Single nucleotide polymorphisms (SNPs) are likely in the near future to have a fundamental role in forensics in both human identification and description. However, considerable research is necessary ...to establish adequate scientific foundations for these applications. In the case of identification, because allele frequencies can vary greatly among populations, the population genetics of match probabilities is a critical issue. Some SNPs, however, show little allele frequency variation among populations while remaining highly informative. We describe here both an efficient strategy for identifying and characterizing such SNPs, and test that strategy on a broad representation of world populations. Markers with high heterozygosity and little frequency variation among African American, European American, and East Asian populations are selected for additional screening on seven populations that provide a sampling of genetic variation from the world's major geographical regions. Those with little allele frequency variation on the seven populations are then screened on a total of 40 populations (∼2100 individuals) and the most promising retained. The preliminary panel of 19 SNPs, from an initial selection of 195 SNPs, gives an average match probability of <10
−7 in most of 40 populations studied and no greater than 10
−6 in the most isolated, inbred populations. Expansion of this panel to ∼50 comparable SNPs should give match probabilities of about 10
−15 with a small global range.
Objectives
To characterize the size and procoagulant activity of extracellular vesicles (EV) that accumulate in canine packed red blood cells (pRBCs) over time and the effect of leukocyte reduction ...on these characteristics.
Design
Prospective cohort study.
Setting
Private small animal specialty referral hospital and university research laboratories.
Animals
Ten healthy blood donor dogs.
Interventions
Five pRBCs units were obtained according to standard protocols, and 5 were leukocyte‐reduced prior to processing. Platelet‐free supernatant from the pRBC units was collected on days 0, 10, 20, 32, and 42.
Measurements and main results
Nanoparticle tracking analysis was performed to determine the size and concentration of EVs. Thrombin generation associated with phosphatidylserine‐positive EVs was determined using a capture assay. Factor Xa generation associated with phosphatidylserine‐positive EVs and tissue factor‐positive EVs was measured in a subset of EVs isolated by centrifugation of the supernatant at 20,000 × g. R package nparLD and the Mann–Whitney U‐test were used to determine the effect of duration of storage and the effect of leukocyte reduction, respectively. Small (mean < 125 nm) procoagulant EVs accumulated over time, with significant increases occurring on or after day 20 in both non‐leukocyte reduced and leukocyte‐reduced units. The procoagulant activity of the EVs was due to phosphatidylserine, not tissue factor. Increases in EV concentration and procoagulant activity occurred earlier in non‐leukocyte reduced units. Extracellular vesicle accumulation and procoagulant activity were not decreased at any individual time point by leukocyte reduction.
Conclusions
Further studies characterizing and determining the clinical relevance of small procoagulant EVs in pRBCs are warranted.
Background Self-management improves outcomes in asthma and COPD and is strongly recommended in national and international guidelines; however implementation of the guidelines such as use of written ...action plans in practice is often poor.
Setting A questionnaire survey was undertaken to identify the healthcare professional barriers to im-plementation of self-management for asthma and COPD in West London.
Question Why is self-management education not being undertaken in respiratory conditions?
Methods A questionnaire was designed to elicit healthcare professionals' views about barriers to implementation of self-management in asthma and COPD.
Results Response rates were 33% (58/175). Results showed strong support for guideline recommenda-tions, however implementation was patchy. Seventy six percent of respondents discussed asthma self-management with patients; however only 47.8% of patients received a written action plan. For COPD patients, 55.1% discussed self-management, with 41% receiving a written action plan. In COPD, there was greater GP involvement and less delegation of self-management. Barriers to implementation in-cluded patient factors (compliance, literacy and patient understanding), time constraints and in-sufficient resources. Those who believed they had witnessed improved health outcomes with self-management (53%, 31/58) were more likely to give written action plans (78%, 24/31, 'nearly always/ sometimes' gave written action plans), Nearly a third of healthcare professionals reported lacking confidence in constructing written action plans (33% 19/58; GPs 43%, nurses 43%).
Conclusion Despite overwhelming evidence self-management support is still not being implemented into routine clinical practice, identified barriers included time constraints, lack of training, lack of belief in patients ability to self-manage and lack of confidence completing self-management plans.
Practice implications These issues need to be addressed if self-management support is to be delivered in a meaningful and effective way.
The average mass composition of cosmic rays with primary energies between 10(17) and 10(18) eV has been studied using a hybrid detector consisting of the High Resolution Fly's Eye (HiRes) prototype ...and the MIA muon array. Measurements have been made of the change in the depth of shower maximum and the muon density as a function of energy. The results show that the composition is changing from a heavy to lighter mix as the energy increases.
ATP activates damage-sensing neurons (nociceptors) and can evoke a sensation of pain. The ATP receptor P2X3 is selectively expressed by nociceptors and is one of seven ATP-gated, cation-selective ion ...channels. Here we demonstrate that ablation of the P2X3 gene results in the loss of rapidly desensitizing ATP-gated cation currents in dorsal root ganglion neurons, and that the responses of nodose ganglion neurons to ATP show altered kinetics and pharmacology resulting from the loss of expression of P2X(2/3) heteromultimers. Null mutants have normal sensorimotor function. Behavioural responses to noxious mechanical and thermal stimuli are also normal, although formalin-induced pain behaviour is reduced. In contrast, deletion of the P2X3 receptor causes enhanced thermal hyperalgesia in chronic inflammation. Notably, although dorsal-horn neuronal responses to mechanical and noxious heat application are normal, P2X3-null mice are unable to code the intensity of non-noxious 'warming' stimuli.
The prototype high-resolution Fly's Eye cosmic ray detector Abu-Zayyad, T; Al-Seady, M; Belov, K ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
08/2000, Volume:
450, Issue:
2
Journal Article
Peer reviewed
The High-Resolution Fly's Eye (HiRes) is an observatory for the highest energy cosmic rays. It detects the nitrogen fluorescence light induced by the passage of giant cosmic ray extensive air showers ...through the atmosphere. A two-site prototype of the observatory was operated from September 1994 to November 1996. In this paper we describe the components of that detector, and the procedures used to calibrate the detector and characterise the atmosphere. Data collected by the HiRes prototype are being used for physics studies, including an analysis of the cosmic ray mass composition in the energy range from 10
17 to
10
18
eV
.
The kidney-specific gene
encodes for uromodulin, the most abundant protein excreted in normal urine. Rare large-effect variants in
cause autosomal dominant tubulointerstitial kidney disease (ADTKD), ...while common low-impact variants strongly associate with kidney function and the risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in
contribute to CKD. Here, candidate intermediate-effect
variants were identified using large-population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations, patient samples, and international databases and biobanks. Eight
missense variants reported in ADTKD are present in the Genome Aggregation Database (gnomAD), with minor allele frequency (MAF) ranging from 10
to 10
. Among them, the missense variant p.Thr62Pro is detected in ∼1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD, and is associated with kidney failure in the 100,000 Genomes Project (odds ratio OR = 3.99 1.84 to 8.98) and the UK Biobank (OR = 4.12 1.32 to 12.85). Compared with canonical ADTKD mutations, the p.Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD and an intermediate reduction of urinary uromodulin levels, in line with an intermediate trafficking defect in vitro and modest induction of endoplasmic reticulum (ER) stress. Identification of an intermediate-effect
variant completes the spectrum of
-associated kidney diseases and provides insights into the mechanisms of ADTKD and the genetic architecture of CKD.
Summary
The catalytic deficiency of human aldehyde dehydrogenase 2 (ALDH2) is caused by a nucleotide substitution (G1510A; Glu487Lys) in exon 12 of the ALDH2 locus. This SNP, and four non‐coding ...SNPs, including one in the promoter, span 40 kb of ALDH2; these and one downstream STRP have been tested in 37 worldwide populations. Only four major SNP‐defined haplotypes account for almost all chromosomes in all populations. A fifth haplotype harbours the functional variant and is only found in East Asians. Though the SNPs showed virtually no historic recombination, LD values are quite variable because of varying haplotype frequencies, demonstrating that LD is a statistical ion and not a fundamental aspect of the genome, and is not a function solely of recombination. Among populations, different sets of tagging SNPs, sometimes not overlapping, can be required to identify the common haplotypes. Thus, solely because haplotype frequencies vary, there is no common minimum set of tagging SNPs globally applicable. The Fst values of the promoter region SNP and the functional SNP were about two S.D. above the mean for a reference distribution of 117 autosomal biallelic markers. These high Fst values may indicate selection has operated at these or very tightly linked sites.
PDF
