Spontaneous dormancy protects Trypanosoma cruzi during extended drug exposure

The ability of the Chagas disease agent Trypanosoma cruzi to resist extended in vivo exposure to highly effective trypanocidal compounds prompted us to explore the potential for dormancy and its contribution to failed drug treatments in this infection. We document the development of non-proliferating intracellular amastigotes in vivo and in vitro in the absence of drug treatment. Non-proliferative amastigotes ultimately converted to trypomastigotes and established infections in new host cells. Most significantly, dormant amastigotes were uniquely resistant to extended drug treatment in vivo and in vitro and could re-establish a flourishing infection after as many as 30 days of drug exposure. These results demonstrate a dormancy state in T. cruzi that accounts for the failure of highly cytotoxic compounds to completely resolve the infection. The ability of T. cruzi to establish dormancy throws into question current methods for identifying curative drugs but also suggests alternative therapeutic approaches.Fil: Sánchez Valdéz, Fernando Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentina. University of Georgia; Estados UnidosFil: Poveda Padilla, Angélica Gabriela. University of Georgia; Estados UnidosFil: Wang, Wei. University of Georgia; Estados UnidosFil: Orr, Dylan. University of Georgia; Estados UnidosFil: Tarleton, Rick L.. University of Georgia; Estados Unido

Coordinated Multi-Robot Shared Autonomy Based on Scheduling and Demonstrations

Shared autonomy methods, where a human operator and a robot arm work together, have enabled robots to complete a range of complex and highly variable tasks. Existing work primarily focuses on one human sharing autonomy with a single robot. By contrast, in this paper we present an approach for multi-robot shared autonomy that enables one operator to provide real-time corrections across two coordinated robots completing the same task in parallel. Sharing autonomy with multiple robots presents fundamental challenges. The human can only correct one robot at a time, and without coordination, the human may be left idle for long periods of time. Accordingly, we develop an approach that aligns the robot's learned motions to best utilize the human's expertise. Our key idea is to leverage Learning from Demonstration (LfD) and time warping to schedule the motions of the robots based on when they may require assistance. Our method uses variability in operator demonstrations to identify the types of corrections an operator might apply during shared autonomy, leverages flexibility in how quickly the task was performed in demonstrations to aid in scheduling, and iteratively estimates the likelihood of when corrections may be needed to ensure that only one robot is completing an action requiring assistance. Through a preliminary simulated study, we show that our method can decrease the overall time spent sanding by iteratively estimating the times when each robot could need assistance and generating an optimized schedule that allows the operator to provide corrections to each robot during these times.Comment: This work has been submitted to the IEEE for possible publication. Copyright may be transferred without notice, after which this version may no longer be accessibl

Discovery of an orally active benzoxaborole prodrug effective in the treatment of Chagas disease in non-human primates

Trypanosoma cruzi, the agent of Chagas disease, probably infects tens of millions of people, primarily in Latin America, causing morbidity and mortality. The options for treatment and prevention of Chagas disease are limited and underutilized. Here we describe the discovery of a series of benzoxaborole compounds with nanomolar activity against extra- and intracellular stages of T. cruzi. Leveraging both ongoing drug discovery efforts in related kinetoplastids, and the exceptional models for rapid drug screening and optimization in T. cruzi, we have identified the prodrug AN15368 that is activated by parasite carboxypeptidases to yield a compound that targets the messenger RNA processing pathway in T. cruzi. AN15368 was found to be active in vitro and in vivo against a range of genetically distinct T. cruzi lineages and was uniformly curative in non-human primates (NHPs) with long-term naturally acquired infections. Treatment in NHPs also revealed no detectable acute toxicity or long-term health or reproductive impact. Thus, AN15368 is an extensively validated and apparently safe, clinically ready candidate with promising potential for prevention and treatment of Chagas disease

Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia.

BACKGROUND: Genetic mutations underlying familial Alzheimer\u27s disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression of mutated transgenes have yielded key insights in mechanisms of disease, those models are subject to artifacts, including random genetic integration of the transgene, ectopic expression and non-physiological protein levels. The genetic engineering of novel mouse models using knock-in approaches addresses some of those limitations. With mounting evidence of the role played by microglia in AD, high-dimensional approaches to phenotype microglia in those models are critical to refine our understanding of the immune response in the brain. METHODS: We engineered a novel App knock-in mouse model (App RESULTS: Leveraging multi-omics approaches, we discovered profound alteration of diverse lipids and metabolites as well as an exacerbated disease-associated transcriptomic response in microglia with high intracellular Aβ content. The App DISCUSSION: Our findings demonstrate that fibrillar Aβ in microglia is associated with lipid dyshomeostasis consistent with lysosomal dysfunction and foam cell phenotypes as well as profound immuno-metabolic perturbations, opening new avenues to further investigate metabolic pathways at play in microglia responding to AD-relevant pathogenesis. The in-depth characterization of pathological hallmarks of AD in this novel and open-access mouse model should serve as a resource for the scientific community to investigate disease-relevant biology

Learning Progression: Implications for Curriculum and Assessment

This short brief is targeted to policy makers in governments and school districts who may be thinking about learning progressions and the implications for curriculum, teaching, and assessment