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In 2009, we reported on a new Intelligent Tutoring Systems (ITS) technology, example-tracing tutors, that can be built without programming using the Cognitive Tutor Authoring Tools (CTAT). Creating example-tracing tutors was shown to be 4-8 times as cost-effective as estimates for ITS development from the literature. Since 2009, CTAT and its associated learning management system, the "Tutorshop," have been extended and have been used for both research and real-world instruction. As evidence that example-tracing tutors are an effective and mature ITS paradigm, CTAT-built tutors have been used by approximately 44,000 students and account for 40% of the data sets in "DataShop," a large open repository for educational technology data sets. We review 18 example-tracing tutors built since 2009, which have been shown to be effective in helping students learn in real educational settings, often with large pre/post effect sizes. These tutors support a variety of pedagogical approaches, beyond step-based problem solving, including collaborative learning, educational games, and guided invention activities. CTAT and other ITS authoring tools illustrate that non-programmer approaches to building ITS are viable and useful and will likely play a key role in making ITS widespread.

Vaccines containing mRNA with the capacity to self-amplify represent an alternative to the mRNA vaccines that came to prominence during the COVID-19 pandemic. To gain further insights on the safety profile of self-amplifying mRNA- (SAM-) vaccines, this preclinical toxicology study in rats evaluated the effect of (i) the type of delivery system (lipid nanoparticle [LNP] vs cationic nano-emulsion [CNE]); (ii) antigen-encoding sequence (rabies glycoprotein G vs SARS-CoV-2 Spike); and (iii) RNA amplification. Further analyses also evaluated gene expression in peripheral blood after vaccination, and the biodistribution of vaccine RNA. The SAM vaccines administered as two doses 2-weeks apart had acceptable safety profiles in rats, with respect to clinical signs, blood biochemistry, and macroscopic and microscopic pathology. A transient increase in ALT/AST ratio occurred only in female rats and in the absence of muscle and liver damage was dependent on RNA amplification and appeared related to the greater quantities of vaccine RNA in the muscle and livers of female rats vs male rats. The RNA and delivery-vehicle components, but not the nature of the antigen-coding sequence or the requirement for RNA amplification, affected aspects of the stimulation of innate-immune activity, which was consistent with the transient activation of type I and type II interferon signaling. The delivery vehicle, LNP, differed from CNE as vaccine RNA in CNE compositions appeared independently to stimulate innate-immune activity at 4 hours after vaccination. Our analysis supports further studies to assess whether these differences in innate-immune activity affect safety and efficacy of the SAM vaccine. [ABSTRACT FROM AUTHOR]

Two studies, one animal and one human, were conducted to evaluate the role of soy protein on diabetic nephropathy and blood lipids in type 2 diabetes. The objective of the animal study was to determine the qualitative and quantitative effects of dietary protein on the progression of diabetic nephropathy in a type 2 diabetes animal model (BKS.cg-m +/+ [Lepr.sup.db]). Twenty-four diabetic (db/db) and 24 control (db/m+) mice were given free access to one of four diets (12% or 20% soy protein or 12% or 20% casein) from 35 d old until they were killed (age 184-217 d). Blood and urine were collected throughout the study to measure biomarkers of diabetes and diabetic nephropathy. The results show that diets rich in soy protein prevent an increase in urinary albumin excretion, which is typically seen in male BKS.cg-m +/+ [Lepr.sup.db] diabetic mice. This suggests an improvement in glomerular macromolecular permeability and indicates slower development of diabetic nephropathy. The objective of the human study was to determine whether incorporating soy protein in the diet of type 2 diabetics with diabetic nephropathy would decrease urinary albumin excretion and improve lipid profile. Fourteen patients were studied in a crossover design. The study consisted of a 4-wk lead-in, two 8-wk interventions separated by a 4-wk washout and a final 4-wk washout. Diets were similar to a step I diet but with 1 g protein'kg body [weight.sup.1] * [d.sup.1] during the lead-in and washout periods and with 1.4 g protein .kg body [weight.sup.-1] * [d.sup.-1] during the two interventions. During the 8-wk interventions, 0.5 g protein'kg body [weight.sup.1] * [d.sup.1] was either soy protein or casein. Blood and urine were collected at the beginning of each period to measure biomarkers of diabetes, kidney function and blood lipids. The results indicate that the consumption of soy protein instead of casein leads to a statistically significant reduction in urinary albumin excretion and total-to-HDL cholesterol ratio, whereas HDL cholesterol, plasma arginine and the arginine-to-lysine ratio are significantly increased. (Supported in part by the Illinois Council for Food and Agricultural Research and Protein Technologies International.)

Most microorganisms do not produce sialic acid (sialate), andthose that do appear to use a biosynthetic mechanism distinct frommammals. Genetic hybrids of nonpathogenic, sialate-negative laboratory Escherichia coli K-12 strains designed for the de novo synthesis of the polysialic acid capsulefrom E. coli K1 proved useful in elucidating the geneticsand biochemistry of capsule biosynthesis. In this article we proposea dynamic model of sialometabolism to investigate the effects ofbiosynthetic neu (N-acetylneuraminicacid) and catabolic nan (N-acylneuraminate) mutationson the flux of intermediates through the sialate synthetic pathway.Intracellular sialate concentrations were determined by high pHanion exchange chromatography with pulsed amperometric detection.The results indicated that a strain carrying a null defect in thegene encoding polysialyltransferase (neuS) accumulated > 50times more CMP–sialic acid than the wild type when strainswere grown in a minimal medium supplemented with glucose and casaminoacids. Metabolic accumulation of CMP–sialic acid dependedon a functional sialic acid synthase (neuB), as shownby the inability of a strain lacking this enzyme to accumulate adetectable endogenous sialate pool. The neuB mutantconcentrated trace sialate from the medium, indicating its potentialvalue for quantitative analysis of free sialic acids in complexbiological samples. The function of the sialate aldolase (encodedby nanA) in limiting intermediate flux throughthe synthetic pathway was determined by analyzing free sialate accumulationin neuA (CMP–sialic acid synthetase) nanA double mutants. The combined results demonstratehow E. coli avoids a futile cycle in which biosyntheticsialate induces the system for its own degradation and indicatethe feasibility of generating sialooligosaccharide precursors throughtargeted manipulation of sialate metabolism. [ABSTRACT FROM PUBLISHER]

Coccidioides spp. are saprophytic, dimorphic fungi that are endemic to arid climates, are capable of infecting many species, and result in diverse clinical presentations. An indoor-housed laboratory rhesus macaque presented with weight loss and decreased activity and appetite. During the diagnostic evaluation, a bronchiolar-alveolar pattern in the cranial lung lobes, consistent with bronchopneumonia, was noted on radiographs. Given the poor prognosis, the macaque was euthanized. Confirming the radiographic assessment, gross necropsy findings included multifocal to coalescing areas of consolidation in the right and left cranial lung lobes. Microscopically, the consolidated regions were consistent with a pyogranulomatous bronchopneumonia and contained round, nonbudding, fungal yeast structures considered to be morphologically consistent with Coccidioides immitis. Culture and colony morphology results were confirmed through additional diagnostic testing. Sequencing of the D1-D2 domain of the 28S large ribosomal subunit positively matched with a known sequence specific to C. immitis. Serology for Coccidioides spp. by both latex agglutination (IgM) and immunodiffusion (IgG) was positive. In this rhesus macaque, the concordant results from histology, culture, DNA sequencing, and serology were collectively used to confirm the diagnosis of coccidioidomycosis. This animal likely acquired a latent pulmonary infection with Coccidioides months prior to arrival, when housed outdoors in a Coccidioides-endemic area. The nonspecific clinical presentation in this macaque, coupled with the recent history of indoor housing and lag between clinical presentation and outdoor housing, can make similar diagnostic cases challenging and highlights the need for awareness regarding animal source when making an accurate diagnosis in an institutional laboratory setting.

Unlabelled: Purpose- This study assessed the pharmacological effect of a novel selective C-C chemokine receptor (CCR) 2 antagonist (GSK1344386B) on monocyte/macrophage infiltration into atherosclerotic plaque using magnetic resonance imaging (MRI) in an atherosclerotic mouse model., Methods and Results: Apolipoprotein E(-/-) mice expressing human CCR2 were fed a Western diet (vehicle group) or a Western diet plus10 mg/kg per day of GSK1344386B (GSK1344386B group). After the baseline MRI, mice were implanted with osmotic pumps containing angiotensin II, 1000 ng/kg per minute, to accelerate lesion formation. After five weeks of angiotensin II administration, mice received ultrasmall superparamagnetic iron oxide, an MRI contrast agent for the assessment of monocyte/macrophage infiltration to the plaque, and underwent imaging. After imaging, mice were euthanized, and the heart and aorta were harvested for ex vivo MRI and histopathological examination. After 5 weeks of dietary dosing, there were no significant differences between groups in body or liver weight or plasma cholesterol concentrations. An in vivo MRI reflected a decrease in ultrasmall superparamagnetic iron oxide contrast agent uptake in the aortic arch of the GSK1344386B group (P<0.05). An ex vivo MRI of the aortic root also reflected decreased ultrasmall superparamagnetic iron oxide uptake in the GSK1344386B group and was verified by absolute iron analysis (P<0.05). Although there was no difference in aortic root lesion area between groups, there was a 30% reduction in macrophage area observed in the GSK1344386B group (P<0.05)., Conclusions: An MRI was used to noninvasively assess the decreased macrophage content in the atherosclerotic plaque after selective CCR2 inhibition.