Interplay between Mitochondrial Protein Import and Respiratory Complexes Assembly in Neuronal Health and Degeneration

The fact that >99% of mitochondrial proteins are encoded by the nuclear genome and synthesised in the cytosol renders the process of mitochondrial protein import fundamental for normal organelle physiology. In addition to this, the nuclear genome comprises most of the proteins required for respiratory complex assembly and function. This means that without fully functional protein import, mitochondrial respiration will be defective, and the major cellular ATP source depleted. When mitochondrial protein import is impaired, a number of stress response pathways are activated in order to overcome the dysfunction and restore mitochondrial and cellular proteostasis. However, prolonged impaired mitochondrial protein import and subsequent defective respiratory chain function contributes to a number of diseases including primary mitochondrial diseases and neurodegeneration. This review focuses on how the processes of mitochondrial protein translocation and respiratory complex assembly and function are interlinked, how they are regulated, and their importance in health and disease

Order by disorder and spiral spin liquid in frustrated diamond lattice antiferromagnets

Frustration refers to competition between different interactions that cannot be simultaneously satisfied, a familiar feature in many magnetic solids. Strong frustration results in highly degenerate ground states, and a large suppression of ordering by fluctuations. Key challenges in frustrated magnetism are characterizing the fluctuating spin-liquid regime and determining the mechanism of eventual order at lower temperature. Here, we study a model of a diamond lattice antiferromagnet appropriate for numerous spinel materials. With sufficiently strong frustration a massive ground state degeneracy develops amongst spirals whose propagation wavevectors reside on a continuous two-dimensional ``spiral surface'' in momentum space. We argue that an important ordering mechanism is entropic splitting of the degenerate ground states, an elusive phenomena called order-by-disorder. A broad ``spiral spin-liquid'' regime emerges at higher temperatures, where the underlying spiral surface can be directly revealed via spin correlations. We discuss the agreement between these predictions and the well characterized spinel MnSc2S4

Prior event rate ratio adjustment produced estimates consistent with randomized trial: a diabetes case study

Objectives: Electronic health records (EHR) provide a valuable resource for assessing drug side-effects, but treatments are not randomly allocated in routine care creating the potential for bias. We conduct a case study using the Prior Event Rate Ratio (PERR) Pairwise method to reduce unmeasured confounding bias in side-effect estimates for two second-line therapies for type 2 diabetes, thiazolidinediones, and sulfonylureas. Study design and settings: Primary care data were extracted from the Clinical Practice Research Datalink (n = 41,871). We utilized outcomes from the period when patients took first-line metformin to adjust for unmeasured confounding. Estimates for known side-effects and a negative control outcome were compared with the A Diabetes Outcome Progression Trial (ADOPT) trial (n = 2,545). Results: When on metformin, patients later prescribed thiazolidinediones had greater risks of edema, HR 95% CI 1.38 (1.13, 1.68) and gastrointestinal side-effects (GI) 1.47 (1.28, 1.68), suggesting the presence of unmeasured confounding. Conventional Cox regression overestimated the risk of edema on thiazolidinediones and identified a false association with GI. The PERR Pairwise estimates were consistent with ADOPT: 1.43 (1.10, 1.83) vs. 1.39 (1.04, 1.86), respectively, for edema, and 0.91 (0.79, 1.05) vs. 0.94 (0.80, 1.10) for GI. Conclusion: The PERR Pairwise approach offers potential for enhancing postmarketing surveillance of side-effects from EHRs but requires careful consideration of assumptions.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.The MASTERMIND (MRC APBI Stratification and Extreme Response Mechanism IN Diabetes) consortium is funded by the U.K Medical Research Council funded study grant number MR/N00633X/1. The funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report. IQVIA provided some funding for this project.published version, accepted version (12 month embargo), submitted versio

Development of oedema is associated with an improved glycaemic response in patients initiating thiazolidinediones: a MASTERMIND study

Abstracts of the 51st EASD Annual Meeting, Stockholm, Sweden, 14–18 September 2015This is the author accepted manuscript. The final version is available from Springer VerlagBackground and aims: Oedema is a common and serious side effect of thiazolidinedione therapy. A stratified medicines approach would aim to give thiazolidinediones to patients likely to have a good glycaemic response but to not develop oedema. We investigated whether oedema was associated with glycaemic response to thiazolidinedione therapy. Materials and methods: We retrospectively studied 11,459 patients initiating a thiazolidinedione from UK primary care data (Clinical Practice Research Datalink), and identified medical records of new oedema in the subsequent twelve months. Response was defined as change in HbA1c at twelve months and was adjusted for baseline HbA1c, baseline BMI, gender and compliance (medication possession ratio). In secondary analyses we restricted oedema classification to patients with concomitant weight gain. As a comparison the same analysis was performed in 13,089 patients initiating a sulfonylurea. Results: The 5% of patients with recorded oedema on thiazolidinediones had a mean (CI) 2.2 (1.1-3.2)mmol/mol greater fall in HbA1c (p3 kg (p< 0.001) and a 3.6 (1.8-5.4)mmol/mol greater fall when weight gain >5 kg (p3 kg (p=0.19). Conclusion: Patients with Type 2 diabetes who develop oedema on initiating thiazolidinediones have an improved glycaemic response, and more severe oedema may be associated with greater reductions in HbA1c. An association between oedema and glycaemic response was not observed in patients initiating sulfonylureas. This supports glycaemic lowering and fluid retention being mediated by a common pathway of thiazolidinedione drug action.Supported by: MRC grant MR-K005707-

Patients who develop oedema on initiating thiazolidinedione therapy have an improved glycaemic response: a MASTERMIND study

Special Issue: Abstracts of the Diabetes UK Professional Conference 2015, ExCeL London, 11–13 March 2015This is the author accepted manuscript. The final version is available from WileyBackground/aim: Oedema is a common and serious side effect ofthiazolidinedione therapy. A stratified medicine approach wouldaim to give thiazolidinediones to patients likely to have a goodglycaemic response but not to develop oedema. We investigatedwhether oedema was associated with glycaemic response tothiazolidinedione therapy.Methods: We studied 10,486 patients initiating a thiazolidinedionefrom Clinical Practice Research Datalink (CPRD), and identifiedmedical records of oedema in the subsequent 12 months. Responsewas defined as change in HbA1c at 12 months and was adjusted forbaseline HbA1c, baseline body mass index, gender and adherence(medication possession ratio). In secondary analyses we restrictedoedema classification to patients with concomitant weight gain. As acomparison the same analysis was performed in 13,089 patientsinitiating a sulfonylurea.Results: The 3% of patients with recorded oedema onthiazolidinediones had a mean (confidence interval) 3 (1.7–4.3)mmol/mol greater fall in HbA1c (p 3kg (p 8kg (p 3kg (p=0.19).Conclusion: Patients with Type 2 diabetes who develop oedemaon initiating thiazolidinediones have an improved glycaemicresponse, and more severe oedema is associated with greaterHbA1c reduction. This supports glycaemic lowering andfluid retention being mediated by a common pathway ofthiazolidinedione drug action

Are the new drugs better? Changing UK prescribing of Type 2 diabetes medications and effects on HbA1c and weight, 2010 to 2016

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.Aim: The availability of new glucose‐lowering drugs has changed UK National Institute of Clinical Excellence Type 2 diabetes guidelines, but there has been little evaluation of real‐world use of these drugs, or of the population‐level impact of their use. We examined changes in UK prescribing for patients starting second‐ and third‐line medications, and population‐level trends in glycaemic response and weight change. Methods: We extracted incident second‐ and third‐line oral prescription records for patients with Type 2 diabetes in the UK‐representative Clinical Practice Research Datalink, 2010 to 2016 (n = 68,902). Each year we calculated the proportion of each drug prescribed as the percentage of the total prescribed. We estimated annual mean six‐month HbA1c response and weight change using linear regression, standardised for clinical characteristics. Results: Use of Dipeptidyl peptidase‐4 (DPP4) inhibitors has increased markedly to overtake sulfonylureas as the most commonly prescribed second‐line drug in 2016 (43% vs 34% of total prescriptions compared with 18% v 59% in 2010). Use of sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors has increased rapidly to 14% of second‐line and 27% of third‐line prescriptions in 2016. Mean HbA1c response at six months was stable over time (2016: 13.5 (95% confidence interval 12.8, 14.1) mmol/mol vs 2010: 13.9 (13.6;14.2) mmol/mol, p = 0.21). We found mean weight loss at six months in 2016, in contrast to 2010 where there was mean weight gain (2016: −1.2 (−0.9; −1.5) kg vs 2010: +0.4 (+0.3; +0.5) kg, p < 0.001). Conclusion: The pattern of drug prescribing to manage patients with Type 2 diabetes has changed rapidly in the United Kingdom. Increasing use of DPP4 inhibitors and SGLT2 inhibitors has not resulted in improved glycaemic control but has improved the body weight of patients starting second‐ and third‐line therapy. Acknowledgement: This abstract is submitted on behalf of the MASTERMIND consortium

Cognition at age 70: Life course predictors and associations with brain pathologies

Objective: To investigate predictors of performance on a range of cognitive measures including the Preclinical Alzheimer Cognitive Composite (PACC) and test for associations between cognition and dementia biomarkers in Insight 46, a substudy of the Medical Research Council National Survey of Health and Development. // Methods: A total of 502 individuals born in the same week in 1946 underwent cognitive assessment at age 69–71 years, including an adapted version of the PACC and a test of nonverbal reasoning. Performance was characterized with respect to sex, childhood cognitive ability, education, and socioeconomic position (SEP). In a subsample of 406 cognitively normal participants, associations were investigated between cognition and β-amyloid (Aβ) positivity (determined from Aβ-PET imaging), whole brain volumes, white matter hyperintensity volumes (WMHV), and APOE ε4. // Results: Childhood cognitive ability was strongly associated with cognitive scores including the PACC more than 60 years later, and there were independent effects of education and SEP. Sex differences were observed on every PACC subtest. In cognitively normal participants, Aβ positivity and WMHV were independently associated with lower PACC scores, and Aβ positivity was associated with poorer nonverbal reasoning. Aβ positivity and WMHV were not associated with sex, childhood cognitive ability, education, or SEP. Normative data for 339 cognitively normal Aβ-negative participants are provided. // Conclusions: This study adds to emerging evidence that subtle cognitive differences associated with Aβ deposition are detectable in older adults, at an age when dementia prevalence is very low. The independent associations of childhood cognitive ability, education, and SEP with cognitive performance at age 70 have implications for interpretation of cognitive data in later life

Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing

This is the final version. Available on open access from Wiley via the DOI in this recordSummary: Aging is a major risk factor for chronic disease in the human population, but there are little human data on gene expression alterations that accompany the process. We examined human peripheral blood leukocyte in-vivo RNA in a large-scale transcriptomic microarray study (subjects aged 30-104years). We tested associations between probe expression intensity and advancing age (adjusting for confounding factors), initially in a discovery set (n=458), following-up findings in a replication set (n=240). We confirmed expression of key results by real-time PCR. Of 16571 expressed probes, only 295 (2%) were robustly associated with age. Just six probes were required for a highly efficient model for distinguishing between young and old (area under the curve in replication set; 95%). The focused nature of age-related gene expression may therefore provide potential biomarkers of aging. Similarly, only 7 of 1065 biological or metabolic pathways were age-associated, in gene set enrichment analysis, notably including the processing of messenger RNAs (mRNAs); [P<0.002, false discovery rate (FDR) q<0.05]. This is supported by our observation of age-associated disruption to the balance of alternatively expressed isoforms for selected genes, suggesting that modification of mRNA processing may be a feature of human aging. © 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.National Institute for Health Research (NIHR