The Free and Cued Selective Reminding Test in Parkinson's Disease Mild Cognitive Impairment : Discriminative Accuracy and Neural Correlates

Altres ajuts: This work was partially supported by grants from La Marató TV3 (20142910, 2014/U/477); FIS (PI14/02058, PI15/00962); CIBERNED.Introduction: Memory alterations are common in Parkinson's disease (PD) patients but the mechanisms involved in these deficits remain poorly understood. The study aims to explore the profile of episodic memory deficits in non-demented early PD patients. Methods: We obtained neurological, cognitive and behavioral data from 114 PD patients and 41 healthy controls (HC). PD participants were grouped as normal cognition (PD-NC) and mild cognitive impairment (PD-MCI) according to the Level II criteria of the Movement Disorders Society Task Force (MDS-TF). We evaluate the performance amongst groups on an episodic memory task using the Free and Cued Selective Reminding Test (FCSRT). Additionally, gray matter volume (GMV) voxel based morphometry, and mean diffusivity (MD) analyses were conducted in a subset of patients to explore the structural brain correlates of FCSRT performance. Results: Performance on all subscores of the FCSRT was significantly worse in PD-MCI than in PD-NC and HC. Delayed total recall (DTR) subscore was the best at differentiating PD-NC from PD-MCI. Using crosstabulation, DTR allowed identification of PD-MCI patients with an accuracy of 80%. Delayed free and cued recall was associated with decreased GMV and increased MD in multiple fronto-temporal and parietal areas. Conclusion: Encoding and retrieval deficits are a main characteristic of PD-MCI and are associated with structural damage in temporal, parietal and prefrontal areas

Autophagy and Apoptosis Have a Role in the Survival or Death of Stallion Spermatozoa during Conservation in Refrigeration

Apoptosis has been recognized as a cause of sperm death during cryopreservation and a cause of infertility in humans, however there is no data on its role in sperm death during conservation in refrigeration; autophagy has not been described to date in mature sperm. We investigated the role of apoptosis and autophagy during cooled storage of stallion spermatozoa. Samples from seven stallions were split; half of the ejaculate was processed by single layer centrifugation, while the other half was extended unprocessed, and stored at 5°C for five days. During the time of storage, sperm motility (CASA, daily) and membrane integrity (flow cytometry, daily) were evaluated. Apoptosis was evaluated on days 1, 3 and 5 (active caspase 3, increase in membrane permeability, phosphatidylserine translocation and mitochondrial membrane potential) using flow cytometry. Furthermore, LC3B processing was investigated by western blotting at the beginning and at the end of the period of storage. The decrease in sperm quality over the period of storage was to a large extent due to apoptosis; single layer centrifugation selected non-apoptotic spermatozoa, but there were no differences in sperm motility between selected and unselected sperm. A high percentage of spermatozoa showed active caspase 3 upon ejaculation, and during the period of storage there was an increase of apoptotic spermatozoa but no changes in the percentage of live sperm, revealed by the SYBR-14/PI assay, were observed. LC3B was differentially processed in sperm after single layer centrifugation compared with native sperm. In processed sperm more LC3B-II was present than in non-processed samples; furthermore, in non-processed sperm there was an increase in LC3B-II after five days of cooled storage. These results indicate that apoptosis plays a major role in the sperm death during storage in refrigeration and that autophagy plays a role in the survival of spermatozoa representing a new pro-survival mechanism in spermatozoa not previously described

Melatonin induces the expression of Nrf2-regulated antioxidant enzymes via PKC and Ca2+ influx activation in mouse pancreatic acinar cells

The goal of this study was to evaluate the potential activation of the nuclear factor erythroid 2-related factor and the antioxidant-responsive element (Nrf2–ARE) signaling pathway in response to melatonin in isolated mouse pancreatic acinar cells. Changes in intracellular free Ca2+ concentration were followed by fluorimetric analysis of fura-2-loaded cells. The activations of PKC and JNK were measured by Western blot analysis. Quantitative reverse transcription–polymerase chain reaction was employed to detect the expression of Nrf2-regulated antioxidant enzymes. Immunocytochemistry was employed to determine nuclear location of phosphorylated Nrf2, and the cellular redox state was monitored following MitoSOX Red-derived fluorescence. Our results show that stimulation of fura-2-loaded cells with melatonin (1 µM to 1 mM), in the presence of Ca2+ in the extracellular medium, induced a slow and progressive increase of [Ca2+]c toward a stable level. Melatonin did not inhibit the typical Ca2+ response induced by CCK-8 (1 nM). When the cells were challenged with indoleamine in the absence of Ca2+ in the extracellular solution (medium containing 0.5 mM EGTA) or in the presence of 1 mM LaCl3, to inhibit Ca2+ entry, we could not detect any change in [Ca2+]c. Nevertheless, CCK-8 (1 nM) was able to induce the typical mobilization of Ca2+. When the cells were incubated with the PKC activator PMA (1 µM) in the presence of Ca2+ in the extracellular medium, we observed a response similar to that noted when the cells were challenged with melatonin 100 µM. However, in the presence of Ro31-8220 (3 µM), a PKC inhibitor, stimulation of cells with melatonin failed to evoke changes in [Ca2+]c. Immunoblots, using an antibody specific for phospho-PKC, revealed that melatonin induces PKCα activation, either in the presence or in the absence of external Ca2+. Melatonin induced the phosphorylation and nuclear translocation of the transcription factor Nrf2, and evoked a concentration-dependent increase in the expression of the antioxidant enzymes NAD(P)H-quinone oxidoreductase 1, catalytic subunit of glutamate-cysteine ligase, and heme oxygenase-1. Incubation of MitoSOX Red-loaded pancreatic acinar cells in the presence of 1 nM CCK-8 induced a statistically significant increase in dye-derived fluorescence, reflecting an increase in oxidation, that was abolished by pretreatment of cells with melatonin (100 µM) or PMA (1 µM). On the contrary, pretreatment with Ro31-8220 (3 µM) blocked the effect of melatonin on CCK-8-induced increase in oxidation. Finally, phosphorylation of JNK in the presence of CCK-8 or melatonin was also observed. We conclude that melatonin, via modulation of PKC and Ca2+ signaling, could potentially stimulate the Nrf2-mediated antioxidant response in mouse pancreatic acinar cells.This work was supported by Junta de Extremadura-FEDER. Patricia Santofimia-Castaño was granted a fellowship from Fundacion Tatiana Perez de Guzman el Bueno. J.P.B. is funded by the Spanish Ministerio de Economia y Competitividad (SAF2013-41177-R), the Instituto de Salud Carlos III (RD12/0043/0021), the SP3-People-MC-ITN programme of the European Commission (608381), the National Institute on Drug Abuse (National Institutes of Health; 1R21DA037678-01), and the European Regional Development Fund.Peer Reviewe

NF-κB Activity Initiates Human ESC-Derived Neural Progenitor Cell Differentiation by Inducing a Metabolic Maturation Program

Human neural development begins at embryonic day 19 and marks the beginning of organogenesis. Neural stem cells in the neural tube undergo profound functional, morphological, and metabolic changes during neural specification, coordinated by a combination of exogenous and endogenous cues. The temporal cell signaling activities that mediate this process, during development and in the postnatal brain, are incompletely understood. We have applied gene expression studies and transcription factor-activated reporter lentiviruses during in vitro neural specification of human pluripotent stem cells. We show that nuclear factor κB orchestrates a multi-faceted metabolic program necessary for the maturation of neural progenitor cells during neurogenesis. In this research article, FitzPatrick and colleagues have highlighted the requirement for NF-κB signaling in neural specification of human embryonic stem cells. They demonstrate that its activity orchestrates a metabolic shift toward oxidative phosphorylation in committing neural progenitor cells. Moreover, they demonstrate that progenitor cells with increased endogenous NF-κB activity have a higher propensity for maturation

Design and Synthesis of CNS-targeted Flavones and Analogues with Neuroprotective Potential Against H; 2; O; 2; - and Aβ; 1-42; -Induced Toxicity in SH-SY5Y Human Neuroblastoma Cells

With the lack of available drugs able to prevent the progression of Alzheimer's disease (AD), the discovery of new neuroprotective treatments able to rescue neurons from cell injury is presently a matter of extreme importance and urgency. Here, we were inspired by the widely reported potential of natural flavonoids to build a library of novel flavones, chromen-4-ones and their; C; -glucosyl derivatives, and to explore their ability as neuroprotective agents with suitable pharmacokinetic profiles. All compounds were firstly evaluated in a parallel artificial membrane permeability assay (PAMPA) to assess their effective permeability across biological membranes, namely the blood-brain barrier (BBB). With this test, we aimed not only at assessing if our candidates would be well-distributed, but also at rationalizing the influence of the sugar moiety on the physicochemical properties. To complement our analysis, log; D; 7.4; was determined. From all screened compounds, the; p; -morpholinyl flavones stood out for their ability to fully rescue SH-SY5Y human neuroblastoma cells against both H; 2; O; 2; - and Aβ; 1-42; -induced cell death. Cholinesterase inhibition was also evaluated, and modest inhibitory activities were found. This work highlights the potential of; C; -glucosylflavones as neuroprotective agents, and presents the; p; -morpholinyl; C; -glucosylflavone; 37; , which did not show any cytotoxicity towards HepG2 and Caco-2 cells at 100 μM, as a new lead structure for further development against AD

NanoElectronics roadmap for Europe: From nanodevices and innovative materials to system integration

© 2019 Elsevier Ltd The NEREID project (“NanoElectronics Roadmap for Europe: Identification and Dissemination”) is dedicated to mapping the future of European Nanoelectronics. NEREID's objective is to develop a medium and long term roadmap for the European nanoelectronics industry, starting from the needs of applications to address societal challenges and leveraging the strengths of the European eco-system. The roadmap will also identify promising novel nanoelectronic technologies, based on the advanced concepts developed by Research Centres and Universities, as well as identification of potential bottlenecks along the innovation (value) chain. Industry applications include Energy, Automotive, Medical/Life Science, Security, loT, Mobile Convergence and Digital Manufacturing. The NEREID roadmap covers Advanced Logic and Connectivity, Functional Diversification (Smart Sensors, Smart Energy and Energy for Autonomous Systems), Beyond-CMOS, Heterogeneous Integration and System Design as well as Equipment, Materials and Manufacturing Science. This article gives an overview of the roadmap's structure and content.status: publishe