Suchergebnisse

This research approaches same factors that have been affecting the competitiveness faced by the Algarve citrus culture since the European Single Market came into force and before a more and more global economy. According to the conceptual and theoretical framework, in a global economy any competitive strategy must have underlying quality(ies).These understood as the capacity to satisfy the market considered as a whole of the main types of agents at the different levels of Algarve citrus system. So, the main object of this work is to identify eventual (technical and institutional) malfunctions concerning the Algarve citrus system, that can fail either directly or indirectly to meet the principal clients/consumers'expectations. The study focus on the analysis of the general context where the Algarve citrus culture is inserted, under the socio-cultural, political-legal and economic point of view. The aim is to identify the constraints faced by the sector in order to understand the main clients, suppliers and competitors behaviours, being this part what we consider as the present thesis core. The results have allowed us to characterize the quality attributes considered as determinants when citrus are acquired, namely the Algarve citrus, by the national consumers as well as by the main distribution channels, in case they are presented in the market as differentiated or undifferentiated. The facts identified in the empirical research indicate that limitations of technical and institutional order can make unfeasible or strongly condition the capacity of the Algarve citrus culture (production subsystem, the chain's first link) to meet the market requirements. The conclusions reached for the development of the Algarve citrus culture, were based on Hayami and Ruttan's "induced technical and institutional innovation" theory (1998). We think we have given a contribution towards the definition of strategies for the Algarve citrus culture development, bearing in mind both the market and the available resources.

The main objective of this dissertation is to acess the state of the art regarding civil society influence and participation at WTO's governance system, analyze it and draw conclusions out of it. Upon evidence found in studies of several authors, a conceptual and historical analysis is made to Civil Society, WTO and the relationship between both. Evidences of existing transparency standards and participation means for civil society at WTO are put under critical analysis of key points regarding WTO legitimacy crisis. WTO legitimacy crisis ( also the legitimacy for civil society demands for more voice) is explained to be connected to deficits of transparency, lack of representation and formal participation means towards some of its internal and external stakeholders. Conclusions and future suggestions are drawn recommending that WTO needs to become more representative, open and responsive by correcting or strengthening some of its transparency standards and participation venues in the short-term and ultimately, walk towards the creation of a Parliamentary Assembly included in its formal decision-making hierarchy. ; O objetivo principal desta dissertação é avaliar o estado da arte acerca da influência e participação da sociedade civil no sistema de governança da Organização Mundial do Comércio (OMC), analisá-lo e extrair conclusões. A partir de evidências encontradas em estudos de vários autores, uma análise conceptual e histórica é feita sobre a Sociedade Civil, a OMC e a relação entre ambos. Padrões de transparência e meios de participação existentes para a sociedade civil na OMC são submetidos a análise crítica de pontos-chave relacionados com a crise de legitimidade da OMC. A crise de legitimidade da OMC (e também a legitimidade das exigências da sociedade civil para maior representação dos seus interesses no seu processo de decisão) é explicada através de deficits de transparência, falta de representação e representatividade, e inexistência da meios formais de participação mais efectivos para alguns dos seus stakeholders internos e externos. Conclusões e sugestões futuras são sugeridas, recomendando que a OMC e o seu processo de decisão se tornem mais representativos, abertos e responsivos, corrigindo ou fortalecendo alguns dos seus padrões de transparência e participação no curto prazo e, finalmente, caminhando para a criação gradual de uma Assembleia Parlamentar incluída na hierarquia formal de governança desta organização intergovernamental.

The airborne fungus Aspergillus fumigatus poses a serious health threat to humans by causing numerous invasive infections and a notable mortality in humans, especially in immunocompromised patients. Mould-active azoles are the frontline therapeutics employed to treat aspergillosis. The global emergence of azole-resistant A. fumigatus isolates in clinic and environment, however, notoriously limits the therapeutic options of mould-active antifungals and potentially can be attributed to a mortality rate reaching up to 100 %. Although specific mutations in CYP51A are the main cause of azole resistance, there is a new wave of azole-resistant isolates with wild-type CYP51A genotype challenging the efficacy of the current diagnostic tools. Therefore, applications of whole-genome sequencing are increasingly gaining popularity to overcome such challenges. Prominent echinocandin tolerance, as well as liver and kidney toxicity posed by amphotericin B, necessitate a continuous quest for novel antifungal drugs to combat emerging azole-resistant A. fumigatus isolates. Animal models and the tools used for genetic engineering require further refinement to facilitate a better understanding about the resistance mechanisms, virulence, and immune reactions orchestrated against A. fumigatus. This review paper comprehensively discusses the current clinical challenges caused by A. fumigatus and provides insights on how to address them. ; AA, RGR, and DSP were supported by NIH AI 109025. MH was supported by NIH UL1TR001442. AC was supported by the Fundação para a Ciência e a Tecnologia (FCT) (CEECIND/03628/2017 and PTDC/MED GEN/28778/2017). Additional support was provided by FCT (UIDB/50026/2020 and UIDP/50026/2020), the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) (NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023), the European Union's Horizon 2020 Research and Innovation programme under grant agreement no. 847507, and the "la Caixa" Foundation (ID 100010434) and FCT under the agreement LCF/PR/HP17/52190003. DJA was supported by CF Trust Strategic Research Centre TrIFIC (SRC015), Wellcome Trust Collaborative Award 219551/Z/19/Z and the NIHR Centre for Antimicrobial Optimisation. ; Peer Reviewed ; "Article signat per 21 autors/es: A.Arastehfar, A.Carvalho, J.Houbraken, L.Lombardi, R.Garcia-Rubio, J.D.Jenks, O.Rivero Menendez, R. Aljohani, I.D.Jacobsen, J.Berman, N.Osherov, M.T.Hedayati, M.Ilkit, D.James-Armstrong, T.Gabaldón, J.Meletiadis, M.Kostrzewa, W.Pan, C.Lass-Flörl, D.S.Perlin, M.Hoenigl" ; Postprint (published version)

Toll-like receptors (TLRs) are important components of innate immunity. We investigated the association between polymorphisms in the TLR2, TLR4, and TLR9 genes and susceptibility to noninvasive forms of pulmonary aspergillosis. A significant association was observed between allele G on Asp299Gly (TLR4) and chronic cavitary pulmonary aspergillosis (odds ratio [OR], 3.46; P =.003). Susceptibility to allergic bronchopulmonary aspergillosis was associated with allele C on T-1237C (TLR9) (OR, 2.49; P =. 043). No particular polymorphism was associated with severe asthma with fungal sensitization. These findings reinforce the importance of innate immunity in the pathogenesis of different forms of aspergillosis. ; Fundação para a Ciência e Tecnologia, Portugal (POCI/SAU-ESP/61080/ 2004 and fellowship to A.C., contract SFRH/BD/11837/2003); CAPES (Brazilian government) (grant to A.P); and the Fungal Research Trust, United ...

Abstract Rationale Recent studies have revealed that the lung microbiota of critically ill patients is altered and predicts clinical outcomes. The incidence of invasive fungal infections, namely, invasive pulmonary aspergillosis (IPA), in immunocompromised patients is increasing, but the clinical significance of variations in lung bacterial communities is unknown. Objectives To define the contribution of the lung microbiota to the development and course of IPA. Methods and measurements We performed an observational cohort study to characterise the lung microbiota in 104 immunocompromised patients using bacterial 16S ribosomal RNA gene sequencing on bronchoalveolar lavage samples sampled on clinical suspicion of infection. Associations between lung dysbiosis in IPA and pulmonary immunity were evaluated by quantifying alveolar cytokines and chemokines and immune cells. The contribution of microbial signatures to patient outcome was assessed by estimating overall survival. Main results Patients diagnosed with IPA displayed a decreased alpha diversity, driven by a markedly increased abundance of the Staphylococcus, Escherichia, Paraclostridium and Finegoldia genera and a decreased proportion of the Prevotella and Veillonella genera. The overall composition of the lung microbiome was influenced by the neutrophil counts and associated with differential levels of alveolar cytokines. Importantly, the degree of bacterial diversity at the onset of IPA predicted the survival of infected patients. Conclusions Our results reveal the lung microbiota as an understudied source of clinical variation in patients at risk of IPA and highlight its potential as a diagnostic and therapeutic target in the context of respiratory fungal diseases. ; This work was supported by the Fundação para a Ciência e a Tecnologia (FCT) (PTDC/SAU-SER/29635/2017 to CC and PTDC/MED-GEN/28778/2017 to AC). Additional support was provided by FCT (UIDB/50026/2020 and UIDP/50026/2020); the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) (NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023); the European Union's Horizon 2020 Research and Innovation Programme under grant agreement number 847507 (to AC); and the "la Caixa" Foundation (ID 100010434) and FCT under the agreement LCF/PR/HR17/52190003 (to AC). Individual support was provided by FCT (SFRH/BD/136814/2018 to SMG, CEECIND/03628/2017 to AC and CEECIND/04058/2018 to CC). The TG group acknowledges support from the Spanish Ministry of Science and Innovation for grant PGC2018-099921-B-I00, cofounded by the ERDF, the CERCA Programme/Generalitat de Catalunya, the Catalan Research Agency (AGAUR) SGR423, the European Union's Horizon 2020 Research and Innovation Programme under grant agreement ERC-2016-724173 and an INB Grant (PT17/0009/0023—ISCIII-SGEFI/ERDF). ; Peer Reviewed ; Postprint (author's final draft)

Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Through network-level integration of transcriptomics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by ß-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming by inhibiting KDM5 histone demethylases. Furthermore, fumarate itself induced an epigenetic program similar to ß-glucan-induced trained immunity. In line with this, inhibition of glutaminolysis and cholesterol synthesis in mice reduced the induction of trained immunity by ß-glucan. Identification of the metabolic pathways leading to induction of trained immunity contributes to our understanding of innate immune memory and opens new therapeutic avenues. ; Netherlands Organization for Scientific Research (NWO). B.N. is supported by an NHMRC (Australia) CJ Martin Early Career Fellowship. N.P.R. Netherlands Heart Foundation (2012T051). N.P.R. and M.G.N. received a H2020 grant (H2020-PHC-2015-667873-2) from the European Union (grant agreement 667837). Fundação para a Ciência e Tecnologia, FCT (IF/00735/2014 to A.C., IF/00021/2014 to R.S., RECI/BBB-BQB/0230/2012 to L.G.G., and SFRH/BPD/96176/2013 to C. Cunha). The NMR spectrometers are part of the National NMR Facility supported by FCT (RECI/BBB-BQB/0230/2012). The research leading to these results received funding from the Fundação para a Ciência e Tecnologia (FCT), cofunded by Programa Operacional Regional do Norte (ON.2—O Novo Norte); from the Quadro de Referência Estratégico Nacional (QREN) through the Fundo Europeu de Desenvolvimento Regional (FEDER) and from the Projeto Estratégico – LA 26 – 2013–2014 (PEst-C/SAU/LA0026/2013). NIH (DK43351 and DK097485) and Helmsley Trust. D.L.W. is supported, in ...

Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4 rs7526628T/T genotype had a significantly increased risk of developing IA ( p = 0.00022). We also found that carriers of the TNFSF4 rs7526628T allele showed decreased serum levels of TNFSF14 protein ( p = 0.0027), and that their macrophages had a decreased fungicidal activity ( p = 0.048). In addition, we observed that each copy of the MAPKAPK2 rs12137965G allele increased the risk of IA by 60% ( p = 0.0017), whereas each copy of the MAPKAPK2 rs17013271T allele was estimated to decrease the risk of developing the disease ( p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2 rs12137965G allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood ( p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin ( p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2 rs17013271T allele had decreased numbers of CD27-IgM-IgD- B cells ( p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells ( p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk. ; This study was supported by grants PI20/01845, PI12/02688, and ISCIII-FEDER PI17/02276 from Fondo de Investigaciones Sanitarias (Madrid, Spain), PIM2010EPA-00756 from the ERA-NET PathoGenoMics (0315900A), the Collaborative Research Center/Transregio 124 FungiNet, the Fundacao para a Ciencia e Tecnologia (FCT) (PTDC/SAU-SER/29635/2017, PTDC/MED-GEN/28778/2017, CEECIND/03628/2017, and CEECIND/04058/2018), the European Union's Horizon ...

Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4rs7526628T/T genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4rs7526628T allele showed decreased serum levels of TNFSF14 protein (p = 0.0027), and that their macrophages had a decreased fungicidal activity (p = 0.048). In addition, we observed that each copy of the MAPKAPK2rs12137965G allele increased the risk of IA by 60% (p = 0.0017), whereas each copy of the MAPKAPK2rs17013271T allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2rs12137965G allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood (p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2rs17013271T allele had decreased numbers of CD27-IgM-IgD- B cells (p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells (p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk. ; This study was supported by grants PI20/01845, PI12/02688, and ISCIII-FEDER PI17/02276 from Fondo de Investigaciones Sanitarias (Madrid, Spain), PIM2010EPA-00756 from the ERA-NET PathoGenoMics (0315900A), the Collaborative Research Center/Transregio 124 FungiNet, the Fundação para a Ciência e Tecnologia (FCT) (PTDC/SAU-SER/29635/2017, PTDC/MED-GEN/28778/2017, CEECIND/03628/2017, and CEECIND/04058/2018), the European Union's Horizon 2020 research ...