The role of the methyl-CpG binding protein 2 (MECP2) in shaping vulnerability for psychopathology

Exposure to trauma is a common experience worldwide, which may lead to multiple adverse consequences for physical and mental health, and is compulsory for the diagnosis of post-traumatic stress disorder (PTSD), a chronic mental disorder characterized by symptoms of persistent anxiety and hypervigilance. Considering the key role played by susceptibility in determining the outcome of traumatic experiences, and the well-documented contribution of epigenetic mechanisms in the establishment of interindividual differences in PTSD risk and resilience, this dissertation aimed at translationally addressing the potential contribution of the X-linked epigenetic regulator methyl-CpG binding protein 2 (MECP2) in shaping vulnerability to develop stress and trauma-related disorders. With this goal, taking advantage of a transgenic mouse line, we evaluated whether disruptions in MeCP2 functionality may predispose to the onset of PTSD-like symptomatology in the aftermath of a traumatic event. Male mice constitutively expressing a hypofunctional form of MeCP2 protein and exposed to unescapable footshocks, displayed exaggerated fear and increased avoidance of trauma cues, overgeneralization of fear responses and altered circadian rhythms, mimicking the psychopathological symptoms experienced by patients. Also, traumatized mutants displayed peripheral alterations in gene expression mirroring patterns already evidenced in people suffering from PTSD. Interestingly, although mutant females displayed similar disruptions in fear memory compared to males, sex-dependent alterations in stress responsivity were evidenced among mutants, with females releasing lower and males higher levels of glucocorticoids compared to sex-matched wild type (wt) controls. At the brain level, a region- and sex- specific pattern of stress-related alterations in gene expression was found. We also aimed at confirming that reduced MECP2 functionality was associated with increased stress vulnerability in human cohorts. This issue was addressed in two different studies. The first, including healthy participants, explored the link between blood MECP2 expression and childhood adversities, and addressed its effect on symptoms of depression and anxiety, which could confer vulnerability to stress-related disorders. The second study focused on the evaluation of blood MECP2 levels in PTSD patients and healthy traumatized and non-traumatized controls, with or without stress during childhood, and their correlation with the severity of PTSD symptomatology. In the first study we found that decreased MECP2 expression was indirectly associated with increased depressed mood and trait anxiety in healthy participants, a correlation mediated by childhood stress and moderated by gender. In line with this, in the second study we observed that childhood stress mediated the association between decreased MECP2 expression and increased PTSD symptom severity in traumatized participants, especially among women, further corroborating a role for MECP2 downregulation in promoting trauma vulnerability. Interestingly, men traumatized at adulthood overexpressed MECP2, independently from the severity of childhood stress. Overall, the present work presents strong evidence for the role of decreased MECP2 functionality in boosting susceptibility to develop PTSD in the aftermath of traumatic experiences, opening to the possibility that MECP2-related epigenetic pathways might be involved in the etiology of the disorder. Importantly, gender emerges as an important modulator of the association between MECP2 and PTSD susceptibility

da teoria à realidade do mercado

Este artigo tem como principal proposta apresentar um panorama global sobre a evolução da sustentabilidade na construção civil. Como o mercado lida com a necessidade de projetos sustentáveis, tanto no âmbito econômico como no social, gera questionamentos acerca da eficácia de sistemas de produção atuais. Serão apresentadas revisões bibliográficas sobre o tema de construções sustentáveis e sua aplicação. Espera-se alcançar as razões sobre a realidade do andamento lento no que diz respeito a projetos sustentáveis no Brasil, seja esta devido ao desenvolvimento econômico local ou pela desigualdade social, fatos que ainda lidam com a cultural de resistência que vem se quebrando aos poucos no país. A necessidade de maior controle na gestão dos recursos naturais se torna evidente. Como contribuição fica a fundamentação teórica e a possibilidade de continuação do trabalh

Treatment with FRAX486 rescues neurobehavioral and metabolic alterations in a female mouse model of CDKL5 deficiency disorder

Introduction: CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental condition, primarily affecting girls for which no cure currently exists. Neuronal morphogenesis and plasticity impairments as well as metabolic dysfunctions occur in CDD patients. The present study explored the potential therapeutic value for CDD of FRAX486, a brain-penetrant molecule that was reported to selectively inhibit group I p21-activated kinases (PAKs), serine/threonine kinases critically involved in the regulation of neuronal morphology and glucose homeostasis.Methods: The effects of treatment with FRAX486 on CDD-related alterations were assessed in vitro (100 nM for 48h) on primary hippocampal cultures from Cdkl5-knockout male mice (Cdkl5-KO) and in vivo (20 mg/Kg, s.c. for 5 days) on Cdkl5-KO heterozygous females (Cdkl5-Het).Results: The in vitro treatment with FRAX486 completely rescued the abnormal neuronal maturation and the number of PSD95-positive puncta in Cdkl5-KO mouse neurons. In vivo, FRAX486 normalized the general health status, the hyperactive profile and the fear learning defects of fully symptomatic Cdkl5-Het mice. Systemically, FRAX486 treatment normalized the levels of reactive oxidizing species in the whole blood and the fasting-induced hypoglycemia displayed by CdklS-Het mice. In the hippocampus of Cdkl5-Het mice, treatment with FRAX486 rescued spine maturation and PSD95 expression and restored the abnormal PAKs phosphorylation at sites which are critical for their activation (P-PAK-Ser144/141/139) or for the control cytoskeleton remodeling (P-PAK1-Thr212).Conclusions: Present results provide evidence that PAKs may represent innovative therapeutic targets for CDD

The GAPS Programme at TNG. XXI. A GIARPS case study of known young planetary candidates: confirmation of HD 285507 b and refutation of AD Leonis b

Context. The existence of hot Jupiters is still not well understood. Two main channels are thought to be responsible for their current location: a smooth planet migration through the protoplanetary disk or the circularization of an initial highly eccentric orbit by tidal dissipation leading to a strong decrease in the semimajor axis. Different formation scenarios result in different observable effects, such as orbital parameters (obliquity and eccentricity) or frequency of planets at different stellar ages. Aims: In the context of the GAPS Young Objects project, we are carrying out a radial velocity survey with the aim of searching and characterizing young hot-Jupiter planets. Our purpose is to put constraints on evolutionary models and establish statistical properties, such as the frequency of these planets from a homogeneous sample. Methods: Since young stars are in general magnetically very active, we performed multi-band (visible and near-infrared) spectroscopy with simultaneous GIANO-B + HARPS-N (GIARPS) observing mode at TNG. This helps in dealing with stellar activity and distinguishing the nature of radial velocity variations: stellar activity will introduce a wavelength-dependent radial velocity amplitude, whereas a Keplerian signal is achromatic. As a pilot study, we present here the cases of two known hot Jupiters orbiting young stars: HD 285507 b and AD Leo b. Results: Our analysis of simultaneous high-precision GIARPS spectroscopic data confirms the Keplerian nature of the variation in the HD 285507 radial velocities and refines the orbital parameters of the hot Jupiter, obtaining an eccentricity consistent with a circular orbit. Instead, our analysis does not confirm the signal previously attributed to a planet orbiting AD Leo. This demonstrates the power of the multi-band spectroscopic technique when observing active stars. Photometry, RV, and time series are only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/cat/J/A+A/638/A5 Based on observations made with the Italian Telescopio Nazionale Galileo (TNG) operated by the Fundación Galileo Galilei (FGG) of the Istituto Nazionale di Astrofisica (INAF) at the Observatorio del Roque de los Muchachos (La Palma, Canary Islands, Spain). Partly based on data obtained with the STELLA robotic telescopes in Tenerife, an AIP facility jointly operated by AIP and IAC

Sustentabilidade na construção civil: proposta de diretrizes baseadas nos selos de certificação ambiental

Sustainable development, despite being recurring theme in academic, scientific and political meetings, walks slowly in regard to the conditions of the planet Earth. Whereas the construction industry is responsible for a significant amount of pollutant emissions in the atmosphere and general damage to the environment, this dissertation concentrates on elements of sustainable construction, focusing on the requirements of environmental certifications in Brazil. The main objective of this work is to define guidelines for sustainable projects, based on the environmental assessment categories and criteria of the most used seals in Brazil: LEED, AQUA and Selo Casa Azul, considering the contribution to the four life support systems on Earth, which are: Atmosphere, Water, Soil and Living Beings. In addition, a brief analysis of market practices allows us to map the landscape of construction as sustainable. The method used is based on a literature review on sustainability and its evaluation systems in the environment built at the first moment. The development of the research is based on the foundations of Design Science Research as a way of generating knowledge. A qualitative analysis of the certifications is made to synthesize them in guidelines. As a result, the guidelines generated are contrasted with market practices, allowing us to quantify the level of sustainability in our built environment. This dissertation contributes to the improvement of the sustainable management of the built environment, as well as to the awareness of the urgent need of sustainability in it.O desenvolvimento sustentável, apesar de ser tema recorrente em encontros acadêmicos, científicos e políticos, anda a passos lentos no que diz respeito às condições do planeta Terra. Considerando que a construção civil é responsável por significativa quantidade das emissões de poluentes na atmosfera e danos gerais causados ao meio ambiente, esta dissertação se concentra nos elementos da construção sustentável, focando nos requisitos dos selos de certificações ambientais presentes no Brasil. O objetivo deste trabalho é definir diretrizes para projetos sustentáveis, baseando-se nas categorias e critérios de avaliação ambiental dos selos mais utilizados no Brasil: LEED, AQUA e Selo Casa Azul, considerando a contribuição para os quatro sistemas de suporte à vida na Terra, são eles: Atmosfera, Água, Solo e Seres Vivos. Além disso, uma breve análise das práticas do mercado nos permite traçar o panorama da construção enquanto sustentável. O método utilizado se baseia numa revisão bibliográfica sobre sustentabilidade e seus sistemas de avaliação no ambiente construído no primeiro momento. O desenvolvimento da pesquisa tem como base metodológica os fundamentos da Design Science Research, como forma de geração de conhecimento. É feita uma análise qualitativa das certificações citadas a fim de sintetizá-las em diretrizes. Como resultado, as diretrizes geradas são contrastadas com as práticas de mercado, permitindo-nos quantificar o nível da sustentabilidade no nosso ambiente construído. Esta dissertação contribui para o aprimoramento da gestão sustentável do ambiente construído, assim como para a conscientização da urgente necessidade da sustentabilidade neste meio

A Review of Natural Bio-Based Insulation Materials

Within the context of climate change and the environmental impact of the building industry, insulation materials contribute to improving the thermal performance of buildings, thus reducing energy demand and carbon emissions during the operation phase. Although most of them are responsible for significant carbon emissions during their production, bio-based insulation materials can provide good performance with low carbon emissions. This paper aims to investigate natural insulation materials’ properties and environmental impacts through a literature review. Due to the growing importance of Environmental Product Declarations (EPDs) on specification requirements, many manufacturers already disclose environmental data related to their products, allowing for a comparison between thermal insulation solutions. In academic research, embodied environmental impacts are not as explored as physical properties. In addition, from the analysis of results, it is possible to conclude that the characterization of the physical properties of this type of material is normally focused on thermal conductivity. Nevertheless, most studies overlook other important parameters of these materials, such as the thermal capacity, lifetime, and environmental impacts. This is something that is necessary to overcome in future developments to allow for a comprehensive comparison between the properties of different (conventional and bio-based) insulation materials

Development of an ecological thermal insulation product for a regenerative design

Although thermal insulation materials contribute to reducing energy demand, the most used materials have high embodied energy. Bio-based thermal insulation products stock CO2 and therefore have lower embodied energy. The research work aims to develop a modern bio-based thermal insulation product based on invasive species in Portugal. Its use has a positive impact on controlling the spread and creates a value chain for this resource

Genes and sex hormones interaction in neurodevelopmental disorders

The prevalence, age of onset and symptomatology of many neurodevelopmental disorders strongly differ between genders. This review examines sex biases in human neurodevelopmental disorders and in validated animal models. A focus is made on disorders of well-established genetic origin, such as Rett syndrome, CDKL5-associated disorders, Fragile X and Down syndrome. Autism is also addressed, given its paradigmatic role as a sex-biased neurodevelopmental disorder. Reviewed literature confirms that a complex interaction between genetic factors and sex hormones may underlie the differential susceptibility of genders and may impact the severity of symptoms in most of the analyzed neurodevelopmental disorders. Even though further studies addressing the advantages and disadvantages conferred by biological sex in this class of disorders are needed to disentangle the underlying mechanisms, present findings suggest that modulation of sex steroid-related pathways may represent an innovative approach for these diseases. Much effort is now expected to unravel the potential therapeutic efficacy of drugs targeting sex hormones-related signaling pathways in neurodevelopmental disorders of well-established genetic origin