Paraoxonase 2 overexpression inhibits tumor development in a mouse model of ovarian cancer.

Ovarian cancer (OC) is most lethal malignancy among all gynecological cancer. Large bodies of evidences suggest that mitochondrial-derived ROS play a critical role in the development and progression of OC. Paraoxonase 2 (PON2) is a membrane-associated lactonase with anti-oxidant properties. PON2 deficiency aggravates mitochondrial ROS formation, systemic inflammation, and atherosclerosis. The role of PON2 in cancer development remains unknown. In this report, in human, we identified that PON2 expression is higher in early stages (but not in late stages) of OC when compared to normal tissue. Using a mouse xenograft model of OC, we demonstrate that overexpression of PON2 prevents tumor formation. Mechanistically, PON2 decreases OC cell proliferation by inhibiting insulin like growth factor-1 (IGF-1) expression and signaling. Intriguingly, PON2 reduces c-Jun-mediated transcriptional activation of IGF-1 gene by decreasing mitochondrial superoxide generation. In addition, PON2 impairs insulin like growth factor-1 receptor (IGF-1R) signaling in OC cells by altering cholesterol homeostasis, which resulted in reduced caveolin-1/IGF-1R interaction and IGF-1R phosphorylation. Taken together, we report for the first time that PON2 acts as a tumor suppressor in the early stage of OC by reducing IGF-1 production and its signaling, indicating PON2 activation might be a fruitful strategy to inhibit early stage ovarian tumor

Seeking Optimum System Settings for Physical Activity Recognition on Smartwatches

Physical activity recognition (PAR) using wearable devices can provide valued information regarding an individual's degree of functional ability and lifestyle. In this regards, smartphone-based physical activity recognition is a well-studied area. Research on smartwatch-based PAR, on the other hand, is still in its infancy. Through a large-scale exploratory study, this work aims to investigate the smartwatch-based PAR domain. A detailed analysis of various feature banks and classification methods are carried out to find the optimum system settings for the best performance of any smartwatch-based PAR system for both personal and impersonal models. To further validate our hypothesis for both personal (The classifier is built using the data only from one specific user) and impersonal (The classifier is built using the data from every user except the one under study) models, we tested single subject validation process for smartwatch-based activity recognition.Comment: 15 pages, 2 figures, Accepted in CVC'1

Scope and Mechanistic Study of the Coupling Reaction of α,β-Unsaturated Carbonyl Compounds with Alkenes: Uncovering Electronic Effects on Alkene Insertion vs Oxidative Coupling Pathways

The cationic ruthenium-hydride complex [(C6H6)(PCy3)(CO)RuH]+BF4– (1) was found to be a highly effective catalyst for the intermolecular conjugate addition of simple alkenes to α,β-unsaturated carbonyl compounds to give (Z)-selective tetrasubstituted olefin products. The analogous coupling reaction of cinnamides with electron-deficient olefins led to the oxidative coupling of two olefinic C–H bonds in forming (E)-selective diene products. The intramolecular version of the coupling reaction efficiently produced indene and bicyclic fulvene derivatives. The empirical rate law for the coupling reaction of ethyl cinnamate with propene was determined as follows: rate = k[1]1[propene]0[cinnamate]−1. A negligible deuterium kinetic isotope effect (kH/kD = 1.1 ± 0.1) was measured from both (E)-C6H5CH═C(CH3)CONHCH3 and (E)-C6H5CD═C(CH3)CONHCH3 with styrene. In contrast, a significant normal isotope effect (kH/kD = 1.7 ± 0.1) was observed from the reaction of (E)-C6H5CH═C(CH3)CONHCH3 with styrene and styrene-d8. A pronounced carbon isotope effect was measured from the coupling reaction of (E)-C6H5CH═CHCO2Et with propene (13C(recovered)/13C(virgin) at Cβ = 1.019(6)), while a negligible carbon isotope effect (13C(recovered)/13C(virgin) at Cβ = 0.999(4)) was obtained from the reaction of (E)-C6H5CH═C(CH3)CONHCH3 with styrene. Hammett plots from the correlation of para-substituted p-X-C6H4CH═CHCO2Et (X = OCH3, CH3, H, F, Cl, CO2Me, CF3) with propene and from the treatment of (E)-C6H5CH═CHCO2Et with a series of para-substituted styrenes p-Y-C6H4CH═CH2 (Y = OCH3, CH3, H, F, Cl, CF3) gave the positive slopes for both cases (ρ = +1.1 ± 0.1 and +1.5 ± 0.1, respectively). Eyring analysis of the coupling reaction led to the thermodynamic parameters, ΔH⧧ = 20 ± 2 kcal mol–1 and ΔS⧧ = −42 ± 5 eu. Two separate mechanistic pathways for the coupling reaction have been proposed on the basis of these kinetic and spectroscopic studies

Bristol Girls Dance Project: A cluster randomised controlled trial of an after-school dance programme to increase physical activity among 11- to 12-year-old girls

Background: Many children do not meet UK physical activity (PA) guidelines. Girls are less active than boys, and the age-related decline in activity is steeper for girls. Dance is the favourite form of PA among adolescent girls in the UK. Participation in after-school dance classes could significantly contribute to girls’ PA. Therefore, after-school dance may be effective for increasing PA levels.Objectives: To determine the effectiveness and cost effectiveness of a dance-based intervention to increase the objectively assessed mean weekday minutes of moderate- to vigorous-intensity physical activity (MVPA) of Year 7 girls (11- and 12-year olds) 1 year after baseline measurement.Design: Two-arm cluster randomised controlled trial and economic evaluation. Year 7 girls in participant schools received a ‘taster’ session and were invited to participate. Up to 33 girls per school were able to participate. Schools were randomly assigned (equal numbers) to intervention or control arms.Setting: A total of 18 mainstream secondary schools across greater Bristol.Participants: Year 7 girls in participating schools who could participate in physical education.Intervention: Nine intervention schools received an after-school dance intervention (40 × 75-minute sessions) underpinned by self-determination theory, which attempts to improve intrinsic motivation for being active, and delivered by external dance instructors. Control schools continued as normal.Main outcome measures: The main outcome was accelerometer-assessed mean minutes of MVPA at T2. Measures were assessed at baseline (T0), the end of the intervention (T1) and at T0 + 52 weeks (T2).Results: Baseline MVPA levels were high. A total of 508 girls were included in the primary analysis, which found no difference in weekday MVPA between trial arms. There was no effect on secondary accelerometer outcomes. Data were subjected to a per-protocol analysis and no effect was found. However, at T1, girls who attended dance classes had 4.61 minutes more of MVPA and 14.27 minutes more of light-intensity activity between 15.00 and 17.00 on the days on which they attended intervention sessions. The intervention was inexpensive at £73 per participant (£63 when excluding dance instructor travel) but was not cost-effective owing to the ineffectiveness of the intervention. The European Quality of Life-5 Dimensions Youth survey data were unresponsive to changes in the sample. The process evaluation reported that girls in attendance enjoyed the sessions, that exertion levels were low during sessions and that attendance was low and declined. Fidelity to the session-plan manual was low but theoretical fidelity (to self-determination theory) was good. Qualitative information provides information for improving future interventions.Conclusions: The intervention was enjoyed by participants. However, there was no difference in the MVPA levels (which were high at baseline) of girls allocated to receive dance compared with girls receiving the control. High baseline MVPA levels indicate that the study appealed to an already active cohort and, therefore, may not have targeted those most in need of an intervention. Dance is an enjoyable activity for adolescent girls and could be further trialled as a means by which to increase PA. Research might consider the impact of dividing the intervention period into smaller blocks

Physical environmental factors related to walking and cycling in older adults: the Belgian aging studies

<p>Abstract</p> <p>Background</p> <p>Socio-ecological models emphasize the relationship between the physical environment and physical activity (PA). However, knowledge about this relationship in older adults is limited. Therefore, the present study aims to investigate the relationship between area of residence (urban, semi-urban or rural) and older adults' walking and cycling for transportation and recreation. Additionally, relationships between several physical environmental factors and walking and cycling and possible moderating effects of area of residence, age and gender were studied.</p> <p>Methods</p> <p>Data from 48,879 Flemish older adults collected in 2004-2010 through peer research were analyzed. Walking, cycling and environmental perceptions were assessed using self-administered questionnaires. The Study Service of the Flemish Government provided objective data on municipal characteristics. Multilevel logistic regression analyses were applied.</p> <p>Results</p> <p>Urban participants were more likely to walk daily for transportation compared to rural (OR = 1.43; 95% CI = 1.22, 1.67) and semi-urban participants (OR = 1.32; 95% CI = 1.13, 1.54). Urban participants were less likely to cycle daily for transportation compared to semi-urban participants (OR = 0.72; 95% CI = 0.56, 0.92). Area of residence was unrelated to weekly recreational walking/cycling. Perceived short distances to services (ORs ranging from 1.04 to 1.19) and satisfaction with public transport (ORs ranging from 1.07 to 1.13) were significantly positively related to all walking/cycling behaviors. Feelings of unsafety was negatively related to walking for transportation (OR = 0.93, 95% CI = 0.91, 0.95) and recreational walking/cycling (OR = 0.95, 95% CI = 0.92, 0.97). In females, it was also negatively related to cycling for transportation (OR = 0.94, 95% CI = 0.90, 0.98).</p> <p>Conclusions</p> <p>Urban residents were more likely to walk for transportation daily compared to semi-urban and rural residents. Daily cycling for transportation was less prevalent among urban compared to semi-urban residents. Access to destinations appeared to be important for promoting both walking and cycling for transportation and recreation across all demographic subgroups. Additionaly, feelings of unsafety were associated with lower rates of walking for transportation and walking/cycling for recreation in all subgroups and cycling for transportation in females. No clear patterns emerged for other environmental factors.</p

Role of ER Stress in Ventricular Contractile Dysfunction in Type 2 Diabetes

BACKGROUND: Diabetes mellitus (DM) is associated with an increased risk of ischemic heart disease and of adverse outcomes following myocardial infarction (MI). Here we assessed the role of endoplasmic reticulum (ER) stress in ventricular dysfunction and outcomes after MI in type 2 DM (T2DM). METHODOLOGY AND PRINCIPAL FINDINGS: In hearts of OLETF, a rat model of T2DM, at 25∼30 weeks of age, GRP78 and GRP94, markers of ER stress, were increased and sarcoplasmic reticulum calcium ATPase (SERCA)2a protein was reduced by 35% compared with those in LETO, a non-diabetic control. SERCA2a mRNA levels were similar, but SERCA2a protein was more ubiquitinated in OLETF than in LETO. Left ventricular (LV) end-diastolic elastance (Eed) was higher in OLETF than in LETO (53.9±5.2 vs. 20.2±5.6 mmHg/µl), whereas LV end-systolic elastance and positive inotropic responses to β-adrenergic stimulation were similar in OLETF and LETO. 4-Phenylbutyric acid (4-PBA), an ER stress modulator, suppressed both GRP up-regulation and SERCA2a ubiquitination and normalized SERCA2a protein level and Eed in OLETF. Sodium tauroursodeoxycholic acid, a structurally different ER stress modulator, also restored SERCA2a protein level in OLETF. Though LV dysfunction was modest, mortality within 48 h after coronary occlusion was markedly higher in OLETF than in LETO (61.3% vs. 7.7%). Telemetric recording showed that rapid progression of heart failure was responsible for the high mortality rate in OLETF. ER stress modulators failed to reduce the mortality rate after MI in OLETF. CONCLUSIONS: ER stress reduces SERCA2a protein via its augmented ubiquitination and degradation, leading to LV diastolic dysfunction in T2DM. Even at a stage without systolic LV dysfunction, susceptibility to lethal heart failure after infarction is markedly increased, which cannot be explained by ER stress or change in myocardial response to sympathetic nerve activation

Diabetes Alters Intracellular Calcium Transients in Cardiac Endothelial Cells

Diabetic cardiomyopathy (DCM) is a diabetic complication, which results in myocardial dysfunction independent of other etiological factors. Abnormal intracellular calcium ([Ca2+]i) homeostasis has been implicated in DCM and may precede clinical manifestation. Studies in cardiomyocytes have shown that diabetes results in impaired [Ca2+]i homeostasis due to altered sarcoplasmic reticulum Ca2+ ATPase (SERCA) and sodium-calcium exchanger (NCX) activity. Importantly, altered calcium homeostasis may also be involved in diabetes-associated endothelial dysfunction, including impaired endothelium-dependent relaxation and a diminished capacity to generate nitric oxide (NO), elevated cell adhesion molecules, and decreased angiogenic growth factors. However, the effect of diabetes on Ca2+ regulatory mechanisms in cardiac endothelial cells (CECs) remains unknown. The objective of this study was to determine the effect of diabetes on [Ca2+]i homeostasis in CECs in the rat model (streptozotocin-induced) of DCM. DCM-associated cardiac fibrosis was confirmed using picrosirius red staining of the myocardium. CECs isolated from the myocardium of diabetic and wild-type rats were loaded with Fura-2, and UTP-evoked [Ca2+]i transients were compared under various combinations of SERCA, sarcoplasmic reticulum Ca2+ ATPase (PMCA) and NCX inhibitors. Diabetes resulted in significant alterations in SERCA and NCX activities in CECs during [Ca2+]i sequestration and efflux, respectively, while no difference in PMCA activity between diabetic and wild-type cells was observed. These results improve our understanding of how diabetes affects calcium regulation in CECs, and may contribute to the development of new therapies for DCM treatment

Redox regulation of cell proliferation: Bioinformatics and redox proteomics approaches to identify redox-sensitive cell cycle regulators

Plant stem cells are the foundation of plant growth and development. The balance of quiescence and division is highly regulated, while ensuring that proliferating cells are protected from the adverse effects of environment fluctuations that may damage the genome. Redox regulation is important in both the activation of proliferation and arrest of the cell cycle upon perception of environmental stress. Within this context, reactive oxygen species serve as ‘pro-life’ signals with positive roles in the regulation of the cell cycle and survival. However, very little is known about the metabolic mechanisms and redox-sensitive proteins that influence cell cycle progression. We have identified cysteine residues on known cell cycle regulators in Arabidopsis that are potentially accessible, and could play a role in redox regulation, based on secondary structure and solvent accessibility likelihoods for each protein. We propose that redox regulation may function alongside other known posttranslational modifications to control the functions of core cell cycle regulators such as the retinoblastoma protein. Since our current understanding of how redox regulation is involved in cell cycle control is hindered by a lack of knowledge regarding both which residues are important and how modification of those residues alters protein function, we discuss how critical redox modifications can be mapped at the molecular level

Influence of cutting parameters on the depth of subsurface deformed layer in nano-cutting process of single crystal copper

Large-scale molecular dynamics simulation is performed to study the nano-cutting process of single crystal copper realized by single-point diamond cutting tool in this paper. The centro-symmetry parameter is adopted to characterize the subsurface deformed layers and the distribution and evolution of the subsurface defect structures. Three-dimensional visualization and measurement technology are used to measure the depth of the subsurface deformed layers. The influence of cutting speed, cutting depth, cutting direction, and crystallographic orientation on the depth of subsurface deformed layers is systematically investigated. The results show that a lot of defect structures are formed in the subsurface of workpiece during nano-cutting process, for instance, stair-rod dislocations, stacking fault tetrahedron, atomic clusters, vacancy defects, point defects. In the process of nano-cutting, the depth of subsurface deformed layers increases with the cutting distance at the beginning, then decreases at stable cutting process, and basically remains unchanged when the cutting distance reaches up to 24 nm. The depth of subsurface deformed layers decreases with the increase in cutting speed between 50 and 300 m/s. The depth of subsurface deformed layer increases with cutting depth, proportionally, and basically remains unchanged when the cutting depth reaches over 6 nm