Stabilized Wittig olefination for bioconjugation Lum, Kenneth M; Xavier, Vanessa J; Ong, Michelle J-H ...
Chemical communications (Cambridge, England),
2013-Dec-11, Letnik:
49, Številka:
95
Journal Article
Recenzirano
Stabilized Wittig olefination holds great potential as a bioconjugation reaction. We demonstrate that the reaction of stabilized phosphorus ylides (or phosphonium salts) with aryl aldehydes is ...sufficiently robust to be used for live cell affinity isolation and fluorescence tagging of a protein, FKBP12.
Background
Assessing future risk of exacerbations is an important component of asthma management. Existing studies have investigated short‐ but not long‐term risk. Problematic asthma patients with ...unfavorable long‐term disease trajectory and persistently frequent severe exacerbations need to be identified early to guide treatment.
Aim
To identify distinct trajectories of severe exacerbation rates among “problematic asthma” patients and develop a risk score to predict the most unfavorable trajectory.
Methods
Severe exacerbation rates over five years for 177 “problematic asthma” patients presenting to a specialist asthma clinic were tracked. Distinct trajectories of severe exacerbation rates were identified using group‐based trajectory modeling. Baseline predictors of trajectory were identified and used to develop a clinical risk score for predicting the most unfavorable trajectory.
Results
Three distinct trajectories were found: 58.5% had rare intermittent severe exacerbations (“infrequent”), 32.0% had frequent severe exacerbations at baseline but improved subsequently (“nonpersistently frequent”), and 9.5% exhibited persistently frequent severe exacerbations, with the highest incidence of near‐fatal asthma (“persistently frequent”). A clinical risk score composed of ≥2 severe exacerbations in the past year (+2 points), history of near‐fatal asthma (+1 point), body mass index ≥25kg/m2 (+1 point), obstructive sleep apnea (+1 point), gastroesophageal reflux (+1 point), and depression (+1 point) was predictive of the “persistently frequent” trajectory (area under the receiver operating characteristic curve: 0.84, sensitivity 72.2%, specificity 81.1% using cutoff ≥3 points). The trajectories and clinical risk score had excellent performance in an independent validation cohort.
Conclusions
Patients with problematic asthma follow distinct illness trajectories over a period of five years. We have derived and validated a clinical risk score that accurately identifies patients who will have persistently frequent severe exacerbations in the future.
We present observations of the dwarf galaxies Draco and Ursa Minor, the Local Group galaxies M32 and M33, and the globular cluster M15 conducted with the Whipple 10 m gamma-ray telescope to search ...for the gamma-ray signature of self-annihilating weakly interacting massive particles (WIMPs), which may constitute astrophysical dark matter (DM). We review the motivations for selecting these sources based on their unique astrophysical environments and report the results of the data analysis that produced upper limits on the excess rate of gamma rays for each source. We consider models for the DM distribution in each source based on the available observational constraints and discuss possible scenarios for the enhancement of the gamma-ray luminosity. Limits on the thermally averaged product of the total self- annihilation cross section and velocity of the WIMP, image, are derived using conservative estimates for the magnitude of the astrophysical contribution to the gamma-ray flux. Although these limits do not constrain predictions from the currently favored theoretical models of supersymmetry (SUSY), future observations with VERITAS will probe a larger region of the WIMP parameter phase space, image, and WIMP particle mass.
The β-decay half-lives of 38 neutron-rich isotopes from (36)Kr to (43)Tc have been measured; the half-lives of (100)Kr, (103-105)Sr, (106-108)Y, (108-110)Zr, (111,112)Nb, (112-115)Mo, and (116,117)Tc ...are reported here. The results when compared with previous standard models indicate an overestimation in the predicted half-lives by a factor of 2 or more in the A≈110 region. A revised model based on the second generation gross theory of β decay better predicts the measured half-lives and suggests a more rapid flow of the rapid neutron-capture process (r-matter flow) through this region than previously predicted.
•Substance use behaviours were re-examined by genetic correlations, and two-sample MR.•Most substance use traits were genetically correlated but not causally associated.•We found a positive causal ...effect of starting regular smoking on caffeine consumption.
Caffeine, alcohol, nicotine and cannabis are commonly used psychoactive substances. While the use of these substances has been previously shown to be genetically correlated, causality between these substance use traits remains unclear. We aimed to revisit the genetic relationships among different measures of SU using genome-wide association study (GWAS) summary statistics from the UK Biobank, International Cannabis Consortium, and GWAS & Sequencing Consortium of Alcohol and Nicotine use.
We obtained GWAS summary statistics from the aforementioned consortia for ten substance use traits including various measures of alcohol consumption, caffeine consumption, cannabis initiation and smoking behaviours. We then conducted SNP-heritability (h2) estimation for individual SU traits, followed by genetic correlation analyses and two-sample Mendelian randomisation (MR) studies between substance use trait pairs.
SNP h2 of the ten traits ranged from 0.03 to 0.11. After multiple testing correction, 29 of the 45 trait pairs showed evidence of being genetically correlated. MR analyses revealed that most SU traits were not causally associated with each other. However, we found evidence for an MR association between regular smoking initiation and caffeine consumption 40.17 mg; 95 % CI: 24.01, 56.33 increase in caffeine intake per doubling of odds in smoking initiation). Our findings were robust against horizontal pleiotropy, SNP-outliers, and the direction of causality was consistent in all MR analyses.
Most of the substance traits were genetically correlated but there is little evidence to establish causality apart from the relationship between smoking initiation and caffeine consumption.
Vaccination has successfully controlled several infectious diseases although better vaccines remain desirable. Host response to vaccination studies have identified correlates of vaccine ...immunogenicity that could be useful to guide development and selection of future vaccines. However, it remains unclear whether these findings represent mere statistical correlations or reflect functional associations with vaccine immunogenicity. Functional associations, rather than statistical correlates, would offer mechanistic insights into vaccine-induced adaptive immunity. Through a human experimental study to test the immunomodulatory properties of metformin, an anti-diabetic drug, we chanced upon a functional determinant of neutralizing antibodies. Although vaccine viremia is a known correlate of antibody response, we found that in healthy volunteers with no detectable or low yellow fever 17D viremia, metformin-treated volunteers elicited higher neutralizing antibody titers than placebo-treated volunteers. Transcriptional and metabolomic analyses collectively showed that a brief course of metformin, started 3 days prior to YF17D vaccination and stopped at 3 days after vaccination, expanded oxidative phosphorylation and protein translation capacities. These increased capacities directly correlated with YF17D neutralizing antibody titers, with reduced reactive oxygen species response compared to placebo-treated volunteers. Our findings thus demonstrate a functional association between cellular respiration and vaccine-induced humoral immunity and suggest potential approaches to enhancing vaccine immunogenicity.
Synopsis
Host response studies have identified multiple correlates of vaccine immunogenicity, yet their functional role in shaping vaccine-induced adaptive responses remain undefined. We demonstrate that mitochondrial activity is functionally involved in live-attenuated yellow fever 17D (YF17D) vaccine immunogenicity.
In healthy volunteers, a brief course of metformin given three-days-before to three-days-after live-attenuated YF17D vaccination enhances humoral immune responses in those with low or undetectable viremia.
This brief course of metformin expanded oxidative phosphorylation and protein translation capacities without over-activation of antioxidant defenses.
In a mouse model, cessation of metformin at Day 3 but not Day 10 post YF17D vaccination enhanced immunogenicity compared to untreated mice.
Our findings suggest a way to enhance antibody response to vaccination in patients on long-term metformin treatment.
Host response studies have identified multiple correlates of vaccine immunogenicity, yet their functional role in shaping vaccine-induced adaptive responses remain undefined. We demonstrate that mitochondrial activity is functionally involved in live-attenuated yellow fever 17D (YF17D) vaccine immunogenicity.
New measurements of the beam normal single spin asymmetry in the electron elastic and quasielastic scattering on the proton and deuteron, respectively, at large backward angles and at ⟨Q^{2}⟩=0.22 ...(GeV/c)^{2} and ⟨Q^{2}⟩=0.35 ( GeV/c)^{2} are reported. The experimentally observed asymmetries are compared with the theoretical calculation of Pasquini and Vanderhaeghen Phys. Rev. C 70, 045206 (2004).PRVCAN0556-281310.1103/PhysRevC.70.045206. The agreement of the measurements with the theoretical calculations shows a dominance of the inelastic intermediate excited states of the nucleon, πN and the Δ resonance. The measurements explore a new, important parameter region of the exchanged virtual photon virtualities.
Aims/hypothesis
Genetic pleiotropy may contribute to the clustering of obesity and metabolic conditions. We assessed whether genetic variants that are robustly associated with BMI and waist-to-hip ...ratio (WHR) also influence metabolic and cardiovascular traits, independently of obesity-related traits, in meta-analyses of up to 37,874 individuals from six European population-based studies.
Methods
We examined associations of 32 BMI and 14 WHR loci, individually and combined in two genetic predisposition scores (GPSs), with glycaemic traits, blood lipids and BP, with and without adjusting for BMI and/or WHR.
Results
We observed significant associations of BMI-increasing alleles at five BMI loci with lower levels of 2 h glucose (
RBJ
also known as
DNAJC27
,
QPTCL
: effect sizes −0.068 and −0.107 SD, respectively), HDL-cholesterol (
SLC39A8
: −0.065 SD,
MTCH2
: −0.039 SD), and diastolic BP (
SLC39A8
: −0.069 SD), and higher and lower levels of LDL- and total cholesterol (
QPTCL
: 0.041 and 0.042 SDs, respectively,
FLJ35779
also known as
POC5
: −0.042 and −0.041 SDs, respectively) (all
p
< 2.4 × 10
−4
), independent of BMI. The WHR-increasing alleles at two WHR loci were significantly associated with higher proinsulin (
GRB14
: 0.069 SD) and lower fasting glucose levels (
CPEB4
: −0.049 SD), independent of BMI and WHR. A higher GPS-BMI was associated with lower systolic BP (−0.005 SD), diastolic BP (−0.006 SD) and 2 h glucose (−0.013 SD), while a higher GPS-WHR was associated with lower HDL-cholesterol (−0.015 SD) and higher triacylglycerol levels (0.014 SD) (all
p
< 2.9 × 10
−3
), independent of BMI and/or WHR.
Conclusions/interpretation
These pleiotropic effects of obesity-susceptibility loci provide novel insights into mechanisms that link obesity with metabolic abnormalities.
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