Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Design, construction and operation of the ProtoDUNE-SP Liquid Argon TPC

The ProtoDUNE-SP detector is a single-phase liquid argon time projection chamber (LArTPC) that was constructed and operated in the CERN North Area at the end of the H4 beamline. This detector is a prototype for the first far detector module of the Deep Underground Neutrino Experiment (DUNE), which will be constructed at the Sandford Underground Research Facility (SURF) in Lead, South Dakota, U.S.A. The ProtoDUNE-SP detector incorporates full-size components as designed for DUNE and has an active volume of 7 × 6 × 7.2 m3. The H4 beam delivers incident particles with well-measured momenta and high-purity particle identification. ProtoDUNE-SP's successful operation between 2018 and 2020 demonstrates the effectiveness of the single-phase far detector design. This paper describes the design, construction, assembly and operation of the detector components

Discovery of New Anti-Schistosomal Hits by Integration of QSAR-Based Virtual Screening and High Content Screening.

Schistosomiasis is a debilitating neglected tropical disease, caused by flatworms of Schistosoma genus. The treatment relies on a single drug, praziquantel (PZQ), making the discovery of new compounds extremely urgent. In this work, we integrated QSAR-based virtual screening (VS) of Schistosoma mansoni thioredoxin glutathione reductase (SmTGR) inhibitors and high content screening (HCS) aiming to discover new antischistosomal agents. Initially, binary QSAR models for inhibition of SmTGR were developed and validated using the Organization for Economic Co-operation and Development (OECD) guidance. Using these models, we prioritized 29 compounds for further testing in two HCS platforms based on image analysis of assay plates. Among them, 2-[2-(3-methyl-4-nitro-5-isoxazolyl)vinyl]pyridine and 2-(benzylsulfonyl)-1,3-benzothiazole, two compounds representing new chemical scaffolds have activity against schistosomula and adult worms at low micromolar concentrations and therefore represent promising antischistosomal hits for further hit-to-lead optimization

Distribuição espacial de doenças endêmicas no município de Ribeirão Preto (SP) Spatial distribution of endemic diseases in Ribeirão Preto, São Paulo State

A percepção de que algumas doenças acontecem em determinados lugares é antiga. A preocupação em estudar as relações entre o homem e o meio resultou em diversos trabalhos de geografia médica, voltados à análise da distribuição espacial das doenças. Este estudo seccional foi desenvolvido no município de Ribeirão Preto (SP) e teve como objetivo ilustrar, por meio de agravos de saúde (dengue, hanseníase e tuberculose), de que forma uma ferramenta de um sistema de informação geográfica permite a identificação de áreas heterogêneas, fornecendo subsídios para a escolha de estratégias e intervenções específicas de acordo com a necessidade dos moradores, bem como a priorização de recursos para grupos mais vulneráveis. A população compreendeu os casos de dengue, hanseníase e tuberculose notificados no ano 2000 em Ribeirão Preto. Os dados foram coletados na Vigilância Epidemiológica da Secretaria Municipal de Saúde do município. Para a obtenção dos mapas temáticos, os dados foram geocodificados com auxílio do software MapInfo 7.8 e Spring 4.3. Os mapas temáticos ilustraram a distribuição da densidade de casos de dengue, hanseníase e tuberculose no município como uma maneira complementar de análise de informações de saúde, apontando as áreas prioritárias para o controle destas doenças.<br>The perception that some diseases happen in certain places is old. The concern in studying the relation between the human being and the environment resulted in several studies of medical geography, directed to the analysis of diseases spatial distribution. This sectional study was carried out in Ribeirão Preto, São Paulo State, and aimed to illustrate, through health problems (dengue, leprosy and tuberculosis), how a Geographic Information System tool allows the identification of heterogeneous areas, providing support for the choice of strategies and specific interventions according to the need of residents, as well as, priority of resources to more vulnerable groups. The population comprised cases of dengue, leprosy and tuberculosis notified in Ribeirão Preto in 2000. Data were collected in the Health Secretary Epidemiological Surveillance of the city. In order to obtain the thematic maps, data were geo-codified with the software MapInfo 7.8 e Spring 4.3. The thematic maps showed the density distribution of dengue, leprosy and tuberculosis cases in the city as a way to complement the analysis of health information, pointing priority areas for the control of these diseases