Diverse interventions that extend mouse lifespan suppress shared age-associated epigenetic changes at critical gene regulatory regions

Background: Age-associated epigenetic changes are implicated in aging. Notably, age-associated DNA methylation changes comprise a so-called aging “clock”, a robust biomarker of aging. However, while genetic, dietary and drug interventions can extend lifespan, their impact on the epigenome is uncharacterised. To fill this knowledge gap, we defined age-associated DNA methylation changes at the whole-genome, single-nucleotide level in mouse liver and tested the impact of longevity-promoting interventions, specifically the Ames dwarf Prop1 df/df mutation, calorie restriction and rapamycin. Results: In wild-type mice fed an unsupplemented ad libitum diet, age-associated hypomethylation was enriched at super-enhancers in highly expressed genes critical for liver function. Genes harbouring hypomethylated enhancers were enriched for genes that change expression with age. Hypermethylation was enriched at CpG islands marked with bivalent activating and repressing histone modifications and resembled hypermethylation in liver cancer. Age-associated methylation changes are suppressed in Ames dwarf and calorie restricted mice and more selectively and less specifically in rapamycin treated mice. Conclusions: Age-associated hypo- and hypermethylation events occur at distinct regulatory features of the genome. Distinct longevity-promoting interventions, specifically genetic, dietary and drug interventions, suppress some age-associated methylation changes, consistent with the idea that these interventions exert their beneficial effects, in part, by modulation of the epigenome. This study is a foundation to understand the epigenetic contribution to healthy aging and longevity and the molecular basis of the DNA methylation clock

The Significance of African Lions for the Financial Viability of Trophy Hunting and the Maintenance of Wild Land

Recent studies indicate that trophy hunting is impacting negatively on some lion populations, notably in Tanzania. In 2004 there was a proposal to list lions on CITES Appendix I and in 2011 animal-welfare groups petitioned the United States government to list lions as endangered under their Endangered Species Act. Such listings would likely curtail the trophy hunting of lions by limiting the import of lion trophies. Concurrent efforts are underway to encourage the European Union to ban lion trophy imports. We assessed the significance of lions to the financial viability of trophy hunting across five countries to help determine the financial impact and advisability of the proposed trade restrictions. Lion hunts attract the highest mean prices (US$24,000–US$71,000) of all trophy species. Lions generate 5–17% of gross trophy hunting income on national levels, the proportional significance highest in Mozambique, Tanzania, and Zambia. If lion hunting was effectively precluded, trophy hunting could potentially become financially unviable across at least 59,538 km2 that could result in a concomitant loss of habitat. However, the loss of lion hunting could have other potentially broader negative impacts including reduction of competitiveness of wildlife-based land uses relative to ecologically unfavourable alternatives. Restrictions on lion hunting may also reduce tolerance for the species among communities where local people benefit from trophy hunting, and may reduce funds available for anti-poaching. If lion off-takes were reduced to recommended maximums (0.5/1000 km2), the loss of viability and reduction in profitability would be much lower than if lion hunting was stopped altogether (7,005 km2). We recommend that interventions focus on reducing off-takes to sustainable levels, implementing age-based regulations and improving governance of trophy hunting. Such measures could ensure sustainability, while retaining incentives for the conservation of lions and their habitat from hunting

Artificial Nightlight Alters the Predator–Prey Dynamics of an Apex Carnivore

Artificial nightlight is increasingly recognized as an important environmental disturbance that influences the habitats and fitness of numerous species. However, its effects on wide‐ranging vertebrates and their interactions remain unclear. Light pollution has the potential to amplify land‐use change, and as such, answering the question of how this sensory stimulant affects behavior and habitat use of species valued for their ecological roles and economic impacts is critical for conservation and land‐use planning. Here, we combined satellite‐derived estimates of light pollution, with GPS‐data from cougars Puma concolor (n = 56), mule deer Odocoileus hemionus (n = 263) and locations of cougar‐killed deer (n = 1562 carcasses), to assess the effects of light exposure on mammal behavior and predator–prey relationships across wildland–urban gradients in the southwestern United States. Our results indicate that deer used the anthropogenic environments to access forage and were more active at night than their wildland conspecifics. Despite higher nightlight levels, cougars killed deer at the wildland–urban interface, but hunted them in the relatively darkest locations. Light had the greatest effect of all covariates on where cougars killed deer at the wildland–urban interface. Both species exhibited functional responses to light pollution at fine scales; individual cougars and deer with less light exposure increasingly avoided illuminated areas when exposed to greater radiance, whereas deer living in the wildland–urban interface selected elevated light levels. We conclude that integrating estimates of light pollution into ecological studies provides crucial insights into how the dynamic human footprint can alter animal behavior and ecosystem function across spatial scales

Neisseria meningitidis Differentially Controls Host Cell Motility through PilC1 and PilC2 Components of Type IV Pili

Neisseria meningitidis is a strictly human pathogen that has two facets since asymptomatic carriage can unpredictably turn into fulminant forms of infection. Meningococcal pathogenesis relies on the ability of the bacteria to break host epithelial or endothelial cellular barriers. Highly restrictive, yet poorly understood, mechanisms allow meningococcal adhesion to cells of only human origin. Adhesion of encapsulated and virulent meningococci to human cells relies on the expression of bacterial type four pili (T4P) that trigger intense host cell signalling. Among the components of the meningococcal T4P, the concomitantly expressed PilC1 and PilC2 proteins regulate pili exposure at the bacterial surface, and until now, PilC1 was believed to be specifically responsible for T4P-mediated meningococcal adhesion to human cells. Contrary to previous reports, we show that, like PilC1, the meningococcal PilC2 component is capable of mediating adhesion to human ME180 epithelial cells, with cortical plaque formation and F-actin condensation. However, PilC1 and PilC2 promote different effects on infected cells. Cellular tracking analysis revealed that PilC1-expressing meningococci caused a severe reduction in the motility of infected cells, which was not the case when cells were infected with PilC2-expressing strains. The amount of both total and phosphorylated forms of EGFR was dramatically reduced in cells upon PilC1-mediated infection. In contrast, PilC2-mediated infection did not notably affect the EGFR pathway, and these specificities were shared among unrelated meningococcal strains. These results suggest that meningococci have evolved a highly discriminative tool for differential adhesion in specific microenvironments where different cell types are present. Moreover, the fine-tuning of cellular control through the combined action of two concomitantly expressed, but distinctly regulated, T4P-associated variants of the same molecule (i.e. PilC1 and PilC2) brings a new model to light for the analysis of the interplay between pathogenic bacteria and human host cells

Moral expansiveness around the world:The role of societal factors across 36 countries

International audienceWhat are the things that we think matter morally, and how do societal factors influence this? To date, research has explored several individual-level and historical factors that influence the size of our ‘moral circles.' There has, however, been less attention focused on which societal factors play a role. We present the first multi-national exploration of moral expansiveness—that is, the size of people’s moral circles across countries. We found low generalized trust, greater perceptions of a breakdown in the social fabric of society, and greater perceived economic inequality were associated with smaller moral circles. Generalized trust also helped explain the effects of perceived inequality on lower levels of moral inclusiveness. Other inequality indicators (i.e., Gini coefficients) were, however, unrelated to moral expansiveness. These findings suggest that societal factors, especially those associated with generalized trust, may influence the size of our moral circles

Decisions that hasten death: double effect and the experiences of physicians in Australia

BACKGROUND: In Australian end-of-life care, practicing euthanasia or physician-assisted suicide is illegal. Despite this, death hastening practices are common across medical settings. Practices can be clandestine or overt but in many instances physicians are forced to seek protection behind ambiguous medico-legal imperatives such as the Principle of Double Effect. Moreover, the way they conceptualise and experience such practices is inconsistent. To complement the available statistical data, the purpose of this study was to understand the reasoning behind how and why physicians in Australia will hasten death. METHOD: A qualitative investigation was focused on palliative and critical/acute settings. A thematic analysis was conducted on semi-structured in-depth interviews with 13 specialist physicians. Attention was given to eliciting meanings and experiences in Australian end-of-life care. RESULTS: Highlighting the importance of a multidimensional approach, physicians negotiated multiple influences when death was regarded as hastened. The way they understood and experienced end-of-life care practices were affected by politico-religious and cultural influences, medico-legal imperatives, and personal values and beliefs. Interpersonal and intrapsychic aspects further emphasised the emotional and psychological investment physicians have with patients and others. In most cases death occurred as a result of treating suffering, and sometimes to fulfil the wishes of patients and others who requested death. Experience was especially subject to the efficacy with which physicians negotiated complex but context-specific situations, and was reflective of how they considered a good death. Although many were compelled to draw on the Principle of Double Effect, every physician reported its inadequacy as a medico-legal guideline. CONCLUSIONS: The Principle of Double Effect, as a simplistic and generalised guideline, was identified as a convenient mechanism to protect physicians who inadvertently or intentionally hastened death. But its narrow focus on the physician’s intent illuminated how easily it may be manipulated, thus impairing transparency and a physician’s capacity for honesty. It is suggested the concept of “force majeure” be examined for its applicability in Australian medical end-of-life law where, consistent with a multidimensional and complex world, a physician’s motivations can also be understood in terms of the emotional and psychological pressures they face in situations that hasten death

Abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5-year follow-up results from the STAMPEDE randomised trial (NCT00268476)

Abiraterone acetate plus prednisolone (AAP) previously demonstrated improved survival in STAMPEDE, a multiarm, multistage platform trial in men starting long-term hormone therapy for prostate cancer. This long-term analysis in metastatic patients was planned for 3 years after the first results. Standard-of-care (SOC) was androgen deprivation therapy. The comparison randomised patients 1:1 to SOC-alone with or without daily abiraterone acetate 1000 mg + prednisolone 5 mg (SOC + AAP), continued until disease progression. The primary outcome measure was overall survival. Metastatic disease risk group was classified retrospectively using baseline CT and bone scans by central radiological review and pathology reports. Analyses used Cox proportional hazards and flexible parametric models, accounting for baseline stratification factors. One thousand and three patients were contemporaneously randomised (November 2011 to January 2014): median age 67 years; 94% newly-diagnosed; metastatic disease risk group: 48% high, 44% low, 8% unassessable; median PSA 97 ng/mL. At 6.1 years median follow-up, 329 SOC-alone deaths (118 low-risk, 178 high-risk) and 244 SOC + AAP deaths (75 low-risk, 145 high-risk) were reported. Adjusted HR = 0.60 (95% CI: 0.50-0.71; P = 0.31 × 10−9) favoured SOC + AAP, with 5-years survival improved from 41% SOC-alone to 60% SOC + AAP. This was similar in low-risk (HR = 0.55; 95% CI: 0.41-0.76) and high-risk (HR = 0.54; 95% CI: 0.43-0.69) patients. Median and current maximum time on SOC + AAP was 2.4 and 8.1 years. Toxicity at 4 years postrandomisation was similar, with 16% patients in each group reporting grade 3 or higher toxicity. A sustained and substantial improvement in overall survival of all metastatic prostate cancer patients was achieved with SOC + abiraterone acetate + prednisolone, irrespective of metastatic disease risk group

Differential Pathogenesis of Lung Adenocarcinoma Subtypes Involving Sequence Mutations, Copy Number, Chromosomal Instability, and Methylation

Lung adenocarcinoma (LAD) has extreme genetic variation among patients, which is currently not well understood, limiting progress in therapy development and research. LAD intrinsic molecular subtypes are a validated stratification of naturally-occurring gene expression patterns and encompass different functional pathways and patient outcomes. Patients may have incurred different mutations and alterations that led to the different subtypes. We hypothesized that the LAD molecular subtypes co-occur with distinct mutations and alterations in patient tumors.The LAD molecular subtypes (Bronchioid, Magnoid, and Squamoid) were tested for association with gene mutations and DNA copy number alterations using statistical methods and published cohorts (n = 504). A novel validation (n = 116) cohort was assayed and interrogated to confirm subtype-alteration associations. Gene mutation rates (EGFR, KRAS, STK11, TP53), chromosomal instability, regional copy number, and genomewide DNA methylation were significantly different among tumors of the molecular subtypes. Secondary analyses compared subtypes by integrated alterations and patient outcomes. Tumors having integrated alterations in the same gene associated with the subtypes, e.g. mutation, deletion and underexpression of STK11 with Magnoid, and mutation, amplification, and overexpression of EGFR with Bronchioid. The subtypes also associated with tumors having concurrent mutant genes, such as KRAS-STK11 with Magnoid. Patient overall survival, cisplatin plus vinorelbine therapy response and predicted gefitinib sensitivity were significantly different among the subtypes.The lung adenocarcinoma intrinsic molecular subtypes co-occur with grossly distinct genomic alterations and with patient therapy response. These results advance the understanding of lung adenocarcinoma etiology and nominate patient subgroups for future evaluation of treatment response

Processed pseudogenes acquired somatically during cancer development

Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5′ truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context