36 results on '"Tyler A. Johnson"'
Search Results
2. In Vivo Evaluation of (−)-Zampanolide Demonstrates Potent and Persistent Antitumor Efficacy When Targeted to the Tumor Site
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Leila Takahashi-Ruiz, Joseph D. Morris, Phillip Crews, Tyler A. Johnson, and April L. Risinger
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triple-negative breast cancer ,microtubule stabilizers ,zampanolide ,paclitaxel ,covalent ,Organic chemistry ,QD241-441 - Abstract
Microtubule-stabilizing agents (MSAs) are a class of compounds used in the treatment of triple-negative breast cancer (TNBC), a subtype of breast cancer where chemotherapy remains the standard-of-care for patients. Taxanes like paclitaxel and docetaxel have demonstrated efficacy against TNBC in the clinic, however new classes of MSAs need to be identified due to the rise of taxane resistance in patients. (−)-Zampanolide is a covalent microtubule stabilizer that can circumvent taxane resistance in vitro but has not been evaluated for in vivo antitumor efficacy. Here, we determine that (−)-zampanolide has similar potency and efficacy to paclitaxel in TNBC cell lines, but is significantly more persistent due to its covalent binding. We also provide the first reported in vivo antitumor evaluation of (−)-zampanolide where we determine that it has potent and persistent antitumor efficacy when delivered intratumorally. Future work on zampanolide to further evaluate its pharmacophore and determine ways to improve its systemic therapeutic window would make this compound a potential candidate for clinical development through its ability to circumvent taxane-resistance mechanisms.
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- 2022
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3. Case report: use of pleural dialysis as an alternate means of renal replacement therapy in three cats
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Mara E. Vernier, Meghan E. Fick, Tyler E. Johnson, Yu Ueda, and Alessio Vigani
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dialysis ,pleural ,kidney ,feline ,azotemia ,Veterinary medicine ,SF600-1100 - Abstract
ObjectiveThe objective of this case series is to describe the indications, methodology, and short-term outcomes of three cats with severe azotemia managed with pleural dialysis.Case summaryThree cats were presented separately to the emergency room (ER) on referral for severe azotemia of varying etiologies. Despite aggressive medical and/or surgical management, none of the cats showed improvement in their blood urea nitrogen (BUN) or creatinine values. Renal replacement therapy was recommended, but for varying reasons, the patients were unable to undergo a traditional extracorporeal method, such as intermittent hemodialysis (IDH). Instead, pleural dialysis was performed, and all three cats showed improvement in their renal values during and after their treatment. No significant complications were documented as a result of pleural dialysis. Two of the three cats were discharged from the hospital and the third cat was humanely euthanized due to poor prognosis.New or unique information providedPleural dialysis is a novel therapeutic procedure that is not documented in veterinary or human literature. This method of renal replacement therapy was well-tolerated and had no reported complications. Careful case selection and risk-benefit analysis should be considered before attempting this procedure. Further studies are necessary to further define the utility of this therapeutic intervention, evaluate the incidence of complications, and determine long term outcomes following the procedure.
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- 2024
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4. Beyond Abandonment: Diachronically Mapping the Transformation of Domestic Sites in Rome and its Environs (1st-7th centuries CE)
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Tyler Duane Johnson
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archaeology ,abandonment ,reuse ,household archaeology ,late antiquity ,medieval ,rome ,unity ,game engines ,Archaeology ,CC1-960 - Abstract
This article presents some preliminary findings on the transformation and abandonment of domestic sites in and around Rome from the 1st to 7th centuries Common Era (CE). I utilize an innovative interactive map developed in Unity to showcase 46 sites in the study area, devising a methodology that draws upon the stratigraphic record of human activities in charting the trajectory of ancient houses over time. This contrasts with the standard approaches used over the last few decades, which have focused almost entirely on key moments of architectural and decorative remodelling, underemphasizing the constant and diachronic nature of change in domestic environments. My findings highlight the need to reassess conventional narratives surrounding the "end of the Roman house". Based on the data in this study, the Roman house emerges as more variable and less programmatic than often acknowledged, including in periods predating Late Antiquity. Future work is planned for presenting the full results of the research introduced in this paper, including those related to the application of game engines for mapping archaeological data from household excavations.
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- 2024
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5. NF1+/ex42del miniswine model the cellular disruptions and behavioral presentations of NF1‐associated cognitive and motor impairment
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Vicki J. Swier, Katherine A. White, Pedro L. Negrão de Assis, Tyler B. Johnson, Hannah G. Leppert, Mitchell J. Rechtzigel, David K. Meyerholz, Rebecca D. Dodd, Dawn E. Quelle, Rajesh Khanna, Christopher S. Rogers, and Jill M. Weimer
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Therapeutics. Pharmacology ,RM1-950 ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract Cognitive or motor impairment is common among individuals with neurofibromatosis type 1 (NF1), an autosomal dominant tumor‐predisposition disorder. As many as 70% of children with NF1 report difficulties with spatial/working memory, attention, executive function, and fine motor movements. In contrast to the utilization of various Nf1 mouse models, here we employ an NF1+/ex42del miniswine model to evaluate the mechanisms and characteristics of these presentations, taking advantage of a large animal species more like human anatomy and physiology. The prefrontal lobe, anterior cingulate, and hippocampus from NF1+/ex42del and wild‐type miniswine were examined longitudinally, revealing abnormalities in mature oligodendrocytes and astrocytes, and microglial activation over time. Imbalances in GABA: Glutamate ratios and GAD67 expression were observed in the hippocampus and motor cortex, supporting the role of disruption in inhibitory neurotransmission in NF1 cognitive impairment and motor dysfunction. Moreover, NF1+/ex42del miniswine demonstrated slower and shorter steps, indicative of a balance‐preserving response commonly observed in NF1 patients, and progressive memory and learning impairments. Collectively, our findings affirm the effectiveness of NF1+/ex42del miniswine as a valuable resource for assessing cognitive and motor impairments associated with NF1, investigating the involvement of specific neural circuits and glia in these processes, and evaluating potential therapeutic interventions.
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- 2024
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6. Web-Based Scaffolds: The Feasibility of a Constructivist Approach to Oncology Fellow Learning
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Sam Brondfield, Matthew Schwede, Tyler P Johnson, and Shagun Arora
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
In this 2-institution feasibility pilot, oncology fellows used and updated freely available web-based learning tools (scaffolds) in a constructivist fashion.
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- 2024
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7. Clodronate disodium does not produce measurable effects on bone metabolism in an exercising, juvenile, large animal model.
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Fernando B Vergara-Hernandez, Brian D Nielsen, John M Popovich, Char L Panek, Alyssa A Logan, Cara I Robison, Richard A Ehrhardt, Tyler N Johnson, Nicholas J Chargo, Thomas H Welsh, Amanda N Bradbery, Jessica L Leatherwood, and Aimee C Colbath
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Medicine ,Science - Abstract
Bisphosphonates are commonly used to treat and prevent bone loss, but their effects in active, juvenile populations are unknown. This study examined the effects of intramuscular clodronate disodium (CLO) on bone turnover, serum bone biomarkers (SBB), bone mineral density (BMD), bone microstructure, biomechanical testing (BT), and cartilage glycosaminoglycan content (GAG) over 165 days. Forty juvenile sheep (253 ± 6 days of age) were divided into four groups: Control (saline), T0 (0.6 mg/kg CLO on day 0), T84 (0.6 mg/kg CLO on day 84), and T0+84 (0.6 mg/kg CLO on days 0 and 84). Sheep were exercised 4 days/week and underwent physical and lameness examinations every 14 days. Blood samples were collected for SBB every 28 days. Microstructure and BMD were calculated from tuber coxae (TC) biopsies (days 84 and 165) and bone healing was assessed by examining the prior biopsy site. BT and GAG were evaluated postmortem. Data, except lameness data, were analyzed using a mixed-effects model; lameness data were analyzed as ordinal data using a cumulative logistic model. CLO did not have any measurable effects on the skeleton of sheep. SBB showed changes over time (p ≤ 0.03), with increases in bone formation and decreases in some bone resorption markers. TC biopsies showed increasing bone volume fraction, trabecular spacing and thickness, and reduced trabecular number on day 165 versus day 84 (p ≤ 0.04). These changes may be attributed to exercise or growth. The absence of a treatment effect may be explained by the lower CLO dose used in large animals compared to humans. Further research is needed to examine whether low doses of bisphosphonates may be used in active juvenile populations for analgesia without evidence of bone changes.
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- 2024
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8. An Analysis of Financial Aid Offers and Parent PLUS Loan Borrowing from 2015-2019 at Missouri, Public Four-Year Universities
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Tyler L. Johnson
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The Parent PLUS loan covers the financial gap of a student's educational expenses after other forms of financial assistance. Depending on the unmet need, the PLUS loan amount borrowed can be tens of thousands of dollars for a single academic year. In this research article, I provide results from evaluating financial aid offers at Missouri public, four-year higher education institutions and present findings from two focus group sessions of financial aid directors. I find practically significant differences in the average amount of Parent PLUS borrowing at institutions that include the PLUS loan in their financial aid offer versus institutions that do not. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]
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- 2022
9. A novel porcine model of CLN3 Batten disease recapitulates clinical phenotypes
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Vicki J. Swier, Katherine A. White, Tyler B. Johnson, Xiaojun Wang, Jimin Han, David A. Pearce, Ruchira Singh, Arlene V. Drack, Wanda Pfeifer, Christopher S. Rogers, Jon J. Brudvig, and Jill M. Weimer
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neuronal ceroid lipofuscinosis ,jncl ,animal disease models ,neuropediatric disease ,Medicine ,Pathology ,RB1-214 - Published
- 2023
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10. Sex-split analysis of pathology and motor-behavioral outcomes in a mouse model of CLN8-Batten disease reveals an increased disease burden and trajectory in female Cln8 mnd mice
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Andrew D. Holmes, Katherine A. White, Melissa A. Pratt, Tyler B. Johnson, Shibi Likhite, Kathrin Meyer, and Jill M. Weimer
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CLN8 ,Batten disease ,Sex differences ,Lysosomal storage disorders ,Disease progression ,AAV9 gene therapy ,Medicine - Abstract
Abstract Background CLN8-Batten disease (CLN8 disease) is a rare neurodegenerative disorder characterized phenotypically by progressive deterioration of motor and cognitive abilities, visual symptoms, epileptic seizures, and premature death. Mutations in CLN8 results in characteristic Batten disease symptoms and brain-wide pathology including accumulation of lysosomal storage material, gliosis, and neurodegeneration. Recent investigations of other subforms of Batten disease (CLN1, CLN3, CLN6) have emphasized the influence of biological sex on disease and treatment outcomes; however, little is known about sex differences in the CLN8 subtype. To determine the impact of sex on CLN8 disease burden and progression, we utilized a Cln8 mnd mouse model to measure the impact and progression of histopathological and behavioral outcomes between sexes. Results Several notable sex differences were observed in the presentation of brain pathology, including Cln8 mnd female mice consistently presenting with greater GFAP+ astrocytosis and CD68+ microgliosis in the somatosensory cortex, ventral posteromedial/ventral posterolateral nuclei of the thalamus, striatum, and hippocampus when compared to Cln8 mnd male mice. Furthermore, sex differences in motor-behavioral assessments revealed Cln8 mnd female mice experience poorer motor performance and earlier death than their male counterparts. Cln8 mnd mice treated with an AAV9-mediated gene therapy were also examined to assess sex differences on therapeutics outcomes, which revealed no appreciable differences between the sexes when responding to the therapy. Conclusions Taken together, our results provide further evidence of biologic sex as a modifier of Batten disease progression and outcome, thus warranting consideration when conducting investigations and monitoring therapeutic impact.
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- 2022
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11. Early postnatal administration of an AAV9 gene therapy is safe and efficacious in CLN3 disease
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Tyler B. Johnson, Jon J. Brudvig, Shibi Likhite, Melissa A. Pratt, Katherine A. White, Jacob T. Cain, Clarissa D. Booth, Derek J. Timm, Samantha S. Davis, Brandon Meyerink, Ricardo Pineda, Cassandra Dennys-Rivers, Brian K. Kaspar, Kathrin Meyer, and Jill M. Weimer
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neuronal ceroid lipofuscinosis ,neurodegenerative disease ,gene therapy ,adeno-associated virus ,rare disease ,Genetics ,QH426-470 - Abstract
CLN3 disease, caused by biallelic mutations in the CLN3 gene, is a rare pediatric neurodegenerative disease that has no cure or disease modifying treatment. The development of effective treatments has been hindered by a lack of etiological knowledge, but gene replacement has emerged as a promising therapeutic platform for such disorders. Here, we utilize a mouse model of CLN3 disease to test the safety and efficacy of a cerebrospinal fluid-delivered AAV9 gene therapy with a study design optimized for translatability. In this model, postnatal day one administration of the gene therapy virus resulted in robust expression of human CLN3 throughout the CNS over the 24-month duration of the study. A range of histopathological and behavioral parameters were assayed, with the therapy consistently and persistently rescuing a number of hallmarks of disease while being safe and well-tolerated. Together, the results show great promise for translation of the therapy into the clinic, prompting the launch of a first-in-human clinical trial (NCT03770572).
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- 2023
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12. Source terms for benchmarking models of SARS-CoV-2 transmission via aerosols and droplets
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Marc E. J. Stettler, Robert T. Nishida, Pedro M. de Oliveira, Léo C. C. Mesquita, Tyler J. Johnson, Edwin R. Galea, Angus Grandison, John Ewer, David Carruthers, David Sykes, Prashant Kumar, Eldad Avital, Asiri I. B. Obeysekara, Denis Doorly, Yannis Hardalupas, David C. Green, Simon Coldrick, Simon Parker, and Adam M. Boies
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source terms ,SARS-CoV-2 ,model benchmarking ,exhaled aerosols ,disease transmission ,Science - Abstract
There is ongoing and rapid advancement in approaches to modelling the fate of exhaled particles in different environments relevant to disease transmission. It is important that models are verified by comparison with each other using a common set of input parameters to ensure that model differences can be interpreted in terms of model physics rather than unspecified differences in model input parameters. In this paper, we define parameters necessary for such benchmarking of models of airborne particles exhaled by humans and transported in the environment during breathing and speaking.
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- 2022
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13. The Meritocracy Trap and Kinesiology
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Gregg Twietmeyer and Tyler G. Johnson
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Public Health, Environmental and Occupational Health ,Physical Therapy, Sports Therapy and Rehabilitation - Abstract
Meritocracy continues to dominate conventional thinking in the postmodern West. Yet, recently, an increasing number of critics have highlighted how meritocracy has gone wrong. One such critic is Daniel Markovits, author of The Meritocracy Trap. In this article, we highlight the major themes of Markovits’s book, identify how the ideology of meritocracy has infiltrated kinesiology and sport, and then propose how to reconceptualize and redirect kinesiology toward a more humane and morally sound discipline, which can avoid the pitfalls of the meritocracy trap. Most notably, we propose that kinesiology should (a) recognize the frailty and temporality of humans, (b) embrace the wide middle of human skill performance capabilities, (c) value mid-level jobs and occupations such as physical education teaching and YMCA and/or city recreation department positions, and (d) redefine what counts as success.
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- 2023
14. Quality of Groundwater Used for Public Supply in the Continental United States: A Comprehensive Assessment
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Kenneth Belitz, Miranda S. Fram, Bruce D. Lindsey, Paul E. Stackelberg, Laura M. Bexfield, Tyler D. Johnson, Bryant C. Jurgens, James A. Kingsbury, Peter B. McMahon, and Neil M. Dubrovsky
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Chemistry (miscellaneous) ,Environmental Chemistry ,Chemical Engineering (miscellaneous) ,Water Science and Technology - Published
- 2022
15. Perfluoroalkyl and Polyfluoroalkyl Substances in Groundwater Used as a Source of Drinking Water in the Eastern United States
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Peter B. McMahon, Andrea K. Tokranov, Laura M. Bexfield, Bruce D. Lindsey, Tyler D. Johnson, Melissa A. Lombard, and Elise Watson
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Fluorocarbons ,Drinking Water ,Environmental Chemistry ,General Chemistry ,Groundwater ,United States ,Water Pollutants, Chemical ,Environmental Monitoring - Abstract
In 2019, 254 samples were collected from five aquifer systems to evaluate perfluoroalkyl and polyfluoroalkyl substance (PFAS) occurrence in groundwater used as a source of drinking water in the eastern United States. The samples were analyzed for 24 PFAS, major ions, nutrients, trace elements, dissolved organic carbon (DOC), volatile organic compounds (VOCs), pharmaceuticals, and tritium. Fourteen of the 24 PFAS were detected in groundwater, with 60 and 20% of public-supply and domestic wells, respectively, containing at least one PFAS detection. Concentrations of tritium, chloride, sulfate, DOC, and manganese + iron; percent urban land use within 500 m of the wells; and VOC and pharmaceutical detection frequencies were significantly higher in samples containing PFAS detections than in samples with no detections. Boosted regression tree models that consider 57 chemical and land-use variables show that tritium concentration, distance to the nearest fire-training area, percentage of urban land use, and DOC and VOC concentrations are the top five predictors of PFAS detections, consistent with the hydrologic position, geochemistry, and land use being important controls on PFAS occurrence in groundwater. Model results indicate that it may be possible to predict PFAS detections in groundwater using existing data sources.
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- 2022
16. 'Does Anyone Even Care That I’m Down Here?': Creating Shared Values in a District-Wide Physical Education Professional Learning Community
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Julianne A. Wenner, Tyler G. Johnson, Lindsey Turner, Hannah G. Calvert, Kimberly Tucker, and Sara Hagenah
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05 social sciences ,050301 education ,Physical Therapy, Sports Therapy and Rehabilitation ,030229 sport sciences ,Creating shared value ,Education ,Physical education ,03 medical and health sciences ,0302 clinical medicine ,Professional learning community ,Pedagogy ,Orthopedics and Sports Medicine ,Psychology ,0503 education - Abstract
Purpose: Physical education teachers often report feeling isolated due to being the only specialist in a building. Professional learning communities (PLCs) are spaces where individuals who hold shared goals come together to build connections, allowing educators to feel connected, valued, and empowered. The authors sought to explore the shared values created by a PLC and the process through which that value emerged. Method: The authors facilitated a PLC for eight physical education teachers within one midsized school district and collected interview and meeting audio data to explore the process and outcomes of the PLC. Results: Coding using a Value Creation Framework revealed themes of building common ground, support for big and small problems of practice, and an increased connection with other school faculty. Discussion: Teachers were able to build a supportive network where ideas could be traded, partner support was provided, and problems of practice were discussed.
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- 2022
17. Role of substrate clamping on anisotropy and domain structure in the canted antiferromagnet α−Fe2O3
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Angela Wittmann, Olena Gomonay, Kai Litzius, Allison Kaczmarek, Alexander E. Kossak, Daniel Wolf, Axel Lubk, Tyler N. Johnson, Elizaveta A. Tremsina, Alexandra Churikova, Felix Büttner, Sebastian Wintz, Mohamad-Assaad Mawass, Markus Weigand, Florian Kronast, Larry Scipioni, Adam Shepard, Ty Newhouse-Illige, James A. Greer, Gisela Schütz, Norman O. Birge, and Geoffrey S. D. Beach
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- 2022
18. Endoscopic Skull Base Surgery
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Tyler J. Johnson, David E. Traul, and Thomas N. Pajewski
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- 2022
19. Reimagining urban success: rhythms of activity at Gabii, 800 BC–AD 600
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Laura M. Banducci, Mattia D’Acri, Eddie Stewart, Victoria Moses, Matthew Naglak, Rachel Opitz, Alison Rittershaus, J. Troy Samuels, Laura C. Motta, Sheira Cohen, and Tyler D. Johnson
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Archeology ,History ,General Arts and Humanities - Abstract
The ancient city of Gabii—an Italian polity of the first millennium BC and a peer to early Rome—has often been presented as an example of urban decline, a counterpoint to Rome's rise from a collection of hilltop huts to a Mediterranean hegemon. Here the authors draw on the results from recent excavations at Gabii that challenge such simplistic models of urban history. Diachronic evidence documenting activity at the site over the course of 1400 years highlights shifting values and rhythms materialised in the maintenance, transformation and abandonment of different urban components. This complex picture of adaptation and resilience provides a model of ancient urbanism that calls into question outdated narratives of urban success and failure.
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- 2021
20. A novel porcine model of CLN3 Batten disease recapitulates clinical phenotypes
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Vicki J. Swier, Katherine A. White, Tyler B. Johnson, Xiaojun Wang, Jimin Han, David A. Pearce, Ruchira Singh, Christopher S. Rogers, Jon J. Brudvig, and Jill M. Weimer
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Mouse models of CLN3 Batten disease, a rare lysosomal storage disorder with no cure, have improved our understanding of CLN3 biology and therapeutics through their ease of use and a consistent display of cellular pathology. However, the translatability of murine models is limited by disparities in anatomy, body size, life span, and inconsistent, subtle behavior deficits that can be difficult to detect in CLN3 mutant mouse models, limiting their utility in preclinical studies. Here we present a longitudinal characterization of a novel miniswine model of CLN3 disease that recapitulates the most common human pathogenic variant, an exon 7-8 deletion (CLN3Δex7/8). Progressive pathology and neuron loss is observed in various regions of the CLN3Δex7/8 miniswine brain and retina. Additionally, mutant miniswine present with vision impairment and motor abnormalities, similar to deficits seen in human patients. Taken together, the CLN3Δex7/8 miniswine model shows consistent and progressive Batten disease pathology and behavioral impairment mirroring clinical presentation, demonstrating its value in studying the role of CLN3 and safety/efficacy of novel disease modifying therapeutics.
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- 2022
21. A Novel Porcine Model of CLN2 Batten Disease that Recapitulates Patient Phenotypes
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Vicki J. Swier, Katherine A. White, Tyler B. Johnson, Jessica C. Sieren, Hans J. Johnson, Kevin Knoernschild, Xiaojun Wang, Frank A. Rohret, Christopher S. Rogers, David A. Pearce, Jon J. Brudvig, and Jill M. Weimer
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Pharmacology ,Mice ,Phenotype ,Swine ,Neuronal Ceroid-Lipofuscinoses ,Seizures ,Animals ,Pharmacology (medical) ,Neurology (clinical) ,Serine Proteases ,Dipeptidyl-Peptidases and Tripeptidyl-Peptidases ,Aminopeptidases - Abstract
CLN2 Batten disease is a lysosomal disorder in which pathogenic variants in CLN2 lead to reduced activity in the enzyme tripeptidyl peptidase 1. The disease typically manifests around 2 to 4 years of age with developmental delay, ataxia, seizures, inability to speak and walk, and fatality between 6 and 12 years of age. Multiple Cln2 mouse models exist to better understand the etiology of the disease; however, these models are unable to adequately recapitulate the disease due to differences in anatomy and physiology, limiting their utility for therapeutic testing. Here, we describe a new CLN2
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- 2022
22. In Vivo Evaluation of (-)-Zampanolide Demonstrates Potent and Persistent Antitumor Efficacy When Targeted to the Tumor Site
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Leila Takahashi-Ruiz, Joseph D. Morris, Phillip Crews, Tyler A. Johnson, and April L. Risinger
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Paclitaxel ,Organic Chemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Triple Negative Breast Neoplasms ,Microtubules ,Analytical Chemistry ,Chemistry (miscellaneous) ,Cell Line, Tumor ,Drug Discovery ,Molecular Medicine ,Humans ,triple-negative breast cancer ,microtubule stabilizers ,zampanolide ,paclitaxel ,covalent ,Macrolides ,Physical and Theoretical Chemistry - Abstract
Microtubule-stabilizing agents (MSAs) are a class of compounds used in the treatment of triple-negative breast cancer (TNBC), a subtype of breast cancer where chemotherapy remains the standard-of-care for patients. Taxanes like paclitaxel and docetaxel have demonstrated efficacy against TNBC in the clinic, however new classes of MSAs need to be identified due to the rise of taxane resistance in patients. (−)-Zampanolide is a covalent microtubule stabilizer that can circumvent taxane resistance in vitro but has not been evaluated for in vivo antitumor efficacy. Here, we determine that (−)-zampanolide has similar potency and efficacy to paclitaxel in TNBC cell lines, but is significantly more persistent due to its covalent binding. We also provide the first reported in vivo antitumor evaluation of (−)-zampanolide where we determine that it has potent and persistent antitumor efficacy when delivered intratumorally. Future work on zampanolide to further evaluate its pharmacophore and determine ways to improve its systemic therapeutic window would make this compound a potential candidate for clinical development through its ability to circumvent taxane-resistance mechanisms.
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- 2022
23. Decreasing Insulin Resistance Reduces Early Progressive Proteinuria by Decreasing Renal Hyperfiltration and Inflammation in Obese Dahl Salt‐Sensitive Rats
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Ubong S. Ekperikpe, Andrea K. Brown, Tyler D. Johnson, Denise C. Cornelius, and Jan M. Williams
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Genetics ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2022
24. Transmembrane peptide effects on bacterial membrane integrity and organization
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Chloe J Mitchell, Tyler S. Johnson, and Charles M. Deber
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Bacteria ,Circular Dichroism ,Cell Membrane ,Biophysics ,Peptides ,Hydrophobic and Hydrophilic Interactions ,Anti-Bacterial Agents - Abstract
As the bacterial multidrug resistance crisis continues, membrane-active antimicrobial peptides are being explored as an alternate treatment to conventional antibiotics. In contrast to antimicrobial peptides, which function by a nonspecific membrane disruption mechanism, here we describe a series of transmembrane (TM) peptides that are designed to act as drug efflux inhibitors by aligning with and out-competing a conserved TM4-TM4 homodimerization motif within bacterial small multidrug resistance proteins. The peptides contain two terminal tags: a C-terminal lysine tag to direct the peptides toward the negatively charged bacterial membrane, and an uncharged N-terminal sarcosine (N-methyl-glycine) tag to promote membrane insertion. While effective at inhibiting efflux activity, ostensibly through their designed mechanism of action, the impact of the peptides on the bacterial inner membrane remains undetermined. To evaluate the extant peptide-membrane interactions, we performed a series of biophysical measurements. Circular dichroism spectroscopy and Trp fluorescence showed that the peptides insert into the membrane generally in helical form. Interestingly, differential scanning calorimetry of the peptides added to bacterial-like membranes (POPE:POPG 3:1) revealed the peptides' ability to demix the POPE and POPG lipids, creating two pools, one of which is likely a peptide-POPG conglomerate, and the other a POPE-rich component where the native POPG content has been depleted. However, dye leakage assays confirmed that these events occur without causing significant membrane disruption both in vitro and in vivo, indicating that the peptides can target the small multidrug resistance TM4-TM4 motif without nonspecific membrane disruption. In related studies, DiOC
- Published
- 2022
25. Viral load of SARS-CoV-2 in droplets and bioaerosols directly captured during breathing, speaking and coughing
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Tyler J. Johnson, Robert T. Nishida, Ashlesha P. Sonpar, Yi-Chan James Lin, Kimberley A. Watson, Stephanie W. Smith, John M. Conly, David H. Evans, Jason S. Olfert, Sonpar, Ashlesha P [0000-0003-1676-1384], and Apollo - University of Cambridge Repository
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Aerosols ,Multidisciplinary ,Cough ,SARS-CoV-2 ,viruses ,Respiration ,Humans ,Speech ,Viral Load - Abstract
Determining the viral load and infectivity of SARS-CoV-2 in macroscopic respiratory droplets, bioaerosols, and other bodily fluids and secretions is important for identifying transmission modes, assessing risks and informing public health guidelines. Here we show that viral load of SARS-CoV-2 Ribonucleic Acid (RNA) in participants’ naso-pharyngeal (NP) swabs positively correlated with RNA viral load they emitted in both droplets >10 $$\upmu \hbox {m}$$ μ m and bioaerosols $$\upmu \hbox {m}$$ μ m directly captured during the combined expiratory activities of breathing, speaking and coughing using a standardized protocol, although the NP swabs had $$\approx$$ ≈ 10$$^3\times$$ 3 × more RNA on average. By identifying highly-infectious individuals (maximum of 18,000 PFU/mL in NP), we retrieved higher numbers of SARS-CoV-2 RNA gene copies in bioaerosol samples (maximum of 4.8$${\times }10^{5}$$ × 10 5 gene copies/mL and minimum cycle threshold of 26.2) relative to other studies. However, all attempts to identify infectious virus in size-segregated droplets and bioaerosols were negative by plaque assay (0 of 58). This outcome is partly attributed to the insufficient amount of viral material in each sample (as indicated by SARS-CoV-2 gene copies) or may indicate no infectious virus was present in such samples, although other possible factors are identified.
- Published
- 2022
26. Molecular-Level Control over Ionic Conduction and Ionic Current Direction by Designing Macrocycle-Based Ionomers
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Shyambo Chatterjee, Ehsan Zamani, Seefat Farzin, Iman Evazzade, Oghenetega Allen Obewhere, Tyler James Johnson, Vitaly Alexandrov, and Shudipto Konika Dishari
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Poor ionic conductivity of the catalyst-binding, sub-micrometer-thick ionomer layers in energy conversion and storage devices is a huge challenge. However, ionomers are rarely designed keeping in mind the specific issues associated with nanoconfinement. Here, we designed nature-inspired ionomers (calix-2) having hollow, macrocyclic, calix[4]arene-based repeat units with precise, sub-nanometer diameter. In ≤100 nm-thick films, the in-plane proton conductivity of calix-2 was up to 8 times higher than the current benchmark ionomer Nafion at 85% relative humidity (RH), while it was 1-2 orders of magnitude higher than Nafion at 20-25% RH. Confocal laser scanning microscopy and other synthetic techniques allowed us to demonstrate the role of macrocyclic cavities in boosting the proton conductivity. The systematic self-assembly of calix-2 chains into ellipsoids in thin films was evidenced from atomic force microscopy and grazing incidence small-angle X-ray scattering measurements. Moreover, the likelihood of alignment and stacking of macrocyclic units, the presence of one-dimensional water wires across this macrocycle stacks, and thus the formation of long-range proton conduction pathways were suggested by atomistic simulations. We not only did see an unprecedented improvement in thin-film proton conductivity but also saw an improvement in proton conductivity of bulk membranes when calix-2 was added to the Nafion matrices. Nafion-calix-2 composite membranes also took advantage of the asymmetric charge distribution across calix[4]arene repeat units collectively and exhibited voltage-gating behavior. The inclusion of molecular macrocyclic cavities into the ionomer chemical structure can thus emerge as a promising design concept for highly efficient ion-conducting and ion-permselective materials for sustainable energy applications.
- Published
- 2022
27. Glycerophosphoinositol is Elevated in Blood Samples From
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Jon J, Brudvig, Vicki J, Swier, Tyler B, Johnson, Jacob C, Cain, Melissa, Pratt, Mitch, Rechtzigel, Hannah, Leppert, An N, Dang Do, Forbes D, Porter, and Jill M, Weimer
- Abstract
CLN3 Batten disease is a rare pediatric neurodegenerative lysosomal disorder caused by biallelic disease-associated variants inWe performed an exhaustive metabolomic screen using serum samples from a novel minipig model of CLN3 Batten disease and validated findings inCLN3 pig serum samples from 4 ages exhibited large elevations in 4 glycerophosphodiester species: glycerophosphoinositol (GPI), glycerophosphoethanolamine (GPE), glycerophosphocholine (GPC), and glycerophosphoserine (GPS). GPI and GPE exhibited the largest elevations, with similar elevations found inGPE and GPI could have utility as biomarkers of CLN3 disease status. GPI, in particular, shows consistent elevations across a diverse cohort of individuals with CLN3. This raises the potential to use these biomarkers as a blood-based diagnostic test or as an efficacy measure for disease-modifying therapies.
- Published
- 2022
28. A comparative study on effective density, shape factor, and volatile mixing of non-spherical particles using tandem aerodynamic diameter, mobility diameter, and mass measurements
- Author
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Mohsen Kazemimanesh, Md Mostafizur Rahman, Dumitru Duca, Tyler J. Johnson, Ahmed Addad, George Giannopoulos, Cristian Focsa, Adam M. Boies, Kazemimanesh, M [0000-0001-7032-6960], Rahman, MM [0000-0002-4074-5459], Johnson, TJ [0000-0002-3641-0381], Giannopoulos, G [0000-0002-4741-4679], Focsa, C [0000-0002-4512-1098], and Apollo - University of Cambridge Repository
- Subjects
Fluid Flow and Transfer Processes ,Atmospheric Science ,Effective density ,Dynamic shape factor ,Environmental Engineering ,Soot ,Mechanical Engineering ,Volatile mixing ,Tandem measurement ,Pollution ,Non-spherical - Abstract
Combustion-generated particles are typically non-spherical (soot aggregates) and sometimes mixed with organic compounds (e.g. in vehicle emissions). The effective density, dynamic shape factor, and volatile mixing of particles are widely studied using aerosol instruments that measure the particle mobility diameter, aerodynamic diameter, and mass. In theory, any of these three physical properties can be obtained from a combination of the other two. In the present study, a tandem arrangement of aerodynamic aerosol classifier (AAC; measuring aerodynamic diameter), differential mobility analyzer (DMA; measuring mobility diameter), optional catalytic stripper (CS), and centrifugal particle mass analyzer (CPMA; measuring particle mass) was used to study the effective density, dynamic shape factor, and volatile mixing of non-spherical non-homogenous particles. In terms of mass, the vast majority of the particles were purely semi-volatile mixed with soot with and without semi-volatile coating. The effective density of polydisperse non-stripped particles was relatively constant (indicating nearly spherical particles), while that of polydisperse stripped particles decreased from ~1200 to ~800 kg/m³ as the particle size increased (indicating a compact structure). The effective density of monodisperse particles, measured by DMA-CPMA, AAC-DMA, and AAC-CPMA methods, was consistent within the measurement uncertainty; however, the latter method had larger discrepancy with the other two methods, particularly for non-spherical particles. The dynamic shape factor, measured by AAC-CPMA and DMA-CPMA methods, increased with the mobility diameter, a trend also supported by electron micrographs. The volatile mass fraction of particles decreased as their mobility diameter increased, with smaller particles having volatile mass fraction of ~20%. This result was further confirmed by chemical characterization of size-selected particles, proving the robustness of online aerosol measurements.
- Published
- 2022
29. Characterisation of the Aerodynamic Aerosol Classifier Transfer Function for Particle Sizes up to 5 Micrometres
- Author
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Simon D. Payne, Tyler J. Johnson, and Jonathan P.R. Symonds
- Subjects
Environmental Chemistry ,Pollution - Published
- 2023
30. Transmembrane Batten Disease Proteins Interact With a Shared Network of Vesicle Sorting Proteins, Impacting Their Synaptic Enrichment
- Author
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Mitchell J. Rechtzigel, Brandon L. Meyerink, Hannah Leppert, Tyler B. Johnson, Jacob T. Cain, Gavin Ferrandino, Danielle G. May, Kyle J. Roux, Jon J. Brudvig, and Jill M. Weimer
- Subjects
General Neuroscience - Abstract
Batten disease is unique among lysosomal storage disorders for the early and profound manifestation in the central nervous system, but little is known regarding potential neuron-specific roles for the disease-associated proteins. We demonstrate substantial overlap in the protein interactomes of three transmembrane Batten proteins (CLN3, CLN6, and CLN8), and that their absence leads to synaptic depletion of key partners (i.e., SNAREs and tethers) and altered synaptic SNARE complexing in vivo, demonstrating a novel shared etiology.
- Published
- 2021
31. BOXR1030, an anti-GPC3 CAR with exogenous GOT2 expression, shows enhanced T cell metabolism and improved antitumor activity
- Author
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Tyler B. Johnson, Taylor Friedman, Eugene Choi, Madaline Gilbert, Barron Luke, Sujatha Muralidharan, Tapasya Pai, Kathleen E. McGinness, Taylor Hickman, Seth Ettenberg, Amy Jensen-Smith, Kathleen R. Whiteman, Binzhang Shen, Greg Motz, Avani Parikh, and Glen J. Weiss
- Subjects
Tumor microenvironment ,Merkel cell carcinoma ,business.industry ,medicine.medical_treatment ,T cell ,medicine.disease ,Tumor antigen ,Chimeric antigen receptor ,Cytokine ,medicine.anatomical_structure ,In vivo ,medicine ,Cancer research ,business ,Lung cancer - Abstract
PurposeThe solid tumor microenvironment (TME) drives T cell dysfunction and inhibits the effectiveness of immunotherapies such as chimeric antigen receptor-based T cell (CAR T) cells. Early data has shown that modulation of T cell metabolism can improve intratumoral T cell function in preclinical models. Experimental DesignWe evaluated GPC3 expression in human normal and tumor tissue specimens. We developed and evaluated BOXR1030, a novel CAR T therapeutic co-expressing glypican-3 (GPC3)-targeted CAR and exogenous glutamic-oxaloacetic transaminase 2 (GOT2) in terms of CAR T cell function both in vitro and in vivo. ResultsExpression of tumor antigen GPC3 was observed by immunohistochemical staining in tumor biopsies from hepatocellular carcinoma, liposarcoma, squamous lung cancer, and Merkel cell carcinoma patients. Compared to control GPC3 CAR alone, BOXR1030 (GPC3-targeted CAR T cell that co-expressed GOT2) demonstrated superior in vivo efficacy in aggressive solid tumor xenograft models, and showed favorable attributes in vitro including an enhanced cytokine production profile, a less-differentiated T cell phenotype with lower expression of stress and exhaustion markers, an enhanced metabolic profile and increased proliferation in TME-like conditions. ConclusionsTogether, these results demonstrated that co-expression of GOT2 can substantially improve the overall antitumor activity of CAR T cells by inducing broad changes in cellular function and phenotype. These data show that BOXR1030 is an attractive approach to targeting select solid tumors. To this end, BOXR1030 will be explored in the clinic to assess safety, dose-finding, and preliminary efficacy (NCT05120271). Statement of Translational RelevanceChimeric antigen receptor-based T cell (CAR T) therapeutics have revolutionized the field of oncology. Despite early successes targeting hematological malignancies, substantial challenges limit application of CAR T therapy in solid tumors, in part due to the suppressive tumor microenvironment which drives T cell exhaustion and metabolic dysfunction. Glutamic-oxaloacetic transaminase 2 (GOT2) is a mitochondrial enzyme in glutamine metabolism and contributes to cellular redox balance. Glypican-3 (GPC3) is an oncofetal tumor antigen with restricted expression on normal tissues and high prevalence in several solid tumors. We describe BOXR1030, a novel CAR T therapeutic co-expressing GPC3-targeted CAR and exogenous GOT2. Compared to T cells expressing CAR alone, BOXR1030 T cells demonstrated superior in vivo efficacy and have favorable attributes including enhanced cytokine production, a less-differentiated phenotype with lower expression of exhaustion markers, and an enhanced metabolic profile. These data support BOXR1030 as a potential treatment to explore in select solid tumor indications.
- Published
- 2021
32. Online scaffolds: A constructivist approach to oncology fellow learning
- Author
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Sam Brondfield, Matthew Schwede, Tyler Paul Johnson, and Shagun Arora
- Subjects
Cancer Research ,Oncology - Abstract
11010 Background: Oncology is a vast and fast-paced field. Fellows must expend significant effort to learn and stay updated. Up-to-date learning tools covering core oncology content in a digestible manner are lacking. Additionally, passive lectures are common in oncology, while constructivist approaches that may improve learning are rare. Therefore, we piloted updatable online modules (“scaffolds”) as a learning tool for oncology fellows. Methods: Author SB, a University of California, San Francisco (UCSF) solid-tumor oncologist, designed 12 scaffolds (breast, non-small cell lung, small cell lung, head/neck, salivary/thyroid, upper gastrointestinal, lower gastrointestinal, germ cell, bladder/renal/adrenal, prostate, melanoma, and sarcoma) using Google Slides between 12/2018 and 6/2019. The scaffolds included bullet points and tables/figures synthesized from the ASCO self-evaluation program textbook’s solid tumor chapters and the National Comprehensive Cancer Network (NCCN) guidelines. We emailed scaffold links to all UCSF and Stanford oncology fellows in 2019-2020, including instructions for fellows to update the scaffolds without exceeding 20 slides per scaffold, 5 lines per slide, or 7 words per line. The scaffolds were reintroduced to new fellows at the beginning of each academic year. SB audited to ensure no erroneous information was added. In December 2021 we reviewed updates tracked in Google Slides and conducted one UCSF and one Stanford focus group with four 1st-3rd year fellows each. Results: Between 7/2019 and 12/2021, fellows made 60 updates to the scaffolds, with a mean of 5 updates per scaffold ranging from new trials to changes in management. During the same period, the auditor made 9 updates and found no erroneous fellow updates. Fellow updates occasionally exceeded specified limits, requiring correction. Content analysis revealed that fellows considered the scaffolds to be accessible and succinct learning tools that 1) addressed a dearth of similar resources, 2) served as effective preparation for clinical work and examinations, 3) provided structured information for rapid review, and 4) made subsequent interactions with complex resources such as NCCN guidelines easier. Barriers to fellows updating the scaffolds included lack of ownership and low confidence in judgment regarding appropriate updates. Conclusions: In this two-institution pilot, oncology fellows used and subsequently updated online scaffolds in a constructivist fashion. This model has the potential to fill a crucial gap in available learning resources and can be applied to other specialties. Assigning scaffolds to fellows with faculty mentorship may facilitate ownership and bolster fellow confidence in updating these tools. Individual institutions may update their own versions of the scaffolds to align with institution-specific needs.
- Published
- 2022
33. Implementation and efficacy of a fellow-led, case-based noon lecture series
- Author
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James Dickerson, Nathaniel James Myall, Mohana Roy, and Tyler Paul Johnson
- Subjects
Cancer Research ,Oncology - Abstract
11011 Background: For new fellows, learning clinical oncology represents an enormous challenge. Few data support specific didactic approaches. The senior author (TPJ) developed a novel curriculum, emphasizing deliberate practice as part of a design grounded in Ericsson’s “expert performance approach”. These noon conferences are case based with a focus on key clinical trials and NCCN guidelines. In comparison to didactics given directly by faculty, these conferences are primarily presented by a senior teaching fellow with an invited faculty member adding additional commentary as an “expert discussant”. We surveyed fellows to assess perception of efficacy and also created a board style test to evaluate knowledge gains. Methods: The curriculum began in 2020. After one year, we surveyed fellows with a five-point likert scale survey to quantify their perception of the curriculum. In 2022, we created a pair of 18-question lung cancer specific board style tests for the five teaching sessions on lung cancer. Prior to the first conference, the pre-test was sent to fellows electronically; after the final lecture the other 18-question test was sent out. Differences in the overall cohort’s test score were examined via a paired student t-test. Results: On the 2021 survey, 59% of fellows responded (17 of 29). Of the respondents, 83% attended at least half of the lectures (14 of 17). When asked to compare this conference series to traditional lecture-based series, 59% (10 of 17) agreed with the statement that "this series is one of the very best I've encountered" and all said it was at least “better than average.” 94% of respondents (16 of 17) said the series equipped them for clinical practice to either a “significant” or “remarkable” degree. 94% of respondents (16 of 17) agreed the conferences helped them learn to “think like oncologists.” For the five session lung cancer block, fellows reported attending an average of 3.6 ± 1.4 sessions (n = 13). On the 18-question pre-test (n = 19), the average score ± one standard deviation was 73% ± 15%. For the post-test (n = 13), the average was 68% ± 17% (p = 0.48). Conclusions: We developed a novel curriculum to replace traditional didactics. Fellows perceived the curriculum to be exceptionally strong as compared to traditional lecture series, felt it prepared them well for practice, and said it taught them to think like oncologists. Pre/post knowledge assessments did not show an improvement in knowledge. Distribution to larger numbers of fellows–especially early learners–may better power a study to detect improvements in learning.
- Published
- 2022
34. Combatting multidrug-resistance with membrane-active peptides
- Author
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Tyler S. Johnson and Charles M. Deber
- Subjects
Biophysics - Published
- 2022
35. Integrated analysis of chain orientation induced anisotropy in nanoimprinted PVDF based copolymers
- Author
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Wen Qian, Shuo Sun, Tyler J. Johnson, Charles Nguyen, Stephen Ducharme, and Joseph A. Turner
- Subjects
Polymers and Plastics ,Organic Chemistry ,Materials Chemistry - Published
- 2022
36. Transmembrane Batten Disease Proteins Interact With a Shared Network of Vesicle Sorting Proteins, Impacting Their Synaptic Enrichment
- Author
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Mitchell J. Rechtzigel, Brandon L. Meyerink, Hannah Leppert, Tyler B. Johnson, Jacob T. Cain, Gavin Ferrandino, Danielle G. May, Kyle J. Roux, Jon J. Brudvig, and Jill M. Weimer
- Subjects
lysosome ,neurodegeneration ,vesicle traffic ,Batten disease ,SNARE (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor) ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Batten disease is unique among lysosomal storage disorders for the early and profound manifestation in the central nervous system, but little is known regarding potential neuron-specific roles for the disease-associated proteins. We demonstrate substantial overlap in the protein interactomes of three transmembrane Batten proteins (CLN3, CLN6, and CLN8), and that their absence leads to synaptic depletion of key partners (i.e., SNAREs and tethers) and altered synaptic SNARE complexing in vivo, demonstrating a novel shared etiology.
- Published
- 2022
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