Small scale energy release driven by supergranular flows on the quiet Sun

In this article we present data and modelling for the quiet Sun that strongly suggest a ubiquitous small-scale atmospheric heating mechanism that is driven solely by converging supergranular flows. A possible energy source for such events is the power transfer to the plasma via the work done on the magnetic field by photospheric convective flows, which exert drag of the footpoints of magnetic structures. In this paper we present evidence of small scale energy release events driven directly by the hydrodynamic forces that act on the magnetic elements in the photosphere, as a result of supergranular scale flows. We show strong spatial and temporal correlation between quiet Sun soft X-ray emission (from <i>Yohkoh</i> and <i>SOHO</i> MDI-derived flux removal events driven by deduced photospheric flows. We also present a simple model of heating generated by flux submergence, based on particle acceleration by converging magnetic mirrors. In the near future, high resolution soft X-ray images from XRT on the <i>Hinode</i> satellite will allow definitive, quantitative verification of our results

Image registration and mutual thresholding enable low interimage variability across dynamic MRI measurements of supraclavicular brown adipose tissue during mild cold exposure

Purpose: Activated brown adipose tissue (BAT) enhances lipid catabolism and improves cardiometabolic health. Quantitative MRI of the fat fraction (FF) of supraclavicular BAT (scBAT) is a promising noninvasive measure to assess BAT activity but suffers from high scan variability. We aimed to test the effects of coregistration and mutual thresholding on the scan variability in a fast (1 min) time-resolution MRI protocol for assessing scBAT FF changes during cold exposure. Methods: Ten volunteers (age 24.8 +/- 3.0 years; body mass index 21.2 +/- 2.1 kg/m(2)) were scanned during thermoneutrality (32 degrees C; 10 min) and mild cold exposure (18 degrees C; 60 min) using a 12-point gradient-echo sequence (70 consecutive scans with breath-holds, 1.03 min per dynamic). Dynamics were coregistered to the first thermoneutral scan, which enabled drawing of single regions of interest in the scBAT depot. Voxel-wise FF changes were calculated at each time point and averaged across regions of interest. We applied mutual FF thresholding, in which voxels were included if their FF was greater than 30% FF in the reference scan and the registered dynamic. The efficacy of the coregistration was determined by using a moving average and comparing the mean squared error of residuals between registered and nonregistered data. Registered scBAT Delta FF was compared with single-scan thresholding using the moving average method. Results: Registered scBAT Delta FF had lower mean square error values than nonregistered data (0.07 +/- 0.05% vs. 0.16 +/- 0.14%; p09150161910073Metabolic health: pathophysiological trajectories and therap

Attenuation of doxorubicin-induced cardiotoxicity in a human in vitro cardiac model by the induction of the NRF-2 pathway

Dose-dependent cardiotoxicity is the leading adverse reaction seen in cancer patients treated with doxorubicin. Currently, dexrazoxane is the only approved drug that can partially protect against this toxicity in patients, however, its administration is restricted to those patients receiving a high cumulative dose of anthracyclines. Investigations into the mechanisms of cardiotoxicity and efforts to improve cardioprotective strategies have been hindered by the limited availability of a phenotypically relevant in vitro adult human cardiac model system. Here, we adapted a readily reproducible, functional 3D human multi-cell type cardiac system to emulate patient responses seen with doxorubicin and dexrazoxane. We show that administration of two NRF2 gene inducers namely the semi-synthetic triterpenoid Bardoxolone methyl, and the isothiocyanate sulfurophane, result in cardioprotection against doxorubicin toxicity comparable to dexrazoxane as evidenced by an increase in cell viability and a decrease in the production of reactive oxygen species. We further show a synergistic attenuation of cardiotoxicity when the NRF2 inducers and dexrazoxane are used in tandem. Taken together, our data indicate that the 3D spheroid is a suitable model to investigate drug induced cardiotoxicity and we reveal an essential role of the NRF2 pathway in cardioprotection providing a novel pharmacological mechanism and intervention route towards the alleviation of doxorubicin-induced toxicity

Baseline fat fraction is a strong predictor of disease progression in Becker muscular dystrophy

In Becker muscular dystrophy (BMD), muscle weakness progresses relatively slowly, with a highly variable rate among patients. This complicates clinical trials, as clinically relevant changes are difficult to capture within the typical duration of a trial. Therefore, predictors for disease progression are needed. We assessed if temporal increase of fat fraction (FF) in BMD follows a sigmoidal trajectory and whether fat fraction at baseline (FFbase) could therefore predict FF increase after 2 years (Delta FF). Thereafter, for two different MR-based parameters, we tested the additional predictive value to FFbase. We used 3-T Dixon data from the upper and lower leg, and multiecho spinecho MRI and 7-T P-31 MRS datasets from the lower leg, acquired in 24 BMD patients (age: 41.4 [SD 12.8] years). We assessed the pattern of increase in FF using mixed-effects modelling. Subsequently, we tested if indicators of muscle damage like standard deviation in water T-2 (stdT(2)) and the phosphodiester (PDE) over ATP ratio at baseline had additional value to FFbase for predicting Delta FF. The association between FFbase and Delta FF was described by the derivative of a sigmoid function and resulted in a peak Delta FF around 0.45 FFbase (fourth-order polynomial term: t = 3.7, p < .001). StdT(2) and PDE/ATP were not significantly associated with Delta FF if FFbase was included in the model. The relationship between FFbase and Delta FF suggests a sigmoidal trajectory of the increase in FF over time in BMD, similar to that described for Duchenne muscular dystrophy. Our results can be used to identify muscles (or patients) that are in the fast progressing stage of the disease, thereby facilitating the conduct of clinical trials.Orthopaedics, Trauma Surgery and Rehabilitatio

What can local authorities do to improve the social care-related quality of life of older adults living at home? Evidence from the Adult Social Care Survey

Local authorities spend considerable resources on social care at home for older adults. Given the expected growth in the population of older adults and budget cuts on local government, it is important to find efficient ways of maintaining and improving the quality of life of older adults. The ageing in place literature suggests that policies in other functions of local authorities may have a significant role to play. This study aims to examine the associations between social care-related quality of life (SCRQoL) in older adults and three potential policy targets for local authorities: (i) accessibility of information and advice, (ii) design of the home and (iii) accessibility of the local area. We used cross-sectional data from the English national Adult Social Care Survey (ASCS) 2010/2011 on service users aged 65 years and older and living at home (N=29,935). To examine the association between SCRQoL, as measured by the ASCOT, and three single-item questions about accessibility of information, design of the home and accessibility of the local area, we estimate linear and quantile regression models. After adjusting for physical and mental health factors and other confounders our findings indicate that SCRQoL is significantly lower for older adults who find it more difficult to find information and advice, for those who report that their home design is inappropriate for their needs and for those who find it more difficult to get around their local area. In addition, these three variables are as strongly associated with SCRQoL as physical and mental health factors. We conclude that in seeking to find ways to maintain and improve the quality of life of social care users living at home, local authorities could look more broadly across their responsibilities. Further research is required to explore the cost-effectiveness of these options compared to standard social care services

Muscle architecture is associated with muscle fat replacement in Duchenne and Becker muscular dystrophies

Introduction/Aims Duchenne and Becker muscular dystrophies (DMD and BMD, respectively) are characterized by fat replacement of different skeletal muscles in a specific temporal order. Given the structural role of dystrophin in skeletal muscle mechanics, muscle architecture could be important in the progressive pathophysiology of muscle degeneration. Therefore, the aim of this study was to assess the role of muscle architecture in the progression of fat replacement in DMD and BMD. Methods We assessed the association between literature-based leg muscle architectural characteristics and muscle fat fraction from 22 DMD and 24 BMD patients. Dixon-based magnetic resonance imaging estimates of fat fractions at baseline and 12 (only DMD) and 24 months were related to fiber length and physiological cross-sectional area (PCSA) using age-controlled linear mixed modeling. Results DMD and BMD muscles with long fibers and BMD muscles with large PCSAs were associated with increased fat fraction. The effect of fiber length was stronger in muscles with larger PCSA. Discussion Muscle architecture may explain the pathophysiology of muscle degeneration in dystrophinopathies, in which proximal muscles with a larger mass (fiber length x PCSA) are more susceptible, confirming the clinical observation of a temporal proximal-to-distal progression. These results give more insight into the mechanical role in the pathophysiology of muscular dystrophies. Ultimately, this new information can be used to help support the selection of current and the development of future therapies.Neuro Imaging Researc

Quantitative N- or C-Terminal Labelling of Proteins with Unactivated Peptides by Use of Sortases and a d-Aminopeptidase

Quantitative and selective labelling of proteins is widely used in both academic and industrial laboratories, and catalytic labelling of proteins using transpeptidases, such as sortases, has proved to be a popular strategy for such selective modification. A major challenge for this class of enzymes is that the majority of procedures require an excess of the labelling reagent or, alternatively, activated substrates rather than simple commercially sourced peptides. We report the use of a coupled enzyme strategy which enables quantitative N- and C-terminal labelling of proteins using unactivated labelling peptides. The use of an aminopeptidase in conjunction with a transpeptidase allows sequence-specific degradation of the peptide by-product, shifting the equilibrium to favor product formation, which greatly enhances the reaction efficiency. Subsequent optimisation of the reaction allows N-terminal labelling of proteins using essentially equimolar ratios of peptide label to protein and C-terminal labelling with only a small excess. Minimizing the amount of substrate required for quantitative labelling has the potential to improve industrial processes and facilitate the use of transpeptidation as a method for protein labelling

The Origin, Early Evolution and Predictability of Solar Eruptions

Coronal mass ejections (CMEs) were discovered in the early 1970s when space-borne coronagraphs revealed that eruptions of plasma are ejected from the Sun. Today, it is known that the Sun produces eruptive flares, filament eruptions, coronal mass ejections and failed eruptions; all thought to be due to a release of energy stored in the coronal magnetic field during its drastic reconfiguration. This review discusses the observations and physical mechanisms behind this eruptive activity, with a view to making an assessment of the current capability of forecasting these events for space weather risk and impact mitigation. Whilst a wealth of observations exist, and detailed models have been developed, there still exists a need to draw these approaches together. In particular more realistic models are encouraged in order to asses the full range of complexity of the solar atmosphere and the criteria for which an eruption is formed. From the observational side, a more detailed understanding of the role of photospheric flows and reconnection is needed in order to identify the evolutionary path that ultimately means a magnetic structure will erupt

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk