Summary
Background
Food allergy affects approximately 6–8% of children, and increasing in prevalence. Some children naturally outgrow their food allergy without intervention, but the mechanisms by ...which this occurs remain poorly understood. We sought to investigate the role of regulatory T cells in the development of naturally acquired tolerance.
Methods
Fifty‐eight children (1–18 years) with either egg or peanut allergy, recent acquisition of natural tolerance to egg or peanut, or no food allergy were studied. Peripheral blood mononuclear cells (PBMC) from these groups were stimulated with relevant antigen for 48 h and flow cytometry performed to characterize both surface (CD3, CD4, CD25, CD14, CD19, and CD127) and intracellular markers (IL‐10, Foxp3, and IL‐5).
Results
Resting PBMC from naturally tolerant patients had significantly increased CD3+CD4+CD25+CD127loFoxp3+ cells, when compared to allergic or control patients (mean 6.36 vs. 2.37 vs. 2.62%, respectively, P < 0.05). Upon stimulation with relevant antigen, naturally tolerant patients also had increased IL‐10‐expressing CD25+CD127lo cells (6.33 vs. 1.65 vs. 0.7, P < 0.01), Foxp3+ cells (mean 12.6 vs. 5.42 vs. 3%, P < 0.01), and CD4+ cells (mean 4.48 vs. 1.59 vs. 0.87%, P < 0.01); the increase was not observed in PBMCs from allergic or control patients. Additionally, this upregulation was only seen with relevant antigen stimulation and not upon stimulation with unrelated antigen.
Conclusion
The increased CD3+CD4+CD25+CD127lo cells at baseline and upon stimulation and increased induction of IL‐10‐producing cells of several types, including Tr1 cells, from naturally tolerant patients suggests an important role for regulatory T cell subsets in the acquisition of natural tolerance.
We assessed associations of genetic loci that contribute to age at menarche and menopause with sentinel menopausal traits in multiple race/ethnic groups.
Genetic data from the Study of Women's Health ...Across the Nation include 738 White, 366 Black, 139 Chinese, and 145 Japanese women aged 42 to 52 at baseline. We constructed standardized polygenic risk scores (PRSs) using single nucleotide polymorphisms identified from large-scale genome-wide association studies meta-analyses of ages at menopause and menarche, evaluating associations with each trait within each race/ethnic group.
Menopause PRS was significantly associated with age at menopause in White women after Bonferroni correction (P < 0.004) and nominally associated in Chinese and Japanese women (P < 0.05) (7.4-8.5 mo delay for one standard deviation SD increase in PRS). Menarche PRS was significantly associated with age at menarche in White (P < 0.004) and nominally associated in Black and Japanese women (P < 0.05) (2.6-4.8 mo delay for one SD increase). In White women, menarche and menopause PRSs were significantly associated (P < 0.004) with shorter and longer (5.9 and 9.6 mo for one SD increase) reproductive lifespans, respectively, and menopause PRS with a longer menopausal transition (7.1 mo for one SD increase). We observed a significant positive association (P < 0.004) between menopause PRS and E2 level 2 years before menopause and a nominal association (P < 0.05) 2 years after menopause in Japanese women.
In addition to menopausal timing, PRSs associated with onset and ending of reproductive life were associated with reproductive lifespan, length of the menopausal transition, and E2 levels in different race/ethnic groups.
The genes that encode for CYP3A4 and CYP3A5 are located in the same region (CYP3A cluster) on chromosome 7. Midazolam (MDZ) is a substrate for both CYP3A4 and CYP3A5. We hypothesize that MDZ ...disposition in vivo is associated with genotypes of the CYP3A cluster. A meta-analysis of the pharmacokinetic (PK) parameters from seven clinical trials was carried out, in which MDZ was administered both intravenously and orally. DNA samples were available from 116 patients. There were significant ethnic differences in the allelic frequencies of these four common single-nucleotide polymorphisms (SNPs) in the CYP3A cluster. Significant linkage disequilibrium was found between CYP3A5(*)3 and CYP3A4(*)1A in Caucasians, and between CYP3A5(*)1 and CYP3A4(*)1B in African Americans. There were no differences in MDZ disposition in vivo between different genotypes, haplotypes and diplotypes in the CYP3A cluster (P>0.05). No significant differences in MDZ PK parameters were observed between Caucasians and African Americans. Women had higher weight-corrected systemic and oral clearance than men, but dose-adjusted AUC and bioavailability differences were not observed between sexes. The clinical importance of elevated CYP3A activity in women remains to be determined. The r(GC)'s of MDZ PK parameters were between 0.3 and 13.6%. In conclusion, the meta-analysis of seven studies suggests that environmental factors explain the majority of CYP3A activity variation. Further studies are necessary to define the functional significance of SNPs in the CYP3A cluster and the effects of CYP3A genotypes on MDZ disposition in vivo.
Vasomotor symptoms (VMS), hot flashes, and night sweats are cardinal symptoms of the menopausal transition. Little is known about genetic influences on VMS. This study evaluated whether previously ...identified genetic factors predictive of VMS, age at menarche, and age at menopause were associated with VMS in a multiracial/ethnic cohort.
For 702 White, 306 Black, 126 Chinese, and 129 Japanese women from the Study of Women's Health Across the Nation (SWAN) Genomic Substudy, we created polygenic risk scores (PRSs) from genome-wide association studies of VMS and ages at menarche and menopause. PRSs and single nucleotide polymorphisms (SNPs) from a previously identified VMS locus (tachykinin receptor 3 TACR3) were evaluated for associations with frequent VMS (VMS ≥6 days in the past 2 weeks at any visit) and with VMS trajectories (persistently low, early onset, final menstrual period onset, persistently high).
The C-allele of rs74827081 in TACR3 was associated with reduced likelihood of frequent VMS in White women (odds ratio OR = 0.49 95% CI, 0.29-0.83). With higher menarche PRS (later menarche), Black women were less likely (OR = 0.55 95% CI, 0.38-0.78) to report frequent VMS. With higher PRS for age at menarche, Black women were also less likely to have a persistently high VMS trajectory (OR = 0.55 95% CI, 0.34-0.91), whereas White women (OR = 0.75 95% CI, 0.58-0.98) were less likely to have a final menstrual period onset trajectory (vs persistently low). Chinese women with higher menopause PRS were more likely to have frequent VMS (OR = 2.29 95% CI, 1.39-3.78). Associations were substantively similar after excluding rs74827081 C-allele carriers.
Genetic factors predictive of reproductive aging are also associated with VMS, suggesting that VMS have a polygenic architecture. Further study in this area may help to identify new targets for novel VMS therapies.
Results are reported from an improved measurement of ν_{μ}→ν_{e} transitions by the NOvA experiment. Using an exposure equivalent to 6.05×10^{20} protons on target, 33 ν_{e} candidates are observed ...with a background of 8.2±0.8 (syst.). Combined with the latest NOvA ν_{μ} disappearance data and external constraints from reactor experiments on sin^{2}2θ_{13}, the hypothesis of inverted mass hierarchy with θ_{23} in the lower octant is disfavored at greater than 93% C.L. for all values of δ_{CP}.
We report results from the first search for sterile neutrinos mixing with active neutrinos through a reduction in the rate of neutral-current interactions over a baseline of 810 km between the NOvA ...detectors. Analyzing a 14-kton detector equivalent exposure of 6.05×1020 protons-on-target in the NuMI beam at Fermilab, we observe 95 neutral-current candidates at the Far Detector compared with 83.5±9.7(stat)±9.4(syst) events predicted assuming mixing only occurs between active neutrino species. No evidence for νμ→νs transitions is found. Interpreting these results within a 3+1 model, we place constraints on the mixing angles θ24<20.8° and θ34<31.2° at the 90% C.L. for 0.05 eV2≤Δm412≤0.5 eV2, the range of mass splittings that produce no significant oscillations over the Near Detector baseline.
Analyses of daytime fair-weather aircraft and surface-flux tower data from the May–June 2002 International H₂O Project (IHOP_2002) and the April–May 1997 Cooperative Atmosphere Surface Exchange Study ...(CASES-97) are used to document the role of vegetation, soil moisture, and terrain in determining the horizontal variability of latent heat LE and sensible heatHalong a 46-km flight track in southeast Kansas. Combining the two field experiments clearly reveals the strong influence of vegetation cover, withHmaxima over sparse/dormant vegetation, andHminima over green vegetation; and, to a lesser extent, LE maxima over green vegetation, and LE minima over sparse/dormant vegetation. If the small number of cases is producing the correct trend, other effects of vegetation and the impact of soil moisture emerge through examining the slope ΔxyLE/Δxy
Hfor the best-fit straight line for plots of time-averaged LE as a function of time-averagedHover the area. Based on the surface energy balance,H+ LE =R
net−G
sfc, whereR
netis the net radiation andG
sfcis the flux into the soil;R
net−G
sfc~ constant over the area implies an approximately −1 slope. Right after rainfall,Hand LE vary too little horizontally to define a slope. After sufficient drying to produce enough horizontal variation to define a slope, a steep (~−2) slope emerges. The slope becomes shallower and better defined with time asHand LE horizontal variability increases. Similarly, the slope becomes more negative with moister soils. In addition, the slope can change with time of day due to phase differences inHand LE. These trends are based on land surface model (LSM) runs and observations collected under nearly clear skies; the vegetation is unstressed for the days examined. LSM runs suggest terrain may also play a role, but observational support is weak.
Using first-principles calculations with a hybrid functional, we examined several fundamental issues for heterojunction structures formed by the same material but in different polytypes including the ...precise location of the boundary and the polarization. Particularly, we demonstrate that the inclusion of 8H in 4H SiC generates a single quantum well (QW) structure, rather than a double well consisting of two 3C regions separated by a single hexagonal layer barrier. The level of the QW states for 8H and 3C inclusions are calculated to be 0.42 and 0.68 eV, respectively, below the conduction band minimum of 4H SiC, in good agreement with the experiments.
CDF Central Outer Tracker Affolder, T; Allspach, D; Ambrose, D ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
07/2004, Letnik:
526, Številka:
3
Journal Article
Recenzirano
The Central Outer Tracker is a large cylindrical drift chamber constructed to replace Collider Detector at Fermilab's original central drift chamber for the higher luminosity expected for Run 2 at ...the Fermilab Tevatron. The chamber's drift properties are described in the context of meeting the operating requirements for Run 2. The design and construction of the chamber, the front-end readout electronics, and the high-voltage system are described in detail. Wire aging considerations are also discussed.
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