Development and assessment of a geographic knowledge-based model for mapping suitable areas for Rift Valley fever transmission in Eastern Africa

Rift Valley fever (RVF), a mosquito-borne disease affecting ruminants and humans, is one of the most important viral zoonoses in Africa. The objective of the present study was to develop a geographic knowledge-based method to map the areas suitable for RVF amplification and RVF spread in four East African countries, namely, Kenya, Tanzania, Uganda and Ethiopia, and to assess the predictive accuracy of the model using livestock outbreak data from Kenya and Tanzania. Risk factors and their relative importance regarding RVF amplification and spread were identified from a literature review. A numerical weight was calculated for each risk factor using an analytical hierarchy process. The corresponding geographic data were collected, standardized and combined based on a weighted linear combination to produce maps of the suitability for RVF transmission. The accuracy of the resulting maps was assessed using RVF outbreak locations in livestock reported in Kenya and Tanzania between 1998 and 2012 and the ROC curve analysis. Our results confirmed the capacity of the geographic information system-based multi-criteria evaluation method to synthesize available scientific knowledge and to accurately map (AUC = 0.786; 95% CI [0.730–0.842]) the spatial heterogeneity of RVF suitability in East Africa. This approach provides users with a straightforward and easy update of the maps according to data availability or the further development of scientific knowledge. (Résumé d'auteur

Direct molecular mimicry enables off-target cardiovascular toxicity by an enhanced affinity TCR designed for cancer immunotherapy

Natural T-cell responses generally lack the potency to eradicate cancer. Enhanced affinity T-cell receptors (TCRs) provide an ideal approach to target cancer cells, with emerging clinical data showing significant promise. Nevertheless, the risk of off target reactivity remains a key concern, as exemplified in a recent clinical report describing fatal cardiac toxicity, following administration of MAGE-A3 specific TCR-engineered T-cells, mediated through cross-reactivity with an unrelated epitope from the Titin protein presented on cardiac tissue. Here, we investigated the structural mechanism enabling TCR cross-recognition of MAGE-A3 and Titin, and applied the resulting data to rationally design mutants with improved antigen discrimination, providing a proof-of-concept strategy for altering the fine specificity of a TCR towards an intended target antigen. This study represents the first example of direct molecular mimicry leading to clinically relevant fatal toxicity, mediated by a modified enhanced affinity TCR designed for cancer immunotherapy. Furthermore, these data demonstrate that self-antigens that are expressed at high levels on healthy tissue should be treated with extreme caution when designing immuno-therapeutics

The Interaction between Early Life Epilepsy and Autistic-Like Behavioral Consequences: A Role for the Mammalian Target of Rapamycin (mTOR) Pathway

Early life seizures can result in chronic epilepsy, cognitive deficits and behavioral changes such as autism, and conversely epilepsy is common in autistic children. We hypothesized that during early brain development, seizures could alter regulators of synaptic development and underlie the interaction between epilepsy and autism. The mammalian Target of Rapamycin (mTOR) modulates protein translation and is dysregulated in Tuberous Sclerosis Complex, a disorder characterized by epilepsy and autism. We used a rodent model of acute hypoxia-induced neonatal seizures that results in long term increases in neuronal excitability, seizure susceptibility, and spontaneous seizures, to determine how seizures alter mTOR Complex 1 (mTORC1) signaling. We hypothesized that seizures occurring at a developmental stage coinciding with a critical period of synaptogenesis will activate mTORC1, contributing to epileptic networks and autistic-like behavior in later life. Here we show that in the rat, baseline mTORC1 activation peaks during the first three postnatal weeks, and induction of seizures at postnatal day 10 results in further transient activation of its downstream targets phospho-4E-BP1 (Thr37/46), phospho-p70S6K (Thr389) and phospho-S6 (Ser235/236), as well as rapid induction of activity-dependent upstream signaling molecules, including BDNF, phospho-Akt (Thr308) and phospho-ERK (Thr202/Tyr204). Furthermore, treatment with the mTORC1 inhibitor rapamycin immediately before and after seizures reversed early increases in glutamatergic neurotransmission and seizure susceptibility and attenuated later life epilepsy and autistic-like behavior. Together, these findings suggest that in the developing brain the mTORC1 signaling pathway is involved in epileptogenesis and altered social behavior, and that it may be a target for development of novel therapies that eliminate the progressive effects of neonatal seizures

All for One But Not One for All: Excitatory Synaptic Scaling and Intrinsic Excitability are Coregulated by Camkiv, While Inhibitory Synaptic Scaling is Under Independent Control

Despite being comprised of networks with extensive positive feedback, the brain is able to prevent runaway activity. Neural networks are remarkably good at maintaining an activity setpoint while still permitting learning-related or developmental plasticity. To accomplish the delicate balance between change and stability, neural networks employ a group of homeostatic negative feedback mechanisms. This suite of homeostatic mechanisms sense and adjust neuronal excitability to keep firing rates within some target range. To date, the most well described manner in which neurons homeostatically regulate their excitability is through adjustment of excitatory or inhibitory synaptic weights, or by modulating their intrinsic excitability. It is perplexing why the neuron should have several means to accomplish the same outcome. Experiments demonstrating the collaborative or solo induction of homeostatic mechanisms have provided only limited insight into how homeostatic signaling pathways are organized to generate and maintain firing rate set-points (FRSP). In order for neurons to maintain a FRSP, deviations from this value must modulate an internal signal that subsequently triggers homeostatic mechanisms to restore excitability to its set-point. The CaMKIV pathway is a calcium-dependent signaling element that plays a crucial role in regulating excitatory synaptic strength. The CaMKIV cascade is highly sensitive to activity and can modulate transcription, making it an ideal candidate to integrate incoming activity and modulate the excitability of neurons. Therefore, the major aim of this thesis was to characterize the role of CaMKIV in inducing multiple forms of homeostatic plasticity in tandem. Here we leverage our expertise in measuring homeostasis in neocortical neurons in vitro to determine how manipulating the activation state of nuclear CaMKIV affects neuronal excitability. We found that excitatory synaptic scaling and intrinsic plasticity were bidirectionally induced by manipulating CaMKIV activity even without any perturbations to network activity. In contrast, CaMKIV had no impact on inhibitory synaptic weights. Additionally, we found that CaMKIV activity bidirectionally regulated spontaneous firing rates. Taken together, our data suggests that CaMKIV activity is used by the neuron to monitor the firing set point and gate homeostatic mechanisms to correct for drift from this target. The data presented in this thesis contribute that excitatory synaptic scaling and intrinsic excitability are tightly coordinated through bidirectional changes in the same signaling pathway, while inhibitory synaptic scaling is sensed and regulated through an independent signaling mechanism. This body of work contributes to a better understanding of neuronal homeostasis and will hopefully help us determine how malfunctions in homeostatic plasticity contributes to neurological and neurodevelopmental disorders

Effect of platelet inhibitors on thrombus burden in patients with acute pulmonary embolism

Venous thromboembolism (VTE) whether provoked or not can be life-threatening due to an acute increase in load on the right ventricle (RV) from obstruction of the pulmonary artery (PA). Treatment for and prevention of VTE involves anti-thrombotic agents; more specifically, medications targeting the anticoagulation cascade. In spite of the widespread acceptance of anticoagulants in the treatment of VTE, there appears to be an ongoing belief that platelet reactivity contributes to thrombus burden in patients with acute pulmonary embolism (PE). This investigation of 398 patients presenting with acute PE evaluated whether anti-platelet medication use, which consisted mostly of aspirin therapy, at the time of presentation, affects PA thrombus burden, RV load, or short-term patient outcomes. We conclude that platelets may have been erroneously incriminated as direct thrombotic mediators in patients with acute PE since aspirin neither decreased PA thrombus burden, nor did aspirin improve short-term mortality following acute PE