RESUMEN

INTRODUCTION: Happé's Strange Stories task was developed in 1994 to assess theory of mind, the ability to infer mental states in oneself and others. Since then, it has undergone revisions, translations, and adaptations. A modified version of the task, the Strange Stories-Revised (SS-R), previously showed satisfactory qualities in a study aiming at identifying psychometrically acceptable social cognitive measures. OBJECTIVE: The current study expands upon the psychometric evaluation study by examining the qualities of a short version of the SS-R in a sample of healthy adult subjects. METHODS: One hundred and eighteen healthy adults completed the task along with neurocognitive measures. Mean scores of the long and short versions were compared. Associations between ToM as measured by performance on this abbreviated version of the SS-R, and potential confounders were explored. Internal consistency, dimensionality of the short version, and performance comparisons across three stages of aging (18-34; 35-59; 60-85 years old) were investigated, and standard measurement error was calculated to improve precision and data interpretation. RESULTS: Reliability coefficients were comparable in the short and long versions. Principal component analysis showed that a one-factor structure best fits the data. Significant differences were observed in ToM performance across the three age groups, indicating a decline with time that was also captured by the long version, starting during midlife and increasing in significance with age. CONCLUSION: The short version of the SS-R is a promising measure that can be profitably used in time-limited settings to assess theory of mind.

RESUMEN

Although there has been a marked increase in interest in social cognition (SC) in recent years, psychometric data relating to many tasks used to measure its components remain limited in healthy populations with only five articles published to date. It is accordingly premature to speak of a consensus concerning the specific components, or best tests of the components, and possible cultural differences. The present study sought to partially fill that gap, examining the psychometric properties of a battery of SC tasks in a sample of 100 healthy adults aged 18-85 years old. Initially, nine tasks assessing four SC components were selected: emotion recognition, theory of mind, attributional bias, and social judgment. Construct validity and criterion-related validity were assessed using factor and correlational analyses. Performance across age and sex groups was also investigated. Reliability was assessed through internal consistency, interrater and intercoder agreement. Results indicated satisfactory properties for the Ambiguous Intentions Hostility Questionnaire-blame score, the Social Judgment Task, the Facial Emotions Recognition Test, and a modified version of the Strange Stories Task. Statistically significant differences were found between the groups with regard to age and sex after accounting for demographic and cognitive factors. However, the correlations of these measures with relationship quality were mostly very low, raising questions about their concomitant validity. Other tasks showed sub-optimal properties, suggesting that some frequently used tests require further validation or modifications to ensure the quality of research findings. Based on the results, recommended measures for future studies and limitations are discussed.

Asunto(s)

RESUMEN

Accumulating evidence points toward an association between older age and performance decrements in social cognition (SC). We explored age-related variations in four components of SC: emotion recognition, theory of mind, social judgment, and blame attributions. A total of 120 adults divided into three stages (18-34 years, 35-59 years, 60-85 years) completed a battery of SC. Between and within age-group differences in SC were investigated. Path analyses were used to identify relationships among the components. Emotion recognition and theory of mind showed differences beginning either in midlife, or after. Blame attributions and social judgment did not show a significant difference. However, social judgment varied significantly within groups. Path models revealed a relationship between emotion recognition and theory of mind. Findings highlight age-related differences in some components and a link between two components. Strategies promoting social functioning in aging might help to maintain or improve these abilities over time.

Asunto(s)

RESUMEN

The mTOR is a central regulator of cell growth and is highly activated in cancer cells to allow rapid tumor growth. The use of mTOR inhibitors as anticancer therapy has been approved for some types of tumors, albeit with modest results. We recently reported the synthesis of ICSN3250, a halitulin analogue with enhanced cytotoxicity. We report here that ICSN3250 is a specific mTOR inhibitor that operates through a mechanism distinct from those described for previous mTOR inhibitors. ICSN3250 competed with and displaced phosphatidic acid from the FRB domain in mTOR, thus preventing mTOR activation and leading to cytotoxicity. Docking and molecular dynamics simulations evidenced not only the high conformational plasticity of the FRB domain, but also the specific interactions of both ICSN3250 and phosphatidic acid with the FRB domain in mTOR. Furthermore, ICSN3250 toxicity was shown to act specifically in cancer cells, as noncancer cells showed up to 100-fold less sensitivity to ICSN3250, in contrast to other mTOR inhibitors that did not show selectivity. Thus, our results define ICSN3250 as a new class of mTOR inhibitors that specifically targets cancer cells.Significance: ICSN3250 defines a new class of mTORC1 inhibitors that displaces phosphatidic acid at the FRB domain of mTOR, inducing cell death specifically in cancer cells but not in noncancer cells. Cancer Res; 78(18); 5384-97. ©2018 AACR.

Asunto(s)

RESUMEN

Pyrrolidine dithiocarbamate (PDTC) known as antioxidant and specific inhibitor of NF-κB was also described as pro-oxidant by inducing cell death and reactive oxygen species (ROS) accumulation in cancer. However, the mechanism by which PDTC indices its pro-oxidant effect is unknown. Therefore, we aimed to evaluate the effect of PDTC on the human Cu/Zn superoxide dismutase 1 (SOD1) gene transcription in hematopoietic human cancer cell line U937. We herein show for the first time that PDTC decreases SOD1 transcripts, protein and promoter activity. Furthermore, SOD1 repression by PDTC was associated with an increase in oxidative stress as evidenced by ROS production. Electrophoretic mobility-shift assays (EMSA) show that PDTC increased binding of activating protein-1 (AP-1) in dose dependent-manner suggesting that the MAPkinase up-stream of AP-1 is involved. Ectopic NF-κB p65 subunit overexpression had no effect on SOD1 transcription. In contrast, in the presence of JNK inhibitor (SP600125), p65 induced a marked increase of SOD1 promoter, suggesting that JNK pathway is up-stream of NF-κB signaling and controls negatively its activity. Indeed, using JNK deficient cells, PDTC effect was not observed nether on SOD1 transcription or enzymatic activity, nor on ROS production. Finally, PDTC represses SOD1 in U937 cells through JNK/c-Jun phosphorylation. Taken together, these results suggest that PDTC acts as pro-oxidant compound in JNK/AP-1 dependent-manner by repressing the superoxide dismutase 1 gene leading to intracellular ROS accumulation.

Asunto(s)

RESUMEN

A short synthesis of N-substituted 3,4-diarylpyrroles by condensation of a phenacyl halide with a primary amine and a phenylacetaldehyde is reported. The key step is an intramolecular cyclization of an in situ generated enamine onto a ketone. Using differently substituted aromatic reactants and N-(3-aminopropyl)azatricyclodecane as the amine component, the preparation of analogs of the cytotoxic marine alkaloid halitulin could be achieved. The cytotoxicity of some of the compounds obtained by this method was studied, and one of them proved to be a very potent derivative, acting at a nanomolar concentration, in a caspase-independent cell death mechanism.

Asunto(s)

RESUMEN

Methanol and ethanol have been identified as oil-soluble by-products generated by the aging of oil-impregnated cellulosic insulation materials of power transformers. Their presence provides useful information for diagnostics and end-of-life transformer estimation. Despite their value as cellulose degradation indicators, their sensitive and accurate determination is challenged by the complex oil matrix. To overcome this constraint, we present a simple, fast and direct procedure for their simultaneous determination in mineral insulating oil samples. The procedure uses a static headspace sampler coupled with a gas chromatograph equipped with a mass spectrometer. The selected method parameters permitted adequate separation of these two compounds from the complex oil matrix and quantification at ng g(-1) concentrations. An original internal standard procedure was developed, in which ethanol-d6 was added to all studied samples and blanks, with adequate resolution between the internal standard and its isotopomer ethanol. The method was validated in terms of accuracy and reproducibility for both analytes. The method detection limit, 4 ng g(-1) for methanol and ethanol, is well below the value (µg g(-1)) achieved by a standardized method for methanol determination in crude oil. During method validation studies, a relative error of approximately 6% was obtained for both methanol and ethanol with excellent reproducibility, average %RSD, below 2%. An experiment control chart, constructed to evaluate long-term reproducibility, indicate an overall good reproducibility (%RSD<3%) for 1000 ng g(-1) control solutions. The applicability of the method to the direct analysis of trace methanol and ethanol in oil from field transformer samples was successfully demonstrated. This analytical method is of high relevance to the electrical utilities as it allows indirectly assessment of the level of deterioration of the critical cellulose, an inaccessible part of a power transformer.

Asunto(s)

RESUMEN

The purpose of the present study was to determine the effects of an exercise training programme in high-fat-fed rats on in vitro lipolysis in a visceral (mesenteric) and a non-visceral fat depot (retroperitoneal) and its relationship to perilipin content. Two groups of female rats were fed a high-fat diet (42 % as energy) for 8 weeks, one remaining sedentary (Sed) and the other being exercise trained (Tr) for this entire period. Rats were killed after 2 and 8 weeks of their respective treatment. The significantly (P < 0.01) higher levels in mesenteric and retroperitoneal fat pad weights, plasma leptin, NEFA and glucose observed with time in Sed high-fat-fed rats were significantly (P < 0.05) attenuated in Tr animals. Isoproterenol-stimulated (10- 5-10- 4 m) lipolysis in the mesenteric, but not in the retroperitoneal tissue, was significantly (P < 0.05) lower (about 57 %) in Tr than in Sed rats after 8 weeks of high-fat feeding. The isoproterenol-stimulated lipolysis in the mesenteric tissue of 8-week Tr high-fat-fed rats was lowered to the level measured in 2-week fat-fed rats although mesenteric fat accumulation was still significantly (P < 0.01) higher in 8- than in 2-week Tr rats. Perilipin content (Western blot) was not affected by the exercise training programme. These results indicate that exercise training resulted in a reduction in the high-fat diet-induced elevated levels of lipolysis in the mesenteric tissue. This response appears to be independent of the perilipin content.

Asunto(s)

RESUMEN

Reactive oxygen species (ROS) are produced in many normal and abnormal processes in humans, including atheroma, asthma, joint diseases, aging, and cancer. The superoxide anion O(2)(-) is the main ROS. Increased ROS production leads to tissue damage associated with inflammation. Superoxide dismutases (SODs) convert superoxide to hydrogen peroxide, which is then removed by glutathione peroxidase or catalase. Thus, SODs prevent the formation of highly aggressive ROS, such as peroxynitrite or the hydroxyl radical. Experimental models involving SOD knockout or overexpression are beginning to shed light on the pathophysiological role of SOD in humans. Although the antiinflammatory effects of exogenous native SOD (orgotein) are modest, synthetic SOD mimetics hold considerable promise for modulating the inflammatory response. In this review, we discuss new knowledge about the role of the superoxide anion and its derivates as mediators of inflammation and the role of SODs and SOD mimetics as antioxidant treatments in joint diseases such as rheumatoid arthritis, osteoarthritis, and crystal-induced arthropathies.

Asunto(s)

RESUMEN

Overexpression of Cu/Zn superoxide dismutase 1 (SOD1) in monocytes blocks reactive oxygen species-induced inhibition of cell growth and apoptosis and renders cells resistant to the toxic effect of tumor necrosis factor (TNF)-alpha, suggesting that TNF-alpha represses the SOD1 gene in these cells. We herein show that TNF-alpha decreases SOD1 mRNA, protein, and promoter activity in U937 cells. Electrophoretic mobility-shift assays (EMSA) show that TNF-alpha decreased binding of three different complexes. Ectopic Sp1 overexpression markedly increased SOD1-basal promoter activity and partially antagonized the TNF-alpha inhibitory effect. In contrast, ectopic c-Jun overexpression mimics TNF-alpha inhibitory effects and antagonizes Sp1 stimulatory effects. In agreement with these findings, EMSA shows a TNF-alpha-induced increase in AP-1 and a decrease in Sp1 DNA binding. Disruption of the C/EBP site decreases, whereas mutation in the Sp1/Egr-1 site completely abolishes DNA-binding and promoter activity. A JNK inhibitor antagonized the negative effects of TNF-alpha on SOD1 promoter activity, suggesting that JNK signaling through c-Jun protein activation is critical for the TNF-alpha-dependent SOD1 repression. A greater understanding of the mechanisms of TNF-alpha-induced SOD1 repression could facilitate the design and development of novel therapeutic drugs for inflammatory conditions.

Asunto(s)

RESUMEN

The purpose of the present study was to determine the time course of changes in in vitro lipolysis and in perilipin content (Western blot) in the mesenteric and/or the retroperitoneal fat depots in relation to the development of hepatic steatosis in high-fat diet-fed rats. Female Sprague-Dawley rats were submitted to a high-fat diet (HF diet; 42 % as kJ) or a standard diet (SD diet) for 1, 2, 3 or 8 weeks. Fat accretion in the mesenteric and retroperitoneal tissues was higher (P<0.01) in HF diet-fed than in SD diet-fed rats as soon as 1 week after the beginning of the diet. Liver triacylglycerol concentrations were significantly (P<0.01) higher in HF diet-fed than in SD diet-fed rats throughout the experiment, the highest values being reached at week 2 of the diet. Basal and stimulated lipolysis (10(-4) to 10(-7) M-isoproterienol) in the mesenteric and retroperitoneal fat depots was not changed during the first 3 weeks, regardless of the diet. Lipolysis in the mesenteric adipose tissue in the basal and stimulated states was, however, higher (P<0.01) in HF diet-fed than in SD diet-fed rats after 8 weeks of the diets. There were no significant (P>0.05) effects of diet and time on perilipin content of mesenteric tissue. In spite of a rapid fat accretion, the present results do not provide any evidence of a rapid (3 weeks) increase in in vitro lipolysis in intra-abdominal fat depots upon the undertaking of an HF diet at a time where liver lipid infiltration is the most significant.

Asunto(s)