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•Proteoforms play important role in physiological and pathological processes.•Top-down MS-based approaches are ideally suited for proteoforms detection.•We developed multiplex MS- ...immunoassay for apoC-I, C-II and C-III and their proteoforms.•The multiplexed assay was fast (40min) and high-throughput (96 samples at once).•The concentrations of each proteoform were determined and compared in a cohort of 82 human plasma samples.
The impetus for discovery and evaluation of protein biomarkers has been accelerated by recent development of advanced technologies for rapid and broad proteome analyses. Mass spectrometry (MS)-based protein assays hold great potential for in vitro biomarker studies. Described here is the development of a multiplex mass spectrometric immunoassay (MSIA) for quantification of apolipoprotein C-I (apoC-I), apolipoprotein C-II (apoC-II), apolipoprotein C-III (apoC-III) and their proteoforms. The multiplex MSIA assay was fast (∼40min) and high-throughput (96 samples at a time). The assay was applied to a small cohort of human plasma samples, revealing the existence of multiple proteoforms for each apolipoprotein C. The quantitative aspect of the assay enabled determination of the concentration for each proteoform individually. Low-abundance proteoforms, such as fucosylated apoC-III, were detected in less than 20% of the samples. The distribution of apoC-III proteoforms varied among samples with similar total apoC-III concentrations. The multiplex analysis of the three apolipoproteins C and their proteoforms using quantitative MSIA represents a significant step forward toward better understanding of their physiological roles in health and disease.
Stigma may mediate some of the observed disparity in HIV infection rates between black and white men who have sex with men (MSM).
We used data from the General Social Survey to describe race-specific ...trends in the US population's attitude toward homosexuality, reporting of male same-sex sexual behavior, and behaviors that might mediate the relationship between stigma and HIV transmission among MSM.
The proportion of blacks who indicated that homosexuality was "always wrong" was 72.3% in 2008, largely unchanged since the 1970s. In contrast, among white respondents, this figure declined from 70.8% in 1973 to 51.6% in 2008 with most change occurring since the early 1990s. Participants who knew a gay person were less likely to have negative attitudes toward homosexuality (relative risk, 0.60; 95% confidence interval, 0.52 to 0.69). Among MSM, twice as many black MSM reported that homosexuality is "always wrong" compared with white MSM (57.1% versus 26.8%, P = 0.003). MSM with unfavorable attitudes toward homosexuality were less likely to report ever testing for HIV compared with MSM with more favorable attitudes (relative risk, 0.50; 95% confidence interval, 0.31 to 0.78).
US attitudes toward homosexuality are characterized by persistent racial differences, which may help explain disparities in HIV infection rates between black and white MSM.
AlInN for Vertical Power Electronic Devices Peart, Matthew R.; Tansu, Nelson; Wierer, Jonathan J.
IEEE transactions on electron devices,
10/2018, Letnik:
65, Številka:
10
Journal Article
Recenzirano
The known benefits and challenges of AlInN as a next-generation power electronic semiconductor are presented. Al x In1 − x N is lattice matched to GaN at <inline-formula> <tex-math ...notation="LaTeX">{x} = {0.82} </tex-math></inline-formula> and has the advantages of an available substrate, a wide bandgap (~4.4 eV), and high mobility (~450 cm 2 <inline-formula> <tex-math notation="LaTeX">/\text {V} \cdot \text {s} </tex-math></inline-formula>). The power figure of merit (FOM), determined using empirical and theoretical values of mobility and estimated critical electric fields determined from reported bandgaps, spans from ~20% to 130% times greater than GaN. In order to realize and precisely determine these high AlInN FOM values, experimental challenges will need to be overcome such as polarization-induced electric fields and bandgap discontinuities at AlInN/GaN interfaces, and controlling carrier concentration levels.
Near-infrared diffuse correlation spectroscopy (NIR-DCS) is an optical imaging technique for measuring relative changes in skeletal muscle microvascular perfusion (i.e., fold change above baseline) ...during reactive hyperemia testing and exercise and is reported as a blood flow index (BFI). Although it is generally accepted that changes in BFI are primarily driven by changes in muscle perfusion, it is well known that large, hyperthermia-induced changes in cutaneous blood flow can uncouple this relationship. What remains unknown, is how much of an impact that changes in cutaneous perfusion have on NIR-DCS BFI and estimates of skeletal muscle perfusion under thermoneutral conditions, where changes in cutaneous blood flow are assumed to be relatively low. We therefore used epinephrine iontophoresis to pharmacologically block changes in cutaneous perfusion throughout a battery of experimental procedures. The data show that
) epinephrine iontophoresis attenuates changes in cutaneous perfusion for up to 4-h posttreatment, even in the face of significant neural and local stimuli,
) under thermoneutral conditions, cutaneous perfusion does not significantly impact NIR-DCS BFI during reactive hyperemia testing or moderate-intensity exercise, and
) during passive whole body heat stress, when cutaneous vasodilation is pronounced, epinephrine iontophoresis preserves NIR-DCS measures of skeletal muscle BFI during moderate-intensity exercise. Collectively, these data suggest that cutaneous perfusion is unlikely to have a major impact on NIR-DCS estimates of skeletal muscle BFI under thermoneutral conditions, but that epinephrine iontophoresis can be used to abolish cutaneous contamination of the NIR-DCS BFI signal during studies where skin blood flow may be elevated but skeletal muscle perfusion is of specific interest.
Abstract Background & Aims We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported ...genetic risk factors. Methods We performed a GWAS of 862 persons with DILI and 10588 population-matched controls. The first set of cases was recruited prior to May 2009 in Europe (n=137) or the USA (n=274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the USA and South America. For the GWAS, we included only cases of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze human leukocyte antigen (HLA) genes and single nucleotide polymorphisms (SNPs). After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. Results We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio OR, 2.7; 95% CI, 1.9–3.8; P =2.4x10–8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6–2.5; P =9.7x10–9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant, genome wide, for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the LRBA gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6–2.7; P =4.8x10–9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR=5.4; 95% CI, 3.0–9.5; P =7.1x10–9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. Conclusions In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non–drug-specific risk factors.
For men on active surveillance for prostate cancer, utility of prostate-specific antigen (PSA) kinetics (PSAk) in predicting pathologic reclassification remains controversial.
To develop prediction ...methods for utilizing serial PSA and evaluate frequency of collection.
Data were collected from men enrolled in the multicenter Canary Prostate Active Surveillance Study, for whom PSA data were measured and biopsies performed on prespecified schedules. We developed a PSAk parameter based on a linear mixed-effect model (LMEM) that accounted for serial PSA levels.
The association of diagnostic PSA and/or PSAk with time to reclassification (increase in cancer grade and/or volume) was evaluated using multivariable Cox proportional hazards models.
A total of 851 men met the study criteria; 255 (30%) had a reclassification event within 5 yr. Median follow-up was 3.7 yr. After adjusting for prostate size, time since diagnosis, biopsy parameters, and diagnostic PSA, PSAk was a significant predictor of reclassification (hazard ratio for each 0.10 increase in PSAk=1.6 95% confidence interval 1.2–2.1, p<0.001). The PSAk model improved stratification of risk prediction for the top and bottom deciles of risk over a model without PSAk. Model performance was essentially identical using PSA data measured every 6 mo to those measured every 3 mo. The major limitation is the reliability of reclassification as an end point, although it drives most treatment decisions.
PSAk calculated using an LMEM statistically significantly predicts biopsy reclassification. Models that use repeat PSA measurements outperform a model incorporating only diagnostic PSA. Model performance is similar using PSA assessed every 3 or 6 mo. If validated, these results should inform optimal incorporation of PSA trends into active surveillance protocols and risk calculators.
In this report, we looked at whether repeat prostate-specific antigen (PSA) measurements, or PSA kinetics, improve prediction of biopsy outcomes in men using active surveillance to manage localized prostate cancer. We found that in a large multicenter active surveillance cohort, PSA kinetics improves the prediction of surveillance biopsy outcome.
In this report, we looked at whether repeat prostate-specific antigen (PSA) measurements, or PSA kinetics, improve prediction of biopsy outcomes in men using active surveillance to manage localized prostate cancer. We found that in a large multicenter active surveillance cohort, PSA kinetics improves the prediction of surveillance biopsy outcome.
Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains ...unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 × 10−33) seen for rs2395029G, a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B*5701 (OR = 80.6, P = 9.0 × 10−19). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 × 10−8). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.
ABSTRACT
We present the discovery of NGTS-19b, a high-mass transiting brown dwarf discovered by the Next Generation Transit Survey. We investigate the system using follow-up photometry from the South ...African Astronomical Observatory, as well as sector 11 Transiting Exoplanet Survey Satellite data, in combination with radial velocity measurements from the CORALIE spectrograph to precisely characterize the system. We find that NGTS-19b is a brown dwarf companion to a K-star, with a mass of $69.5 ^{+5.7}_{-5.4}$ MJup and radius of $1.034 ^{+0.055}_{-0.053}$RJup. The system has a reasonably long period of 17.84 d, and a high degree of eccentricity of $0.3767 ^{+0.0061}_{-0.0061}$. The mass and radius of the brown dwarf imply an age of $0.46 ^{+0.26}_{-0.15}$ Gyr, however, this is inconsistent with the age determined from the host star spectral energy distribution, suggesting that the brown dwarf may be inflated. This is unusual given that its large mass and relatively low levels of irradiation would make it much harder to inflate. NGTS-19b adds to the small, but growing number of brown dwarfs transiting main-sequence stars, and is a valuable addition as we begin to populate the so-called brown dwarf desert.
We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility.
We performed a genome-wide ...association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings.
We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio OR 1.44; 95% confidence interval CI 1.28–1.62; P = 1.2 × 10–9 and replicated the finding in the validation set (OR 1.48; 95% CI 1.09–1.99; P = .01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32–1.98; P = 4.0 × 10–6; allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21–1.56; P = 1.5 × 10–6; allele frequency = 11.5%). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01.
In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.
β-lactam antibiotics are associated with a variety of immune-mediated or hypersensitivity reactions, including immediate (type I) reactions mediated by antigen-specific IgE.
We sought to identify ...genetic predisposing factors for immediate reactions to β-lactam antibiotics.
Patients with a clinical history of immediate hypersensitivity reactions to either penicillins or cephalosporins, which were immunologically confirmed, were recruited from allergy clinics. A genome-wide association study was conducted on 662 patients (the discovery cohort) with a diagnosis of immediate hypersensitivity and the main finding was replicated in a cohort of 98 Spanish cases, recruited using the same diagnostic criteria as the discovery cohort.
Genome-wide association study identified rs71542416 within the Class II HLA region as the top hit (P = 2 × 10−14); this was in linkage disequilibrium with HLA-DRB1∗10:01 (odds ratio, 2.93; P = 5.4 × 10−7) and HLA-DQA1∗01:05 (odds ratio, 2.93, P = 5.4 × 10−7). Haplotype analysis identified that HLA-DRB1∗10:01 was a risk factor even without the HLA-DQA1∗01:05 allele. The association with HLA-DRB1∗10:01 was replicated in another cohort, with the meta-analysis of the discovery and replication cohorts showing that HLA-DRB1∗10:01 increased the risk of immediate hypersensitivity at a genome-wide level (odds ratio, 2.96; P = 4.1 × 10−9). No association with HLA-DRB1∗10:01 was identified in 268 patients with delayed hypersensitivity reactions to β-lactams.
HLA-DRB1∗10:01 predisposed to immediate hypersensitivity reactions to penicillins. Further work to identify other predisposing HLA and non-HLA loci is required.
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