Combining radial and continuous flow synthesis to optimize and scale-up the production of medicines

Current drug production in batch cannot adapt rapidly to market demands, evidenced by recent shortages in many markets globally of essential medicines. Flow chemistry is a valuable tool for on-demand production of active pharmaceutical ingredients (APIs). Here, we reveal a new concept to develop and produce APIs, where an automated synthesizer that works with discrete volumes of solutions is employed at the discovery stage to identify the optimal synthetic route and conditions before a commercially available continuous flow system is used for scale-up. This concept is illustrated by the synthesis of nifedipine and paracetamol, in short supply in Germany during the COVID-19 pandemic, and the local anesthetic lidocaine

O dispositivo da idade, a produção da velhice e regimes de subjetivação: rastreamentos genealógicos

Este artículo problematiza la producción histórica de la vejez a partir del dispositivo de la edad. Se delinea un rastreo genealógico que busca apuntar algunas líneas que fueron configurando enunciados sobre la vejez a partir de diversas correlaciones de fuerzas, especialmente en contextos biopolíticos. Se destaca como los discursos de verdad que enuncian la vejez producen regímenes de subjetivación y constituyen sujetos a partir de referenciales normalizadores y masificadores. A partir de la deconstrucción de discursos relativos a la vejez, se apunta para la posibilidad de considerar las experiencias de la vejez para más allá de formas de tutela y de gestiones calculistas de la vida.This paper discusses the historical production of the old age considering the dispositif of age. A genealogical tracking is outlined in order to point out some lines that have configured statements about the old age, especially in biopolitical contexts. It is emphasized how the discourses of truth about the old age do produce regimes of subjectification and constitute subjects from normalizing and generalizing references. Starting from the deconstructing of discourses regarding the old age, it is indicated the possibility of considering the experiences of the old age aside from the forms of tutelage and from the forms of calculated management of life.Cet article met en question la production historique de la vieillesse en partant du dispositif de l'âge. Un traçage généalogique est fait afin de signaler quelques lignes qui édifient des énoncés sur la vieillesse à partir de plusieurs correlations de forces, en particulier dans des contextes biopolitiques. On souligne comment les discours de vérité qui énoncent la vieillesse produisent des régimes de subjectivation et constituent des sujets selon des référentiels normalisateurs et massificateurs. À partir de la déconstruction des discours liés à la vieillesse, on signale la possibilité de considérer les expériences de vieillesse au-delà des formes de tutelle et de gestions calculatrices de la vie.Este artigo problematiza a produção histórica da velhice a partir do dispositivo da idade. Traça-se um rastreio genealógico que visa apontar algumas linhas que foram configurando enunciados sobre a velhice a partir de diversas correlações de forças, especialmente em contextos biopolíticos. Destaca-se como os discursos de verdade que enunciam a velhice produzem regimes de subjetivação e constituem sujeitos a partir de referenciais normalizadores e massificadores. A partir da desconstrução dos discursos relativos à velhice, aponta-se para a possibilidade de considerar as experiências das velhices para além das formas de tutela e de gestões calculistas da vida

Isolation of human monoclonal autoantibodies derived from pancreatic lymph node and peripheral blood B cells of islet autoantibody-positive patients

Aims/hypothesis Autoantibodies against pancreatic islets and infections by enteroviruses are associated with type 1 diabetes, but the specificity of immune responses within the type 1 diabetic pancreas is poorly characterised. We investigated whether pancreatic lymph nodes could provide a source of antigen-specific B cells for analysis of immune responses within the (pre)diabetic pancreas. Methods Human IgG antibodies were cloned from single B lymphocytes sorted from pancreatic lymph node cells of three organ donors positive for islet autoantibodies, and from the peripheral blood of a patient with type 1 diabetes. Antibodies to insulinoma-associated antigen 2 (IA-2), GAD65, zinc trans- porter 8 (ZnT8) and Coxsackie B virus proteins were assayed by immunoprecipitation and by immunofluorescence on pan- creatic sections. Results Human IgG antibodies (863) were successfully cloned and produced from 4,092 single B cells from lymph nodes and peripheral blood. Reactivity to the protein tyrosine phosphatase domain of the IA-2 autoantigen was detected in two cloned antibodies: one derived from a pancreatic lymph node and one from peripheral blood. Epitopes for these two antibodies were similar to each other and to those for circulat- ing antibodies in type 1 diabetes. The remaining 861 antibod- ies were negative for reactivity to IA-2, GAD65 or ZnT8 by both assays tested. Reactivity to a Coxsackie viral protein 2 was detected in one antibody derived from a peripheral blood B cell, but not from lymph nodes. Conclusions/interpretation We show evidence for the infre- quent presence of autoantigen-specific IgG+ B lymphocytes in the pancreatic-draining lymph nodes of islet autoantibody- positive individuals

The \u27Healthy Parks-Healthy People\u27 Movement in Canada: Progress, Challenges, and an Emerging Knowledge and Action Agenda

In this article, we outline progress and challenges in establishing effective health promotion tied to visitor experiences provided by protected and conserved areas in Canada. Despite an expanding global evidence base, case studies focused on aspects of health and well-being within Canada’s protected and conserved areas remain limited. Data pertaining to motivations, barriers and experiences of visitors are often not collected by governing agencies and, if collected, are not made generally available or reported on. There is an obvious, large gap in research and action focused on the needs and rights of groups facing systemic barriers related to a variety of issues including, but not limited to, access, nature experiences, and needs with respect to health and well-being outcomes. Activation of programmes at the site level continue to grow, and Park Prescription programmes, as well as changes to the Accessible Canada Act, represent significant, positive examples of recent cross-sector policy integration. Evaluations of outcomes associated with HPHP programmes have not yet occurred but will be important to adapting interventions and informing cross-sector capacity building. We conclude by providing an overview of gaps in evidence and practice that, if addressed, can lead to more effective human health promotion vis-à-vis nature contact in protected and conserved areas in Canada

The historical ecology of subsistence and early commercial fisheries in mangrove systems in Brazil

Human population growth and the technological advancements of the 20th and 21st centuries have significantly altered human-environment interactions and led to unprecedented anthropogenic footprints on coastal and ocean systems. Despite thousands of years of exploitation for subsistence and, later, commercial purposes, the ecology of mangrove fisheries along the Brazilian coast and the consequences of these activities remain poorly understood. This is largely due to a pervasive lack of historical baselines, and highlights the conservation crises affecting some of the world's biodiversity hotspots. In this study, we used otolith metrics and stable isotope analysis to investigate changes in the body length and trophic ecology of several demersal species recovered from pre-colonial (4500 cal BP to 1500 AD) and historical (late 19th and early 20th centuries AD) archaeological sites in Babitonga Bay, the largest mangrove system in southern Brazil. Our results revealed that pre-colonial and historical fisheries exploited a wide range of mangrove habitats, encompassing brackish to marine systems. Pre-colonial subsistence fisheries, however, targeted predominantly small and juvenile individuals in nursery areas, while early commercial fisheries targeted larger adult specimens, likely due to their higher commercial value. Our study shows that some drivers of stock overexploitation, such as the preferential capture of large and adult individuals, were found to be occurring more than 150 years ago along the southern Brazilian coast. Given the deep roots of human footprints in Brazil, our findings underscore the significance of incorporating historical data into the formulation of fisheries management strategies in subtropical and tropical regions

Governing urban vacancy in post-crash Dublin: contested property and alternative social projects

© 2017, © 2017 Informa UK Limited, trading as Taylor & Francis Group. The scale and severity of property crashes following the global financial crisis has made vacancy a more visible and politically significant feature of cities. Although research has focused on urban experiments in vacant spaces, there has been less emphasis on how the contested property relations around vacancy remake urban governance. In this paper, we argue that debates about vacancy have been a central concern in post-crisis urban governance. In the first part of the paper we draw two conceptual approaches into a dialogue and apply them to an analysis of vacant space: that of Nicholas Blomley on property and Elizabeth Povinelli on “alternative social projects”. In the second part of the paper, we critically analyse how three groups discursively construct the need to “activate” and “re-use” vacant spaces in Dublin: grassroots groups, urban policy-makers, and financial actors. We argue that governing vacancy will be a key feature of post-crisis urbanisation

Can scenario-planning support community-based natural resource management? Experiences from three countries in latin america

Community Based Natural Resource Management (CBNRM) is a concept critical to managing socio-ecological systems, but whose implementation needs strengthening. Scenario-planning is one approach that may offer benefits relevant to CBNRM, but whose potential is not yet well understood. We therefore designed, trialled and evaluated a scenario-planning method intended to support CBNRM at three cases, located in Colombia, Mexico and Argentina. Implementing scenario-planning was judged as worthwhile in all three cases, although aspects of it could be challenging to facilitate. The benefits generated were relevant to strengthening CBNRM: encouraging the participation of local people and using their knowledge; enhanced consideration and adaption of future change; and supporting the development of systems thinking. Tracing exactly when and how these benefits arise is challenging, but two elements of the method seemed particularly useful. Firstly, using a systematic approach to discuss how drivers of change may affect local socio-ecological systems helped to foster systems thinking and identify connections between issues. Secondly, explicitly focusing on how to use and respond to scenarios helped identify specific practical activities ('response options') that would support CBNRM despite the pressures of future change. Discussions about response options also highlighted the need for support by other actors (e.g. policy groups): this raises the question of when and how other actors and other sources of knowledge should be involved in scenario-planning, so as to encourage their buy-in to actions identified by the process. We suggest other CBNRM initiatives may benefit from adapting and applying scenario-planning. However, these initiatives should be carefully monitored since further research is required to understand how and when scenario-planning methods may produce benefits, and their strengths and weaknesses versus other methods

Ocean-based climate action and human rights implications under the international climate change regime

After drawing attention to the crucial role of marine biodiversity, including that of deep-sea ecosystems, in current scientific understanding of the ocean-climate nexus, this article highlights the limited extent to which the international climate change regime has so far addressed the ocean. The focus then shifts to how the international climate change regime could contribute to the protection of marine biodiversity as part of mitigation, adaptation and finance, taking into account human rights impacts and standards, drawing a comparison with REDD+. The article concludes with an original proposal, inspired by the Climate and Clean Air Coalition, to develop urgent, synergistic approaches to ocean- and human rights-based climate action through a multi-actor coalition, including different international treaties and United Nations bodies, to ‘protect and restore the ocean’s contributions to climate regulation, human well-being and planetary health’

A phosphatidylinositol transfer protein integrates phosphoinositide signaling with lipid droplet metabolism to regulate a developmental program of nutrient stress-induced membrane biogenesis

The Sec14-like phosphatidylinositol transfer protein Sfh3 associates with bulk LDs in vegetative cells but targets to a neutral lipid hydrolase-rich LD pool during sporulation. Sfh3 inhibits LD utilization by a PtdIns-4-phosphate–dependent mechanism, and this inhibition prevents prospore membrane biogenesis in sporulating cells.Lipid droplet (LD) utilization is an important cellular activity that regulates energy balance and release of lipid second messengers. Because fatty acids exhibit both beneficial and toxic properties, their release from LDs must be controlled. Here we demonstrate that yeast Sfh3, an unusual Sec14-like phosphatidylinositol transfer protein, is an LD-associated protein that inhibits lipid mobilization from these particles. We further document a complex biochemical diversification of LDs during sporulation in which Sfh3 and select other LD proteins redistribute into discrete LD subpopulations. The data show that Sfh3 modulates the efficiency with which a neutral lipid hydrolase-rich LD subclass is consumed during biogenesis of specialized membrane envelopes that package replicated haploid meiotic genomes. These results present novel insights into the interface between phosphoinositide signaling and developmental regulation of LD metabolism and unveil meiosis-specific aspects of Sfh3 (and phosphoinositide) biology that are invisible to contemporary haploid-centric cell biological, proteomic, and functional genomics approaches

Partial Meal Replacement Plan and Quality of the Diet at 1 Year: Action for Health in Diabetes (Look AHEAD) Trial

Little is known about diet quality with a reduced-energy, low-fat, partial meal replacement (PMR) plan, especially in individuals with type 2 diabetes. The Action for Health in Diabetes (Look AHEAD) trial implemented a PMR plan in the intensive lifestyle intervention (ILI)