From cannabinoids and neurosteroids to statins and the ketogenic diet: new therapeutic avenues in Rett syndrome?

Copyright © 2019 Mouro, Miranda-Lourenço, Sebastião and Diógenes. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused mainly by mutations in the MECP2 gene, being one of the leading causes of mental disability in females. Mutations in the MECP2 gene are responsible for 95% of the diagnosed RTT cases and the mechanisms through which these mutations relate with symptomatology are still elusive. Children with RTT present a period of apparent normal development followed by a rapid regression in speech and behavior and a progressive deterioration of motor abilities. Epilepsy is one of the most common symptoms in RTT, occurring in 60 to 80% of RTT cases, being associated with worsening of other symptoms. At this point, no cure for RTT is available and there is a pressing need for the discovery of new drug candidates to treat its severe symptoms. However, despite being a rare disease, in the last decade research in RTT has grown exponentially. New and exciting evidence has been gathered and the etiopathogenesis of this complex, severe and untreatable disease is slowly being unfolded. Advances in gene editing techniques have prompted cure-oriented research in RTT. Nonetheless, at this point, finding a cure is a distant reality, highlighting the importance of further investigating the basic pathological mechanisms of this disease. In this review, we focus our attention in some of the newest evidence on RTT clinical and preclinical research, evaluating their impact in RTT symptomatology control, and pinpointing possible directions for future research.FM was in receipt of a fellowship (IMM/CT/8-2018). The authors would like to thank the following organizations for their funding: AdoRett – LISBOA-01-0145-FEDER-031929; the Association Française du Syndrome de Rett Program “Educação pela Ciência” | Bolsas CHLN/FMUL; GAPIC. Project No. 20190017; Twinning action (SynaNet) from the EU H2020 Programme; and the UID/BIM/50005/2019, project financed by the FCT/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES), through the Fundos do Orçamento de Estado.info:eu-repo/semantics/publishedVersio

Therapeutic testing and epigenetic characterization of Friedreich Ataxia

Friedreich ataxia (FRDA) is an autosomal recessive, neurodegenerative disorder with severely debilitating effects and no current cure. FRDA is mainly caused by the hyper-expansion of a GAA repeat present in intron 1 of the FXN gene, which results in decreased gene expression and consequently a deficiency of the mitochondrial protein frataxin. In the first instance, frataxin deficiency renders an impaired protection from oxidative stress. Antioxidant therapy with cannabinoids (CBD and THC) and CTMIO was investigated in GAA repeat FXN YAC transgenic mouse models of FRDA, but no significant improvements were detected on functional measurements such as rotarod performance and locomotor activity. Additionally such compounds failed to protect the brain of treated mice from oxidative insults. Therefore, the use of such antioxidant compounds cannot be advocated for FRDA therapy. Recent findings indicate that FXN silencing in FRDA may be mediated by repressive heterochromatin, suggesting the use of histone deacetylase inhibitors (HDACi) as FXN up-regulators. Therefore, therapy with a benzamide-type HDACi (106) was similarly investigated on the FXN YAC GAA mouse model. No significant improvements were detected by functional and histochemical analysis. However, significant changes were produced in global acetylation levels of H3 and H4 in the brain of treated mice, suggesting that the drug is capable of crossing the blood-brain barrier and producing an effect. Additionally, significant increases in frataxin expression were detected in the brain of treated mice. To identify further FRDA disease mechanisms, characterization of the FXN gene for the presence of the CCCTC-binding factor (CTCF) was also performed on FRDA patient cerebellum samples. Overall, lower levels of CTCF were detected in FRDA-associated FXN alleles, suggesting the potential involvement of CTCF in the regulation of FXN transcription.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Therapeutic testing and epigenetic characterization of Friedreich Ataxia

Friedreich ataxia (FRDA) is an autosomal recessive, neurodegenerative disorder with severely debilitating effects and no current cure. FRDA is mainly caused by the hyper-expansion of a GAA repeat present in intron 1 of the FXN gene, which results in decreased gene expression and consequently a deficiency of the mitochondrial protein frataxin. In the first instance, frataxin deficiency renders an impaired protection from oxidative stress. Antioxidant therapy with cannabinoids (CBD and THC) and CTMIO was investigated in GAA repeat FXN YAC transgenic mouse models of FRDA, but no significant improvements were detected on functional measurements such as rotarod performance and locomotor activity. Additionally such compounds failed to protect the brain of treated mice from oxidative insults. Therefore, the use of such antioxidant compounds cannot be advocated for FRDA therapy. Recent findings indicate that FXN silencing in FRDA may be mediated by repressive heterochromatin, suggesting the use of histone deacetylase inhibitors (HDACi) as FXN up-regulators. Therefore, therapy with a benzamide-type HDACi (106) was similarly investigated on the FXN YAC GAA mouse model. No significant improvements were detected by functional and histochemical analysis. However, significant changes were produced in global acetylation levels of H3 and H4 in the brain of treated mice, suggesting that the drug is capable of crossing the blood-brain barrier and producing an effect. Additionally, significant increases in frataxin expression were detected in the brain of treated mice. To identify further FRDA disease mechanisms, characterization of the FXN gene for the presence of the CCCTC-binding factor (CTCF) was also performed on FRDA patient cerebellum samples. Overall, lower levels of CTCF were detected in FRDA-associated FXN alleles, suggesting the potential involvement of CTCF in the regulation of FXN transcription.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Nanoelectromechanical relay without pull-in instability for high-temperature non-volatile memory

Emerging applications such as the Internet-of-Things and more-electric aircraft require electronics with integrated data storage that can operate in extreme temperatures with high energy efficiency. As transistor leakage current increases with temperature, nanoelectromechanical relays have emerged as a promising alternative. However, a reliable and scalable non-volatile relay that retains its state when powered off has not been demonstrated. Part of the challenge is electromechanical pull-in instability, causing the beam to snap in after traversing a section of the airgap. Here we demonstrate an electrostatically actuated nanoelectromechanical relay that eliminates electromechanical pull-in instability without restricting the dynamic range of motion. It has several advantages over conventional electrostatic relays, including low actuation voltages without extreme reduction in critical dimensions and near constant actuation airgap while the device moves, for improved electrostatic control. With this nanoelectromechanical relay we demonstrate the first high-temperature non-volatile relay operation, with over 40 non-volatile cycles at 200 ∘C

Contributos para uma cartografia da investigação em Psicologia em Portugal: uma análise a partir dos trabalhos apresentados no V Simpósio Nacional de Investigação em Psicologia

O presente artigo constitui um balanço do V Simpósio Nacional de Investigação em Psicologia. Procurou-se, em primeiro lugar, analisar a distribuição temática e institucional da investigação apresentada, que se mostrou heterogénea e diversificada e, na sua grande maioria, realizada ou liderada por psicólogos vinculados a instituições universitárias. Foi também analisada a saliência dos diversos temas e a sua estrutura de associação, através da frequência das palavras-chave dos trabalhos apresentados e de uma análise de correspondências múltiplas, a qual permitiu elaborar uma cartografia das tendências de pesquisa em Portugal, mostrando as várias lógicas que organizam as diferentes linhas temáticas e as instituições universitárias a elas mais associadas

Submarine Cascais Canyon as a sediment conduit to the deep sea : comparison with adjacent slopes

Submarine canyons are known to be important conduits that trap, accumulate and deliver both natural and anthropogenic sediments from the shelf to the deep sea. Ten multi-cores from the Cascais Canyon and from the neighbour slopes (off Estremadura and Sines) were dated by 21Opb methodologies and analyzed for texture, major and trace metals to evaluate the role of submarine canyons in the transport of anthropogenic metals to the abyssal plains. Higher accumulation mass rates were determined in the upper Cascais Canyon than in the lower canyon and slopes. Enrichment factors (EF) were used to evaluate the level of metal enrichment in the studied areas. EF values exceeding natural background concentrations were obtained for Pb suggesting an anthropogenic and/or diagenetic source for Pb enrichment in the Cascais Canyon, but also, to a lesser extent, in the Estremadura and Sines slopes. Studies of provenance based on the ratio of different stable Pb isotopes can help to determinethe origin of such metal in the sediments

Alterações recentes nas razões isotópicas de Pb em sedimentos do Canhão Submarino de Cascais, Portugal

Temporal variations in lead concentrations and stable lead isotopic ratios in two sediment cores from the Cascais Canyon shows changes in sources of Pb during the last two centuries. The increase of total Pb contents wIth the evolution of Pb ratio recorded in both cores reveals the Increase of Pb from industrial sources. Nevertheless, this increase is lower in deeper core location (252-32) due to dilution and mixing with uncontaminated marine materials. An isotopic shift towards lower Pb/Pb in the shallower core (252-35) during the 1970s may reflect the increasing number of vehicles in the Lisboa area during that time

Cluster temporal de metales en un testigo corto de sedimento del Cañón Submarino de Cascais (Margen de Portugal)

The Cascais Canyon delivers contaminated sediments from the shelf to the deep marine environment. Multi-core PE252-32, located at 2100 m water depth in the canyon, records the latest 300 years of sedimentation. It was dated by 210Pb and analyzed texturally and geochemically for major elements and selected trace metals (Cu, Cr, Hg, Li, Ni, Pb and Zn). Cluster analysis performed on the down-core geochemical data identified four groups of variables related by grain-size, geochemical source and composition. Mercury, Pb and Zn were grouped in a cluster representing the anthropogenic component. Cluster analysis was applied again particularly to the latter cluster relatively to depth, in order to constrain the onset and temporal evolution of anthropogenic contamination. A second clustering, made on the basis of Hg, Pb and Zn, grouped samples by age and degree of anthropogenic contamination. One cluster contained relatively uncontaminated samples older than 1900 AD, and another cluster samples younger than 1900 AD with distinct metal enrichment. Maximum enrichments occurred during the early 1980s, followed by a slight recovery from the mid-1980s to the present. Mercury was the element with the highest enrichment factor (EFHg=5). Despite relatively low accumulation rates at this core location, our results show the importance of the Cascais Canyon as a transport route for contaminated sediments from the Tagus prodelta into the deep regions of the Portuguese Margin.El Cañón submarino de Cascais distribuye sedimentos contaminados de la plataforma continental al medio marino profundo. El testigo PE252-32, situado a 2100 metros de profundidad dentro del cañón, registra los últimos 300 años de su sedimentación. Se ha datado con 210Pb y ha sido analizada su granulometría, elementos mayoritarios y traza (cobre, cromo, mercurio, litio, níquel, plomo y zinc). Se ha llevado a cabo un análisis estadístico clúster, inicialmente aplicado a las series de datos geoquímicos en función de la profundidad, identificándose 4 grupos de variables, relacionados por la granulometría, procedencia y composición geoquímica. Los metales mercurio, plomo y zinc aparecen agrupados en un clúster que representa la componente antropogénica. A continuación el mismo análisis estadístico se aplicó específicamente a este grupo, en función de la profundidad, organizando las muestras según la edad de contaminación antropogénica. Como resultado las muestras quedan agrupadas en dos clústers principales, el de las muestras no contaminadas y más antiguas de 1900 AC, y el de las muestras más recientes de 1900 AC, marcando esta fecha el inicio de la contaminación por impacto de la actividad humana. Los máximos enriquecimientos ocurren durante el inicio de la década de los años ochenta, seguidos de un ligero descenso a partir de mediados de la misma década hasta la actualidad. De entre los demás, el mercurio es el elemento con el mayor grado de enriquecimiento (EFHg=5). Aunque la tasa de acumulación de sedimentos en este lugar es relativamente baja, los resultados obtenidos ponen en evidencia la importancia del Cañón submarino de Cascais como vía de transporte de sedimentos contaminados depositados en el pro-delta del Tajo a las regiones profundas del margen de Portugal

Chronic administration of anticonvulsants but not antidepressants impairs bone strength: clinical implications

Major depression and bipolar disorder are associated with decreased bone mineral density (BMD). Antidepressants such as imipramine (IMIP) and specific serotonin reuptake inhibitors (SSRIs) have been implicated in reduced BMD and/or fracture in older depressed patients. Moreover, anticonvulsants such as valproate (VAL) and carbamazepine (CBZ) are also known to increase fracture rates. Although BMD is a predictor of susceptibility to fracture, bone strength is a more sensitive predictor. We measured mechanical and geometrical properties of bone in 68 male Sprague Dawley rats on IMIP, fluoxetine (FLX), VAL, CBZ, CBZ vehicle and saline (SAL), given intraperitoneally daily for 8 weeks. Distinct regions were tested to failure by four-point bending, whereas load displacement was used to determine stiffness. The left femurs were scanned in a MicroCT system to calculate mid-diaphyseal moments of inertia. None of these parameters were affected by antidepressants. However, VAL resulted in a significant decrease in stiffness and a reduction in yield, and CBZ induced a decrease in stiffness. Only CBZ induced alterations in mechanical properties that were accompanied by significant geometrical changes. These data reveal that chronic antidepressant treatment does not reduce bone strength, in contrast to chronic anticonvulsant treatment. Thus, decreased BMD and increased fracture rates in older patients on antidepressants are more likely to represent factors intrinsic to depression that weaken bone rather than antidepressants per se. Patients with affective illness on anticonvulsants may be at particularly high risk for fracture, especially as they grow older, as bone strength falls progressively with age.PW Gold, MG Pavlatou, D Michelson, CM Mouro, MA Kling, M-L Wong, J Licinio and SA Goldstei

Integrated biocatalytic platform based on aqueous biphasic systems for the sustainable oligomerization of rutin

Rutin is a known antioxidant compound that displays a broad range of biological activities and health-related benefits but presents a low water solubility that can be overcome by its polymerization. In this work, biocompatible aqueous biphasic systems composed of the ionic liquid cholinium dihydrogen phosphate ([CH][DHph]) and the polymer poly(ethylene glycol) 600 (PEG 600) were investigated as an efficient integrated reaction–separation platform for the laccase-catalyzed oligomerization of rutin. Two different approaches were studied to reuse laccase in several oligorutin production cycles, the main difference between them being the use of monophasic or biphasic regimes during the oligomerization reaction. The use of a biphasic regime in the second approach (heterogeneous reaction medium) allowed the successful reuse of the biocatalyst in three consecutive reaction–separation cycles while achieving noteworthy rutin oligomerization yields (95% in the first cycle, 91% in the second cycle, and 89% in the last cycle). These remarkable results were caused by the combination of the increased solubility of rutin in the PEG-rich phase together with the enhanced catalytic performance of laccase in the [Ch][DHph]-rich phase, alongside with the optimization of the pH of the reaction medium straightly linked to enzyme stability. Finally, a life-cycle assessment was performed to compare this integrated reaction–separation platform to three alternative processes, reinforcing its sustainabilityThis research was supported by the Spanish Government (AEI) through the RTI2018-094482-J-I00 project. This work was developed within the scope of the project CICECO-Aveiro Institute of Materials, UIDB/50011/2020 & UIDP/50011/2020, financed by national funds through the Portuguese Foundation for Science and Technology/MCTES. The programme is cofunded by FEDER (UE). A.P.M.T. thanks the FCT for the research contract CEECIND/2020/01867. G.E. thanks the Spanish MICIU for her Ramón y Cajal contract (RYC2018- 024846-I). A.M.-M. thanks the Programa de axudas á etapa predoutoral da Xunta de Galicia (ED481A-2018/023)S