We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC family amplifications and P53 pathway defects ...commonly emerged at relapse, and all patients in this group died of rapidly progressive disease postrelapse. To study this interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of p53 function in this model produced aggressive tumors that mimicked characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity and genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53-MYC interactions at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically.
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•Combined P53 and MYC family defects emerge at medulloblastoma relapse•P53-MYC defects are a biomarker for rapidly progressive relapsed disease•Trp53 and MYCN interact to drive aggressive medulloblastoma development in mice•Targeting MYCN or P53 pathway reactivation reduces tumor growth and prolongs survival
Hill et al. find that coincident MYC amplifications and p53 pathway defects are common in relapsed medulloblastoma (MB) and correlate with poor postrelapse prognosis. The authors go on to explore this MYC-p53 interaction in a mouse MB model and show that these tumors are dependent on both aberrations.
Early excision and autografting are standard care for deeper burns. However, donor sites are a source of significant morbidity. To address this, the ReCell
®
Autologous Cell Harvesting Device ...(ReCell) was designed for use at the point-of-care to prepare a noncultured, autologous skin cell suspension (ASCS) capable of epidermal regeneration using minimal donor skin. A prospective study was conducted to evaluate the clinical performance of ReCell vs meshed split-thickness skin grafts (STSG, Control) for the treatment of deep partial-thickness burns. Effectiveness measures were assessed to 1 year for both ASCS and Control treatment sites and donor sites, including the incidence of healing, scarring, and pain. At 4 weeks, 98% of the ASCS-treated sites were healed compared with 100% of the Controls. Pain and assessments of scarring at the treatment sites were reported to be similar between groups. Significant differences were observed between ReCell and Control donor sites. The mean ReCell donor area was approximately 40 times smaller than that of the Control (
P
< .0001), and after 1 week, significantly more ReCell donor sites were healed than Controls (
P
= .04). Over the first 16 weeks, patients reported significantly less pain at the ReCell donor sites compared with Controls (
P
≤ .05 at each time point). Long-term patients reported higher satisfaction with ReCell donor site outcomes compared with the Controls. This study provides evidence that the treatment of deep partial-thickness burns with ASCS results in comparable healing, with significantly reduced donor site size and pain and improved appearance relative to STSG.
Abstract Background General cognitive function predicts psychiatric illness across the life course. This study examines the role of pleiotropy in explaining the link between cognitive function and ...psychiatric disorder. Methods We used two large genome-wide association study data sets on cognitive function—one from older age, n = 53,949, and one from childhood, n = 12,441. We also used genome-wide association study data on educational attainment, n = 95,427, to examine the validity of its use as a proxy phenotype for cognitive function. Using a new method, linkage disequilibrium regression, we derived genetic correlations, free from the confounding of clinical state between psychiatric illness and cognitive function. Results We found a genetic correlation of .711, ( p = 2.26e-12) across the life course for general cognitive function. We also showed a positive genetic correlation between autism spectrum disorder and cognitive function in childhood ( rg = .360, p = .0009) and for educational attainment ( rg = .322, p = 1.37e-5) but not in older age. In schizophrenia, we found a negative genetic correlation between older age cognitive function ( rg = −.231, p = 3.81e-12) but not in childhood or for educational attainment. For Alzheimer’s disease, we found negative genetic correlations with childhood cognitive function ( rg = −.341, p = .001), educational attainment ( rg = −.324, p = 1.15e-5), and with older age cognitive function ( rg = −.324, p = 1.78e-5). Conclusions The pleiotropy exhibited between cognitive function and psychiatric disorders changed across the life course. These age-dependent associations might explain why negative selection has not removed variants causally associated with autism spectrum disorder or schizophrenia.
Autosomal variants have successfully been associated with trait neuroticism in genome-wide analysis of adequately powered samples. But such studies have so far excluded the X chromosome from ...analysis. Here, we report genetic association analyses of X chromosome and XY pseudoautosomal single nucleotide polymorphisms (SNPs) and trait neuroticism using UK Biobank samples (N = 405,274). Significant association was found with neuroticism on the X chromosome for 204 markers found within three independent loci (a further 783 were suggestive). Most of the lead neuroticism-related X chromosome variants were located in intergenic regions (n = 397). Involvement of HS6ST2, which has been previously associated with sociability behaviour in the dog, was supported by single SNP and gene-based tests. We found that the amino acid and nucleotide sequences are highly conserved between dogs and humans. From the suggestive X chromosome variants, there were 19 nearby genes which could be linked to gene ontology information. Molecular function was primarily related to binding and catalytic activity; notable biological processes were cellular and metabolic, and nucleic acid binding and transcription factor protein classes were most commonly involved. X-variant heritability of neuroticism was estimated at 0.22% (SE = 0.05) from a full dosage compensation model. A polygenic X-variant score created in an independent sample (maximum N ≈ 7,300) did not predict significant variance in neuroticism, psychological distress, or depressive disorder. We conclude that the X chromosome harbours significant variants influencing neuroticism, and might prove important for other quantitative traits and complex disorders.
Abstract
Objectives
To examine whether educational attainment and intelligence have causal effects on risk of Alzheimer’s disease (AD), independently of each other.
Design
Two-sample univariable and ...multivariable Mendelian randomization (MR) to estimate the causal effects of education on intelligence and vice versa, and the total and independent causal effects of both education and intelligence on AD risk.
Participants
17 008 AD cases and 37 154 controls from the International Genomics of Alzheimer’s Project (IGAP) consortium.
Main outcome measure
Odds ratio (OR) of AD per standardized deviation increase in years of schooling (SD = 3.6 years) and intelligence (SD = 15 points on intelligence test).
Results
There was strong evidence of a causal, bidirectional relationship between intelligence and educational attainment, with the magnitude of effect being similar in both directions OR for intelligence on education = 0.51 SD units, 95% confidence interval (CI): 0.49, 0.54; OR for education on intelligence = 0.57 SD units, 95% CI: 0.48, 0.66. Similar overall effects were observed for both educational attainment and intelligence on AD risk in the univariable MR analysis; with each SD increase in years of schooling and intelligence, odds of AD were, on average, 37% (95% CI: 23–49%) and 35% (95% CI: 25–43%) lower, respectively. There was little evidence from the multivariable MR analysis that educational attainment affected AD risk once intelligence was taken into account (OR = 1.15, 95% CI: 0.68–1.93), but intelligence affected AD risk independently of educational attainment to a similar magnitude observed in the univariate analysis (OR = 0.69, 95% CI: 0.44–0.88).
Conclusions
There is robust evidence for an independent, causal effect of intelligence in lowering AD risk. The causal effect of educational attainment on AD risk is likely to be mediated by intelligence.
Intelligence, health and death Deary, Ian J; Hill, W David; Gale, Catharine R
Nature human behaviour,
04/2021, Letnik:
5, Številka:
4
Journal Article
Recenzirano
The field of cognitive epidemiology studies the prospective associations between cognitive abilities and health outcomes. We review research in this field over the past decade and describe how our ...understanding of the association between intelligence and all-cause mortality has consolidated with the appearance of new, population-scale data. To try to understand the association better, we discuss how intelligence relates to specific causes of death, diseases/diagnoses and biomarkers of health through the adult life course. We examine the extent to which mortality and health associations with intelligence might be attributable to people's differences in education, other indicators of socioeconomic status, health literacy and adult environments and behaviours. Finally, we discuss whether genetic data provide new tools to understand parts of the intelligence-health associations. Social epidemiologists, differential psychologists and behavioural and statistical geneticists, among others, contribute to cognitive epidemiology; advances will occur by building on a common cross-disciplinary knowledge base.
Intelligence and educational attainment are strongly genetically correlated. This relationship can be exploited by Multi-Trait Analysis of GWAS (MTAG) to add power to Genome-wide Association Studies ...(GWAS) of intelligence. MTAG allows the user to meta-analyze GWASs of different phenotypes, based on their genetic correlations, to identify association's specific to the trait of choice. An MTAG analysis using GWAS data sets on intelligence and education was conducted by Lam et al. (2017). Lam et al. (2017) reported 70 loci that they described as ‘trait specific’ to intelligence. This article examines whether the analysis conducted by Lam et al. (2017) has resulted in genetic information about a phenotype that is more similar to education than intelligence.
Greenhouse gas emissions associated with pesticide applications against invasive species constitute an environmental cost of species invasions that has remained largely unrecognized. Here we ...calculate greenhouse gas emissions associated with the invasion of an agricultural pest from Asia to North America. The soybean aphid, Aphis glycines, was first discovered in North America in 2000, and has led to a substantial increase in insecticide use in soybeans. We estimate that the manufacture, transport, and application of insecticides against soybean aphid results in approximately 10.6 kg of carbon dioxide (CO2) equivalent greenhouse gasses being emitted per hectare of soybeans treated. Given the acreage sprayed, this has led to annual emissions of between 6 and 40 million kg of CO2 equivalent greenhouse gasses in the United States since the invasion of soybean aphid, depending on pest population size. Emissions would be higher were it not for the development of a threshold aphid density below which farmers are advised not to spray. Without a threshold, farmers tend to spray preemptively and the threshold allows farmers to take advantage of naturally occurring biological control of the soybean aphid, which can be substantial. We find that adoption of the soybean aphid economic threshold can lead to emission reductions of approximately 300 million kg of CO2 equivalent greenhouse gases per year in the United States. Previous studies have documented that biological control agents such as lady beetles are capable of suppressing aphid densities below this threshold in over half of the soybean acreage in the U.S. Given the acreages involved this suggests that biological control results in annual emission reductions of over 200 million kg of CO2 equivalents. These analyses show how interactions between invasive species and organisms that suppress them can interact to affect greenhouse gas emissions.
The purpose of this study was to investigate the effects of one night's sleep loss on mood state and exercise performance, for the purpose of identifying relationships between mood state and ...performance. A within-subjects repeated-measures design was used. Seven women (21 ± 2 y, 164 ± 9 cm, 62 ± 14 kg) participated. They completed Profile of Mood States questionnaires and performed exhaustive extreme intensity cycle ergometer tests (310 ± 70 W) before, and on three consecutive days following, one night's sleep loss. Mean time to exhaustion was not affected by sleep loss. Mean total mood state disturbance was elevated on days 1 and 2 after sleep loss compared to baseline. There were strong correlations (r > 0.82) between individual changes (day 1 minus baseline, day 2 minus baseline, day 3 minus baseline) in time to exhaustion and individual changes in mood state: changes in time to exhaustion were associated with changes in the fatigue subscore on day 1; with changes in the vigour subscore on day 2, and with changes in the fatigue subscore on day 3. These results demonstrate a relationship, which may or may not reflect causality, between mood state and performance.
In contrast to the situation in plants inhabiting most of the world’s ecosystems, mycorrhizal fungi are usually absent from roots of the only two native vascular plant species of maritime Antarctica, ...Deschampsia antarctica and Colobanthus quitensis. Instead, a range of ascomycete fungi, termed dark septate endophytes (DSEs), frequently colonise the roots of these plant species. We demonstrate that colonisation of Antarctic vascular plants by DSEs facilitates not only the acquisition of organic nitrogen as early protein breakdown products, but also as non‐proteinaceous d‐amino acids and their short peptides, accumulated in slowly‐decomposing organic matter, such as moss peat. Our findings suggest that, in a warming maritime Antarctic, this symbiosis has a key role in accelerating the replacement of formerly dominant moss communities by vascular plants, and in increasing the rate at which ancient carbon stores laid down as moss peat over centuries or millennia are returned to the atmosphere as CO2.
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