SIRT1 Activity Is Linked to Its Brain Region-Specific Phosphorylation and Is Impaired in Huntington’s Disease Mice

Huntingtons disease (HD) is a neurodegenerative disorder for which there are no disease-modifying treatments. SIRT1 is a NAD+-dependent protein deacetylase that is implicated in maintaining neuronal health during development, differentiation and ageing. Previous studies suggested that the modulation of SIRT1 activity is neuroprotective in HD mouse models, however, the mechanisms controlling SIRT1 activity are unknown. We have identified a striatum-specific phosphorylation-dependent regulatory mechanism of SIRT1 induction under normal physiological conditions, which is impaired in HD. We demonstrate that SIRT1 activity is down-regulated in the brains of two complementary HD mouse models, which correlated with altered SIRT1 phosphorylation levels. This SIRT1 impairment could not be rescued by the ablation of DBC1, a negative regulator of SIRT1, but was linked to changes in the sub-cellular distribution of AMPK-α1, a positive regulator of SIRT1 function. This work provides insights into the regulation of SIRT1 activity with the potential for the development of novel therapeutic strategies

Outstanding Issues in Solar Dynamo Theory

The magnetic activity of the Sun, as manifested in the sunspot cycle, originates deep within its convection zone through a dynamo mechanism which involves non-trivial interactions between the plasma and magnetic field in the solar interior. Recent advances in magnetohydrodynamic dynamo theory have led us closer towards a better understanding of the physics of the solar magnetic cycle. In conjunction, helioseismic observations of large-scale flows in the solar interior has now made it possible to constrain some of the parameters used in models of the solar cycle. In the first part of this review, I briefly describe this current state of understanding of the solar cycle. In the second part, I highlight some of the outstanding issues in solar dynamo theory related to the the nature of the dynamo $\alpha$-effect, magnetic buoyancy and the origin of Maunder-like minima in activity. I also discuss how poor constraints on key physical processes such as turbulent diffusion, meridional circulation and turbulent flux pumping confuse the relative roles of these vis-a-vis magnetic flux transport. I argue that unless some of these issues are addressed, no model of the solar cycle can claim to be ``the standard model'', nor can any predictions from such models be trusted; in other words, we are still not there yet.Comment: To appear in "Magnetic Coupling between the Interior and the Atmosphere of the Sun", eds. S.S. Hasan and R.J. Rutten, Astrophysics and Space Science Proceedings, Springer-Verlag, Heidelberg, Berlin, 200

The devil is in the detail:tobacco industry political influence in the Dutch implementation of the 2001 EU Tobacco Products Directive

Introduction - The Dutch implementation of the black border provision in the 2001 European Union Tobacco Products Directive (TPD) is studied to examine the implications of tobacco industry involvement in the implementation phase of the policy process. Methods - A qualitative analysis was conducted of Dutch government documents obtained through Freedom of Information Act requests, triangulated with in-depth interviews with key informants and secondary data sources (publicly available government documents, scientific literature, and news articles). Results - Tobacco manufacturers’ associations were given the opportunity to set implementation specifications via a fast-track deal with the government. The offer of early implementation of the labelling section of the TPD was used as political leverage by the industry, and underpinned by threats of litigation and arguments highlighting the risks of additional public costs and the benefits to the government of expediency and speed. Ultimately, the government agreed to the industry's interpretation, against the advice of the European Commission. Conclusions - The findings highlight the policy risks associated with corporate actors’ ability to use interactions over technical product specifications to influence the implementation of health policy and illustrate the difficulties in limiting industry interference in accordance with Article 5.3 of the Framework Convention on Tobacco Control (FCTC). The implementation phase is particularly vulnerable to industry influence, where negotiation with industry actors may be unavoidable and the practical implications of relatively technical considerations are not always apparent to policymakers. During the implementation of the new TPD 2014/40/EU, government officials are advised to take a proactive role in stipulating technical specifications

Consanguinity and rare mutations outside of MCCC genes underlie nonspecific phenotypes of MCCD

Purpose: 3-Methylcrotonyl-CoA carboxylase deficiency (MCCD) is an autosomal recessive disorder of leucine catabolism that has a highly variable clinical phenotype, ranging from acute metabolic acidosis to nonspecific symptoms such as developmental delay, failure to thrive, hemiparesis, muscular hypotonia, and multiple sclerosis. Implementation of newborn screening for MCCD has resulted in broadening the range of phenotypic expression to include asymptomatic adults. The purpose of this study was to identify factors underlying the varying phenotypes of MCCD. Methods: We performed exome sequencing on DNA from 33 cases and 108 healthy controls. We examined these data for associations between either MCC mutational status, genetic ancestry, or consanguinity and the absence or presence/specificity of clinical symptoms in MCCD cases. Results: We determined that individuals with nonspecific clinical phenotypes are highly inbred compared with cases that are asymptomatic and healthy controls. For 5 of these 10 individuals, we discovered a homozygous damaging mutation in a disease gene that is likely to underlie their nonspecific clinical phenotypes previously attributed to MCCD. Conclusion: Our study shows that nonspecific phenotypes attributed to MCCD are associated with consanguinity and are likely not due to mutations in the MCC enzyme but result from rare homozygous mutations in other disease genes

Inflammation causes tissue-specific depletion of vitamin B(6)

Previously we observed strong and consistent associations between vitamin B(6 )status and several indicators of inflammation in patients with rheumatoid arthritis. Clinical indicators, including the disability score, the length of morning stiffness, and the degree of pain, and biochemical markers, including the erythrocyte sedimentation rate and C-reactive protein levels, were found to be inversely correlated with circulating vitamin B(6 )levels. Such strong associations imply that impaired vitamin B(6 )status in these patients results from inflammation. In the present study we examined whether inflammation directly alters vitamin B(6 )tissue contents and its excretion in vivo. A cross-sectional case-controlled human clinical trial was performed in parallel with experiments in an animal model of inflammation. Plasma and erythrocyte and pyridoxal 5'-phosphate concentrations, urinary 4-pyridoxic acid excretion, and the activity coefficient of erythrocyte aspartate aminotransferase were compared between patients and healthy subjects. Adjuvant arthritis was induced in rats for investigating hepatic and muscle contents as well as the urinary excretion of vitamin B(6 )during acute and chronic inflammation. Patients with rheumatoid arthritis had low plasma pyridoxal 5'-phosphate compared with healthy control subjects, but normal erythrocyte pyridoxal 5'-phosphate and urinary 4-pyridoxic acid excretion. Adjuvant arthritis in rats did not affect 4-pyridoxic acid excretion or muscle storage of pyridoxal 5'-phosphate, but it resulted in significantly lower pyridoxal 5'-phosphate levels in circulation and in liver during inflammation. Inflammation induced a tissue-specific depletion of vitamin B(6). The low plasma pyridoxal 5'-phosphate levels seen in inflammation are unlikely to be due to insufficient intake or excessive vitamin B(6 )excretion. Possible causes of decreased levels of vitamin B(6 )are discussed

Increased hyperpolarized [1-13 C] lactate production in a model of joint inflammation is not accompanied by tissue acidosis as assessed using hyperpolarized 13 C-labelled bicarbonate.

Arthritic conditions are a major source of chronic pain. Furthering our understanding of disease mechanisms creates the opportunity to develop more targeted therapeutics. In rheumatoid arthritis (RA), measurements of pH in human synovial fluid suggest that acidosis occurs, but that this is highly variable between individuals. Here we sought to determine if tissue acidosis occurs in a widely used rodent arthritis model: complete Freund's adjuvant (CFA)-induced inflammation. CFA robustly evoked paw and ankle swelling, concomitant with worsening clinical scores over time. We used magnetic resonance spectroscopic imaging of hyperpolarized [1-13 C]pyruvate metabolism to demonstrate that CFA induces an increase in the lactate-to-pyruvate ratio. This increase is indicative of enhanced glycolysis and an increased lactate concentration, as has been observed in the synovial fluid from RA patients, and which was correlated with acidosis. We also measured the 13 CO2 /H13 CO3- ratio, in animals injected with hyperpolarized H13 CO3- , to estimate extracellular tissue pH and showed that despite the apparent increase in glycolytic activity in CFA-induced inflammation there was no accompanying decrease in extracellular pH. The pH was 7.23 ± 0.06 in control paws and 7.32 ± 0.09 in inflamed paws. These results could explain why mice lacking acid-sensing ion channel subunits 1, 2 and 3 do not display any changes in mechanical or thermal hyperalgesia in CFA-induced inflammation

Investigating the inequalities in route to diagnosis amongst patients with diffuse large B-cell or follicular lymphoma in England

Introduction: Diagnostic delay is associated with lower chances of cancer survival. Underlying comorbidities are known to affect the timely diagnosis of cancer. Diffuse large B-cell (DLBCL) and follicular lymphomas (FL) are primarily diagnosed amongst older patients, who are more likely to have comorbidities. Characteristics of clinical commissioning groups (CCG) are also known to impact diagnostic delay. We assess the association between comorbidities and diagnostic delay amongst patients with DLBCL or FL in England during 2005–2013. Methods: Multivariable generalised linear mixed-effect models were used to assess the main association. Empirical Bayes estimates of the random effects were used to explore between-cluster variation. The latent normal joint modelling multiple imputation approach was used to account for partially observed variables. Results: We included 30,078 and 15,551 patients diagnosed with DLBCL or FL, respectively. Amongst patients from the same CCG, having multimorbidity was strongly associated with the emergency route to diagnosis (DLBCL: odds ratio 1.56, CI 1.40–1.73; FL: odds ratio 1.80, CI 1.45–2.23). Amongst DLBCL patients, the diagnostic delay was possibly correlated with CCGs that had higher population densities. Conclusions: Underlying comorbidity is associated with diagnostic delay amongst patients with DLBCL or FL. Results suggest a possible correlation between CCGs with higher population densities and diagnostic delay of aggressive lymphomas

Nuclear structure of 178Hf related to the spin-16, 31-year isomer

The projected shell model is used to study the multi-quasiparticle and collective excitations of 178Hf. With an axially symmetric basis, the spin-16 isomer at 2.4 MeV appears to be well separated in energy/spin space from other configurations. However, projected energy surface calculations suggest that 178Hf has significant softness to axially asymmetric shapes, which can strongly modify the level distribution. The implications for photodeexitation of the isomer are discussed.Comment: 8 pages, 4 figure

Skin biopsy analysis of concurrent keloidal morphoea and systemic sclerosis confirms overlapping pathogenic pathways

OBJECTIVES: Although localised forms of scleroderma (morphoea) have very different clinical features and outcomes from systemic sclerosis the two conditions can occur together in some patients. In this study we have explored skin gene expression in a series of patients with keloidal morphoea, a distinct clinical variant, concurrently with systemic sclerosis. METHODS: We have compared skin gene expression from the keloidal lesions with that from skin elsewhere. We have also examined a series of patients with diffuse or limited cutaneous SSc without morphoea and some healthy control skin biopsies. RESULTS: Keloidal morphoea has a distinct gene expression signature that is mainly driven by differential expression of fibroblast related genes compared with other cell types. Indeed, the signature reflects a profibrotic pattern seen in diffuse cutaneous SSc but is much more extreme. We propose that keloidal morphoea skin provides a unique insight into the profibrotic population of cells driving dcSSc. CONCLUSIONS: Understanding the biology of keloidal morphoea may give valuable insight into the molecular and cellular pathology of systemic sclerosis. The discrete nature of keloidal lesions raises the possibility of haematogenous spread and we suggest that the driving cells could represent blood derived cells derived from circulating progenitors

Stratified slopes, numerical and empirical stability analysis

Urbanisation means that many natural slopes in and around cities are often subjected to cuts resulting in dramatic changes in the geometry of slope faces mostly by increasing slope angle which could lead to failures with catastrophic consequences. As most natural slopes are of nonhomogeneous layered nature, understanding the stability behaviour of such slopes will be of utmost importance. The current practice in analysing slopes of complicated nature, geometrically and materially, is mostly to apply simplifications sacrificing accuracy leading to use of large factors of safety, which could undermine analytical and economic feasibility of projects. In this research limit-equilibrium and finite element methods are used, respectively by OASYS Slope and PLAXIS 2D, to empirically and numerically model and analyse geometrically non-homogeneous stratified slopes with the aim of understanding the effects of non-homogeneity of geometry and materials on stability under various inclination angles of slope face. The analysis included determination of factors of safety as well as a sensitivity analysis looking into the combined effects of contributing parameters