The JNK inhibitor, SP600125, potentiates the glial response and cell death induced by methamphetamine in the mouse striatum

This study investigates the effect of the selective Jun NH2-terminal kinase 1/2 (JNK1/2) inhibitor, (SP600125) on the striatal dopamine nerve terminal loss and on the increased interleukin-15 (IL-15) expression and glial response induced by methamphetamine (METH). Mice were given repeated low doses of METH (4Â mg/kg, i.p., three times separated by 3Â h) and killed 24Â h or 7 d after the last dose. SP600125 (30Â mg/kg, i.p) was administered 30Â min before the last METH injection. Results indicate that METH produced dopaminergic axonal neurotoxicity reflected as a marked decrease in the striatal density of tyrosine hydroxylase-immunoreactive (TH-ir) fibres and dopamine transporter-immunoreactivity (DAT-ir) 24Â h after dosing. These effects were not modified by SP600125. This compound also failed to prevent the long-term loss of dopamine levels and DAT observed 7 d following METH injection. Nevertheless, SP600125 potentiated METH-induced striatal cell loss reflected by an increase in Fluoro-Jade immunostaining, cleaved capase-3 immunoreactivity and the number of terminal deoxyncleotidyl transferase-mediated dUTP nick end labelling (TUNEL) positive cells. In line with a deleterious effect of JNK1/2 inhibition, SP600125 increased the astroglial and microglial response induced by METH and interfered with drug-induced IL-15 expression. Together these data indicate that, not only does SP600125 fail to protect against the dopaminergic damage induced by METH but also, in fact, it potentiates the glial response and the non-dopaminergic striatal cell loss caused by the drug. © 2013 CINP.Peer Reviewe

Niveles De Motivación Y Las Competencias Laborales Específicas De Los Trabajadores A Distancia

The aim of this study was to determine the relationship between motivation and specific job skills of teleworkers. The methodology was applied, descriptive and correlational. The study was hypothetical deductive, non experimental, transactional and quantitative. The sampling was non probabilistic by quotas, was included telecommuters from different companies that use this type of work, located in the interior of Mexico, USA and Canada. The sample size was 27 teleworkers. A questionnaire of 52 questions was used as a measuring tool. The data analysis was descriptive and chi square test was used to identify the relationship of the independent variable motivation with the dependent variable specific job skills of teleworkers. The main results showed that motivation is high and teleworkers have a high development in most of their job skills. Also among the most outstanding results it was found that the variable motivation in the three indicators analyzed: the need for existence, value and growth, have a closer relationship with labor competition autonomy, than the rest of labor skills analyzed

First constraints from DAMIC-M on Sub-GeV dark-matter particles interacting with electrons

We report constraints on sub-GeV dark matter particles interacting with electrons from the first underground operation of DAMIC-M detectors. The search is performed with an integrated exposure of 85.23 g days, and exploits the subelectron charge resolution and low level of dark current of DAMIC-M charge-coupled devices (CCDs). Dark-matter-induced ionization signals above the detector dark current are searched for in CCD pixels with charge up to 7e−. With this dataset we place limits on dark matter particles of mass between 0.53 and 1000 MeV/c², excluding unexplored regions of parameter space in the mass ranges [1.6; 1000] MeV/c² and [1.5; 15.1] MeV/c² for ultralight and heavy mediator interactions, respectively.IFCA was supported by project PID2019–109829GB-I00 funded by MCIN/ AEI /10.13039/501100011033

Mitochondrial ultrastructure and markers of dynamics in hepatocytes from aged, calorie restricted mice fed with different dietary fats

PMCID: PMC4104696In this paper we analyzed changes in hepatocyte mitochondrial mass and ultrastructure as well as in mitochondrial markers of fission/fusion and biogenesis in mice subjected to 40% calorie restriction (CR) for 18. months versus ad libitum-fed controls. Animals subjected to CR were separated into three groups with different dietary fats: soybean oil (also in controls), fish oil and lard. Therefore, the effect of the dietary fat under CR was studied as well. Our results show that CR induced changes in hepatocyte and mitochondrial size, in the volume fraction occupied by mitochondria, and in the number of mitochondria per hepatocyte. Also, mean number of mitochondrial cristae and lengths were significantly higher in all CR groups compared with controls. Finally, CR had no remarkable effects on the expression levels of fission and fusion protein markers. However, considerable differences in many of these parameters were found when comparing the CR groups, supporting the idea that dietary fat plays a relevant role in the modulation of CR effects in aged mice.Supported by NIH grant 1R01AG028125-01A1 (to JJR, PN and JMV), Ministerio de Economía y Competitividad and European FEDERBFU2011-23578 (to JMV), Junta de Andalucía Proyectos de Excelencia grant P09-CVI-4887 (to JMV), Junta de Andalucía Proyectos Internacionales (to JMV), and BIO-276 (Junta de Andalucía and the University of Córdoba, to JMV and EGC). JALD and LFdR were funded by predoctoral fellowships of the Spanish Ministerio de Educación and by BIO-276. HK was funded by a predoctoral fellowship of the Agencia Española de Cooperación Internacional al Desarrollo and by BIO-276.Peer Reviewe

The influence of dietary fat source on liver and skeletal muscle mitochondrial modifications and lifespan changes in calorie-restricted mice

The Membrane Theory of Aging proposes that lifespan is inversely related to the level of unsaturation in membrane phospholipids. Calorie restriction (CR) without malnutrition extends lifespan in many model organisms, which may be related to alterations in membrane phospholipids fatty acids. During the last few years our research focused on studying how altering the predominant fat source affects the outcome of CR in mice. We have established four dietary groups: one control group fed 95 % of a pre-determined ad libitum intake (in order to prevent obesity), and three CR groups fed 40 % less than ad libitum intake. Lipid source for the control and one of the CR groups was soybean oil (high in n-6 PUFA) whereas the two remaining CR groups were fed diets containing fish oil (high in n-3 PUFA), or lard (high in saturated and monounsaturated fatty acids). Dietary intervention periods ranged from 1 to 18 months. We performed a longitudinal lifespan study and a cross-sectional study set up to evaluate several mitochondrial parameters which included fatty acid composition, H+ leak, activities of electron transport chain enzymes, ROS generation, lipid peroxidation, mitochondrial ultrastructure, and mitochondrial apoptotic signaling in liver and skeletal muscle. These approaches applied to different cohorts of mice have independently indicated that lard as a fat source often maximizes the effects of 40 % CR on mice. These effects could be due to significant increases of monounsaturated fatty acids levels, in accordance with the Membrane Theory of Aging.Supported by NIH grant 1R01AG028125 (to JJR, PN and JMV), Ministerio de Economía y Competitividad BFU2011-23578 (to JMV), Junta de Andalucía Proyectos de Excelencia grant P09-CVI-4887 (to JMV), Junta de Andalucía Proyectos Internacionales grant (to JMV), and BIO-276 (Junta de Andalucía and the University of Córdoba, to JMV). RdC is funded by the Intramural Research program of the NIA/NIH. JALD, JA, LFdR and EGC were funded by a predoctoral fellowship of the Spanish Ministerio de Educación and BIO-276. HK was funded by a predoctoral fellowship of the Agencia Española de Cooperación Internacional al Desarrollo and BIO-276. MCR and MdR were supported by BIO-276.Peer Reviewe

Signaling through the leukocyte integrin LFA-1 in T cells induces a transient activation of Rac-1 that is regulated by Vav and PI3K/Akt-1

12 p.-8 fig.Integrin LFA-1 is a receptor that is able to transmit multiple intracellular signals in leukocytes. Herein we show that LFA-1 induces a potent and transient increase in the activity of the small GTPase Rac-1 in T cells. Maximal Rac-1 activity peaked 10-15 min after LFA-1 stimulation and rapidly declined to basal levels at longer times. We have identified Vav, a guanine nucleotide exchange factor for Rac-1, and PI3K/Akt, as regulators of the activation and inactivation phases of the activity of Rac-1, respectively, in the context of LFA-1 signaling based on the following experimental evidence: (i) LFA-1 induced activation of Vav and PI3K/Akt with kinetics consistent with a regulatory role for these molecules on Rac-1, (ii) overexpression of a constitutively active Vav mutant induces activation of Rac independently of LFA-1 stimulation whereas overexpression of a dominant-negative Vav mutant blocks LFA-1-mediated Rac activation, (iii) pharmacological inhibition of PI3K/Akt prevented the fall in the activity of Rac-1 after its initial activation but had no effect on Vav activity, and (iv) overexpression of a dominant-negative or a constitutively active Akt-1 induced or inhibited, respectively, Rac-1 activity. Finally, we show that T cells with a sustained Rac activity have impaired capacity to elongate onto ICAM-1. These results demonstrate that down-regulation of the activity of this GTPase is a requirement for the regulation of T cell morphology and motility and highlight the importance of temporal regulation of the signaling triggered from this integrin.This work was supported in part by Grants CICYT SAF 2001–2807 from Ministerio de Ciencia y Tecnología and FIS-01/1367 from Ministerio de Sanidad y Consumo (to C. C.), a fellowship from Comunidad de Madrid (to L. S.-M.), a Formación de Profesorado Universitario predoctoral fellowship from Ministerio de Educación, Cultura y Deporte (to N. S.-S.), and a postdoctoral fellowship from Ministerio de Educación, Cultura y Deporte (to M. D. G.-L.).Peer reviewe

MONITORING THE SEVERITY AND VARIABILITY OF BROWN RUST (Puccinia melanocephala) IN SUGARCANE VARIETIES IN THE CAUCA VALLEY, COLOMBIA

Abstract THE VARIETIES CC 85-92 and CC 84-75 are grown on more than 80% of the area planted with cane in the Colombian sugar industry; these varieties were initially resistant to brown rust disease. Brown rust has been present in Colombia since 1979. Genetic variability in Puccinia melanocephala is thought to have affected resistance in some varieties through the appearance of what are thought to be new races of the pathogen. This situation has been observed in some resistant varieties (e.g. CC [85][86][87][88][89][90][91][92], where recently the disease has occurred at low severity. Therefore, an evaluation was made of the severity and possible variability of brown rust in the varieties selected by CENICAÑA in the Cauca River Valley. Samples were taken from plants from 1-14 months of age in the varieties CC 84-75, CC 85-92, CC 93-3895, CC 92-2804 and MZC 74-275 on 91 estates (10 sugar mills). On each plantation 20 stalks were selected at random, and the third leaf from the top visible dewlap leaf was taken from each stalk. Both disease reaction and severity were evaluated. Morphological and microscopic analyses of the structures found in the rust pustules were undertaken in leaf samples taken from each variety. Simultaneously, pathogen samples were collected and molecular techniques used (focusing on initiators of the ribosomal DNA (rDNA)) to detect possible genetic variation of P. melanocephala. The results showed that the disease reaction type in the varieties evaluated was 5 or less, with severities ranging from 0-12% leaf area affected. Variety MZC 74-275 showed susceptibility, with a reaction of 6 and a severity of 20% on the estates where it was evaluated. No differences were found among the morphological structures in the samples evaluated, all of which corresponded to P. melanocephala. The results obtained from the amplification of the ITS1 and ITS2 regions of the rDNA and from the PCR-RFLP did not show differences among the samples evaluated. These results could indicate that the variation of the pathogen is not reflected in its rDNA or that the molecular technique used was not sufficiently sensitive to detect small variations in the genome. Initial results about the presence or absence of gene Bru1 and susceptibility to brown rust are discussed

FGF21 serum levels are related to insulin resistance, metabolic changes and obesity in Mexican people living with HIV (PLWH).

Antiretroviral therapy has significantly improved prognosis in treatment against HIV infection, however, prolonged exposure is associated to cardiovascular diseases, lipodystrophy, type 2 diabetes, insulin resistance, metabolic alteration, as obesity which includes the accumulation of oxidative stress in adipose tissue. FGF21 is a peptide hormone that is known to regulate glucose and lipid metabolism. FGF21 is expressed and secreted primarily in the liver and adipose tissue, promoting oxidation of glucose/fatty acids and insulin sensitivity. Alterations in FGF21 may be associated with the development of insulin resistance, metabolic syndrome and cardiovascular disease. We hypothesized that FGF21 protein levels are associated with metabolic abnormalities, placing special attention to the alterations in relation to the concurrence of overweight/obesity in people living with HIV (PLWH)

Functional relevance of the switch of VEGF receptors/co-receptors during peritoneal dialysis-induced mesothelial to mesenchymal transition

Vascular endothelial growth factor (VEGF) is up-regulated during mesothelial to mesenchymal transition (MMT) and has been associated with peritoneal membrane dysfunction in peritoneal dialysis (PD) patients. It has been shown that normal and malignant mesothelial cells (MCs) express VEGF receptors (VEGFRs) and co-receptors and that VEGF is an autocrine growth factor for mesothelioma. Hence, we evaluated the expression patterns and the functional relevance of the VEGF/VEGFRs/co-receptors axis during the mesenchymal conversion of MCs induced by peritoneal dialysis. Omentum-derived MCs treated with TGF-β1 plus IL-1β (in vitro MMT) and PD effluent-derived MCs with non-epithelioid phenotype (ex vivo MMT) showed down-regulated expression of the two main receptors Flt-1/VEGFR-1 and KDR/VEGFR-2, whereas the co-receptor neuropilin-1 (Nrp-1) was up-regulated. The expression of the Nrp-1 ligand semaphorin-3A (Sema-3A), a functional VEGF competitor, was repressed throughout the MMT process. These expression pattern changes were accompanied by a reduction of the proliferation capacity and by a parallel induction of the invasive capacity of MCs that had undergone an in vitro or ex vivo MMT. Treatment with neutralizing anti-VEGF or anti-Nrp-1 antibodies showed that these molecules played a relevant role in cellular proliferation only in naïve omentum-derived MCs. Conversely, treatment with these blocking antibodies, as well as with recombinant Sema-3A, indicated that the switched VEGF/VEGFRs/co-receptors axis drove the enhanced invasion capacity of MCs undergoing MMT. In conclusion, the expression patterns of VEGFRs and co-receptors change in MCs during MMT, which in turn would determine their behaviour in terms of proliferation and invasion in response to VEGFThis work was supported by grant SAF2010-21249 from the ‘‘Ministerio de Economía y Competitividad’’ to M.L.C. and by grant S2010/BMD-2321 from ‘‘Comunidad Autónoma de Madrid’’ to M.L.C. and R.S. This work was also partially supported by grants PI 09/0776 from ‘‘Fondo de Investigaciones Sanitarias’’ to A.A., and RETICS 06/0016 (REDinREN, Fondos FEDER, EU) to R.S

Los Poyos del Molinillo (Frigiliana): new site of the Bronze Age in the East Axarquía (Málaga, Andalucía)

En este trabajo damos a conocer un nuevo yacimiento descubierto recientemente en el municipio de Frigiliana. La delimitación del área denominada Los Poyos del Molinillo permitió definir la existencia de un poblado y una covacha con restos de una inhumación. El estudio de los materiales arqueológicos, que incluye cerámica, piezas metálicas o elementos de molturación, o la datación AMS obtenida, permiten adscribir el yacimiento a la Edad del Bronce y ampliar el conocimiento de esta etapa en la Axarquía oriental (Málaga, Andalucía).In this work we present a new site recently discovered in the Frigiliana municipality (Málaga). The spatial delimitation of the so called Los Poyos del Molinillo area let us define a Bronze age settlement and an inhumation burial cave. The archaeological record includes ceramic, metallic items or grinding elements, all of them belonging to the Bronze Age, as well as an AMS Radiocarbon data. This site extends the knowledge about this period in the Eastern Axarquía (Málaga, Andalucía)