregation of some keloids and the large differences in risk among populations. Yet, no well-established genetic risk factors for keloids have been identified. In this study, we conducted admixture mapping and whole-exome association using 478 African Americans (AAs) samples (122 cases, 356 controls) with exome genotyping data to identify regions where local ancestry associated with keloid risk. Logistic regression was used to evaluate associations under admixture peaks. A significant mapping peak was observed on chr15q21.2-22.3. This peak included NEDD4, a gene previously implicated in a keloid genome-wide association study (GWAS) of Japanese individuals later validated in a Chinese cohort. While we observed modest evidence for association with NEDD4, a more significant association was observed at (myosin 1E) MYO1E. A genome scan not including the 15q21-22 region also identified associations at MYO7A (rs35641839, odds ratio [OR] = 4.71, 95 % confidence interval [CI] 2.38-9.32, p = 8.34 × 10(-6)) at 11q13.5. The identification of SNPs in two myosin genes strongly associated with keloid formation suggests that an altered cytoskeleton contributes to the enhanced migratory and invasive properties of keloid fibroblasts. Our findings support the admixture mapping approach for the study of keloid risk, and indicate potentially common genetic elements on chr15q21.2-22.3 in causation of keloids in AAs, Japanese, and Chinese populations.
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Association between lifestyle-related disorders and visceral fat mass in Japanese males: a hospital based cross-sectional study.
Environ Health Prev Med
PUBLISHED: 07-02-2014
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This study aimed to examine the association between lifestyle-related disorders and visceral fat mass, and to estimate an appropriate cutoff value for visceral fat mass that correlated with body mass index (BMI) and waist circumference (WC).
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"Lucy" (A.L. 288-1) had five sacral vertebrae.
Am. J. Phys. Anthropol.
PUBLISHED: 06-25-2014
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A "long-backed" scenario of hominin vertebral evolution posits that early hominins possessed six lumbar vertebrae coupled with a high frequency of four sacral vertebrae (7:12-13:6:4), a configuration acquired from a hominin-panin last common ancestor (PLCA) having a vertebral formula of 7:13:6-7:4. One founding line of evidence for this hypothesis is the recent assertion that the "Lucy" sacrum (A.L. 288-1an, Australopithecus afarensis) consists of four sacral vertebrae and a partially-fused first coccygeal vertebra (Co1), rather than five sacral vertebrae as in modern humans. This study reassesses the number of sacral vertebrae in Lucy by reexamining the distal end of A.L.288-1an in the context of a comparative sample of modern human sacra and Co1 vertebrae, and the sacrum of A. sediba (MH2). Results demonstrate that, similar to S5 in modern humans and A. sediba, the last vertebra in A.L. 288-1an exhibits inferiorly-projecting (right side) cornua and a kidney-shaped inferior body articular surface. This morphology is inconsistent with that of fused or isolated Co1 vertebrae in humans, which either lack cornua or possess only superiorly-projecting cornua, and have more circularly-shaped inferior body articular surfaces. The level at which the hiatus' apex is located is also more compatible with typical five-element modern human sacra and A. sediba than if only four sacral vertebrae are present. Our observations suggest that A.L. 288-1 possessed five sacral vertebrae as in modern humans; thus, sacral number in "Lucy" does not indicate a directional change in vertebral count that can provide information on the PLCA ancestral condition. Am J Phys Anthropol, 2014. © 2014 Wiley Periodicals, Inc.
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The impact of sleep on soldier performance.
Curr Psychiatry Rep
PUBLISHED: 06-20-2014
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The military population is particularly vulnerable to a multitude of sleep-related disorders owing to the type of work performed by active duty servicemembers (ADSMs). Inadequate sleep, due to insufficient quantity or quality, is increasingly recognized as a public health concern. Traditionally, ADSMs have been encouraged that they can adapt to insufficient sleep just as the body adapts to physical training, but there is a substantial body of scientific literature which argues that this is not possible. Additionally, the military work environment creates unique challenges with respect to treatment options for common sleep disorders like obstructive sleep apnea, restless legs syndrome, and parasomnias. This review highlights sleep disorders which are prevalent in the modern military force and discusses the impact of poor sleep on overall performance. Medical treatments and recommendations for unit leaders are also discussed.
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A Phase III trial to investigate the timing of radiotherapy for prostate cancer with high-risk features: background and rationale of the Radiotherapy -- Adjuvant Versus Early Salvage (RAVES) trial.
BJU Int.
PUBLISHED: 06-05-2014
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To test the hypothesis that observation with early salvage radiotherapy (SRT) is not inferior to 'standard' treatment with adjuvant RT (ART) with respect to biochemical failure in patients with pT3 disease and/or positive surgical margins (SMs) after radical prostatectomy (RP). To compare the following secondary endpoints between the two arms: patient-reported outcomes, adverse events, biochemical failure-free survival, overall survival, disease-specific survival, time to distant failure, time to local failure, cost utility analysis, quality adjusted life years and time to androgen deprivation.
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Tissue-specific regulation of the mouse Pkhd1 (ARPKD) gene promoter.
Am. J. Physiol. Renal Physiol.
PUBLISHED: 06-04-2014
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Autosomal recessive polycystic kidney disease, an inherited disorder characterized by the formation of cysts in renal collecting ducts and biliary dysgenesis, is caused by mutations of the polycystic kidney and hepatic disease 1 (PKHD1) gene. Expression of PKHD1 is tissue specific and developmentally regulated. Here, we show that a 2.0-kb genomic fragment containing the proximal promoter of mouse Pkhd1 directs tissue-specific expression of a lacZ reporter gene in transgenic mice. LacZ is expressed in renal collecting ducts beginning during embryonic development but is not expressed in extrarenal tissues. The Pkhd1 promoter contains a binding site for the transcription factor hepatocyte nuclear factor (HNF)-1?, which is required for activity in transfected cells. Mutation of the HNF-1?-binding site abolishes the expression of the lacZ reporter gene in renal collecting ducts. Transgenes containing the 2.0-kb promoter and 2.7 kb of additional genomic sequence extending downstream to the second exon are expressed in the kidney, intrahepatic bile ducts, and male reproductive tract. This pattern overlaps with the endogenous expression of Pkhd1 and coincides with sites of expression of HNF-1?. We conclude that the proximal 2.0-kb promoter is sufficient for tissue-specific expression of Pkhd1 in renal collecting ducts in vivo and that HNF-1? is required for Pkhd1 promoter activity in collecting ducts. Additional genomic sequences located from exons 1-2 or elsewhere in the gene locus are required for expression in extrarenal tissues.
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Par3-mInsc and G?i3 cooperate to promote oriented epidermal cell divisions through LGN.
Nat. Cell Biol.
PUBLISHED: 05-30-2014
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Asymmetric cell divisions allow stem cells to balance proliferation and differentiation. During embryogenesis, murine epidermis expands rapidly from a single layer of unspecified basal layer progenitors to a stratified, differentiated epithelium. Morphogenesis involves perpendicular (asymmetric) divisions and the spindle orientation protein LGN, but little is known about how the apical localization of LGN is regulated. Here, we combine conventional genetics and lentiviral-mediated in vivo RNAi to explore the functions of the LGN-interacting proteins Par3, mInsc and G?i3. Whereas loss of each gene alone leads to randomized division angles, combined loss of Gnai3 and mInsc causes a phenotype of mostly planar divisions, akin to loss of LGN. These findings lend experimental support for the hitherto untested model that Par3-mInsc and G?i3 act cooperatively to polarize LGN and promote perpendicular divisions. Finally, we uncover a developmental switch between delamination-driven early stratification and spindle-orientation-dependent differentiation that occurs around E15, revealing a two-step mechanism underlying epidermal maturation.
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Proteolytic degradation of topoisomerase II (Top2) enables the processing of Top2·DNA and Top2·RNA covalent complexes by tyrosyl-DNA-phosphodiesterase 2 (TDP2).
J. Biol. Chem.
PUBLISHED: 05-07-2014
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Eukaryotic type II topoisomerases (Top2? and Top2?) are homodimeric enzymes; they are essential for altering DNA topology by the formation of normally transient double strand DNA cleavage. Anticancer drugs (etoposide, doxorubicin, and mitoxantrone) and also Top2 oxidation and DNA helical alterations cause potentially irreversible Top2·DNA cleavage complexes (Top2cc), leading to Top2-linked DNA breaks. Top2cc are the therapeutic mechanism for killing cancer cells. Yet Top2cc can also generate recombination, translocations, and apoptosis in normal cells. The Top2 protein-DNA covalent complexes are excised (in part) by tyrosyl-DNA-phosphodiesterase 2 (TDP2/TTRAP/EAP2/VPg unlinkase). In this study, we show that irreversible Top2cc induced in suicidal substrates are not processed by TDP2 unless they first undergo proteolytic processing or denaturation. We also demonstrate that TDP2 is most efficient when the DNA attached to the tyrosyl is in a single-stranded configuration and that TDP2 can efficiently remove a tyrosine linked to a single misincorporated ribonucleotide or to polyribonucleotides, which expands the TDP2 catalytic profile with RNA substrates. The 1.6-Å resolution crystal structure of TDP2 bound to a substrate bearing a 5'-ribonucleotide defines a mechanism through which RNA can be accommodated in the TDP2 active site, albeit in a strained conformation.
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Risk of cardiac arrhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk.
Diabetes
PUBLISHED: 04-24-2014
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Recent trials of intensive glycemic control suggest a possible link between hypoglycemia and excess cardiovascular mortality in patients with type 2 diabetes. Hypoglycemia might cause arrhythmias through effects on cardiac repolarization and changes in cardiac autonomic activity. Our aim was to study the risk of arrhythmias during spontaneous hypoglycemia in type 2 diabetic patients with cardiovascular risk. Twenty-five insulin-treated patients with type 2 diabetes and a history of cardiovascular disease or two or more risk factors underwent simultaneous continuous interstitial glucose and ambulatory electrocardiogram monitoring. Frequency of arrhythmias, heart rate variability, and markers of cardiac repolarization were compared between hypoglycemia and euglycemia and between hyperglycemia and euglycemia matched for time of day. There were 134 h of recording at hypoglycemia, 65 h at hyperglycemia, and 1,258 h at euglycemia. Bradycardia and atrial and ventricular ectopic counts were significantly higher during nocturnal hypoglycemia compared with euglycemia. Arrhythmias were more frequent during nocturnal versus daytime hypoglycemia. Excessive compensatory vagal activation after the counterregulatory phase may account for bradycardia and associated arrhythmias. QT intervals, corrected for heart rate, >500 ms and abnormal T-wave morphology were observed during hypoglycemia in some participants. Hypoglycemia, frequently asymptomatic and prolonged, may increase the risk of arrhythmias in patients with type 2 diabetes and high cardiovascular risk. This is a plausible mechanism that could contribute to increased cardiovascular mortality during intensive glycemic therapy.
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A single nucleotide polymorphism in SLC7A5 is associated with gastrointestinal toxicity after high-dose melphalan and autologous stem cell transplantation for multiple myeloma.
Biol. Blood Marrow Transplant.
PUBLISHED: 03-20-2014
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Multiple myeloma is the most frequent indication for high-dose melphalan (HDM) chemotherapy with autologous stem cell transplantation (ASCT). Gastrointestinal symptoms represent the most significant nonhematological toxicity of HDM. However, specific, especially genetic, predictors of their incidence or clinical severity are lacking. The amino acid transporters LAT1 and LAT2 encoded by the SLC7A5 and SLC7A8 genes, respectively, are the principal mediators of melphalan uptake into cells. To determine whether genetic variability at these loci contributed to interindividual differences in the development of gastrointestinal complications of HDM, we analyzed single nucleotide polymorphisms (SNPs) in these genes in 135 patients with multiple myeloma treated with HDM and ASCT and correlated these with the need for total parenteral nutrition (TPN). Seven SNPs in SLC7A5 and 20 in SLC7A8 were genotyped. Multiple analyses indicated that 1 SNP in the first intron of SLC7A5, rs4240803, was significantly associated with TPN use (odds ratio = .45, 95% confidence interval, .25 to .79; P = .007). Further, every haplotype that correlated with TPN requirement included this SNP. These results suggest that variability in melphalan transport affects mucosal injury after HDM. This finding could help in individualizing the dose of this effective and widely used chemotherapeutic agent for multiple myeloma.
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A dozen years of American Academy of Sleep Medicine (AASM) International Mini-Fellowship: program evaluation and future directions.
J Clin Sleep Med
PUBLISHED: 03-18-2014
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Sleep medicine remains an underrepresented medical specialty worldwide, with significant geographic disparities with regard to training, number of available sleep specialists, sleep laboratory or clinic infrastructures, and evidence-based clinical practices. The American Academy of Sleep Medicine (AASM) is committed to facilitating the education of sleep medicine professionals to ensure high-quality, evidence-based clinical care and improve access to sleep centers around the world, particularly in developing countries. In 2002, the AASM launched an annual 4-week training program called Mini-Fellowship for International Scholars, designed to support the establishment of sleep medicine in developing countries. The participating fellows were generally chosen from areas that lacked a clinical infrastructure in this specialty and provided with training in AASM Accredited sleep centers. This manuscript presents an overview of the program, summarizes the outcomes, successes, and lessons learned during the first 12 years, and describes a set of programmatic changes for the near-future, as assembled and proposed by the AASM Education Committee and recently approved by the AASM Board of Directors.
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Expansion of zoonotic babesiosis and reported human cases, Connecticut, 2001-2010.
J. Med. Entomol.
PUBLISHED: 03-11-2014
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To document the expansion of human babesiosis in Connecticut, we analyzed reservoir host sera for seroreactivity to Babesia microti Franca and reviewed Connecticut human surveillance case data collected during 2001-2010. Sera from white-footed mice, Peromyscus leucopus Rafinesque, from 10 towns in 5 counties, collected at 4-7-yr periods between 2001 and 2010, were tested for total immunoglobulins. The prevalence of B. microti-positive mice was compared with confirmed and probable human case reports tabulated by the Connecticut Department of Public Health. The highest babesiosis and rodent seroprevalence rates were in New London County, where this protozoan disease was first documented in the state. However, human cases and reservoir host infection increased significantly from 2001-2005 to 2005-2010 and in other parts of the state. Clinicians should be aware that the disease is not confined to long-established endemic areas of the state.
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G6PD A- deficiency and severe malaria in The Gambia: heterozygote advantage and possible homozygote disadvantage.
Am. J. Trop. Med. Hyg.
PUBLISHED: 03-10-2014
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Glucose-6-phosphate dehydrogenase (G6PD) deficiency is frequent in Africa, because it confers resistance to Plasmodium falciparum malaria; however, the nature of the protection and the genotypes associated with it have been controversial. In 1972, Bienzle and others described protection from malaria in West African females heterozygous for G6PD A-. They determined that G6PD A- heterozygotes had lower parasite counts than A- homozygotes, hemizygous males, and normal individuals. However, other studies have reached different conclusions about the protective genotypes. DNA samples from 135 children with severe malaria and 146 children with mild malaria from The Gambia were genotyped for the G6PD A- mutation that is most frequent among Gambians (G6PD 968 T->C); there was a marked deficiency of heterozygotes and an excess of homozygotes with severe malaria, producing a strong deviation from Hardy-Weinberg equilibrium. Our results support the protective effect in G6PD A- heterozygous females and suggest that homozygotes might be more susceptible to severe malaria attacks.
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Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2.
Jie Huang, Jennifer E Huffman, Munekazu Yamakuchi, Munekazu Yamkauchi, Stella Trompet, Folkert W Asselbergs, Maria Sabater-Lleal, David-Alexandre Trégouët, Wei-Min Chen, Nicholas L Smith, Marcus E Kleber, So-Youn Shin, Diane M Becker, Weihong Tang, Abbas Dehghan, Andrew D Johnson, Vinh Truong, Lasse Folkersen, Qiong Yang, Tiphaine Oudot-Mellkah, Brendan M Buckley, Jason H Moore, Frances M K Williams, Harry Campbell, Günther Silbernagel, Veronique Vitart, Igor Rudan, Geoffrey H Tofler, Gerjan J Navis, Anita DeStefano, Alan F Wright, Ming-Huei Chen, Anton J M de Craen, Bradford B Worrall, Alicja R Rudnicka, Ann Rumley, Ebony B Bookman, Bruce M Psaty, Fang Chen, Keith L Keene, Oscar H Franco, Bernhard O Böhm, André G Uitterlinden, Angela M Carter, J Wouter Jukema, Naveed Sattar, Joshua C Bis, Mohammad A Ikram, , Michèle M Sale, Barbara McKnight, Myriam Fornage, Ian Ford, Kent Taylor, P Eline Slagboom, Wendy L McArdle, Fang-Chi Hsu, Anders Franco-Cereceda, Alison H Goodall, Lisa R Yanek, Karen L Furie, Mary Cushman, Albert Hofman, Jacqueline C M Witteman, Aaron R Folsom, Saonli Basu, Nena Matijevic, Wiek H van Gilst, James F Wilson, Rudi G J Westendorp, Sekar Kathiresan, Muredach P Reilly, Russell P Tracy, Ozren Polašek, Bernhard R Winkelmann, Peter J Grant, Hans L Hillege, Francois Cambien, David J Stott, Gordon D Lowe, Timothy D Spector, James B Meigs, Winfried März, Per Eriksson, Lewis C Becker, Pierre-Emmanuel Morange, Nicole Soranzo, Scott M Williams, Caroline Hayward, Pim van der Harst, Anders Hamsten, Charles J Lowenstein, David P Strachan, Christopher J O'Donnell.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 02-27-2014
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Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases. We conducted a meta-analysis of genome-wide association studies to identify novel correlates of circulating levels of tPA.
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'What is this active surveillance thing?' Men's and partners' reactions to treatment decision making for prostate cancer when active surveillance is the recommended treatment option.
Psychooncology
PUBLISHED: 02-16-2014
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In the past decade, localised prostate cancer (LPC) management has been shifting from three radical treatment options (radical prostatectomy, external beam radiotherapy, or brachytherapy) to also include active surveillance (AS). This study examines men with LPC and partners' experiences of choosing between AS and radical treatments, and their experiences of AS when selected.
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Successful MDR-TB treatment regimens including Amikacin are associated with high rates of hearing loss.
BMC Infect. Dis.
PUBLISHED: 02-03-2014
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Aminoglycosides are a critical component of multidrug-resistant tuberculosis (MDR-TB) treatment but data on their efficacy and adverse effects in this population is scarce. We determined the effect of amikacin over treatment outcomes and development of hearing loss in MDR-TB patients.
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ATP-driven Rad50 conformations regulate DNA tethering, end resection, and ATM checkpoint signaling.
EMBO J.
PUBLISHED: 02-03-2014
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The Mre11-Rad50 complex is highly conserved, yet the mechanisms by which Rad50 ATP-driven states regulate the sensing, processing and signaling of DNA double-strand breaks are largely unknown. Here we design structure-based mutations in Pyrococcus furiosus Rad50 to alter protein core plasticity and residues undergoing ATP-driven movements within the catalytic domains. With this strategy we identify Rad50 separation-of-function mutants that either promote or destabilize the ATP-bound state. Crystal structures, X-ray scattering, biochemical assays, and functional analyses of mutant PfRad50 complexes show that the ATP-induced 'closed' conformation promotes DNA end binding and end tethering, while hydrolysis-induced opening is essential for DNA resection. Reducing the stability of the ATP-bound state impairs DNA repair and Tel1 (ATM) checkpoint signaling in Schizosaccharomyces pombe, double-strand break resection in Saccharomyces cerevisiae, and ATM activation by human Mre11-Rad50-Nbs1 in vitro, supporting the generality of the P. furiosus Rad50 structure-based mutational analyses. These collective results suggest that ATP-dependent Rad50 conformations switch the Mre11-Rad50 complex between DNA tethering, ATM signaling, and 5' strand resection, revealing molecular mechanisms regulating responses to DNA double-strand breaks.
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The effects of nonspecific HIF1? inhibitors on development of castrate resistance and metastases in prostate cancer.
Cancer Med
PUBLISHED: 01-27-2014
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Expression of hypoxia-inducible factor (HIF)1? increases the risk of castrate-resistant prostate cancer (CRPC) and metastases in patients on androgen deprivation therapy (ADT) for prostate cancer (PC). We aimed to investigate the effects of nonspecific HIF1? inhibitors (Digoxin, metformin, and angiotensin-2 receptor blockers) on development of CRPC and metastases while on ADT. A retrospective review of prospectively collected medical records was conducted of all men who had continuous ADT as first-line therapy for CRPC at the Austin Hospital from 1983 to 2011. Association between HIF1? inhibitor medications and time to develop CRPC was investigated using actuarial statistics. Ninety-eight patients meeting the criteria were identified. Eighteen patients (21.4%) were treated with the nonspecific HIF1? inhibitors. Both groups had similar characteristics, apart from patients on HIF1? inhibitors being older (70 years vs. 63.9 years). The median CRPC-free survival was longer in men using HIF1? inhibitors compared to those not on inhibitors (6.7 years vs. 2.7 years, P = 0.01) and there was a 71% reduction in the risk of developing CRPC (HR 0.29 [95% CI 0.10-0.78] P = 0.02) after adjustment for Gleason score, age, and prostate-specific antigen (PSA). The median metastasis-free survival in men on HIF1? inhibitors was also significantly longer compared to those on no inhibitors (5.1 years vs. 2.6 years, P = 0.01) with an 81% reduction in the risk of developing metastases (HR 0.19 [CI 0.05-0.76] P = 0.02) after adjustment for Gleason score, age, and PSA. Nonspecific HIF1? inhibitors appear to increase the progression-free survival and reduce the risk of developing CRPC and metastases in patients on continuous ADT.
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The multiscale backbone of the human phenotype network based on biological pathways.
BioData Min
PUBLISHED: 01-25-2014
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Networks are commonly used to represent and analyze large and complex systems of interacting elements. In systems biology, human disease networks show interactions between disorders sharing common genetic background. We built pathway-based human phenotype network (PHPN) of over 800 physical attributes, diseases, and behavioral traits; based on about 2,300 genes and 1,200 biological pathways. Using GWAS phenotype-to-genes associations, and pathway data from Reactome, we connect human traits based on the common patterns of human biological pathways, detecting more pleiotropic effects, and expanding previous studies from a gene-centric approach to that of shared cell-processes.
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Sleep disorders in combat-related PTSD.
Sleep Breath
PUBLISHED: 01-18-2014
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We sought to assess the rate of sleep complaints and sleep disorders among active duty soldiers with deployment-related PTSD and to determine whether any clinical features differentiated those with sleep disorders.
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Human and Helicobacter pylori coevolution shapes the risk of gastric disease.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 01-13-2014
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Helicobacter pylori is the principal cause of gastric cancer, the second leading cause of cancer mortality worldwide. However, H. pylori prevalence generally does not predict cancer incidence. To determine whether coevolution between host and pathogen influences disease risk, we examined the association between the severity of gastric lesions and patterns of genomic variation in matched human and H. pylori samples. Patients were recruited from two geographically distinct Colombian populations with significantly different incidences of gastric cancer, but virtually identical prevalence of H. pylori infection. All H. pylori isolates contained the genetic signatures of multiple ancestries, with an ancestral African cluster predominating in a low-risk, coastal population and a European cluster in a high-risk, mountain population. The human ancestry of the biopsied individuals also varied with geography, with mostly African ancestry in the coastal region (58%), and mostly Amerindian ancestry in the mountain region (67%). The interaction between the host and pathogen ancestries completely accounted for the difference in the severity of gastric lesions in the two regions of Colombia. In particular, African H. pylori ancestry was relatively benign in humans of African ancestry but was deleterious in individuals with substantial Amerindian ancestry. Thus, coevolution likely modulated disease risk, and the disruption of coevolved human and H. pylori genomes can explain the high incidence of gastric disease in the mountain population.
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Disrupted human-pathogen co-evolution: a model for disease.
Front Genet
PUBLISHED: 01-01-2014
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A major goal in infectious disease research is to identify the human and pathogenic genetic variants that explain differences in microbial pathogenesis. However, neither pathogenic strain nor human genetic variation in isolation has proven adequate to explain the heterogeneity of disease pathology. We suggest that disrupted co-evolution between a pathogen and its human host can explain variation in disease outcomes, and that genome-by-genome interactions should therefore be incorporated into genetic models of disease caused by infectious agents. Genetic epidemiological studies that fail to take both the pathogen and host into account can lead to false and misleading conclusions about disease etiology. We discuss our model in the context of three pathogens, Helicobacter pylori, Mycobacterium tuberculosis and human papillomavirus, and generalize the conditions under which it may be applicable.
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A dietary-wide association study (DWAS) of environmental metal exposure in US children and adults.
PLoS ONE
PUBLISHED: 01-01-2014
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A growing body of evidence suggests that exposure to toxic metals occurs through diet but few studies have comprehensively examined dietary sources of exposure in US populations.
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Diverse convergent evidence in the genetic analysis of complex disease: coordinating omic, informatic, and experimental evidence to better identify and validate risk factors.
BioData Min
PUBLISHED: 01-01-2014
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In omic research, such as genome wide association studies, researchers seek to repeat their results in other datasets to reduce false positive findings and thus provide evidence for the existence of true associations. Unfortunately this standard validation approach cannot completely eliminate false positive conclusions, and it can also mask many true associations that might otherwise advance our understanding of pathology. These issues beg the question: How can we increase the amount of knowledge gained from high throughput genetic data? To address this challenge, we present an approach that complements standard statistical validation methods by drawing attention to both potential false negative and false positive conclusions, as well as providing broad information for directing future research. The Diverse Convergent Evidence approach (DiCE) we propose integrates information from multiple sources (omics, informatics, and laboratory experiments) to estimate the strength of the available corroborating evidence supporting a given association. This process is designed to yield an evidence metric that has utility when etiologic heterogeneity, variable risk factor frequencies, and a variety of observational data imperfections might lead to false conclusions. We provide proof of principle examples in which DiCE identified strong evidence for associations that have established biological importance, when standard validation methods alone did not provide support. If used as an adjunct to standard validation methods this approach can leverage multiple distinct data types to improve genetic risk factor discovery/validation, promote effective science communication, and guide future research directions.
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Management of prostate cancer in Asia: resource-stratified guidelines from the Asian Oncology Summit 2013.
Lancet Oncol.
PUBLISHED: 11-02-2013
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Many local and systemic options for prostate cancer have emerged in recent years, but existing management guidelines do not account for diversity in health resources between different countries. We present recommendations for the management of prostate cancer, stratified according to the extent of resource availability-based on a four-tier system of basic, limited, enhanced, and maximum resources-to enable applicability to Asian countries with differing levels of health-care resources. This statement of recommendations was formulated by a multidisciplinary panel from Asia-Pacific countries, at a consensus session on prostate cancer that was held as part of the 2013 Asian Oncology Summit in Bangkok, Thailand.
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Recurrent tissue-specific mtDNA mutations are common in humans.
PLoS Genet.
PUBLISHED: 11-01-2013
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Mitochondrial DNA (mtDNA) variation can affect phenotypic variation; therefore, knowing its distribution within and among individuals is of importance to understanding many human diseases. Intra-individual mtDNA variation (heteroplasmy) has been generally assumed to be random. We used massively parallel sequencing to assess heteroplasmy across ten tissues and demonstrate that in unrelated individuals there are tissue-specific, recurrent mutations. Certain tissues, notably kidney, liver and skeletal muscle, displayed the identical recurrent mutations that were undetectable in other tissues in the same individuals. Using RFLP analyses we validated one of the tissue-specific mutations in the two sequenced individuals and replicated the patterns in two additional individuals. These recurrent mutations all occur within or in very close proximity to sites that regulate mtDNA replication, strongly implying that these variations alter the replication dynamics of the mutated mtDNA genome. These recurrent variants are all independent of each other and do not occur in the mtDNA coding regions. The most parsimonious explanation of the data is that these frequently repeated mutations experience tissue-specific positive selection, probably through replication advantage.
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Efficacy and safety 48 weeks after switching from efavirenz to rilpivirine using emtricitabine/tenofovir disoproxil fumarate-based single-tablet regimens.
HIV Clin Trials
PUBLISHED: 10-23-2013
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Due to ongoing neuropsychiatric adverse events in some efavirenz (EFV)-treated patients, a switch to an alternative non-nucleoside reverse transcriptase inhibitor may be considered. Rilpivirine (RPV) has been coformulated as a single-tablet regimen (STR) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), and the components have demonstrated noninferior efficacy to EFV+FTC/TDF, good tolerability profile, and high adherence. After discontinuation, EFV has an extended inductive effect on cytochrome P450 (CYP) 3A4 that, after switching, may reduce RPV exposures and adversely impact clinical outcomes.
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A Progress Report on a Prospective Randomised Trial of Open and Robotic Prostatectomy.
Eur. Urol.
PUBLISHED: 10-09-2013
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A randomised trial of robotic and open prostatectomy commenced in October 2010 and is progressing well. Clinical and quality of life outcomes together with economic costs to individuals and the health service are being examined critically to compare outcomes.
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A mutation in the FHA domain of Coprinus cinereus Nbs1 Leads to Spo11-independent meiotic recombination and chromosome segregation.
G3 (Bethesda)
PUBLISHED: 09-25-2013
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Nbs1, a core component of the Mre11-Rad50-Nbs1 complex, plays an essential role in the cellular response to DNA double-strand breaks (DSBs) and poorly understood roles in meiosis. We used the basidiomycete Coprinus cinereus to examine the meiotic roles of Nbs1. We identified the C. cinereus nbs1 gene and demonstrated that it corresponds to a complementation group previously known as rad3. One allele, nbs1-2, harbors a point mutation in the Nbs1 FHA domain and has a mild spore viability defect, increased frequency of meiosis I nondisjunction, and an altered crossover distribution. The nbs1-2 strain enters meiosis with increased levels of phosphorylated H2AX, which we hypothesize represent unrepaired DSBs formed during premeiotic replication. In nbs1-2, there is no apparent induction of Spo11-dependent DSBs during prophase. We propose that replication-dependent DSBs, resulting from defective replication fork protection and processing by the Mre11-Rad50-Nbs1 complex, are competent to form meiotic crossovers in C. cinereus, and that these crossovers lead to high levels of faithful chromosome segregation. In addition, although crossover distribution is altered in nbs1-2, the majority of crossovers were found in subtelomeric regions, as in wild-type. Therefore, the location of crossovers in C. cinereus is maintained when DSBs are induced via a Spo11-independent mechanism.
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Contemporary issues in radiotherapy for clinically localized prostate cancer.
Hematol. Oncol. Clin. North Am.
PUBLISHED: 09-21-2013
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Radiotherapy is a valid curative alternative to surgery for prostate cancer. However, patient selection is critical to ensure patients obtain benefits from therapy delivered with curative intent. Dose-escalated radiation has been shown to improve patient outcomes, facilitated by development of robust image guidance and better target delineation imaging technologies. These concepts have also rekindled interest in hypofractionated radiotherapy in the forms of stereotactic body radiotherapy and brachytherapy. Postprostatectomy radiotherapy also improves long-term biochemical outcome in men at high risk of local recurrence.
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Multi-Locus Candidate Gene Analyses of Lipid Levels in a Pediatric Turkish Cohort: Lessons Learned on LPL, CETP, LIPC, ABCA1, and SHBG.
OMICS
PUBLISHED: 08-29-2013
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Abstract Cardiovascular risk factors and atherosclerosis precursors were examined in 365 Turkish children and adolescents. Study participants were recruited at five different state schools. We tested single and multi-locus effects of six polymorphisms from five candidate genes, chosen based on prior known association with lipid levels in adults, for association with low (?10(th) percentile) high density lipoprotein cholesterol (HDL-C) and high (?90(th) percentile) triglycerides (TG), and the related continuous outcomes. We observed an association between CETP variant rs708272 and low HDL-C (allelic p=0.020, genotypic p=0.046), which was supported by an independent analysis, PRAT (PRAT control p=0.027). Sex-stratified logistic regression analysis showed that the B2 allele of rs708272 decreased odds of being in the lower tenth percentile of HDL-C measurements (OR=0.36, p=0.02) in girls; this direction of effect was also seen in boys but was not significant (OR=0.64, p=0.21). Logistic regression analysis also revealed that the T allele of rs6257 (SHBG) decreased odds of being in the top tenth percentile of TG measurements in boys (OR=0.43, p=0.03). Analysis of lipid levels as a continuous trait revealed a significant association between rs708272 (CETP) and LDL-C levels in males (p=0.02) with the B2B2 genotype group having the lowest mean LDL-C; the same direction of effect was also seen in females (p=0.05). An effect was also seen between rs708272 and HDL-C levels in girls (p=0.01), with the B2B2 genotype having the highest mean HDL-C levels. Multi-locus analysis, using quantitative multifactor dimensionality reduction (qMDR) identified the previously mentioned CETP variant as the best single locus model, and overall model, for predicting HDL-C levels in children. This study provides evidence for association between CETP and low HDL-C phenotype in children, but the results appear to be weaker in children than previous results in adults and may also be subject to gender effects.
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Preterm Birth Genome Project (PGP) -- validation of resources for preterm birth genome-wide studies.
J Perinat Med
PUBLISHED: 08-21-2013
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We determined a series of quality control (QC) analyses to assess the usability of DNA collected and processed from different countries utilizing different DNA extraction techniques prior to genome-wide association studies (GWAS). The quality of DNA collected utilizing four different DNA extraction techniques and the impact of shipping DNA at different temperatures on array performance were evaluated. Fifteen maternal-fetal pairs were used from four countries. DNA was extracted using four approaches: whole blood, blood spots with whole genome amplification (WGA), saliva and buccal swab. Samples were sent to a genotyping facility, either on dry ice or at room temperature and genotyped using Affymetrix SNP array 6.0. QC measured included extraction techniques, effect of shipping temperatures, accuracy and Mendelian concordance. Significantly fewer (50 % ) single nucleotide polymorphisms (SNPs) passed QC metrics for buccal swab DNA (P < 0.0001) due to missing genotype data (P < 0.0001). Whole blood or saliva DNA had the highest call rates (99.2 0.4 % and 99.3 0.2 % , respectively) and Mendelian concordance. Shipment temperature had no effect. DNA from blood or saliva had the highest call rate accuracy, and buccal swabs had the lowest. DNA extracted from blood, saliva and blood spots were found suitable for GWAS in our study.
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Oriented divisions, fate decisions.
Curr. Opin. Cell Biol.
PUBLISHED: 07-31-2013
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During development, the establishment of proper tissue architecture depends upon the coordinated control of cell divisions not only in space and time, but also direction. Execution of an oriented cell division requires establishment of an axis of polarity and alignment of the mitotic spindle along this axis. Frequently, the cleavage plane also segregates fate determinants, either unequally or equally between daughter cells, the outcome of which is either an asymmetric or symmetric division, respectively. The last few years have witnessed tremendous growth in understanding both the extrinsic and intrinsic cues that position the mitotic spindle, the varied mechanisms in which the spindle orientation machinery is controlled in diverse organisms and organ systems, and the manner in which the division axis influences the signaling pathways that direct cell fate choices.
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Diagnostic tools for hypertension and salt sensitivity testing.
Curr. Opin. Nephrol. Hypertens.
PUBLISHED: 06-05-2013
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One-third of the worlds population has hypertension and it is responsible for almost 50% of deaths from stroke or coronary heart disease. These statistics do not distinguish salt-sensitive from salt-resistant hypertension or include normotensives who are salt-sensitive even though salt sensitivity, independent of blood pressure, is a risk factor for cardiovascular and other diseases, including cancer. This review describes new personalized diagnostic tools for salt sensitivity.
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Putting pleiotropy and selection into context defines a new paradigm for interpreting genetic data.
Circ Cardiovasc Genet
PUBLISHED: 04-24-2013
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Natural selection shapes many human genes, including some related to complex diseases. Understanding how selection affects genes, especially pleiotropic ones, may be important in evaluating disease associations and the role played by environmental variation. This may be of particular interest for genes with antagonistic roles that cause divergent patterns of selection. The lectin-like low-density lipoprotein 1 receptor, encoded by OLR1, is exemplary. It has antagonistic functions in the cardiovascular and immune systems because the same protein domain binds oxidized low-density lipoprotein and bacterial cell wall proteins, the former contributing to atherosclerosis and the latter presumably protecting from infection. We studied patterns of selection in this gene, in humans and nonhuman primates, to determine whether variable selection can lead to conflicting results in cardiovascular disease association studies.
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Aprataxin resolves adenylated RNA-DNA junctions to maintain genome integrity.
Nature
PUBLISHED: 04-22-2013
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Faithful maintenance and propagation of eukaryotic genomes is ensured by three-step DNA ligation reactions used by ATP-dependent DNA ligases. Paradoxically, when DNA ligases encounter nicked DNA structures with abnormal DNA termini, DNA ligase catalytic activity can generate and/or exacerbate DNA damage through abortive ligation that produces chemically adducted, toxic 5-adenylated (5-AMP) DNA lesions. Aprataxin (APTX) reverses DNA adenylation but the context for deadenylation repair is unclear. Here we examine the importance of APTX to RNase-H2-dependent excision repair (RER) of a lesion that is very frequently introduced into DNA, a ribonucleotide. We show that ligases generate adenylated 5 ends containing a ribose characteristic of RNase H2 incision. APTX efficiently repairs adenylated RNA-DNA, and acting in an RNA-DNA damage response (RDDR), promotes cellular survival and prevents S-phase checkpoint activation in budding yeast undergoing RER. Structure-function studies of human APTX-RNA-DNA-AMP-Zn complexes define a mechanism for detecting and reversing adenylation at RNA-DNA junctions. This involves A-form RNA binding, proper protein folding and conformational changes, all of which are affected by heritable APTX mutations in ataxia with oculomotor apraxia 1. Together, these results indicate that accumulation of adenylated RNA-DNA may contribute to neurological disease.
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The vertebral column of Australopithecus sediba.
Science
PUBLISHED: 04-13-2013
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Two partial vertebral columns of Australopithecus sediba grant insight into aspects of early hominin spinal mobility, lumbar curvature, vertebral formula, and transitional vertebra position. Au. sediba likely possessed five non-rib-bearing lumbar vertebrae and five sacral elements, the same configuration that occurs modally in modern humans. This finding contrasts with other interpretations of early hominin regional vertebral numbers. Importantly, the transitional vertebra is distinct from and above the last rib-bearing vertebra in Au. sediba, resulting in a functionally longer lower back. This configuration, along with a strongly wedged last lumbar vertebra and other indicators of lordotic posture, would have contributed to a highly flexible spine that is derived compared with earlier members of the genus Australopithecus and similar to that of the Nariokotome Homo erectus skeleton.
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Serum antibodies to Borrelia burgdorferi, Anaplasma phagocytophilum, and Babesia microti in recaptured white-footed mice.
J. Wildl. Dis.
PUBLISHED: 04-10-2013
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A mark-release-recapture study was conducted during 2007 through 2010 in six, tick-infested sites in Connecticut, United States to measure changes in antibody titers for Borrelia burgdorferi sensu stricto, Anaplasma phagocytophilum, and Babesia microti in Peromyscus leucopus (white-footed mice). There was an overall recapture rate of 40%, but only four tagged mice were caught in ?2 yr. Sera from 561 mice were analyzed for total antibodies to B. burgdorferi and A. phagocytophilum by using whole-cell or recombinant (VlsE or protein 44) antigens in a solid-phase enzyme-linked immunosorbent assay or to whole-cell B. microti by indirect fluorescent antibody staining. Antibody prevalences were highly variable for B. burgdorferi (from 56% to 98%), A. phagocytophilum (from 11% to 85%), and B. microti (from 11% to 84%) depending on the site and time of sampling. Of 463 mice with antibodies, 206 (45%) had antibodies to all three pathogens. Changes in antibody status for some mice from negative to positive (117 seroconversions) or from positive to negative (55 reversions) were observed. Seroconversions were observed in 10.1% of 417 mice for B. burgdorferi, 18.0% of 306 mice for A. phagocytophilum, and 6.6% of 304 mice for B. microti; reversion rates were 5.3, 5.9, and 4.9%, respectively. Antibodies to all pathogens persisted in some mice over several weeks while, in others, there were marked declines in titration end points to negative status. The latter may indicate elimination of a certain pathogen, such as A. phagocytophilum, or that mouse immune systems ceased to produce antibodies despite an existing patent infection.
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A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry.
Keri L Monda, Gary K Chen, Kira C Taylor, Cameron Palmer, Todd L Edwards, Leslie A Lange, Maggie C Y Ng, Adebowale A Adeyemo, Matthew A Allison, Lawrence F Bielak, Guanjie Chen, Mariaelisa Graff, Marguerite R Irvin, Suhn K Rhie, Guo Li, Yongmei Liu, Youfang Liu, Yingchang Lu, Michael A Nalls, Yan V Sun, Mary K Wojczynski, Lisa R Yanek, Melinda C Aldrich, Adeyinka Ademola, Christopher I Amos, Elisa V Bandera, Cathryn H Bock, Angela Britton, Ulrich Broeckel, Quiyin Cai, Neil E Caporaso, Chris S Carlson, John Carpten, Graham Casey, Wei-Min Chen, Fang Chen, Yii-Der I Chen, Charleston W K Chiang, Gerhard A Coetzee, Ellen Demerath, Sandra L Deming-Halverson, Ryan W Driver, Patricia Dubbert, Mary F Feitosa, Ye Feng, Barry I Freedman, Elizabeth M Gillanders, Omri Gottesman, Xiuqing Guo, Talin Haritunians, Tamara Harris, Curtis C Harris, Anselm J M Hennis, Dena G Hernandez, Lorna H McNeill, Timothy D Howard, Barbara V Howard, Virginia J Howard, Karen C Johnson, Sun J Kang, Brendan J Keating, Suzanne Kolb, Lewis H Kuller, Abdullah Kutlar, Carl D Langefeld, Guillaume Lettre, Kurt Lohman, Vaneet Lotay, Helen Lyon, JoAnn E Manson, William Maixner, Yan A Meng, Kristine R Monroe, Imran Morhason-Bello, Adam B Murphy, Josyf C Mychaleckyj, Rajiv Nadukuru, Katherine L Nathanson, Uma Nayak, Amidou N'Diaye, Barbara Nemesure, Suh-Yuh Wu, M Cristina Leske, Christine Neslund-Dudas, Marian Neuhouser, Sarah Nyante, Heather Ochs-Balcom, Adesola Ogunniyi, Temidayo O Ogundiran, Oladosu Ojengbede, Olufunmilayo I Olopade, Julie R Palmer, Edward A Ruiz-Narváez, Nicholette D Palmer, Michael F Press, Evandine Rampersaud, Laura J Rasmussen-Torvik, Jorge L Rodriguez-Gil, Babatunde Salako, Eric E Schadt, Ann G Schwartz, Daniel A Shriner, David Siscovick, Shad B Smith, Sylvia Wassertheil-Smoller, Elizabeth K Speliotes, Margaret R Spitz, Lara Sucheston, Herman Taylor, Bamidele O Tayo, Margaret A Tucker, David J Van Den Berg, Digna R Velez Edwards, Zhaoming Wang, John K Wiencke, Thomas W Winkler, John S Witte, Margaret Wrensch, Xifeng Wu, James J Yang, Albert M Levin, Taylor R Young, Neil A Zakai, Mary Cushman, Krista A Zanetti, Jing Hua Zhao, Wei Zhao, Yonglan Zheng, Jie Zhou, Regina G Ziegler, Joseph M Zmuda, Jyotika K Fernandes, Gary S Gilkeson, Diane L Kamen, Kelly J Hunt, Ida J Spruill, Christine B Ambrosone, Stefan Ambs, Donna K Arnett, Larry Atwood, Diane M Becker, Sonja I Berndt, Leslie Bernstein, William J Blot, Ingrid B Borecki, Erwin P Bottinger, Donald W Bowden, Gregory Burke, Stephen J Chanock, Richard S Cooper, Jingzhong Ding, David Duggan, Michele K Evans, Caroline Fox, W Timothy Garvey, Jonathan P Bradfield, Hakon Hakonarson, Struan F A Grant, Ann Hsing, Lisa Chu, Jennifer J Hu, Dezheng Huo, Sue A Ingles, Esther M John, Joanne M Jordan, Edmond K Kabagambe, Sharon L R Kardia, Rick A Kittles, Phyllis J Goodman, Eric A Klein, Laurence N Kolonel, Loic Le Marchand, Simin Liu, Barbara McKnight, Robert C Millikan, Thomas H Mosley, Badri Padhukasahasram, L Keoki Williams, Sanjay R Patel, Ulrike Peters, Curtis A Pettaway, Patricia A Peyser, Bruce M Psaty, Susan Redline, Charles N Rotimi, Benjamin A Rybicki, Michèle M Sale, Pamela J Schreiner, Lisa B Signorello, Andrew B Singleton, Janet L Stanford, Sara S Strom, Michael J Thun, Mara Vitolins, Wei Zheng, Jason H Moore, Scott M Williams, Shamika Ketkar, Xiaofeng Zhu, Alan B Zonderman, , Charles Kooperberg, George J Papanicolaou, Brian E Henderson, Alex P Reiner, Joel N Hirschhorn, Ruth J F Loos, Kari E North, Christopher A Haiman.
Nat. Genet.
PUBLISHED: 03-18-2013
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Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.
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Genome-wide association analysis of blood-pressure traits in African-ancestry individuals reveals common associated genes in African and non-African populations.
Nora Franceschini, Ervin Fox, Zhaogong Zhang, Todd L Edwards, Michael A Nalls, Yun Ju Sung, Bamidele O Tayo, Yan V Sun, Omri Gottesman, Adebawole Adeyemo, Andrew D Johnson, J Hunter Young, Ken Rice, Qing Duan, Fang Chen, Yun Li, Hua Tang, Myriam Fornage, Keith L Keene, Jeanette S Andrews, Jennifer A Smith, Jessica D Faul, Zhang Guangfa, Wei Guo, Yu Liu, Sarah S Murray, Solomon K Musani, Sathanur Srinivasan, Digna R Velez Edwards, Heming Wang, Lewis C Becker, Pascal Bovet, Murielle Bochud, Ulrich Broeckel, Michel Burnier, Cara Carty, Daniel I Chasman, Georg Ehret, Wei-Min Chen, Guanjie Chen, Wei Chen, Jingzhong Ding, Albert W Dreisbach, Michele K Evans, Xiuqing Guo, Melissa E Garcia, Rich Jensen, Margaux F Keller, Guillaume Lettre, Vaneet Lotay, Lisa W Martin, Jason H Moore, Alanna C Morrison, Thomas H Mosley, Adesola Ogunniyi, Walter Palmas, George Papanicolaou, Alan Penman, Joseph F Polak, Paul M Ridker, Babatunde Salako, Andrew B Singleton, Daniel Shriner, Kent D Taylor, Ramachandran Vasan, Kerri Wiggins, Scott M Williams, Lisa R Yanek, Wei Zhao, Alan B Zonderman, Diane M Becker, Gerald Berenson, Eric Boerwinkle, Erwin Bottinger, Mary Cushman, Charles Eaton, Fredrik Nyberg, Gerardo Heiss, Joel N Hirschhron, Virginia J Howard, Konrad J Karczewsk, Matthew B Lanktree, Kiang Liu, Yongmei Liu, Ruth Loos, Karen Margolis, Michael Snyder, , Bruce M Psaty, Nicholas J Schork, David R Weir, Charles N Rotimi, Michèle M Sale, Tamara Harris, Sharon L R Kardia, Steven C Hunt, Donna Arnett, Susan Redline, Richard S Cooper, Neil J Risch, D C Rao, Jerome I Rotter, Aravinda Chakravarti, Alex P Reiner, Daniel Levy, Brendan J Keating, Xiaofeng Zhu.
Am. J. Hum. Genet.
PUBLISHED: 03-01-2013
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High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 × 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.
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Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production.
PLoS Genet.
PUBLISHED: 02-18-2013
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Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22-24 (LOD=6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ~1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [P(meta) = 5.20×10(-14); odds ratio, 95% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [P(meta) = 3.08×10(-7); 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [P(dom) = 1.16×10(-8); 0.70 (0.62-0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.
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Multifactor dimensionality reduction reveals a three-locus epistatic interaction associated with susceptibility to pulmonary tuberculosis.
BioData Min
PUBLISHED: 02-11-2013
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Identifying high-order genetics associations with non-additive (i.e. epistatic) effects in population-based studies of common human diseases is a computational challenge. Multifactor dimensionality reduction (MDR) is a machine learning method that was designed specifically for this problem. The goal of the present study was to apply MDR to mining high-order epistatic interactions in a population-based genetic study of tuberculosis (TB).
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An information-gain approach to detecting three-way epistatic interactions in genetic association studies.
J Am Med Inform Assoc
PUBLISHED: 02-08-2013
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Epistasis has been historically used to describe the phenomenon that the effect of a given gene on a phenotype can be dependent on one or more other genes, and is an essential element for understanding the association between genetic and phenotypic variations. Quantifying epistasis of orders higher than two is very challenging due to both the computational complexity of enumerating all possible combinations in genome-wide data and the lack of efficient and effective methodologies.
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Real-time individual predictions of prostate cancer recurrence using joint models.
Biometrics
PUBLISHED: 02-04-2013
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Patients who were previously treated for prostate cancer with radiation therapy are monitored at regular intervals using a laboratory test called Prostate Specific Antigen (PSA). If the value of the PSA test starts to rise, this is an indication that the prostate cancer is more likely to recur, and the patient may wish to initiate new treatments. Such patients could be helped in making medical decisions by an accurate estimate of the probability of recurrence of the cancer in the next few years. In this article, we describe the methodology for giving the probability of recurrence for a new patient, as implemented on a web-based calculator. The methods use a joint longitudinal survival model. The model is developed on a training dataset of 2386 patients and tested on a dataset of 846 patients. Bayesian estimation methods are used with one Markov chain Monte Carlo (MCMC) algorithm developed for estimation of the parameters from the training dataset and a second quick MCMC developed for prediction of the risk of recurrence that uses the longitudinal PSA measures from a new patient.
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Validation of a radiobiological model for low-dose-rate prostate boost focal therapy treatment planning.
Brachytherapy
PUBLISHED: 02-01-2013
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Low-dose-rate brachytherapy using iodine-125 seeds is a highly efficacious treatment for low-risk prostate cancer. We propose a bioeffect model may be used to target an ablative dose to the tumor with a lower, therapeutic dose to low-risk regions to maintain high rates of tumor control with reduced toxicity. We report on the validation of the model and derivation of the optimal cutpoint value of tumor control probability (TCP) that predicts for freedom from biochemical failure.
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Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease.
EMBO J.
PUBLISHED: 01-22-2013
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Adenosine diphosphate (ADP)-ribosylation is a post-translational protein modification implicated in the regulation of a range of cellular processes. A family of proteins that catalyse ADP-ribosylation reactions are the poly(ADP-ribose) (PAR) polymerases (PARPs). PARPs covalently attach an ADP-ribose nucleotide to target proteins and some PARP family members can subsequently add additional ADP-ribose units to generate a PAR chain. The hydrolysis of PAR chains is catalysed by PAR glycohydrolase (PARG). PARG is unable to cleave the mono(ADP-ribose) unit directly linked to the protein and although the enzymatic activity that catalyses this reaction has been detected in mammalian cell extracts, the protein(s) responsible remain unknown. Here, we report the homozygous mutation of the c6orf130 gene in patients with severe neurodegeneration, and identify C6orf130 as a PARP-interacting protein that removes mono(ADP-ribosyl)ation on glutamate amino acid residues in PARP-modified proteins. X-ray structures and biochemical analysis of C6orf130 suggest a mechanism of catalytic reversal involving a transient C6orf130 lysyl-(ADP-ribose) intermediate. Furthermore, depletion of C6orf130 protein in cells leads to proliferation and DNA repair defects. Collectively, our data suggest that C6orf130 enzymatic activity has a role in the turnover and recycling of protein ADP-ribosylation, and we have implicated the importance of this protein in supporting normal cellular function in humans.
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A small number of candidate gene SNPs reveal continental ancestry in African Americans.
Ann. Hum. Genet.
PUBLISHED: 01-03-2013
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Using genetic data from an obesity candidate gene study of self-reported African Americans and European Americans, we investigated the number of Ancestry Informative Markers (AIMs) and candidate gene SNPs necessary to infer continental ancestry. Proportions of African and European ancestry were assessed with STRUCTURE (K = 2), using 276 AIMs. These reference values were compared to estimates derived using 120, 60, 30, and 15 SNP subsets randomly chosen from the 276 AIMs and from 1144 SNPs in 44 candidate genes. All subsets generated estimates of ancestry consistent with the reference estimates, with mean correlations greater than 0.99 for all subsets of AIMs, and mean correlations of 0.99 ± 0.003; 0.98 ± 0.01; 0.93 ± 0.03; and 0.81 ± 0.11 for subsets of 120, 60, 30, and 15 candidate gene SNPs, respectively. Among African Americans, the median absolute difference from reference African ancestry values ranged from 0.01 to 0.03 for the four AIMs subsets and from 0.03 to 0.09 for the four candidate gene SNP subsets. Furthermore, YRI/CEU Fst values provided a metric to predict the performance of candidate gene SNPs. Our results demonstrate that a small number of SNPs randomly selected from candidate genes can be used to estimate admixture proportions in African Americans reliably.
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Effects of developmental bisphenol A exposure on reproductive-related behaviors in California mice (Peromyscus californicus): a monogamous animal model.
PLoS ONE
PUBLISHED: 01-02-2013
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Bisphenol A (BPA), a pervasive, endocrine disrupting compound (EDC), acts as a mixed agonist-antagonist with respect to estrogens and other steroid hormones. We hypothesized that sexually selected traits would be particularly sensitive to EDC. Consistent with this concept, developmental exposure of males from the polygynous deer mouse, Peromyscus maniculatus, to BPA resulted in compromised spatial navigational ability and exploratory behaviors, while there was little effect on females. Here, we have examined a related, monogamous species, the California mouse (Peromyscus californicus), where we predicted that males would be less sensitive to BPA in terms of navigational and exploratory behaviors, while displaying other traits related to interactions with females and territorial marking that might be vulnerable to disruption. As in the deer mouse experiments, females were fed either a phytoestrogen-free CTL diet through pregnancy and lactation or the same diet supplemented with BPA (50 mg/kg feed weight) or ethinyl estradiol (EE) (0.1 part per billion) to provide a "pure" estrogen control. After weaning, pups were maintained on CTL diet until they had reached sexual maturity, at which time behaviors were evaluated. In addition, territorial marking was assessed in BPA-exposed males housed alone and when a control male was visible in the testing arena. In contrast to deer mice, BPA and EE exposure had no effect on spatial navigational skills in either male or female California mice. While CTL females exhibited greater exploratory behavior than CTL males, BPA exposure abolished this sex difference. BPA-exposed males, however, engaged in less territorial marking when CTL males were present. These studies demonstrate that developmental BPA exposure can disrupt adult behaviors in a sex- and species-dependent manner and are consistent with the hypothesis that sexually selected traits are particularly vulnerable to endocrine disruption and should be a consideration in risk assessment studies.
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Identifying population differences in genes that affect body mass index.
Genome Med
PUBLISHED: 01-01-2013
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Genomic regions of interest can be narrowed by studying populations that have patterns of low linkage disequilibrium. A recent study of body mass index in African Americans demonstrated this point and, through cross-population analyses, revealed additional genomic associations. This comparative analysis showed how rare alleles that associate with traits in specific populations can be detected in cohorts where the same alleles are not rare, and highlights how population diversity can aid genetic analyses.
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X-Linked MTMR8 Diversity and Evolutionary History of Sub-Saharan Populations.
PLoS ONE
PUBLISHED: 01-01-2013
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The genetic diversity within an 11 kb segment of the MTMR8 gene in a sample of 111 sub-Saharan and 49 non-African X chromosomes was investigated to assess the early evolutionary history of sub-Saharan Africans and the out-of-Africa expansion. The analyses revealed a complex genetic structure of the Africans that contributed to the emergence of modern humans. We observed partitioning of two thirds of old lineages among southern, west/central and east African populations indicating ancient population stratification predating the out of Africa migration. Age estimates of these lineages, older than coalescence times of uniparentally inherited markers, raise the question whether contemporary humans originated from a single population or as an amalgamation of different populations separated by years of independent evolution, thus suggesting a greater antiquity of our species than generally assumed. While the oldest sub-Saharan lineages, ?500 thousand years, are found among Khoe-San from southern-Africa, a distinct haplotype found among Biaka is likely due to admixture from an even older population. An East African population that gave rise to non-Africans underwent a selective sweep affecting the subcentromeric region where MTMR8 is located. This and similar sweeps in four other regions of the X chromosome, documented in the literature, effectively reduced genetic diversity of non-African chromosomes and therefore may have exacerbated the effect of the demographic bottleneck usually ascribed to the out of Africa migration. Our data is suggestive, however, that a bottleneck, occurred in Africa before range expansion.
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A Simple and Computationally Efficient Approach to Multifactor Dimensionality Reduction Analysis of Gene-Gene Interactions for Quantitative Traits.
PLoS ONE
PUBLISHED: 01-01-2013
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We present an extension of the two-class multifactor dimensionality reduction (MDR) algorithm that enables detection and characterization of epistatic SNP-SNP interactions in the context of a quantitative trait. The proposed Quantitative MDR (QMDR) method handles continuous data by modifying MDRs constructive induction algorithm to use a T-test. QMDR replaces the balanced accuracy metric with a T-test statistic as the score to determine the best interaction model. We used a simulation to identify the empirical distribution of QMDRs testing score. We then applied QMDR to genetic data from the ongoing prospective Prevention of Renal and Vascular End-Stage Disease (PREVEND) study.
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Language services in hospitals: discordance in availability and staff use.
J Healthc Manag
PUBLISHED: 12-29-2011
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Despite efforts to advance effective patient-provider communication, many patients language needs continue to be unmet or inappropriately addressed by healthcare providers (Wielawski 2010; Patek et al. 2009; Wilson-Stronks and Galvez 2007). This study presents a picture of the language resources currently provided by hospitals and those resources practitioners actually use. Questionnaire data were collected from 14 hospitals in Floridas Palm Beach, St. Lucie, and Martin counties on availability, staff awareness, and staff use of linguistic resources and services. Inconsistencies were identified between the language tools, services, and resources hospitals provide and those staff use. In addition, a large majority of staff respondents still rely upon someone accompanying the patient for communication with patients who have limited English proficiency, despite evidence that this practice contributes to miscommunication and serious medical errors (Flores et al. 2003; Flores 2005; HHS OMH 2001; Patek et al. 2009). Hospitals that use bilingual staff as interpreters often do not test the competency of these staff, nor do they assess the utilization or effectiveness of the tools and resources they provide. Hospitals can improve the cultural and linguistic care they provide if they (1) address the practice of using ad hoc interpreters, (2) effectively disseminate information to hospital staff regarding how and when to access available resources, and (3) collect patient population data and use it to plan for and evaluate the language services they provide to their patients.
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Radioimmunotherapy of non-Hodgkins lymphoma: from the magic bullets to radioactive magic bullets.
Yale J Biol Med
PUBLISHED: 12-20-2011
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Radioimmunotherapy (RIT) of lymphoma with Zevalin and Bexxar was approved by FDA in 2002 and 2003, respectively, for the treatment of relapsed or refractory CD20+ follicular B-cell non-Hodgkin´s lymphoma. In 2009, Zevalin was also approved for consolidation therapy in patients with follicular non-Hodgkins lymphoma that achieve a partial or complete response to first-line chemotherapy. For follicular lymphoma patients, the overall response and progression-free survival rates have significantly improved since the implementation of RIT. The predominant complication of RIT is hematological toxicity that is usually manageable. There are ongoing trials to further define the expanding role of RIT as first line or concomitant therapy in the treatment of lymphoma as well as for certain antibiotic resistant infections and aggressive malignancies. There is also growing interest in the development of newer protocols for increased and more uniform dose delivery resulting in better outcomes and improved patient survival. This review will primarily focus on the role of RIT in treatment of non-Hodgkins lymphoma, which is of established clinical utility and FDA approved. The mechanism of RIT, available radionuclides and pharmacokinetics, therapy administration, clinical utility and toxicities, and future directions would be discussed.
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HTR1B, ADIPOR1, PPARGC1A, and CYP19A1 and obesity in a cohort of Caucasians and African Americans: an evaluation of gene-environment interactions and candidate genes.
Am. J. Epidemiol.
PUBLISHED: 11-20-2011
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The World Health Organization estimates that the number of obese and overweight adults has increased to 1.6 billion, with concomitant increases in comorbidity. While genetic factors for obesity have been extensively studied in Caucasians, fewer studies have investigated genetic determinants of body mass index (BMI; weight (kg)/height (m)(2)) in African Americans. A total of 38 genes and 1,086 single nucleotide polymorphisms (SNPs) in African Americans (n = 1,173) and 897 SNPs in Caucasians (n = 1,165) were examined in the Southern Community Cohort Study (2002-2009) for associations with BMI and gene × environment interactions. A statistically significant association with BMI survived correction for multiple testing at rs4140535 (? = -0.04, 95% confidence interval: -0.06, -0.02; P = 5.76 × 10(-5)) in African Americans but not in Caucasians. Gene-environment interactions were observed with cigarette smoking and a SNP in ADIPOR1 in African Americans, as well as between a different SNP in ADIPOR1 and physical activity in Caucasians. A SNP in PPARGC1A interacted with alcohol consumption in African Americans, and a different SNP in PPARGC1A was nominally associated in Caucasians. A SNP in CYP19A1 interacted with dietary energy intake in African Americans, and another SNP in CYP191A had an independent association with BMI in Caucasians.
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Real-time ophthalmoscopic findings of superselective intraophthalmic artery chemotherapy in a nonhuman primate model.
Arch. Ophthalmol.
PUBLISHED: 11-16-2011
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To report real-time ophthalmoscopic findings during superselective intraophthalmic artery chemotherapy (SSIOAC) in a nonhuman primate model.
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Hospital performance trends on national quality measures and the association with Ioint Commission accreditation.
J Hosp Med
PUBLISHED: 10-13-2011
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Evaluations of the impact of hospital accreditation have been previously hampered by the lack of nationally standardized data. One way to assess this impact is to compare accreditation status with other evidence-based measures of quality, such as the process measures now publicly reported by The Joint Commission and the Centers for Medicare and Medicaid Services (CMS).
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Optical pulse-shaping for internal cooling of molecules.
Phys Chem Chem Phys
PUBLISHED: 09-26-2011
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We consider the use of pulse-shaped broadband femtosecond lasers to optically cool rotational and vibrational degrees of freedom of molecules. Since this approach relies on cooling rotational and vibrational quanta by exciting an electronic transition, it is most easily applicable to molecules with similar ground and excited potential energy surfaces, such that the vibrational state is usually unchanged during electronic relaxation. Compared with schemes that cool rotations by exciting vibrations, this approach achieves internal cooling on the orders-of-magnitude faster electronic decay timescale and is potentially applicable to apolar molecules. For AlH(+), a candidate species, a rate-equation simulation indicates that rovibrational equilibrium should be achievable in 8 ?s. In addition, we report laboratory demonstration of optical pulse shaping with sufficient resolution and power for rotational cooling of AlH(+).
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Peroxisome proliferator-activated receptor delta (PPARD) genetic variation and type 2 diabetes in middle-aged Chinese women.
Ann. Hum. Genet.
PUBLISHED: 08-13-2011
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Animal studies have shown that the peroxime proliferator-activated receptor delta (PPARD) gene regulates glucose metabolism and insulin sensitivity. Genetic variation in the PPARD gene might affect physical endurance and has been associated with obesity. We investigated the independent and modifying effect of variants in the PPARD gene with exercise participation and body mass index (BMI) on type 2 diabetes (T2D), using data from a genome-wide association study (GWAS) of middle-aged women living in Shanghai, China, with 1019 T2D cases and 1709 controls. The genotyping was performed using the Affymetrix Genome-Wide Human SNP Array 6.0 platform. Imputation was used to determine missing genotypes. Participation in exercise was assessed by a questionnaire. Anthropometric variables were measured by trained interviewers. The association between polymorphisms and T2D was assessed by logistic regression analyses. The combined effects of polymorphisms in the PPARD gene with exercise participation and BMI on T2D risk was assessed by conducting stratified analysis with exercise participation and BMI categories. No significant associations between PPARD and T2D were found in either genotyped or imputed SNPs and no effect modification between exercise participation and PPARD genetic variation was found, suggesting that PPARD is not a risk factor for T2D in this population.
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The perceived impact of public reporting hospital performance data: interviews with hospital staff.
Int J Qual Health Care
PUBLISHED: 08-12-2011
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To assess perceptions about the value and impact of publicly reporting hospital performance measure data.
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Ethnic disparity in spontaneous preterm birth and maternal pre-pregnancy body mass index.
Arch. Gynecol. Obstet.
PUBLISHED: 07-18-2011
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To investigate differences in pre-pregnancy BMI status in patients with spontaneous preterm birth (PTB) compared with term birth and assess the role of ethnicity as a risk modifier in BMI-associated PTB.
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Exploring genomic studies in Africa.
Genome Med
PUBLISHED: 07-08-2011
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A report on the African Society of Human Genetics meeting, Cape Town, South Africa, 6-9 March 2011.
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Common variation in vitamin D pathway genes predicts circulating 25-hydroxyvitamin D Levels among African Americans.
PLoS ONE
PUBLISHED: 07-01-2011
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Vitamin D is implicated in a wide range of health outcomes, and although environmental predictors of vitamin D levels are known, the genetic drivers of vitamin D status remain to be clarified. African Americans are a group at particularly high risk for vitamin D insufficiency but to date have been virtually absent from studies of genetic predictors of circulating vitamin D levels. Within the Southern Community Cohort Study, we investigated the association between 94 single nucleotide polymorphisms (SNPs) in five vitamin D pathway genes (GC, VDR, CYP2R1, CYP24A1, CYP27B1) and serum 25-hydroxyvitamin D (25(OH)D) levels among 379 African American and 379 Caucasian participants. We found statistically significant associations with three SNPs (rs2298849 and rs2282679 in the GC gene, and rs10877012 in the CYP27B1 gene), although only for African Americans. A genotype score, representing the number of risk alleles across the three SNPs, alone accounted for 4.6% of the variation in serum vitamin D among African Americans. A genotype score of 5 (vs. 1) was also associated with a 7.1 ng/mL reduction in serum 25(OH)D levels and a six-fold risk of vitamin D insufficiency (<20 ng/mL) (odds ratio 6.0, p?=?0.01) among African Americans. With African ancestry determined from a panel of 276 ancestry informative SNPs, we found that high risk genotypes did not cluster among those with higher African ancestry. This study is one of the first to investigate common genetic variation in relation to vitamin D levels in African Americans, and the first to evaluate how vitamin D-associated genotypes vary in relation to African ancestry. These results suggest that further evaluation of genetic contributors to vitamin D status among African Americans may help provide insights regarding racial health disparities or enable the identification of subgroups especially in need of vitamin D-related interventions.
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Copy number variants in extended autism spectrum disorder families reveal candidates potentially involved in autism risk.
PLoS ONE
PUBLISHED: 06-24-2011
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Copy number variations (CNVs) are a major cause of genetic disruption in the human genome with far more nucleotides being altered by duplications and deletions than by single nucleotide polymorphisms (SNPs). In the multifaceted etiology of autism spectrum disorders (ASDs), CNVs appear to contribute significantly to our understanding of the pathogenesis of this complex disease. A unique resource of 42 extended ASD families was genotyped for over 1 million SNPs to detect CNVs that may contribute to ASD susceptibility. Each family has at least one avuncular or cousin pair with ASD. Families were then evaluated for co-segregation of CNVs in ASD patients. We identified a total of five deletions and seven duplications in eleven families that co-segregated with ASD. Two of the CNVs overlap with regions on 7p21.3 and 15q24.1 that have been previously reported in ASD individuals and two additional CNVs on 3p26.3 and 12q24.32 occur near regions associated with schizophrenia. These findings provide further evidence for the involvement of ICA1 and NXPH1 on 7p21.3 in ASD susceptibility and highlight novel ASD candidates, including CHL1, FGFBP3 and POUF41. These studies highlight the power of using extended families for gene discovery in traits with a complex etiology.
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Acute toxicity in prostate cancer patients treated with and without image-guided radiotherapy.
Radiat Oncol
PUBLISHED: 06-08-2011
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Image-guided radiotherapy (IGRT) increases the accuracy of treatment delivery through daily target localisation. We report on toxicity symptoms experienced during radiotherapy treatment, with and without IGRT in prostate cancer patients treated radically.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.