Uncovering the role of IFNAR1 in Experimental Cerebral malaria

Dissertation presented the Ph.D degree in BiologyCerebral malaria is a severe and fatal form of clinical Plasmodium falciparum infection, resulting in brain injury from a damaging cascade of vascular, inflammatory and immunological host responses. However progression to cerebral malaria can be modified by host genetic factors. This thesis work extensively reveals the role of Interferon type I receptor (IFNAR1) in the development of Experimental cerebral malaria, through the use of the mouse model Ifnar1-/-. We found Ifnar1-/- mice protected from Experimental cerebral malaria upon infection with Plasmodium berghei ANKA-GFP, compared with susceptible wild-type C57BL/6 mice. Ifnar1-/- mice showed diminished blood brain barrier breakage, despite parasite accumulation in the periphery and accumulation of immune cells within the brain tissue during infection.(...

An Incremental Process for the Development of Multi-agent Systems in Event-B

A multi-agent system is a group of software or hardware agents that cooperate or compete to achieve individual or shared goals. A method for developing a multi-agent system must be capable of modelling the concepts that are central to multi-agent systems. These concepts are identified in a review of Agent Oriented Software Engineering methodologies. The rigorous development of complex systems using formal methods can reduce the number of design faults. Event-B is a formal method for modelling and reasoning about reactive and distributed systems. There is currently no method that guides the developer specifically in the modelling of agent-based concepts in Event-B. The use of formal methods is seen by some developers as inaccessible. This thesis presents an Incremental Development Process for the development of multi-agent systems in Event-B. Development following the Incremental Development Process begins with the construction of informal models, based on agent concepts. The informal models relate system goals using a set of relationships. The developer is provided with guidance to construct formal Event-B models based on the informal design. The concepts that are central to multi-agent systems are captured in the Event-B models through the translation from the goal models. The Event-B models are refined and decomposed into specifications of roles that will be performed by the agents of the system. Two case studies illustrate how the Incremental Development Process can be applied to multi-agent systems. An additional aid to the developer presented in this thesis is a set of modelling patterns that provide fault-tolerance for Event-B models of interacting agents

An incremental process for the development of multi-agent systems in Event-B

A multi-agent system is a group of software or hardware agents that cooperate or compete to achieve individual or shared goals. A method for developing a multi-agent system must be capable of modelling the concepts that are central to multi-agent systems. These concepts are identified in a review of Agent Oriented Software Engineering methodologies. The rigorous development of complex systems using formal methods can reduce the number of design faults. Event-B is a formal method for modelling and reasoning about reactive and distributed systems. There is currently no method that guides the developer specifically in the modelling of agent-based concepts in Event-B. The use of formal methods is seen by some developers as inaccessible. This thesis presents an Incremental Development Process for the development of multi-agent systems in Event-B. Development following the Incremental Development Process begins with the construction of informal models, based on agent concepts. The informal models relate system goals using a set of relationships. The developer is provided with guidance to construct formal Event-B models based on the informal design. The concepts that are central to multi-agent systems are captured in the Event-B models through the translation from the goal models. The Event-B models are refined and decomposed into specifications of roles that will be performed by the agents of the system. Two case studies illustrate how the Incremental Development Process can be applied to multi-agent systems. An additional aid to the developer presented in this thesis is a set of modelling patterns that provide fault-tolerance for Event-B models of interacting agents.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The generation of a lactate-rich environment stimulates cell cycle progression and modulates gene expression on neonatal and hiPSC-derived cardiomyocytes

In situ tissue engineering strategies are a promising approach to activate the endogenous regenerative potential of the cardiac tissue helping the heart to heal itself after an injury. However, the current use of complex reprogramming vectors for the activation of reparative pathways challenges the easy translation of these therapies into the clinic. Here, we evaluated the response of mouse neonatal and human induced pluripotent stem cell-derived cardiomyocytes to the presence of exogenous lactate, thus mimicking the metabolic environment of the fetal heart. An increase in cardiomyocyte cell cycle activity was observed in the presence of lactate, as determined through Ki67 and Aurora-B kinase. Gene expression and RNA-sequencing data revealed that cardiomyocytes incubated with lactate showed upregulation of BMP10, LIN28 or TCIM in tandem with downregulation of GRIK1 or DGKK among others. Lactate also demonstrated a capability to modulate the production of inflammatory cytokines on cardiac fibroblasts, reducing the production of Fas, Fraktalkine or IL-12p40, while stimulating IL-13 and SDF1a. In addition, the generation of a lactate-rich environment improved ex vivo neonatal heart culture, by affecting the contractile activity and sarcomeric structures and inhibiting epicardial cell spreading. Our results also suggested a common link between the effect of lactate and the activation of hypoxia signaling pathways. These findings support a novel use of lactate in cardiac tissue engineering, modulating the metabolic environment of the heart and thus paving the way to the development of lactate-releasing platforms for in situ cardiac regeneration.Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved

Repeatability of radiographic assessments for feline hip dysplasia suggest consensus scores in radiology are more uncertain than commonly assumed

Variation in the diagnostic interpretation of radiographs is a well-recognised problem in human and veterinary medicine. One common solution is to create a 'consensus' score based on a majority or unanimous decision from multiple observers. While consensus approaches are generally assumed to improve diagnostic repeatability, the extent to which consensus scores are themselves repeatable has rarely been examined. Here we use repeated assessments by three radiologists of 196 hip radiographs from 98 cats within a health-screening programme to examine intra-observer, interobserver, majority-consensus and unanimous-consensus repeatability scores for feline hip dysplasia. In line with other studies, intra-observer and inter-observer repeatability was moderate (63-71%), and related to the reference assessment and time taken to reach a decision. Consensus scores did show reduced variation between assessments compared to individuals, but consensus repeatability was far from perfect. Only 75% of majority consensus scores were in agreement between assessments, and based on Bayesian multinomial modelling we estimate that unanimous consensus scores can have repeatabilities as low as 83%. These results clearly show that consensus scores in radiology can have large uncertainties, and that future studies in both human and veterinary medicine need to include consensus-uncertainty estimates if we are to properly interpret radiological diagnoses and the extent to which consensus scores improve diagnostic accuracy

Replicating group-based education interventions for the management of type 2 diabetes: a review of intervention reporting

Aims To assess the completeness of reporting of group-based education interventions for the management of type 2 diabetes. Methods A previous systematic review of group-based education programmes for adults with type 2 diabetes identified eligible intervention studies. Data were extracted and assessed using the Template for Intervention Description and Replication ('TIDieR') checklist. Missing data were sourced from other published material, or by contacting authors. Results Fifty-three publications describing 47 studies were included. No publications sufficiently described all items. Authors of 43 of the 47 included studies (91%) were contacted via e-mail to obtain missing data in order to complete the TIDieR checklist. Seven (16%) did not respond. Additional data were obtained for 33/47 studies (70%). Most studies (45/47, 96%) described the intervention duration and frequency, detailed the procedures and rationale (40/47, 85%), provided a brief intervention name and explained any individual tailoring (38/47, 81%), defined whether providers received training and adequately described how the programme was delivered (37/47, 79%). However, few described any modifications (28/47, 60%), whether the intervention was delivered as planned (27/47, 57%), where it was delivered (21/47, 45%), whether materials were provided (19/47, 40%), and who delivered the intervention (13/47, 28%). Conclusions Group-based education interventions for the management of type 2 diabetes are poorly reported. To translate effective research into practice, practitioners need sufficient detail to implement evidence-based interventions. Researcher adoption of the TIDieR checklist will assist the translation and replication of published interventions

Revealing Charge Carrier Mobility and Defect Densities in Metal Halide Perovskites via Space-Charge-Limited Current Measurements

Space-charge-limited current (SCLC) measurements have been widely used to study the charge carrier mobility and trap density in semiconductors. However, their applicability to metal halide perovskites is not straightforward, due to the mixed ionic and electronic nature of these materials. Here, we discuss the pitfalls of SCLC for perovskite semiconductors, and especially the effect of mobile ions. We show, using drift-diffusion (DD) simulations, that the ions strongly affect the measurement and that the usual analysis and interpretation of SCLC need to be refined. We highlight that the trap density and mobility cannot be directly quantified using classical methods. We discuss the advantages of pulsed SCLC for obtaining reliable data with minimal influence of the ionic motion. We then show that fitting the pulsed SCLC with DD modeling is a reliable method for extracting mobility, trap, and ion densities simultaneously. As a proof of concept, we obtain a trap density of 1.3 × 1013 cm-3, an ion density of 1.1 × 1013 cm-3, and a mobility of 13 cm2 V-1 s-1 for a MAPbBr3 single crystal

VUV photon induced fluorescence study of SF5CF3

The interaction of SF$_5$CF$_3$ with vacuum-UV radiation has been investigated by photon induced fluorescence spectroscopy. Total fluorescence yield and dispersed fluorescence spectra of SF$_5$CF$_3$ were recorded in the 200-1000 nm fluorescence window. In all cases, the fluorescence spectra resemble those of CF$_3$X (X=H, F, Cl, and Br) molecules. At photon energies below 20 eV, the emission is attributed to the excited CF$_3$ and CF$_2$ fragments. The threshold for the CF$_3$ emission is 10.2 ± 0.2 eV, giving an upper-limit estimate for the SF$_5$-CF$_3$ bond dissociation energy of 3.9 ± 0.3 eV. The excitation functions of the CF3 and CF2 emissions were measured in the photon energy range 13.6 – 27.0 eV. The resonant structures observed in SF$_5$CF$_3$ are attributed to electronic transitions from valence to Rydberg orbitals, following similar assignments in CF$_3$X molecules. The photoabsorption spectrum of SF$_5$CF$_3$ shows features at the same energies, indicating a strong contribution from Rydberg excitations

Mercury in Hair Is Inversely Related to Disease Associated Damage in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease, and environmental factors are proposed to exacerbate existing symptoms. One such environmental factor is mercury. The aim of this study was to investigate the relationship between exposure to mercury (Hg) and disease activity and disease associated damage in Total Hg concentrations in hair and urine were measured in 52 SLE patients. Dental amalgams were quantified. Disease activity was assessed using three indexes including the British Isles Lupus Assessment Group Index (BILAG). Disease associated damage was measured using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology SLICC/ACR Damage Index. Pearson’s correlation identified a significant negative correlation between hair Hg and BILAG (r = −0.323, p = 0.029) and SLICC/ACR (r = −0.377, p = 0.038). Multiple regression analysis identified hair Hg as a significant predictor of disease associated damage as determined by SLICC/ACR (β = −0.366, 95% confidence interval (CI): −1.769, −0.155 p = 0.019). Urinary Hg was not related to disease activity or damage. Fish consumption is the primary route of MeHg exposure in humans and the inverse association of hair Hg with disease activity observed here might be explained by the anti-inflammatory effects of n-3 long chain polyunsaturated fatty acids also found in fish

Adjuvant formulated virus-like particles expressing native-like forms of the Lassa virus envelope surface glycoprotein are immunogenic and induce antibodies with broadly neutralizing activity

Lassa mammarenavirus (LASV) is a rodent-borne arenavirus endemic to several West African countries. It is the causative agent of human Lassa fever, an acute viral hemorrhagic fever disease. To date, no therapeutics or vaccines against LASV have obtained regulatory approval. Polyclonal neutralizing antibodies derived from hyperimmunized animals may offer a useful strategy for prophylactic and therapeutic intervention to combat human LASV infections. The LASV envelope surface glycoprotein complex (GP) is the major target for neutralizing antibodies, and it is the main viral antigen used for the design of an LASV vaccine. Here, we assessed the immunogenic potential of mammalian cell-derived virus-like particles (VLPs) expressing GP from the prototypic LASV strain Josiah in a native-like conformation as the sole viral antigen. We demonstrate that an adjuvanted prime-boost immunization regimen with GP-derived VLPs elicited neutralizing antibody responses in rabbits, suggesting that effective antigenic epitopes of GP were displayed. Notably, these antibodies exhibited broad reactivity across five genetic lineages of LASV. VLP-based immunization strategies may represent a powerful approach for generating polyclonal sera containing cross-reactive neutralizing antibodies against LASV