Socioeconomic position (SEP) is a multi-dimensional construct reflecting (and influencing) multiple socio-cultural, physical, and environmental factors. In a sample of 286,301 participants from UK ...Biobank, we identify 30 (29 previously unreported) independent-loci associated with income. Using a method to meta-analyze data from genetically-correlated traits, we identify an additional 120 income-associated loci. These loci show clear evidence of functionality, with transcriptional differences identified across multiple cortical tissues, and links to GABAergic and serotonergic neurotransmission. By combining our genome wide association study on income with data from eQTL studies and chromatin interactions, 24 genes are prioritized for follow up, 18 of which were previously associated with intelligence. We identify intelligence as one of the likely causal, partly-heritable phenotypes that might bridge the gap between molecular genetic inheritance and phenotypic consequence in terms of income differences. These results indicate that, in modern era Great Britain, genetic effects contribute towards some of the observed socioeconomic inequalities.
Hexokinase-II (HK-II) catalyzes the first step of glycolysis and also functions as a protective molecule; however, its role in protective autophagy has not been determined. Results showed that ...inhibition of HK-II diminished, while overexpression of HK-II potentiated, autophagy induced by glucose deprivation in cardiomyocyte and noncardiomyocyte cells. Immunoprecipitation studies revealed that HK-II binds to and inhibits the autophagy suppressor, mTOR complex 1 (TORC1), and that this binding was increased by glucose deprivation. The TOS motif, a scaffold sequence responsible for binding TORC1 substrates, is present in HK-II, and mutating it blocked its ability to bind to TORC1 and regulate protective autophagy. The transition from glycolysis to autophagy appears to be regulated by a decrease in glucose-6 phosphate. We suggest that HK-II binds TORC1 as a decoy substrate and provides a previously unrecognized mechanism for switching cells from a metabolic economy, based on plentiful energy, to one of conservation, under starvation.
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•In the absence of glucose, HK-II stimulates autophagy•HK-II promotes autophagy by binding to, and inhibiting, TORC1•The interaction with TORC1 is mediated by a TOS motif in HK-II•Glucose-6 phosphate appears to suppress the autophagic role of HK-II
Hexokinase-II (HK-II) catalyzes the first step of glycolysis. Roberts et al. show that HK-II binds to TORC1 through a TOS motif, leading to TORC1 inhibition and development of autophagy in response to glucose deprivation. The study reveals that HK-II detects glucose depletion to adapt to metabolic suppression by facilitating autophagy.
Purpose
While the use of transthoracic echocardiography (TTE) in the ICU is rapidly expanding, the contribution of TTE to altering patient outcomes among ICU patients with sepsis has not been ...examined. This study was designed to examine the association of TTE with 28-day mortality specifically in that population.
Methods and results
The MIMIC-III database was employed to identify patients with sepsis who had and had not received TTE. The statistical approaches utilized included multivariate regression, propensity score analysis, doubly robust estimation, the gradient boosted model, and an inverse probability-weighting model to ensure the robustness of our findings. Significant benefit in terms of 28-day mortality was observed among the TTE patients compared to the control (no TTE) group (odds ratio = 0.78, 95% CI 0.68–0.90,
p
< 0.001). The amount of fluid administered (2.5 vs. 2.1 L on day 1,
p
< 0.001), use of dobutamine (2% vs. 1%,
p
= 0.007), and the maximum dose of norepinephrine (1.4 vs. 1 mg/min,
p
= 0.001) were significantly higher for the TTE patients. Importantly, the TTE patients were weaned off vasopressors more quickly than those in the no TTE group (vasopressor-free days on day 28 of 21 vs. 19,
p
= 0.004).
Conclusion
In a general population of critically ill patients with sepsis, use of TTE is associated with an improvement in 28-day mortality.
Elucidation of mutagenic processes shaping cancer genomes is a fundamental problem whose solution promises insights into new treatment, diagnostic and prevention strategies. Single-strand ...DNA-specific APOBEC cytidine deaminase(s) are major source(s) of mutation in several cancer types. Previous indirect evidence implicated APOBEC3B as the more likely major mutator deaminase, whereas the role of APOBEC3A is not established. Using yeast models enabling the controlled generation of long single-strand genomic DNA substrates, we show that the mutation signatures of APOBEC3A and APOBEC3B are statistically distinguishable. We then apply three complementary approaches to identify cancer samples with mutation signatures resembling either APOBEC. Strikingly, APOBEC3A-like samples have over tenfold more APOBEC-signature mutations than APOBEC3B-like samples. We propose that APOBEC3A-mediated mutagenesis is much more frequent because APOBEC3A itself is highly proficient at generating DNA breaks, whose repair can trigger the formation of single-strand hypermutation substrates.
A difficult year… so keep on keeping on Roberts, David J.
Transfusion medicine (Oxford, England),
December 2022, 2022-12-00, 20221201, Letnik:
32, Številka:
6
Journal Article
Purpose
PET can image neuroinflammation by targeting the translocator protein (TSPO), which is upregulated in activated microglia. The high nonspecific binding of the first-generation TSPO ...radioligand
11
CPK-11195 limits accurate quantification.
18
FGE-180, a novel TSPO ligand, displays superior binding to
11
CPK-11195 in vitro. Our objectives were to: (1) evaluate tracer characteristics of
18
FGE-180 in the brains of healthy human subjects; and (2) investigate whether the TSPO Ala147Thr polymorphism influences outcome measures.
Methods
Ten volunteers (five high-affinity binders, HABs, and five mixed-affinity binders, MABs) underwent a dynamic PET scan with arterial sampling after injection of
18
FGE-180. Kinetic modelling of time–activity curves with one-tissue and two-tissue compartment models and Logan graphical analysis was applied to the data. The primary outcome measure was the total volume of distribution (
V
T
) across various regions of interest (ROIs). Secondary outcome measures were the standardized uptake values (SUV), the distribution volume and SUV ratios estimated using a pseudoreference region.
Results
The two-tissue compartment model was the best model. The average regional delivery rate constant (
K
1
) was 0.01 mL cm
−3
min
−1
indicating low extraction across the blood–brain barrier (1 %). The estimated median
V
T
across all ROIs was also low, ranging from 0.16 mL cm
−3
in the striatum to 0.38 mL cm
−3
in the thalamus. There were no significant differences in
V
T
between HABs and MABs across all ROIs.
Conclusion
A reversible two-tissue compartment model fitted the data well and determined that the tracer has a low first-pass extraction (approximately 1 %) and low
V
T
estimates in healthy individuals. There was no observable dependency on the rs6971 polymorphism as compared to other second-generation TSPO PET tracers. Investigation of
18
FGE-180 in populations with neuroinflammatory disease is needed to determine its suitability for quantitative assessment of TSPO expression.
The evidence for vitamin D and other agents that experimentally modulate T regulatory cells (Tregs) for the treatment of patients with autoimmune or allergic diseases has not been established.
We ...have undertaken a systematic review of randomised controlled trials to assess the efficacy of vitamin D, vitamin A, niacin and short-chain fatty acids in enhancing absolute Treg numbers and phenotypes in patients with inflammatory or autoimmune disease.
This systematic review was conducted using a predefined protocol (PROSPERO International prospective register of systematic reviews, ID = CRD42016048648/ CRD42016048646). Randomised controlled trials of patients with inflammatory or autoimmune disease or healthy participants which compared either oral vitamin D or vitamin A or short-chain fatty acids with control or placebo and measured the absolute concentration of proportion of Tregs were eligible for inclusion. Searches of electronic databases (CENTRAL, MEDLINE, EMBASE, CINAHL, PUBMED and Web of Science) identified eight eligible independent trials (seven autoimmune disease trials, one trial of healthy subjects). Data were extracted by two reviewers and the risk of study bias was assessed using Cochrane Collaboration methodology.
Planned meta-analysis was not possible due to the heterogeneous nature of the studies. Nevertheless, in five trials of autoimmune disorders which measured the proportion of Tregs, a higher proportion was observed in the vitamin D group compared to controls at 12 months in all but one trial. In the trial of healthy subjects, a significant difference was reported, with a higher percentage of Tregs observed in the vitamin D group (at 12 weeks, mean 6.4% (SD 0.8%) (vitamin D) vs 5.5% (1.0%) (placebo). There were no trials to assess the efficacy of vitamin A, niacin and short-chain fatty acids in enhancing absolute Treg numbers.
Vitamin D supplementation may increase Treg/CD3 ratios in both healthy individuals and patients with autoimmune disorders and may increase Treg function. There remains a need for further suitably powered clinical studies aimed at enhancing Treg numbers and/or function.
This paper links new firm survival with growth, with a focus on the patterns in firms' growth paths. We theorise a Gambler's Ruin framework by arguing that new firm performance is best modelled as a ...random walk process, but that survival is nonrandom and depends primarily on the stock of accumulated resources. A firm's resources are either there when the business begins or are generated by successful periods — ‘wins’. The empirical section tracks, over six years, the sales and survival/non-survival of 6247 UK start-ups which all began trading in the same quarter of 2004. We do not find strong evidence in favour of a taxonomy of growth paths, because we observe that every possible growth path seems to occur with roughly equal probability. However, we observe that growth paths influence subsequent survival. Controlling for lagged size, we observe that longer lags of growth, and even start-up size, have significant effects on survival.
► We investigate the growth and survival of nascent businesses by analyzing their bank records. ► We do not find strong evidence in favour of a taxonomy of growth paths. ► Every possible growth path seems to occur with roughly equal probability. ► We observe that survival depends on the business' growth path. ► Even when controlling for lagged size, lagged growth has significant effects on survival.
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