Mechanisms of pulmonary fibrosis: role of activated myofibroblasts and NADPH oxidase

A common feature of pathological fibrosis involving the lung and other organs is the persistent activation of myofibroblasts in injured tissues. Recent evidence supports the role of a member of the NADPH oxidase (NOX) gene family, NOX4, in myofibroblast differentiation, matrix synthesis and contractility. Additionally, NOX4 may contribute directly or indirectly to alveolar epithelial cell death, while myofibroblasts themselves acquire an apoptosis-resistant phenotype. Thus, NOX4 may be responsible for the cardinal features of progressive fibrosis - myofibroblast activation and epithelial cell dysrepair. Therapeutic targeting of NOX4 is likely to be effective in progressive cases of fibrosis involving multiple organs

Eustachian tube dysfunction: consensus statement on definition, types, clinical presentation and diagnosis

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The regulatory subunit of PKA-I remains partially structured and undergoes β-aggregation upon thermal denaturation

Background: The regulatory subunit (R) of cAMP-dependent protein kinase (PKA) is a modular flexible protein that responds with large conformational changes to the binding of the effector cAMP. Considering its highly dynamic nature, the protein is rather stable. We studied the thermal denaturation of full-length RIα and a truncated RIα(92-381) that contains the tandem cyclic nucleotide binding (CNB) domains A and B. Methodology/Principal Findings: As revealed by circular dichroism (CD) and differential scanning calorimetry, both RIα proteins contain significant residual structure in the heat-denatured state. As evidenced by CD, the predominantly α-helical spectrum at 25°C with double negative peaks at 209 and 222 nm changes to a spectrum with a single negative peak at 212-216 nm, characteristic of β-structure. A similar α→β transition occurs at higher temperature in the presence of cAMP. Thioflavin T fluorescence and atomic force microscopy studies support the notion that the structural transition is associated with cross-β-intermolecular aggregation and formation of non-fibrillar oligomers. Conclusions/Significance: Thermal denaturation of RIα leads to partial loss of native packing with exposure of aggregation-prone motifs, such as the B' helices in the phosphate-binding cassettes of both CNB domains. The topology of the β-sandwiches in these domains favors inter-molecular β-aggregation, which is suppressed in the ligand-bound states of RIα under physiological conditions. Moreover, our results reveal that the CNB domains persist as structural cores through heat-denaturation. © 2011 Dao et al

Ensemble-Based Computational Approach Discriminates Functional Activity of p53 Cancer and Rescue Mutants

The tumor suppressor protein p53 can lose its function upon single-point missense mutations in the core DNA-binding domain (“cancer mutants”). Activity can be restored by second-site suppressor mutations (“rescue mutants”). This paper relates the functional activity of p53 cancer and rescue mutants to their overall molecular dynamics (MD), without focusing on local structural details. A novel global measure of protein flexibility for the p53 core DNA-binding domain, the number of clusters at a certain RMSD cutoff, was computed by clustering over 0.7 µs of explicitly solvated all-atom MD simulations. For wild-type p53 and a sample of p53 cancer or rescue mutants, the number of clusters was a good predictor of in vivo p53 functional activity in cell-based assays. This number-of-clusters (NOC) metric was strongly correlated (r2 = 0.77) with reported values of experimentally measured ΔΔG protein thermodynamic stability. Interpreting the number of clusters as a measure of protein flexibility: (i) p53 cancer mutants were more flexible than wild-type protein, (ii) second-site rescue mutations decreased the flexibility of cancer mutants, and (iii) negative controls of non-rescue second-site mutants did not. This new method reflects the overall stability of the p53 core domain and can discriminate which second-site mutations restore activity to p53 cancer mutants

The role of the myosin ATPase activity in adaptive thermogenesis by skeletal muscle

Resting skeletal muscle is a major contributor to adaptive thermogenesis, i.e., the thermogenesis that changes in response to exposure to cold or to overfeeding. The identification of the “furnace” that is responsible for increased heat generation in resting muscle has been the subject of a number of investigations. A new state of myosin, the super relaxed state (SRX), with a very slow ATP turnover rate has recently been observed in skeletal muscle (Stewart et al. in Proc Natl Acad Sci USA 107:430–435, 2010). Inhibition of the myosin ATPase activity in the SRX was suggested to be caused by binding of the myosin head to the core of the thick filament in a structural motif identified earlier by electron microscopy. To be compatible with the basal metabolic rate observed in vivo for resting muscle, most myosin heads would have to be in the SRX. Modulation of the population of this state, relative to the normal relaxed state, was proposed to be a major contributor to adaptive thermogenesis in resting muscle. Transfer of only 20% of myosin heads from the SRX into the normal relaxed state would cause muscle thermogenesis to double. Phosphorylation of the myosin regulatory light chain was shown to transfer myosin heads from the SRX into the relaxed state, which would increase thermogenesis. In particular, thermogenesis by myosin has been proposed to play a role in the dissipation of calories during overfeeding. Up-regulation of muscle thermogenesis by pharmaceuticals that target the SRX would provide new approaches to the treatment of obesity or high blood sugar levels

Deep reinforcement learning for drone navigation using sensor data

Mobile robots such as unmanned aerial vehicles (drones) can be used for surveillance, monitoring and data collection in buildings, infrastructure and environments. The importance of accurate and multifaceted monitoring is well known to identify problems early and prevent them escalating. This motivates the need for flexible, autonomous and powerful decision-making mobile robots. These systems need to be able to learn through fusing data from multiple sources. Until very recently, they have been task specific. In this paper, we describe a generic navigation algorithm that uses data from sensors on-board the drone to guide the drone to the site of the problem. In hazardous and safety-critical situations, locating problems accurately and rapidly is vital. We use the proximal policy optimisation deep reinforcement learning algorithm coupled with incremental curriculum learning and long short-term memory neural networks to implement our generic and adaptable navigation algorithm. We evaluate different configurations against a heuristic technique to demonstrate its accuracy and efficiency. Finally, we consider how safety of the drone could be assured by assessing how safely the drone would perform using our navigation algorithm in real-world scenarios

Genome-Wide Analysis of Structural Variants in Parkinson Disease

OBJECTIVE: Identification of genetic risk factors for Parkinson disease (PD) has to date been primarily limited to the study of single nucleotide variants, which only represent a small fraction of the genetic variation in the human genome. Consequently, causal variants for most PD risk are not known. Here we focused on structural variants (SVs), which represent a major source of genetic variation in the human genome. We aimed to discover SVs associated with PD risk by performing the first large-scale characterization of SVs in PD. METHODS: We leveraged a recently developed computational pipeline to detect and genotype SVs from 7,772 Illumina short-read whole genome sequencing samples. Using this set of SV variants, we performed a genome-wide association study using 2,585 cases and 2,779 controls and identified SVs associated with PD risk. Furthermore, to validate the presence of these variants, we generated a subset of matched whole-genome long-read sequencing data. RESULTS: We genotyped and tested 3,154 common SVs, representing over 412 million nucleotides of previously uncatalogued genetic variation. Using long-read sequencing data, we validated the presence of three novel deletion SVs that are associated with risk of PD from our initial association analysis, including a 2 kb intronic deletion within the gene LRRN4. INTERPRETATION: We identified three SVs associated with genetic risk of PD. This study represents the most comprehensive assessment of the contribution of SVs to the genetic risk of PD to date. ANN NEUROL 202

Relationship of obesity to physical activity, domestic activities, and sedentary behaviours: cross-sectional findings from a national cohort of over 70,000 Thai adults

Background: Patterns of physical activity (PA), domestic activity and sedentary behaviours are changing rapidly in Asia. Little is known about their relationship with obesity in this context. This study investigates in detail the relationship between obesity, physical activity, domestic activity and sedentary behaviours in a Thai population. Methods. 74,981 adult students aged 20-50 from all regions of Thailand attending the Sukhothai Thammathirat Open University in 2005-2006 completed a self-administered questionnaire, including providing appropriate self-reported data on height, weight and PA. We conducted cross-sectional analyses of the relationship between obesity, defined according to Asian criteria (Body Mass Index (BMI) 25), and measures of physical activity and sedentary behaviours (exercise-related PA; leisure-related computer use and television watching ("screen-time"); housework and gardening; and sitting-time) adjusted for age, sex, income and education and compared according to a range of personal characteristics. Results: Overall, 15.6% of participants were obese, with a substantially greater prevalence in men (22.4%) than women (9.9%). Inverse associations between being obese and total weekly sessions of exercise-related PA were observed in men, with a significantly weaker association seen in women (p(interaction) < 0.0001). Increasing obesity with increasing screen-time was seen in all population groups examined; there was an overall 18% (15-21%) increase in obesity with every two hours of additional daily screen-time. There were 33% (26-39%) and 33% (21-43%) reductions in the adjusted risk of being obese in men and women, respectively, reporting housework/gardening daily versus seldom or never. Exercise-related PA, screen-time and housework/gardening each had independent associations with obesity. Conclusions: Domestic activities and sedentary behaviours are important in relation to obesity in Thailand, independent of exercise-related physical activity. In this setting, programs to prevent and treat obesity through increasing general physical activity need to consider overall energy expenditure and address a wide range of low-intensity high-volume activities in order to be effective