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Folate Network Genetic Variation, Plasma Homocysteine, and Global Genomic Methylation Content: A Genetic Association Study
Background: Sequence variants in genes functioning in folate-mediated one-carbon metabolism are hypothesized to lead to changes in levels of homocysteine and DNA methylation, which, in turn, are associated with risk of cardiovascular disease. Methods: 330 SNPs in 52 genes were studied in relation to plasma homocysteine and global genomic DNA methylation. SNPs were selected based on functional effects and gene coverage, and assays were completed on the Illumina Goldengate platform. Age-, smoking-, and nutrient-adjusted genotype--phenotype associations were estimated in regression models. Results: Using a nominal P 0.005 threshold for statistical significance, 20 SNPs were associated with plasma homocysteine, 8 with Alu methylation, and 1 with LINE-1 methylation. Using a more stringent false discovery rate threshold, SNPs in FTCD, SLC19A1, and SLC19A3 genes remained associated with plasma homocysteine. Gene by vitamin B-6 interactions were identified for both Alu and LINE-1 methylation, and epistatic interactions with the MTHFR rs1801133 SNP were identified for the plasma homocysteine phenotype. Pleiotropy involving the MTHFD1L and SARDH genes for both plasma homocysteine and Alu methylation phenotypes was identified. Conclusions: No single gene was associated with all three phenotypes, and the set of the most statistically significant SNPs predictive of homocysteine or Alu or LINE-1 methylation was unique to each phenotype. Genetic variation in folate-mediated one-carbon metabolism, other than the well-known effects of the MTHFR c.665C>T (known as c.677 C>T, rs1801133, p.Ala222Val), is predictive of cardiovascular disease biomarkers
Folate network genetic variation, plasma homocysteine, and global genomic methylation content: a genetic association study
BACKGROUND:
Sequence variants in genes functioning in folate-mediated one-carbon metabolism are hypothesized to lead to changes in levels of homocysteine and DNA methylation, which, in turn, are associated with risk of cardiovascular disease.
METHODS:
330 SNPs in 52 genes were studied in relation to plasma homocysteine and global genomic DNA methylation. SNPs were selected based on functional effects and gene coverage, and assays were completed on the Illumina Goldengate platform. Age-, smoking-, and nutrient-adjusted genotype--phenotype associations were estimated in regression models.
RESULTS:
Using a nominal P 64 0.005 threshold for statistical significance, 20 SNPs were associated with plasma homocysteine, 8 with Alu methylation, and 1 with LINE-1 methylation. Using a more stringent false discovery rate threshold, SNPs in FTCD, SLC19A1, and SLC19A3 genes remained associated with plasma homocysteine. Gene by vitamin B-6 interactions were identified for both Alu and LINE-1 methylation, and epistatic interactions with the MTHFR rs1801133 SNP were identified for the plasma homocysteine phenotype. Pleiotropy involving the MTHFD1L and SARDH genes for both plasma homocysteine and Alu methylation phenotypes was identified.
CONCLUSIONS:
No single gene was associated with all three phenotypes, and the set of the most statistically significant SNPs predictive of homocysteine or Alu or LINE-1 methylation was unique to each phenotype. Genetic variation in folate-mediated one-carbon metabolism, other than the well-known effects of the MTHFR c.665C>T (known as c.677 C>T, rs1801133, p.Ala222Val), is predictive of cardiovascular disease biomarkers
Analysis of preterm deliveries below 35 weeks' gestation in a tertiary referral hospital in the UK. A case-control survey
<p>Abstract</p> <p>Background</p> <p>Preterm birth remains a major public health problem and its incidence worldwide is increasing. Epidemiological risk factors have been investigated in the past, but there is a need for a better understanding of the causes of preterm birth in well defined obstetric populations in tertiary referral centres; it is important to repeat surveillance and identify possible changes in clinical and socioeconomic factors associated with preterm delivery. The aim of this study was to identify current risk factors associated with preterm delivery and highlight areas for further research.</p> <p>Findings</p> <p>We studied women with singleton deliveries at St Michael's Hospital, Bristol during 2002 and 2003. 274 deliveries between 23-35 weeks' gestation (preterm group), were compared to 559 randomly selected control deliveries at term (37-42 weeks) using standard statistical procedures. Both groups were >80% Caucasian. Previous preterm deliveries, high maternal age (> 39 years), socioeconomic problems, smoking during pregnancy, hypertension, psychiatric disorders and uterine abnormalities were significantly associated with preterm deliveries. Both lean and obese mothers were more common in the preterm group. Women with depression/psychiatric disease were significantly more likely to have social problems, to have smoked during pregnancy and to have had previous preterm deliveries; when adjustments for these three factors were made the relationship between psychiatric disease and pregnancy outcome was no longer significant. 53% of preterm deliveries were spontaneous, and were strongly associated with episodes of threatened preterm labour. Medically indicated preterm deliveries were associated with hypertension and fetal growth restriction. Preterm premature rupture of the membranes, vaginal bleeding, anaemia and oligohydramnios were significantly increased in both spontaneous and indicated preterm deliveries compared to term controls.</p> <p>Conclusions</p> <p>More than 50% of preterm births are potentially preventable, but remain associated with risk factors such as increased uterine contractility, preterm premature rupture of the membranes and uterine bleeding whose aetiology is unknown. Despite remarkable advances in perinatal care, preterm birth continues to cause neonatal deaths and long-term morbidity. Significant breakthroughs in the management of preterm birth are likely to come from research into the mechanisms of human parturition and the pathophysiology of preterm labour using multidisciplinary clinical and laboratory approaches.</p
Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial
Background
Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy
The Balloon-Borne Large Aperture Submillimeter Telescope Observatory
The BLAST Observatory is a proposed superpressure balloon-borne polarimeter
designed for a future ultra-long duration balloon campaign from Wanaka, New
Zealand. To maximize scientific output while staying within the stringent
superpressure weight envelope, BLAST will feature new 1.8m off-axis optical
system contained within a lightweight monocoque structure gondola. The payload
will incorporate a 300L He cryogenic receiver which will cool 8,274
microwave kinetic inductance detectors (MKIDs) to 100mK through the use of an
adiabatic demagnetization refrigerator (ADR) in combination with a He
sorption refrigerator all backed by a liquid helium pumped pot operating at 2K.
The detector readout utilizes a new Xilinx RFSOC-based system which will run
the next-generation of the BLAST-TNG KIDPy software. With this instrument we
aim to answer outstanding questions about dust dynamics as well as provide
community access to the polarized submillimeter sky made possible by
high-altitude observing unrestricted by atmospheric transmission. The BLAST
Observatory is designed for a minimum 31-day flight of which 70 will be
dedicated to observations for BLAST scientific goals and the remaining 30
will be open to proposals from the wider astronomical community through a
shared-risk proposals program.Comment: Presented at SPIE Ground-based and Airborne Telescopes VIII, December
13-18, 202
Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas
This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing
molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin
Small farmers and sustainability: Institutional barriers to investment and innovation in the Malaysian palm oil industry in Sabah
The Malaysian palm oil industry is well known for the social, environmental and sustainability challenges associated with its rapid growth over the past ten years. Technologies exist to reduce the conflict between national development aims of economic uplift for the rural poor, on the one hand, and ecological conservation, on the other hand, by raising yields and incomes from areas already under cultivation. But the uptake of these technologies has been slow, particularly in the smallholder sector.
In this paper we explore the societal and institutional challenges that influence the investment and innovation decisions of micro and small enterprise (MSE) palm oil smallholders in Sabah, Malaysia. Based on interviews with 38 smallholders, we identify a number of factors that reduce the smallholders' propensity to invest in more sustainable practices. We discuss why more effective practices and innovations are not being adopted using the concepts of, firstly, institutional logics to explore the internal dynamics of smallholder production systems, including attitudes to sustainability and innovation; and, secondly, institutional context to explore the pressures the smallholders face, including problems of access to land, labour, capital, knowledge and technical resources. These factors include limited access to global market information, corruption and uncertainties of legal title, weak economic status and social exclusion. In discussing these factors we seek to contribute to wider theoretical debates about the factors that block innovation and investment in business improvements in marginal regions and in marginalised groups
Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context
Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts
Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas
Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN
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