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The inflammasome is a conserved structure for the intracellular detection of danger or pathogen signals. As a large intracellular multiprotein signaling platform, it activates downstream effectors that initiate a rapid necrotic programmed cell death (PCD) termed pyroptosis and activation and secretion of pro-inflammatory cytokines to warn and activate surrounding cells. However, inflammasome activation is difficult to control experimentally on a single-cell level using canonical triggers. We constructed Opto-ASC, a light-responsive form of the inflammasome adaptor protein ASC (Apoptosis-Associated Speck-Like Protein Containing a CARD) which allows tight control of inflammasome formation in vivo. We introduced a cassette of this construct under the control of a heat shock element into zebrafish in which we can now induce ASC inflammasome (speck) formation in individual cells of the skin. We find that cell death resulting from ASC speck formation is morphologically distinct from apoptosis in periderm cells but not in basal cells. ASC-induced PCD can lead to apical or basal extrusion from the periderm. The apical extrusion in periderm cells depends on Caspb and triggers a strong Ca2+ signaling response in nearby cells. [ABSTRACT FROM AUTHOR]

Mozambique is one of the four African countries which account for over half of all malaria deaths worldwide, yet little is known about the parasite genetic structure in that country. We performed P. falciparum amplicon and whole genome sequencing on 2251 malaria-infected blood samples collected in 2015 and 2018 in seven provinces of Mozambique to genotype antimalarial resistance markers and interrogate parasite population structure using genome-wide microhaplotyes. Here we show that the only resistance-associated markers observed at frequencies above 5% were pfmdr1-184F (59%), pfdhfr-51I/59 R/108 N (99%) and pfdhps-437G/540E (89%). The frequency of pfdhfr/pfdhps quintuple mutants associated with sulfadoxine-pyrimethamine resistance increased from 80% in 2015 to 89% in 2018 (p < 0.001), with a lower expected heterozygosity and higher relatedness of microhaplotypes surrounding pfdhps mutants than wild-type parasites suggestive of recent selection. pfdhfr/pfdhps quintuple mutants also increased from 72% in the north to 95% in the south (2018; p < 0.001). This resistance gradient was accompanied by a concentration of mutations at pfdhps-436 (17%) in the north, a south-to-north increase in the genetic complexity of P. falciparum infections (p = 0.001) and a microhaplotype signature of regional differentiation. The parasite population structure identified here offers insights to guide antimalarial interventions and epidemiological surveys. A comprehensive genomics approach reveals the spatial and temporal distribution of antimalarial drug resistance markers and geographic structure of P. falciparum parasites collected in seven provinces of Mozambique in 2015 and 2018. [ABSTRACT FROM AUTHOR]

The polyhydroxyalkanoates (PHAs) are biobased, biocompatible and biodegradable polyesters. To enhance their biodegradability and flexibility, we develop low density PHAs by an emulsion-templated method without organic solvent. Polycaprolactone (PCL) and castor oil are required to improve the flexibility and to generate the porosity, respectively. To overcome the well-known lack of compatibility between PHA and PCL, pluronic is introduced to improve the miscibility of these polyesters The densities of native PHA and PCL are 1.2 g.cm−3 and the densities decreased to 0.49 g.cm−3 in presence of castor oil (40 wt%). Different PHAs were studied: polyhydroxybutyrate (PHB), polyhydroxybutyrate-co-hydroxyvalerate (PHBHV) and polyhydroxybutyrate-co-hydroxyhexanoate (PHBHHx). The porous PHBHHx based material showed the best colonization by Pseudomonas, followed by the PHBHV and PHB. This colonization only occurred in the surface and no bacterial diffusion was observed inside the material. The biodegradability study in presence of lipase showed that after 8 days, the weight losses are, respectively, 20% and 75% when the densities decreased from 0.82 g.cm−3 to 0.49 g.cm−3. These results showed the importance of the porosity on the biodegradation of PHAs. The polyhydroxyalkanoates (PHAs) are biobased, biocompatible and biodegradable polyesters. To enhance their biodegradability and flexibility, we develop low density PHAs by an emulsion-templated method without organic solvent. Polycaprolactone (PCL) and castor oil are required to improve the flexibility and to generate the porosity, respectively. To overcome the well-known lack of compatibility between PHA and PCL, pluronic is introduced to improve the miscibility of these polyesters The densities of native PHA and PCL are 1.2 g.cm−3 and the densities decreased to 0.49 g.cm−3 in presence of castor oil (40 wt%). Different PHAs were studied: polyhydroxybutyrate (PHB), polyhydroxybutyrate-co-hydroxyvalerate (PHBHV) and polyhydroxybutyrate-co-hydroxyhexanoate (PHBHHx). The porous PHBHHx based material showed the best colonization by Pseudomonas, followed by the PHBHV and PHB. This colonization only occurred in the surface and no bacterial diffusion was observed inside the material. The biodegradability study in presence of lipase showed that after 8 days, the weight losses are, respectively, 20% and 75% when the densities decreased from 0.82 g.cm−3 to 0.49 g.cm−3. These results showed the importance of the porosity on the biodegradation of PHAs. [ABSTRACT FROM AUTHOR]

Background: Seasonal malaria chemoprevention (SMC) is a highly effective community-based intervention to prevent malaria infections in areas where the malaria burden is high and transmission occurs mainly during the rainy season. In Africa, so far, SMC has been implemented in the Sahel region. Mozambique contributes 4% of the global malaria cases, and malaria is responsible for one-quarter of all deaths in the country. Based on recommendations in the Malaria Strategic Plan, the Malaria Consortium, in partnership with the National Malaria Control Programme in Mozambique, initiated a phased SMC implementation study in the northern province of Nampula. The first phase of this 2-year implementation study was conducted in 2020-2021 and focused on the feasibility and acceptability of SMC. The second phase will focus on demonstrating impact. This paper describes phase 2 of the implementation study. Objective: Specific objectives include the following: (1) to determine the effectiveness of SMC in terms of its reduction in incidence of malaria infection among children aged 3 to 59 months; (2) to determine the chemoprevention efficacy of sulfadoxine-pyrimethamine plus amodiaquine (SP+AQ) when used for SMC in Nampula Province, Mozambique, and the extent to which efficacy is impacted by drug resistance and drug concentrations; (3) to investigate the presence and change in SP+AQ- and piperaquine-resistance markers over time as a result of SMC implementation; and (4) to understand the impact of the SMC implementation model, determining the process and acceptability outcomes for the intervention. Methods: This type 2, hybrid, effectiveness-implementation study uses a convergent mixed methods approach. SMC will be implemented in four monthly cycles between December 2021 and March 2022 in four districts of Nampula Province. Phase 2 will include four components: (1) a cluster randomized controlled trial to establish confirmed malaria cases, (2) a prospective cohort to determine the chemoprevention efficacy of the antimalarials used for SMC and whether drug concentrations or resistance influence the duration of protection, (3) a resistance marker study in children aged 3 to 59 months to describe changes in resistance marker prevalence over time, and (4) a process evaluation to determine feasibility and acceptability of SMC. Results: Data collection began in mid-January 2022, and data analysis is expected to be completed by October 2022. Conclusions: This is the first effectiveness trial of SMC implemented in Mozambique. The findings from this trial will be crucial to policy change and program expansion to other suitable geographies outside of the Sahel. The chemoprevention efficacy cohort study is a unique opportunity to better understand SMC drug efficacy in this new SMC environment. [ABSTRACT FROM AUTHOR]

The differentiation of T cells from lymphoid progenitors in the thymus follows sequential developmental stages that constantly require interaction with thymic epithelial cells. Several distinct aspects of early T cell development depend on the activation of Notch receptors on thymocytes, while the selection of thymocytes at later stages are believed to be Notch independent. Using reverse genetic approaches and whole‐thymus live imaging in an in vivo teleost model, the medaka, we report that Notch1 signals is required for proliferation and specification of developing T cells as well as involved in their selection in the thymus. We reveal that Notch1 controls the migratory behavior of thymocytes through controlling the chemokine receptor Ccr9b and thereby influence the T cell receptor (TCR) activation. Hence, we propose that, in lower vertebrates, the function of Notch signaling extends to all stages of T cell development, except when thymocytes undergo TCRβ rearrangement. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization (WHO) launched an initiative to plan for the sustainability of integrated community case management (iCCM) programmes supported by the Rapid Access Expansion (RAcE) Programme in five African countries in 2016. WHO contracted experts to facilitate sustainability planning among Ministries of Health, WHO, nongovernmental organisation grantees, and other stakeholders.Methods: We designed an iterative and unique process for each RAcE project area which involved creating a sustainability framework to guide planning; convening meetings to identify and prioritise elements of the framework; forming technical working groups to build country ownership; and, ultimately, creating roadmaps to guide efforts to fully transfer ownership of the iCCM programmes to host countries. For this analysis, we compared priorities identified in roadmaps across RAcE project sites, examined progress against roadmaps via transition plans, and produced recommendations for short-term actions based on roadmap priorities that were unaddressed or needed further attention.Results: This article describes the sustainability planning process, roadmap priorities, progress against roadmaps, and recommendations made for each project area. We found a few patterns among the prioritised roadmap elements. Overall, every project area identified priorities related to policy and coordination of external stakeholders including funders; supply chain management; service delivery and referral system; and communication and social mobilisation, indicating that these factors have persisted despite iCCM programme maturity, and are also of concern to new programmes. We also found that a facilitated process to identify and document programme priorities in roadmaps, along with deliberately planning for transition from an external implementer to a national system could support the sustainability of iCCM programmes by facilitating teams of stakeholders to accomplish explicit tasks related to transitioning the programme.Conclusions: Certain common elements are of concern for sustaining iCCM programmes across countries, among them political leadership, supply chain management, data processes, human resources, and community engagement. Adapting and using a sustainability planning approach created an inclusive and comprehensive dialogue about systemic factors that influence the sustainability of iCCM services and facilitated changes to health systems in each country. [ABSTRACT FROM AUTHOR]

The cytokine interleukin 1 (IL-1) is an evolutionary innovation of vertebrates. Fish and amphibian have one IL1 gene, while mammals have two copies of IL1 , IL1A and IL1B , with distinct expression patterns and differences in their proteolytic activation. Our current understanding of the evolutionary history of IL-1 is mainly based on phylogenetic analysis, but this approach provides no information on potentially different functions of IL-1 homologues, and it remains unclear which biological activities identified for IL-1α and IL-1β in mammals are present in lower vertebrates. Here, we use in vitro and in vivo experimental models to examine the expression patterns and cleavage of IL-1 proteins from various species. We found that IL-1 in the teleost medaka shares the transcriptional patterns of mammalian IL-1α, and its processing also resembles that of mammalian IL-1α, which is sensitive to cysteine protease inhibitors specific for the calpain and cathepsin families. By contrast, IL-1 proteins in reptiles also include biological properties of IL-1β. Therefore, we propose that the duplication of the ancestral IL1 gene led to the segregation of expression patterns and protein processing that characterizes the two extant forms of IL-1 in mammals.

Targeted and specific induction of cell death in an individual or groups of cells hold the potential for new insights into the response of tissues or organisms to different forms of death. Here, we report the development of optogenetically controlled cell death effectors (optoCDEs), a novel class of optogenetic tools that enables light-mediated induction of three types of programmed cell death (PCD)-apoptosis, pyroptosis, and necroptosis-using Arabidopsis thaliana photosensitive protein Cryptochrome-2. OptoCDEs enable a rapid and highly specific induction of PCD in human, mouse, and zebrafish cells and are suitable for a wide range of applications, such as sub-lethal cell death induction or precise elimination of single cells or cell populations in vitro and in vivo. As the proof-of-concept, we utilize optoCDEs to assess the differences in neighboring cell responses to apoptotic or necrotic PCD, revealing a new role for shingosine-1-phosphate signaling in regulating the efferocytosis of the apoptotic cell by epithelia., (© 2022 Shkarina et al.)