Heavy-load exercise in older adults activates vasculogenesis and has a stronger impact on muscle gene expression than in young adults

This is the final version. Available on open access from BMC via the DOI in this recordAvailability of data and materials: Microarray data from the BSU cohort have been submitted to the GEO database (www.ncbi.nlm.nih.gov/geo/): GSE28422, GSE28392, and GSE25941. Microarray data from the Oslo cohort is available on request.BACKGROUND: A striking effect of old age is the involuntary loss of muscle mass and strength leading to sarcopenia and reduced physiological functions. However, effects of heavy-load exercise in older adults on diseases and functions as predicted by changes in muscle gene expression have been inadequately studied. METHODS: Thigh muscle global transcriptional activity (transcriptome) was analyzed in cohorts of older and younger adults before and after 12-13 weeks heavy-load strength exercise using Affymetrix microarrays. Three age groups, similarly trained, were compared: younger adults (age 24 ± 4 years), older adults of average age 70 years (Oslo cohort) and above 80 years (old BSU cohort). To increase statistical strength, one of the older cohorts was used for validation. Ingenuity Pathway analysis (IPA) was used to identify predicted biological effects of a gene set that changed expression after exercise, and Principal Component Analysis (PCA) was used to visualize differences in muscle gene expressen between cohorts and individual participants as well as overall changes upon exercise. RESULTS: Younger adults, showed few transcriptome changes, but a marked, significant impact was observed in persons of average age 70 years and even more so in persons above 80 years. The 249 transcripts positively or negatively altered in both cohorts of older adults (q-value < 0.1) were submitted to gene set enrichment analysis using IPA. The transcripts predicted increase in several aspects of "vascularization and muscle contractions", whereas functions associated with negative health effects were reduced, e.g., "Glucose metabolism disorder" and "Disorder of blood pressure". Several genes that changed expression after intervention were confirmed at the genome level by containing single nucleotide variants associated with handgrip strength and muscle expression levels, e.g., CYP4B1 (p = 9.2E-20), NOTCH4 (p = 9.7E-8), and FZD4 (p = 5.3E-7). PCA of the 249 genes indicated a differential pattern of muscle gene expression in young and elderly. However, after exercise the expression patterns in both young and old BSU cohorts were changed in the same direction for the vast majority of participants. CONCLUSIONS: The positive impact of heavy-load strength training on the transcriptome increased markedly with age. The identified molecular changes translate to improved vascularization and muscular strength, suggesting highly beneficial health effects for older adults.South East Norway Health AuthorityOslo University Hospital, Ullevaal6th EU Framework ProgramLegat til Forskning, Lovisenberg Diaconal HospitalNational Institutes of Health (NIH)Eli Lilly and Compan

Policy relevant Results from an Expert Elicitation on the Human Health Risks of Decabromodiphenyl ether (decaBDE) and Hexabromocyclododecane (HBCD)

Aim: Apply a recently developed expert elicitation procedure to evaluate the state of the current knowledge of the two brominated flame retardants (BFRs) most commonly used today; decabromo-diphenyl ether (decaBDE) and hexabromocyclododecane (HBCD) and their potential impact on human health in order to support policy considerations. This expert elicitation was organized by the HENVINET (Health and Environment Network) Consortium. Method: The HENVINET expert elicitation procedure that was used in the evaluations of decaBDE and HBCD is a rapid assessment tool aimed at highlighting areas of agreement and areas of disagreement on knowledge-related key issues for environment and health policy decision making. Results: The outcome of the expert consultation on BFRs was concrete expert advice for policy makers with specific priorities for further action made clear for both stakeholders and policy makers. The experts were not in agreement whether or not the knowledge currently available on decaBDE or HBCD is sufficient to justify policy actions, but most experts considered that enough data already exists to support a ban or restriction on the use of these compounds. All experts agreed on the necessity of more research on the compounds. Priority issues for further research were, among others: more studies on the extent of human exposure to the compounds. more studies on the fate and concentration in the human body of the compounds

Regulation of Translation in Haloarchaea: 5′- and 3′-UTRs Are Essential and Have to Functionally Interact In Vivo

Recently a first genome-wide analysis of translational regulation using prokaryotic species had been performed which revealed that regulation of translational efficiency plays an important role in haloarchaea. In fact, the fractions of genes under differential growth phase-dependent translational control in the two species Halobacterium salinarum and Haloferax volcanii were as high as in eukaryotes. However, nothing is known about the mechanisms of translational regulation in archaea. Therefore, two genes exhibiting opposing directions of regulation were selected to unravel the importance of untranslated regions (UTRs) for differential translational control in vivo

The PlcR Virulence Regulon of Bacillus cereus

PlcR is a Bacillus cereus transcriptional regulator, which activates gene expression by binding to a nucleotidic sequence called the ‘PlcR box’. To build a list of all genes included in the PlcR regulon, a consensus sequence was identified by directed mutagenesis. The reference strain ATCC14579 sequenced genome was searched for occurrences of this consensus sequence to produce a virtual regulon. PlcR control of these genes was confirmed by comparing gene expression in the reference strain and its isogenic Δ-plcR strain using DNA microarrays, lacZ fusions and proteomics methods. The resulting list included 45 genes controlled by 28 PlcR boxes. Forty of the PlcR controlled proteins were exported, of which 22 were secreted in the extracellular medium and 18 were bound or attached to cell wall structures (membrane or peptidoglycan layer). The functions of these proteins were related to food supply (phospholipases, proteases, toxins), cell protection (bacteriocins, toxins, transporters, cell wall biogenesis) and environment-sensing (two-component sensors, chemotaxis proteins, GGDEF family regulators). Four genes coded for cytoplasmic regulators. The PlcR regulon appears to integrate a large range of environmental signals, including food deprivation and self cell-density, and regulate the transcription of genes designed to overcome obstacles that hinder B. cereus growth within the host: food supply, host barriers, host immune defenses, and competition with other bacterial species. PlcR appears to be a key component in the efficient adaptation of B. cereus to its host environment

HENVINET. Evaluation questionnaire - causal chain for phthalates.

The HENVINET consortium has developed a questionnaire to identify knowledge gaps in the state of the art in scientific knowledge. Literature reviews covered all elements that compose the causal chain of the different environmental health issues from emissions to exposures, to effects and to health impacts. Ultimately, the aim is to discuss the implications of these for policy and research. In this evaluation we focus on the cause¿effect relationship between phthalates in the environment and endocrine disruption in humans. The questionnaire consists of two separate parts. In Part A, you will be asked to comments on the completeness and structure of a diagram illustrating our current understanding of the cause¿effect relationship. In Part B, you will be asked to express your level of confidence in the scientists¿ ability to predict the magnitude of a variety of effects of phthalates in the environment

We’re only in it for the knowledge? : a problem solving turn in environment and health expert elicitation

Background: The FP6 EU HENVINET project aimed at synthesizing the scientific information available on a number of topics of high relevance to policy makers in environment and health. The goal of the current paper is to reflect on the methodology that was used in the project, in view of exploring the usefulness of this and similar methodologies to the policy process. The topics investigated included health impacts of the brominated flame retardants decabrominated diphenylether (decaBDE) and hexabromocyclododecane (HBCD), phthalates highlighting di(2-ethylhexyl)phthalate (DEHP), the pesticide chlorpyrifos (CPF), nanoparticles, the impacts of climate change on asthma and other respiratory disorders, and the influence of environment health stressors on cancer induction. Methods: Initially the focus was on identifying knowledge gaps in the state of the art in scientific knowledge. Literature reviews covered all elements that compose the causal chain of the different environmental health issues from emissions to exposures, to effects and to health impacts. Through expert elicitation, knowledge gaps were highlighted by assessing expert confidence using calibrated confidence scales. During this work a complementary focus to that on knowledge gaps was developed through interdisciplinary reflections. By extending the scope of the endeavour from only a scientific perspective, to also include the more problem solving oriented policy perspective, the question of which kind of policy action experts consider justifiable was addressed. This was addressed by means of a questionnaire. In an expert workshop the results of both questionnaires were discussed as a basis for policy briefs. Results: The expert elicitation, the application of the calibrated confidence levels and the problem solving approach were all experienced as being quite challenging for the experts involved, as these approaches did not easily relate to mainstream environment and health scientific practices. Even so, most experts were quite positive about it. In particular, the opportunity to widen one's own horizon and to interactively exchange knowledge and debate with a diversity of experts seemed to be well appreciated in this approach. Different parts of the approach also helped in focussing on specific relevant aspects of scientific knowledge, and as such can be considered of reflective value. Conclusions: The approach developed by HENVINET was part of a practice of learning by doing and of interdisciplinary cooperation and negotiation. Ambitions were challenged by unforeseen complexities and difference of opinion and as no Holy Grail approach was at hand to copy or follow, it was quite an interesting but also complicated endeavour. Perfection, if this could be defined, seemed out of reach all the time. Nevertheless, many involved were quite positive about it. It seems that many felt that it fitted some important needs in current science when addressing the needs of policy making on such important issues, without anyone really having a clue on how to actually do this. Challenging questions remain on the quality of such approach and its product. Practice tells us that there probably is no best method and that the best we can do is dependent on contextual negotiation and learning from experiences that we think are relevant