Cortical synaptogenesis and excitatory synapse number are determined via a Neuroligin-1-dependent intercellular competition

Members of the neuroligin (NL) family of cell-adhesion proteins are found at excitatory and inhibitory synapses and are mutated in some familial forms of autism spectrum disorders. Although they display synaptogenic properties in heterologous systems, a function of NLs in vivo in regulating synapse formation and synapse number has been difficult to establish. Here we show that neuroligin-1 (NL1), which is located at excitatory post-synaptic densities, does regulate activity-dependent synaptogenesis as well as mature synapse number on cortical layer 2/3 pyramidal neurons in vivo. However, synapse number is not sensitive to absolute NL1 levels but rather to transcellular differences in the relative amounts of NL1. These effects are independent of the cell-autonomous regulation of NMDA-type glutamate receptors by absolute levels of NL1. Our data indicate that transcellular competitive processes govern synapse formation and number in developing cortex and that NL1 plays a central function in these processes

Transsynaptic Signaling by Activity-Dependent Cleavage of Neuroligin-1

Adhesive contact between pre- and postsynaptic neurons initiates synapse formation during brain development and provides a natural means of trans-synaptic signaling. Numerous adhesion molecules and their role during synapse development have been described in detail. However, once established, the mechanisms of adhesive disassembly and its function in regulating synaptic transmission have been unclear. Here, we report that synaptic activity induces acute proteolytic cleavage of neuroligin-1 (NLG1), a postsynaptic adhesion molecule at glutamatergic synapses. NLG1 cleavage is triggered by NMDA receptor activation, requires Ca2+/calmodulin-dependent protein kinase, and is mediated by proteolytic activity of matrix metalloprotease 9 (MMP9). Cleavage of NLG1 occurs at single activated spines, is regulated by neural activity in vivo, and causes rapid destabilization of its presynaptic partner neurexin-1β (NRX1β). In turn, NLG1 cleavage depresses synaptic transmission by abruptly reducing presynaptic release probability. Thus, local proteolytic control of synaptic adhesion tunes synaptic transmission during brain development and plasticity

Aminodi(hetero)arylamines in the thieno[3,2-b]pyridine series: synthesis, effects in human tumor cells growth, cell cycle analysis, apoptosis and evaluation of toxicity using non-tumor cells

Three aminodi(hetero)arylamines were prepared via a palladium-catalyzed C-N Buchwald-Hartwig coupling of methyl 3-aminothieno[3,2-b]pyridine-2-carboxylate with different bromonitrobenzenes, followed by reduction of the nitro groups of the coupling products to the corresponding amino compounds. The aminodi(hetero)arylamines thus obtained were evaluated for their growth inhibitory effect on four human tumor cell lines MCF-7 (breast adenocarcinoma), A375-C5 (melanoma), NCI-H460 (non-small cell lung cancer) and HepG2 (hepatocellular carcinoma). The toxicity to non-tumor cells was also evaluated using a porcine liver primary cell culture (PLP1), established by us. The aminodi(hetero)arylamine with the NH2 group in the ortho position and an OMe group in the para position to the NH of the di(hetero)arylamine, is the most promising compound giving the lowest GI50 values (1.30–1.63 μM) in all the tested human tumor cell lines, presenting no toxicity to PLP1 at those concentrations. The effect of this compound on the cell cycle and induction of apoptosis was analyzed in the NCI-H460 cell line. It was observed that it altered the cell cycle profile causing a decrease in the percentage of cells in the G0/G1 phase and an increase of the apoptosis levels.Foundation for the Science and Technology (FCT–Portugal) for financial support through the NMR Portuguese network (Bruker 400 Avance III-Univ Minho). FCT and FEDER (European Fund for Regional Development) for financial support through the research centers PEst-C/QUI/UI686/2011and PEst-OE/AGR/UI0690/2011, the research project PTDC/QUI-QUI/111060/2009 and the post-Doctoralgrants attributed to R.C.C. and R.T.L. (SFRH/BPD/68344/2010 and SFRH/BPD/68787/2010, respectively). IPATIMUP is an Associate Laboratory of the Portuguese Ministry of Science, Technology and Higher Education and is partially supported by FCT

New di(hetero)arylethers and di(hetero)arylamines in the thieno[3,2-b]pyridine series: Synthesis, growth inhibitory activity on human tumor cell lines and non-tumor cells, effects on cell cycle and on programmed cell death

New fluorinated and methoxylated di(hetero)arylethers and di(hetero)arylamines were prepared functionalizing the 7-position of the thieno[3,2-blpyridine, using copper (C-O) or palladium (C N) catalyzed couplings, respectively, of the 7-bromothieno[3,2-blpyridine, also prepared, with ortho, meta and para fluoro or methoxy phenols and anilines. The compounds obtained were evaluated for their growth inhibitory activity on the human tumor cell lines MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer), HCI15 (colon carcinoma), HepG2 (hepatocellular carcinoma) and HeLa (cervical carcinoma). The most active compounds, a di(hetero)arylether with a methoxy group in the meta position relative to the ether function and two di(hetero)arylamines with a methoxy group either in the ortho or in the meta position relative to the NH, were further tested at their GI(50) concentrations on NCI-H460 cells causing pronounced alterations in the cell cycle profile and a strong and significant increase in the programmed death of these cells. The fluorinated and the other methoxylated compounds did not show important activity, presenting high GI(50) values in all the cell lines tested. Furthermore, the hepatotoxicity of the compounds was assessed using porcine liver primary cells (PLP2), established by some of us. Results showed that one of the most active compounds was not toxic to the non-tumor cells at their GI(50) concentrations showing to be the most promising as antitumoral.The authors would like to thank to the Foundation for the Science and Technology (PCT Portugal) for financial support through the NMR Portuguese network (Bruker 400 Avance III-Univ Minho); to FCT and FEDER-COMPETE/QREN/EU for financial support through the research unities PEst-C/QUI/UI686/2011 and PEst-OE/AGR/UI0690/2011, the research project PTDC/QUI-QUI/111060/2009 and the post-Doctoral grants attributed to R.C.C. (SFRH/BPD/68344/2010) and R.T.L. (SRH/BPD/68787/2010). IPATIMUP is an Associate Laboratory of the Portuguese Ministry of Science, Technology and Higher Education and is partially supported by FCT

New Emigration and Portuguese Society: Transnationalism and Return

This chapter addresses the theme of transnationalism and return in recent Portuguese emigration, namely the flows that occurred after the turn of the century. It starts with a brief theoretical overview on those topics, which constitute two relatively neglected characteristics of Portuguese emigration. Next, based on a survey carried out in 2014–2015 to more than 6000 recent emigrants, it reveals some of the links that they maintain with their home country, as well as their plans for the future, which include settlement in the destination country, return and re-emigration. Lastly, it examines data on returning emigrants – especially those that returned between 2001 and 2011 – extracted from the 2011 Census. The evidence reveals a significant number of returns, including individuals at both working and retirement ages and at all skill levels, thus exposing the unexpected complexity of movements. The results are based on the research project “Back to the future: new emigration and links with Portuguese society” (REMIGR), which aimed to ascertain the extent and characteristics of the new emigration wave. The project included an overview of emigration and return to and from all regions of the world, as well as case studies in UK, France, Luxembourg, Angola, Mozambique and Brazil.info:eu-repo/semantics/publishedVersio

Stress ocupacional e alteração do Estatuto da Carreira Docente português

Este estudo foi realizado com 1162 professores, tendo como objetivo analisar a experiência de stress e a síndrome de “burnout”, antes a após a alteração do Estatuto da Carreira Docente em Portugal. Assim, foram efetuadas duas avaliações em momentos temporais distintos, assumindo-se um plano transversal de recolha de dados (2004/2005, n=689 e 2008/2009, n=473). O protocolo de avaliação incluiu medidas de fontes de stress (Questionário de Stress nos Professores, Gomes, Silva, Mourisco, Mota, & Montenegro, 2006) e de “burnout” (Inventário de “Burnout” de Maslach – Versão para Professores, Maslach, Jackson, & Leiter, 1996; Maslach, Jackson, & Schwab, 1996, Adaptação de Gomes et al., 2006). Os resultados indicaram que a experiência de stress e de “burnout” aumentou entre as duas avaliações, verificando-se em 2008/2009 aumentos em áreas relacionadas com as pressões de tempo/excesso de trabalho e com o trabalho burocrático/administrativo e, inversamente, diminuições em áreas relacionadas com as diferentes capacidades e motivações dos alunos. Quanto à predição da síndrome de “burnout”, não se verificaram alterações substanciais nas variáveis preditoras nos dois momentos. Em síntese, os resultados indicaram aumentos nas exigências profissionais dos professores, mas não se pode afirmar que tal se deva às alterações do Estatuto da Carreira Docente uma vez que não observámos alterações no stress associado à carreira docente.(undefined

Determination of total and available fractions of PAHs by SPME in oily wastewaters : overcoming interference from NAPL and NOM

Background, aim, and scope Polycyclic aromatic hydrocarbons (PAHs) are often found in oily wastewaters. Their presence is usually the result of human activities and has a negative effect on the environment. One important step in addressing this problem is to evaluate the effectiveness of PAH removal by biological processes since these are the most cost-effective treatments known today. Many techniques are presently available for PAH determination in wastewaters. Solid phase microextracion (SPME) is known to be one of the most effective techniques for this purpose. When analyzing complex matrices with substances such as natural organic matter (NOM) and non-aqueous phase liquids (NAPL), it is important to differentiate the free dissolved PAH from matrix-bonded PAH. PAHs associated with the bonded fraction are less susceptible to biological treatment. The present study concerns the development of a simple and suitable methodology for the determination of the freely dissolved and the total fraction of PAHs present in oily wastewaters. The methodology was then applied to an oily wastewater from a fuel station retention basin. Material and methods Headspace SPME was used for analyzing PAH since the presence of a complex or dirty matrix in direct contact with the fiber may damage it. Four model PAHs—anthracene, fluorene, phenanthrene, and pyrene—were analyzed by GC-MS. Negligible depletion SPME technique was used to determine the free fraction. Total PAH was determined by enhancing the mass transfer from the bonded phase to the freely dissolved phase by temperature optimization and the use of the method of standard additions. The PAH absorption kinetics were determined in order to define the optimal sampling conditions for this method. The fitting of the experimental data to a mathematical model was accomplished using Berkeley Madonna software. Humic acid and silicon oil were used as model NOM and NAPL, respectively, to study the effect of these compounds on the decrease of SPME response. Then, the method was evaluated with wastewater from a fuel station spill retention basin. Results The SPME kinetic parameters—k 1 (uptake rate), k 2 (desorption rate), and K SPME (partition coefficient)—were determined from experimental data modeling. The determination of the free fraction required 15-min sampling to ensure that PAH depletion from sample was below 1%. For total PAH, a 30-min extraction at 100°C ensured the maximum signal response in the GC-MS. For the determination of free and total PAHs, extractions were performed before reaching the SPME equilibrium. The wastewater used in this study had no free fraction of the analyzed PAHs. However, the four studied PAHs were found when the method for total PAH was used. Discussion The addition of NOM and NAPL dramatically decreased the efficiency of the SPME. This decrease was the result of a greater partition of the PAHs to the NAPL and NOM phases. This fact was also observed in the analysis of the fuel station spill retention basin, where no free PAH was measured. However, using the method of standard addition for the determination of total PAH, it was possible to quantify all four PAHs. Conclusions The method developed in the present study was found to be adequate to differentiate between free and total PAH present in oily wastewater. It was determined that the presence of NOM and NAPL had a negative effect on SPME efficiency. Recommendations and perspectives The presence of binding substances had a great influence on SPME kinetics. Therefore, it is of extreme importance to determine their degree of interference when analyzing oily wastewaters or results can otherwise be erroneous. Other factors influencing the total PAH determinations should be considered in further studies.Fundação para a Ciência e a Tecnologia (FCT) - SFRH/BD/ 18816/2004, POCI/AMB/61044/200

Stress ocupacional no ensino : um estudo com professores dos 3º ciclo e ensino secundário

Este trabalho foi realizado com 689 professores portugueses, a leccionarem nos terceiro ciclo e ensino secundário. Foram avaliados indicadores de stress, “burnout”, saúde física e satisfação profissional. Observaram-se valores significativos de stress ocupacional (perto de 40%), e de “burnout” (10% na exaustão emocional, 3% na baixa realização pessoal e 1% na despersonalização), vários problemas de saúde física e valores de insatisfação profissional perto dos 20%. As análises de regressão múltipla apontaram diferentes variáveis preditoras para as três dimensões do “burnout” (62% de variância explicada na exaustão emocional, 16% na realização pessoal e 13% na despersonalização). As análises discriminantes e “t-test” para amostras independentes demonstraram maior stress ocupacional nas mulheres, nos professores mais velhos, nos profissionais com vínculos profissionais mais precários, nos professores com mais horas de trabalho e com mais alunos em sala de aula. No final, apresentam-se as limitações do estudo e as implicações para a investigação futura.(undefined

Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants

BACKGROUND: One of the global targets for non-communicable diseases is to halt, by 2025, the rise in the age-standardised adult prevalence of diabetes at its 2010 levels. We aimed to estimate worldwide trends in diabetes, how likely it is for countries to achieve the global target, and how changes in prevalence, together with population growth and ageing, are affecting the number of adults with diabetes. METHODS: We pooled data from population-based studies that had collected data on diabetes through measurement of its biomarkers. We used a Bayesian hierarchical model to estimate trends in diabetes prevalence—defined as fasting plasma glucose of 7·0 mmol/L or higher, or history of diagnosis with diabetes, or use of insulin or oral hypoglycaemic drugs—in 200 countries and territories in 21 regions, by sex and from 1980 to 2014. We also calculated the posterior probability of meeting the global diabetes target if post-2000 trends continue. FINDINGS: We used data from 751 studies including 4 372 000 adults from 146 of the 200 countries we make estimates for. Global age-standardised diabetes prevalence increased from 4·3% (95% credible interval 2·4–7·0) in 1980 to 9·0% (7·2–11·1) in 2014 in men, and from 5·0% (2·9–7·9) to 7·9% (6·4–9·7) in women. The number of adults with diabetes in the world increased from 108 million in 1980 to 422 million in 2014 (28·5% due to the rise in prevalence, 39·7% due to population growth and ageing, and 31·8% due to interaction of these two factors). Age-standardised adult diabetes prevalence in 2014 was lowest in northwestern Europe, and highest in Polynesia and Micronesia, at nearly 25%, followed by Melanesia and the Middle East and north Africa. Between 1980 and 2014 there was little change in age-standardised diabetes prevalence in adult women in continental western Europe, although crude prevalence rose because of ageing of the population. By contrast, age-standardised adult prevalence rose by 15 percentage points in men and women in Polynesia and Micronesia. In 2014, American Samoa had the highest national prevalence of diabetes (>30% in both sexes), with age-standardised adult prevalence also higher than 25% in some other islands in Polynesia and Micronesia. If post-2000 trends continue, the probability of meeting the global target of halting the rise in the prevalence of diabetes by 2025 at the 2010 level worldwide is lower than 1% for men and is 1% for women. Only nine countries for men and 29 countries for women, mostly in western Europe, have a 50% or higher probability of meeting the global target. INTERPRETATION: Since 1980, age-standardised diabetes prevalence in adults has increased, or at best remained unchanged, in every country. Together with population growth and ageing, this rise has led to a near quadrupling of the number of adults with diabetes worldwide. The burden of diabetes, both in terms of prevalence and number of adults affected, has increased faster in low-income and middle-income countries than in high-income countries. FUNDING: Wellcome Trust

Contributions of mean and shape of blood pressure distribution to worldwide trends and variations in raised blood pressure: A pooled analysis of 1018 population-based measurement studies with 88.6 million participants

© The Author(s) 2018. Background: Change in the prevalence of raised blood pressure could be due to both shifts in the entire distribution of blood pressure (representing the combined effects of public health interventions and secular trends) and changes in its high-blood-pressure tail (representing successful clinical interventions to control blood pressure in the hypertensive population). Our aim was to quantify the contributions of these two phenomena to the worldwide trends in the prevalence of raised blood pressure. Methods: We pooled 1018 population-based studies with blood pressure measurements on 88.6 million participants from 1985 to 2016. We first calculated mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP) and prevalence of raised blood pressure by sex and 10-year age group from 20-29 years to 70-79 years in each study, taking into account complex survey design and survey sample weights, where relevant. We used a linear mixed effect model to quantify the association between (probittransformed) prevalence of raised blood pressure and age-group- and sex-specific mean blood pressure. We calculated the contributions of change in mean SBP and DBP, and of change in the prevalence-mean association, to the change in prevalence of raised blood pressure. Results: In 2005-16, at the same level of population mean SBP and DBP, men and women in South Asia and in Central Asia, the Middle East and North Africa would have the highest prevalence of raised blood pressure, and men and women in the highincome Asia Pacific and high-income Western regions would have the lowest. In most region-sex-age groups where the prevalence of raised blood pressure declined, one half or more of the decline was due to the decline in mean blood pressure. Where prevalence of raised blood pressure has increased, the change was entirely driven by increasing mean blood pressure, offset partly by the change in the prevalence-mean association. Conclusions: Change in mean blood pressure is the main driver of the worldwide change in the prevalence of raised blood pressure, but change in the high-blood-pressure tail of the distribution has also contributed to the change in prevalence, especially in older age groups