miRNA-31 Improves Cognition and Abolishes Amyloid-beta Pathology by Targeting APP and BACE1 in an Animal Model of Alzheimer's Disease

Alzheimer's disease (AD) is the most common form of dementia worldwide, characterized by progressive memory impairment, behavioral changes, and, ultimately, loss of consciousness and death. Recently, microRNA (miRNA) dysfunction has been associated with increased production and impaired clearance of amyloid-β (Aβ) peptides, whose accumulation is one of the most well-known pathophysiological markers of this disease. In this study, we identified several miRNAs capable of targeting key proteins of the amyloidogenic pathway. The expression of one of these miRNAs, miR-31, previously found to be decreased in AD patients, was able to simultaneously reduce the levels of APP and Bace1 mRNA in the hippocampus of 17-month-old AD triple-transgenic (3xTg-AD) female mice, leading to a significant improvement of memory deficits and a reduction in anxiety and cognitive inflexibility. In addition, lentiviral-mediated miR-31 expression significantly ameliorated AD neuropathology in this model, drastically reducing Aβ deposition in both the hippocampus and subiculum. Furthermore, the increase of miR-31 levels was enough to reduce the accumulation of glutamate vesicles in the hippocampus to levels found in non-transgenic age-matched animals. Overall, our results suggest that miR-31-mediated modulation of APP and BACE1 can become a therapeutic option in the treatment of AD.This work was financed by the European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme under the project CENTRO-01-0145-FEDER-000008: BrainHealth 2020 and through the COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation and Portuguese national funds via FCT - Fundação para a Ciência e a Tecnologia, under the project POCI- 01-0145-FEDER-007440 (reference UID/NEU/04539/2013). This work was also supported by the FCT Investigator Programme (IF/ 00694/2013 to J.P.), the Marie Curie Carrier Integration Grant (PCIG13-GA-2013-618525 to J.P.), HEALTHYAGING 2020 (CENTRO-01-0145-FEDER-000012 to A.T.B.-V.), and Bial Foundation Grant 264/16. A.T.B.-V., J.G., and A.L.C. are recipients of fellowships from the FCT (Grants PTDC/BIM-MEC/0651/2012, SFRH/ BPD/120611/2016, and SFRH/BPD/108312/2015)

O câncer e a criança: um impacto familiar

The aim of this work is a bibliographic review concerning the children living with cancer and their family, in order to identify the themes that have been already studied and to understand the impact on the family during the phases of childhood cancer. The information acquisition was based on documents from the Ministry of Health and on scientific studies available on the following databases: the Google Scholar, the Health virtual Library, the Scielo, the CAPES Journals, the MEDLINE, the LILACS and the Cochrane. The choice of the documents and journals was mainly justified by its link with the childhood health theme. The systematic of the studies research covered the period from 1999 to 2015. The keywords used for the research’s strategy were: childhood health, childhood cancer, family caregivers and grief. The results were presented in three themes: childhood cancer impact on the family, adaptation process of the family facing the sickness and the mourning regarding the death of the sick child. The review enabled to identify the need for special follow-up of the person, which is in direct contact with the child, usually the mother, since the moment of the diagnostic, until after the death.O objetivo desse estudo é revisar a literatura relativa à criança com câncer e sua família, a fim de identificar temas que têm sido pesquisados, e compreender o impacto causado na família durante as fases do câncer infantil. O levantamento de dados foi embasado em documentos do Ministério da Saúde e em trabalhos científicos disponibilizados no Google Acadêmico, Biblioteca virtual da Saúde, Scielo, Periodicos Capes, MEDLINE, LILACS e Cochrane. A escolha dos documentos e periódicos se deu pela sua relação com os temas Saúde da criança. A busca sistematizada de trabalhos abrangeram o período de 1999 a 2015. A estratégia de busca desse referencial utilizou as seguintes palavras-chave: Saúde da Criança, Câncer Infantil, Cuidadores Familiares e Luto. Os resultados foram apresentados em três temas: impacto do câncer infantil na familiar; processo de adaptação da família diante da doença e o luto diante da morte da criança. A revisão demonstrou que uma necessidade de acompanhamento especial a pessoa em contato direto com a criança, geralmente a mãe, desde o momento do diagnostico, e até após a morte

Doenças endocrinológicas com repercussões psiquiátricas: revisão sistemática / Endocrinological disorders with psychiatric repercussions: a systematic review

O objetivo do estudo foi realizar uma revisão sistemática de literatura sobre doenças endocrinológicas com repercussões psiquiátricas. Para isso, realizou-se uma revisão sistemática de literatura, através de uma busca nas bases de dados Latino-Americana e do Caribe em Ciências da Saúde, Google Scholar e Scientific Electronic Library Online, utilizando-se os descritores: Endocrinology, Mental Disorders, Psychiatric Symptoms, Cushing’s syndrome, Hyperthyroidism, Hypothyroidism, Addison disease. Através disso, foram selecionados 12 artigos que compunham os critérios de inclusão e exclusão do presente estudo. Dessa forma, destaca-se que os estudos evidenciaram que diversos são as repercussões psiquiátricas em pacientes com doenças endocrinológicas, variando desde transtornos de ansiedade, depressão, transtorno de déficit de atenção/hiperatividade e psicose, cabendo aos profissionais o diagnóstico correto e em tempo hábil para auxiliar na qualidade de vida do indivíduo. 

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Physics case for an LHCb Upgrade II - Opportunities in flavour physics, and beyond, in the HL-LHC era

The LHCb Upgrade II will fully exploit the flavour-physics opportunities of the HL-LHC, and study additional physics topics that take advantage of the forward acceptance of the LHCb spectrometer. The LHCb Upgrade I will begin operation in 2020. Consolidation will occur, and modest enhancements of the Upgrade I detector will be installed, in Long Shutdown 3 of the LHC (2025) and these are discussed here. The main Upgrade II detector will be installed in long shutdown 4 of the LHC (2030) and will build on the strengths of the current LHCb experiment and the Upgrade I. It will operate at a luminosity up to 2×1034 cm−2s−1, ten times that of the Upgrade I detector. New detector components will improve the intrinsic performance of the experiment in certain key areas. An Expression Of Interest proposing Upgrade II was submitted in February 2017. The physics case for the Upgrade II is presented here in more depth. CP-violating phases will be measured with precisions unattainable at any other envisaged facility. The experiment will probe b → sl+l−and b → dl+l− transitions in both muon and electron decays in modes not accessible at Upgrade I. Minimal flavour violation will be tested with a precision measurement of the ratio of B(B0 → μ+μ−)/B(Bs → μ+μ−). Probing charm CP violation at the 10−5 level may result in its long sought discovery. Major advances in hadron spectroscopy will be possible, which will be powerful probes of low energy QCD. Upgrade II potentially will have the highest sensitivity of all the LHC experiments on the Higgs to charm-quark couplings. Generically, the new physics mass scale probed, for fixed couplings, will almost double compared with the pre-HL-LHC era; this extended reach for flavour physics is similar to that which would be achieved by the HE-LHC proposal for the energy frontier

LHCb upgrade software and computing : technical design report

This document reports the Research and Development activities that are carried out in the software and computing domains in view of the upgrade of the LHCb experiment. The implementation of a full software trigger implies major changes in the core software framework, in the event data model, and in the reconstruction algorithms. The increase of the data volumes for both real and simulated datasets requires a corresponding scaling of the distributed computing infrastructure. An implementation plan in both domains is presented, together with a risk assessment analysis

Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH(2)O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure <= 30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.Hospital do Coracao (HCor) as part of the Program 'Hospitais de Excelencia a Servico do SUS (PROADI-SUS)'Brazilian Ministry of Healt

Measurement of the J/ψ pair production cross-section in pp collisions at s=13 \sqrt{s}=13 TeV

The production cross-section of J/ψ pairs is measured using a data sample of pp collisions collected by the LHCb experiment at a centre-of-mass energy of $\sqrt{s}=13$ TeV, corresponding to an integrated luminosity of 279 ±11 pb$^{−1}$. The measurement is performed for J/ψ mesons with a transverse momentum of less than 10 GeV/c in the rapidity range 2.0 < y < 4.5. The production cross-section is measured to be 15.2 ± 1.0 ± 0.9 nb. The first uncertainty is statistical, and the second is systematic. The differential cross-sections as functions of several kinematic variables of the J/ψ pair are measured and compared to theoretical predictions.The production cross-section of $J/\psi$ pairs is measured using a data sample of $pp$ collisions collected by the LHCb experiment at a centre-of-mass energy of $\sqrt{s} = 13 \,{\mathrm{TeV}}$, corresponding to an integrated luminosity of $279 \pm 11 \,{\mathrm{pb^{-1}}}$. The measurement is performed for $J/\psi$ mesons with a transverse momentum of less than $10 \,{\mathrm{GeV}}/c$ in the rapidity range $2.0<y<4.5$. The production cross-section is measured to be $15.2 \pm 1.0 \pm 0.9 \,{\mathrm{nb}}$. The first uncertainty is statistical, and the second is systematic. The differential cross-sections as functions of several kinematic variables of the $J/\psi$ pair are measured and compared to theoretical predictions