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Disorders of the autonomic nervous system (ANS) are common conditions, but it is unclear whether access to ANS healthcare provision is homogeneous across European countries. The aim of this study was to identify neurology-driven or interdisciplinary clinical ANS laboratories in Europe, describe their characteristics and explore regional differences.We contacted the European national ANS and neurological societies, as well as members of our professional network, to identify clinical ANS laboratories in each country and invite them to answer a web-based survey.We identified 84 laboratories in 22 countries and 46 (55%) answered the survey. All laboratories perform cardiovascular autonomic function tests, and 83% also perform sweat tests. Testing for catecholamines and autoantibodies are performed in 63% and 56% of laboratories, and epidermal nerve fiber density analysis in 63%. Each laboratory is staffed by a median of two consultants, one resident, one technician and one nurse. The median (interquartile range [IQR]) number of head-up tilt tests/laboratory/year is 105 (49-251). Reflex syncope and neurogenic orthostatic hypotension are the most frequently diagnosed cardiovascular ANS disorders. Thirty-five centers (76%) have an ANS outpatient clinic, with a median (IQR) of 200 (100-360) outpatient visits/year; 42 centers (91%) also offer inpatient care (median 20 [IQR 4-110] inpatient stays/year). Forty-one laboratories (89%) are involved in research activities. We observed a significant difference in the geographical distribution of ANS services among European regions: 11 out of 12 countries from North/West Europe have at least one ANS laboratory versus 11 out of 21 from South/East/Greater Europe (p = 0.021).This survey highlights disparities in the availability of healthcare services for people with ANS disorders across European countries, stressing the need for improved access to specialized care in South, East and Greater Europe.

Insomnia and sleep-disordered breathing (SDB) are prevalent sleep disorders. These disorders can therefore be concurrently present - comorbid insomnia and sleep apnea (COMISA). The prevalence of COMISA in the paediatric age range is unclear. As such, phenotypic constructs should help better define this comorbid condition if it exists in children and improve both diagnostic sensitivity and ultimately clinical care outcomes. We aimed to evaluate the frequency of insomnia in children and adolescents referred for evaluation of sleep symptoms suggestive of SDB in one initial (Cohort#1) and verify such findings in an independent cohort (Cohort#2) using a retrospective cross-sectional approach in patients aged 9-19 years presenting at a sleep centre to be evaluated for symptoms of SDB. Cohort #1 comprised 50 consecutive children (58% males; mean [SD] age 13.6 [3.3] years; median [interquartile range, IQR] Epworth Sleepiness Scale score 10 [6-12]) who were evaluated using validated SDB and insomnia questionnaires. Cohort#2 was extracted from electronic medical records and included 384 polysomnographically evaluated children (mean [SD] age 12.9 [3.6] years; mean [SD] body mass index z score 1.27 [0.28]; median Epworth Sleepiness Scale score 9.7 [4-17]). In Cohort #1, 56% were at high risk of SDB, 36% had insomnia alone, and 18% were at high risk of COMISA. The prevalence of COMISA in Cohort #2 was 16%, 72% had SDB alone, and 12% had insomnia alone. In both cohorts, COMISA manifested as increased propensity for sleepiness and fatigue during both waking and daytime. Thus, the presence of COMISA is frequent in the paediatric age range and accompanied by a more prominent symptomatic phenotype.

Tese de Doutoramento em Sociologia, apresentada à Faculdade de Economia da Universidade de Coimbra. Em Portugal e em muitos países europeus, os cuidados prestados à doença mental estão concentrados no Hospital. Ainda que tenham existido vários esforços para a desinstitucionalização, atrasos sucessivos na reestruturação dos serviços e pouco interesse político, público e científico têm contribuído para a pouca visibilidade da experiência da doença mental e de outras formas de lidar com esta além da psiquiatria. Este estudo contribui para diminuir essa lacuna e muito embora se centre num estudo etnográfico em contexto hospitalar, permitiu documentar a variedade de atividades que lá se praticavam e a multiplicidade de combinações que essas vão assumindo consoante os intervenientes, os espaços e os recursos disponíveis, além da dinâmica usual entre psiquiatra, enfermeira e utente. A análise das notas, registadas durante seis meses de observação participante em duas unidades de cuidado ambulatório, num hospital geral em Portugal, norteia-se pela ética empírica e pelo método de montagem, enquadrando-se nos estudos da ciência e tecnologia e da semiótica material. Situo-me assim dentro de uma abordagem pragmática e pós-moderna da doença mental, em que a experiência de investigação desiste de ser neutra e se imbrica na experiência da investigadora. Esta opção além de procurar o rigor da análise radica-se também numa postura ética que atravessa todas as etapas da pesquisa e aceita as suas consequências metodológicas na produção do conhecimento apresentado. Tendo-me proposto a estudar o que significava o bom cuidado na doença mental grave e como este se concretizava na prática dinâmica de utentes, profissionais e familiares, descrevi e analisei atividades relacionadas com comida e bebida, psicomedicação e cuidados performativos, identifiquei empiricamente os ideais éticos que se pretendiam realizar e as tensões que diferentes medidas de bom produziam no dia a dia daquelas unidades. Dessa análise, pude identificar os hospitais dentro do hospital, ou seja, quatro repertórios de hospital baseados em quatro dimensões de cuidado: psiquiátrico, reabilitativo, lúdico e colaborativo. Este último constitui uma alternativa emergente e menos desenvolvida de práticas de cuidado, e surge como proposta de conciliação dos vários contributos e recursos existentes nas demais composições de hospital. O seu benefício assenta na interpenetração de vários ideais e estratégias para lidar com a doença mental e sugere a constante intercomunicação e adaptação de saberes dentro de um coletivo de cuidado, em que o utente é apenas um dos nós, consoante a situação que se apresente em necessidade de melhoria. Perante as diversas modalidades de bom cuidado identificadas, concluo que este é um compromisso quotidiano entre o perfeito imaginado e o presente possível, dentro das condições materiais e simbólicas disponíveis a cada momento. Por conseguinte, estas podem ser tão desfavoráveis dentro de uma instituição hospitalar como na comunidade para que se orientam as políticas de saúde mental, sempre que num e noutro contexto não se procurem negociar as normas de pertença, ação e pensamento para que incluam quem e o que é diferente. In Portugal and many European countries, mental illness care is frequently centred in the hospital. Although efforts have been made to deinstitutionalize, successive delays in restructuring services and little interest from the political, public, and scientific fields have contributed to the lesser visibility of what it means to experience mental illness, and other ways of dealing with it beyond psychiatry. This study contributes to shortening the knowledge gap and even though it is based on an ethnographic account of a hospital context, it documented the variety of activities practiced there and the multiplicity of combinations they assume according to the different parties involved, spaces and resources available, beyond the customary dynamic between psychiatrist, nurse and user. The analysis of the fieldwork notes registered during six months participant observation in two day-care units, in a Portuguese general hospital, is based on empirical ethics and method assemblage, therefore fitting in science and technology and material semiotics studies. I situate myself within a pragmatic and postmodern approach to mental illness, one where the research experience gives up on neutrality and interweaves the researcher’s experience. This option, alongside its commitment with rigorous analysis, is rooted in an ethical posture present in every research phase and accepting of the methodological consequences it entails for the knowledge presented. In pursuit of my declared goal of studying what good care for severe mental illness meant and how it was reified in the lively practice of users, professionals and relatives, I have described and analysed activities related to food and drinking, psychiatric medication and performative care, have empirically identified the ethical ideals in the making and the tensions produced by different measures of what is good in the daily life of these units. From this analysis, I was able to identify the hospitals inside the hospital, that is four hospital repertoires based on four care dimensions: psychiatric, rehabilitative, recreational and collaborative. The latter is an emergent and less developed alternative for care practices, and it is set as a reconciliatory proposal between the different contributes and resources available in the remaining hospital compositions. Its advantage resides on weaving together several ideals and strategies to deal with mental illness and suggesting a constant intercommunication and knowledge adaptation inside a care collective, where the user is only one of the knots, according to the situation in need of improvement. Faced with the different modalities of good care identified, I conclude that this is a daily compromise between an idealised perfectness and a feasible present, within the material and symbolic conditions available at each moment. Hence, these may be as unfavourable inside a hospital institution as in the community to which mental health policies are directed, whenever a negotiation of the norms of belonging, action and thinking is not sought for as to include who and what is different.

Obstructive Sleep Apnea (OSA) is one of the most common sleep disorders, and invokes numerous negative health-related outcomes and physiopathological processes. Understanding the mechanisms by which OSA potentiates cardiometabolic risk of patients remains a current challenge. Sleep disruption is highly prevalent among shift workers and shift work (SW) is an important modulator of circadian rhythms, with health consequences intimately related to cardiometabolic health. Since the circadian timing system (CTS) interacts with the normal functioning of the ANS, CTS impact on OSA patients should be closely assessed. This review raises the question of whether SW-induced circadian misalignment potentiates the cardiometabolic risk of OSA patients, providing a novel perspective on the role of autonomic modulation as a key downstream mechanism linking cardiometabolic risk with both OSA and CTS misalignment.

Literature has shown that citizens' mistrust in national institutions has a negative impact on their involvement with, and commitment to, their national group. We examine the idea that citizenship efficacy beliefs may revert this process. We propose that facing institutional inefficacy to exert social control, beliefs that civic participation is effective, strengthens individuals' commitment to the national group. Participants (

Supplementary information is available for this paper at https://doi.org/10.1038/s41587-020-0446-y, Reconstructing metabolic reaction networks enables the development of testable hypotheses of an organisms metabolism under different conditions1. State-of-the-art genome-scale metabolic models (GEMs) can include thousands of metabolites and reactions that are assigned to subcellular locations. Geneproteinreaction (GPR) rules and annotations using database information can add meta-information to GEMs. GEMs with metadata can be built using standard reconstruction protocols2, and guidelines have been put in place for tracking provenance and enabling interoperability, but a standardized means of quality control for GEMs is lacking3. Here we report a community effort to develop a test suite named MEMOTE (for metabolic model tests) to assess GEM quality., We acknowledge D. Dannaher and A. Lopez for their supporting work on the Angular parts of MEMOTE; resources and support from the DTU Computing Center; J. Cardoso, S. Gudmundsson, K. Jensen and D. Lappa for their feedback on conceptual details; and P. D. Karp and I. Thiele for critically reviewing the manuscript. We thank J. Daniel, T. Kristjánsdóttir, J. Saez-Saez, S. Sulheim, and P. Tubergen for being early adopters of MEMOTE and for providing written testimonials. J.O.V. received the Research Council of Norway grants 244164 (GenoSysFat), 248792 (DigiSal) and 248810 (Digital Life Norway); M.Z. received the Research Council of Norway grant 244164 (GenoSysFat); C.L. received funding from the Innovation Fund Denmark (project “Environmentally Friendly Protein Production (EFPro2)”); C.L., A.K., N. S., M.B., M.A., D.M., P.M, B.J.S., P.V., K.R.P. and M.H. received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement 686070 (DD-DeCaF); B.G.O., F.T.B. and A.D. acknowledge funding from the US National Institutes of Health (NIH, grant number 2R01GM070923-13); A.D. was supported by infrastructural funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections; N.E.L. received funding from NIGMS R35 GM119850, Novo Nordisk Foundation NNF10CC1016517 and the Keck Foundation; A.R. received a Lilly Innovation Fellowship Award; B.G.-J. and J. Nogales received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no 686585 for the project LIAR, and the Spanish Ministry of Economy and Competitivity through the RobDcode grant (BIO2014-59528-JIN); L.M.B. has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement 633962 for project P4SB; R.F. received funding from the US Department of Energy, Offices of Advanced Scientific Computing Research and the Biological and Environmental Research as part of the Scientific Discovery Through Advanced Computing program, grant DE-SC0010429; A.M., C.Z., S.L. and J. Nielsen received funding from The Knut and Alice Wallenberg Foundation, Advanced Computing program, grant #DE-SC0010429; S.K.’s work was in part supported by the German Federal Ministry of Education and Research (de.NBI partner project “ModSim” (FKZ: 031L104B)); E.K. and J.A.H.W. were supported by the German Federal Ministry of Education and Research (project “SysToxChip”, FKZ 031A303A); M.K. is supported by the Federal Ministry of Education and Research (BMBF, Germany) within the research network Systems Medicine of the Liver (LiSyM, grant number 031L0054); J.A.P. and G.L.M. acknowledge funding from US National Institutes of Health (T32-LM012416, R01-AT010253, R01-GM108501) and the Wagner Foundation; G.L.M. acknowledges funding from a Grand Challenges Exploration Phase I grant (OPP1211869) from the Bill & Melinda Gates Foundation; H.H. and R.S.M.S. received funding from the Biotechnology and Biological Sciences Research Council MultiMod (BB/N019482/1); H.U.K. and S.Y.L. received funding from the Technology Development Program to Solve Climate Changes on Systems Metabolic Engineering for Biorefineries (grants NRF-2012M1A2A2026556 and NRF-2012M1A2A2026557) from the Ministry of Science and ICT through the National Research Foundation (NRF) of Korea; H.U.K. received funding from the Bio & Medical Technology Development Program of the NRF, the Ministry of Science and ICT (NRF-2018M3A9H3020459); P.B., B.J.S., Z.K., B.O.P., C.L., M.B., N.S., M.H. and A.F. received funding through Novo Nordisk Foundation through the Center for Biosustainability at the Technical University of Denmark (NNF10CC1016517); D.-Y.L. received funding from the Next-Generation BioGreen 21 Program (SSAC, PJ01334605), Rural Development Administration, Republic of Korea; G.F. was supported by the RobustYeast within ERA net project via SystemsX.ch; V.H. received funding from the ETH Domain and Swiss National Science Foundation; M.P. acknowledges Oxford Brookes University; J.C.X. received support via European Research Council (666053) to W.F. Martin; B.E.E. acknowledges funding through the CSIRO-UQ Synthetic Biology Alliance; C.D. is supported by a Washington Research Foundation Distinguished Investigator Award. I.N. received funding from National Institutes of Health (NIH)/National Institute of General Medical Sciences (NIGMS) (grant P20GM125503)., info:eu-repo/semantics/publishedVersion

Recent studies have brought forward the critical role of emergent properties in shaping microbial communities and the ecosystems of which they are a part. Emergent properties---patterns or functions that cannot be deduced linearly from the properties of the constituent parts---underlie important ecological characteristics such as resilience, niche expansion and spatial self-organization. While it is clear that emergent properties are a consequence of interactions within the community, their non-linear nature makes mathematical modelling imperative for establishing the quantitative link between community structure and function. As the need for conservation and rational modulation of microbial ecosystems is increasingly apparent, so is the consideration of the benefits and limitations of the approaches to model emergent properties. Here we review ecosystem modelling approaches from the viewpoint of emergent properties. We consider the scope, advantages and limitations of Lotka--Volterra, consumer--resource, trait-based, individual-based and genome-scale metabolic models. Future efforts in this research area would benefit from capitalizing on the complementarity between these approaches towards enabling rational modulation of complex microbial ecosystems., This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement no. 866028), and from the UK Medical Research Council (project number MC_UU_00025/11). SM would like to thank the Swiss National Science Foundation for funding the NCCR Microbiomes and an Eccellenza project, and the ERC for Starting grant no. 715097. WH received funding from NIH through R01-GM121498, SS received funding from the Portuguese Foundation for Science and Technology (FCT) under the scope of a Ph.D grant (SFRH/BD/121695/2016) and the strategic funding of UIDB/04469/2020 unit., info:eu-repo/semantics/publishedVersion

Hate crime rates grow steadily, although official statistics fail to express the real extent of such crimes. A cause of this gap is the fact that citizens often fail to report witnessed hate crimes. By failing to report, they blur the real magnitude of these crimes, legitimize and perpetuate their occurrence. According to the EU, civil society should be accountable in this process and cooperate with victims, namely by reporting hate crime. Hate speech is the most common hate crime and the one that most enacts a bystander effect. Hate speech is even more problematic in online contexts, in which people feel protected from face-to-face interaction. Moreover, in online contexts, social control mechanisms are perceived to be ineffective in controlling online misbehaviour. This project relies on a social responsibility enhancing approach to combat online hate speech. We will study psychosocial processes underlying bystander apathy facing online hate speech and test the effectiveness of prosocial determinants on stimulating individuals’ moral self-regulation aimed at decreasing their own bystander apathy and at the increasing report of online hate speech. Results might be promising to inform social media platforms about additional strategies to combat this misbehaviour and to provide information for anti-discrimination NGOs’ activists, politicians and moral entrepreneurs acting in anti-discrimination domains to decide the best strategies towards empowering "citizens against hate".

The main objective of this project is to develop and explore the potential of introducing rural tourism to the Herdade das Laranjeiras, trying to elevate the sense individuals have regarding rural tourism and take away the old image they associate with it. Being in the heart of Algarve, Almancil has already gained a great reputation for foreign visitors and of course domestic visitors as well. This business plan hopes to explain the importance of rural tourism and the benefits it can bring to the local economy and its visitors, trying to set the idea that the Algarve is more than just beach resorts. This enterprise hopes to develop new touristic opportunities for this region, not only through accommodation but also by giving away new concepts and activities related to local culture. To gain knowledge of the surrounding market, many studies were conducted throughout the development of this business plan along with the data collection and extensive research for the literature review. A market analysis, competitive analysis, strategy analysis, the creation of a marketing mix, and a survey, as well as an economic and financial study, were made. On the final steps of this business plan, with a general analysis of all studies made plus the results of the economic and financial assessment, it is safe to say that the implementation of rural tourism on Herdede das Laranjeiras is viable and has the potential to be a successful enterprise, in the future. O principal objetivo deste projeto de trabalho é desenvolver e explorar a viabilidade de introduzir o conceito de turismo rural à Herdade das Laranjeiras, tentando sempre incutir aos seus visitantes que o turismo rural é mais do que aquilo que muitos têm como estereotipo deste tipo de turismo. Localizada no centro do Algarve, Almancil é uma localidade que tem vindo a ganhar uma distinta reputação e reconhecimento no que toca ao turismo, sendo um destino muito procurado tanto por visitantes estrangeiros como nacionais. O presente plano de negócios, tenta explicar a importância do turismo rural e os benefícios que este pode trazer, não só para a economia local, mas também para os seus visitantes, tentando retirar a presente ideia de que o Algarve é apenas praia e resorts. A Herdade das Laranjeiras, vem assim por este meio tentar desenvolver novas oportunidades turísticas na região, também ligadas à cultura. Para compreender o mercado em que este projeto se insere, vários estudos foram elaborados também como recolha de dados e uma vasta pesquisa que acompanha a revisão literária. No que toca aos estudos, o foco foram análises de mercado, do competidor, estratégicas, a criação de um marketing mix e de um questionário assim como a análise económico-financeira deste projeto. Depois de toda a informação recolhida e dos vários estudos elaborados, os resultados finais da avaliação económico-financeira mostra que a implementação de turismo rural na Herdade das Laranjeiras e todo o processo de restauração é viável e tem potencial para o seu futuro.

Doxorubicin (DOX) is a chemotherapeutic agent that improves the survival and quality of life of patients with solid tumours. However, these improvements are counterbalanced by various dose-dependent side effects including cardiac dysfunction, which may occur in a subset of patients leading to treatment discontinuation. In addition, despite overall insufficiently studied, available data clearly show that women are more susceptible to drugs toxicity due to sex differences in drug metabolism or sensitivity. Regarding doxorubicin, apart its acute toxicity, women are also more vulnerable to late cardiotoxicity. Currently, there are no robust clinical imaging techniques or biomarkers available to detect DOX-cardiotoxicity before functional decline and, despite treatment personalization, subclinical signs of toxicity are not yet well identified. Thus, in the present work, we sought to characterize the toxic effects of a sub-therapeutic dose of doxorubicin upon cardiovascular and autonomic function. For that, adult healthy female wistar rats (n=14), aged >3 months, were intraperitoneally treated with doxorubicin (2 mg/kg) at weekly intervals for up to 4 weeks. A control (Ctrl, n=7) group received saline solution 0,9% NaCl as a vehicle. Rats underwent an echocardiographic evaluation at 4 weeks. Blood pressure, heart rate and respiratory frequency were assessed in an acute experiment. Cardiovascular variability studies in the time-frequency domain (LF, HF and LF/HF calculation) and cardiorespiratory reflexes assessment were performed. T-Student test for paired observations was applied (level significance p DOX-treated animals showed a severe bradypnea and hypotension, significant decrease in ejection fraction and fractional shortening, sympatho-inhibition and reduced baroreceptor reflex gain and chemoreflex sensitivity. Our functional results might be due to cellular respiratory dysfunction and vascular adaptations induced by doxorubicin via TNF alpha actions at central nervous system (CNS) and peripheral level. In fact, peripheral TNF alpha release elicits NO production, which through vasodilation will induce hypotension and baroreceptor reflex adjustments. Reinforcing these actions, and despite doxorubicin low ability to pass BBB, TNF alpha acting at CNS induces neuronal apoptosis and impairment of mitochondrial function which might also contribute to affect autonomic and respiratory function, expressed by a decreased chemoreflex sensitivity and sympathetic tone. In conclusion, sub-therapeutic doses of doxorubicin are able to produce per se the impairment of autonomic and cardiac functions. Thus, a tight monitoring of these functions in patients treated with therapeutic doses of doxorubicin is highly recommended. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fundação para a Ciência e a Tecnologia

Pro-independence movements in the Basque Country and in Catalonia have old historical roots. Whereas in Catalonia the pro-independence social mobilization has recently gained energy, in the Basque Country it seems less prominent nowadays. We explore the psychosocial predictors associated with individuals’ involvement in collective efforts towards independence in both these contexts. We distributed an online questionnaire among Basque (n=132) and Catalonian (n=152) independence supporters. Among the Basque independence supporters, pro-independence collective action tendencies were negatively predicted by perceived social status and identification with Spain, and positively predicted by patriotism and collective efficacy. Among the pro-independence Catalonians, only identification with Catalonia and collective efficacy beliefs predicted pro-independence collective action tendencies. These results are discussed considering historical, political, and socioeconomic factors. Los movimientos independentistas en País Vasco y Cataluña tienen viejas raíces históricas. En Cataluña la movilización pro-independencia ha ganado energía, pero en el País Vasco parece menos prominente. Exploramos los predictores psicosociales asociados con la participación en esfuerzos colectivos pro-independencia en ambos contextos. Distribuimos uncuestionario en línea entre partidarios de la independencia de País Vasco (N=132) y Cataluña (N=152). Entre los vascos, las tendencias de acción colectiva pro-independencia fueron predichas negativamente por la percepción del estatus y la identificación con España, y positivamente por el patriotismo y la eficacia colectiva; entre los catalanes, la acción colectiva se predijo solo por la identificación con Cataluña y creencias de eficacia colectiva. Estos resultados se discuten considerando factores históricos, políticos y socioeconómicos. Les mouvements pro-indépendance basque et catalan ont des racines anciennes. En Catalogne, la mobilisation pro-indépendance s’est récemment intensifiée, alors qu’elle a diminué au Pays Basque. Nous explorons des prédicteurs psychosociaux de l’implication des individus dans des actions collectives visant l’indépendance, dans ces deux contextes. Nous avons distribué un questionnaire en-ligne à des partisans de l’indépendance basques (N=132) et catalans (N=152). Pour les répondants basques, le statut social et l’identification à l’Espagne prédisent négativement, tandis que le patriotisme et l’efficacité collective prédisent positivement, l’adhésion à l’action collective. Pour les catalans, l’identification à la Catalogne et les croyances à l’efficacité collective sont les seuls prédicteurs de l’adhésion à l’action pro-indépendance. Nous discutons les facteurs historiques, politiques et socio-culturels associés à ces résultats. Os movimentos independentistas no País Basco e Catalunha e têm raízes históricas antigas. Na Catalunha a mobilização social pró-independência ganhou energia recentemente, no País Basco ela parece ser menos proeminente. Neste estudo exploramos preditores psicossociais associados ao envolvimento em esforços coletivos pró-independência nestes dois contextos. Distribuímos um questionário “on-line” a apoiantes da independência da do País Basco (N=132) e da Catalunha (N=152). Entre os catalães pró-independência, apenas a identificação com a Catalunha e crenças na eficácia coletiva predizem as tendências de ação coletiva; entre os bascos, as tendências de ação coletiva são preditas negativamente pelo estatuto social e pela identificação com Espanha, e positivamente pelo patriotismo e pela eficácia coletiva. Estes resultados são discutidos considerando fatores históricos, políticos e socioeconómicos.

First-principle metabolic modelling holds potential for designing microbial chassis that are resilient against phenotype reversal due to adaptive mutations. Yet, the theory of model-based chassis design has rarely been put to rigorous experimental test. Here, we report the development of Saccharomyces cerevisiae chassis strains for dicarboxylic acid production using genome-scale metabolic modelling. The chassis strains, albeit geared for higher flux towards succinate, fumarate and malate, do not appreciably secrete these metabolites. As predicted by the model, introducing product-specific TCA cycle disruptions resulted in the secretion of the corresponding acid. Adaptive laboratory evolution further improved production of succinate and fumarate, demonstrating the evolutionary robustness of the engineered cells. In the case of malate, multi-omics analysis revealed a flux bypass at peroxisomal malate dehydrogenase that was missing in the yeast metabolic model. In all three cases, flux balance analysis integrating transcriptomics, proteomics and metabolomics data confirmed the flux re-routing predicted by the model. Taken together, our modelling and experimental results have implications for the computer-aided design of microbial cell factories., We would like to acknowledge the support of R. Mattel and F. Stein from the Proteomics Core Facility and the Genomics Core Facility at the European Molecular Biology Laboratory (EMBL Heidelberg, Germany). This study was supported by national funds through FCT/MCTES (Portugal, Ref. ERA-IB-2/0003/2013) and BMBF (Germany, Grant number: 031A343A, Ref. ERA-IB-2/0003/2013). The Portuguese Foundation for Science and Technology (FCT) supported HL through grant ref. PD/BD/52336/2013. FCT also supported this study under the scope of the strategic funding of UID/BIO/04469/2013 unit and COMPETE 2020 (POCI-01-0145-FEDER-006684) and through the Project RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462). Open Access funding enabled and organized by Projekt DEAL., info:eu-repo/semantics/publishedVersion

We propose that low-status group members' support for group-based hierarchy and inequality (i.e., social dominance orientation; SDO) may represent an ideological strategy to guarantee the legitimacy of future ingroup status-enhancement. Specifically, we argue that, under unstable social structure conditions, SDO serves as an ideological justification for collective action tendencies aimed at competing for a higher status. In such context, SDO should be positively related with actions aimed to favor the ingroup (i.e., collective actions) by increasing group members' motivation to engage in direct competition with a relevant higher-status outgroup. We conducted two studies under highly competitive and unstable social structure contexts using real life groups. In Study 1 (N = 77), we induced Low vs. High Ingroup (University) Status and in Study 2 (N = 220) we used competing sports groups. Overall, results showed that, among members of low-status groups, SDO consistently increased individuals' motivation to get involved in actions favoring the ingroup, by boosting their motivation to compete with the opposing high-status outgroup. We discuss the results in light of the social dominance and collective action framework. This research was funded by an individual doctoral grant awarded to CC from the Fundacao para a Ciencia e a Tecnologia, Portugal (FCT), PD/BD/128211/2016

Chinese hamster ovary (CHO) cells are the leading platform for the production of biopharmaceuticals with human-like glycosylation. The standard practice for cell line generation relies on trial and error approaches such as adaptive evolution and high-throughput screening, which typically take several months. Metabolic modeling could aid in designing better producer cell lines and thus shorten development times. The genome-scale metabolic model (GSMM) of CHO can accurately predict growth rates. However, in order to predict rational engineering strategies it also needs to accurately predict intracellular fluxes. In this work we evaluated the agreement between the fluxes predicted by parsimonious flux balance analysis (pFBA) using the CHO GSMM and a wide range of 13C metabolic flux data from literature. While glycolytic fluxes were predicted relatively well, the fluxes of tricarboxylic acid (TCA) cycle were vastly underestimated due to too low energy demand. Inclusion of computationally estimated maintenance energy significantly improved the overall accuracy of intracellular flux predictions. Maintenance energy was therefore determined experimentally by running continuous cultures at different growth rates and evaluating their respective energy consumption. The experimentally and computationally determined maintenance energy were in good agreement. Additionally, we compared alternative objective functions (minimization of uptake rates of seven nonessential metabolites) to the biomass objective. While the predictions of the uptake rates were quite inaccurate for most objectives, the predictions of the intracellular fluxes were comparable to the biomass objective function., COMET center acib: Next Generation Bioproduction, which is funded by BMK, BMDW, SFG, Standortagentur Tirol, Government of Lower Austria and Vienna Business Agency in the framework of COMET - Competence Centers for Excellent Technologies. The COMET-Funding Program is managed by the Austrian Research Promotion Agency FFG; D.S., J.S., M.W., M.H., D. E.R. This work has also been supported by the PhD program BioToP of the Austrian Science Fund (FWF Project W1224), info:eu-repo/semantics/publishedVersion

Supine hypertension commonly occurs in patients with neurogenic orthostatic hypotension due to autonomic failure. Supine hypertension promotes nocturnal sodium excretion and orthostatic hypotension, thus, interfering with quality of life. Perusal of the literature on essential hypertension and smaller scale investigations in autonomic failure patients also suggest that supine hypertension may predispose to cardiovascular and renal disease. These reasons provide a rationale for treating supine hypertension. Yet, treatment of supine hypertension, be it through nonpharmacological or pharmacological approaches, may exacerbate orthostatic hypotension when patients get up during the night. Fall-related complications may occur. More research is needed to define the magnitude of the deleterious effects of supine hypertension on cardiovascular, cerebrovascular, and renal morbidity and mortality. Integration of more precise cardiovascular risk assessment, efficacy, and safety data, and the prognosis of the underlying condition causing autonomic failure is required for individualized management recommendations.

In the last years, Salmonella has been extensively studied not only due to its importance as a pathogen, but also as a host to produce pharmaceutical compounds. However, the full exploitation of Salmonella as a platform for bioproduct delivery has been hampered by the lack of information about its metabolism. Genome-scale metabolic models can be valuable tools to delineate metabolic engineering strategies as long as they closely represent the actual metabolism of the target organism. In the present study, a 13C-MFA approach was applied to map the fluxes at the central carbon pathways of S. typhimurium LT2 growing at glucose-limited chemostat cultures. The experiments were carried out in a 2L bioreactor, using defined medium enriched with 20% 13C-labeled glucose. Metabolic flux distributions in central carbon pathways of S. typhimurium LT2 were estimated using OpenFLUX2 based on the labeling pattern of biomass protein hydrolysates together with biomass composition. The results suggested that pentose phosphate is used to catabolize glucose, with minor fluxes through glycolysis. In silico simulations, using Optflux and pFBA as simulation method, allowed to study the performance of the genome-scale metabolic model. In general, the accuracy of in silico simulations was improved by the superimposition of estimated intracellular fluxes to the existing genome-scale metabolic model, showing a better fitting to the experimental extracellular fluxes, whereas the intracellular fluxes of pentose phosphate and anaplerotic reactions were poorly described.

Research on the transgression credit shows that groups may sometimes turn a blind eye to ingroup leaders who transgress moral norms. Although there is substantial research investigating the underlying criteria of what makes a “good” leader, research often neglects to investigate the role of followers in leader-group dynamics. In this paper, we offer a novel approach to transgressive leadership by proposing that leader legitimacy is a key factor that determines whether followers’ reactions to transgressive leaders are positive or negative. Across two experiments, participants ascribed transgression credit only to transgressive ingroup leaders perceived as legitimate (Studies 1–2, total n = 308). Transgressive illegitimate leaders were viewed as more threatening to the group, were targeted for formal punishment, received less validation for their behavior, triggered negative emotions (anger and shame), and raised higher consensus for their removal from the leadership position than did legitimate leaders. This effect also occurred irrespective of the absence of formal social control measures implemented toward the transgressive leader (Study 2). Mediation analysis showed that leader illegitimacy triggered stronger feelings of group threat and stronger negative emotions which, consequently, fuelled agreement with collective protest against the transgressive leader. Theoretical and practical implications of these findings are discussed.

Obstructive sleep apnea (OSA) is the most prevalent sleep-disordered breathing in the adult population and if untreated remains a significant cause of morbidity and mortality. Continuous positive airway pressure (CPAP) therapy is still the gold standard treatment for OSA, but patient acceptance and adherence are often poor due to a multitude of factors, thereby compromising treatment success. Mandibular advancement devices (MADs) have been proposed not only as a first line therapy for symptomatic snoring patients, but also for those suffering from mild to moderate OSA, or those who refuse or do not tolerate CPAP. Yet, improved understanding of MAD regarding design, construction, and mechanisms of action is an important requirement to successfully implement MAD as a therapeutic tool. Therefore, the main focus of this paper is to focus on the general concepts and mechanisms of action of MAD, while highlighting important characteristics in the context of their use as a viable and effective treatment option for OSA patients.

In the last decade, genome-scale metabolic models have been increasingly used to study plant metabolic behavior at the tissue and multi-tissue level under different environmental conditions. Quercus suber, also known as the cork oak tree, is one of the most important forest communities of the Mediterranean/Iberian region. In this work, we present the genome-scale metabolic model of the Q. suber (iEC7871), the first of a woody plant. The metabolic model comprises 7871 genes, 6231 reactions, and 6481 metabolites across eight compartments. Transcriptomics data was integrated into the model to obtain tissue-specific models for the leaf, inner bark, and phellogen, with specific biomass compositions. The tissue-specific models were merged into a diel multi-tissue metabolic model to predict interactions among the three tissues at the light and dark phases. The metabolic models were also used to analyze the pathways associated with the synthesis of suberin monomers. Nevertheless, the models developed in this work can provide insights into other aspects of the metabolism of Q. suber, such as its secondary metabolism and cork formation.

Cuidado paliativo e um cuidado em saude representando por um conjunto de acoes designadas a uma equipe multiprofissional junto a um paciente que possui alguma patologia incuravel com o objetivo de controle de sintomas e, consequentemente, a melhoria da qualidade de vida do paciente, de forma continua. Nesse sentido, foi objetivo deste estudo avaliar o conhecimento dos estudantes internos de medicina de diferentes faculdades brasileiras acerca da dor em cuidados paliativos. Trata-se de um estudo descritivo com abordagem quantitativa. A amostra do estudo abrangeu 180 alunos de faculdades de medicina brasileiras que estavam cursando os quatro ultimos periodos da faculdade. A estes alunos, aplicou-se um questionario online utilizando a ferramenta Google Forms. O periodo de coleta foi entre os meses de agosto a outubro do ano de 2020. Os dados obtidos foram compilados no programa Microsoft Excel e no Programa Statistical Package for the Social Sciences (SPSS - versao 21.0), com realizacao de dupla digitacao e, posteriormente, conferidos eletronicamente. A analise dos dados, por sua vez, foi efetivada ora por meio da estatistica descritiva. Ao final, percebeu-se que Diante do clara a necessidade de incentivar a academia medica no ensino do manejo terapeutico da dor, tanto durante a faculdade quanto durante a residencia, haja vista sua importância e prevalencia, sendo assim necessario haver um enfoque maior na formacao academica sobre o assunto.

The current survey aims to describe the main methodologies for extending the reconstruction and analysis of genome-scale metabolic models and phenotype simulation with Flux Balance Analysis mathematical frameworks, via the integration of Transcriptional Regulatory Networks and/or gene expression data. Although the surveyed methods are aimed at improving phenotype simulations obtained from these models, the perspective of reconstructing integrated genome-scale models of metabolism and gene expression for diverse prokaryotes is still an open challenge., This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UIDB/04 469/2020 unit and BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020 -Programa Operacional Regional do Norte. Fernando Cruz holds a doctoral fellowship (SFRH/BD/139198/2018) funded by the FCT. This study was supported by the European Commission through project SHIKIFACTORY100 -Modular cell factories for the production of 100 compounds from the shikimate pathway (Reference 814408). The submitted manuscript has been created by UChicago Argonne, LLC as Operator of Argonne National Laboratory (`Argonne') under Contract No. DE-AC02-06CH11357 with the U.S. Department of Energy. The U.S. Government retains for itself, and others acting on its behalf, a paid-up, nonexclusive, irrevocable worldwide license in said article to reproduce, prepare derivative works, distribute copies to the public, and perform publicly and display publicly, by or on behalf of the Government. The Department of Energy will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan., info:eu-repo/semantics/publishedVersion

Candida albicans is one of the most impactful fungal pathogens and the most common cause of invasive candidiasis, which is associated with very high mortality rates. With the rise in the frequency of multidrug-resistant clinical isolates, the identification of new drug targets and new drugs is crucial in overcoming the increase in therapeutic failure. In this study, the first validated genome-scale metabolic model for Candida albicans, iRV781, is presented. The model consists of 1221 reactions, 926 metabolites, 781 genes, and four compartments. This model was reconstructed using the open-source software tool merlin 4.0.2. It is provided in the well-established systems biology markup language (SBML) format, thus, being usable in most metabolic engineering platforms, such as OptFlux or COBRA. The model was validated, proving accurate when predicting the capability of utilizing different carbon and nitrogen sources when compared to experimental data. Finally, this genome-scale metabolic reconstruction was tested as a platform for the identification of drug targets, through the comparison between known drug targets and the prediction of gene essentiality in conditions mimicking the human host. Altogether, this model provides a promising platform for global elucidation of the metabolic potential of C. albicans, possibly guiding the identification of new drug targets to tackle human candidiasis., “Fundação para a Ciência e a Tecnologia” (FCT) [Contract PTDC /BII-BIO/28216/2017] and by Programa Operacional Regional de Lisboa 2020 [LISBOA-01-0145-FEDER-022231], through the Biodata.pt Research Infrastructure. Funding received by iBB-Institute for Bioengineering and Biosciences from FCT [Contract UIDB/04565/2020], info:eu-repo/semantics/publishedVersion