In Science Journals Smith, Keith T.; Maroso, Mattia; Osborne, Ian S. ...
Science (American Association for the Advancement of Science),
06/2024, Letnik:
384, Številka:
6700
Journal Article
Reports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting conclusions. We resolve this issue through the inclusion of molecular subgroup profiles.
We determined ...subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort of 156 medulloblastomas.
TP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%) medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P < .001). Patients with SHH/TP53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically different from the general SHH distribution (P < .001). Children with SHH/TP53 mutant tumors harbor 56% germline TP53 mutations, which are not observed in children with WNT/TP53 mutant tumors. Five-year overall survival (OS; ± SE) was 41% ± 9% and 81% ± 5% for patients with SHH medulloblastomas with and without TP53 mutations, respectively (P < .001). Furthermore, TP53 mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas. In contrast, 5-year OS rates were 90% ± 9% and 97% ± 3% for patients with WNT tumors with and without TP53 mutations (P = .21). Multivariate analysis revealed that TP53 status was the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to patients with SHH medulloblastomas (P = .012) and not WNT tumors.
Subgroup-specific analysis reconciles prior conflicting publications and confirms that TP53 mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and account for a large proportion of treatment failures in these patients.
The Zoonomia Project is investigating the genomics of shared and specialized traits in eutherian mammals. Here we provide genome assemblies for 131 species, of which all but 9 are previously ...uncharacterized, and describe a whole-genome alignment of 240 species of considerable phylogenetic diversity, comprising representatives from more than 80% of mammalian families. We find that regions of reduced genetic diversity are more abundant in species at a high risk of extinction, discern signals of evolutionary selection at high resolution and provide insights from individual reference genomes. By prioritizing phylogenetic diversity and making data available quickly and without restriction, the Zoonomia Project aims to support biological discovery, medical research and the conservation of biodiversity.
In Science Journals Grocholski, Brent; Hurtley, Stella M; Hodges, Kip ...
Science (American Association for the Advancement of Science),
2022-Mar-11, 2022-03-11, 20220311, Letnik:
375, Številka:
6585
Journal Article
In Science Journals Lopez, Bianca; Jiang, Di; Smith, Keith T ...
Science (American Association for the Advancement of Science),
2023-Jun-30, 2023-06-30, 20230630, Letnik:
380, Številka:
6652
Journal Article
Objective: The aim of this research was to assess tertiary student distress levels with regards to (i) comparisons with normative population data, and (ii) the effects of discipline, year level, and ...student characteristics. Self-reported treatment rates and level of concern regarding perceived distress were also collected.
Method: Students from all six years of an undergraduate medical course were compared with samples from Psychology, Law and Mechanical Engineering courses at the University of Adelaide, Australia. Students participated in one of three studies that were either web-based or paper-based. All studies included Kessler's Measure of Psychological Distress (K10), and questions pertaining to treatment for any mental health problems and concern regarding distress experienced.
Results: Of the 955 tertiary students who completed the K10, 48% were psychologically distressed (a K10 score ≥ 22) which equated to a rate 4.4 times that of age-matched peers. The non-health disciplines were significantly more distressed than the health disciplines. Distress levels were statistically equivalent across all six years of the medical degree. Of tertiary students, 11% had been treated for a mental health problem. Levels of concern correlated with the K10 score.
Conclusion: The results from this research suggest that high distress levels among the tertiary student body may be a phenomenon more widely spread than first thought. Low treatment rates suggest that traditional models of support may be inadequate or not appropriate for tertiary cohorts.
Stratification by eosinophil and neutrophil counts increases our understanding of asthma and helps target therapy, but there is room for improvement in our accuracy in prediction of treatment ...responses and a need for better understanding of the underlying mechanisms.
We sought to identify molecular subphenotypes of asthma defined by proteomic signatures for improved stratification.
Unbiased label-free quantitative mass spectrometry and topological data analysis were used to analyze the proteomes of sputum supernatants from 246 participants (206 asthmatic patients) as a novel means of asthma stratification. Microarray analysis of sputum cells provided transcriptomics data additionally to inform on underlying mechanisms.
Analysis of the sputum proteome resulted in 10 clusters (ie, proteotypes) based on similarity in proteomic features, representing discrete molecular subphenotypes of asthma. Overlaying granulocyte counts onto the 10 clusters as metadata further defined 3 of these as highly eosinophilic, 3 as highly neutrophilic, and 2 as highly atopic with relatively low granulocytic inflammation. For each of these 3 phenotypes, logistic regression analysis identified candidate protein biomarkers, and matched transcriptomic data pointed to differentially activated underlying mechanisms.
This study provides further stratification of asthma currently classified based on quantification of granulocytic inflammation and provided additional insight into their underlying mechanisms, which could become targets for novel therapies.
In 2020, the Australian and New Zealand flux research and monitoring network, OzFlux, celebrated its 20th anniversary by reflecting on the lessons learned through two decades of ecosystem studies on ...global change biology. OzFlux is a network not only for ecosystem researchers, but also for those ‘next users’ of the knowledge, information and data that such networks provide. Here, we focus on eight lessons across topics of climate change and variability, disturbance and resilience, drought and heat stress and synergies with remote sensing and modelling. In distilling the key lessons learned, we also identify where further research is needed to fill knowledge gaps and improve the utility and relevance of the outputs from OzFlux. Extreme climate variability across Australia and New Zealand (droughts and flooding rains) provides a natural laboratory for a global understanding of ecosystems in this time of accelerating climate change. As evidence of worsening global fire risk emerges, the natural ability of these ecosystems to recover from disturbances, such as fire and cyclones, provides lessons on adaptation and resilience to disturbance. Drought and heatwaves are common occurrences across large parts of the region and can tip an ecosystem's carbon budget from a net CO2 sink to a net CO2 source. Despite such responses to stress, ecosystems at OzFlux sites show their resilience to climate variability by rapidly pivoting back to a strong carbon sink upon the return of favourable conditions. Located in under‐represented areas, OzFlux data have the potential for reducing uncertainties in global remote sensing products, and these data provide several opportunities to develop new theories and improve our ecosystem models. The accumulated impacts of these lessons over the last 20 years highlights the value of long‐term flux observations for natural and managed systems. A future vision for OzFlux includes ongoing and newly developed synergies with ecophysiologists, ecologists, geologists, remote sensors and modellers.
The Australian and New Zealand ecosystem observation network—OzFlux—celebrated 20 years making ecosystem measurements in 2020. Important insights and new knowledge from this 20‐year period were identified and discussed as eight key lessons. Our vision for the future of OzFlux is also discussed, and includes training the next generation and providing ecosystem data to improve understanding of Australia's and New Zealand's rapidly changing environments.
The American alligator,
, like all crocodilians, has temperature-dependent sex determination, in which the sex of an embryo is determined by the incubation temperature of the egg during a critical ...period of development. The lack of genetic differences between male and female alligators leaves open the question of how the genes responsible for sex determination and differentiation are regulated. Insight into this question comes from the fact that exposing an embryo incubated at male-producing temperature to estrogen causes it to develop ovaries. Because estrogen response elements are known to regulate genes over long distances, a contiguous genome assembly is crucial for predicting and understanding their impact. We present an improved assembly of the American alligator genome, scaffolded with in vitro proximity ligation (Chicago) data. We use this assembly to scaffold two other crocodilian genomes based on synteny. We perform RNA sequencing of tissues from American alligator embryos to find genes that are differentially expressed between embryos incubated at male- versus female-producing temperature. Finally, we use the improved contiguity of our assembly along with the current model of CTCF-mediated chromatin looping to predict regions of the genome likely to contain estrogen-responsive genes. We find that these regions are significantly enriched for genes with female-biased expression in developing gonads after the critical period during which sex is determined by incubation temperature. We thus conclude that estrogen signaling is a major driver of female-biased gene expression in the post-temperature sensitive period gonads.
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