5,194 results on '"Steven, D"'
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2. Using Chemistry as a Medium for Energy Education: Suggestions for Content and Pedagogy in a Nonmajors Course
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Shane, Joseph W., Bennett, Steven D., and Hirschl-Mike, Rhonda
- Abstract
This article describes a university chemistry course for nonscience majors that provides a comprehensive understanding of energy by coupling traditional chemical concepts and scientific technologies with appropriate economic, political, and legal mechanisms for monitoring and regulating energy both domestically and internationally. The scientific content of the course is taught in a lecture-style format and students are required to demonstrate proficiency on quizzes and exams. Two additional assessments are used to measure students' ability to apply relevant chemical concepts to a specific energy-related topic: class presentations and newspaper-style articles written for and reviewed by laypersons. Sample course materials, supplementary tables of assessment criteria, and student data from a recent class are provided in the online supporting information. (Contains 1 table.)
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- 2010
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3. Digitizing a Heritage of Faded Memories: A Case Study on Extending Historical Research Capabilities
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Branting, Steven D.
- Abstract
A historical fact is like a fata morgana, "always less than what really happened." Even consensus does not establish truth; otherwise history is merely the version of the past that people agree to accept. The students who participated in the acclaimed 5th Street Cemetery Necrogeographical Study innocently found themselves clashing with accepted local history when, in 2001, they began to investigate the historicity of the persistent anecdotal lore from their town's pioneer days. The conundrum that would keep the students busy for five years emerged early, very early, long before the students, their parents, or their grandparents were born. Founded in 1861 as a supply station for the north Idaho gold rush, Lewiston had a very fragile economic future by the 1870s. Even more depressing was the image of the city graveyard located on a bluff above the town, which hugged the banks of the Clearwater River. One of the first important historical lessons students must learn is that different eras can be completely satisfied with antipodal solutions to the same concern. Used since the early 1860s for burials, the cemetery grounds had the look of an unkempt, insecure patch of weeds. The mowed and trimmed appearance of today's cemeteries would not be the vogue in the West until the twentieth century. This is not to say that the people who made Lewiston their homes after the gold claims played out had no civic pride. Acting on repeated petitions from its constituents, the city council finally authorized "a good substantial [white-washed, five-foot] picket fence" to be erected at public expense to keep roaming cattle from dislodging the markers and befouling the grounds, and to make the cemetery more presentable. A movement to relocate the cemetery altogether began as early as 1886, and by late 1888, further burial at the old site was forbidden by city ordinance; 40 acres had been purchased, platted, and readied for new burials and reinterments. Within a decade, the old grounds were ploughed and the fence removed to establish Lewiston's first municipal park--now known as Pioneer Park. The nature of a local history project, especially one enacted over such a span of time, offers students a multitude of learning opportunities. To provide a structure to analyze this necrogeographical project, the author considers in turn the context of the six facets of the national Historical Thinking Standard 4 (Historical Research Capabilities) and their applications to the project. (Contains 34 notes.)
- Published
- 2009
4. Contemporary Moral Problems in Chemistry: Effect of Peer Presentations on Students' Awareness of Science and Society Issues
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White, Harold B., III, Brown, Steven D., and Johnston, Murray V.
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A study is conducted about including a course curriculum that would inform and sensitize students to social issues relating to science in a setting that emphasizes oral and visual communication. This would help students to develop critical thinking skills, practice communication skills, and gain confidence in their ability to think through public policy issues relating to science.
- Published
- 2005
5. The Utility of Human Milk Oligosaccharides against Group B Streptococcus Infections of Reproductive Tissues and Cognate Adverse Pregnancy Outcomes
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Rebecca E. Moore, Sabrina K. Spicer, Jacky Lu, Schuyler A. Chambers, Kristen N. Noble, Jonathan Lochner, Rebecca C. Christofferson, Karla A. Vasco, Shannon D. Manning, Steven D. Townsend, and Jennifer A. Gaddy
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Chemistry ,QD1-999 - Published
- 2023
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6. Novel Kraft Softwood Lignin-Derived Carbon Quantum Dots: Synthesis, Characterization, and In Vitro Cytocompatibility
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Eli Christoph, Lu Yu, Steven D. Newby, Michael A. Rivera Orsini, Jakob Scroggins, David J. Keffer, David P. Harper, and Madhu Dhar
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lignin ,carbon quantum dots (CQDs) ,human mesenchymal stem cells (hMSCs) ,proliferation ,Chemistry ,QD1-999 - Abstract
Carbon quantum dots (CQDs) have been investigated for biomedical applications in medical imaging due to their fluorescent properties, overall long-term stability, and excellent cytocompatibility and biocompatibility. Lignin is an organic polymer in the tissues of woody plants. It is also considered a byproduct of the wood and pulp industries. Hence, it presents as a renewable source of carbon nanoparticles. In this study, we report the synthesis and material and biological characterization of two colloidal suspensions of CQDs in water derived from lignin-based carbon. One was the native form of CQDs derived from lignin carbon, and the second was doped with nitrogen to evaluate material differences. Material characterization was carried out using various commonly used techniques, including Fourier transform infrared spectroscopy (FTIR), emission and absorbance spectra, zeta potential, transmission electron microscopy (TEM), and scanning electron microscopy (SEM). Thin films of CQDs were formed on glass and silicon substrates to assess the in vitro cytocompatibility with human mesenchymal stem cells (hMSCs). Observations suggest that the two forms of CQDs promote cell attachment within 24 h and sustain it for at least 7 days. The overall structure and shape of cells suggest a lack of any adverse or toxic effects of CQDs. The data lay down the novel foundation to support the use of lignin-derived CQDs in tissue engineering applications.
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- 2024
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7. An Empirical Formula From Ion Exchange Chromatography and Colorimetry.
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Johnson, Steven D.
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Presents a detailed procedure for finding an empirical formula from ion exchange chromatography and colorimetry. Introduces students to more varied techniques including volumetric manipulation, titration, ion-exchange, preparation of a calibration curve, and the use of colorimetry. (JRH)
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- 1996
8. Saliva microRNA Profile in Children with and without Severe SARS-CoV-2 Infection
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Steven D. Hicks, Dongxiao Zhu, Rhea Sullivan, Nirupama Kannikeswaran, Kathleen Meert, Wei Chen, Srinivasan Suresh, and Usha Sethuraman
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COVID-19 ,children ,miRNA ,saliva ,SARS-CoV-2 ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) may impair immune modulating host microRNAs, causing severe disease. Our objectives were to determine the salivary miRNA profile in children with SARS-CoV-2 infection at presentation and compare the expression in those with and without severe outcomes. Children p-value < 0.05). The majority (31/43) were downregulated in severe cases. The largest between-group differences involved miR-4495, miR-296-5p, miR-548ao-3p and miR-1273c. These microRNAs displayed enrichment for 32 gene ontology pathways including viral processing and transforming growth factor beta and Fc-gamma receptor signaling. In conclusion, salivary miRNA levels are perturbed in children with severe COVID-19, with the majority of miRNAs being down regulated. Further studies are required to validate and determine the utility of salivary miRNAs as biomarkers of severe COVID-19.
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- 2023
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9. Synthesis and Cytotoxic Evaluation of Arimetamycin A and Its Daunorubicin and Doxorubicin Hybrids
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Eric D. Huseman, Jo Ann W. Byl, Scott M. Chapp, Nathan D. Schley, Neil Osheroff, and Steven D. Townsend
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Chemistry ,QD1-999 - Published
- 2021
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10. Xenogenic Implantation of Human Mesenchymal Stromal Cells Using a Novel 3D-Printed Scaffold of PLGA and Graphene Leads to a Significant Increase in Bone Mineralization in a Rat Segmental Femoral Bone Defect
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Steven D. Newby, Chris Forsynth, Austin J. Bow, Shawn E. Bourdo, Man Hung, Joseph Cheever, Ryan Moffat, Andrew J. Gross, Frank W. Licari, and Madhu S. Dhar
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poly(lactic-co-glycolic acid) ,additive manufacturing ,3D bioprinting ,PLGA blends ,rat femur ,Chemistry ,QD1-999 - Abstract
Tissue-engineering technologies have the potential to provide an effective approach to bone regeneration. Based on the published literature and data from our laboratory, two biomaterial inks containing PLGA and blended with graphene nanoparticles were fabricated. The biomaterial inks consisted of two forms of commercially available PLGA with varying ratios of LA:GA (65:35 and 75:25) and molecular weights of 30,000–107,000. Each of these forms of PLGA was blended with a form containing a 50:50 ratio of LA:GA, resulting in ratios of 50:65 and 50:75, which were subsequently mixed with a 0.05 wt% low-oxygen-functionalized derivative of graphene. Scanning electron microscopy showed interconnected pores in the lattice structures of each scaffold. The cytocompatibility of human ADMSCs transduced with a red fluorescent protein (RFP) was evaluated in vitro. The in vivo biocompatibility and the potential to repair bones were evaluated in a critically sized 5 mm mechanical load-bearing segmental femur defect model in rats. Bone repair was monitored by radiological, histological, and microcomputed tomography methods. The results showed that all of the constructs were biocompatible and did not exhibit any adverse effects. The constructs containing PLGA (50:75)/graphene alone and with hADMSCs demonstrated a significant increase in mineralized tissues within 60 days post-treatment. The percentage of bone volume to total volume from microCT analyses in the rats treated with the PLGA + cells construct showed a 50% new tissue formation, which matched that of a phantom. The microCT results were supported by Von Kossa staining.
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- 2023
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11. Multiple Reaction Pathways in the Morphinone Reductase-Catalyzed Hydride Transfer Reaction
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Xi Chen and Steven D. Schwartz
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Chemistry ,QD1-999 - Published
- 2020
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12. What Comes Next? Simple Practices to Improve Diversity in Science
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Olugbeminiyi O. Fadeyi, Marie C. Heffern, Shanina Sanders Johnson, and Steven D. Townsend
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Chemistry ,QD1-999 - Published
- 2020
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13. A Photodeactivatable Antagonist for Controlling CREB-Dependent Gene Expression
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Takuma Imoto, Masafumi Minoshima, Tatsushi Yokoyama, Ben P. Emery, Steven D. Bull, Haruhiko Bito, and Kazuya Kikuchi
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Chemistry ,QD1-999 - Published
- 2020
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14. Infant Saliva Levels of microRNA miR-151a-3p Are Associated with Risk for Neurodevelopmental Delay
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Steven D. Hicks and Alexandra Confair
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non-coding RNA ,epigenetic ,pediatric ,development ,prognostic ,miRNA ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Prompt recognition of neurodevelopmental delay is critical for optimizing developmental trajectories. Currently, this is achieved with caregiver questionnaires whose sensitivity and specificity can be limited by socioeconomic and cultural factors. This prospective study of 121 term infants tested the hypothesis that microRNA measurement could aid early recognition of infants at risk for neurodevelopmental delay. Levels of four salivary microRNAs implicated in childhood autism (miR-125a-5p, miR-148a-5p, miR-151a-3p, miR-28-3p) were measured at 6 months of age, and compared between infants who displayed risk for neurodevelopmental delay at 18 months (n = 20) and peers with typical development (n = 101), based on clinical evaluation aided by the Survey of Wellbeing in Young Children (SWYC). Accuracy of microRNAs for predicting neurodevelopmental concerns at 18 months was compared to the clinical standard (9-month SWYC). Infants with neurodevelopmental concerns at 18 months displayed higher levels of miR-125a-5p (d = 0.30, p = 0.018, adj p = 0.049), miR-151a-3p (d = 0.30, p = 0.017, adj p = 0.048), and miR-28-3p (d = 0.31, p = 0.014, adj p = 0.048). Levels of miR-151a-3p were associated with an 18-month SWYC score (R = −0.19, p = 0.021) and probability of neurodevelopmental delay at 18 months (OR = 1.91, 95% CI, 1.14–3.19). Salivary levels of miR-151a-3p enhanced predictive accuracy for future neurodevelopmental delay (p = 0.010, X2 = 6.71, AUC = 0.71) compared to the 9-month SWYC score alone (OR = 0.56, 95% CI, 0.20–1.58, AUC = 0.567). This pilot study provides evidence that miR-151a-3p may aid the identification of infants at risk for neurodevelopmental delay. External validation of these findings is necessary.
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- 2023
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15. Multi-Omic Factors Associated with Frequency of Upper Respiratory Infections in Developing Infants
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Ramin Beheshti, E. Scott Halstead, Bryan Cusack, and Steven D. Hicks
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multi-omic ,upper respiratory infections ,infants ,miRNA ,viral infections ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Susceptibility to upper respiratory infections (URIs) may be influenced by host, microbial, and environmental factors. We hypothesized that multi-omic analyses of molecular factors in infant saliva would identify complex host-environment interactions associated with URI frequency. A cohort study involving 146 infants was used to assess URI frequency in the first year of life. Saliva was collected at 6 months for high-throughput multi-omic measurement of cytokines, microRNAs, transcripts, and microbial RNA. Regression analysis identified environmental (daycare attendance, atmospheric pollution, breastfeeding duration), microbial (Verrucomicrobia, Streptococcus phage), and host factors (miR-22-5p) associated with URI frequency (p < 0.05). These results provide pathophysiologic clues about molecular factors that influence URI susceptibility. Validation of these findings in a larger cohort could one day yield novel approaches to detecting and managing URI susceptibility in infants.
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- 2023
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16. A Simple Near‐Infrared Fluorescent Probe for the Detection of Peroxynitrite
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Luling Wu, Xue Tian, Hai‐Hao Han, Jie Wang, Robin R. Groleau, Paramabhorn Tosuwan, Dr. Boontana Wannalerse, Dr. Adam C. Sedgwick, Prof. Steven D. Bull, Prof. Xiao‐Peng He, and Prof. Tony D. James
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near-infrared ,fluorescence ,boronate ,peroxynitrite ,probe ,Chemistry ,QD1-999 - Abstract
Abstract Herein, we report the evaluation and synthesis of a reaction based fluorescent probe DCM‐Bpin for the detection of Peroxynitrite (ONOO−). DCM‐Bpin exhibits selective fluorescence off‐on response for ONOO− over other reactive oxygen species, including H2O2. Moreover, DCM‐Bpin is biocompatible and has been used to visualize exogenous ONOO− in HeLa cells.
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- 2019
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17. Proof of Principle that Molecular Modeling Followed by a Biophysical Experiment Can Develop Small Molecules that Restore Function to the Cardiac Thin Filament in the Presence of Cardiomyopathic Mutations
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Lukasz Szatkowski, Melissa L. Lynn, Teryn Holeman, Michael R. Williams, Anthony P. Baldo, Jil C. Tardiff, and Steven D. Schwartz
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Chemistry ,QD1-999 - Published
- 2019
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18. The Molecular Basis and Pathophysiology of Trigeminal Neuralgia
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QiLiang Chen, Dae Ik Yi, Josiah Nathan Joco Perez, Monica Liu, Steven D. Chang, Meredith J. Barad, Michael Lim, and Xiang Qian
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trigeminal neuralgia ,pathophysiology ,sensitization ,classifications ,treatments ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Trigeminal neuralgia (TN) is a complex orofacial pain syndrome characterized by the paroxysmal onset of pain attacks in the trigeminal distribution. The underlying mechanism for this debilitating condition is still not clearly understood. Decades of basic and clinical evidence support the demyelination hypothesis, where demyelination along the trigeminal afferent pathway is a major driver for TN pathogenesis and pathophysiology. Such pathological demyelination can be triggered by physical compression of the trigeminal ganglion or another primary demyelinating disease, such as multiple sclerosis. Further examination of TN patients and animal models has revealed significant molecular changes, channelopathies, and electrophysiological abnormalities in the affected trigeminal nerve. Interestingly, recent electrophysiological recordings and advanced functional neuroimaging data have shed new light on the global structural changes and the altered connectivity in the central pain-related circuits in TN patients. The current article aims to review the latest findings on the pathophysiology of TN and cross-examining them with the current surgical and pharmacologic management for TN patients. Understanding the underlying biology of TN could help scientists and clinicians to identify novel targets and improve treatments for this complex, debilitating disease.
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- 2022
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19. Protein Encapsulation: A Nanocarrier Approach to the Fluorescence Imaging of an Enzyme-Based Biomarker
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Zhiyuan Jia, Hai-Hao Han, Adam C. Sedgwick, George T. Williams, Lauren Gwynne, James T. Brewster, Steven D. Bull, A. Toby A. Jenkins, Xiao-Peng He, Holger Schönherr, Jonathan L. Sessler, and Tony D. James
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elastase detection ,BSA-based nanocarrier ,nanocarrier-based enzyme detection ,fluorescence imaging ,cell imaging ,Chemistry ,QD1-999 - Abstract
Here, we report a new pentafluoropropanamido rhodamine fluorescent probe (ACS-HNE) that allows for the selective detection of neutrophil elastase (NE). ACS-HNE displayed high sensitivity, with a low limit of detection (
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- 2020
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20. Sensing Peroxynitrite in Different Organelles of Murine RAW264.7 Macrophages With Coumarin-Based Fluorescent Probes
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Maria Weber, Namiko Yamada, Xue Tian, Steven D. Bull, Masafumi Minoshima, Kazuya Kikuchi, Amanda B. Mackenzie, and Tony D. James
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peroxynitrite ,fluorescence ,molecular probe ,reactive oxygen species ,inflammation ,Chemistry ,QD1-999 - Abstract
The elucidation of biological processes involving reactive oxygen species (ROS) facilitates a better understanding of the underlying progression of non-communicable diseases. Fluorescent probes are a powerful tool to study various ROS and have the potential to become essential diagnostic tools. We have developed a series of coumarin fluorescent probes for the selective and sensitive detection of peroxynitrite (ONOO−), a key ROS. Coumarin based probes exhibit good photostability, large Stokes shift and high quantum yields. The three ratiometric probes all contain a boronate ester motif for the detection of ONOO− and a distinctive organelle targeting group. The study of ONOO− generation in a particular organelle will allow more precise disease profiling. Hence, targeting groups for the mitochondria, lysosome and endoplasmic reticulum were introduced into a coumarin scaffold. The three ratiometric probes displayed sensitive and selective detection of ONOO− over other ROS species. All three coumarin probes were evaluated in murine RAW264.7 macrophages for detection of basal and stimulated ONOO− formation.
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- 2020
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21. Controlled Arrangement of Neuronal Cells on Surfaces Functionalized with Micropatterned Polymer Brushes
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Maria Pardo-Figuerez, Neil R. W. Martin, Darren J. Player, Paul Roach, Steven D. R. Christie, Andrew J. Capel, and Mark P. Lewis
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Chemistry ,QD1-999 - Published
- 2018
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22. Peroxynitrite Activated Drug Conjugate Systems Based on a Coumarin Scaffold Toward the Application of Theranostics
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Maria L. Odyniec, Hai-Hao Han, Jordan E. Gardiner, Adam C. Sedgwick, Xiao-Peng He, Steven D. Bull, and Tony D. James
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theranostic ,peroxynitrite ,coumarin ,chemosensor ,fluorescence ,Chemistry ,QD1-999 - Abstract
Two novel drug-conjugates based on a “coumarin linker” have been designed for the synergic release of a therapeutic agent and fluorescent probe for the potential application of theranostics. The drug conjugates; CC-RNS and CI-RNS were designed to be activated by reactive oxygen species or reactive nitrogen species (ROS/RNS). The fluorescence OFF-ON response was triggered by the peroxynitrite-mediated transformation of a boronic acid pinacol ester to a phenol moiety with simultaneous release of the therapeutic agents (Confirmed by HRMS). The limit of detection for peroxynitrite using CC-RNS and CI-RNS was 0.29 and 37.2 μM, respectively. Both CC-RNS and CI-RNS demonstrated the ability to visualize peroxynitrite production thus demonstrating the effectiveness of these probes for use as tools to monitor peroxynitrite-mediated drug release in cancer cell lines.
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- 2019
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23. Chemical speciation and fate of tripolyphosphate after application to a calcareous soil
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Jordan G. Hamilton, Jay Grosskleg, David Hilger, Kris Bradshaw, Trevor Carlson, Steven D. Siciliano, and Derek Peak
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Tripolyphosphate adsorption ,Phosphorus amendment ,Phosphorus XANES ,Calcium phosphate minerals ,Environmental sciences ,GE1-350 ,Chemistry ,QD1-999 - Abstract
Abstract Adsorption and precipitation reactions often dictate the availability of phosphorus in soil environments. Tripolyphosphate (TPP) is considered a form of slow release P fertilizer in P limited soils, however, investigations of the chemical fate of TPP in soils are limited. It has been proposed that TPP rapidly hydrolyzes in the soil solution before adsorbing or precipitating with soil surfaces, but in model systems, TPP also adsorbs rapidly onto mineral surfaces. To study the adsorption behavior of TPP in calcareous soils, a short-term (48 h) TPP spike was performed under laboratory conditions. To determine the fate of TPP under field conditions, two different liquid TPP amendments were applied to a P limited subsurface field site via an in-ground injection system. Phosphorus speciation was assessed using X-ray absorption spectroscopy, total and labile extractable P, and X-ray diffraction. Adsorption of TPP to soil mineral surfaces was rapid (
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- 2018
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24. Human Antibody Domains and Fragments Targeting Neutrophil Elastase as Candidate Therapeutics for Cancer and Inflammation-Related Diseases
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Xiaojie Chu, Zehua Sun, Du-San Baek, Wei Li, John W. Mellors, Steven D. Shapiro, and Dimiter S. Dimitrov
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therapeutic antibodies ,neutrophil elastase ,inflammatory disease ,cancer ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Neutrophil elastase (NE) is a serine protease released during neutrophil maturation. High levels of NE are related to lung tissue damage and poor prognosis in cancer; thus, NE is a potential target for therapeutic immunotherapy for multiple lung diseases and cancers. Here, we isolate and characterize two high-affinity, specific, and noncompetitive anti-NE antibodies Fab 1C10 and VH 1D1.43 from two large phage-displayed human Fab and VH libraries. After fusion with human IgG1 Fc, both of them (VH-Fc 1D1.43 and IgG1 1C10) inhibit NE enzymatic activity with VH-Fc 1D1.43 showing comparable inhibitory effects to that of the small molecule NE inhibitor SPCK and IgG1 1C10 exhibiting even higher (2.6-fold) activity than SPCK. Their epitopes, as mapped by peptide arrays combined with structural modeling, indicate different mechanisms for blocking NE activity. Both VH-Fc and IgG1 antibodies block NE uptake by cancer cells and fibroblast differentiation. VH-Fc 1D1.43 and IgG1 1C10 are promising for the antibody-based immunotherapy of cancer and inflammatory diseases.
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- 2021
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25. Sex-Specific Differences in Lysine, 3-Hydroxybutyric Acid and Acetic Acid in Offspring Exposed to Maternal and Postnatal High Linoleic Acid Diet, Independent of Diet
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Nirajan Shrestha, Steven D Melvin, Daniel R. McKeating, Olivia J. Holland, James S. M. Cuffe, Anthony V. Perkins, Andrew J. McAinch, and Deanne H. Hryciw
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linoleic acid ,sex ,metabolite ,offspring ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Background: Linoleic acid (LA) is an essential polyunsaturated fatty acid (PUFA) that is required for foetal growth and development. Excess intake of LA can be detrimental for metabolic health due to its pro-inflammatory properties; however, the effect of a diet high in LA on offspring metabolites is unknown. In this study, we aimed to determine the role of maternal or postnatal high linoleic acid (HLA) diet on plasma metabolites in adult offspring. Methods: Female Wistar Kyoto (WKY) rats were fed with either low LA (LLA) or HLA diet for 10 weeks prior to conception and during gestation/lactation. Offspring were weaned at postnatal day 25 (PN25), treated with either LLA or HLA diets and sacrificed at PN180. Metabolite analysis was performed in plasma samples using Nuclear Magnetic Resonance. Results: Maternal and postnatal HLA diet did not alter plasma metabolites in male and female adult offspring. There was no specific clustering among different treatment groups as demonstrated by principal component analysis. Interestingly, there was clustering among male and female offspring independent of maternal and postnatal dietary intervention. Lysine was higher in female offspring, while 3-hydroxybutyric acid and acetic acid were significantly higher in male offspring. Conclusion: In summary, maternal or postnatal HLA diet did not alter the plasma metabolites in the adult rat offspring; however, differences in metabolites between male and female offspring occurred independently of dietary intervention.
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- 2021
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26. In Situ High Temperature Synthesis of Single-Component Metallic Nanoparticles
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Yonggang Yao, Fengjuan Chen, Anmin Nie, Steven D. Lacey, Rohit Jiji Jacob, Shaomao Xu, Zhennan Huang, Kun Fu, Jiaqi Dai, Lourdes Salamanca-Riba, Michael R. Zachariah, Reza Shahbazian-Yassar, and Liangbing Hu
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Chemistry ,QD1-999 - Published
- 2017
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27. Long Wavelength TCF-Based Fluorescent Probe for the Detection of Alkaline Phosphatase in Live Cells
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Lauren Gwynne, Adam C. Sedgwick, Jordan E. Gardiner, George T. Williams, Gyoungmi Kim, John P. Lowe, Jean-Yves Maillard, A. Toby A. Jenkins, Steven D. Bull, Jonathan L. Sessler, Juyoung Yoon, and Tony D. James
- Subjects
reaction-based fluorescent probe ,alkaline phosphatase ,cell imaging ,fluorescence ,colorimetric ,Chemistry ,QD1-999 - Abstract
A long wavelength TCF-based fluorescent probe (TCF-ALP) was developed for the detection of alkaline phosphatase (ALP). ALP-mediated hydrolysis of the phosphate group of TCF-ALP resulted in a significant fluorescence “turn on” (58-fold), which was accompanied by a colorimetric response from yellow to purple. TCF-ALP was cell-permeable, which allowed it to be used to image ALP in HeLa cells. Upon addition of bone morphogenic protein 2, TCF-ALP proved capable of imaging endogenously stimulated ALP in myogenic murine C2C12 cells. Overall, TCF-ALP offers promise as an effective fluorescent/colorimetric probe for evaluating phosphatase activity in clinical assays or live cell systems.
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- 2019
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28. Soil Buffering Capacity Can Be Used To Optimize Biostimulation of Psychrotrophic Hydrocarbon Remediation
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Amy Jimmo, Alireza Talebitaher, Derek Peak, Zisis Papandreou, Whitney Shannon, Steven D. Mamet, Steven D. Siciliano, Aram Teymurazyan, Yu-Fen Chang, and Alexandra J. Conway
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positron emission tomography ,Environmental remediation ,010501 environmental sciences ,microbial ecology ,biodegradation ,01 natural sciences ,Biostimulation ,Soil ,chemistry.chemical_compound ,Bioremediation ,bioremediation ,Soil Pollutants ,Environmental Chemistry ,Soil Microbiology ,phosphate ,0105 earth and related environmental sciences ,2. Zero hunger ,VDP::Technology: 500 ,General Chemistry ,15. Life on land ,Biodegradation ,Phosphate ,Hydrocarbons ,Bioavailability ,VDP::Teknologi: 500 ,Biodegradation, Environmental ,Petroleum ,Soil structure ,chemistry ,13. Climate action ,Environmental chemistry ,Soil water ,Environmental science ,permafrost - Abstract
Effective bioremediation of hydrocarbons requires innovative approaches to minimize phosphate precipitation in soils of different buffering capacities. Understanding the mechanisms underlying sustained stimulation of bacterial activity remains a key challenge for optimizing bioremediation—particularly in northern regions. Positron emission tomography (PET) can trace microbial activity within the naturally occurring soil structure of intact soils. Here, we use PET to test two hypotheses: (1) optimizing phosphate bioavailability in soil will outperform a generic biostimulatory solution in promoting hydrocarbon remediation and (2) oligotrophic biostimulation will be more effective than eutrophic approaches. In so doing, we highlight the key bacterial taxa that underlie aerobic and anaerobic hydrocarbon degradation in subarctic soils. In particular, we showed that (i) optimized phosphate bioavailability outperformed generic biostimulatory solutions in promoting hydrocarbon degradation, (ii) oligotrophic biostimulation is more effective than eutrophic approaches, and (iii) optimized biostimulatory solutions stimulated specific soil regions and bacterial consortia. The knowledge gleaned from this study will be crucial in developing field-scale biodegradation treatments for sustained stimulation of bacterial activity in northern regions.
- Published
- 2021
29. A Phase Transfer Catalyzed Permanganate Oxidation: Preparation of Vanillin from Isoeugenol Acetate.
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Lampman, Gary M. and Sharpe, Steven D.
- Abstract
Background information, laboratory procedures, and results are provided for the preparation of vanillin from isoeugenol acetate. Reaction scheme used to prepare the vanillin and a table indicating the different oxidation experiments carried out on isoeugenol or isoeugenol acetate are also provided. (JN)
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- 1983
30. Discovery of FeBi2
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James P. S. Walsh, Samantha M. Clarke, Yue Meng, Steven D. Jacobsen, and Danna E. Freedman
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Chemistry ,QD1-999 - Published
- 2016
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31. Site-independent confirmation of primary site-based PANSS ratings in a schizophrenia trial
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Stephen K. Brannan, Steven D. Targum, Alan Breier, and Christopher J. Murphy
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Adult ,Psychosis ,medicine.medical_specialty ,Exacerbation ,Positive and Negative Syndrome Scale ,business.industry ,Concordance ,medicine.disease ,Placebo ,Psychiatry and Mental health ,chemistry.chemical_compound ,Treatment Outcome ,Double-Blind Method ,Psychotic Disorders ,Tolerability ,chemistry ,Schizophrenia ,Internal medicine ,medicine ,Humans ,business ,Xanomeline ,Biological Psychiatry ,Antipsychotic Agents - Abstract
Blinded, site-independent (remote) ratings from audio-digital recordings of site-based Positive and Negative Syndrome Scale (PANSS) interviews were obtained in a 5-week, randomized, double-blinded study assessing the safety, tolerability, and efficacy of KarXT (a fixed combination of xanomeline and trospium chloride) in hospitalized adults with schizophrenia experiencing an acute exacerbation of psychosis (EMERGENT-1; ClinicalTrials.gov identifier: NCT3697252). The blinded site-independent raters had no knowledge of site location, study visit, drug vs. placebo assignment, or any treatment emergent adverse events (TEAEs). Concordance analyses of 561 paired site-based and site-independent PANSS ratings across all visits revealed a high correlation (ICC = 0.775). Paired scoring differences were positively correlated with the PANSS total score (Spearman's rho = 0.37, p 0.0001). Paired PANSS scores were available from 148 subjects at both the baseline and end of study visits (KarXT = 72, Placebo = 76). Site-based PANSS total scores (primary aim) revealed a significantly greater improvement from baseline in the KarXT group compared to the placebo group (p 0.0001). The blinded site-independent PANSS total scores derived from listening to and scoring the recorded site-based PANSS interviews replicated this finding (p 0.001) and yielded an overall predictive value of 85.1% for matching the site-based response/non-response outcomes. TEAE's have the potential to "unblind" site-based ratings. In this study, the site-independent raters were blinded to TEAEs, affirmed the site-based PANSS ratings, and mitigated concerns about possible functional unblinding of site-based raters. This method of blinded assessment via audio-digital recordings may have utility for other studies concerned with ratings precision and/or functional unblinding.
- Published
- 2021
32. Use of indocyanine green fluorescence guidance in redo ileocolic resection for Crohn's disease
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Ilan Kent, Michael R. Freund, Samir Agarwal, and Steven D. Wexner
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Indocyanine Green ,medicine.medical_specialty ,genetic structures ,Colon ,medicine.medical_treatment ,Anastomotic Leak ,Anastomosis ,chemistry.chemical_compound ,Crohn Disease ,medicine ,Humans ,Retrospective Studies ,Crohn's disease ,business.industry ,Anastomosis, Surgical ,Gastroenterology ,Postoperative complication ,Bowel resection ,medicine.disease ,Surgery ,body regions ,Ileocolic resection ,chemistry ,Complication ,business ,Perfusion ,Indocyanine green - Abstract
Aim Redo ileocolic resection in patients with Crohn's disease (CD) is associated with significant technical challenges that may be associated with high complication rates. The aim of this study was to evaluate the feasibility of near-infrared fluorescence angiography with indocyanine green (ICG), often used to evaluate blood supply to the anastomosis in CD patients undergoing repeat ileocolic resection. Method This study was a retrospective analysis of patients who underwent redo ileocolic resection using ICG bowel perfusion assessment between 2015 and 2021. Patients were matched and compared on a 1:2 basis with a control group undergoing the same procedure without perfusion assessment. Results Twelve patients underwent redo ileocolic resection with ICG perfusion assessment (ICG group). These were compared with 24 patients who underwent the procedure without ICG (control group). Both groups were similar in demographics and operative characteristics including median operating time (255 vs. 255.5 min, p = 0.39) and conversion rate (22% vs. 36.8%, p = 0.68). Median estimated blood loss was significantly higher in the ICG group [150 (50-400) vs. 100 ml (20-125)]. Successful ICG perfusion assessment was seen in all patients in the ICG group and did not change management in any case. Overall postoperative complication rates were comparable between the groups (58.3% vs. 54.1%, p = 0.72). No anastomotic leaks occurred in the ICG group compared with one (1/24, 4.2%) in the control group (p = 0.99). Conclusion Fluorescence ICG perfusion assessment is feasible and safe in redo ileocolic resection in patients with CD. Larger studies are needed to evaluate whether this technique should be routinely used in these complex surgical interventions.
- Published
- 2021
33. PIGMENT EPITHELIAL DETACHMENT IN AGE-RELATED MACULAR DEGENERATION
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Anat Loewenstein, Shai Cohen, Gilad Rabina, Hamid Hosseini, Adrian Au, Dua Masarwa, Noa Kapelushnik, Gad Heilweil, Wei Gui, Steven D. Schwartz, and Shulamit Schwartz
- Subjects
Male ,Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,Time Factors ,Visual acuity ,Fundus Oculi ,Snellen VA ,Visual Acuity ,Angiogenesis Inhibitors ,Retinal Pigment Epithelium ,Macular Degeneration ,chemistry.chemical_compound ,Ranibizumab ,Ophthalmology ,Age related ,medicine ,Humans ,Fluorescein Angiography ,Aged ,Retrospective Studies ,business.industry ,Retinal Detachment ,Retrospective cohort study ,General Medicine ,Macular degeneration ,medicine.disease ,Bevacizumab ,Vascular endothelial growth factor ,Pigment epithelial detachment ,Treatment Outcome ,chemistry ,Baseline characteristics ,Intravitreal Injections ,Female ,medicine.symptom ,business ,Tomography, Optical Coherence ,Follow-Up Studies - Abstract
Purpose To define injection index (II) and assess its impact on visual acuity (VA) in pigment epithelial detachment from age-related macular degeneration over 5 years. Methods Injection index is defined as the mean anti-vascular endothelial growth factor injections per year from presentation. A retrospective study of 256 eyes in 213 patients was performed. Patients were stratified by II (high: ≥9, low: Results Baseline characteristics showed no differences across II groups. Mean (range) follow-up, in years, was 5.02 (1.04-12.74) for all patients. Mean logMAR VA (Snellen VA) were 0.60 (20/80) and 0.56 (20/73) at baseline, 0.52 (20/66) and 0.59 (20/78) at Year 1, 0.45 (20/56) and 0.67 (20/94) at Year 2, 0.38 (20/48) and 0.66 (20/91) at Year 3, 0.41 (20/51) and 0.89 (20/155) at Year 4, and 0.35 (20/45) and 0.79 (20/123) at Year 5 for the high and low II groups, respectively. Linear regression analysis showed a gain of 0.5 approxETDRS letters with each additional injection per year. Conclusion Increased II was associated with better mean VA, suggesting that long-term continuous vascular endothelial growth factor suppression may improve VA in eyes thought to carry poor prognoses.
- Published
- 2021
34. Saliva microRNA Biomarkers of Cumulative Concussion
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Steven D. Hicks, Robert P. Olympia, Cayce Onks, Raymond Y. Kim, Kevin J. Zhen, Gregory Fedorchak, Samantha DeVita, Aakanksha Rangnekar, Matthew Heller, Hallie Zwibel, Chuck Monteith, Zofia Gagnon, Callan D. McLoughlin, Jason Randall, Miguel Madeira, Thomas R. Campbell, Elise Fengler, Michael N. Dretsch, Christopher Neville, and Frank A. Middleton
- Subjects
saliva ,microRNA ,sports-related concussion ,mild traumatic brain injury ,biomarker ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Recurrent concussions increase risk for persistent post-concussion symptoms, and may lead to chronic neurocognitive deficits. Little is known about the molecular pathways that contribute to persistent concussion symptoms. We hypothesized that salivary measurement of microribonucleic acids (miRNAs), a class of epitranscriptional molecules implicated in concussion pathophysiology, would provide insights about the molecular cascade resulting from recurrent concussions. This hypothesis was tested in a case-control study involving 13 former professional football athletes with a history of recurrent concussion, and 18 age/sex-matched peers. Molecules of interest were further validated in a cross-sectional study of 310 younger individuals with a history of no concussion (n = 230), a single concussion (n = 56), or recurrent concussions (n = 24). There was no difference in neurocognitive performance between the former professional athletes and their peers, or among younger individuals with varying concussion exposures. However, younger individuals without prior concussion outperformed peers with prior concussion on three balance assessments. Twenty salivary miRNAs differed (adj. p < 0.05) between former professional athletes and their peers. Two of these (miR-28-3p and miR-339-3p) demonstrated relationships (p < 0.05) with the number of prior concussions reported by younger individuals. miR-28-3p and miR-339-5p may play a role in the pathophysiologic mechanism involved in cumulative concussion effects.
- Published
- 2020
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35. A Pre-Existing Myogenic Temporomandibular Disorder Increases Trigeminal Calcitonin Gene-Related Peptide and Enhances Nitroglycerin-Induced Hypersensitivity in Mice
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Hui Shu, Sufang Liu, Yuanyuan Tang, Brian L. Schmidt, John C. Dolan, Larry L. Bellinger, Phillip R. Kramer, Steven D. Bender, and Feng Tao
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temporomandibular disorder ,migraine pain ,comorbidity ,spinal trigeminal nucleus caudalis ,calcitonin gene-related peptide ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Migraine is commonly reported among patients with temporomandibular disorders (TMDs), especially myogenic TMD. The pathophysiologic mechanisms related to the comorbidity of the two conditions remain elusive. In the present study, we combined masseter muscle tendon ligation (MMTL)-produced myogenic TMD with systemic injection of nitroglycerin (NTG)-induced migraine-like hypersensitivity in mice. Facial mechanical allodynia, functional allodynia, and light-aversive behavior were evaluated. Sumatriptan, an FDA-approved medication for migraine, was used to validate migraine-like hypersensitivity. Additionally, we examined the protein level of calcitonin gene-related peptide (CGRP) in the spinal trigeminal nucleus caudalis using immunohistochemistry. We observed that mice with MMTL pretreatment have a prolonged NTG-induced migraine-like hypersensitivity, and MMTL also enabled a non-sensitizing dose of NTG to trigger migraine-like hypersensitivity. Systemic injection of sumatriptan inhibited the MMTL-enhanced migraine-like hypersensitivity. MMTL pretreatment significantly upregulated the protein level of CGRP in the spinal trigeminal nucleus caudalis after NTG injection. Our results indicate that a pre-existing myogenic TMD can upregulate NTG-induced trigeminal CGRP and enhance migraine-like hypersensitivity.
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- 2020
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36. Synergy Between Proline-Rich Antimicrobial Peptides and Small Molecule Antibiotics Against Selected Gram-Negative Pathogens in vitro and in vivo
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Laszlo Otvos Jr., Eszter Ostorhazi, Dora Szabo, Steven D. Zumbrun, Lynda L. Miller, Stephanie A. Halasohoris, Puvi D. Desai, Sharon M. Int Veldt, and Carl N. Kraus
- Subjects
carbapenems ,colistin ,enzyme inhibition ,melioidosis ,resistant bacteria ,synergy ,Chemistry ,QD1-999 - Abstract
As monotherapy, modified proline-rich antimicrobial peptides (PrAMPs) protect animals from experimental bacteremia in a dose-dependent manner. We evaluated the in vitro synergy of a modified PrAMP, A3-APO, a dimer, previously shown to inhibit the 70 kDa bacterial heat shock protein DnaK, with imipenem or colistin against two antibiotic-resistant pathogens; a carbapenemase-expressing Klebsiella pneumoniae strain K97/09 and Acinetobacter baumannii (ATCC BAA-1605). Combining antimicrobials resulted in synergy for PrAMP/colistin combination against both K. pneumoniae and A. baumannii (ΣFIC = 0.08 both) and additive activity for the A3-APO/imipenem combination against K. pneumoniae (ΣFIC = 0.53). Chex1-Arg20, (designated as ARV-1502 in preclinical development), the single chain PrAMP monomer of A3-APO, showed synergy with meropenem against a carbapenem-resistant uropathogenic Escherichia coli strain (ΣFIC = 0.38). In a murine bacteremia model using K97/09, A3-APO at 1 mg/kg demonstrated improved survival when co-administered with standard (10 mg/kg) or subtherapeutic (1 mg/kg) doses of colistin at 36 h (p < 0.05). Surprisingly, the survival benefit of A3-APO was augmented when the A3-APO dose was decreased by 50% to 0.5 mg/kg (p < 0.02) in conjunction with a subtherapeutic colistin dose (1 mg/kg). ARV-1502, as monotherapy demonstrated prolonged (>24 h) activity in a mouse Escherichia coli infection assay. Co-treatment with ARV-1502 and subtherapeutic doses of ceftazidime (150 mg/kg) was studied in a mouse model of melioidosis. ARV-1502 provided a 50% improvement in long-term (62 days) survival, but only at the lowest of 3 administered doses; survival advantage was demonstrated at 2.5 mg/kg but not at 5 or 10 mg/kg. The mortality benefit of combination therapies was not routinely accompanied by a parallel decline in blood or tissue bacterial counts in surviving animals, suggesting that the anti-infective activity of the host defense peptides (HDP) is broader than simply bacterial eradication. In fact, the hormetic effect observed in either animal models suggest that low dose HDP treatment may change the dominant mode of action in experimental bacteremia.
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- 2018
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37. Structural and biochemical studies of an iterative ribosomal peptide macrocyclase
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Jackson K. Pugmire, Gengnan Li, Steven D. Bruner, Yousong Ding, Yi Zhang, and Krishna Patel
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Models, Molecular ,Peptide Biosynthesis ,Proteases ,Protein Conformation ,Stereochemistry ,Peptide ,Crystallography, X-Ray ,Cyanobacteria ,Peptides, Cyclic ,Biochemistry ,Cyclase ,Catalysis ,Article ,chemistry.chemical_compound ,Biosynthesis ,Structural Biology ,Amino Acid Sequence ,Structural motif ,Molecular Biology ,chemistry.chemical_classification ,Biological Products ,Ribosomal RNA ,Biosynthetic Pathways ,Benchmarking ,Enzyme ,chemistry ,Cyclization ,Protein Processing, Post-Translational ,Ribosomes ,Function (biology) ,Protein Binding - Abstract
Microviridins, tricyclic peptide natural products originally isolated from cyanobacteria, function as inhibitors of diverse serine-type proteases. Here we report the structure and biochemical characterization of AMdnB, a unique iterative macrocyclase involved in a microviridin biosynthetic pathway from Anabaena sp. PCC 7120. The ATP-dependent cyclase, along with the homologous AMdnC, introduce up to nine macrocyclizations on three distinct core regions of a precursor peptide, AMdnA. The results presented here provide structural and mechanistic insight into the iterative chemistry of AMdnB. In vitro AMdnB-catalyzed cyclization reactions demonstrate the synthesis of the two predicted tricyclic products from a multi-core precursor peptide substrate, consistent with a distributive mode of catalysis. The X-ray structure of AMdnB shows a structural motif common to ATP-grasp cyclases involved in RiPPs biosynthesis. Additionally, comparison with the non-iterative MdnB allows insight into the structural basis for the iterative chemistry. Overall, the presented results provide insight into the general mechanism of iterative enzymes in ribosomally synthesized and post-translationally modified peptide biosynthetic pathways.
- Published
- 2021
38. A sustainable colloidal material with sorption and nutrient‐supply capabilities for in situ groundwater bioremediation
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Arantxa P. Persico, Derek Peak, Steven D. Siciliano, David Bulmer, Essouassi Elikem, and Paolo Mussone
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Environmental Engineering ,Phosphorus ,chemistry.chemical_element ,Sorption ,Nutrients ,Management, Monitoring, Policy and Law ,Pollution ,chemistry.chemical_compound ,Biodegradation, Environmental ,Adsorption ,Bioremediation ,chemistry ,Environmental chemistry ,medicine ,Microbial biodegradation ,Benzene ,Groundwater ,Waste Management and Disposal ,Water Pollutants, Chemical ,Water Science and Technology ,Activated carbon ,medicine.drug - Abstract
Microbial degradation of subsurface organic contaminants is often hindered by the low availability of both contaminants and nutrients, especially phosphorus (P). The use of activated carbon and traditional P fertilizers to overcome these challenges has proved ineffective; therefore, we sought to find an innovative and effective solution. By heating bone meal-derived organic residues in water in a closed reactor, we synthesized nonporous colloids composed of aromatic and aliphatic structures linked to P groups. X-ray absorption near edge spectroscopy analysis revealed that the materials contain mostly bioavailable forms of P (i.e., adsorbed P and magnesium-bearing brushite). The capacity of the materials to adsorb organic contaminants was investigated using benzene and batch isotherm experiments. The adsorption isotherms were fitted to the linearized Freundlich model; isotherm capacity (logKF ) values for the materials ranged between 1.6 and 2.8 μg g-1 . These results indicate that the colloidal materials have a high affinity for organic contaminants. This, coupled with their possession of bioavailable P, should make them effective amendments for in situ groundwater bioremediation. Also, the materials' chemical properties suggest that they are not recalcitrant, implying that they will not become potential contaminants when released into the environment.
- Published
- 2021
39. Epoxyqueuosine Reductase QueH in the Biosynthetic Pathway to tRNA Queuosine Is a Unique Metalloenzyme
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Brian S. MacTavish, Rémi Zallot, You Hu, Valérie de Crécy-Lagard, Daniel J. Payan, Steven D. Bruner, Alexander Angerhofer, Alvaro Montoya, John A. Gerlt, and Qiang Li
- Subjects
Iron-Sulfur Proteins ,chemistry.chemical_classification ,Oxidoreductases Acting on CH-CH Group Donors ,TRNA modification ,biology ,Iron ,Queuosine ,Active site ,biology.organism_classification ,Biochemistry ,Article ,Cofactor ,chemistry.chemical_compound ,Enzyme ,Bacterial Proteins ,chemistry ,Catalytic Domain ,Thermotoga maritima ,Transfer RNA ,biology.protein ,Gene - Abstract
Queuosine is a structurally unique and functionally important tRNA modification, widely distributed in eukaryotes and bacteria. The final step of queuosine biosynthesis is the reduction/deoxygenation of epoxyqueuosine to form the cyclopentene motif of the nucleobase. The chemistry is performed by the structurally and functionally characterized cobalamin-dependent QueG. However, the queG gene is absent from several bacteria that otherwise retain queuosine biosynthesis machinery. Members of the IPR003828 family (previously known as DUF208) have been recently identified as nonorthologous replacements of QueG, and this family was renamed QueH. Here, we present the structural characterization of QueH from Thermotoga maritima. The structure reveals an unusual active site architecture with a [4Fe-4S] metallocluster along with an adjacent coordinated iron metal. The juxtaposition of the cofactor and coordinated metal ion predicts a unique mechanism for a two-electron reduction/deoxygenation of epoxyqueuosine. To support the structural characterization, in vitro biochemical and genomic analyses are presented. Overall, this work reveals new diversity in the chemistry of iron/sulfur-dependent enzymes and novel insight into the last step of this widely conserved tRNA modification.
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- 2021
40. Halogenation of used aluminum matrix test reactor fuel – a bench-scale demonstration with surrogate materials
- Author
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Michael N. Patterson, Steven D. Herrmann, Haiyan Zhao, Matthew M. Jones, and Meng Shi
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Nuclear and High Energy Physics ,Matrix (mathematics) ,Materials science ,Nuclear Energy and Engineering ,chemistry ,Aluminium ,Bench scale ,chemistry.chemical_element ,Halogenation ,Composite material - Published
- 2021
41. The effectiveness and value of belimumab and voclosporin for lupus nephritis
- Author
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James Fotheringham, Steven D. Pearson, Jeffrey A. Tice, Olena Mandrik, and Praveen Thokala
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Health plan ,medicine.medical_specialty ,business.industry ,Health Policy ,Lupus nephritis ,Pharmaceutical Science ,Foundation (evidence) ,Pharmacy ,medicine.disease ,Belimumab ,Voclosporin ,chemistry.chemical_compound ,chemistry ,Family medicine ,Health care ,medicine ,business ,health care economics and organizations ,medicine.drug - Abstract
DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan ...
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- 2021
42. Cytochrome P450 isoforms 1A1, 1B1 AND 2W1 as targets for therapeutic intervention in head and neck cancer
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Laurence H. Patterson, James McCaul, Sneha Smarakan, Daniela Presa, Klaus Pors, Amir Zaki Abdullah Zubir, Syed Ali Khurram, Maria Sadiq, Paul M. Loadman, Mark Sutherland, Patricia A. Cooper, Goreti Ribeiro Morais, and Steven D. Shnyder
- Subjects
Indoles ,CYP1B1 ,Science ,Antineoplastic Agents ,Cohort Studies ,Mice ,chemistry.chemical_compound ,In vivo ,Cell Line, Tumor ,Cytochrome P-450 CYP1A1 ,Animals ,Humans ,Prodrugs ,Pyrroles ,Cytochrome P450 Family 2 ,Carcinogen ,Duocarmycin ,Multidisciplinary ,biology ,Chemistry ,Cytochrome P450 ,Prodrug ,Xenograft Model Antitumor Assays ,Head and Neck Neoplasms ,Cell culture ,Cytochrome P-450 CYP1B1 ,Cancer research ,biology.protein ,Medicine ,Female ,CYP2W1 ,Heterocyclic Compounds, 3-Ring - Abstract
Epidemiological studies have shown that head and neck cancer (HNC) is a complex multistage process that in part involves exposure to a combination of carcinogens and the capacity of certain drug-metabolising enzymes including cytochrome P450 (CYP) to detoxify or activate such carcinogens. In this study, CYP1A1, CYP1B1 and CYP2W1 expression in HNC was correlated with potential as target for duocarmycin prodrug activation and selective therapy. In the HNC cell lines, elevated expression was shown at the gene level for CYP1A1 and CYP1B1 whereas CYP2W1 was hardly detected. However, CYP2W1 was expressed in FaDu and Detroit-562 xenografts and in a cohort of human HNC samples. Functional activity was measured in Fadu and Detroit-562 cells using P450-Glo™ assay. Antiproliferative results of duocarmycin prodrugs ICT2700 and ICT2706 revealed FaDu and Detroit-562 as the most sensitive HNC cell lines. Administration of ICT2700 in vivo using a single dose of ICT2700 (150 mg/kg) showed preferential inhibition of small tumour growth (mean size of 60 mm3) in mice bearing FaDu xenografts. Significantly, our findings suggest a potential targeted therapeutic approach to manage HNCs by exploiting intratumoural CYP expression for metabolic activation of duocarmycin-based prodrugs such as ICT2700.
- Published
- 2021
43. Structure and function of aerotolerant, multiple-turnover THI4 thiazole synthases
- Author
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Steven D. Bruner, Bryan J. Leong, You Hu, Qiang Li, Jaya Joshi, Andrew D. Hanson, and Jorge D. García-García
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Plant Biology ,comparative genomics ,medicine.disease_cause ,Biochemistry ,thiamin ,chemistry.chemical_compound ,Structural Biology ,Catalytic Domain ,Thiamine ,Research Articles ,chemistry.chemical_classification ,biology ,Escherichia coli Proteins ,Cobalt ,Genomics ,Complementation ,Microorganisms, Genetically-Modified ,Crystallization ,Saccharomyces cerevisiae Proteins ,Sulfide ,Stereochemistry ,Bioinformatics ,Archaeal Proteins ,Iron ,suicide enzyme ,chemistry.chemical_element ,Saccharomyces cerevisiae ,Sulfides ,Microbiology ,Cofactor ,thiazole biosynthesis ,Chemical Biology ,medicine ,Escherichia coli ,Cysteine ,Thiazole ,Molecular Biology ,Bacteria ,Prokaryote ,Cell Biology ,biology.organism_classification ,Sulfur ,Archaea ,Hyperthermophile ,Oxygen ,chemistry ,biology.protein ,Biocatalysis - Abstract
Plant and fungal THI4 thiazole synthases produce the thiamin thiazole moiety in aerobic conditions via a single-turnover suicide reaction that uses an active-site Cys residue as sulfur donor. Multipleturnover (i.e. catalytic) THI4s lacking an active-site Cys (non-Cys THI4s) that use sulfide as sulfur donor have been characterized – but only from archaeal methanogens that are anaerobic, O2-sensitive hyperthermophiles from sulfide-rich habitats. These THI4s prefer iron as cofactor. A survey of prokaryote genomes uncovered non-Cys THI4s in aerobic mesophiles from sulfide-poor habitats, suggesting that multiple-turnover THI4 operation is possible in aerobic, mild, low-sulfide conditions. This was confirmed by testing 23 representative non-Cys THI4s for complementation of an Escherichia coli ΔthiG thiazole auxotroph in aerobic conditions. Sixteen were clearly active, and more so when intracellular sulfide level was raised by supplying Cys, demonstrating catalytic function in the presence of O2 at mild temperatures and indicating use of sulfide or a sulfide metabolite as sulfur donor. Comparative genomic evidence linked non-Cys THI4s with proteins from families that bind, transport, or metabolize cobalt or other heavy metals. The crystal structure of the aerotolerant bacterial Thermovibrio ammonificans THI4 was determined to probe the molecular basis of aerotolerance. The structure suggested no large deviations compared to the structures of THI4s from O2-sensitive methanogens, but is consistent with an alternative catalytic metal. Together with complementation data, the use of cobalt rather than iron was supported. We conclude that catalytic THI4s can indeed operate aerobically and that the metal cofactor inserted is a likely natural determinant of aerotolerance.
- Published
- 2021
44. Hyperactive RAS/PI3-K/MAPK Signaling Cascade in Migration and Adhesion of Nf1 Haploinsufficient Mesenchymal Stem/Progenitor Cells
- Author
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Yuan Zhou, Yongzheng He, Richa Sharma, Wen Xing, Selina A. Estwick, Xiaohua Wu, Steven D. Rhodes, Mingjiang Xu, and Feng-Chun Yang
- Subjects
neurofibromatosis 1 ,neurofibroma ,oncogene protein p21 (ras) ,mesenchymal stem/progenitor cells ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant disease caused by mutations in the NF1 tumor suppressor gene, which affect approximately 1 out of 3000 individuals. Patients with NF1 suffer from a range of malignant and nonmalignant manifestations such as plexiform neurofibromas and skeletal abnormalities. We previously demonstrated that Nf1 haploinsufficiency in mesenchymal stem/progenitor cells (MSPCs) results in impaired osteoblastic differentiation, which may be associated with the skeletal manifestations in NF1 patients. Here we sought to further ascertain the role of Nf1 in modulating the migration and adhesion of MSPCs of the Nf1 haploinsufficient (Nf1+/−) mice. Nf1+/− MSPCs demonstrated increased nuclear-cytoplasmic ratio, increased migration, and increased actin polymerization as compared to wild-type (WT) MSPCs. Additionally, Nf1+/− MSPCs were noted to have significantly enhanced cell adhesion to fibronectin with selective affinity for CH271 with an overexpression of its complimentary receptor, CD49e. Nf1+/− MSPCs also showed hyperactivation of phosphoinositide 3-kinase (PI3-K) and mitogen activated protein kinase (MAPK) signaling pathways when compared to WT MSPCs, which were both significantly reduced in the presence of their pharmacologic inhibitors, LY294002 and PD0325901, respectively. Collectively, our study suggests that both PI3-K and MAPK signaling pathways play a significant role in enhanced migration and adhesion of Nf1 haploinsufficient MSPCs.
- Published
- 2015
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45. Total Synthesis of the Photorhabdus temperata ssp. Cinereal 3240 Zwitterionic Trisaccharide Repeating Unit
- Author
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Johny M. Nguyen and Steven D. Townsend
- Subjects
chemistry.chemical_classification ,Photorhabdus temperata ,biology ,Stereochemistry ,Chemistry ,Organic Chemistry ,Total synthesis ,Trisaccharide ,Physical and Theoretical Chemistry ,Carbohydrate ,biology.organism_classification ,Biochemistry - Abstract
Zwitterionic carbohydrate modifications, such as phosphoethanolamine (PEtN), govern host-pathogen interactions. Whereas it is recognized that these modifications stimulate the host immune system, the purpose of PEtN modification remains largely descriptive. As an enabling step toward studying this carbohydrate modification, we report a synthesis of the P. temperata zwitterionic trisaccharide repeating unit. The 32-step synthesis was enabled by H-phosphonate chemistry to install the PEtN arm on a poorly reactive and sterically hindered C4-alcohol.
- Published
- 2021
46. Synthesis as an Expanding Resource in Human Milk Science
- Author
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Lianyan L Xu and Steven D. Townsend
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0303 health sciences ,Milk, Human ,010405 organic chemistry ,Chemistry ,Scale (chemistry) ,Oligosaccharides ,Translational research ,General Chemistry ,01 natural sciences ,Biochemistry ,Data science ,Biological Science Disciplines ,Catalysis ,0104 chemical sciences ,03 medical and health sciences ,Synthetic biology ,Colloid and Surface Chemistry ,Resource (project management) ,Homogeneous ,Carbohydrate Conformation ,Humans ,Biological sciences ,030304 developmental biology - Abstract
Few classes of natural products rival the structural audacity of oligosaccharides. Their complexity, however, has stood as an immense roadblock to translational research, as access to homogeneous material from nature is challenging. Thus, while carbohydrates are critical to the myriad functional and structural aspects of the biological sciences, their behavior is largely descriptive. This challenge presents an attractive opportunity for synthetic chemistry, particularly in the area of human milk science. First, there is an inordinate need for synthesizing homogeneous human milk oligosaccharides (HMOs). Superimposed on this goal is the mission of conducting syntheses at scale to enable animal studies. Herein, we present a personalized rumination of our involvement, and that of our colleagues, which has led to the synthesis and characterization of HMOs and mechanistic probes. Along the way, we highlight chemical, chemoenzymatic, and synthetic biology based approaches. We close with a discussion on emergent challenges and opportunities for synthesis, broadly defined, in human milk science.
- Published
- 2021
47. Structure-Based Engineering of Peptide Macrocyclases for the Chemoenzymatic Synthesis of Microviridins
- Author
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Lily M Silsby, Krishna Patel, Steven D. Bruner, and Gengnan Li
- Subjects
chemistry.chemical_classification ,Signal peptide ,Depsipeptide ,Serine Proteinase Inhibitors ,Stereochemistry ,Organic Chemistry ,Substrate (chemistry) ,Enzyme Interaction ,Peptide ,Cyanobacteria ,Ligases ,chemistry.chemical_compound ,Enzyme ,Biosynthesis ,chemistry ,Peptides ,Function (biology) - Abstract
Microviridins are cyanobacterial tricyclic depsipeptides with unique ring architectures and function as serine protease inhibitors. In this study, we explore two strategies to probe the structure and mechanism of macrocyclases involved in microviridin biosynthesis. The results both provide approaches for in vitro chemoenzymatic synthesis and insight into the molecular interactions and function of the biosynthetic enzymes. The first strategy involves generating constitutively activated macrocyclases whereby the leader portion of the substrate peptide is covalently attached to the ATP-grasp ligases to examine leader peptide/enzyme interactions. The second strategy uses a structure-based design to create disulfide cross-linked peptide/enzyme complexes. Together, the strategies provide constitutively active enzymes and tools to study the catalysis of the macrocyclizations on synthetic core peptides.
- Published
- 2021
48. Study of the Reaction of Hydroxylamine with Iridium Atomic and Cluster Anions (n = 1–5)
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Zhaoguo Zhu, Ghanshyam L. Vaghjiani, Jerry A. Boatz, Steven D. Chambreau, Robert J. Buszek, Mary Marshall, Tatsuya Chiba, Moritz Blankenhorn, Sara Marquez, Sandra M. Ciborowski, Kit H. Bowen, Rachel M. Harris, Evan Collins, and Gaoxiang Liu
- Subjects
chemistry.chemical_compound ,Reaction mechanism ,Hydroxylamine ,chemistry ,Ionic liquid ,Hydrazine ,Cluster (physics) ,chemistry.chemical_element ,Iridium ,Physical and Theoretical Chemistry ,Photochemistry ,Hydroxylammonium nitrate ,Catalysis - Abstract
Elucidating the multifaceted processes of molecular activation and subsequent reactions gives a fundamental view into the development of iridium catalysts as they apply to fuels and propellants, for example, for spacecraft thrusters. Hydroxylamine, a component of the well-known hydroxylammonium nitrate (HAN) ionic liquid, is a safer alternative and mimics the chemistry and performance standards of hydrazine. The activation of hydroxylamine by anionic iridium clusters, Irn- (n = 1-5), depicts a part of the mechanism, where two hydrogen atoms are removed, likely as H2, and Irn(NOH)- clusters remain. The significant photoelectron spectral differences between these products and the bare clusters illustrate the substantial electronic changes imposed by the hydroxylamine fragment on the iridium clusters. In combination with DFT calculations, a preliminary reaction mechanism is proposed, identifying the possible intermediate steps leading to the formation of Ir(NOH)-.
- Published
- 2021
49. Harnessing anomeric anions to synthesize α- and β-deoxyaminoglycosides
- Author
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Steven D. Townsend, Alexander J. Hughes, and C. Elizabeth Adams
- Subjects
chemistry.chemical_classification ,animal structures ,Anomer ,General method ,chemistry.chemical_element ,Glycoside ,macromolecular substances ,General Chemistry ,Nitrogen ,Combinatorial chemistry ,carbohydrates (lipids) ,chemistry.chemical_compound ,chemistry ,lipids (amino acids, peptides, and proteins) ,Glycosyl ,Reactivity (chemistry) ,Organic synthesis - Abstract
The synthesis of glycosides incorporating basic nitrogen atoms is a longstanding challenge in organic synthesis. By leveraging the reactivity of glycosyl anions, a general method has been developed that enables use of glycosyl donors incorporating unprotected, basic amines.
- Published
- 2021
50. Strains induced in the vagina by smooth muscle contractions
- Author
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Pamela Moalli, Alyssa Huntington, Raffaella De Vita, and Steven D. Abramowitch
- Subjects
0206 medical engineering ,Biomedical Engineering ,Strain (injury) ,02 engineering and technology ,Isometric exercise ,Biochemistry ,Pelvic Organ Prolapse ,Biomaterials ,Contractility ,Smooth muscle ,Ultimate tensile strength ,medicine ,Animals ,Molecular Biology ,Mechanical Phenomena ,Chemistry ,Muscle, Smooth ,General Medicine ,Anatomy ,Smooth muscle contraction ,021001 nanoscience & nanotechnology ,Compression (physics) ,medicine.disease ,020601 biomedical engineering ,Rats ,medicine.anatomical_structure ,Vagina ,Female ,0210 nano-technology ,Muscle Contraction ,Biotechnology - Abstract
The ability of the vagina to contract gives rise to a set of active mechanical properties that contribute to the complex function of this organ in-vivo. Regional differences in the morphology of the vagina have been long recognized, but the large heterogeneous deformations that the vagina experiences during contractions have never been quantified. Furthermore, there is no consensus regarding differences in contractility along the two primary anatomical directions of the vagina: the longitudinal direction (LD) and the circumferential direction (CD). In this study, square vaginal specimens from healthy virgin rats ( n = 15 ) were subjected to isometric planar biaxial tests at four equi-biaxial stretches of 1.0, 1.1, 1.2, and 1.3. Contractions were induced at each stretch by a high concentration potassium solution. The digital image correlation method was used to perform full-field strain measurements during contractions. The vagina was found to undergo significantly higher compressive strains, tensile strains, and contractile forces along the LD than along the CD during contractions. Specifically, when computed over all the applied equi-biaxial stretches, mean ( ± std. dev.) absolute maximum compressive strains were -(13.43 ± 1.56) % along the LD and -(3.19 ± 0.25) % along the CD, mean absolute maximum tensile strains were (10.92 ± 1.73) % along the LD and (3.62 ± 0.57) % along the CD, and mean maximum contractile forces were 6.24 ± 0.55 mN along the LD and 3.35 ± 0.56 mN along the CD. Moreover, the vaginal tissue appeared to undergo compression in the proximal region and tension in the distal region while kept at constant equi-biaxial stretches. The active mechanical properties of the healthy vagina need to be fully investigated so that detrimental alterations in vaginal contractility, such as those caused by pelvic floor disorders and current treatment strategies, can be prevented. Statement of significance Contractile forces of the vagina have been measured by several investigators using uniaxial tensile testing methods. Unlike previous studies, in this study planar-biaxial tests of vaginal specimens were performed while the full-field strains of the vagina, as induced by smooth muscle contraction, were measured. The vagina was found to generate significantly larger contractile strains and forces in the longitudinal direction than in the circumferential direction. Knowledge of the contractile mechanics of the healthy vagina is essential to understand the detrimental effects that pelvic organ prolapse and the use of surgical meshes have on the functionality of smooth muscle in the vagina.
- Published
- 2021
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