Mechanism of action of VP1-001 in cryAB(R120G)-associated and age-related cataracts

PurposeWe previously identified an oxysterol, VP1-001 (also known as compound 29), that partially restores the transparency of lenses with cataracts. To understand the mechanism of VP1-001, we tested the ability of its enantiomer, ent-VP1-001, to bind and stabilize αB-crystallin (cryAB) in vitro and to produce a similar therapeutic effect in cryAB(R120G) mutant and aged wild-type mice with cataracts. VP1-001 and ent-VP1-001 have identical physicochemical properties. These experiments are designed to critically evaluate whether stereoselective binding to cryAB is required for activity.MethodsWe compared the binding of VP1-001 and ent-VP1-001 to cryAB using in silico docking, differential scanning fluorimetry (DSF), and microscale thermophoresis (MST). Compounds were delivered by six topical administrations to mouse eyes over 2 weeks, and the effects on cataracts and lens refractive measures in vivo were examined. Additionally, lens epithelial and fiber cell morphologies were assessed via transmission electron microscopy.ResultsDocking studies suggested greater binding of VP1-001 into a deep groove in the cryAB dimer compared with ent-VP1-001. Consistent with this prediction, DSF and MST experiments showed that VP1-001 bound cryAB, whereas ent-VP1-001 did not. Accordingly, topical treatment of lenses with ent-VP1-001 had no effect, whereas VP1-001 produced a statistically significant improvement in lens clarity and favorable changes in lens morphology.ConclusionsThe ability of VP1-001 to bind native cryAB dimers is important for its ability to reverse lens opacity in mouse models of cataracts

Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden

Abstract Background It has traditionally been thought that the pathological accumulation of tau in Alzheimer's disease and other tauopathies facilitates neurodegeneration, which in turn leads to cognitive impairment. However, recent evidence suggests that tau tangles are not the entity responsible for memory loss, rather it is an intermediate tau species that disrupts neuronal function. Thus, efforts to discover therapeutics for tauopathies emphasize soluble tau reductions as well as neuroprotection. Results Here, we found that neuroprotection alone caused by methylene blue (MB), the parent compound of the anti-tau phenothiaziazine drug, Rember™, was insufficient to rescue cognition in a mouse model of the human tauopathy, progressive supranuclear palsy (PSP) and fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP17): Only when levels of soluble tau protein were concomitantly reduced by a very high concentration of MB, was cognitive improvement observed. Thus, neurodegeneration can be decoupled from tau accumulation, but phenotypic improvement is only possible when soluble tau levels are also reduced. Conclusions Neuroprotection alone is not sufficient to rescue tau-induced memory loss in a transgenic mouse model. Development of neuroprotective agents is an area of intense investigation in the tauopathy drug discovery field. This may ultimately be an unsuccessful approach if soluble toxic tau intermediates are not also reduced. Thus, MB and related compounds, despite their pleiotropic nature, may be the proverbial "magic bullet" because they not only are neuroprotective, but are also able to facilitate soluble tau clearance. Moreover, this shows that neuroprotection is possible without reducing tau levels. This indicates that there is a definitive molecular link between tau and cell death cascades that can be disrupted.http://deepblue.lib.umich.edu/bitstream/2027.42/78314/1/1750-1326-5-45.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/2/1750-1326-5-45.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/3/1750-1326-5-45-S1.PDFPeer Reviewe

A Pilot Study on the Impact of Creative Achievement on Academic Achievement in Media-Oriented CS1

Abstract We present the results of a pilot study relating creative achievement and academic performance in introductory computer science courses. The experimental CS1 course was based on the Java-based Media Computing approach, with some deviations to emphasize concepts of object-oriented programming. Students' creative achievement was measured quantitatively using the Creative Achievement Questionnaire, a reliable and valid instrument. The study data comprises questionnaire results along with lab scores, exam scores, course grade, GPA, ethnicity, and gender for fifteen students, including four CS majors and eleven non-CS majors. No significant relationship was found between creative achievement and either GPA or course grade, although some more fine-grained relationships were discovered between creative achievement and specific kinds of assignments. A discussion of these relationships is provided, along with implications for practice and recommendations for future work. Introduction Teaching introductory Computer Science courses poses significant challenge. Students in introductory courses often have vastly different experiences and expectations, and hence motivating them to succeed is a difficult course design problem. There has been a great deal of research devoted to increasing student's motivation through engaging projects, with the goal that this will result in corresponding increases in retention, recruitment, and performance. Popular examples include multimedia computing This work is an attempt to discover and quantify the relationships between creativity and success in introductory computer science, and we do so by integrating techniques from creativity research and computer science education research. There are important differences between these two bodies of work, one of the most significant being that educators, by and large, agree that students' academic achievements can be assessed and validated; on the other hand, the quantification of creativity is more hotly contested. We therefore begin by identifying specifically what we mean by "creativity" and its measurement before explaining the context of the study. Creativity and Creative Achievement Creativity research explores many themes, including individual creativity, influences, creative products, and collaborative creativit

Making Community Engaged Games (Fall 2021)

The students in this immersive learning experience were enrolled in CS215: Introduction to Game Design. This course provides a practical introduction to game design using a systems thinking approach, emphasizing the iterative and creative processes used to create engaging games. The first half of the semester was spent exploring fundamental theories of game design, including an introduction to educational game design. The students devoted their second half of the semester to iterative development of an original game based on the core stories of Minnetrista. George Buss, Jr, Vice President of Visitor Experience at Minnetrista, made several visits to the class to talk about Minnetrista's role in the community and give students feedback on their design ideas. Contained in this showcase are near-final drafts of many students' final projects, all of which are print-and-play games. That means you can download the files, print them up, and try the games for yourself! The authors' contact information should be provided in each packet in case you would like to send them feedback on their designs. Note that the students' projects will be finalized after the deadline for submission to this online showcase, and so the versions submitted to Minnetrista may vary slightly from what is available here. The games created by this semester's students will provide the input into next semester's continuation of this immersive project. The Spring team will work with Minnetrista and their faculty mentor to choose the designs most amenable to digital production, and then we will work together to produce an original video game based on these designs

It Seemed Like a Good Idea at the Time (Covid-19 Edition)

Conference presentations usually focus on successful innovations: new ideas that yield significant improvements to current practice. Yet we often learn more from failure than from success. In this panel, we present five case studies of good ideas for improving CS education (most related to the COVID-19 pandemic) that didn\u27t go as planned. Each contributor will describe their good idea , the situation that resulted, and wider lessons for the CS community