Intragenic repeat expansion in the cell wall protein gene HPF1 controls yeast chronological aging

Aging varies among individuals due to both genetics and environment, but the underlying molecular mechanisms remain largely unknown. Using a highly recombined Saccharomyces cerevisiae population, we found 30 distinct quantitative trait loci (QTLs) that control chronological life span (CLS) in calorie-rich and calorie-restricted environments and under rapamycin exposure. Calorie restriction and rapamycin extended life span in virtually all genotypes but through different genetic variants. We tracked the two major QTLs to the cell wall glycoprotein genes FLO11 and HPF1. We found that massive expansion of intragenic tandem repeats within the N-terminal domain of HPF1 was sufficient to cause pronounced life span shortening. Life span impairment by HPF1 was buffered by rapamycin but not by calorie restriction. The HPF1 repeat expansion shifted yeast cells from a sedentary to a buoyant state, thereby increasing their exposure to surrounding oxygen. The higher oxygenation altered methionine, lipid, and purine metabolism, and inhibited quiescence, which explains the life span shortening. We conclude that fast-evolving intragenic repeat expansions can fundamentally change the relationship between cells and their environment with profound effects on cellular lifestyle and longevity

A frame-shift mutation in COMTD1 is associated with impaired pheomelanin pigmentation in chicken

Author summaryVertebrates possess two types of melanin, red/yellow pheomelanin and black/brown eumelanin. In this study, we report that the recessive Inhibitor of gold phenotype in chicken, which causes a severe defect in pheomelanin pigmentation, is associated with a mutation that most likely inactivates the COMTD1 gene. This gene encodes an O-methyltransferase enzyme and is present throughout vertebrate evolution, but is one of the many genes in vertebrate genomes for which the biological function is still poorly understood. This is the first report of a COMTD1 mutation associated with a phenotypic effect. We show that the COMTD1 protein is present in mitochondria in pigment cells. Furthermore, inactivation of the gene in a mouse pigment cell line results in a significant reduction in metabolites that are important for the synthesis of pheomelanin. We hypothesize that COMTD1 activity protects pigment cells from oxidative stress and that inactivation of this function impairs the production of pheomelanin. It is likely that COMTD1 has a similar function in other cell types. This study establishes this chicken mutation as a model for further studies of COMTD1 function.The biochemical pathway regulating the synthesis of yellow/red pheomelanin is less well characterized than the synthesis of black/brown eumelanin. Inhibitor of gold (IG phenotype) is a plumage colour variant in chicken that provides an opportunity to further explore this pathway since the recessive allele (IG) at this locus is associated with a defect in the production of pheomelanin. IG/IG homozygotes display a marked dilution of red pheomelanin pigmentation, whilst black pigmentation (eumelanin) is only slightly affected. Here we show that a 2-base pair insertion (frame-shift mutation) in the 5(th) exon of the Catechol-O-methyltransferase containing domain 1 gene (COMTD1), expected to cause a complete or partial loss-of-function of the COMTD1 enzyme, shows complete concordance with the IG phenotype within and across breeds. We show that the COMTD1 protein is localized to mitochondria in pigment cells. Knockout of Comtd1 in a mouse melanocytic cell line results in a reduction in pheomelanin metabolites and significant alterations in metabolites of glutamate/glutathione, riboflavin, and the tricarboxylic acid cycle. Furthermore, COMTD1 overexpression enhanced cellular proliferation following chemical-induced transfection, a potential inducer of oxidative stress. These observations suggest that COMTD1 plays a protective role for melanocytes against oxidative stress and that this supports their ability to produce pheomelanin

Not just bricks and mortar: planning hospital cancer services for Aboriginal people

<p>Abstract</p> <p>Background</p> <p>Aboriginal people in Australia experience higher mortality from cancer compared with non-Aboriginal Australians, despite an overall lower incidence. A notable contributor to this disparity is that many Aboriginal people do not take up or continue with cancer treatment which almost always occurs within major hospitals.</p> <p>Thirty in-depth interviews with urban, rural and remote Aboriginal people affected by cancer were conducted between March 2006 and September 2007. Interviews explored participants' beliefs about cancer and experiences of cancer care and were audio-recorded, transcribed verbatim and coded independently by two researchers. NVivo7 software was used to assist data management and analysis. Information from interviews relevant to hospital services including and building design was extracted.</p> <p>Findings</p> <p>Relationships and respect emerged as crucial considerations of participants although many aspects of the hospital environment were seen as influencing the delivery of care. Five themes describing concerns about the hospital environment emerged: (i) being alone and lost in a big, alien and inflexible system; (ii) failure of open communication, delays and inefficiency in the system; (iii) practicalities: costs, transportation, community and family responsibilities; (iv) the need for Aboriginal support persons; and (v) connection to the community.</p> <p>Conclusions</p> <p>Design considerations and were identified but more important than the building itself was the critical need to build trust in health services. Promotion of cultural safety, support for Aboriginal family structures and respecting the importance of place and community to Aboriginal patients are crucial in improving cancer outcomes.</p

The ocean sampling day consortium

Ocean Sampling Day was initiated by the EU-funded Micro B3 (Marine Microbial Biodiversity, Bioinformatics, Biotechnology) project to obtain a snapshot of the marine microbial biodiversity and function of the world’s oceans. It is a simultaneous global mega-sequencing campaign aiming to generate the largest standardized microbial data set in a single day. This will be achievable only through the coordinated efforts of an Ocean Sampling Day Consortium, supportive partnerships and networks between sites. This commentary outlines the establishment, function and aims of the Consortium and describes our vision for a sustainable study of marine microbial communities and their embedded functional traits

Contribution of Recipient-Derived Cells in Allograft Neointima Formation and the Response to Stent Implantation

Allograft coronary disease is the dominant cause of increased risk of death after cardiac transplantation. While the percutaneous insertion of stents is the most efficacious revascularization strategy for allograft coronary disease there is a high incidence of stent renarrowing. We developed a novel rabbit model of sex-mismatched allograft vascular disease as well as the response to stent implantation. In situ hybridization for the Y-chromosome was employed to detect male cells in the neointima of stented allograft, and the population of recipient derived neointimal cells was measured by quantitative polymerase chain reaction and characterized by immunohistochemistry. To demonstrate the participation of circulatory derived cells in stent neointima formation we infused ex vivo labeled peripheral blood mononuclear cells into native rabbit carotid arteries immediately after stenting. Fourteen days after stenting the neointima area was 58% greater in the stented vs. non-stented allograft segments (p = 0.02). Male cells were detected in the neointima of stented female-to-male allografts. Recipient-derived cells constituted 72.1±5.7% and 81.5±4.2% of neointimal cell population in the non-stented and stented segments, respectively and the corresponding proliferation rates were only 2.7±0.5% and 2.3±0.2%. Some of the recipient-derived neointimal cells were of endothelial lineage. The ex vivo tagged cells constituted 9.0±0.4% of the cells per high power field in the stent neointima 14 days after stenting. These experiments provide important quantitative data regarding the degree to which host-derived blood-borne cells contribute to neointima formation in allograft vasculopathy and the early response to stent implantation

The role of the cerebellum in multiple sclerosis—150 years after Charcot

Despite its functional importance and well known clinical impact in Multiple Sclerosis (MS), the cerebellum has only received significant attention over the past few years. It is now established that the cerebellum plays a key role not only in various sensory-motor networks, but also in cognitive-behavioural processes, domains primarily affected in patients with MS. Evidence from histopathological and magnetic resonance imaging (MRI) studies on cerebellar involvement in MS is increasingly available, however linking these pathological findings with clinical dysfunction remains challenging. There are promising advances in technology that are likely to improve the detection of pathological changes within the cerebellum, which may elucidate how pathology relates to disability

Ten facts about land systems for sustainability

Land use is central to addressing sustainability issues, including biodiversity conservation, climate change, food security, poverty alleviation, and sustainable energy. In this paper, we synthesize knowledge accumulated in land system science, the integrated study of terrestrial social-ecological systems, into 10 hard truths that have strong, general, empirical support. These facts help to explain the challenges of achieving sustainability in land use and thus also point toward solutions. The 10 facts are as follows: 1) Meanings and values of land are socially constructed and contested; 2) land systems exhibit complex behaviors with abrupt, hard-to-predict changes; 3) irreversible changes and path dependence are common features of land systems; 4) some land uses have a small footprint but very large impacts; 5) drivers and impacts of land-use change are globally interconnected and spill over to distant locations; 6) humanity lives on a used planet where all land provides benefits to societies; 7) land-use change usually entails trade-offs between different benefits—"win–wins" are thus rare; 8) land tenure and land-use claims are often unclear, overlapping, and contested; 9) the benefits and burdens from land are unequally distributed; and 10) land users have multiple, sometimes conflicting, ideas of what social and environmental justice entails. The facts have implications for governance, but do not provide fixed answers. Instead they constitute a set of core principles which can guide scientists, policy makers, and practitioners toward meeting sustainability challenges in land use

Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: r(g) = 0.098, p = 2.3 x 10(-8)) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: r(g) = 0.137, p = 2.0 x 10(-12)). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis

Obesity, Metabolic Factors and Risk of Different Histological Types of Lung Cancer: A Mendelian Randomization Study

Background: Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. Methods and findings: We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01–1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15–2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79–1.08]) (Pheterogeneity = 4.3x10-3). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10-3), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95%CI] = 0.90 [0.84–0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95%CI] = 1.63 [1.25–2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. Conclusions: Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior