A confirmatory assay using liquid chromatography-electrospray mass spectrometry (LC-EMS) is presented for the simultaneous determination of penicillins V and G along with oxacillin, cloxacillin and ...dicloxacillin in muscle, kidney and milk. Nafcillin is used as an internal standard. Samples are extracted using acetonitrile and cleaned up using liquid-liquid extraction into dichloromethane. The extracts are injected into a dedicated LC-EMS instrument and any penicillins present are detected using multiple single-ion monitoring. Three or four ions can be detected for each penicillin, meeting one of the recommended EU criteria for confirmatory residue analyses using low-resolution mass spectrometry. The detection limits are below the stipulated EU maximum residue limits for each of the penicillins.
Intraocular pressure (IOP) is currently the sole modifiable risk factor for primary open-angle glaucoma (POAG), one of the leading causes of blindness worldwide
. Both IOP and POAG are highly ...heritable
. We report a combined analysis of participants from the UK Biobank (n = 103,914) and previously published data from the International Glaucoma Genetic Consortium (n = 29,578)
that identified 101 statistically independent genome-wide-significant SNPs for IOP, 85 of which have not been previously reported
. We examined these SNPs in 11,018 glaucoma cases and 126,069 controls, and 53 SNPs showed evidence of association. Gene-based tests implicated an additional 22 independent genes associated with IOP. We derived an allele score based on the IOP loci and loci influencing optic nerve head morphology. In 1,734 people with advanced glaucoma and 2,938 controls, participants in the top decile of the allele score were at increased risk (odds ratio (OR) = 5.6; 95% confidence interval (CI): 4.1-7.6) of glaucoma relative to the bottom decile.
We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 individuals with severe visual field loss (cases) and 3,956 controls. We identified ...associated loci at TMCO1 (rs4656461G odds ratio (OR) = 1.68, P = 6.1 × 10(-10)) and CDKN2B-AS1 (rs4977756A OR = 1.50, P = 4.7 × 10(-9)). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010; rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 × 10(-14), OR = 1.51, 95% CI 1.35-1.68; rs4977756 combined P = 1.35 × 10(-14), OR = 1.39, 95% CI 1.28-1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma.
While immune checkpoint inhibitors such as anti-PD-L1 are rapidly becoming the standard of care in the treatment of many cancers, only a subset of treated patients have long-term responses. IL12 ...promotes antitumor immunity in mouse models; however, systemic recombinant IL12 had significant toxicity and limited efficacy in early clinical trials.
We therefore designed a novel intratumoral IL12 mRNA therapy to promote local IL12 tumor production while mitigating systemic effects.
A single intratumoral dose of mouse (m)IL12 mRNA induced IFNγ and CD8
T-cell-dependent tumor regression in multiple syngeneic mouse models, and animals with a complete response demonstrated immunity to rechallenge. Antitumor activity of mIL12 mRNA did not require NK and NKT cells. mIL12 mRNA antitumor activity correlated with TH1 tumor microenvironment (TME) transformation. In a PD-L1 blockade monotherapy-resistant model, antitumor immunity induced by mIL12 mRNA was enhanced by anti-PD-L1. mIL12 mRNA also drove regression of uninjected distal lesions, and anti-PD-L1 potentiated this response. Importantly, intratumoral delivery of mRNA encoding membrane-tethered mIL12 also drove rejection of uninjected lesions with very limited circulating IL12p70, supporting the hypothesis that local IL12 could induce a systemic antitumor immune response against distal lesions. Furthermore, in
patient tumor slice cultures, human IL12 mRNA (MEDI1191) induced dose-dependent IL12 production, downstream IFNγ expression and TH1 gene expression.
These data demonstrate the potential for intratumorally delivered IL12 mRNA to promote TH1 TME transformation and robust antitumor immunity.
.
Given the attendant risks of mortality and morbidity, acute MI remains a principal focus of cardiovascular therapeutics. ...30-day mortality and rehospitalization rates for acute MI are publicly ...reported in an effort to promote optimal acute MI care, and aspects of MI care delivery are the focus of local, regional, and national quality initiatives (1-3). Updates or revisions to the American College of Cardiology (ACC)/American Heart Association (AHA) practice guidelines for PCI, ST-segment elevation myocardial infarction (STEMI), and unstable angina (UA)/non-ST-segment elevation myocardial infarction (NSTEMI) have been published within the last 3 years, building upon prior versions published earlier in the decade (5-7).
Given the rapid development during the early years (0-4 years), an understanding of the health implications of physical activity is needed. The purpose of this systematic review was to examine the ...relationships between objectively and subjectively measured physical activity and health indicators in the early years.
Electronic databases were originally searched in April, 2016. Included studies needed to be peer-reviewed, written in English or French, and meet a priori study criteria. The population was apparently healthy children aged 1 month to 59.99 months/4.99 years. The intervention/exposure was objectively and subjectively measured physical activity. The comparator was various volumes, durations, frequencies, patterns, types, and intensities of physical activity. The outcomes were health indicators ranked as critical (adiposity, motor development, psychosocial health, cognitive development, fitness) and important (bone and skeletal health, cardiometabolic health, and risks/harm). The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was used to assess the quality of evidence for each health indicator by each study design.
Ninety-six studies representing 71,291 unique participants from 36 countries were included. Physical activity interventions were consistently (>60% of studies) associated with improved motor and cognitive development, and psychosocial and cardiometabolic health. Across observational studies, physical activity was consistently associated with favourable motor development, fitness, and bone and skeletal health. For intensity, light- and moderate-intensity physical activity were not consistently associated with any health indicators, whereas moderate- to vigorous-intensity, vigorous-intensity, and total physical activity were consistently favourably associated with multiple health indicators. Across study designs, consistent favourable associations with health indicators were observed for a variety of types of physical activity, including active play, aerobic, dance, prone position (infants; ≤1 year), and structured/organized. Apart from ≥30 min/day of the prone position for infants, the most favourable frequency and duration of physical activity was unclear. However, more physical activity appeared better for health. Evidence ranged from "very low" to "high" quality.
Specific types of physical activity, total physical activity, and physical activity of at least moderate- to vigorous-intensity were consistently favourably associated with multiple health indicators. The majority of evidence was in preschool-aged children (3-4 years). Findings will inform evidence-based guidelines.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Meta-analysis of genetic association studies increases sample size and the power for mapping complex traits. Existing methods are mostly developed for datasets without missing values, i.e. the ...summary association statistics are measured for all variants in contributing studies. In practice, genotype imputation is not always effective. This may be the case when targeted genotyping/sequencing assays are used or when the un-typed genetic variant is rare. Therefore, contributed summary statistics often contain missing values. Existing methods for imputing missing summary association statistics and using imputed values in meta-analysis, approximate conditional analysis, or simple strategies such as complete case analysis all have theoretical limitations. Applying these approaches can bias genetic effect estimates and lead to seriously inflated type-I or type-II errors in conditional analysis, which is a critical tool for identifying independently associated variants. To address this challenge and complement imputation methods, we developed a method to combine summary statistics across participating studies and consistently estimate joint effects, even when the contributed summary statistics contain large amounts of missing values. Based on this estimator, we proposed a score statistic called PCBS (partial correlation based score statistic) for conditional analysis of single-variant and gene-level associations. Through extensive analysis of simulated and real data, we showed that the new method produces well-calibrated type-I errors and is substantially more powerful than existing approaches. We applied the proposed approach to one of the largest meta-analyses to date for the cigarettes-per-day phenotype. Using the new method, we identified multiple novel independently associated variants at known loci for tobacco use, which were otherwise missed by alternative methods. Together, the phenotypic variance explained by these variants was 1.1%, improving that of previously reported associations by 71%. These findings illustrate the extent of locus allelic heterogeneity and can help pinpoint causal variants.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Throughout its history, Operational Research has evolved to include a variety of methods, models and algorithms that have been applied to a diverse and wide range of contexts. This encyclopedic ...article consists of two main sections: methods and applications. The first aims to summarise the up-to-date knowledge and provide an overview of the state-of-the-art methods and key developments in the various subdomains of the field. The second offers a wide-ranging list of areas where Operational Research has been applied. The article is meant to be read in a nonlinear fashion. It should be used as a point of reference or first-port-of-call for a diverse pool of readers: academics, researchers, students, and practitioners. The entries within the methods and applications sections are presented in alphabetical order. The authors dedicate this paper to the 2023 Turkey/Syria earthquake victims. We sincerely hope that advances in OR will play a role towards minimising the pain and suffering caused by this and future catastrophes.
Cell senescence is an important tumour suppressor mechanism and driver of ageing. Both functions are dependent on the development of the senescent phenotype, which involves an overproduction of ...pro‐inflammatory and pro‐oxidant signals. However, the exact mechanisms regulating these phenotypes remain poorly understood. Here, we show the critical role of mitochondria in cellular senescence. In multiple models of senescence, absence of mitochondria reduced a spectrum of senescence effectors and phenotypes while preserving ATP production via enhanced glycolysis. Global transcriptomic analysis by RNA sequencing revealed that a vast number of senescent‐associated changes are dependent on mitochondria, particularly the pro‐inflammatory phenotype. Mechanistically, we show that the ATM, Akt and mTORC1 phosphorylation cascade integrates signals from the DNA damage response (DDR) towards PGC‐1β‐dependent mitochondrial biogenesis, contributing to a ROS‐mediated activation of the DDR and cell cycle arrest. Finally, we demonstrate that the reduction in mitochondrial content in vivo, by either mTORC1 inhibition or PGC‐1β deletion, prevents senescence in the ageing mouse liver. Our results suggest that mitochondria are a candidate target for interventions to reduce the deleterious impact of senescence in ageing tissues.
Synopsis
Cellular senescence serves as an important anticancer growth arrest mechanism, but also contributes to ageing. This study shows that mitochondria are necessary for the pro‐inflammatory phenotype during senescence and that senescence can be induced by mitochondrial biogenesis.
Mitochondria are required for the development of the pro‐oxidant and pro‐inflammatory features of senescence.
ATM, Akt, mTOR and PGC‐1β‐mediated mitochondrial biogenesis are involved in a novel senescence signalling pathway.
Mitochondrial biogenesis stabilizes senescence via a positive feedback loop involving ROS and the DDR.
Cellular senescence serves as an important anticancer growth arrest mechanism, but also contributes to ageing. This study shows that mitochondria are necessary for the pro‐inflammatory phenotype during senescence and that senescence can be induced by mitochondrial biogenesis.
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