Cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. Previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. The ...effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. This randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up. Instructions to participants and staff minimized expectancy effects. Participants, staff, and community observers rated participant moods, attitudes, and behaviors throughout the study. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. Community observer ratings showed corresponding changes. Mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes.
Trial Registration
ClinicalTrials.gov identifier: NCT00465595
Huntington disease (HD) is caused by a CAG repeat expansion in the huntingtin (HTT) gene. Although the length of this repeat is inversely correlated with age of onset (AOO), it does not fully explain ...the variability in AOO. We assessed the sequence downstream of the CAG repeat in HTT reference: (CAG)n-CAA-CAG, since variants within this region have been previously described, but no study of AOO has been performed. These analyses identified a variant that results in complete loss of interrupting (LOI) adenine nucleotides in this region (CAG)n-CAG-CAG. Analysis of multiple HD pedigrees showed that this LOI variant is associated with dramatically earlier AOO (average of 25 years) despite the same polyglutamine length as in individuals with the interrupting penultimate CAA codon. This LOI allele is particularly frequent in persons with reduced penetrance alleles who manifest with HD and increases the likelihood of presenting clinically with HD with a CAG of 36–39 repeats. Further, we show that the LOI variant is associated with increased somatic repeat instability, highlighting this as a significant driver of this effect. These findings indicate that the number of uninterrupted CAG repeats, which is lengthened by the LOI, is the most significant contributor to AOO of HD and is more significant than polyglutamine length, which is not altered in these individuals. In addition, we identified another variant in this region, where the CAA-CAG sequence is duplicated, which was associated with later AOO. Identification of these cis-acting modifiers have potentially important implications for genetic counselling in HD-affected families.
Teaching has been characterised as a stressful profession that is prone to burnout. Less is known about the specific ways in which teachers experience and navigate stressors associated with their ...work. This study aimed to qualitatively understand how teachers who perceive high and low levels of burnout characterise their lived experiences in school environments. Data were collected through interviews with 28 inservice teachers (11 male, 17 female) from the US Midwest who reported high- or low-burnout on a psychometric survey. Data were analysed by two experienced qualitative researchers. Results indicated that (a) low-burnout teachers perceived nurturing teaching environments, (b) high-burnout teachers perceived combative and constraining teaching environments, and (c) all teachers had to manage workplace stress. Building from these findings, we present a model for understanding how the school environment influences teacher burnout. This model highlights the importance of developing optimal working conditions that nurture teacher development.
Abbreviation: MBI-ES = Maslach Burnout Iventory-Educators Survey; IEP = Individualized Education Plan
The Ecology and Evolution of Pangenomes Brockhurst, Michael A.; Harrison, Ellie; Hall, James P.J. ...
Current biology,
10/2019, Letnik:
29, Številka:
20
Journal Article
Recenzirano
Odprti dostop
Since the first genome-scale comparisons, it has been evident that the genomes of many species are unbound by strict vertical descent: Large differences in gene content can occur among genomes ...belonging to the same prokaryotic species, with only a fraction of genes being universal to all genomes. These insights gave rise to the pangenome concept. The pangenome is defined as the set of all the genes present in a given species and can be subdivided into the accessory genome, present in only some of the genomes, and the core genome, present in all the genomes. Pangenomes arise due to gene gain by genomes from other species through horizontal gene transfer and differential gene loss among genomes, and have been described in both prokaryotes and eukaryotes. Our current view of pangenome variation is phenomenological and incomplete. In this review, we outline the mechanistic, ecological and evolutionary drivers of and barriers to horizontal gene transfer that are likely to structure pangenomes. We highlight the key role of conflict between the host chromosome(s) and the mobile genetic elements that mediate gene exchange. We identify shortcomings in our current models of pangenome evolution and suggest directions for future research to allow a more complete understanding of how and why pangenomes evolve.
The observation of large differences in gene content when comparing genomes within a species gave rise to the concept of the pangenome. Brockhurst et al. provide an ecological perspective on the evolution of pangenomes, and how their origin and structure derive from the dynamics of horizontal gene transfer.
The bacterium Vibrio coralliilyticus can threaten vital reef ecosystems by causing disease in a variety of coral genera, and, for some strains, increases in virulence at elevated water temperatures. ...In addition, strains of V. coralliilyticus (formally identified as V. tubiashii) have been implicated in mass mortalities of shellfish larvae causing significant economic losses to the shellfish industry. Recently, strain BAA-450, a coral pathogen, was demonstrated to be virulent towards larval Pacific oysters (Crassostrea gigas). However, it is unclear whether other coral-associated V. coralliilyticus strains can cause shellfish mortalities and if infections are influenced by temperature. This study compared dose dependence, temperature impact, and gross pathology of four V. coralliilyticus strains (BAA-450, OCN008, OCN014 and RE98) on larval C. gigas raised at 23°C and 27°C, and evaluated whether select virulence factors are required for shellfish infections as they are for corals. All strains were infectious to larval oysters in a dose-dependent manner with OCN014 being the most pathogenic and BAA-450 being the least. At 27°C, higher larval mortalities (p < 0.05) were observed for all V. coralliilyticus strains, ranging from 38.8-93.7%. Gross pathological changes to the velum and cilia occurred in diseased larvae, but there were no distinguishable differences between oysters exposed to different V. coralliilyticus strains or temperatures. Additionally, in OCN008, the predicted transcriptional regulator ToxR and the outer membrane protein OmpU were important for coral and oyster disease, while mannose sensitive hemagglutinin type IV pili were required only for coral infection. This study demonstrated that multiple coral pathogens can infect oyster larvae in a temperature-dependent manner and identified virulence factors required for infection of both hosts.
In molecular phylogenetics, partition models and mixture models provide different approaches to accommodating heterogeneity in genomic sequencing data. Both types of models generally give a superior ...fit to data than models that assume the process of sequence evolution is homogeneous across sites and lineages. The Akaike Information Criterion (AIC), an estimator of Kullback-Leibler divergence, and the Bayesian Information Criterion (BIC) are popular tools to select models in phylogenetics. Recent work suggests that AIC should not be used for comparing mixture and partition models. In this work, we clarify that this difficulty is not fully explained by AIC misestimating the Kullback-Leibler divergence. We also investigate the performance of the AIC and BIC at comparing amongst mixture models and amongst partition models. We find that under nonstandard conditions (i.e. when some edges have small expected number of changes), AIC underestimates the expected Kullback-Leibler divergence. Under such conditions, AIC preferred the complex mixture models and BIC preferred the simpler mixture models. The mixture models selected by AIC had a better performance in estimating the edge length, while the simpler models selected by BIC performed better in estimating the base frequencies and substitution rate parameters. In contrast, AIC and BIC both prefer simpler partition models over more complex partition models under nonstandard conditions, despite the fact that the more complex partition model was the generating model. We also investigated how mispartitioning (i.e., grouping sites that have not evolved under the same process) affects both the performance of partition models compared with mixture models and the model selection process. We found that as the level of mispartitioning increases, the bias of AIC in estimating the expected Kullback-Leibler divergence remains the same, and the branch lengths and evolutionary parameters estimated by partition models become less accurate. We recommend that researchers are cautious when using AIC and BIC to select among partition and mixture models; other alternatives, such as cross-validation and bootstrapping, should be explored, but may suffer similar limitations AIC; BIC; mispartitioning; partitioning; partition model; mixture model.
Human APOBEC3H and homologous single-stranded DNA cytosine deaminases are unique to mammals. These DNA-editing enzymes function in innate immunity by restricting the replication of viruses and ...transposons. APOBEC3H also contributes to cancer mutagenesis. Here, we address the fundamental nature of RNA in regulating human APOBEC3H activities. APOBEC3H co-purifies with RNA as an inactive protein, and RNase A treatment enables strong DNA deaminase activity. RNA-binding-defective mutants demonstrate clear separation of function by becoming DNA hypermutators. Biochemical and crystallographic data demonstrate a mechanism in which double-stranded RNA mediates enzyme dimerization. Additionally, APOBEC3H separation-of-function mutants show that RNA binding is required for cytoplasmic localization, packaging into HIV-1 particles, and antiviral activity. Overall, these results support a model in which structured RNA negatively regulates the potentially harmful DNA deamination activity of APOBEC3H while, at the same time, positively regulating its antiviral activity.
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•RNA negatively regulates human APOBEC3H DNA cytosine deaminase activity•RNA-binding-defective mutants are DNA hypermutators•Crystal structures demonstrate an RNA duplex-mediated APOBEC3H dimerization mechanism•RNA binding positively regulates packaging into HIV-1 particles and antiviral activity
Shaban et al. define positive and negative roles for RNA in regulating the activities of human APOBEC3H. RNA is essential for APOBEC3H localization, packaging into HIV-1 particles, and virus restriction. RNA also blocks DNA deaminase activity. Crystal structures demonstrate duplex RNA as a central feature of the underlying molecular mechanism.
The authors consider whether differences in stage at diagnosis could explain the variation in lung cancer survival between six developed countries in 2004-2007.
Routinely collected population-based ...data were obtained on all adults (15-99 years) diagnosed with lung cancer in 2004-2007 and registered in regional and national cancer registries in Australia, Canada, Denmark, Norway, Sweden and the UK. Stage data for 57 352 patients were consolidated from various classification systems. Flexible parametric hazard models on the log cumulative scale were used to estimate net survival at 1 year and the excess hazard up to 18 months after diagnosis.
Age-standardised 1-year net survival from non-small cell lung cancer ranged from 30% (UK) to 46% (Sweden). Patients in the UK and Denmark had lower survival than elsewhere, partly because of a more adverse stage distribution. However, there were also wide international differences in stage-specific survival. Net survival from TNM stage I non-small cell lung cancer was 16% lower in the UK than in Sweden, and for TNM stage IV disease survival was 10% lower. Similar patterns were found for small cell lung cancer.
There are comparability issues when using population-based data but, even given these constraints, this study shows that, while differences in stage at diagnosis explain some of the international variation in overall lung cancer survival, wide disparities in stage-specific survival exist, suggesting that other factors are also important such as differences in treatment. Stage should be included in international cancer survival studies and the comparability of population-based data should be improved.
Since the inception of the profession of occupational therapy a century ago, a clarion call to link health with occupation and occupational engagement has been heard. For decades, leaders in the ...profession have emphasized the need for prevention and health promotion as well as for development of assessments and models linking health with occupation. This article addresses the need for an increased presence of occupational therapy in health and wellness, emphasizing participation over performance, to optimize the health, well-being, and quality of life of individuals, communities, and populations.
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