57 research outputs found

    Metabolic and vascular effects of thiosulfate sulfurtransferase deletion

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    Hydrogen sulfide (H2S), is a gasotransmitter with several key roles in metabolism and vascular function. The effects of H2S are dependent on concentration and target organ. For example, increased H2S concentrations impair liver metabolic function but protect against vascular dysfunction and atherosclerosis. Thiosulfate sulfurtransferase (TST), a nuclear encoded mitochondrial matrix enzyme, is proposed to be a component of the sulfide oxidising unit (SOU) which metabolises H2S. Preliminary data has shown that Tst deletion in mice (Tst–/–) increases circulating H2S levels measured in whole blood. Therefore, it was hypothesised that Tst–/– mice would exhibit worsened metabolic function in the liver but also protection of vascular function under conditions of vascular stress e.g. atherosclerosis. Liver metabolism was assessed by extensive metabolic phenotyping of Tst–/–mice fed control diet and in conditions of metabolic dysfunction induced by a high fat diet (HFD). Tst deletion altered glucose metabolism in mice; gluconeogenesis was increased in liver from Tst–/–mice fed control diet. Glucose intolerance in HFD-fed Tst–/–mice was also more severe than HFDfed C57BL/6 controls. In vitro metabolic investigations in primary hepatocytes isolated from Tst–/–mice demonstrated that mitochondrial ATP-linked and leak respiration were increased compared to controls. The effect of Tst deletion on vascular function was investigated in Tst– /–mice fed control or HFD using myography. Tst deletion did not alter vessel function when mice were maintained on a normal diet. HFD feeding (20 weeks) reduced maximal vessel constriction in the presence of endothelial nitric oxide synthase and cyclooxygenase inhibitors in C57BL/6 aorta. However, in Tst–/–mice fed HFD there was no reduction in maximal constriction suggesting a protective action of Tst deletion. The effects of Tst deletion on atherosclerotic lesions was investigated by generating double knock-out (DKO) mice by deletion of the Tst gene in ApoE–/– mice and (ApoE–/–Tst–/–). Atherosclerotic lesion formation was accelerated by feeding mice a western diet. Within the brachiocephalic branch lesion volume and total vessel volume were reduced in DKO mice fed western diet for 12 weeks, indicating that Tst deletion reduced lesion formation. Plasma cholesterol was reduced in DKO mice compared to ApoE–/– controls and a trend towards reduced systolic blood pressure was also noted. Overall this work supported the hypothesis that Tst deletion engenders metabolic dysfunction but vascular protection. The findings are consistent with the reported effects of increased H2S signalling. Overall inhibition of TST represents a novel target for treatment of atherosclerosis, with the caveat that glycaemia may be worsened due to hepatic metabolic dysfunction

    Slot Antenna Performance and Signal Quality in a Smartphone Prototype

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    Polarised light modular microscopy (Pol-ModMicro) for identifying hemozoin crystals in Plasmodium

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    Plasmodium spp. are the protozoan parasites responsible for malaria. Plasmodium spp. synthesise a biocrystal, hemozoin, which can be observed under cross-polarised light. These birefringent crystals can be seen due to different refractive indices of the hemozoin crystal and red blood cells. Here, we present a polarised light modular microscopy (Pol-ModMicro) solution, complete with illumination sources and a robust imaging system to capture birefringence and identify the parasites. We achieve this by combining ModLight light sources with bespoke components designed for the OpenFlexure microscope to image blood smears. Further, a simple and robust algorithm capable of enhancing birefringence is presented. This solution provides image quality that is comparable to a substantially more expensive proprietary microscope

    Rising Water Temperature in Rivers: Ecological impacts and future resilience

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    Rising water temperatures in rivers due to climate change are already having observable impacts on river ecosystems. Warming water has both direct and indirect impacts on aquatic life, and further aggravates pervasive issues such as eutrophication, pollution, and the spread of disease. Animals can survive higher temperatures through physiological and/or genetic acclimation, behavioral and phenological change, and range shifts to more suitable locations. As such, those animals that are adapted to cool-water regions typically found in high altitudes and latitudes where there are fewer dispersal opportunities are most at risk of future extinction. However, sub-lethal impacts on animal physiology and phenology, body-size, and trophic interactions could have significant population-level effects elsewhere. Rivers are vulnerable to warming because historic management has typically left them exposed to solar radiation through the removal of riparian shade, and hydrologically disconnected longitudinally, laterally, and vertically. The resilience of riverine ecosystems is also limited by anthropogenic simplification of habitats, with implications for the dispersal and resource use of resident organisms. Due to the complex indirect impacts of warming on ecosystems, and the species-specific physiological and behavioral response of organisms to warming, predicting how river ecosystems will change in the future is challenging. Restoring rivers to provide connectivity and heterogeneity of conditions would provide resilience to a range of expected co-occurring pressures, including warming, and should be considered a priority as part of global strategies for climate adaptation and mitigation

    Prevalence, determinants, and clinical associations of high-sensitivity cardiac troponin in patients attending emergency departments

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    Background: High-sensitivity cardiac troponin assays may improve the diagnosis of myocardial infarction but increase the detection of elevated cardiac troponin in patients without acute coronary syndrome. Methods: In a prospective cohort study, we evaluated the prevalence, determinants, and outcome of patients with elevated cardiac troponin attending the emergency department without suspected acute coronary syndrome. We measured high-sensitivity cardiac troponin in 918 consecutive patients attending the emergency department without suspected acute coronary syndrome who had blood sampling performed by the attending clinician. Elevated high-sensitivity cardiac troponin I was defined as concentrations above the sex-specific 99th percentile threshold. Clinical demographics, physiological measures, and all-cause mortality at 1 year associated with elevated high-sensitivity cardiac troponin concentrations were recorded. Results: Elevated cardiac troponin concentration occurred in 114 (12.4%) patients, of whom 2 (0.2%), 3 (0.3%), and 109 (11.9%) were adjudicated as type 1 myocardial infarction, type 2 myocardial infarction, and myocardial injury, respectively. Elevated troponin concentrations were associated with increasing age, worsening renal function, multimorbidity, and adverse physiology. Across a total of 912 patient-years follow-up, cardiac troponin concentration was a strong predictor of death (hazard ratio [HR] 1.26 per 2-fold increase, 95% confidence interval [CI] 1.06 to 1.49) independent of age, sex, multimorbidity, and adverse physiology. Conclusions: High-sensitivity cardiac troponin concentrations were elevated in 1 in 8 consecutive patients without suspected acute coronary syndrome attending the emergency department and were associated with increasing age, multimorbidity, adverse physiology, and death. Elevated cardiac troponin in unselected patients predominantly reflects myocardial injury rather than myocardial infarction

    Low immunogenicity of malaria pre-erythrocytic stages can be overcome by vaccination.

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    Immunogenicity is considered one important criterion for progression of candidate vaccines to further clinical evaluation. We tested this assumption in an infection and vaccination model for malaria pre-erythrocytic stages. We engineered Plasmodium berghei parasites that harbour a well-characterised epitope for stimulation of CD8+ T cells, either as an antigen in the sporozoite surface-expressed circumsporozoite protein or the parasitophorous vacuole membrane associated protein upregulated in sporozoites 4 (UIS4) expressed in exo-erythrocytic forms (EEFs). We show that the antigen origin results in profound differences in immunogenicity with a sporozoite antigen eliciting robust, superior antigen-specific CD8+ T-cell responses, whilst an EEF antigen evokes poor responses. Despite their contrasting immunogenic properties, both sporozoite and EEF antigens gain access to antigen presentation pathways in hepatocytes, as recognition and targeting by vaccine-induced effector CD8+ T cells results in high levels of protection when targeting either antigen. Our study is the first demonstration that poorly immunogenic EEF antigens do not preclude their susceptibility to antigen-specific CD8+ T-cell killing, which has wide-ranging implications on antigen prioritisation for next-generation pre-erythrocytic malaria vaccines

    Importance of the immunodominant CD8+ T cell epitope of Plasmodium berghei circumsporozoite protein in parasite- and vaccine-induced protection

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    The circumsporozoite protein (CSP) builds up the surface coat of sporozoites and is the leading malaria pre-erythrocytic-stage vaccine candidate. CSP has been shown to induce robust CD8+ T cell responses that are capable of eliminating developing parasites in hepatocytes, resulting in protective immunity. In this study, we characterized the importance of the immunodominant CSP-derived epitope SYIPSAEKI of Plasmodium berghei in both sporozoite- and vaccine-induced protection in murine infection models. In BALB/c mice, where SYIPSAEKI is efficiently presented in the context of the major histocompatibility complex class I (MHC-I) molecule H-2-Kd, we established that epitope-specific CD8+ T cell responses contribute to parasite killing following sporozoite immunization. Yet, sterile protection was achieved in the absence of this epitope, substantiating the concept that other antigens can be sufficient for parasite-induced protective immunity. Furthermore, we demonstrated that SYIPSAEKI-specific CD8+ T cell responses elicited by viral-vectored CSP-expressing vaccines effectively targeted parasites in hepatocytes. The resulting sterile protection strictly relied on the expression of SYIPSAEKI. In C57BL/6 mice, which are unable to present the immunodominant epitope, CSP-based vaccines did not confer complete protection, despite the induction of high levels of CSP-specific antibodies. These findings underscore the significance of CSP in protection against malaria pre-erythrocytic stages and demonstrate that a significant proportion of the protection against the parasite is mediated by CD8+ T cells specific for the immunodominant CSP-derived epitope

    Plasmodium falciparum gametocyte density and infectivity in peripheral blood and skin tissue of naturally infected parasite carriers in Burkina Faso

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    Background: Plasmodium falciparum transmission depends on mature gametocytes that can be ingested by mosquitoes taking a blood meal on human skin. Although gametocyte skin sequestration has long been hypothesized as important contributor to efficient malaria transmission, this has never been formally tested. Methods: In naturally infected gametocyte carriers from Burkina Faso, we assessed infectivity to mosquitoes by direct skin feeding and membrane feeding. We directly quantified male and female gametocytes and asexual parasites in finger-prick and venous blood samples, skin biopsy samples, and in of mosquitoes that fed on venous blood or directly on skin. Gametocytes were visualized in skin tissue with confocal microscopy. Results: Although more mosquitoes became infected when feeding directly on skin then when feeding on venous blood (odds ratio, 2.01; 95% confidence interval, 1.21–3.33; P = .007), concentrations of gametocytes were not higher in the subdermal skin vasculature than in other blood compartments; only sparse gametocytes were observed in skin tissue. Discussion: Our data strongly suggest that there is no significant skin sequestration of P. falciparum gametocytes. Gametocyte densities in peripheral blood are thus informative for predicting onward transmission potential to mosquitoes and can be used to target and monitor malaria elimination initiatives

    Plasmodium falciparum Gametocyte Density and Infectivity in Peripheral Blood and Skin Tissue of Naturally Infected Parasite Carriers in Burkina Faso.

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    BACKGROUND: Plasmodium falciparum transmission depends on mature gametocytes that can be ingested by mosquitoes taking a blood meal on human skin. Although gametocyte skin sequestration has long been hypothesized as important contributor to efficient malaria transmission, this has never been formally tested. METHODS: In naturally infected gametocyte carriers from Burkina Faso, we assessed infectivity to mosquitoes by direct skin feeding and membrane feeding. We directly quantified male and female gametocytes and asexual parasites in finger-prick and venous blood samples, skin biopsy samples, and in of mosquitoes that fed on venous blood or directly on skin. Gametocytes were visualized in skin tissue with confocal microscopy. RESULTS: Although more mosquitoes became infected when feeding directly on skin then when feeding on venous blood (odds ratio, 2.01; 95% confidence interval, 1.21-3.33; P = .007), concentrations of gametocytes were not higher in the subdermal skin vasculature than in other blood compartments; only sparse gametocytes were observed in skin tissue. DISCUSSION: Our data strongly suggest that there is no significant skin sequestration of P. falciparum gametocytes. Gametocyte densities in peripheral blood are thus informative for predicting onward transmission potential to mosquitoes and can be used to target and monitor malaria elimination initiatives
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