Disease tolerance and immunity in host protection against infection

The deposited article is a pre-print version.This publication hasn't any creative commons license associated.This deposit is composed by the main article which contains attached the supplementary materials.The immune system probably evolved to limit the negative effects exerted by pathogens on host homeostasis. This defence strategy relies on the concerted action of innate and adaptive components of the immune system, which sense and target pathogens for containment, destruction or expulsion. Resistance to infection refers to these immune functions, which reduce the pathogen load of an infected host as the means to preserve homeostasis. Immune-driven resistance to infection is coupled to an additional, and arguably as important, defence strategy that limits the extent of dysfunction imposed on host parenchymal tissues during infection, without exerting a direct negative effect on pathogens. This defence strategy, known as disease tolerance, relies on tissue damage control mechanisms that prevent the deleterious effects of pathogens and that uncouples immune-driven resistance mechanisms from immunopathology and disease. In this Review, we provide a unifying view of resistance and disease tolerance in the framework of immunity to infection.Instituto Gulbenkian de Ciência; Fundação Calouste Gulbenkian; Fundação para a Ciência e Tecnologia grants: (PTDC/SAU-TOX/116627/2010, HMSP-ICT/0022/2010, PTDC/BEX-GMG/3128/2014); ERC grants: (ERC-2011-AdG 294709-DAMAGECONTROL, ERC-2014-CoG 647888-iPROTECTION).info:eu-repo/semantics/publishedVersio

Os conflitos dos últimos 25 anos (I)

Existem razões para admitir que as grandes transformações do ordenamento internacional têm estado associadas a guerras. Foi assim com a Guerra dos Trinta Anos, que não se limitou a um conflito religioso entre católicos e protestantes, mas constituiu uma guerra internacional de grande dimensão, envolvendo a Suécia, a França e o Império dos Habsburgos, e dela resultou uma nova Europa progressivamente assente em Estados nações. Foi assim com as guerras revolucionárias francesas e as do período napoleónico, que estiveram na origem de novas configurações para as sociedades da Europa e acabaram por gerar o “concerto das potências” europeias, após a vitória inglesa em Waterloo. Foi assim, evidentemente, com as duas guerras mundiais do século XX que abalaram essas mesmas potências europeias, substituindo-as por duas novas super potências que, durante meio século, geriram o mundo em condomínio bipolar

Celastrol: A Spectrum of Treatment Opportunities in Chronic Diseases

This deposit is composed by the main article, and it hasn't any supplementary materials associated.The identification of new bioactive compounds derived from medicinal plants with significant therapeutic properties has attracted considerable interest in recent years. Such is the case of the Tripterygium wilfordii (TW), an herb used in Chinese medicine. Clinical trials performed so far using its root extracts have shown impressive therapeutic properties but also revealed substantial gastrointestinal side effects. The most promising bioactive compound obtained from TW is celastrol. During the last decade, an increasing number of studies were published highlighting the medicinal usefulness of celastrol in diverse clinical areas. Here we systematically review the mechanism of action and the therapeutic properties of celastrol in inflammatory diseases, namely, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel diseases, osteoarthritis and allergy, as well as in cancer, neurodegenerative disorders and other diseases, such as diabetes, obesity, atherosclerosis, and hearing loss. We will also focus in the toxicological profile and limitations of celastrol formulation, namely, solubility, bioavailability, and dosage issues that still limit its further clinical application and usefulness.Fundação para a Ciência e a Tecnologia grants: (SFRH/BPD/92860/2013, PTDC/BIM-MEC/4665/2014); European Research Council grants: (ERC-2014-CoG 647888-iPROTECTION).info:eu-repo/semantics/publishedVersio

Sepsis: the need for tolerance not complacency

Sepsis is a life-threatening condition that arises as a systemic inflammatory response syndrome to an infection. Its uncontrolled progression can in frequent cases lead to multiple organ failure, which is still associated with high mortality rates. Modern antibiotics made clear that the infection is only an initiating, and not always necessary, event of this syndrome as many patients with sepsis die despite effective eradication of the inciting pathogen. This observation critically contributed to a paradigm shift that focused the pathogenesis of sepsis on the host and not on the pathogen. However, therapeutic strategies based on the inhibition of proinflammatory critical mediators of sepsis or immunostimulation have so far failed to improve sepsis outcome and, therefore, this condition urgently needs transformative therapeutic ideas and strategies. Here we argue that the induction of tolerance, a defence strategy that minimises the impact of an infection on organ function without directly affecting the pathogen burden, is perhaps the missing but essential element to add to the current components of sepsis care and treatment.IGC Integrative Biology and Biomedicine (IBB) PhD Program, FCT, European Research Council (ERC-2014-CoG 647888-iPROTECTION)

Proveniência geológica dos esteios de antas no Freixo-Redondo e em Monforte, Centro-Sul de Portugal

O projeto geoarqueológico MEGAGEO relaciona a distribuição de antas com os seus materiais de construção e a paisagem geológica, nas áreas do Freixo-Redondo e em Monforte. Estas áreas apresentam contextos geológicos que permitem uma abordagem interdisciplinar de caracterização e proveniência de megálitos. A área do Freixo-Redondo é constituída por rochas metamórficas (gnaisses, micaxistos, filitos e metagrauvaques), que são intruídas pelo maciço ígneo do Redondo [2]. Este, corresponde a um corpo granodiorítico, com uma pequena intrusão de gabro/diorito e frequentes encraves de rochas encaixantes. As antas estão preferencialmente implantadas no substrato granodiorítico, em torno da intrusão de gabro/diorito, ou nos gnaisses encaixantes e são essencialmente constituídas por granodioritos. Destacam-se deste contexto as antas de Godinhos e Candeira, que se localizam mais a norte, na auréola de metamorfismo (gnaisses, xistos porfiroclásticos, micaxistos e granitos moscovíticos) e que são essencialmente constituídas por rochas metamórficas. A área de Monforte é caracterizada pelo granito de Monforte, que corresponde a um granito rosa de grão médio a grosseiro, que intrui e metamorfiza por contacto o encaixante formado por gneisses, metapelitos, anfibolitos, rochas carbonatadas e calcossilicatadas [1]. As antas estão implantadas quer no granito quer no encaixante e são constituídas por granito, gnaisses, rochas carbonatadas e corneanas calcossilicatadas. Em ambas as áreas foram recolhidos dados de natureza arqueológica e realizados levantamentos de campo, envolvendo a caracterização dos esteios e dos prováveis afloramentos de proveniência. Após recolha de amostras representativas dos esteios e dos prováveis afloramentos de proveniência, realizou-se análise petrográfica pelos métodos convencionais de microscopia de luz polarizada e análises semi-quantitativas por SEM-EDS. Por último, foi efetuada a caracterização geoquímica de todas as amostras envolvendo análises geoquímicas elementares (ICP-MS). Os resultados obtidos, permitiram de um modo geral relacionar esteios com os afloramentos selecionados e confirmar a proveniência dos esteios. Para a região do Freixo-Redondo obtiveram-se, em média, distâncias menores aos afloramentos quando comparado com a região de Monforte

Building monument materials during the 3rd-4rd millennium (Portugal)

Dolmens are the most conspicuous remains of the populations of the 4th and first half of 3rd millennia BCE. These tombs are impressive not only for their monumentality, but also because of the socioeconomic investment they represent for those Neolithic communities, namely from the Central-South of Portugal, who built them. Although dolmens have been studied for their funerary content and typologies, an interdisciplinary approach toward the geological characterization and sourcing of stones used in these constructions has not received enough attention from researchers. With MEGAGEO project a multidisciplinary group of geologist and archaeologists intends to assess the relationship between the distribution of dolmens in Central-South Portugal, their source materials, and the geological landscape. GIS will map the information gathered and will be used to analyse these relationships. The selection of the areas, with distinctive geologies (limestone vs granite), will allow to verify if human patterns of behaviour regarding the selection of megaliths are similar or different regionally. Geologically the first target area (Freixo, Alentejo) is dominated by a small intrusion of gabbro mingled/mixed within a granodioritic intrusion both related with variscan orogeny. Granodiorite exhibit several enclaves of igneous and metamorphic nature attesting the interaction between both igneous rocks as well with enclosing gneisses. Despite Alentejo region have a reduced number of outcrops the granodiorite provides rounded to tabular metric blocks. The gabbro is very coarse grained, sometimes with a cumulate texture, and their fracturing and weathering provide very fresh tabular blocks. The five studied dolmens (Quinta do Freixo #1 to #5) are implanted in a large granodioritic intrusion, around the gabbroic rocks, within an area of approximately 9km2. The medium grained granodiorite is ubiquity in all the dolmens slabs and occasionally it can be observed features of mixing and mingling mechanisms; interpenetration of different magmas and enclaves. There were not identified slabs of gabbros in dolmens slabs. In distances less than 100m from the dolmens, it is possible to identify an outcrop with equal features (petrographic as well geometric) with those found in the slabs. These observations agrees with previous authors (e.g. Boaventura, 2000) that favours a pragmatic attitude of Neolithic populations in the search of the appropriate slabs for construction

Mineral Carbonation of CO2 in Mafic Plutonic Rocks, I—Screening Criteria and Application to a Case Study in Southwest Portugal

This article describes the screening, ranking and characterization of ultramafic and mafic rocks in southern Portugal for mineral carbonation as an alternative to conventional CO2 storage in sedimentary rocks. A set of criteria including mineralogy, structure, surface area, distance to CO2 sources, expected volume, and socioeconomic conditions was applied to screen ultramafic and mafic rock massifs in the Alentejo region, southern Portugal. Ranking of the massifs indicated that the plutonic massifs of Sines and of Torrão-Odivelas were the most promising. A characterization was made of the Sines massif, a subvolcanic massif composed mostly of gabbros and diorites, located immediately adjacent to the CO2 sources and outcropping along 300 km2 onshore and offshore. These studies confirmed that these rock samples exhibited the appropriate mineralogical and geochemical features, but also indicated that the secondary porosity provided by the fracture patterns was very small

Celastrol efficacy by oral administration in the adjuvant-induced arthritis model

Copyright © 2020 Cascão, Vidal, Carvalho, Lopes, Romão, Goncalves, Moita and Fonseca. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Background: We previously demonstrated that celastrol has significant anti-inflammatory and bone protective effects when administered via the intraperitoneal route. For further preclinical evaluation, an effective oral administration of celastrol is crucial. Here we aimed to study the therapeutic dose range for its oral administration. Methods: Celastrol (1-25 μg/g/day, N = 5/group) was administrated orally to female adjuvant-induced arthritis (AIA) rats after 8 days of disease induction for a period of 14 days. A group of healthy (N = 8) and arthritic (N = 15) gender- and age-matched Wistar rats was used as controls. During the treatment period, the inflammatory score, ankle perimeter, and body weight were measured. At the end of the treatment, the animals were sacrificed, blood was collected for clinical pathology, necropsy was performed with collection of internal organs for histopathological analysis, and paw samples were used for disease scoring. Results: Doses higher than 2.5 μg/g/day of celastrol reduced the inflammatory score and ankle swelling, preserved joint structure, halted bone destruction, and diminished the number of synovial CD68+ macrophages. Bone resorption and turnover were also reduced at 5 and 7.5 μg/g/day doses. However, the dose of 7.5 μg/g/day was associated with thymic and liver lesions, and higher doses showed severe toxicity. Conclusion: Oral administration of celastrol above 2.5 μg/g/day ameliorates arthritis. This data supports and gives relevant information for the development of a preclinical test of celastrol in the setting of a chronic model of arthritis since rheumatoid arthritis is a long-term disease.info:eu-repo/semantics/publishedVersio