Role of mTOR-regulated autophagy in spine pruning defects and memory impairments induced by binge-like ethanol treatment in adolescent mice

Adolescence is a brain maturation developmental period during which remodeling and changes in synaptic plasticity and neural connectivity take place in some brain regions. Different mechanism participates in adolescent brain maturation, including autophagy that plays a role in synaptic development and plasticity. Alcohol is a neurotoxic compound and its abuse in adolescence induces neuroinflammation, synaptic and myelin alterations, neural damage and behavioral impairments. Changes in synaptic plasticity and its regulation by mTOR have also been suggested to play a role in the behavioral dysfunction of binge ethanol drinking in adolescence. Therefore, by considering the critical role of mTOR in both autophagy and synaptic plasticity in the developing brain, the present study aims to evaluate whether binge ethanol treatment in adolescence would induce dysfunctions in synaptic plasticity and cognitive functions and if mTOR inhibition with rapamycin is capable of restoring both effects. Using C57BL/6 adolescent female and male mice (PND30) treated with ethanol (3 g/kg) on two consecutive days at 48-hour intervals over 2 weeks, we show that binge ethanol treatment alters the density and morphology of dendritic spines, effects that are associated with learning and memory impairments and changes in the levels of both transcription factor CREB phosphorylation and miRNAs. Rapamycin administration (3 mg/kg) prior to ethanol administration restores ethanol-induced changes in both plasticity and behavior dysfunctions in adolescent mice. These results support the critical role of mTOR/autophagy dysfunctions in the dendritic spines alterations and cognitive alterations induced by binge alcohol in adolescence

Age-Mediated Transcriptomic Changes in Adult Mouse Substantia Nigra

Substantia nigra pars compacta (SNpc) is highly sensitive to normal aging and selectively degenerates in Parkinson's disease (PD). Until now, molecular mechanisms behind SNpc aging have not been fully investigated using high throughput techniques. Here, we show early signs of aging in SNpc, which are more evident than in ventral tegmental area (VTA), a region adjacent to SNpc but less affected in PD. Aging-associated early changes in transcriptome were investigated comparing late middle-aged (18 months old) to young (2 months old) mice in both SNpc and VTA. A meta-analysis of published microarray studies allowed us to generate a common >transcriptional signature> of the aged (≥ 24 months old) mouse brain. SNpc of late-middle aged mice shared characteristics with the transcriptional signature, suggesting an accelerated aging in SNpc. Age-dependent changes in gene expression specific to SNpc were also observed, which were related to neuronal functions and inflammation. Future studies could greatly help determine the contribution of these changes to SNpc aging. These data help understand the processes underlying SNpc aging and their potential contribution to age-related disorders like PD. © 2013 Gao et al.This work was funded by Spanish Ministry of Science and Education, Andalusian Government, and “Marcelino Botín” Foundation. “CIBERNED” (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas) was funded by the Spanish “Carlos III” Institute of Health. LME was supported by the Spanish “Carlos III” Institute of Health. Support from the Spanish Ministry of Science and Education for MHF (“FPI” predoctoral fellowship) is also acknowledged.Peer Reviewe

ERK5 signalling pathway is a novel target of sorafenib: Implication in EGF biology

© 2021 The Authors.Sorafenib is a multikinase inhibitor widely used in cancer therapy with an antitumour effect related to biological processes as proliferation, migration or invasion, among others. Initially designed as a Raf inhibitor, Sorafenib was later shown to also block key molecules in tumour progression such as VEGFR and PDGFR. In addition, sorafenib has been connected with key signalling pathways in cancer such as EGFR/EGF. However, no definitive clue about the molecular mechanism linking sorafenib and EGF signalling pathway has been established so far. Our data in HeLa, U2OS, A549 and HEK293T cells, based on in silico, chemical and genetic approaches demonstrate that the MEK5/ERK5 signalling pathway is a novel target of sorafenib. In addition, our data show how sorafenib is able to block MEK5-dependent phosphorylation of ERK5 in the Ser218/Tyr220, affecting the transcriptional activation associated with ERK5. Moreover, we demonstrate that some of the effects of this kinase inhibitor onto EGF biological responses, such as progression through cell cycle or migration, are mediated through the effect exerted onto ERK5 signalling pathway. Therefore, our observations describe a novel target of sorafenib, the ERK5 signalling pathway, and establish new mechanistic insights for the antitumour effect of this multikinase inhibitor.This work was supported by grants from Fundación Leticia Castillejo Castillo, Ministerio de Ciencia, Innovación y Universidades (MCIU), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) (RTI2018-094093-B-I00) to RSP and MJRH. OR holds a contract for accessing the Spanish System of Science, Technology, and Innovation (SECTI) funded by the University of Castilla-La Mancha (UCLM) and received partial support from the European Social Fund (FSE) through its Operative Program for Castilla-La Mancha (2007–2013). RSP and MJRH's Research Institute, and the work carried out in their laboratory, received partial support from the European Community through the FEDER. RPS and EAL hold a research predoctoral contract cofounded by the European Social Fund and UCLM. The Spanish Ministry of Economy and Competitiveness (MINECO, Project RTI2018-096724-B-C21) and the Generalitat Valenciana (PROMETEO/2016/006) support work in the Encinar´s laboratory. Authors are grateful to Dr.G- Ferrer Mayorga for her assistance in the transwell assays, and to the ‘Centro de Computación Científica’ (CCC-UAM) for letting us to take advantage of the computer cluster Cibeles (https://www.ccc.uam.es/) and for providing computing facilities

Classification of primary and incisional abdominal wall hernias

A classification for primary and incisional abdominal wall hernias is needed to allow comparison of publications and future studies on these hernias. It is important to know whether the populations described in different studies are comparable.Comparative StudyConsensus Development ConferenceJournal ArticleReviewSCOPUS: ar.jinfo:eu-repo/semantics/publishe

A colorectal cancer susceptibility new variant at 4q26 in the Spanish population identified by genome-wide association analysis

This work was partially supported by the CENIT program from the Centro Tecnológico Industrial (CEN-20091016), grants from the Spanish Institute of Health Carlos III (ADE10/00026, PI09/02444, PI12/00511, Acción Transversal de Cáncer) grants from the Fondo de Investigacion Sanitaria/FEDER (08/1276, 08/0024, PS09/02368, 11/00219, 11/00681), and by COST office through COST action BM1206. SCB is supported by contracts from the Fondo de Investigación Sanitaria (CP 03-0070). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Centro Tecnológico IndustrialInstituto de Salud Carlos IIIFondo de Investigación Sanitaria / FEDE

Lupinus mutabilis oil obtained by expeller press: Yield, physicochemical characterization, antioxidant capacity, fatty acids and oxidative stability analyses

The oil of debittered and dehulled grains from two Andean lupins (Lupinus mutabilis) from Peru, Andenes and Común, was extracted by expellerpress. The extraction yield and the proximal composition of both varieties were assessed. The oil and the cake, as well as the defatted flour from thevariety with the highest extraction yield, werecharacterised for physico-chemical properties, total polyphenol content andantioxidant capacity. Theoil shelf-life at 25 °C was extrapolated by Rancimat test. Andenes presented an oil yield of 22.1% (vs. 18.4% of Común), CIELAB colour coordinates ofL* = 36.5, a* = 2.2, b* = 20, refractive index and density at 25 ºC of 1.469 and 0.903 g/mL, acid number of 3.2 mg KOH/g, free fatty acids content of1.6%, peroxide number of 2.7 meqO2/kg, p-anisidine number of 1.3, unsaponificable content of 58%, total antioxidant capacity 21.4 μmol TE/g and total polyphenol content of 7.0 mg AGE/100 g. The predominant fatty acid, tocopherol and phytosterol in the oil were oleic acid (56.2%), γ-tocopherol (555 mg/kg) and β-sitosterol (41900 mg/100 g), respectively. The oil shelf-life at 25 ºC was 2.7 years. The Lupinus mutabilis oil extracted by expeller presented an acceptable quality with a lower environmental negative impact than the oils obtained by solvent extraction

Aceite de Lupinus mutabilis obtenido por prensa expeller: Análisis de rendimiento, caracterización fisicoquímica, capacidad antioxidante, ácidos grados y estabilidad oxidativa

The oil of debittered and dehulled grains from two Andean lupins (Lupinus mutabilis) from Peru, Andenes and Común, was extracted by expeller press. The extraction yield and the proximal composition of both varieties were assessed. The oil and the cake, as well as the defatted flour from the variety with the highest extraction yield, were characterised for physico-chemical properties, total polyphenol content and antioxidant capacity. The oil shelf-life at 25 °C was extrapolated by Rancimat test. Andenes presented an oil yield of 22.1% (vs. 18.4% of Común), CIELAB colour coordinates of L* = 36.5, a* = 2.2, b* = 20, refractive index and density at 25 ºC of 1.469 and 0.903 g/mL, acid number of 3.2 mg KOH/g, free fatty acids content of 1.6%, peroxide number of 2.7 meqO2/kg, p-anisidine number of 1.3, unsaponificable content of 58%, total antioxidant capacity 21.4 µmol TE/g and total polyphenol content of 7.0 mg AGE/100 g. The predominant fatty acid, tocopherol and phytosterol in the oil were oleic acid (56.2%), γ-tocopherol (555 mg/kg) and β-sitosterol (41900 mg/100 g), respectively. The oil shelf-life at 25 ºC was 2.7 years. The Lupinus mutabilis oil extracted by expeller presented an acceptable quality with a lower environmental negative impact than the oils obtained by solvent extraction.Se extrajo por prensa expeller el aceite de los granos desamargados y descascarados de las variedades peruanas de tarwi (Lupinus mutabilis “Común” y “Andenes”). Se evaluó el rendimiento de extracción y, composición proximal de ambas variedades. Se caracterizaron propiedades fisicoquímicas, contenido total de polifenoles y capacidad antioxidante del aceite, la torta y la harina desengrasada para la variedad con el mayor rendimiento de extracción. Se extrapoló el tiempo de vida útil del aceite a 25 ºC por el test Rancimat. La variedad andenes presentó un rendimiento de 22,1% m/m (frente al 18,4% m/m de la variedad Común), color CIELAB L*= 36,5; a*= 2,2; b* = 20, índice de refracción a 25 ºC de 1,469, densidad a 25 ºC de 0,903 g/mL, índice de acidez de 3,2 mg KOH/g, ácidos grasos libres de 1,6% m/m, índice de peróxidos de 2,7 meq O2/kg, índice de p-Anisidina de 1,3, contenido de insaponificables del 58,0% m/m, capacidad antioxidante ABTS total de 21,4 µmol TE/g y, contenido de compuestos polifenólicos totales de 7,0 mg AGE/100g. El ácido graso, tocoferol y fitoesterol predominantes en el aceite fueron el ácido oleico (56,2% m/m), el γ-tocoferol (555 mg/kg) y el β-sitosterol (41900 mg/100g), respectivamente. A 25 ºC la vida útil del aceite fue de 2,7 años. El aceite de Lupinus mutabilis extraído por expeller presentó una calidad aceptable, pero con un menor impacto ambiental negativo, en comparación con la extracción de aceites utilizando solventes

Opcions disponibles en la cirurgia de la malaltia de Parkinson i la tremolor essencial

Parkinson; Tremolor; CirurgiaParkinson; Temblor; CirugíaParkinson's; Shaking; SurgeryAquest document conté una revisió de revisions i d’informes de síntesi, en què s’han seleccionat els informes d’avaluació de tecnologies sanitàries i les guies de pràctica clínica, s’han descrit de forma narrativa els resultats i, mitjançant la tècnica qualitativa de grup nominal, s’ha elaborat una taula comparativa amb recomanacions sobre les indicacions per a cada tipus de tècnica quirúrgica.Este documento contiene una revisión de revisiones y de informes de síntesis, en que se han seleccionado los informes de evaluación de tecnologías sanitarias y las guías de práctica clínica. Se han descrito de forma narrativa los resultados y, mediante la técnica cualitativa de grupo nominal, se ha elaborado una mesa comparativa con recomendaciones sobre las indicaciones para cada tipo de técnica quirúrgica.This document contains review of reviews and synthesis reports has been prepared, in which health technology assessment reports and clinical practice guidelines were selected. The results have been described narratively, and, through a qualitative nominal group technique, a comparative table has been drawn up with recommendations on indications for each type surgical intervention

Ret is essential to mediate GDNF’s neuroprotective and neuroregenerative effect in a Parkinson disease mouse model

Glial cell line-derived neurotrophic factor (GDNF) is a potent survival and regeneration-promoting factor for dopaminergic neurons in cell and animal models of Parkinson disease (PD). GDNF is currently tested in clinical trials on PD patients with so far inconclusive results. The receptor tyrosine kinase Ret is the canonical GDNF receptor, but several alternative GDNF receptors have been proposed, raising the question of which signaling receptor mediates here the beneficial GDNF effects. To address this question we overexpressed GDNF in the striatum of mice deficient for Ret in dopaminergic neurons and subsequently challenged these mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Strikingly, in this established PD mouse model, the absence of Ret completely abolished GDNF’s neuroprotective and regenerative effect on the midbrain dopaminergic system. This establishes Ret signaling as absolutely required for GDNF’s effects to prevent and compensate dopaminergic system degeneration and suggests Ret activation as the primary target of GDNF therapy in PD

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes