Search

Purpose: Harsh parenting is positively correlated with adolescents' smartphone addiction, according to a growing corpus of studies. The various mediating processes that could underlie this link, however, are not well understood. Based upon the experiential avoidance model, the current research aimed to identify the relation between harsh parenting and adolescents' smartphone addiction and the mediating roles of adolescents' depression and experiential avoidance.Methods: We recruited 456 adolescents (female = 52.6%; Mage = 13.19 years, SD = 0.85) at a public junior high school in China to complete the harsh discipline scale, 90-item Hopkins symptom checklist, acceptance and action questionnaire version II, and smartphone addiction scale short version. SPSS24.0 was used to conduct independent samples t-test, descriptive statistics, Pearson correlation analysis and common method bias test, PROCESS were used to conduct a significance test of the chain mediation effect on the data. Age, gender, and grade were used as con-founders that were controlled in order to make cautious predictions.Results: The results showed that (1) harsh parenting was positively correlated with adolescents' depression, experiential avoidance, and smartphone addiction; (2) both depression and experiential avoidance fully mediated the link between harsh parenting and smartphone addiction; and (3) depression and experiential avoidance also sequentially mediated the link between harsh parenting and smartphone addiction. These findings have significant implications for the prevention and intervention of adolescents' smartphone addiction.Conclusion: These findings suggested that harsh parenting may have an indirect impact on smartphone addiction in both a simple way (parallel mediation) and a complicated way (serial mediation). In addition, these studies shed light on smartphone addiction prevention and intervention. [ABSTRACT FROM AUTHOR]

The current study explored the mediating role of boredom and anxiety on the relationship between alexithymia and mobile phone addiction among Chinese college students. Participants (n = 354; female = 49.7%, mean age = 19.30 years, SD = 1.28 years) completed the Toronto Alexithymia Scale, the Boredom Proneness Scale-Short Form, the Symptom Check List 90, and the Mobile Phone Addiction Index. Regression analysis showed that higher alexithymia was a risk for mobile phone addiction (MPA). Boredom proneness and anxiety mediated the relationship between alexithymia and mobile phone addiction. There were no significant sex differences in the mediating pathways between alexithymia, boredom proneness, anxiety and MPA. The current findings are consistent with the compensatory internet use theory. College student support services should formulate student social engagement interventions to improve healthy mobile phone use and reducing the risk for MPA. [ABSTRACT FROM AUTHOR]

This study aimed to investigate (i) the relationship between loneliness and mobile phone addiction; (ii) the mediating role of negative affect in the association between loneliness and mobile phone addiction; and (iii) the moderating effect of perceived stress in the relationship between loneliness and mobile phone addiction. A total of 359 Chinese college students were recruited (female = 216; mean age = 19.56 years, SD = 1.61 years). Results showed that loneliness was associated with risk for mobile phone addiction. Mediation analysis highlighted that negative affect fully mediated the association between loneliness and increased mobile phone addiction. Moreover, moderated mediation analysis indicated that the association between negative affect and mobile phone addiction was moderated by perceived stress, so that risk for mobile phone addiction was higher when perceived stress was increased. In conclusion, our findings revealed that risk for mobile phone addiction was higher with loneliness and mood disorder indicators of negative affect and perceived stress. [ABSTRACT FROM AUTHOR]

Purpose: With the widespread use of the Internet and mobile phone, cyberbullying has become a new type of bullying among adolescents. It is of great practical significance to explore the relevant factors affecting cyberbullying for prevention and intervention of adolescents' cyberbullying. However, few studies have considered the effect of both the family and social factors on cyberbullying. Therefore, the current study examines whether the parent-adolescent conflict as a family factor and deviant peer affiliation as a social factor have an effect on adolescents' cyberbullying, as well as the role of moral disengagement and gender. Methods: A total of 777 middle school students (females = 336; mean age = 13.57; SD = 0.98) were surveyed by using the Parent-child Relationship Questionnaire, Deviant Peer Affiliation Questionnaire, Moral Disengagement Questionnaire and Cyber Bullying Behavior Questionnaire. SPSS21.0 was used to conduct descriptive statistics, Pearson correlation analysis and T-test, PROCESS were used to conduct significance test of moderated mediation effect on the data. Results: Parent-adolescent conflict does not directly predict cyberbullying. Moral disengagement played a complete mediating role between parent-adolescent conflict and cyberbullying, and gender played a moderating role between moral disengagement and cyberbullying. Deviant peer affiliation directly predict cyberbullying. Moral disengagement played a partially mediating role between parent-adolescent conflict and cyberbullying, and gender played a moderating role between moral disengagement and cyberbullying. Conclusion: Attention should be paid to the effect of moral disengagement on cyberbullying in family and social factors, as well as the role of gender. [ABSTRACT FROM AUTHOR]

The high temperature superconducting (HTS) cable has shown promising prospects in megacities for the advantages of high transmission power density and low loss. However, when HTS cable is working on grid, various kinds of faults may cause irreversible damage, resulting in the failure of reclosing. In this paper, the resistive superconducting fault current limiter (R-SFCL) is introduced into the power system to cooperate with the HTS cable, so as to reduce the potential damage caused by fault current. Firstly, the equivalent circuit models are established, and then transient response of HTS cables under fault condition is analyzed, the recovery time of HTS tapes are used to define the design of R-SFCL. Finally, the operating reliability of HTS cable has been evaluated and measures about adaptive reclosing times were proposed under different fault currents. [ABSTRACT FROM AUTHOR]

The high temperature superconducting (HTS) cable has shown promising prospects in megacities for the advantages of high transmission power density and low loss. However, when HTS cable is working on grid, various kinds of faults may cause irreversible damage, resulting in the failure of reclosing. In this paper, the resistive superconducting fault current limiter (R-SFCL) is introduced into the power system to cooperate with the HTS cable, so as to reduce the potential damage caused by fault current. Firstly, the equivalent circuit models are established, and then transient response of HTS cables under fault condition is analyzed, the recovery time of HTS tapes are used to define the design of R-SFCL. Finally, the operating reliability of HTS cable has been evaluated and measures about adaptive reclosing times were proposed under different fault currents. [ABSTRACT FROM AUTHOR]

Purpose: Adolescent bullying has varying degrees of negative impact on both bullies and victims. Bullying in adolescents is complex, and the influence of individual factors and social factors should not be underestimated. Normative beliefs about aggression play an important role in adolescents' bullying. However, the mediating and moderating mechanisms underlying this association remain largely unknown. The current study investigated the mediating role of moral disengagement between normative beliefs about aggression and bullying, as well as the moderating role of self-control in this relationship from the perspective of individual cognition. Methods: A sample of 491 Chinese adolescents (female = 38.9%; mean age = 13.05 years) were study participants. They completed questionnaires about normative beliefs about aggression, bullying, moral disengagement and self-control. SPSS21.0 statistical software was used to collate the obtained data, analyze descriptive statistics, and carry out reliability analysis and correlation analysis. Results: Moral disengagement mediated the relationship between normative beliefs about aggression and bullying (ab=0.13, 95% CI=[0.07, 0.21]). The association between normative beliefs about aggression and moral disengagement was moderated by self-control (β=− 0.08, t=− 2.25, p< 0.05). The association between moral disengagement and bullying was moderated by self-control (β=− 0.09, t=− 2.42, p< 0.05). Conclusion: Results revealed that moral disengagement mediates the link between normative beliefs about aggression and bullying. Self-control moderated the relationship between normative beliefs about aggression and moral disengagement, and between moral disengagement and bullying. [ABSTRACT FROM AUTHOR]

Thrombosis is a frequent predisposing factor in high‐mortality cardiovascular diseases, which underscores the urgent need to precisely diagnose thrombosis formation at a less severe stage. However, it is still challenging to realize in vivo early thrombosis imaging due to lack of high sensitivity/‐specificity molecular imaging strategy. To address such problems, thrombin‐activatable scintillating nanoprobes are developed for background‐free X‐ray‐excited luminescence (XEL) imaging of in vivo early thrombosis. The nanoprobes are constructed by designing bright XEL‐emitting lanthanide‐doped scintillator nanocrystals (NCs) with dye labeled‐peptide modification. Such nanoprobes show XEL‐off originally and enable robust turn‐on XEL upon thrombin‐specific cleavage of the peptide, resulting from the rational manipulation of energy transfer between dye and NCs. Specially, due to high tissue penetration depth and background‐free attributes in XEL imaging, this strategy achieves high‐efficiency XEL imaging of the early thrombosis on the basis of in situ elevated thrombin levels. Moreover, XEL and magnetic resonance imaging capabilities can be integrated to further improve imaging accuracy and monitor thrombosis progression. As such, the exploited strategy demonstrates a novel paradigm for realizing timely thrombosis imaging and provides a new readily tailorable platform for sensitive in vivo deep‐tissue imaging. [ABSTRACT FROM AUTHOR]

Objective: The root cause behind the low-grade inflammatory state seen in insulin resistant (obesity and type 2 diabetes) states is unclear. Insulin resistant subjects have elevations in plasma free fatty acids (FFA), which are ligands for the pro-inflammatory toll-like receptor (TLR)4 pathway. We tested the hypothesis that an experimental elevation in plasma FFA (within physiological levels) in lean individuals would upregulate TLR4 and activate downstream pathways (e.g., MAPK) in circulating monocytes. Research design and methods: Twelve lean, normal glucose-tolerant subjects received a low dose (30 ml/h) 48 h lipid or saline infusion on two different occasions. Monocyte TLR4 protein level, MAPK phosphorylation, and expression of genes in the TLR pathway were determined before and after each infusion. Results: The lipid infusion significantly increased monocyte TLR4 protein and phosphorylation of JNK and p38 MAPK. Lipid-mediated increases in TLR4 and p38 phosphorylation directly correlated with reduced peripheral insulin sensitivity (M value). Lipid increased levels of multiple genes linked to inflammation, including several TLRs, CD180, MAP3K7, and CXCL10. Monocytes exposed in vivo to lipid infusion exhibited enhanced in vitro basal and LPS-stimulated IL-1β secretion. Conclusions: In lean subjects, a small increase in plasma FFA (as seen in insulin resistant subjects) is sufficient to upregulate TLR4 and stimulate inflammatory pathways (MAPK) in monocytes. Moreover, lipids prime monocytes to endotoxin. We provide proof-of-concept data in humans indicating that the low-grade inflammatory state characteristic of obesity and type 2 diabetes could be caused (at least partially) by pro-inflammatory monocytes activated by excess lipids present in these individuals. [ABSTRACT FROM AUTHOR]

Aims: To evaluate whether pharmacological TLR4 inhibition protects against acute and chronic fat-induced insulin resistance in rats. Materials and Methods: For the acute experiment, rats received a TLR4 inhibitor [TAK-242 or E5564 (2x5 mg/kg i.v. bolus)] or vehicle, and an 8-h Intralipid (20%, 8.5 mg/kg/min) or saline infusion, followed by a two-step hyperinsulinemic-euglycemic clamp. For the chronic experiment, rats were subcutaneously implanted with a slow-release pellet of TAK-242 (1.5 mg/d) or placebo. Rats then received a high fat diet (HFD) or a low fat control diet (LFD) for 10 weeks, followed by a two-step insulin clamp. Results: Acute experiment; the lipid-induced reduction (18%) in insulin-stimulated glucose disposal (Rd) was attenuated by TAK-242 and E5564 (the effect of E5564 was more robust), suggesting improved peripheral insulin action. Insulin was able to suppress hepatic glucose production (HGP) in saline- but not lipid-treated rats. TAK-242, but not E5564, partially restored this effect, suggesting improved HGP. Chronic experiment; insulin-stimulated Rd was reduced ~30% by the HFD, but completely restored by TAK-242. Insulin could not suppress HGP in rats fed a HFD and TAK-242 had no effect on HGP. Conclusions: Pharmacological TLR4 inhibition provides partial protection against acute and chronic fat-induced insulin resistance in vivo. [ABSTRACT FROM AUTHOR]

Key points Reducing free fatty acids in the circulation gives protection against muscle insulin resistance., In the present study, we investigated the mechanism by which free fatty acid reduction improves muscle insulin sensitivity., The antilipolytic drug acipimox reduced the plasma concentration of unsaturated and saturated fatty acids in insulin-resistant (obese and type 2 diabetic) subjects., The reduction in plasma free fatty acid concentration caused by acipimox led to an improvement in local inflammation and insulin signalling in skeletal muscle., The improvements in local inflammation and insulin signalling were more pronounced in obese type 2 diabetic subjects than obese non-diabetic individuals, suggesting that diabetic subjects are more susceptible to the toxic effect of circulating free fatty acids., Abstract Free fatty acids (FFAs) have been implicated in the pathogenesis of insulin resistance. Reducing plasma FFA concentration in obese and type 2 diabetic (T2DM) subjects improves insulin sensitivity. However, the molecular mechanism by which FFA reduction improves insulin sensitivity in human subjects is not fully understood. In the present study, we tested the hypothesis that pharmacological FFA reduction enhances insulin action by reducing local (muscle) inflammation, leading to improved insulin signalling. Insulin-stimulated total glucose disposal (TGD), plasma FFA species, muscle insulin signalling, IκBα protein, c-Jun phosphorylation, inflammatory gene (toll-like receptor 4 and monocyte chemotactic protein 1) expression, and ceramide and diacylglycerol (DAG) content were measured in muscle from a group of obese and T2DM subjects before and after administration of the antilipolytic drug acipimox for 7 days, and the results were compared to lean individuals. We found that obese and T2DM subjects had elevated saturated and unsaturated FFAs in plasma, and acipimox reduced all FFA species. Acipimox-induced reductions in plasma FFAs improved TGD and insulin signalling in obese and T2DM subjects. Acipimox increased IκBα protein (an indication of decreased IκB kinase-nuclear factor κB signalling) in both obese and T2DM subjects, but did not affect c-Jun phosphorylation in any group. Acipimox also decreased inflammatory gene expression, although this reduction only occurred in T2DM subjects. Ceramide and DAG content did not change. To summarize, pharmacological FFA reduction improves insulin signalling in muscle from insulin-resistant subjects. This beneficial effect on insulin action could be related to a decrease in local inflammation. Notably, the improvements in insulin action were more pronounced in T2DM, indicating that these subjects are more susceptible to the toxic effect of FFAs. [ABSTRACT FROM AUTHOR]

Highlights: [•] Observed elevated protein carbonylation in long-living NMRs. [•] Both Prdx1 and TPI are highly carbonylated in NMRs. [•] Protein carbonylation does not impair TPI enzyme function. [•] Oxidative stress does not induce oligomers of TPI and Prdx in NMRs. [•] Cellular environment of NMRs prevents oxidative stress-induced oligomer formation. [ABSTRACT FROM AUTHOR]

Accumulating evidence from animal studies suggest that chronic elevation of circulating intestinal-generated lipopolysaccharide (LPS) (i.e., metabolic endotoxemia) could play a role in the pathogenesis of insulin resistance. However, the effect of LPS in human muscle is unclear. Moreover, it is unknown whether blockade/down regulation of toll-like receptor (TLR)4 can prevent the effect of LPS on insulin action and glucose metabolism in human muscle cells. In the present study we compared plasma LPS concentration in insulin resistant [obese non-diabetic and obese type 2 diabetic (T2DM)] subjects versus lean individuals. In addition, we employed a primary human skeletal muscle cell culture system to investigate the effect of LPS on glucose metabolism and whether these effects are mediated via TLR4. Obese non-diabetic and T2DM subjects had significantly elevated plasma LPS and LPS binding protein (LBP) concentrations. Plasma LPS (r = −0.46, P = 0.005) and LBP (r = −0.49, P = 0.005) concentrations negatively correlated with muscle insulin sensitivity (M). In human myotubes, LPS increased JNK phosphorylation and MCP-1 and IL-6 gene expression. This inflammatory response led to reduced insulin-stimulated IRS-1, Akt and AS160 phosphorylation and impaired glucose transport. Both pharmacologic blockade of TLR4 with TAK-242, and TLR4 gene silencing, suppressed the inflammatory response and insulin resistance caused by LPS in human muscle cells. Taken together, these findings suggest that elevations in plasma LPS concentration found in obese and T2DM subjects could play a role in the pathogenesis of insulin resistance and that antagonists of TLR4 may improve insulin action in these individuals. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests that TLR (Toll-like receptor) 4 and downstream pathways [MAPKs (mitogen-activated protein kinases) and NF-?B (nuclear factor ?B)] play an important role in the pathogenesis of insulin resistance. LPS (lipopolysaccharide) and saturated NEFA (non-esterified fatty acids) activate TLR4, and plasma concentrations of these TLR4 ligands are elevated in obesity and Type 2 diabetes. Our goals were to define the role of TLR4 on the insulin resistance caused by LPS and saturated NEFA, and to dissect the independent contribution of LPS and NEFA to the activation of TLR4-driven pathways by employing TAK-242, a specific inhibitor of TLR4. LPS caused robust activation of the MAPK and NF-?B pathways in L6 myotubes, along with impaired insulin signalling and glucose transport. TAK-242 completely prevented the inflammatory response (MAPK and NF-?B activation) caused by LPS, and, in turn, improved LPS-induced insulin resistance. Similar to LPS, stearate strongly activated MAPKs, although stimulation of the NF-?B axis was modest. As seen with LPS, the inflammatory response caused by stearate was accompanied by impaired insulin action. TAK-242 also blunted stearate-induced inflammation; yet, the protective effect conferred by TAK-242 was partial and observed only on MAPKs. Consequently, the insulin resistance caused by stearate was only partially improved by TAK-242. In summary, TAK-242 provides complete and partial protection against LPS- and NEFA-induced inflammation and insulin resistance, respectively. Thus, LPS-induced insulin resistance depends entirely on TLR4, whereas NEFA works through TLR4-dependent and -independent mechanisms to impair insulin action. [ABSTRACT FROM AUTHOR]

Abstract: Glutathione peroxidase 4 (Gpx4) is a unique antioxidant enzyme that repairs oxidative damage to biomembranes. In this study, we examined the effects of Gpx4 on the release of various apoptogenic proteins from mitochondria using transgenic mice overexpressing Gpx4 [Tg(GPX4 +/0)] and mice deficient in Gpx4 (Gpx4 +/− mice). Diquat exposure triggered apoptosis that occurred through an intrinsic pathway and resulted in the mitochondrial release of cytochrome c (Cyt c), Smac/DIABLO, and Omi/HtrA2 in the liver of wild-type (Wt) mice. Liver apoptosis and Cyt c release were suppressed in Tg(GPX4 +/0) mice but exacerbated in Gpx4 +/− mice; however, neither the Tg(GPX4 +/0) nor the Gpx4 +/− mice showed any alterations in the levels of Smac/DIABLO or Omi/HtrA2 released from mitochondria. Submitochondrial fractionation data showed that Smac/DIABLO and Omi/HtrA2 existed primarily in the intermembrane space and matrix, whereas Cyt c and Gpx4 were both associated with the inner membrane. In addition, diquat exposure induced cardiolipin peroxidation in the liver of Wt mice; the levels of cardiolipin peroxidation were reduced in Tg(GPX4 +/0) mice but elevated in Gpx4 +/− mice. These data suggest that Gpx4 differentially regulates apoptogenic protein release owing to its inner membrane location in mitochondria and its ability to repair cardiolipin peroxidation. [Copyright &y& Elsevier]

Abstract: Mitochondrial ATP production can be impaired by oxidative stress. Glutathione peroxidase 4 (Gpx4) is an antioxidant defense enzyme found in mitochondria as well as other subcellular organelles that directly detoxifies membrane lipid hydroperoxides. To determine if Gpx4 protects ATP production in vivo, we compared mitochondrial ATP production between wild-type mice and Gpx4 transgenic mice using a diquat model. Diquat (50mg/kg) significantly decreased mitochondrial ATP synthesis in livers of wild-type mice; however, no decrease in mitochondrial ATP synthesis was detected in Gpx4 transgenic mice after diquat. We observed no differences in activities of mitochondrial respiratory chain complexes between Gpx4 transgenic mice and wild-type mice. However, compared to wild-type mice, diquat-induced loss of mitochondrial membrane potential was attenuated in Gpx4 transgenic mice. Therefore, our results indicate that decreased ATP production under oxidative stress is primarily due to reduced mitochondrial membrane potential and overexpression of Gpx4 maintains mitochondrial membrane potential under oxidative stress. [Copyright &y& Elsevier]

The role of catalase in the antioxidant defense system was studied using transgenic mice [Tg(CAT)] harboring a human genomic clone containing the entire human CAT gene. Catalase activity was 2-fold higher in the tissues of hemizygous [Tg(CAT)+/o] mice and 3- to 4-fold higher in the tissues of homozygous [Tg(CAT)+/+] mice compared to wild type mice. The human CAT transgene was expressed in a tissue-specific pattern that was similar to the endogenous catalase gene. The levels of other major antioxidant enzymes were not altered in the tissues of the transgenic mice. Hepatocytes and fibroblasts from the Tg(CAT)+/+ mice were more resistant to hydrogen peroxide-induced cell death but were more sensitive to paraquat and TNFα toxicity. Fibroblasts from the Tg(CAT)+/+ mice showed reduced growth rate in culture without treatment and reduced colony-forming capability after γ-irradiation compared to fibroblasts from wild type mice. In addition, the Tg(CAT)+/+ animals were more sensitive to γ-irradiation. [Copyright &y& Elsevier]

Since 1996, seven genetic mouse models have been reported to show increased lifespan: Ames and Snell dwarf mice, the ‘little mouse’ (Ghrhrlit/lit), mice null for either growth hormone receptor/binding protein (GHR/BP−/−) or p66shc (p66shc−/−), mice heterozygous for the IGF-I receptor (Igf1r+/−), and fat-specific insulin receptor knockout mice. In this article, we describe and evaluate these mouse models with respect to their relevance for aging studies. While these seven genetic models all show a significant increase in lifespan, issues of sample size and animal husbandry procedures require further evaluation before firm conclusions can be drawn on the reproducibility of life extension in most of these mouse models. Because data on the age-related pathology and physiological functions are lacking for all of the models, except the dwarf mice, it is too early to conclude that aging is retarded in these mouse models. However, these mouse models are already providing new information about the mechanism underlying mammalian aging. [Copyright &y& Elsevier]

The human gut and its microbial content (microbiome) may contribute to the pathogenesis of obesity, insulin resistance and type 2 diabetes. Possible mechanisms include altered bacterial profile, increased intestinal permeability, and elevated bacterial lipopolysaccharide (LPS) leading to low-grade systemic inflammation termed metabolic endotoxemia. We hypothesized that two interventions with putative LPS-lowering effects, sevelamer and a synbiotic (combination pre- and probiotic), would improve peripheral insulin sensitivity in obese subjects. Based upon pre-clinical studies, sevelamer is reported to sequester LPS in the GI tract, whereas a synbiotic of Bifidobacterium longum plus oligofructose can improve intestinal barrier integrity. We randomized 22, normal glucose tolerant (NGT), lean (15F/7M, BMI=23.0, age=45.4yr, A1c=5.3%) and 28 NGT, obese subjects (20F/8M, BMI=32.7, age=51.9yr, A1c=5.5%) to receive oral sevelamer, synbiotic or placebo daily for 28 days. Insulin sensitivity (euglycemic clamp), cholesterol, endotoxemia (LPS, LBP, CD14), and intestinal permeability (lactulose/mannitol ratio, zonulin) were assessed before and after intervention. Obese subjects had reduced baseline insulin sensitivity compared to lean subjects (M value, -28.6%, p=0.0001 based on 2-sample t-test). Generalized estimating equation analysis showed that sevelamer increased insulin sensitivity (M value, +25.6%, p=0.022) and lowered plasma LDL (-16.4%, p=0.016) in obese subjects compared to placebo-treated obese subjects. Synbiotic did not significantly alter insulin sensitivity or lipids compared to placebo in obese subjects. Lean subjects saw no change in insulin sensitivity with either treatment. Neither treatment significantly altered plasma LPS or intestinal permeability in lean or obese subjects. In conclusion, sevelamer improves insulin sensitivity and LDL in obese subjects, and this effect is mostly independent of parameters of endotoxemia and intestinal permeability. Disclosure: E. Baeuerle: None. H. Liang: None. V. Ganapathy: None. R. Fernandez: None. N. Sathavarodom: None. C. Wang: None. S.E. Espinoza: None. N. Musi: None. Funding: American Diabetes Association (7-13-GSK-01 to N.M.); National Institutes of Health (T32GM113896) [ABSTRACT FROM AUTHOR]

Obese subjects have increased levels of free fatty acids (FFA) in plasma that may mediate the inflammation and insulin resistance seen in these individuals. Data generated mostly in cells and rodents suggest that toll like receptor 4 (TLR4) mediates the inflammatory and insulin resistant states induced by FFA. In the present study, we tested the hypothesis that pharmacologic blockade of TLR4 with eritoran would prevent lipid-induced insulin resistance. We recruited 10 lean, healthy subjects (Age: 51 ± 1 y, Sex: 6M/4F, BMI: 23.8 ± 0.7 kg/m2, Fasting plasma glucose (FPG): 5.5 ± 0.1 mmol/l). They were randomized to receive the following 72 h long i.v. treatments on separate occasions: saline (30 ml/h)+vehicle (12 mg every 12 h); Intralipid (30 ml/h)+vehicle; Intralipid (30 ml/h)+eritoran (12 mg every 12 h). After these infusions, insulin sensitivity was measured with an hyperinsulinemic clamp. Infusion of Intralipid significantly decreased insulin sensitivity (M value) by 14%. FPG and fasting plasma insulin concentrations increased with Intralipid infusion by 7% and 22%, respectively. Intralipid also caused a low-grade inflammatory state, evidenced by increases in plasma levels of TNFa (32%), lipopolysaccharide (14%), LPS binding protein (21%), and blood monocytes counts (15%). However, metabolic and inflammatory outcomes were not different between the Intralipid+vehicle and the Intralipid+eritoran groups. We conclude that short-term TLR4 inhibition with eritoran fails to prevent lipid-induced inflammation and insulin resistance. Studies with longer acting TLR4 inhibitors may be needed to clarify the role of TLR4 on the pro-inflammatory and insulin resistant states seen obesity and type 2 diabetes. Disclosure: H. Liang: None. N. Sathavarodom: None. C.V. Colmenares: None. V. Ganapathy: None. N. Musi: None. Funding: American Diabetes Association (7-13-GSK-01 to N.M.); National Institutes of Health (R01DK080157) [ABSTRACT FROM AUTHOR]

Introduction: The pneumatic tube system (PTS) is widely used for sample delivery. We aimed to investigate the impacts of PTS on hemostasis assays. Methods: Triplicate samples from 30 healthy volunteers were delivered to the core laboratory manually by human courier or via the 500 m long‐distance PTS or via the 1000 m long‐distance PTS. Comparisons of 19 hemostasis tests were conducted. Results: Although PT, INR, APTT, FII, FV, FVII FIX, FX, FXII, DD, α2‐PI, and PC had statistical significance (all P <.05), all had low average bias remaining within clinical acceptable limits. PTS transportation only resulted in a statistically significant and clinically relevant decrease in FVIII activity. In the 500 m‐PTS group, 66.7% (20/30) of samples for FVIII testing had a bias greater than 8.3%. Moreover, in the 1000 m‐PTS group, 96.7% (29/30) of samples had a bias of over 8.3%, and the maximal bias achieved 42.1%. Conclusions: Pneumatic tube system in our institution could be used to deliver blood samples for hemostasis tests evaluated in this study except FVIII activity assay. [ABSTRACT FROM AUTHOR]

The title synthesis uses chlorovinyl aromatic ketones [e.g. (I)] or bromovinyl aromatic ketones [e.g. (XIV)] and amines as starting material and the products can be obtained in good to excellent yields. [ABSTRACT FROM AUTHOR]

Inhibition of the mechanistic target of rapamycin (mTOR) pathway by rapamycin (RAPA), an FDA-approved immunosuppressive drug used as a clinical therapy to prevent solid organ allograft rejection, enhances longevity in mice. Importantly, RAPA was efficacious even when initiated in relatively old animals, suggesting that mTOR inhibition could potentially slow the progression of aging-associated pathologies in older humans (Harrison et al., 2009; Miller et al., 2011). However, the safety and tolerability of RAPA in older human subjects have not yet been demonstrated. Towards this end, we undertook a placebo-controlled pilot study in 25 generally healthy older adults (aged 70–95 years); subjects were randomized to receive either 1 mg RAPA or placebo daily. Although three subjects withdrew, 11 RAPA and 14 controls completed at least 8 weeks of treatment and were included in the analysis. We monitored for changes that would indicate detrimental effects of RAPA treatment on metabolism, including both standard clinical laboratory assays (CBC, CMP, HbA1c) and oral glucose tolerance tests (OGTTs). We also monitored parameters typically associated with aging that could potentially be modified by RAPA; these included cognitive function which was assessed by three different tools: Executive Interview-25 (EXIT25); Saint Louis University Mental Status Exam (SLUMS); and Texas Assessment of Processing Speed (TAPS). In addition, physical performance was measured by handgrip strength and 40-foot timed walks. Lastly, changes in general parameters of healthy immune aging, including serum pro-inflammatory cytokine levels and blood cell subsets, were assessed. Five subjects reported potential adverse side effects; in the RAPA group, these were limited to facial rash (1 subject), stomatitis (1 subject) and gastrointestinal issues (2 subjects) whereas placebo treated subjects only reported stomatitis (1 subject). Although no other adverse events were reported, statistically significant decrements in several erythrocyte parameters including hemoglobin (HgB) and hematocrit (Hct) as well as in red blood cell count (RBC), red blood cell distribution width (RDW), mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) were observed in the RAPA-treatment group. None of these changes manifested clinically significant effects during the short duration of this study. Similarly, no changes were noted in any other clinical laboratory, cognitive, physical performance, or self-perceived health status measure over the study period. Immune parameters were largely unchanged as well, possibly due to the advanced ages of the cohort (70–93 years; mean age 80.5). RAPA-associated increases in a myeloid cell subset and in T REGS were detected, but changes in most other PBMC cell subsets were not statistically significant. Importantly, the OGTTs revealed no RAPA-induced change in blood glucose concentration, insulin secretion, and insulin sensitivity. Thus, based on the results of our pilot study, it appears that short-term RAPA treatment can be used safely in older persons who are otherwise healthy; a trial with a larger sample size and longer treatment duration is warranted. [ABSTRACT FROM AUTHOR]

Adolescence is a high‐risk age for exposure to violent media (EVM) and bullying. Some previous theories and empirical studies have highlighted a moderated mediating model that normative beliefs about aggression (NBA) as a mediator and self‐control (SC) as a moderator for the link between EVM and aggressive behaviors (including bullying behaviors). However, most previous studies analyzed traditional bullying (TB) and cyberbullying (CB) separately, which is not conducive to finding the differences between the two bullying behaviors. Therefore, this study aims to compare the differences between risk prediction models of TB and CB among adolescents. A total of 777 Chinese adolescent students (336 girls; Mage = 13.57 ± 0.98) completed questionnaires including EVM, NBA, TB, CB, and SC. The results showed that: (1) EVM was positively related to adolescent TB/CB; (2) NBA mediated the above relations; and (3) SC buffers the direct effect of EVM on TB and the effect of NBA on TB. However, SC buffers the effect of NBA on adolescent CB but not buffers the direct effect of EVM on CB. This study highlights the necessity of distinguishing offline and online situations in aggressive behavior research. We suggested "online disinhibit hypothesis" would be adopted to explain why protector factors (e.g., SC) do not buffer the link between aggression‐related risk factors (e.g., EVM) and online aggression (e.g., CB). [ABSTRACT FROM AUTHOR]

BackgroundStudies in cell cultures and rodents suggest that TLR4 is involved in the pathogenesis of insulin resistance, but direct data in humans are limited. We tested the hypothesis that pharmacologic blockade of TLR4 with the competitive inhibitor eritoran would improve insulin resistance in humans.MethodsIn protocol I, 10 lean, healthy individuals received the following 72-hour i.v. infusions in a randomized crossover design: saline (30 mL/h) plus vehicle; Intralipid (30 mL/h) plus vehicle; or Intralipid (30 mL/h) plus eritoran (12 mg i.v. every 12 hours). In protocol II, also a randomized crossover design, 9 nondiabetic individuals with obesity received eritoran or vehicle for 72 hours. The effect of eritoran was assessed with euglycemic hyperinsulinemic clamps.ResultsIn protocol I, lipid infusion significantly decreased peripheral insulin sensitivity (M value) by 14% and increased fasting plasma glucose (FPG) concentrations, fasting plasma insulin (FPI) concentrations, and the homeostatic model assessment of insulin resistance (HOMA-IR) index by 7%, 22%, and 26%, respectively. Eritoran did not prevent lipid-induced alterations of these metabolic parameters. Eritoran also failed to improve any baseline metabolic parameters (M, FPG, FPI, HOMA-IR) in individuals with obesity and insulin resistance (protocol II).ConclusionsAcute TLR4 inhibition with eritoran did not protect against lipid-induced insulin resistance. Short-term eritoran administration also failed to improve obesity-associated insulin resistance. These data do not support a role for TLR4 in insulin resistance. Future studies with a different class of TLR4 inhibitors, longer drug exposure, and/or lipid-enhancing interventions richer in saturated fats may be needed to further clarify the role of TLR4 in metabolic dysfunction in humans.Trial registrationClinicalTrials.gov NCT02321111 and NCT02267317.FundingNIH grants R01DK080157, P30AG044271, P30AG013319, and UL1TR002645. [ABSTRACT FROM AUTHOR]

How do we assess the value of our lives? What makes the life we live a good or worthy one in our own eyes? What are its aims? The answers to these questions are implicit in the often unarticulated commitments by which people define their selves, purposes, and actions. These commitments structure the moral framework that guides our everyday qualitative distinctions and positions us within a unified narrative of continuity and change. The substantive conception of a good life, we argue, presupposes but is not reducible to a set of basic values. As an initial exploration of cultural variation, Canadian, Chinese, Indian, and Japanese university students were compared on what they held to be most important for assessing the worth of their lives. The results revealed considerable commonality of content with notable differences consistent with the cultural ethos of each group. [ABSTRACT FROM AUTHOR]

The purpose of this study is to provide detailed data on treatment persistence and clinical outcomes in Chinese patients with nonvalvular atrial fibrillation (NVAF). A single-center retrospective observational study was conducted. A total of 26,663 NVAF patients were enrolled from January 1, 2014 to December 31, 2017, clinical information of whom were from inpatient and outpatients data system was collected. The 1-year treatment persistence rates of 11,350 dabigatran users were 24.5% in 2014, 36.6% in 2015, 37.7% in 2016 and 51.8% in 2017. The predominant reason of non-persistence patients was the cost of treatment. Incidence rates of all-cause death, ischemic stroke and embolism were 1.99/100 person-years, 2.56/100 person-years and 0.77/100 person-years, respectively. Incidence rates of minor bleeding events, intracranial hemorrhage and gastrointestinal hemorrhage were 10.05/100 person-years, 0.51/100 person-years and 0.85/100 person-years, respectively. In conclusion, it is of importance for Chinese clinicians to know about these information because dabigatran is a relatively new drug in China. Compared with other reported data, patients of this study have (1) lower dabigatran persistence and lower incident rates of all-cause death, systemic embolism, minor bleeding events and gastrointestinal hemorrhage and (2) higher incident rates of ischemic stroke and intracranial hemorrhage. [ABSTRACT FROM AUTHOR]

Metformin has beneficial effects on several age-related diseases (e.g., diabetes, obesity, cancer) and extends lifespan in nematodes and mice. Acarbose, an FDA-approved agent for treating type 2 diabetes, prevents breakdown of complex carbohydrates. Both compounds have been suggested as potential anti-aging interventions and acarbose has been shown to extend mouse longevity by the Intervention Testing Program (ITP). One potential next step is to assess the effect of these interventions on healthspan and lifespan in non-human primates. The common marmoset (Callithrix jacchus) is a small new world monkey with a relatively short life span and small size, both valuable for the translation potential of this nonhuman primate species for the study of aging and chronic disease. However, the dosing and assessment of potential side effects of either metformin or acarbose in this species have yet to be assessed. This study evaluated the pharmacokinetics of two dosage levels each of metformin or acarbose (given separately) in two small groups of young marmosets (n = 5/group) treated for 24 h to define the pharmacokinetics of each drug. The ability to rapidly and reliably dose socially housed marmosets with an oral form of acarbose or metformin that is well tolerated indicates that this species is a reliable model for testing acarbose and metformin in a safe and efficient way in a long-term intervention. [ABSTRACT FROM AUTHOR]

Premature baboons exhibit peripheral insulin resistance and impaired insulin signaling. 5’ AMP-activated protein kinase (AMPK) activation improves insulin sensitivity by enhancing glucose uptake (via increased glucose transporter type 4 [GLUT4] translocation and activation of the extracellular signal-regulated kinase [ERK]/ atypical protein kinase C [aPKC] pathway), and increasing fatty acid oxidation (via inhibition of acetyl-CoA carboxylase 1 [ACC]), while downregulating gluconeogenesis (via induction of small heterodimer partner [SHP] and subsequent downregulation of the gluconeogenic enzymes: phosphoenolpyruvate carboxykinase [PEPCK], glucose 6-phosphatase [G6PASE], fructose- 1,6-bisphosphatase 1 [FBP1], and forkhead box protein 1 [FOXO1]). The purpose of this study was to investigate whether pharmacologic activation of AMPK with AICAR (5-aminoimidazole-4-carboximide riboside) administration improves peripheral insulin sensitivity in preterm baboons. 11 baboons were delivered prematurely at 125±2 days (67%) gestation. 5 animals were randomized to receive 5 days of continuous AICAR infusion at a dose of 0.5 mg·g-1·day-1. 6 animals were in the placebo group. Euglycemic hyperinsulinemic clamps were performed at 5±2 and 14±2 days of life. Key molecules potentially altered by AICAR (AMPK, GLUT4, ACC, PEPCK, G6PASE, FBP1, and FOXO1), and the insulin signaling molecules: insulin receptor (INSR), insulin receptor substrate 1 (IRS-1), protein kinase B (AKT), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) were measured using RT-PCR and western blotting. AICAR infusion did not improve whole body insulin-stimulated glucose disposal in preterm baboons (12.8±2.4 vs 12.4±2.0 mg/(kg·min), p = 0.8, placebo vs AICAR). One animal developed complications during treatment. In skeletal muscle, AICAR infusion did not increase phosphorylation of ACC, AKT, or AMPK whereas it increased mRNA expression of ACACA (ACC), AKT, and PPARGC1A (PGC1α). In the liver, INSR, IRS1, G6PC3, AKT, PCK1, FOXO1, and FBP1 were unchanged, whereas PPARGC1A mRNA expression increased after AICAR infusion. This study provides evidence that AICAR does not improve insulin sensitivity in premature euglycemic baboons, and may have adverse effects. [ABSTRACT FROM AUTHOR]

Older adults universally suffer from sarcopenia and approximately 60-70% are diabetic or prediabetic. Nonetheless, the mechanisms underlying these aging-related metabolic disorders are unknown. NFκB has been implicated in the pathogenesis of several aging-related pathologies including sarcopenia and type 2 diabetes and has been proposed as a target against them. NFκB also is thought to mediate muscle wasting seen with disuse, denervation, and some systemic diseases ( e.g., cancer, sepsis). We tested the hypothesis that lifelong inhibition of the classical NFκB pathway would protect against aging-related sarcopenia and insulin resistance. Aged mice with muscle-specific overexpression of a super-repressor IκBα mutant ( MISR) were protected from insulin resistance. However, MISR mice were not protected from sarcopenia; to the contrary, these mice had decreases in muscle mass and strength compared to wild-type mice. In MISR mice, NFκB suppression also led to an increase in proteasome activity and alterations in several genes and pathways involved in muscle growth and atrophy ( e.g., myostatin). We conclude that the mechanism behind aging-induced sarcopenia is NFκB independent and differs from muscle wasting due to pathologic conditions. Our findings also indicate that, while suppressing NFκB improves insulin sensitivity in aged mice, this transcription factor is important for normal muscle mass maintenance and its sustained inhibition is detrimental to muscle function. [ABSTRACT FROM AUTHOR]

Abstract: Oxidative stress plays a significant role in the development of insulin resistance; however, the cellular targets of oxidation that cause insulin resistance have yet to be fully elucidated. Methionine sulfoxide reductases reduce oxidized methionine residues, thereby repairing and protecting proteins from oxidation. Recently, several genome-wide analyses have found human obesity to be strongly correlated with polymorphisms near the methionine sulfoxide reductase A (MsrA) locus. In this study, we tested whether modulation of MsrA expression significantly alters the development of obesity and/or insulin resistance in mice. We show that mice lacking MsrA (MsrA −/−) are prone to the development of high-fat-diet-induced insulin resistance and a reduced physiological insulin response compared to high-fat-fed wild-type mice. We also show that oxidative stress in C2C12 cell cultures reduces both insulin-stimulated phosphorylation and autophosphorylation of the insulin receptor. Tissues from high-fat-fed mice show similar reduction in insulin receptor function and increase in insulin receptor oxidation, which are further exacerbated by the lack of MsrA. Together, these data demonstrate for the first time that MsrA and protein oxidation play a role in the regulation of glucose homeostasis. In addition, these data support a novel hypothesis that obesity-induced insulin resistance is caused in part by reduced function of insulin signaling proteins arising from protein oxidation. [Copyright &y& Elsevier]

Genetic manipulations of Mn superoxide dismutase (MnSOD), SOD2 expression have demonstrated that altering the level of MnSOD activity is critical for cellular function and life span in invertebrates. In mammals, Sod2 homozygous knockout mice die shortly after birth, and alterations of MnSOD levels are correlated with changes in oxidative damage and in the generation of mitochondrial reactive oxygen species. In this study, we directly tested the effects of overexpressing MnSOD in young (4–6 months) and old (26–28 months) mice on mitochondrial function, levels of oxidative damage or stress, life span, and end-of-life pathology. Our data show that an approximately twofold overexpression of MnSOD throughout life in mice resulted in decreased lipid peroxidation, increased resistance against paraquat-induced oxidative stress, and decreased age-related decline in mitochondrial ATP production. However, this change in MnSOD expression did not alter either life span or age-related pathology. [ABSTRACT FROM PUBLISHER]

Previously, we demonstrated that mitochondria from denervated muscle exhibited dramatically higher Amplex Red dependent fluorescence (thought to be highly specific for hydrogen peroxide) compared with control muscle mitochondria. We now demonstrate that catalase only partially inhibits the Amplex Red signal in mitochondria from denervated muscle. In contrast, ebselen (a glutathione peroxidase mimetic and inhibitor of fatty acid hydroperoxides) significantly inhibits the Amplex Red signal. This suggests that the majority of the Amplex Red signal in mitochondria from denervated muscle is not derived from hydrogen peroxide. Because Amplex Red cannot react with substrates in the lipid environment, we hypothesize that lipid hydroperoxides formed within the mitochondrial lipid bilayer are released as fatty acid hydroperoxides and react with the Amplex Red probe. We also suggest that the release of fatty acid hydroperoxides from denervated muscle mitochondria may be an important determinant of muscle atrophy. In support of this, muscle atrophy and the Amplex Red signal are inhibited in caloric restricted mice and in transgenic mice that overexpress the lipid hydroperoxide-detoxifying enzyme glutathione peroxidase 4. Finally, we propose that cytosolic phospholipase A[sub2] may be a potential source of these hydroperoxides. [ABSTRACT FROM AUTHOR]

H2O2 is a major reactive oxygen species produced by mitochondria that is implicated to be important in aging and pathogenesis of diseases such as diabetes; however, the cellular and physiological roles of mitochondrial H2O2 remain poorly understood. Peroxiredoxin 3 (Prdx3/Prx3) is a thioredoxin peroxidase localized in mitochondria. To understand the cellular and physiological roles of mitochondrial H2O2 in aging and pathogenesis of age-associated diseases, we generated transgenic mice overexpressing Prdx3 (Tg(PRDX3) mice). Tg(PRDX3) mice overexpress Prdx3 in a broad range of tissues, and the Prdx3 overexpression occurs exclusively in the mitochondria. As a result of increased Prdx3 expression, mitochondria from Tg(PRDX3) mice produce significantly reduced amount of H2O2, and cells from Tg(PRDX3) mice have increased resistance to stress-induced cell death and apoptosis. Interestingly, Tg(PRDX3) mice show improved glucose homeostasis, as evidenced by their reduced levels of blood glucose and increased glucose clearance. Tg(PRDX3) mice are also protected against hyperglycemia and glucose intolerance induced by high-fat diet feeding. Our results further show that the inhibition of GSK3 may play a role in mediating the improved glucose tolerance phenotype in Tg(PRDX3) mice. Thus, our results indicate that reduction of mitochondrial H2O2 by overexpressing Prdx3 improves glucose tolerance. [ABSTRACT FROM AUTHOR]