Universal DNA methylation age across mammalian tissues.

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.

Objectively Assessing the Effect of a Messenger-based Intervention to Reduce Sedentary Behavior in University Students: A Pilot Study.

AIM: Sedentary behavior poses a serious health risk. Students in particular are highly affected by prolonged, uninterrupted periods of sitting due to routines in everyday university life, such as attending lectures, self-study periods in the library, etc. Whereas university students are mostly young and therefore appear to be healthy, evidence-based consequences of prolonged sitting may come to pass in prospective times. Therefore, primary prevention must be initiated to shield university students from the occurrence of non-communicable diseases (NCDs). Consequently, the study aims to evaluate a messenger-based intervention designed to reduce sedentary time among university students. SUBJECTS AND METHODS: The effectiveness of the intervention was assessed in a randomized controlled trial with a convenience sample of thirty-four German university students. ActivPal devices (Pal Technologies Ltd., Glasgow) were applied to measure sedentary behavior objectively before and after a 3-week intervention of messages to interrupt sedentary time. An additional evaluation of the messages was carried out. RESULTS: Sedentary behavior decreased by about one hour in the intervention group. Explorative analysis shows a statistically significant, negative correlation between sedentary time at baseline and the change of sedentary behavior over time in the intervention group (r = - .81) indicating effectiveness of the intervention for the participants with the highest sedentary times at baseline. Additionally, the messages were considered appropriate by the participants. CONCLUSION: A reduction of sedentary time of one hour per day in the intervention group is practically significant. The current investigation had similar findings with prior studies where promising results for the reduction of sedentary behavior were observed through mobile-based interventions. The detected effects of the intervention in this pilot study demonstrate an opportunity for further research in this field.

Transcriptomic response and immunological responses to chimpanzee adenovirus- and MVA viral-vectored vaccines for RSV in healthy adults.

Cohorts of healthy younger adults (18-50yrs) and healthy older adults (60-75yrs) were immunized intramuscularly or intranasally with an adenovirus-vectored RSV vaccine (PanAd3-RSV) as a prime dose and boosted with PanAd3-RSV or a poxvirus-vectored vaccine (MVA-RSV) encoding the same insert. Whole blood gene expression was measured at baseline, 3- and 7-days post vaccination. Intramuscular prime vaccination with PanAd3-RSV induced differential expression of 643 genes (DEGs, FDR < 0.05). Intranasal prime vaccination with PanAd3-RSV did not induce any differentially expressed genes (DEGs) in blood samples at 3 days post vaccination. Intranasally primed participants showed greater numbers of DEGS on boosting than intramuscularly primed participants. The most highly enriched biological processes related to DEGs after both prime and boost vaccination were type-1 interferon related pathways, lymphocytic and humoral immune responses.

A novel meningococcal outer membrane vesicle vaccine with constitutive expression of FetA: A phase I clinical trial.

OBJECTIVES: Outer membrane vesicle (OMV) vaccines are used against outbreaks of capsular group B Neisseria meningitidis (MenB) caused by strains expressing particular PorA outer membrane proteins (OMPs). Ferric enterobactin receptor (FetA) is another variable OMP that induces type-specific bactericidal antibodies, and the combination of judiciously chosen PorA and FetA variants in vaccine formulations is a potential approach to broaden protection of such vaccines. METHODS: The OMV vaccine MenPF-1 was generated by genetically modifying N. meningitidis strain 44/76 to constitutively express FetA. Three doses of 25 µg or 50 µg of MenPF-1 were delivered intra-muscularly to 52 healthy adults. RESULTS: MenPF-1 was safe and well tolerated. Immunogenicity was measured by serum bactericidal assay (SBA) against wild-type and isogenic mutant strains. After 3 doses, the proportion of volunteers with SBA titres ≥1:4 (the putative protective titre) was 98% for the wild-type strain, and 77% for the strain 44/76 FetA(on)PorA(off) compared to 51% in the strain 44/76 FetA(off)PorA(off), demonstrating that vaccination with MenPF-1 simultaneously induced FetA and PorA bactericidal antibodies. CONCLUSION: This study provides a proof-of-concept for generating bactericidal antibodies against FetA after OMV vaccination in humans. Prevalence-based choice of PorA and FetA types can be used to formulate a vaccine for broad protection against MenB disease.

Freedom from Echinococcus multilocularis: an Irish perspective.

Echinococcus multilocularis, an emerging zoonotic disease is extending its geographical distribution within the European Union (EU). At present, five member states including Ireland are considered free. Previous EU regulations on importing domestic pets allowed these countries to maintain national rules that required all dogs be treated with an anti-cestode compound before entry. The controls on the movement of pet animals within the EU were recently reviewed by the European Commission and it was decided that the five countries had to demonstrate freedom from E. multilocularis before they could continue with the mandatory tapeworm treatment. The intestines of 220, 307 and 216 foxes were examined, using the sedimentation and counting technique, for the presence of E. multilocularis in 2003, 2009 and 2010 respectively. There was no evidence of the parasite in the foxes. These data together with the negative results from 130 foxes examined by other workers during 1999 and 2000 (Wolfe et al., 2001) were used to estimate the probability of freedom using scenario trees. The result of the model suggested that the probability that Ireland was free from E. multilocularis in 2010 was high, 0.98 (95% confidence interval, 0.94-1.00), thus justifying the retention of the mandatory tapeworm treatment for dogs entering the country from other EU member states.

The prevalence and distribution of Alaria alata, a potential zoonotic parasite, in foxes in Ireland.

The digenean trematode Alaria alata, an intestinal parasite of wild canids is widely distributed in Europe. The recent finding of the mesocercarial life cycle stage in the paratenic wild boar host suggests that it may potentially infect humans Mohl et al. (Parasitol Res 105:1-15, 2009). Over 500 foxes were examined during a wildlife survey for zoonotic diseases in 2009 and 2010. The prevalence of A. alata ranged from 21% to 26% in 2009 and 2010, and the intensity of infection varied, with the majority of foxes having between one and ten trematodes, but a small number of animals had parasitic burdens greater than 500. The location of foxes was geo-referenced and mapped using a geographic information system. The results of the spatial analysis suggest that A. alata may have a limited distribution being confined mainly to areas of pasture especially in the central plain and north Munster. Hot spot analysis indicated a clustering and that the level of parasitism was greatest in foxes from those areas where the prevalence of infection was highest.

Genetic influence on the kinetics and associated pathology of the early stage (intestinal-hepatic) migration of Ascaris suum in mice.

The generative mechanism(s) of aggregation and predisposition to Ascaris lumbricoides and A. suum infections in their host population are currently unknown and difficult to elucidate in humans and pigs for ethical/logistical reasons. A recently developed, optimized murine model based on 2 inbred strains, putatively susceptible (C57BL/6j) and resistant (CBA/Ca) to infection, was exploited to elucidate further the basis of the contrasting parasite burdens, most evident at the pulmonary stage. We explored the kinetics of early infection, focusing on the composite lobes of the liver and lung, over the first 8 days in an effort to achieve a more detailed understanding of the larval dispersal over time and the point at which worm burdens diverge. Larval recoveries showed a heterogenous distribution among the lobes of the lungs, being higher in the right lung of both strains, and in the susceptible strain larvae accumulating preferentially in 2 (caudal and middle) of the 4 lobes. Total larval burdens in these 2 lobes were largely responsible for the higher worm burdens in the susceptible strain. While total lung larval recoveries significantly differed between mouse strains, a difference in liver larval burdens was not observed. However, an earlier intense inflammatory response coupled with more rapid tissue repair in the hepatic lobes was observed in CBA/Ca mice, in contrast to C57BL/6j mice, and it is possible that these processes are responsible for restricting onward pulmonary larval migration in the resistant genotype.

Neuronal migration defect: a case of subcortical heterotopia in a California sea lion.

A 2 and a half-year-old male California sea lion (Zalophus californianus) presented with a history of intermittent generalized seizures. Magnetic resonance imaging revealed a large focal mass occupying the right cerebral hemisphere with moderate dilatation of the contralateral lateral ventricle. At necropsy, the right cerebral hemispheric white matter was expanded by numerous irregularly shaped, pale pink nodules up to 10 mm in diameter. The overlying cortex was characterized by increased numbers of small, poorly developed gyri with shallow, often indistinct, sulci (polymicrogyria). Microscopically, nodules were composed of neurons, oligodendroglia, microglia, and supporting neuropil and were well delineated from the surrounding white matter. The gross, histological, and immunohistochemical features of this lesion are consistent with a neuronal migration defect resulting in unilateral subcortical heterotopia.

Magnetic resonance imaging of freely moving objects: prospective real-time motion correction using an external optical motion tracking system.

Subject motion and associated artefacts limit the applicability of MRI and the achievable quality of the images acquired. In this paper, a fully integrated method for prospective correction of arbitrary rigid body motion employing an external motion tracking device is demonstrated for the first time. The position of the imaging volume is updated prior to every excitation of the spin system. The performance of the available tracking hardware and its connection to the MR imager is analyzed in detail. With the introduction of a novel calibration procedure the accuracy of motion correction is improved compared to previous approaches. Together with the high geometry update rate even freely moving objects can be imaged without motion related artefacts. The high performance and image quality improvement in case of subject motion are demonstrated for various imaging techniques such as gradient and spin echo, as well as echo planar imaging.

Escherichia coli hemolysin and Staphylococcus aureas alpha-toxin potently induce neutrophil adhesion to cultured human endothelial cells.

Adhesion of polymorphonuclear leukocytes (PMN) to endothelial cells is an essential step in inflammatory reactions. We characterized the effects of two important bacterial exotoxins, Escherichia coli hemolysin (HlyA) and Staphylococcus aureus alpha-toxin (S. alpha-toxin) on PMN adhesion to cultured HUVEC. Both toxins increased adherence of human PMN to HUVEC in a dose- and time-dependent manner, peaking after 30 min at 0.01 hemolytic units/ml HlyA or 0.5 microg/ml S. alpha-toxin. Pretreatment of HUVEC with anti-P-selectin mAbs or of PMN with anti-CD11b/CD18 mAb reduced HlyA- and S. alpha-toxin-related cell adhesion significantly. Increased P-selectin expression on toxin-treated endothelial cells was demonstrated by cell surface ELISA. Compared with endotoxin, HlyA and S. alpha-toxin did not induce the expression of E-selectin, ICAM-1, or VCAM-1. FACS analysis showed increased CD11b/CD18 expression on HlyA-, but not on S. alpha-toxin-stimulated PMN. Platelet-activating factor, an important costimulatory factor for PMN adhesion and activation, was also active in the exotoxin-stimulated adhesion system, as evidenced by studies using the platelet-activating factor receptor antagonist BN50727. HPLC analysis of endothelial cell extracts confirmed enhanced toxin-mediated PAF synthesis. The capacity of exotoxins to stimulate PMN adhesion to endothelial cells may be relevant in patients with severe local or systemic bacterial infections.