Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of ...DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
2.
Warm storage of whole blood for 72 hours Hughes, J.D.; Macdonald, V.W.; Hess, J.R.
Transfusion (Philadelphia, Pa.),
November 2007, Volume:
47, Issue:
11
Journal Article
Peer reviewed
BACKGROUND: In field emergency medicine, fresh whole‐blood units are stored at room temperature up to 24 hours or occasionally longer. Few data exist on the integrity and in vitro functional ...properties of whole blood stored warm beyond 24 hours.
STUDY DESIGN AND METHODS: Ten citrate phosphate dextrose solution whole‐blood units were collected and divided into two equal volumes. One‐half of each unit was stored at 19°C and the other half was stored at 25°C, encompassing the accepted range for room temperature storage. At 6, 24, 48, and 72 hours, aliquots were collected from each unit and whole blood analyzed for cell counts, gases, and clotting function with thromboelastography, red cells for intracellular analytes, platelet (PLT)‐rich plasma for aggregometry, and the supernatant for hemoglobin, potassium, glucose, lactate, and plasma clotting studies.
RESULTS: Whole‐blood units stored at room temperature maintained cellular counts and coagulation activity for up to 72 hours. Units stored at 19°C demonstrated greater RBC adenosine triphosphate and 2,3‐diphosphoglycerate (DPG) content and stronger responses in PLT aggregation studies when compared with 25°C storage. No significant hemolysis was observed, and no bacterial growth was detected.
CONCLUSION: Storage of whole blood at room temperature for 72 hours leads to marked reductions in pH and DPG, but the observed reduction in PLT function and plasma coagulation factor activity was surprisingly modest compared to literature values. These findings should prompt additional investigation, given their potential importance for whole blood processing and field‐expedient transfusion.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The anomalous magnetic moment of the negative muon has been measured to a precision of 0.7 ppm (ppm) at the Brookhaven Alternating Gradient Synchrotron. This result is based on data collected in ...2001, and is over an order of magnitude more precise than the previous measurement for the negative muon. The result a(mu(-))=11 659 214(8)(3) x 10(-10) (0.7 ppm), where the first uncertainty is statistical and the second is systematic, is consistent with previous measurements of the anomaly for the positive and the negative muon. The average of the measurements of the muon anomaly is a(mu)(exp)=11 659 208(6) x 10(-10) (0.5 ppm).
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Phosphodiesterase-4 (PDE4), which metabolizes the second messenger cyclic adenosine monophosphate (cAMP), has 4 isozymes: PDE4A, PDE4B, PDE4C, and PDE4D. PDE4B and PDE4D have the highest expression ...in the brain and may play a role in the pathophysiology and treatment of depression and dementia. This study evaluated the properties of the newly developed PDE4B-selective radioligand 18F-PF-06445974 in the brains of rodents, monkeys, and humans. Methods: Three monkeys and 5 healthy human volunteers underwent PET scans after intravenous injection of 18F-PF-06445974. Brain uptake was quantified as total distribution volume (VT) using the standard 2-tissue-compartment model and serial concentrations of parent radioligand in arterial plasma. Results: 18F-PF-06445974 readily distributed throughout monkey and human brain and had the highest binding in the thalamus. The value of VT was well identified by a 2-tissue-compartment model but increased by 10% during the terminal portions (40 and 60 min) of the monkey and human scans, respectively, consistent with radiometabolite accumulation in the brain. The average human VT values for the whole brain were 9.5 ± 2.4 mL ⋅ cm−3. Radiochromatographic analyses in knockout mice showed that 2 efflux transporters-permeability glycoprotein (P-gp) and breast cancer resistance protein (BCRP)-completely cleared the problematic radiometabolite but also partially cleared the parent radioligand from the brain. In vitro studies with the human transporters suggest that the parent radioligand was a partial substrate for BCRP and, to a lesser extent, for P-gp. Conclusion: 18F-PF-06445974 quantified PDE4B in the human brain with reasonable, but not complete, success. The gold standard compartmental method of analyzing brain and plasma data successfully identified the regional densities of PDE4B, which were widespread and highest in the thalamus, as expected. Because the radiometabolite-induced error was only about 10%, the radioligand is, in the opinion of the authors, suitable to extend to clinical studies.
Although pre-exposure prophylaxis (PrEP) has dramatically impacted HIV prevention, deep engagement with PrEP-takers' own accounts of their sexual behavior is still rare. We report findings from ...semi-structured interviews with male participants of the US PrEP Demonstration Project. In their narratives, interviewees variously foregrounded their individual selves, interactions with sexual partners, and the biopolitical and historical context of their lives. PrEP served to discursively integrate the multiple selves populating these stories. We argue that medical anthropological notions can help make sense of men's accounts, and PrEP's role in them, advancing a holistic conception of personhood that includes but transcends concern with HIV.
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BFBNIB, NUK, PILJ, SAZU, UL, UM, UPUK
Following a suggestion from Kostelecký et al., we evaluated a test of CPT and Lorentz invariance from the microwave spectroscopy of muonium. Hamiltonian terms beyond the standard model violating CPT ...and Lorentz invariance would contribute frequency shifts deltanu(12) and deltanu(34) to nu(12) and nu(34), the two transitions involving muon spin flip, which were precisely measured in ground state muonium in a strong magnetic field of 1.7 T. The shifts would be indicated by anticorrelated oscillations in nu(12) and nu(34) at the Earth's sidereal frequency. No time dependence was found in nu(12) or nu(34) at the level of 20 Hz, limiting the size of some CPT and Lorentz-violating parameters at the level of 2x10(-23) GeV.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 ...cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10
) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10
), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10
< P < 5 × 10
) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
This paper examines the growing need for a general-purpose ldquoanalytics enginerdquo that can enable next-generation processing platforms to effectively model events, objects, and concepts based on ...end-user input, and accessible datasets, along with an ability to iteratively refine the model in real-time. We find such processing needs at the heart of many emerging applications and services. This processing is further decomposed in terms of an integration of three fundamental compute capabilities-recognition, mining, and synthesis (RMS). The set of RMS workloads is examined next in terms of usage, mathematical models, numerical algorithms, and underlying data structures. Our analysis suggests a workload convergence that is analyzed next for its platform implications. In summary, a diverse set of emerging RMS applications from market segments like graphics, gaming, media-mining, unstructured information management, financial analytics, and interactive virtual communities presents a relatively focused, highly overlapping set of common platform challenges. A general-purpose processing platform designed to address these challenges has the potential for significantly enhancing users' experience and programmer productivity.
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