Isabelle/PIDE as Platform for Educational Tools

The Isabelle/PIDE platform addresses the question whether proof assistants of the LCF family are suitable as technological basis for educational tools. The traditionally strong logical foundations of systems like HOL, Coq, or Isabelle have so far been counter-balanced by somewhat inaccessible interaction via the TTY (or minor variations like the well-known Proof General / Emacs interface). Thus the fundamental question of math education tools with fully-formal background theories has often been answered negatively due to accidental weaknesses of existing proof engines. The idea of "PIDE" (which means "Prover IDE") is to integrate existing provers like Isabelle into a larger environment, that facilitates access by end-users and other tools. We use Scala to expose the proof engine in ML to the JVM world, where many user-interfaces, editor frameworks, and educational tools already exist. This shall ultimately lead to combined mathematical assistants, where the logical engine is in the background, without obstructing the view on applications of formal methods, formalized mathematics, and math education in particular.Comment: In Proceedings THedu'11, arXiv:1202.453

Optical coherence tomography enables imaging of tumor initiation in the TAg-RB mouse model of retinoblastoma

PURPOSE: Retinoblastoma is the most common primary intraocular malignancy in children. Although significant advances in treatment have decreased mortality in recent years, morbidity continues to be associated with these therapies, and therefore, there is a pressing need for new therapeutic options. Transgenic mouse models are popular for testing new therapeutics as well as studying the pathophysiology of retinoblastoma. The T-antigen retinoblastoma (TAg-RB) model has close molecular and histological resemblance to human retinoblastoma tumors; these mice inactivate pRB by retinal-specific expression of the Simian Virus 40 T-antigens. Here, we evaluated whether optical coherence tomography (OCT) imaging could be used to document tumor growth in the TAg-RB model from the earliest stages of tumor development. METHODS: The Micron III rodent imaging system was used to obtain fundus photographs and OCT images of both eyes of TAg-RB mice weekly from 2 to 12 weeks of age and at 16 and 20 weeks of age to document tumor development. Tumor morphology was confirmed with histological analysis. RESULTS: Before being visible on funduscopy, hyperreflective masses arising in the inner nuclear layer were evident at 2 weeks of age with OCT imaging. After most of these hyperreflective cell clusters disappeared around 4 weeks of age, the first tumors became visible on OCT and funduscopy by 6 weeks. The masses grew into discrete, discoid tumors, preferentially in the periphery, that developed more irregular morphology over time, eventually merging and displacing the inner retinal layers into the vitreous. CONCLUSIONS: OCT is a non-invasive imaging modality for tracking early TAg-RB tumor growth in vivo. Using OCT, we characterized TAg-positive cells as early as 2 weeks, corresponding to the earliest stages at which tumors are histologically evident, and well before they are evident with funduscopy. Tracking tumor growth from its earliest stages will allow better analysis of the efficacy of novel therapeutics and genetic factors tested in this powerful mouse model

StimFit — A Data‐Driven Algorithm for Automated Deep Brain Stimulation Programming

Background: Finding the optimal deep brain stimulation (DBS) parameters from a multitude of possible combinations by trial and error is time consuming and requires highly trained medical personnel. Objective: We developed an automated algorithm to identify optimal stimulation settings in Parkinson's disease (PD) patients treated with subthalamic nucleus (STN) DBS based on imaging-derived metrics. Methods: Electrode locations and monopolar review data of 612 stimulation settings acquired from 31 PD patients were used to train a predictive model for therapeutic and adverse stimulation effects. Model performance was then evaluated within the training cohort using cross-validation and on an independent cohort of 19 patients. We inverted the model by applying a brute-force approach to determine the optimal stimulation sites in the target region. Finally, an optimization algorithm was established to identify optimal stimulation parameters. Suggested stimulation parameters were compared to the ones applied in clinical practice. Results: Predicted motor outcome correlated with observed outcome (R = 0.57, P < 10-10 ) across patients within the training cohort. In the test cohort, the model explained 28% of the variance in motor outcome differences between settings. The stimulation site for maximum motor improvement was located at the dorsolateral border of the STN. When compared to two empirical settings, model-based suggestions more closely matched the setting with superior motor improvement. Conclusion: We developed and validated a data-driven model that can suggest stimulation parameters leading to optimal motor improvement while minimizing the risk of stimulation-induced side effects. This approach might provide guidance for DBS programming in the future

Discrimination between bycatch and other causes of cetacean and pinniped stranding

© The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Diseases of Aquatic Organisms 127 (2018): 83-95, doi:10.3354/dao03189.The challenge of identifying cause of death in discarded bycaught marine mammals stems from a combination of the non-specific nature of the lesions of drowning, the complex physiologic adaptations unique to breath-holding marine mammals, lack of case histories, and the diverse nature of fishing gear. While no pathognomonic lesions are recognized, signs of acute external entanglement, bulging or reddened eyes, recently ingested gastric contents, pulmonary changes, and decompression-associated gas bubbles have been identified in the condition of peracute underwater entrapment (PUE) syndrome in previous studies of marine mammals. We reviewed the gross necropsy and histopathology reports of 36 cetaceans and pinnipeds including 20 directly observed bycaught and 16 live stranded animals that were euthanized between 2005 and 2011 for lesions consistent with PUE. We identified 5 criteria which present at significantly higher rates in bycaught marine mammals: external signs of acute entanglement, red or bulging eyes, recently ingested gastric contents, multi-organ congestion, and disseminated gas bubbles detected grossly during the necropsy and histologically. In contrast, froth in the trachea or primary bronchi, and lung changes (i.e. wet, heavy, froth, edema, congestion, and hemorrhage) were poor indicators of PUE. This is the first study that provides insight into the different published parameters for PUE in bycatch. For regions frequently confronted by stranded marine mammals with non-specific lesions, this could potentially aid in the investigation and quantification of marine fisheries interactions.This work was supported by the Nat - ional Oceanic and Atmospheric Administration (NOAA) John H. Prescott Program NA12NMF4390144. The WHOI Marine Mammal Center, Wick and Sloan Simmons, and the University of Las Palmas de Gran Canaria provided postdoctoral funding for Y.B.Q

An assessment of temporal, spatial and taxonomic trends in harmful algal toxin exposure in stranded marine mammals from the US New England coast

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Fire, S. E., Bogomolni, A., DiGiovanni, R. A., Jr., Early, G., Leighfield, T. A., Matassa, K., Miller, G. A., Moore, K. M. T., Moore, M., Niemeyer, M., Pugliares, K., Wang, Z., & Wenzel, F. W. An assessment of temporal, spatial and taxonomic trends in harmful algal toxin exposure in stranded marine mammals from the US New England coast. Plos One, 16(1),(2021): e0243570, https://doi.org/10.1371/journal.pone.0243570.Despite a long-documented history of severe harmful algal blooms (HABs) in New England coastal waters, corresponding HAB-associated marine mammal mortality events in this region are far less frequent or severe relative to other regions where HABs are common. This long-term survey of the HAB toxins saxitoxin (STX) and domoic acid (DA) demonstrates significant and widespread exposure of these toxins in New England marine mammals, across multiple geographic, temporal and taxonomic groups. Overall, 19% of the 458 animals tested positive for one or more toxins, with 15% and 7% testing positive for STX and DA, respectively. 74% of the 23 different species analyzed demonstrated evidence of toxin exposure. STX was most prevalent in Maine coastal waters, most frequently detected in common dolphins (Delphinus delphis), and most often detected during July and October. DA was most prevalent in animals sampled in offshore locations and in bycaught animals, and most frequently detected in mysticetes, with humpback whales (Megaptera novaeangliae) testing positive at the highest rates. Feces and urine appeared to be the sample matrices most useful for determining the presence of toxins in an exposed animal, with feces samples having the highest concentrations of STX or DA. No relationship was found between the bloom season of toxin-producing phytoplankton and toxin detection rates, however STX was more likely to be present in July and October. No relationship between marine mammal dietary preference and frequency of toxin detection was observed. These findings are an important part of a framework for assessing future marine mammal morbidity and mortality events, as well as monitoring ecosystem health using marine mammals as sentinel organisms for predicting coastal ocean changes.S.F. - NOAA John H. Prescott Marine Mammal Rescue Assistance Grant Program #NA16NMF4390151 S.F. - NOAA John H. Prescott Marine Mammal Rescue Assistance Grant Program #NA17NMF4390082 S.F. - Florida Tech Department of Biological Sciences S.F. - Florida Tech John H. Evans Library Open Access Subvention Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Distinct regulatory effects of myeloid cell and endothelial cell Nox2 on blood pressure

Background -Hypertension due to increased renin angiotensin system (RAS) activation is associated with elevated reactive oxygen species (ROS) production. Previous studies implicate NADPH oxidase (Nox) proteins as important ROS sources during RAS activation, with different Nox isoforms being potentially involved. Among these, Nox2 is expressed in multiple cell types including endothelial cells, fibroblasts, immune cells and microglia. Blood pressure (BP) is regulated at central nervous system, renal and vascular levels but the cell-specific role of Nox2 in BP regulation is unknown. Methods -We generated a novel mouse model with a Floxed Nox2 gene and used Tie2-Cre, LysM Cre or Cdh5-CreERT2 driver lines to develop cell-specific models of Nox2 perturbation to investigate its role in BP regulation. Results -Unexpectedly, Nox2 deletion in myeloid but not endothelial cells resulted in a significant reduction in basal BP. Tie2-CreNox2 knockout (KO) mice (in which Nox2 was deficient in both endothelial cells and myeloid cells) and LysM Cre Nox2KO mice (in which Nox2 was deficient in myeloid cells) both had significantly lower BP than littermate controls whereas basal BP was unaltered in Cdh5-CreERT2 Nox2 KO mice (in which Nox2 is deficient only in endothelial cells). The lower BP was attributable to an increased NO bioavailability which dynamically dilated resistance vessels in vivo under basal conditions, without change in renal function. Myeloid-specific Nox2 deletion had no effect on angiotensin II-induced hypertension which, however, was blunted in Tie2-CreNox2KO mice along with preservation of endothelium-dependent relaxation during angiotensin II stimulation. Conclusions -We identify a hitherto unrecognized modulation of basal BP by myeloid cell Nox2 whereas endothelial cell Nox2 regulates angiotensin II-induced hypertension. These results identify distinct cell-specific roles for Nox2 in BP regulation

The effect of BPIFA1/SPLUNC1 genetic variation on its expression and function in asthmatic airway epithelium

Bacterial permeability family member A1 (BPIFA1), also known as short palate, lung, and nasal epithelium clone 1 (SPLUNC1), is a protein involved in the antiinflammatory response. The goal of this study was to determine whether BPIFA1 expression in asthmatic airways is regulated by genetic variations, altering epithelial responses to type 2 cytokines (e.g., IL-13). Nasal epithelial cells from patients with mild to severe asthma were collected from the National Heart, Lung. and Blood Institute Severe Asthma Research Program centers, genotyped for rs750064, and measured for BPIFA1. To determine the function of rs750064, cells were cultured at air-liquid interface and treated with 11-13 with or without recombinant human BPIFA1 (rhBPIFA1). Noncultured nasal cells with the rs750064 CC genotype had significantly less BPIFA1 mRNA expression than the CT and TT genotypes. Cultured CC versus CT and TT cells without stimulation maintained less BPIFA1 expression. With IL-13 treatment, CC genotype cells secreted more eotaxin-3 than CT and TT genotype cells. Also, rhBPIFA1 reduced IL-13-mediated eotaxin-3. BPIFA1 mRNA levels negatively correlated with serum IgE and fractional exhaled nitric oxide. Baseline FEV1% levels were lower in the asthma patients with the CC genotype (n = 1,016). Our data suggest that less BPIFA1 in asthma patients with the CC allele may predispose them to greater eosinophilic inflammation, which could be attenuated by rhBPIFA1 protein therapy.NIH/NHLBI [R01HL125128, U10HL109257, UL1TR00448, U10HL109168]This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]