Repositório RCAAP

Reluctance to start medication has never been investigated before in PD. We studied reluctance to start medication for PD motor symptoms, namely its prevalence, underlying reasons, drug-specificity, and associated delay in the start of PD medication. A cross-sectional observational international study was conducted. Patients with a clinical diagnosis of PD advised to start antiparkinsonian medication in the previous 5 years were invited to complete a questionnaire in three centers located in North America and Europe. An electronic online survey was sent to physicians through the mailing list of the Movement Disorder Society. 469 participants (201 PD patients, 268 physicians). 40.2% (n = 82) of the patients reported reluctance to start medication, but 88.6% (n = 234/264) of the physicians estimated that ≤20% of their patients with PD had been reluctant to start medication. The most common reasons reported by patients were the fear of side effects (n = 35, 55.6%), followed by non-acceptance of diagnosis (n = 23, 36.5%); fear of a temporally limited benefit was more commonly selected by physicians (n = 92/267, 34.5%). Patients indicated reluctance to start DAs more frequently compared with L-DOPA (OR: 2.22, 95% CI: 1.30, 9.03; p = 0.013) while physicians perceived L-DOPA to be associated with more reluctance (OR: 4.7, 95% CI: 3.41; 6.59; p < 0.0001). Patients with PD and physicians have a different perspective on the issue of reluctance to start medication. There is a need to bring physicians and patients with PD closer to a shared vision of the problem reluctance to start medication.

Adult B-cell acute lymphoblastic leukemia remains a major therapeutic challenge, requiring a better characterization of the molecular determinants underlying disease progression and resistance to treatment. Here, using a phospho-flow cytometry approach we show that adult diagnostic B-cell acute lymphoblastic leukemia specimens display PI3K/Akt pathway hyperactivation, irrespective of their BCR-ABL status and despite paradoxically high basal expression of PTEN, the major negative regulator of the pathway. Protein kinase CK2 is known to phosphorylate PTEN thereby driving PTEN protein stabilization and concomitant PTEN functional inactivation. In agreement, we found that adult B-cell acute lymphoblastic leukemia samples show significantly higher CK2 kinase activity and lower PTEN lipid phosphatase activity than healthy controls. Moreover, the clinical-grade CK2 inhibitor CX-4945 (Silmitasertib) reversed PTEN levels in leukemia cells to those observed in healthy controls, and promoted leukemia cell death without significantly affecting normal bone marrow cells. Our studies indicate that CK2-mediated PTEN posttranslational inactivation, associated with PI3K/Akt pathway hyperactivation, are a common event in adult B-cell acute lymphoblastic leukemia and suggest that CK2 inhibition may constitute a valid, novel therapeutic tool in this malignancy.

Constitutively active phosphoinositide 3-kinase (PI3K) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it upregulates cell proliferation, survival and drug resistance. These observations lend compelling weight to the application of PI3K inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of the pan-PI3K inhibitor NVP-BKM120 (BKM120), an orally bioavailable 2,6-dimorpholino pyrimidine derivative, which has entered clinical trials for solid tumors, on both T-ALL cell lines and patient samples. BKM120 treatment resulted in G2/M phase cell cycle arrest and apoptosis, being cytotoxic to a panel of T-ALL cell lines and patient T lymphoblasts, and promoting a dose- and time-dependent dephosphorylation of Akt and S6RP. BKM120 maintained its pro-apoptotic activity against Jurkat cells even when cocultured with MS-5 stromal cells, which mimic the bone marrow microenvironment. Remarkably, BKM120 synergized with chemotherapeutic agents currently used for treating T-ALL patients. Moreover, in vivo administration of BKM120 to a subcutaneous xenotransplant model of human T-ALL significantly delayed tumor growth, thus prolonging survival time. Taken together, our findings indicate that BKM120, either alone or in combination with chemotherapeutic drugs, may be an efficient treatment for T-ALLs that have aberrant upregulation of the PI3K signaling pathway.

Background: Surgery is not a recognised potential amyotrophic lateral sclerosis (ALS) risk factor that might modify the onset or course of ALS. Methods: We studied our database of ALS patients, which includes questions concerning surgical procedures. We defined surgery as an operative procedure requiring general or regional anaesthesia, but not local anaesthesia. Patients were classified as G1-no surgery; G2-surgery performed ≥3 months before disease onset; G3-surgery <3 months before disease onset; and G4-surgery after disease onset. The ALS-FRS score was evaluated every 3 months from presentation. The maximal ALS-FRS score was ascribed to disease onset, itself defined as symptom onset. Results: 657 patients with ALS were studied. In G3 there was a positive correlation between onset-region and surgery-region (p=0.032). In G4, 35 (57.6%) patients had surgery, probably due to initial misdiagnosis. The rate of functional change (%) in G4 was significantly greater in the 3-month period immediately after surgery as compared with the 3-month period before (1.46%±1.35 vs. 6.30%±8.10, p=0.005) and the following 3 months (3.30%±3.10, p=0.006). Conclusions: The site of surgery before ALS onset correlates with the region of onset of ALS. Patients with slower disease progression are at an increased risk of undergoing surgery, probably as part of initial difficulty in diagnosis. We noted accelerated disease progression during the 3-month period after surgery. Definite diagnosis is important to avoid unnecessary surgical trauma and subsequent more rapid deterioration.

In this study we propose a typology which concerns source errors and linguistic structures that might have an impact on Machine Translation (MT). Although most typologies are built on a bilingual level, the source text (ST) also presents issues that cannot be expected to be resolved by MT. In this study, we were able to test whether or not the quality of the ST has an impact on the target text (TT) quality. For that purpose, source data was annotated. The data analyzed was both inbound (user-generated content) and outbound (agent) in the context of chat. Through this analysis, it was possible to build a data driven typology. To aid the construction of a new typology, there was also a comparison between multiple typologies, whether they have a bilingual or a monolingual focus. This allowed us to see what could be applied to a monolingual typology and what was missing. With the annotation results, it was possible to build a new typology — Source Typology. To assist future annotators, we provided annotation guidelines with a listing of all the issue types, an explanation of the different span types, the severities to be used and the tricky cases that might occur during the annotation process. In order to test the reliability of the typology, three different case studies of an internal pilot were conducted. Each case study had a different goal and took into account different language pairs. By testing the Source Typology, we could see its effectiveness and reliability and what should be improved. In the end, we demonstrated that the quality of the ST can actually have an impact on the TT quality, where, at times, minor errors on the source would become or originate critical errors on the target. The typology is now being applied at Unbabel.

The last two decades have been of significant change in the international panorama at all levels. The onset of the internet and content availability has propelled us to a new era: The Information Age. The staggering growth of new digital contents, either in the form of ebooks, on-demand TV shows, blogs or even e-commerce websites, has led to an increase in the need for translated material, influenced by people's demand for a quick access to this shared knowledge in their native languages and dialects. Fortunately, machine translation technologies (MT), which provide in many cases human-like translations, are now more widely available, enabling quicker translations for multiple languages at more affordable prices. This work describes the Natural Language Process (NLP) sub-task known as Named Entity Recognition (NER), performed by Unbabel, a Portuguese Machine-translation start-up that combines MT with human post-edition and focuses strictly on customer service content, to improve translation quality outputs. The main objective of this study is to contribute to furthering MT quality and good-practices by exposing the importance of having a continuously-in-development robust Named Entity Recognition system for generic and client-specific content in an MT pipeline and for General Data Protection Regulation (GDPR) compliance; moreover, having in mind future applications, we have tested strategies that support the creation of Multilingual Named Entities Recognition Systems. In the following work, we will first define the meaning of Named Entity, highlighting its importance in a Machine Translation scenario, followed by a brief historical overview of the subject. We will also provide a reasonable description of the most recent data-driven Machine Translation technologies. Concerning the main topic of this work, we will describe three experiments carried out jointly with Unbabel´s NLP team. The first experiment focuses on assisting the NLP team in the creation of a domain-specific Named Entity Recognition (NER) system. The second and third experiments explore the possibilities to create in a semi-automatically fashion multilingual NER gold standards, by resorting to aligners able to project Named Entities between a parallel corpus.

No summary/description provided

Com a instituição do Direito enquanto ciência fundamental para a regulamentação da vida humana, a tradução jurídica afirma-se como uma atividade indispensável, num mundo interligado a nível político, económico, cultural e linguístico. A crescente importância da tradução jurídica na unificação social incita a curiosidade dos tradutores mais atentos, que procuram, incessantemente, por fontes fidedignas que fundamentem os seus conhecimentos e apoiem as suas opções. Neste enquadramento, o presente relatório visa dar conta da minha experiência de tradução jurídica em estágio e, através dela, desejavelmente, dar um contributo – por pequeno que seja – para dúvidas que possam surgir acerca de matérias específicas da tradução jurídica. Numa secção de abordagem teórica, procede-se à contextualização e definição da tradução jurídica e ao desenvolvimento das temáticas da respetiva linguagem de especialidade e da pluralidade de sistemas jurídicos, assinalando-se as estratégias mais adequadas e competências requeridas durante o processo de tradução de textos do domínio do Direito. Numa secção de abordagem mais prática, discute-se, a partir de exemplos reais, uma panóplia de características da linguagem jurídica, relacionando-se procedimentos ou estratégias de tradução com dilemas ou questões tradutórias mais gerais. Todas as tarefas executadas ao longo do programa de estágio – que são a base desta secção – são descritas minuciosamente no início deste relatório.

Esta dissertação tem como principal objetivo a análise e reflexão sobre opções linguísticas observadas em textos jurídicos recolhidos num corpus bilingue (inglês-português e português-inglês) constituído especificamente para a realização deste trabalho, nomeadamente, questões sintáticas e questões lexicais identificadas em traduções oficiais. Com a finalidade de contribuir para o conhecimento da prática de tradução na área da tradução jurídica de português para inglês e de inglês para português, esta dissertação põe ao serviço da análise as teorias e as estratégias de tradução adquiridas ao longo do primeiro ano de mestrado. No que diz respeito à sua estrutura geral, este trabalho divide-se em três grandes partes. O primeiro capítulo consiste numa breve apresentação do objetivo do trabalho e do corpus recolhido para o realizar. Sendo que os textos constantes do corpus utilizado como ponto de partida para este trabalho correspondem a textos jurídicos originais e as suas respetivas traduções oficiais, a qualidade das traduções consideradas é alta, o que significa que a sistematização de soluções de tradução adotadas constitui uma boa referência e permite identificar exemplos de boas práticas neste domínio. No segundo capítulo é apresentada uma reflexão teórica sobre a Tradução, bem como uma descrição das características principais do texto técnico e da linguagem jurídica. Por fim, no terceiro capítulo faz-se uma análise de fenómenos linguísticos numa perspetiva contrastiva, focando-se em questões sintáticas (distribuição do uso de determinantes possessivos, quantificadores, verbos modais, etc.) e em questões lexicais (tradução de termos e de expressões polissémicas). A identificação de generalizações em termos de opções e de estratégias de tradução utilizadas pelo tradutor de texto jurídico foi igualmente tida em conta.

Apex predator reintroductions have proliferated across southern Africa, yet their ecological effects and proposed umbrella benefits of associated management lack empirical evaluations. Despite a rich theory on top-down ecosystem regulation via mesopredator suppression, a knowledge gap exists relating to the influence of lions (Panthera leo) over Africa's diverse mesocarnivore (less than 20 kg) communities. We investigate how geographical variation in mesocarnivore community richness and occupancy across South African reserves is associated with the presence of lions. An interesting duality emerged: lion reserves held more mesocarnivore-rich communities, yet mesocarnivore occupancy rates and evenness-weighted diversity were lower in the presence of lions. Human population density in the reserve surroundings had a similarly ubiquitous negative effect on mesocarnivore occupancy. The positive association between species richness and lion presence corroborated the umbrella species concept but translated into small differences in community size. Distributional contractions of mesocarnivore species within lion reserves, and potentially corresponding numerical reductions, suggest within-community mesopredator suppression by lions, probably as a result of lethal encounters and responses to a landscape of fear. Our findings offer empirical support for the theoretical understanding of processes underpinning carnivore community assembly and are of conservation relevance under current large-predator orientated management and conservation paradigms.

This chapter discusses the transition from a period when multinormativity operated in Goa under Portuguese rule to one in which the attempts to homogenize it became standard. In the first period, the role of local normativities was relevant to the making of the Portuguese imperial order; in the second, in contrast, there was an increasing tendency to exclude these normativities. Through examining the Foral dos usos e costumes dos Gancares e Lavradores da Ilha de Goa […] of 1526, better known as Foral de Mexia, this process is discussed from the perspective of its production, life, and use by the Portuguese agents and local people. The Foral assembled norms, uses, and customs operating in the Goan villages in the third decade of the 16th century. However, its uses over the next decades and centuries bear witness structural changes in the Portuguese Crown’s relationship with Goan territories and people. Contrary to what historiography has assumed, the process of systematic Christianization of Goan society from 1530 onwards implied, at least theoretically, the end of multinormativity that inspired the Foral, due to the gradual submission of Goans to Portuguese law in private and public matters.

Introdução: A Atrofia Multissistémica é uma doença neurodegenerativa rapidamente progressiva e potencialmente fatal, para a qual ainda não foi identificado um tratamento eficaz. Estimar as respostas Placebo e Nocebo irá providenciar informações úteis para um melhor desenho e interpretação de ensaios clínicos, de forma a assegurar a eficácia e a segurança das intervenções estudadas. Objetivo: Estimar as respostas placebo e nocebo na Atrofia Multissistémica e explorar os seus determinantes. Métodos: Base de dados eletrónicas foram pesquisadas até novembro de 2020. Foram incluídos ensaios clínicos randomizados, duplamente cegos, se houvesse data extraível do braço placebo. O outcome primário foi: resposta placebo, definido pela diferença intra-grupo a partir do início do estudo, usando qualquer escala a avaliar o domínio motor; e a resposta nocebo, definida como a proporção de doentes a experienciar efeitos adversos no braço placebo. Foi utilizada uma meta-análise de efeitos-aleatórios para agrupar os dados. Várias análises de subgrupo predeterminadas e meta-regressões foram realizadas. Número de registo PROSPERO: CRD42021222915. Resultados: Foram incluídos 21 ensaios clínicos randomizados (614 doentes no braço placebo). A resposta placebo agregada foi de um aumento nas partes I e II da Unified Multiple System Atrophy Rating Scale de 9.09 pontos (95% CI 7.78 to 10.31, I2=94.00%, 9 estudos, 304 participantes). A resposta nocebo agregada foi de 63.88% (CI 95% 41.15 to 84.05, I2 =93.03%, 13 studies, 331 participants). Ambas as respostas placebo e nocebo foram maiores em estudos de maior duração, enquanto a resposta nocebo foi também maior em estudos sobre intervenções farmacológicas quando comparadas com intervenções não-farmacológicas. Conclusões: Parece haver uma resposta favorável associada com o placebo, mas estes dados precisam de ser comparados com um “grupo de não tratamento” de maneira a validar o seu impacto real, e a resposta placebo é de um alto impacto e deverá por isso ser tomada em consideração aquando da sua aplicação em ensaios clínicos nestes doentes. Estes resultados são relevantes para o desenho e interpretação de futuros ensaios clínicos, e existe uma margem significante de melhoria do desenho dos estudos nesta patologia.

A Doença de Alzheimer (AD) é caracterizada pela perda progressiva de memória. No contexto neuro-imune, interessa compreender o papel das populações imunitárias no desenvolvimento e progressão de AD. Estudos recentes evidenciam a diversidade das populações imunitárias presentes nas meninges, e as suas contribuições para a função cerebral. Em particular, as células γδ17 têm reunido bastante atenção dado terem sido encontradas em maior frequência em meninges de modelos de murganhos com patologia no SNC. Por outro lado, foi recentemente descoberto pelo laboratório de acolhimento que as células γδ17 contribuem para a memória de curta duração (STM) em condições fisiológicas, promovendo a plasticidade sináptica glutamatérgica. No entanto, o papel das células γδ17 e da IL-17 no início da AD não está ainda estabelecido. Foi utilizado um modelo progressivo de AD com o objetivo de estabelecer a idade de início de défices da STM e caracterizar as possíveis alterações celulares no SNC. Para além disso, foi estudado o impacto do bloqueio intracerebroventricular de IL-17 no início da STM. Os défices de memória foram observados apenas em murganhos fêmeas com AD a partir dos 5 meses de idade. Ao analisar por citometria de fluxo o SNC de WT e AD, foi descoberto que no momento inicial de défices na STM, as meninges e o cérebro das fêmeas com AD apresentam níveis significativamente mais elevados de células produtoras de IL-17, com predominância das células γδ17. Para avaliar o impacto dos níveis aumentados de IL-17 no SNC, anticorpos neutralizantes para IL-17 (aIL-17) ou controlo isotípico (IgG) foram difundidos nos ventrículos hipocampais de murganhos AD e WT, usando um sistema de Alzet. Após o tratamento, observámos que, tal como os controlos (WT+IgG), os animais AD tratados com aIL-17 (AD+aIL-17) não apresentaram défice de STM. Em conclusão, o trabalho desenvolvido nesta tese sugere que níveis exacerbados de IL- 17, oriundos preferencialmente de células γδ17 das meninges, promovem défices cognitivos de STM nas fases iniciais da patologia da AD.

Nos últimos anos, a área da neurobiologia da linguagem tem tido um enorme desenvolvimento. Novos modelos surgiram para explicar este fenómeno que se pensa exclusivamente humano. Acompanhando estes progressos, a neuroimagiologia tem desenvolvido novas formas de mapeamento funcional das áreas relacionadas com a linguagem. No âmbito da crescente relevância deste tema na prática clínica, foi realizada uma revisão da literatura a propósito de um caso clínico. O caso clínico é referente a um doente, J.P.M, com um oligodendroglioma envolvendo a região de Broca, que realizou um estudo de mapeamento funcional da linguagem pré-cirúrgico, de forma a potenciar a área de resseção tumoral, minimizando ao máximo os defeitos linguísticos pósoperatórios. Com esta revisão, enquadrada por um caso clínico concreto, procurámos responder às seguintes questões: - Que métodos de mapeamento funcional para estudo da linguagem existem e quais são as suas principais características? - Como se comparam entre eles ? Tendo por base este caso clínico, complementado pela revisão da literatura, procuraremos ainda enquadrar os métodos de mapeamento funcional, ferramentas fundamentais para o neurorradiologista e neurocirurgião, com a neurobiologia da linguagem.

A disforia de género é um tema que tem vindo, nos últimos anos, a ganhar maior atenção, não só pela comunidade médica, mas também pela população em geral. É um tema que se tem demonstrado controverso, desde o uso do termo “disforia de género” até aos seus critérios de diagnóstico, etiologia e indicações terapêuticas. À medida que a sociedade e comunidade médica se afastam de uma concepção binária de género, as classificações diagnósticas alteram-se no sentido de desestigmatizar a incongruência de género. A abordagem da disforia de género é complexa e exige intervenção multidisciplinar, contudo contribui muito significativamente para a melhoria da qualidade de vida dos indivíduos com esta condição.

Background: 24-hour movement behaviors, including moderate-to-vigorous physical activity (MVPA), sedentary time (ST), and sleep duration, have important implications for health across the lifespan. However, no studies exist that have examined the integration of these 24-hour movement behaviors in Latin America. The purpose of this study was to examine the prevalence of meeting the Canadian 24-Hour Movement Guideline recommendations and sociodemographic correlates of meeting the guidelines in adults from eight Latin American countries. Methods: This was a multi-national cross-sectional study of 2338 adults aged 18 to 64 years from the Latin American Study of Nutrition and Health. MVPA and ST data were collected using accelerometers. Sleep duration was self-reported using a daily log. Socio-demographic correlates included sex, age, education level, and marital status. Meeting the 24-hour movement guidelines was defined as: ≥150 min/week of MVPA; ≤8 h/day of ST; and between 7 and 9 h/day of sleep. Logistic regression models were estimated on pooled data. Results: The prevalence of adults who met the MVPA, ST, sleep duration, and integrated recommendations was 48.3, 22.0, 19.4, and 1.6%, respectively. Overall, being a woman (OR: 0.72; 95%CI: 0.55,0.93) and having a middle (0.63; 0.47,0.85) or high education level (0.31; 0.17,0.56) was associated with lower odds of meeting all three of the 24-hour movement guideline recommendations. Being married (1.70; 1.25,2.29) was associated with greater odds of meeting all three recommendations. Being a woman (0.46; 0.39,0.55), aged 50-64 years (0.77; 0.60,0.97), and married (0.79; 0.65,0.96) were associated with lower odds of meeting the MVPA recommendation. Having a middle (0.64; 0.50,0.80) or high (0.36; 0.23,0.55) education level was associated with lower odds and being married (1.86; 1.46,2.36) was associated with greater odds of meeting the ST recommendation. Being a woman (0.63; 0.51,0.78) was associated with lower odds; whereas being aged 50-64 years (1.40; 1.04,1.88) and having a middle education level (1.37; 1.09,1.73) were associated with greater odds of meeting the sleep duration recommendation. Conclusions: Overall, the proportion of Latin American adults achieving healthy levels of 24-hour movement behaviors was low. Further efforts are needed to promote more MVPA, less ST, and sufficient sleep in Latin American adults.

Kinase signaling fuels growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Yet its role in leukemia initiation is unclear and has not been shown in primary human hematopoietic cells. We previously described activating mutations in interleukin-7 receptor alpha (IL7RA) in poor-prognosis "ph-like" BCP-ALL. Here we show that expression of activated mutant IL7RA in human CD34+ hematopoietic stem and progenitor cells induces a preleukemic state in transplanted immunodeficient NOD/LtSz-scid IL2Rγnull mice, characterized by persistence of self-renewing Pro-B cells with non-productive V(D)J gene rearrangements. Preleukemic CD34+CD10highCD19+ cells evolve into BCP-ALL with spontaneously acquired Cyclin Dependent Kinase Inhibitor 2 A (CDKN2A) deletions, as commonly observed in primary human BCP-ALL. CRISPR mediated gene silencing of CDKN2A in primary human CD34+ cells transduced with activated IL7RA results in robust development of BCP-ALLs in-vivo. Thus, we demonstrate that constitutive activation of IL7RA can initiate preleukemia in primary human hematopoietic progenitors and cooperates with CDKN2A silencing in progression into BCP-ALL.

The twait shad, Alosa fallax (Lacepède, 1803), is an anadromous clupeid threatened by anthropogenic pressures from changes in the hydrological dynamics of river flow to limited connectivity of inland waters due to damming, among others. Population recovery is intrinsically dependent on the implementation of conservation measures for the rehabilitation of riverine ecosystems. The timely application of direct approaches aimed at strengthening population size may also be beneficial to its recovery. Therefore, the optimization of hatchery efforts is crucial to enable restocking programs. In this study we tested growth and mortality of A. fallax larvae from the Guadiana population reared at different temperature, salinity and feeding conditions. Results indicated that the temperature for optimal growth is somewhere between 24°C and 28°C, and that the optimal salinity for minimizing mortality in aquaculture systems in which the larvae are fed with Artemia spp. nauplii is close to 2,5 g/L. Moreover, the larval development of individuals from the same population reared under controlled conditions was described, from the moment of hatching to the completion of metamorphosis, using morphometric and meristic characters to define a series of larval stages easily identifiable. This study allowed obtaining important insights for the optimization of larval culture of A. fallax, as well as a relevant basis for the identification of larvae captured for recruitment assessments.

Frontotemporal dementia in genetic forms is highly heterogeneous and begins many years to prior symptom onset, complicating disease understanding and treatment development. Unifying methods to stage the disease during both the presymptomatic and symptomatic phases are needed for the development of clinical trials outcomes. Here we used the contrastive trajectory inference (cTI), an unsupervised machine learning algorithm that analyzes temporal patterns in high-dimensional large-scale population datasets to obtain individual scores of disease stage. We used cross-sectional MRI data (gray matter density, T1/T2 ratio as a proxy for myelin content, resting-state functional amplitude, gray matter fractional anisotropy, and mean diffusivity) from 383 gene carriers (269 presymptomatic and 115 symptomatic) and a control group of 253 noncarriers in the Genetic Frontotemporal Dementia Initiative. We compared the cTI-obtained disease scores to the estimated years to onset (age-mean age of onset in relatives), clinical, and neuropsychological test scores. The cTI based disease scores were correlated with all clinical and neuropsychological tests (measuring behavioral symptoms, attention, memory, language, and executive functions), with the highest contribution coming from mean diffusivity. Mean cTI scores were higher in the presymptomatic carriers than controls, indicating that the method may capture subtle pre-dementia cerebral changes, although this change was not replicated in a subset of subjects with complete data. This study provides a proof of concept that cTI can identify data-driven disease stages in a heterogeneous sample combining different mutations and disease stages of genetic FTD using only MRI metrics.

A recent work elegantly demonstrated a role of adenosine, through the high afnity Gs-coupled A2A receptors (A2AR), on stabilization of GABAergic synapses during a critical post-natal period, which is discussed here within the context of the most recent advances on our understanding of the neurodevelopmental actions of adenosine. Neuronal activity requires a proper balance between excitatory and inhibitory inputs, GABA being the predominant inhibitory neurotransmitter in the brain. Dysfunction of GABAergic signalling, in particular in the maturation of GABAergic synapses, leads to severe neurodevelopmental diseases, which may express as drug-resistant forms of epilepsy, cognitive impairment and, often, mental retardation or even premature death.