247 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. Another Look at Pyrroloiminoquinone Alkaloids—Perspectives on Their Therapeutic Potential from Known Structures and Semisynthetic Analogues
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Sheng Lin, Erin P. McCauley, Nicholas Lorig-Roach, Karen Tenney, Cassandra N. Naphen, Ai-Mei Yang, Tyler A. Johnson, Thalia Hernadez, Ramandeep Rattan, Frederick A. Valeriote, and Phillip Crews
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makaluvamine ,Zyzzya fuliginosa ,marine sponge ,MS-MS fragmentation profiling ,PANC-1 and OVCAR-5 cytotoxicity ,Biology (General) ,QH301-705.5 - Abstract
This study began with the goal of identifying constituents from Zyzzya fuliginosa extracts that showed selectivity in our primary cytotoxicity screen against the PANC-1 tumor cell line. During the course of this project, which focused on six Z. fuliginosa samples collected from various regions of the Indo-Pacific, known compounds were obtained consisting of nine makaluvamine and three damirone analogues. Four new acetylated derivatives were also prepared. High-accuracy electrospray ionization mass spectrometry (HAESI-MS) m/z ions produced through MS2 runs were obtained and interpreted to provide a rapid way for dereplicating isomers containing a pyrrolo[4,3,2-de]quinoline core. In vitro human pancreas/duct epithelioid carcinoma (PANC-1) cell line IC50 data was obtained for 16 compounds and two therapeutic standards. These results along with data gleaned from the literature provided useful structure activity relationship conclusions. Three structural motifs proved to be important in maximizing potency against PANC-1: (i) conjugation within the core of the ABC-ring; (ii) the presence of a positive charge in the C-ring; and (iii) inclusion of a 4-ethyl phenol or 4-ethyl phenol acetate substituent off the B-ring. Two compounds, makaluvamine J (9) and 15-O-acetyl makaluvamine J (15), contained all three of these frameworks and exhibited the best potency with IC50 values of 54 nM and 81 nM, respectively. These two most potent analogs were then tested against the OVCAR-5 cell line and the presence of the acetyl group increased the potency 14-fold from that of 9 whose IC50 = 120 nM vs. that of 15 having IC50 = 8.6 nM.
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- 2017
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5. 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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6. 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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7. 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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8. 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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9. 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
10. 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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11. 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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12. 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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13. AdaScale SGD: A User-Friendly Algorithm for Distributed Training.
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Tyler B. Johnson, Pulkit Agrawal 0002, Haijie Gu, and Carlos Guestrin
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- 2020
14. 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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15. Intracranial delivery of AAV9 gene therapy partially prevents retinal degeneration and visual deficits in CLN6-Batten disease mice
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Katherine A. White, Hemanth R. Nelvagal, Timothy A. Poole, Bin Lu, Tyler B. Johnson, Samantha Davis, Melissa A. Pratt, Jon Brudvig, Ana B. Assis, Shibi Likhite, Kathrin Meyer, Brian K. Kaspar, Jonathan D. Cooper, Shaomei Wang, and Jill M. Weimer
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CLN6 ,Batten disease ,AAV9 ,NCL ,Gene therapy ,retina ,Genetics ,QH426-470 ,Cytology ,QH573-671 - Abstract
Batten disease is a family of rare, fatal, neuropediatric diseases presenting with memory/learning decline, blindness, and loss of motor function. Recently, we reported the use of an AAV9-mediated gene therapy that prevents disease progression in a mouse model of CLN6-Batten disease (Cln6nclf), restoring lifespans in treated animals. Despite the success of our viral-mediated gene therapy, the dosing strategy was optimized for delivery to the brain parenchyma and may limit the therapeutic potential to other disease-relevant tissues, such as the eye. Here, we examine whether cerebrospinal fluid (CSF) delivery of scAAV9.CB.CLN6 is sufficient to ameliorate visual deficits in Cln6nclf mice. We show that intracerebroventricular (i.c.v.) delivery of scAAV9.CB.CLN6 completely prevents hallmark Batten disease pathology in the visual processing centers of the brain, preserving neurons of the superior colliculus, thalamus, and cerebral cortex. Importantly, i.c.v.-delivered scAAV9.CB.CLN6 also expresses in many cells throughout the central retina, preserving many photoreceptors typically lost in Cln6nclf mice. Lastly, scAAV9.CB.CLN6 treatment partially preserved visual acuity in Cln6nclf mice as measured by optokinetic response. Taken together, we report the first instance of CSF-delivered viral gene reaching and rescuing pathology in both the brain parenchyma and retinal neurons, thereby partially slowing visual deterioration.
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- 2021
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16. Training Deep Models Faster with Robust, Approximate Importance Sampling.
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Tyler B. Johnson and Carlos Guestrin
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- 2018
17. 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
18. StingyCD: Safely Avoiding Wasteful Updates in Coordinate Descent.
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Tyler B. Johnson and Carlos Guestrin
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- 2017
19. Unified Methods for Exploiting Piecewise Linear Structure in Convex Optimization.
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Tyler B. Johnson and Carlos Guestrin
- Published
- 2016
20. 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
21. Blitz: A Principled Meta-Algorithm for Scaling Sparse Optimization.
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Tyler B. Johnson and Carlos Guestrin
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- 2015
22. 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.
- Published
- 2022
23. A Fast, Principled Working Set Algorithm for Exploiting Piecewise Linear Structure in Convex Problems.
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Tyler B. Johnson and Carlos Guestrin
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- 2018
24. '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.
- Published
- 2022
25. 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
26. Endoscopic Skull Base Surgery
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Tyler J. Johnson, David E. Traul, and Thomas N. Pajewski
- Published
- 2022
27. 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.
- Published
- 2021
28. 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
- Abstract
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.
- Published
- 2022
29. 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
- Published
- 2022
30. In Vivo Evaluation of (-)-Zampanolide Demonstrates Potent and Persistent Antitumor Efficacy When Targeted to the Tumor Site
- Author
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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.
- Published
- 2022
31. 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
32. A human model of Batten disease shows role of CLN3 in phagocytosis at the photoreceptor–RPE interface
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Lisa R. Latchney, Vera L. Bonilha, Kannan Vrindavan Manian, Stefanie Volland, Chad A. Galloway, Caroline Milliner, Sonal Dalvi, Tyler B. Johnson, Ruchira Singh, Lauren Winschel, Mina M. Chung, Jonathan W. Mink, Cynthia Tang, Whitney Spencer, Jimin Han, Michael Roll, Erika F. Augustine, David S. Williams, Jill M. Weimer, Vamsi K. Gullapalli, and Celia Soto
- Subjects
0301 basic medicine ,Batten disease ,genetic structures ,QH301-705.5 ,Phagocytosis ,Genetic enhancement ,Induced Pluripotent Stem Cells ,Medicine (miscellaneous) ,Retinal Pigment Epithelium ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Photoreceptor cell ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Neuronal Ceroid-Lipofuscinoses ,medicine ,Humans ,Biology (General) ,Eye diseases ,Membrane Glycoproteins ,Retinal pigment epithelium ,Microvilli ,Genetic Therapy ,Retinal Photoreceptor Cell Outer Segment ,medicine.disease ,Photoreceptor outer segment ,eye diseases ,Paediatric neurological disorders ,Cell biology ,Mechanisms of disease ,030104 developmental biology ,medicine.anatomical_structure ,CLN3 ,Cell culture ,Mutation ,030221 ophthalmology & optometry ,sense organs ,General Agricultural and Biological Sciences ,Neurological disorders ,Molecular Chaperones ,Signal Transduction - Abstract
Mutations in CLN3 lead to photoreceptor cell loss in CLN3 disease, a lysosomal storage disorder characterized by childhood-onset vision loss, neurological impairment, and premature death. However, how CLN3 mutations cause photoreceptor cell death is not known. Here, we show that CLN3 is required for phagocytosis of photoreceptor outer segment (POS) by retinal pigment epithelium (RPE) cells, a cellular process essential for photoreceptor survival. Specifically, a proportion of CLN3 in human, mouse, and iPSC-RPE cells localized to RPE microvilli, the site of POS phagocytosis. Furthermore, patient-derived CLN3 disease iPSC-RPE cells showed decreased RPE microvilli density and reduced POS binding and ingestion. Notably, POS phagocytosis defect in CLN3 disease iPSC-RPE cells could be rescued by wild-type CLN3 gene supplementation. Altogether, these results illustrate a novel role of CLN3 in regulating POS phagocytosis and suggest a contribution of primary RPE dysfunction for photoreceptor cell loss in CLN3 disease that can be targeted by gene therapy., CLN3 disease is characterised by childhood-onset vision loss and premature death. Using patient-derived retinal cells, the authors show that CLN3 is required for retinal pigment epithelium (RPE) cell structure, microvilli and phagocytosis of photoreceptor outer segments that are essential for vision. They further suggest that gene-therapy targeting RPE cells can be effective for CLN3 disease.
- Published
- 2021
33. Transmembrane peptide effects on bacterial membrane integrity and organization
- Author
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Chloe J Mitchell, Tyler S. Johnson, and Charles M. Deber
- Subjects
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
34. Viral load of SARS-CoV-2 in droplets and bioaerosols directly captured during breathing, speaking and coughing
- Author
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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
- Subjects
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
35. Molecular-Level Control over Ionic Conduction and Ionic Current Direction by Designing Macrocycle-Based Ionomers
- Author
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Shyambo Chatterjee, Ehsan Zamani, Seefat Farzin, Iman Evazzade, Oghenetega Allen Obewhere, Tyler James Johnson, Vitaly Alexandrov, and Shudipto Konika Dishari
- Abstract
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
36. Glycerophosphoinositol is Elevated in Blood Samples From
- Author
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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
37. Therapeutic efficacy of antisense oligonucleotides in mouse models of CLN3 Batten disease
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Jessica L. Centa, Frank Rigo, Francine M. Jodelka, Anthony J. Hinrich, Joseph Ochaba, Dominik M. Duelli, Michaela Jackson, Tyler B. Johnson, Jill M. Weimer, and Michelle L. Hastings
- Subjects
0301 basic medicine ,Batten disease ,Disease ,engineering.material ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Mice ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Neuronal Ceroid-Lipofuscinoses ,Lysosomal storage disease ,medicine ,Animals ,Humans ,Frameshift Mutation ,Membrane Glycoproteins ,business.industry ,General Medicine ,Oligonucleotides, Antisense ,medicine.disease ,Exon skipping ,Disease Models, Animal ,Open reading frame ,030104 developmental biology ,Batten ,CLN3 ,Codon, Nonsense ,030220 oncology & carcinogenesis ,Cancer research ,engineering ,business ,Molecular Chaperones - Abstract
CLN3 Batten disease is an autosomal recessive, neurodegenerative, lysosomal storage disease caused by mutations in CLN3, which encodes a lysosomal membrane protein(1–3). There are no disease-modifying treatments for this disease that affects up to 1 in 25,000 births, has an onset of symptoms in early childhood and typically is fatal by 20–30 years of life(4–7). Most patients with CLN3 Batten have a deletion encompassing exons 7 and 8 (CLN3(Δex7/8)), creating a reading frame-shift(7,8). Here we demonstrate that mice with this deletion can be effectively treated using an antisense oligonucleotide (ASO) that induces exon skipping to restore the open reading frame. A single treatment of neonatal mice with an exon 5-targeted ASO-induced robust exon skipping for more than a year, improved motor coordination, reduced histopathology in Cln3(Δex7/8) mice and increased survival in a new mouse model of the disease. ASOs also induced exon skipping in cell lines derived from patients with CLN3 Batten disease. Our findings demonstrate the utility of ASO-based reading-frame correction as an approach to treat CLN3 Batten disease and broaden the therapeutic landscape for ASOs in the treatment of other diseases using a similar strategy.
- Published
- 2020
38. A tailored Cln3 Q352X mouse model for testing therapeutic interventions in CLN3 Batten disease
- Author
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Jill M. Weimer, Attila D. Kovács, Logan Langin, Tyler B. Johnson, and David A. Pearce
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Multidisciplinary ,Batten disease ,business.industry ,media_common.quotation_subject ,Point mutation ,Nonsense ,Nonsense-mediated decay ,lcsh:R ,lcsh:Medicine ,Disease ,medicine.disease ,Bioinformatics ,CLN3 ,Disease Presentation ,medicine ,lcsh:Q ,Cognitive decline ,business ,lcsh:Science ,media_common - Abstract
CLN3 Batten disease (CLN3 disease) is a pediatric lysosomal storage disorder that presents with progressive blindness, motor and cognitive decline, seizures, and premature death. CLN3 disease results from mutations in CLN3 with the most prevalent mutation, a 966 bp deletion spanning exons 7–8, affecting ~ 75% of patients. Mouse models with complete Cln3 deletion or Cln3Δex7/8 mutation have been invaluable for learning about both the basic biology of CLN3 and the underlying pathological changes associated with CLN3 disease. These models, however, vary in their disease presentation and are limited in their utility for studying the role of nonsense mediated decay, and as a consequence, in testing nonsense suppression therapies and read-through compounds. In order to develop a model containing a disease-causing nonsense point mutation, here we describe a first-of-its-kind Cln3Q352X mouse model containing a c.1054C > T (p.Gln352Ter) point mutation. Similar to previously characterized Cln3 mutant mouse lines, this novel model shows pathological deficits throughout the CNS including accumulation of lysosomal storage material and glial activation, and has limited perturbation in behavioral measures. Thus, at the molecular and cellular level, this mouse line provides a valuable tool for testing nonsense suppression therapies or read through compounds in CLN3 disease in the future.
- Published
- 2020
39. Quantitative nanoscale measurements of the thermomechanical properties of poly‐ether‐ether‐ketone ( <scp>PEEK</scp> )
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Tyler J. Johnson, Joseph A. Turner, Charles Nguyen, Wenlong Li, and Wen Qian
- Subjects
Poly ether ether ketone ,Materials science ,Polymers and Plastics ,Chemical engineering ,Atomic force microscopy ,Materials Chemistry ,Peek ,Physical and Theoretical Chemistry ,Nanoscopic scale - Published
- 2020
40. Platelet aggregometry testing during aspirin or clopidogrel treatment and measurement of clopidogrel metabolite concentrations in dogs with protein‐losing nephropathy
- Author
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Sarah B. Shropshire, Tyler M. Johnson, and Christine S. Olver
- Subjects
Male ,medicine.medical_specialty ,endocrine system ,Platelet Aggregation ,040301 veterinary sciences ,aspirin ,Protein-Losing Enteropathies ,medicine.medical_treatment ,Metabolite ,responder ,Standard Article ,030204 cardiovascular system & hematology ,Gastroenterology ,Nephropathy ,0403 veterinary science ,03 medical and health sciences ,chemistry.chemical_compound ,Dogs ,0302 clinical medicine ,renal disease ,Internal medicine ,Animals ,Medicine ,Platelet ,Dog Diseases ,Saline ,Aspirin ,lcsh:Veterinary medicine ,General Veterinary ,business.industry ,Hematology ,04 agricultural and veterinary sciences ,medicine.disease ,Clopidogrel ,Standard Articles ,Adenosine diphosphate ,chemistry ,Case-Control Studies ,lcsh:SF600-1100 ,Female ,Arachidonic acid ,SMALL ANIMAL ,thromboprophylaxis ,business ,Platelet Aggregation Inhibitors ,medicine.drug - Abstract
Background Dogs with protein-losing nephropathy (PLN) are treated with antiplatelet drugs for thromboprophylaxis but no standardized method exists to measure drug response. It is also unknown if clopidogrel metabolite concentrations [CM] differ between healthy and PLN dogs. Objectives Assess response to aspirin or clopidogrel in PLN dogs using platelet aggregometry (PA) and compare [CM] between healthy and PLN dogs. Animals Six healthy and 14 PLN dogs. Methods Platelet aggregometry using adenosine diphosphate (ADP), arachidonic acid (AA), and saline was performed in healthy dogs at baseline and 1-week postclopidogrel administration to identify responders or nonresponders. A decrease of ≥60% for ADP or ≥30% for AA at 1 or 3 hours postpill was used to define a responder. At 1 and 3 hours postclopidogrel, [CM] and PA were measured in healthy and PLN dogs. Platelet aggregometry was performed in PLN dogs at baseline, 1, 6, and 12 weeks after clopidogrel or aspirin administration. Results In PLN dogs receiving clopidogrel, PA differed from baseline at all time points for ADP but not for AA at any time point. Most dogs responded at 1 or both time points except for 1 dog that showed no response. For PLN dogs receiving aspirin, no differences from baseline were observed at any time point for either ADP or AA. No differences in [CM] were found at either time point between healthy and PLN dogs. Conclusions and clinical importance Platelet aggregometry may represent an objective method to evaluate response to clopidogrel or aspirin treatment and PLN dogs appear to metabolize clopidogrel similarly to healthy dogs.
- Published
- 2020
41. Reinvestigation of Mycothiazole Reveals the Penta-2,4-dien-1-ol Residue Imparts Picomolar Potency and 8S Configuration
- Author
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Tyler A. Johnson, David Coppage, Jiajiu Shaw, Phillip Crews, Joseph Media, Marcos A. Ogarrio, Frederick A. Valeriote, Erin P. McCauley, Joseph D. Morris, Lauren N Persi, Mani Maheshwari, Taylor C Garcia, Nicole L. McIntosh, and Colon V. Cook
- Subjects
Stereochemistry ,Chemistry ,Organic Chemistry ,Mycothiazole ,Biochemistry ,Semisynthesis ,Nitrosobenzene ,Residue (chemistry) ,chemistry.chemical_compound ,Cell culture ,Drug Discovery ,Potency ,Enantiomer ,IC50 - Abstract
Reinvestigation of mycothiazole (1) revealed picomolar potency (IC50 = 0.00016, 0.00027, 0.00035 μM) against pancreatic, (PANC-1), liver (HepG2), and colon (HCT-116) tumor cell lines. Reevaluation of 1 provided [α]D data indicating Vanuatu specimens of C. mycofijiensis contain the 8S enantiomer of 1 and not the 8R configuration previously reported. Semisynthesis provided 8-O-acetylmycothiazole (2), 8-oxomycothiazole (8), mycothiazole nitrosobenzene derivatives (MND1, MND2: 9a, 9b), and MND3 (10) with IC50 = 0.00129, >1.0, >1.0, >1.0, >1.0 μM, respectively, against PANC-1 cell lines. These results highlight the significance of the penta-2,4-dien-1-ol residue as a key structural feature of 1 required for its cytotoxicty against tumor cell lines.
- Published
- 2020
42. 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
43. 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
44. Transmembrane Batten Disease Proteins Interact With a Shared Network of Vesicle Sorting Proteins, Impacting Their Synaptic Enrichment
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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
45. 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
46. Devotion to the Adopted Country: U.S. Immigrant Volunteers in the Mexican War
- Author
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Tyler V. Johnson and Tyler V. Johnson
- Published
- 2012
47. A CLN6-CRMP2-KLC4 complex regulates anterograde ER-derived vesicle trafficking in cortical neurites
- Author
-
Hannah Leppert, Rajesh Khanna, Jacob T. Cain, Jon Brudvig, Jill M. Weimer, Brandon Meyerink, Bryon Grove, Katherine A. White, Kenneth Hensley, Derek J. Timm, Tyler B. Johnson, Helen Magee, Mitch Rechtzigel, Seung yon Koh, and Jeremy P. Morgan
- Subjects
Motor protein ,Vesicular transport protein ,chemistry.chemical_compound ,medicine.anatomical_structure ,Neurite ,Microtubule ,Chemistry ,medicine ,Lanthionine Ketimine ,Collapsin response mediator protein family ,Axon ,Cell biology ,Tubulin binding - Abstract
As neurons establish extensive connections throughout the central nervous system, the transport of cargo along the microtubule network of the axon is crucial for differentiation and homeostasis. Specifically, building blocks such as membrane and cytoskeletal components, organelles, transmembrane receptors, adhesion molecules, and peptide neurotransmitters all require proper transport to the presynaptic compartment. Here, we identify a novel complex regulating vesicular endoplasmic reticulum transport in neurites, composed of CLN6: an ER-associated protein of relatively unknown function implicated in CLN6-Batten disease; CRMP2: a tubulin binding protein important in regulating neurite microtubule dynamics; and KLC4: a classic transport motor protein. We show that this “CCK” complex allows ER-derived vesicles to migrate to the distal end of the axon, aiding in proper neurite outgrowth and arborization. In the absence of CLN6, the CCK complex does not function effectively, leading to reduced vesicular transport, stunted neurite outgrowth, and deficits in CRMP2 binding to other protein partners. Treatment with a CRMP2 modulating compound, lanthionine ketimine ester, partially restores these deficits in CLN6-deficient mouse neurons, indicating that stabilization of CRMP2 interacting partners may prove beneficial in lieu of complete restoration of the CCK complex. Taken together, these findings reveal a novel mechanism of ER-derived vesicle transport in the axon and provide new insights into therapeutic targets for neurodegenerative disease.
- Published
- 2021
48. Transmembrane Batten disease proteins interact with a shared network of vesicle sorting proteins to regulate synaptic composition and function
- Author
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Danielle G. May, Tyler B. Johnson, Jill M. Weimer, Brandon Meyerink, Kyle J. Roux, Gavin Ferrandino, Mitchell J. Rechtzigel, Jacob T. Cain, Jon Brudvig, and Hannah Leppert
- Subjects
Batten disease ,Vesicle ,Central nervous system ,engineering.material ,Biology ,medicine.disease ,Transmembrane protein ,Cell biology ,Batten ,medicine.anatomical_structure ,CLN3 ,CLN8 ,engineering ,medicine ,Function (biology) - 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 aberrant synaptic SNARE dynamics in vivo, demonstrating a novel shared etiology.
- Published
- 2021
49. Evolution of Resource Competition between Mutually Dependent Digital Organisms.
- Author
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Tyler J. Johnson and Claus O. Wilke
- Published
- 2004
- Full Text
- View/download PDF
50. Populations using public-supply groundwater in the conterminous U.S. 2010; Identifying the wells, hydrogeologic regions, and hydrogeologic mapping units
- Author
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John T. Wilson, Kenneth Belitz, Elise Watson, Leon J. Kauffman, and Tyler D. Johnson
- Subjects
Environmental Engineering ,Resource (biology) ,Water Wells ,Population ,Aquifer ,Hydrology (agriculture) ,Water Supply ,Environmental Chemistry ,Humans ,education ,Waste Management and Disposal ,Groundwater ,Hydrology ,education.field_of_study ,geography ,Hydrogeology ,geography.geographical_feature_category ,Drinking Water ,Census ,Pollution ,United States ,Environmental science ,Surface water ,Water Pollutants, Chemical ,Environmental Monitoring - Abstract
Most Americans receive their drinking water from publicly supplied sources, a large portion of it from groundwater. Mapping these populations consistently and at a high resolution is important for understanding where the resource is used and needs to be protected. The results show that 269 million people are supplied by public supply, 107 million are supplied by groundwater and 162 million are supplied by surface water. The population using public supply drinking water was mapped in two ways: the census enhanced method (CEM) evenly distributes the population across populated census blocks, and the urban land-use enhanced method (ULUEM) distributes the population only to certain urban land use designations. In addition, a two-dimensional polygon dataset was created for the conterminous U.S. that identifies 177 unique Hydrogeologic Mapping Units (HMUs) with similar hydrogeologic characteristics. The HMUs do not overlap, but they can delineate areas where stacked hydrogeologic regions (HRs) contribute drinking water from below the surface. HRs are waterbearing geologic regions identified as either a principal aquifers (PA) or secondary hydrogeologic regions (SHR). Within each HMU, the wells were used to determine the proportion of each HR that is providing groundwater to the HMU. In 63% of the HMUs, a single HR is providing water to the public supply wells located within it, while the rest of the HMUs show that the wells are tapping up to a maximum of four stacked HRs. In total, groundwater from 108 HRs provide drinking water for public supply, six of which provide more than 50% of the groundwater used for public supply drinking water. The aquifer serving the largest number of equivalent people (>17 million) is the glacial aquifer. The HR providing the greatest number of people per km2 is the Biscayne aquifer in Florida at nearly 453 people per km2.
- Published
- 2021
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