In Silico Approaches and the Role of Ontologies in Aging Research

The 2013 Rostock Symposium on Systems Biology and Bioinformatics in Aging Research was again dedicated to dissecting the aging process using in silico means. A particular focus was on ontologies, as these are a key technology to systematically integrate heterogeneous information about the aging process. Related topics were databases and data integration. Other talks tackled modeling issues and applications, the latter including talks focussed on marker development and cellular stress as well as on diseases, in particular on diseases of kidney and skin

Individual and national financial impacts of informal caring for people with mental illness in Australia, projected to 2030

Background Mental illness has a significant impact not only on patients, but also on their carers\u27 capacity to work. Aims To estimate the costs associated with lost labour force participation due to the provision of informal care for people with mental illness in Australia, such as income loss for carers and lost tax revenue and increased welfare payments for government, from 2015 to 2030. Method The output data of a microsimulation model Care&WorkMOD were analysed to project the financial costs of informal care for people with mental illness, from 2015 to 2030. Care&WorkMOD is a population-representative microsimulation model of the Australian population aged between 15 and 64 years, built using the Australian Bureau of Statistics Surveys of Disability, Ageing and Carers data and the data from other population-representative microsimulation models. Results The total annual national loss of income for all carers due to caring for someone with mental illness was projected to rise from AU$451 million (£219.6 million) in 2015 to AU$645 million (£314 million) in 2030 in real terms. For the government, the total annual lost tax revenue was projected to rise from AU$121 million (£58.9 million) in 2015 to AU$170 million (£82.8 million) in 2030 and welfare payments to increase from AU$170 million (£82.8 million) to AU$220 million (£107 million) in 2030. Conclusions The costs associated with lost labour force participation due to the provision of informal care for people with mental illness are projected to increase for both carers and government, with a widening income gap between informal carers and employed non-carers, putting carers at risk of increased inequality

Combined extracellular matrix cross-linking activity of the peroxidase MLT-7 and the dual oxidase BLI-3 is critical for post-embryonic viability in <i>Caenorhabditis elegans</i>

The nematode cuticle is a protective collagenous extracellular matrix that is modified, cross-linked, and processed by a number of key enzymes. This Ecdysozoan-specific structure is synthesized repeatedly and allows growth and development in a linked degradative and biosynthetic process known as molting. A targeted RNA interference screen using a cuticle collagen marker has been employed to identify components of the cuticle biosynthetic pathway. We have characterized an essential peroxidase, MoLT-7 (MLT-7), that is responsible for proper cuticle molting and re-synthesis. MLT-7 is an active, inhibitable peroxidase that is expressed in the cuticle-synthesizing hypodermis coincident with each larval molt. mlt-7 mutants show a range of body morphology defects, most notably molt, dumpy, and early larval stage arrest phenotypes that can all be complemented with a wild type copy of mlt-7. The cuticles of these mutants lacks di-tyrosine cross-links, becomes permeable to dye and accessible to tyrosine iodination, and have aberrant collagen protein expression patterns. Overexpression of MLT-7 causes mutant phenotypes further supporting its proposed enzymatic role. In combination with BLI-3, an H2O2-generating NADPH dual oxidase, MLT-7 is essential for post-embryonic development. Disruption of mlt-7, and particularly bli-3, via RNA interference also causes dramatic changes to the in vivo cross-linking patterns of the cuticle collagens DPY-13 and COL-12. This points toward a functionally cooperative relationship for these two hypodermally expressed proteins that is essential for collagen cross-linking and proper extracellular matrix formation

The Healthcare and Societal Costs of Familial Intellectual Disability

Most of the studies on the cost of intellectual disability are limited to a healthcare perspective or cohorts composed of individuals where the etiology of the condition is a mixture of genetic and non-genetic factors. When used in policy development, these can impact the decisions made on the optimal allocation of resources. In our study, we have developed a static microsimulation model to estimate the healthcare, societal, and lifetime cost of individuals with familial intellectual disability, an inheritable form of the condition, to families and government. The results from our modeling show that the societal costs outweighed the health costs (approximately 89.2% and 10.8%, respectively). The lifetime cost of familial intellectual disability is approximately AUD 7 million per person and AUD 10.8 million per household. The lifetime costs to families are second to those of the Australian Commonwealth government (AUD 4.2 million and AUD 9.3 million per household, respectively). These findings suggest that familial intellectual disability is a very expensive condition, representing a significant cost to families and government. Understanding the drivers of familial intellectual disability, especially societal, can assist us in the development of policies aimed at improving health outcomes and greater access to social care for affected individuals and their families

The impact of diabetes prevention on labour force participation and income of older Australians: an economic study

Background: Globally, diabetes is estimated to affect 246 million people and is increasing. In Australia diabetes has been made a national health priority. While the direct costs of treating diabetes are substantial, and rising, the indirect costs are considered greater. There is evidence that interventions to prevent diabetes are effective, and cost-effective, but the impact on labour force participation and income has not been assessed. In this study we quantify the potential impact of implementing a diabetes prevention program, using screening and either metformin or a lifestyle intervention on individual economic outcomes of pre-diabetic Australians aged 45-64. Methods. The output of an epidemiological microsimulation model of the reduction in prevalence of diabetes from a lifestyle or metformin intervention, and another microsimulation model, Health&WealthMOD, of health and the associated impacts on labour force participation, personal income, savings, government revenue and expenditure were used to quantify the estimated outcomes of the two interventions. Results: An additional 753 person years in the labour force would have been achieved from 1993 to 2003 for the male cohort aged 60-64 years in 2003, if a lifestyle intervention had been introduced in 1983; with 890 person years for the equivalent female group. The impact on labour force participation was lower for the metformin intervention, and increased with age for both interventions. The male cohort aged 60-64 years in 2003 would have earned an additional $30 million in income with the metformin intervention, and the equivalent female cohort would have earned an additional$25 million. If the lifestyle intervention was introduced, the same male and female cohorts would have earned an additional $34 million and$28 million respectively from 1993 to 2003. For the individuals involved, on average, males would have earned an additional $44,600 per year and females an additional$31,800 per year, if they had continued to work as a result of preventing diabetes. Conclusions: In addition to improved health and wellbeing, considerable benefits to individuals, in terms of both additional working years and increased personal income, could be made by introducing either a lifestyle or metformin intervention to prevent diabetes

Ribosomal oxygenases are structurally conserved from prokaryotes to humans

2-Oxoglutarate (2OG)-dependent oxygenases have important roles in the regulation of gene expression via demethylation of N-methylated chromatin components1,2 and in the hydroxylation of transcription factors3 and splicing factor proteins4. Recently, 2OG-dependent oxygenases that catalyse hydroxylation of transfer RNA5,6,7 and ribosomal proteins8 have been shown to be important in translation relating to cellular growth, TH17-cell differentiation and translational accuracy9,10,11,12. The finding that ribosomal oxygenases (ROXs) occur in organisms ranging from prokaryotes to humans8 raises questions as to their structural and evolutionary relationships. In Escherichia coli, YcfD catalyses arginine hydroxylation in the ribosomal protein L16; in humans, MYC-induced nuclear antigen (MINA53; also known as MINA) and nucleolar protein 66 (NO66) catalyse histidine hydroxylation in the ribosomal proteins RPL27A and RPL8, respectively. The functional assignments of ROXs open therapeutic possibilities via either ROX inhibition or targeting of differentially modified ribosomes. Despite differences in the residue and protein selectivities of prokaryotic and eukaryotic ROXs, comparison of the crystal structures of E. coli YcfD and Rhodothermus marinus YcfD with those of human MINA53 and NO66 reveals highly conserved folds and novel dimerization modes defining a new structural subfamily of 2OG-dependent oxygenases. ROX structures with and without their substrates support their functional assignments as hydroxylases but not demethylases, and reveal how the subfamily has evolved to catalyse the hydroxylation of different residue side chains of ribosomal proteins. Comparison of ROX crystal structures with those of other JmjC-domain-containing hydroxylases, including the hypoxia-inducible factor asparaginyl hydroxylase FIH and histone Nε-methyl lysine demethylases, identifies branch points in 2OG-dependent oxygenase evolution and distinguishes between JmjC-containing hydroxylases and demethylases catalysing modifications of translational and transcriptional machinery. The structures reveal that new protein hydroxylation activities can evolve by changing the coordination position from which the iron-bound substrate-oxidizing species reacts. This coordination flexibility has probably contributed to the evolution of the wide range of reactions catalysed by oxygenases

A novel COVID-19 program, delivering vaccines throughout rural and remote Australia

BackgroundThe Royal Flying Doctor Service of Australia (RFDS) established a unique SARS-CoV-2 vaccination program for vaccinating Australians that live in rural and remote areas. This paper describes the preparation and response phases of the RFDS response.MethodsThis study includes vaccinations conducted by the RFDS from 01 January 2021 until 31 December 2021 when vaccines were mandatory for work and social activities. Prior to each clinic, we conducted community consultation to determine site requirements, patient characteristics, expected vaccination numbers, and community transmission rates.FindingsNinety-five organizations requested support. The majority (n = 60; 63.2%) came from Aboriginal Community Controlled Health Organizations. Following consultation, 360 communities were approved for support. Actual vaccinations exceeded expectations (n = 70,827 vs. 49,407), with a concordance correlation coefficient of 0.88 (95% CI, 0.83, 0.93). Areas that reported healthcare workforce shortages during the preparation phase had the highest population proportion difference between expected and actual vaccinations. Areas that reported high vaccine hesitancy during the preparation phase had fewer than expected vaccines. There was a noticeable increase in vaccination rates in line with community outbreaks and positive polymerase chain reaction cases [r (41) = 0.35, p = 0.021]. Engagement with community leaders prior to clinic deployment was essential to provide a tailored response based on community expectations

Local- and large-scale drivers of variability in the coastal freshwater budget of the Western Antarctic Peninsula

The west Antarctic Peninsula (WAP) is a region of marked climatic variability, exhibiting strong changes in sea ice extent, retreat of most of its glaciers, and shifts in the amount and form of precipitation. These changes can have significant impacts on the oceanic freshwater budget and marine biogeochemical processes; it is thus important to ascertain the relative balance of the drivers, and the spatial scales over which they operate. We present a novel 7‐year summer‐season (October to March; 2011 to 2018) series of oxygen isotopes in seawater (δ18O), augmented with some winter sampling, collected adjacent to Anvers Island at the WAP. These data are used to attribute oceanic freshwater changes to sea ice and meteoric sources, and to deduce information on the spatial scales over which the changes are driven. Sea ice melt shows significant seasonality (∼9% range) and marked interannual changes, with pronounced maxima in seasons 2013/14 and 2016/17. Both of these extrema are driven by anomalous winds, but reflect strongly contrasting dynamic and thermodynamic sea ice responses. Meteoric water also shows seasonality (∼7% range), with interannual variability reflecting changes in the input of accumulated precipitation and glacial melt to the ocean. Unlike sea ice melt, meteoric water extremes are especially pronounced in thin (<10 m) surface layers close to the proximate glacier, associated with enhanced ocean stratification. Isotopic tracers help to deconvolve the complex spatio‐temporal scales inherent in the coastal freshwater budget, and hence improve knowledge of the separate and cumulative physical and ecological impacts

Mutation of von Hippel–Lindau Tumour Suppressor and Human Cardiopulmonary Physiology

BACKGROUND: The von Hippel–Lindau tumour suppressor protein–hypoxia-inducible factor (VHL–HIF) pathway has attracted widespread medical interest as a transcriptional system controlling cellular responses to hypoxia, yet insights into its role in systemic human physiology remain limited. Chuvash polycythaemia has recently been defined as a new form of VHL-associated disease, distinct from the classical VHL-associated inherited cancer syndrome, in which germline homozygosity for a hypomorphic VHL allele causes a generalised abnormality in VHL–HIF signalling. Affected individuals thus provide a unique opportunity to explore the integrative physiology of this signalling pathway. This study investigated patients with Chuvash polycythaemia in order to analyse the role of the VHL–HIF pathway in systemic human cardiopulmonary physiology. METHODS AND FINDINGS: Twelve participants, three with Chuvash polycythaemia and nine controls, were studied at baseline and during hypoxia. Participants breathed through a mouthpiece, and pulmonary ventilation was measured while pulmonary vascular tone was assessed echocardiographically. Individuals with Chuvash polycythaemia were found to have striking abnormalities in respiratory and pulmonary vascular regulation. Basal ventilation and pulmonary vascular tone were elevated, and ventilatory, pulmonary vasoconstrictive, and heart rate responses to acute hypoxia were greatly increased. CONCLUSIONS: The features observed in this small group of patients with Chuvash polycythaemia are highly characteristic of those associated with acclimatisation to the hypoxia of high altitude. More generally, the phenotype associated with Chuvash polycythaemia demonstrates that VHL plays a major role in the underlying calibration and homeostasis of the respiratory and cardiovascular systems, most likely through its central role in the regulation of HIF