Synthesis and biological evaluation of novel quinoline-piperidine scaffolds as antiplasmodium agents

The parasitic disease malaria places almost half of the world's population at risk of infection and is responsible for more than 400,000 deaths each year. The first-line treatment, artemisinin combination therapies (ACT) regimen, is under threat due to emerging resistance of Plasmodium falciparum strains in e.g. the Mekong delta. Therefore, the development of new antimalarial agents is crucial in order to circumvent the growing resistance. Chloroquine, the long-established antimalarial drug, still serves as model compound for the design of new quinoline analogues, resulting in numerous new active derivatives against chloroquine-resistant P. falciparum strains over the past twenty years. In this work, a set of functionalized quinoline analogues, decorated with a modified piperidine-containing side chain, was synthesized. Both amino- and (aminomethyl)quinolines were prepared, resulting in a total of 18 novel quinoline-piperidine conjugates representing four different chemical series. Evaluation of their in vitro antiplasmodium activity against a CQ-sensitive (NF54) and a CQ-resistant (K1) strain of P. falciparum unveiled highly potent activities in the nanomolar range against both strains for five 4-aminoquinoline derivatives. Moreover, no cytotoxicity was observed for all active compounds at the maximum concentration tested. These five new aminoquinoline hit structures are therefore of considerable value for antimalarial research and have the potency to be transformed into novel antimalarial agents upon further hit-to-lead optimization studies

The genomic epidemiology of multi-drug resistant invasive non-typhoidal Salmonella in selected sub-Saharan African countries

Funder: Swedish International Development Cooperation Agency (SIDA)Funder: Government of Republic of KoreaFunder: US Centers for Disease Control and PreventionBackground: Invasive non-typhoidal Salmonella (iNTS) is one of the leading causes of bacteraemia in sub-Saharan Africa. We aimed to provide a better understanding of the genetic characteristics and transmission patterns associated with multi-drug resistant (MDR) iNTS serovars across the continent. Methods: A total of 166 iNTS isolates collected from a multi-centre surveillance in 10 African countries (2010–2014) and a fever study in Ghana (2007–2009) were genome sequenced to investigate the geographical distribution, antimicrobial genetic determinants and population structure of iNTS serotypes–genotypes. Phylogenetic analyses were conducted in the context of the existing genomic frameworks for various iNTS serovars. Population-based incidence of MDR-iNTS disease was estimated in each study site. Results: Salmonella Typhimurium sequence-type (ST) 313 and Salmonella Enteritidis ST11 were predominant, and both exhibited high frequencies of MDR; Salmonella Dublin ST10 was identified in West Africa only. Mutations in the gyrA gene (fluoroquinolone resistance) were identified in S. Enteritidis and S. Typhimurium in Ghana; an ST313 isolate carrying blaCTX-M-15 was found in Kenya. International transmission of MDR ST313 (lineage II) and MDR ST11 (West African clade) was observed between Ghana and neighbouring West African countries. The incidence of MDR-iNTS disease exceeded 100/100 000 person-years-of-observation in children aged <5 years in several West African countries. Conclusions: We identified the circulation of multiple MDR iNTS serovar STs in the sampled sub-Saharan African countries. Investment in the development and deployment of iNTS vaccines coupled with intensified antimicrobial resistance surveillance are essential to limit the impact of these pathogens in Africa

Special issue: Polymer engineering rheology

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Density fluctuations during the early stages of polymer crystallization: An overview

The present work provides a critical review of polymer crystallization studies using SALS; experimental methods, analysis techniques, observations and their relations with respect to other techniques are discussed. Furthermore, the fact that nucleation might be accompanied by large scale density fluctuations has been investigated for the flow-induced crystallization of iPB. SALS was applied to measure density and orientation fluctuations, whereas complementary results were obtained from optical microscopy. The observations from both crystallization and melting experiments seem to indicate that the detected density fluctuations result from the presence of weakly anisotropic structures, ratjer than being an indication of densification before the onset of crystallization.status: publishe

Network governance and coalitions of non-profit organizations

Abstract: During the last decade, networks have become part and parcel of the everyday reality of non-profit organizations (Renz, Brown & Andersson, 2023). Nevertheless, the term networks is approached from different perspectives and receives multiple meanings throughout the literature. This contribution provides a definition of organizational networks, discusses relevant insights on the governance of these networks, and puts forward a research agenda on network governance and non-profit organizations. Importantly, we delineate our network-level perspective from an organizational-level perspective. Whereas organizational-level studies typically provide valuable contributions on interorganizational advantages when organizations engage in networks or strategic alliances (Dyer and Singh, 1998), our contribution focuses on the governance of the whole network of non-profit organizations. By doing so, we provide an answer to the sense of urgency expressed in several literature reviews such as Renz, Brown & Andersson (2023) for more research and conceptual reflection on the governance of non-profit organizations at the network-level. We specifically argue for a research agenda that moves from consensus-driven approaches on network governance to efforts to map formal and informal ties among non-profit organizations (Van Puyvelde & Raeymaeckers, 2020)