61 results on '"Andrew M. King"'
Search Results
2. Functional expression of diverse post-translational peptide-modifying enzymes in Escherichia coli under uniform expression and purification conditions
- Author
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Emerson Glassey, Andrew M. King, Daniel A. Anderson, Zhengan Zhang, and Christopher A. Voigt
- Subjects
Medicine ,Science - Abstract
RiPPs (ribosomally-synthesized and post-translationally modified peptides) are a class of pharmaceutically-relevant natural products expressed as precursor peptides before being enzymatically processed into their final functional forms. Bioinformatic methods have illuminated hundreds of thousands of RiPP enzymes in sequence databases and the number of characterized chemical modifications is growing rapidly; however, it remains difficult to functionally express them in a heterologous host. One challenge is peptide stability, which we addressed by designing a RiPP stabilization tag (RST) based on a small ubiquitin-like modifier (SUMO) domain that can be fused to the N- or C-terminus of the precursor peptide and proteolytically removed after modification. This is demonstrated to stabilize expression of eight RiPPs representative of diverse phyla. Further, using Escherichia coli for heterologous expression, we identify a common set of media and growth conditions where 24 modifying enzymes, representative of diverse chemistries, are functional. The high success rate and broad applicability of this system facilitates: (i) RiPP discovery through high-throughput “mining” and (ii) artificial combination of enzymes from different pathways to create a desired peptide.
- Published
- 2022
3. Evaluation of an Intervention to Improve Quality of Single-best Answer Multiple-choice Questions
- Author
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Andrew M. King, Molly K. Estes, Lauren W. Conlon, Jonathan S. Jones, and Andrew W. Phillips
- Subjects
Medicine ,Medical emergencies. Critical care. Intensive care. First aid ,RC86-88.9 - Abstract
Introduction: Despite the ubiquity of single-best answer multiple-choice questions (MCQ) in assessments throughout medical education, question writers often receive little to no formal training, potentially decreasing the validity of assessments. While lengthy training opportunities in item writing exist, the availability of brief interventions is limited. Methods: We developed and performed an initial validation of an item-quality assessment tool and measured the impact of a brief educational intervention on the quality of single-best answer MCQs. Results: The item-quality assessment tool demonstrated moderate internal structure evidence when applied to the 20 practice questions (κ=.671, p
- Published
- 2019
- Full Text
- View/download PDF
4. Show Me the Money: Successfully Obtaining Grant Funding in Medical Education
- Author
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Sangil Lee, John Burkhardt, Jestin N. Carlson, Andrew M. King, Ambrose H. Wong, and Sally A. Santen
- Subjects
Medicine ,Medical emergencies. Critical care. Intensive care. First aid ,RC86-88.9 - Abstract
Obtaining grant funding is a fundamental component to achieving a successful research career. A successful grant application needs to meet specific mechanistic expectations of reviewers and funders. This paper provides an overview of the importance of grant funding within medical education, followed by a stepwise discussion of strategies for creating a successful grant application for medical education-based proposals. The last section includes a list of available medical education research grants.
- Published
- 2019
- Full Text
- View/download PDF
5. Asteroids® and Electrocardiograms: Proof of Concept of a Simulation for Task-Switching Training
- Author
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Farhad Aziz, Bryan Yeh, Geremiha Emerson, Christopher San Miguel, and Andrew M. King
- Subjects
Medicine ,Medical emergencies. Critical care. Intensive care. First aid ,RC86-88.9 - Abstract
Introduction: Emergency physicians are interrupted during patient care with such tasks as reading electrocardiograms (ECGs). This phenomenon is known as task-switching which may be a teachable skill. Our objective was to evaluate the potential of a video game for simulating the cognitive demands required of task-switching. Methods: Emergency medicine residents took a pretest on ECG interpretation and then a posttest while attending to a video game, Asteroids®. Results: The 35 residents (63%) who participated, scored worse on the ECG posttest then they did on the pretest (p
- Published
- 2019
- Full Text
- View/download PDF
6. A Randomized Comparison of In-hospital Rescuer Positions for Endotracheal Intubation in a Difficult Airway
- Author
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Joanna M. Le Parc, Jason J. Bischof, Andrew M. King, Sarah Greenberger, David P. Way, Ashish R. Panchal, Geoffrey I. Finnegan, and Thomas E. Terndrup
- Subjects
Medicine ,Medical emergencies. Critical care. Intensive care. First aid ,RC86-88.9 - Abstract
Introduction: Emergency endotracheal intubation (ETI) is a common and critical procedure performed in both prehospital and in-hospital settings. Studies of prehospital providers have demonstrated that rescuer position influences ETI outcomes. However, studies of in-hospital rescuer position for ETI are limited. While we adhere to strict standards for the administration of ETI, we posited that perhaps requiring in-hospital rescuers to stand for ETI is an obstacle to effectiveness. Our objective was to compare in-hospital emergency medicine (EM) trainees’ performance on ETI delivered from both the seated and standing positions. Methods: EM residents performed ETI on a difficult airway mannequin from both a seated and standing position. They were randomized to the position from which they performed ETI first. All ETIs were recorded and then scored using a modified version of the Airway Management Proficiency Checklist. Residents also rated the laryngeal view and the difficulty of the procedure. We analyzed comparisons between ETI positions with paired t-tests. Results: Forty-two of our 49 residents (85.7%) participated. Fifteen (35.7%) were female, and all three levels of training were represented. The average number of prior ETI experiences among our subjects was 44 (standard deviation=34). All scores related to ETI performance were statistically equivalent across the two positions (performance score, number of attempts, time to intubation success, and ratings of difficulty and laryngeal view). We also observed no differences across levels of training. Conclusion: The position of the in-hospital provider, whether seated or standing, had no effect on the provider’s ETI performance. Since environmental circumstances sometimes necessitate alternative positioning for effective ETI administration, our findings suggest that there may be value in training residents to perform ETI from both positions.
- Published
- 2018
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- View/download PDF
7. Bringing the Flipped Classroom to Day 1: A Novel Didactic Curriculum for Emergency Medicine Intern Orientation
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Michael G. Barrie, Christopher Amick, Jennifer Mitzman, David P. Way, and Andrew M. King
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Medicine ,Medical emergencies. Critical care. Intensive care. First aid ,RC86-88.9 - Abstract
Most emergency medicine (EM) residency programs provide an orientation program for their incoming interns, with the lecture being the most common education activity during this period. Our orientation program is designed to bridge the gap between undergraduate and graduate medical education by ensuring that all learners demonstrate competency on Level 1 Milestones, including medical knowledge (MK). To teach interns core medical knowledge in EM, we reformulated orientation using the flipped-classroom model by replacing lectures with small group, case-based discussions. Interns demonstrated improvement in medical knowledge through higher scores on a posttest. Evaluation survey results were also favorable for the flipped-classroom teaching format.
- Published
- 2017
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8. Replacing Lectures with Small Groups: The Impact of Flipping the Residency Conference Day
- Author
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Andrew M. King, Chad Mayer, Michael Barrie, Sarah Greenberger, and David P. Way
- Subjects
Medicine ,Medical emergencies. Critical care. Intensive care. First aid ,RC86-88.9 - Abstract
The flipped classroom, an educational alternative to the traditional lecture, has been widely adopted by educators at all levels of education and across many disciplines. In the flipped classroom, learners prepare in advance of the face-to-face meeting by learning content material on their own. Classroom time is reserved for application of the learned content to solving problems or discussing cases. Over the past year, we replaced most residency program lectures with small-group discussions using the flipped-classroom model, case-based learning, simulation and procedure labs. In the new model, residents prepared for conference by reviewing a patient case and studying suggested learning materials. Conference day was set aside for facilitated small-group discussions about the case. This is a cross-cohort study of emergency medicine residents who experienced the lecture-based curriculum to residents in the new flipped-classroom curriculum using paired comparisons (independent t-tests) on in-training exam scores while controlling for program year level. We also compared results of the evaluation of various program components. We observed no differences between cohorts on in-training examination scores. Small-group methods were rated the same across program years. Two program components in the new curriculum, an updated format of both adult and pediatric case conferences, were rated significantly higher on program quality. In preparation for didactics, residents in the new curriculum report spending more time on average with outside learning materials, including almost twice as much time reviewing textbooks. Residents found the new format of the case conferences to be of higher quality because of the inclusion of rapid-fire case discussions with targeted learning points.
- Published
- 2017
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- View/download PDF
9. A First-Class Simulation: In-Situ In-Flight Medical Emergencies Curriculum for Emergency Medicine Residents Aboard a Commercial Airliner
- Author
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Madison B Kommor, Krystin N Miller, Thomas L Powell, Andrew M King, Christopher E San Miguel, Alix Delamare Fauvel, Jennifer A Frey, and Jennifer Yee
- Subjects
General Engineering - Published
- 2023
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10. From the ground up: Creating and leading fellowship programs in emergency medicine
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Allison M. Beaulieu, Kimberly Bambach, N. Shakira Bandolin, David Barnes, Anne Messman, Dimitrios Papanagnou, Niels K. Rathlev, Martin A. Reznek, Benjamin Schnapp, and Andrew M. King
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Emergency Medicine ,Concept Paper ,Emergency Nursing ,Education - Abstract
BACKGROUND: A methodical and evidence‐based approach to the creation and implementation of fellowship programs is not well described in the graduate medical education literature. The Society for Academic Emergency Medicine (SAEM) convened an expert panel to promote standardization and excellence in fellowship training. The purpose of the expert panel was to develop a fellowship guide to give prospective fellowship directors the necessary skills to successfully implement and maintain a fellowship program. METHODS: Under direction of the SAEM Board of Directors, SAEM Education Committee, and SAEM Fellowship Approval Committee, a panel of content experts convened to develop a fellowship guide using an evidence‐based approach and best practices content method. The resource guide was iteratively reviewed by all panel members. RESULTS: Utilizing Kern's six‐step model as a conceptual framework, the fellowship guide summarizes the construction, implementation, evaluation, and dissemination of a novel fellowship curriculum to meet the needs of trainees, educators, and sponsoring institutions. Other key areas addressed include Accreditation Council for Graduate Medical Education and nonaccredited fellowships, programmatic assessment, finances, and recruitment. CONCLUSIONS: The fellowship guide summarizes the conceptual framework, best practices, and strategies to create and implement a new fellowship program.
- Published
- 2022
11. Characterizing chemical signaling between engineered 'microbial sentinels' in porous microplates
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Christopher A Vaiana, Hyungseok Kim, Jonathan Cottet, Keiko Oai, Zhifei Ge, Kameron Conforti, Andrew M King, Adam J Meyer, Haorong Chen, Christopher A Voigt, and Cullen R Buie
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Computational Theory and Mathematics ,General Immunology and Microbiology ,Applied Mathematics ,Escherichia coli ,Quorum Sensing ,Hydrogels ,General Agricultural and Biological Sciences ,Porosity ,General Biochemistry, Genetics and Molecular Biology ,Information Systems ,Signal Transduction - Abstract
Living materials combine a material scaffold, that is often porous, with engineered cells that perform sensing, computing, and biosynthetic tasks. Designing such systems is difficult because little is known regarding signaling transport parameters in the material. Here, the development of a porous microplate is presented. Hydrogel barriers between wells have a porosity of 60% and a tortuosity factor of 1.6, allowing molecular diffusion between wells. The permeability of dyes, antibiotics, inducers, and quorum signals between wells were characterized. A "sentinel" strain was constructed by introducing orthogonal sensors into the genome of Escherichia coli MG1655 for IPTG, anhydrotetracycline, L-arabinose, and four quorum signals. The strain's response to inducer diffusion through the wells was quantified up to 14 mm, and quorum and antibacterial signaling were measured over 16 h. Signaling distance is dictated by hydrogel adsorption, quantified using a linear finite element model that yields adsorption coefficients from 0 to 0.1 mol m
- Published
- 2022
12. Selection for constrained peptides that bind to a single target protein
- Author
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Daniel A. Anderson, Amanda C. Embree, Thomas Williams, Andrew M. King, David L. Niquille, Christopher A. Voigt, Thomas H. Segall-Shapiro, Zhengan Zhang, Katelin Pratt, Emerson Glassey, and D. Benjamin Gordon
- Subjects
Models, Molecular ,Science ,Drug Evaluation, Preclinical ,General Physics and Astronomy ,Peptide ,Plasma protein binding ,medicine.disease_cause ,Antiviral Agents ,General Biochemistry, Genetics and Molecular Biology ,Article ,Synthetic biology ,chemistry.chemical_compound ,RNA polymerase ,medicine ,Humans ,Escherichia coli ,Selectable marker ,chemistry.chemical_classification ,Multidisciplinary ,SARS-CoV-2 ,COVID-19 ,General Chemistry ,COVID-19 Drug Treatment ,Kinetics ,Enzyme ,chemistry ,Biochemistry ,Drug Design ,Spike Glycoprotein, Coronavirus ,Natural product synthesis ,Target protein ,Peptides ,human activities ,Protein Binding - Abstract
Peptide secondary metabolites are common in nature and have diverse pharmacologically-relevant functions, from antibiotics to cross-kingdom signaling. Here, we present a method to design large libraries of modified peptides in Escherichia coli and screen them in vivo to identify those that bind to a single target-of-interest. Constrained peptide scaffolds were produced using modified enzymes gleaned from microbial RiPP (ribosomally synthesized and post-translationally modified peptide) pathways and diversified to build large libraries. The binding of a RiPP to a protein target leads to the intein-catalyzed release of an RNA polymerase σ factor, which drives the expression of selectable markers. As a proof-of-concept, a selection was performed for binding to the SARS-CoV-2 Spike receptor binding domain. A 1625 Da constrained peptide (AMK-1057) was found that binds with similar affinity (990 ± 5 nM) as an ACE2-derived peptide. This demonstrates a generalizable method to identify constrained peptides that adhere to a single protein target, as a step towards “molecular glues” for therapeutics and diagnostics., Peptide secondary metabolites have a diverse range of functions. Here the authors present a method to design and screen a large library of modified peptides in E. coli against a target of interest.
- Published
- 2021
13. Functional expression of diverse post-translational peptide-modifying enzymes in Escherichia coli under uniform expression and purification conditions
- Author
-
Emerson Glassey, Andrew M. King, Daniel A. Anderson, Zhengan Zhang, and Christopher A. Voigt
- Subjects
Biological Products ,Multidisciplinary ,Escherichia coli ,Peptides ,Ribosomes ,Ubiquitins - Abstract
RiPPs (ribosomally-synthesized and post-translationally modified peptides) are a class of pharmaceutically-relevant natural products expressed as precursor peptides before being enzymatically processed into their final functional forms. Bioinformatic methods have illuminated hundreds of thousands of RiPP enzymes in sequence databases and the number of characterized chemical modifications is growing rapidly; however, it remains difficult to functionally express them in a heterologous host. One challenge is peptide stability, which we addressed by designing a RiPP stabilization tag (RST) based on a small ubiquitin-like modifier (SUMO) domain that can be fused to the N- or C-terminus of the precursor peptide and proteolytically removed after modification. This is demonstrated to stabilize expression of eight RiPPs representative of diverse phyla. Further, using Escherichia coli for heterologous expression, we identify a common set of media and growth conditions where 24 modifying enzymes, representative of diverse chemistries, are functional. The high success rate and broad applicability of this system facilitates: (i) RiPP discovery through high-throughput “mining” and (ii) artificial combination of enzymes from different pathways to create a desired peptide.
- Published
- 2021
14. Social Identity and the Book of Amos
- Author
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Andrew M. King
- Subjects
Gender studies ,Sociology ,Social identity theory - Published
- 2021
- Full Text
- View/download PDF
15. Guillain-Barré
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Jennifer Yee, DO, Andrew M King, MD, and Jeremiah Emerson, MD
- Subjects
lcsh:LC8-6691 ,lcsh:Special aspects of education ,emergency medicine ,neurology ,medical simulation ,Guillain-Barré syndrome ,lcsh:L ,lcsh:Education - Abstract
Audience: This scenario was developed to educate emergency medicine residents on the diagnosis and management of Guillain-Barré syndrome in the emergency department. The case is also appropriate for senior medical students and advanced practice providers. The principles of crisis resource management, teamwork, and communication are also incorporated into the case. Introduction: Patients presenting with suspected Guillain-Barré syndrome require a thorough neurologic exam and likely a lumbar puncture. Due to the ascending weakness that may involve the diaphragm, providers must continually reassess the patient’s respiratory and hemodynamic status. If a patient demonstrates respiratory function weakness or has subjective worsening dyspnea, they should be evaluated for intubation. Objectives: At the conclusion of the simulation session, learners will be able to: 1) Recognize the clinical signs and symptoms associated with Guillain-Barré syndrome, including muscle weakness and hyporeflexia. 2) Identify abnormal vital signs secondary to dysautonomia. 3) Discuss evaluation for impending respiratory failure, including bedside pulmonary function testing. 4) Discuss the management of Guillain-Barré, including management of dysautonomia and respiratory failure, as well as definitive management with plasmapheresis versus intravenous immunoglobulin. 5) Appropriately disposition the patient to the intensive care unit. 6) Effectively communicate with team members and nursing staff during resuscitation of a critically ill patient Method: This session was conducted using high-fidelity simulation, followed by a debriefing session and lecture on the diagnosis and management of Guillain-Barré syndrome. Debriefing methods may be left to the discretion of participants, but the authors have utilized advocacy-inquiry techniques. Topics: Medical simulation, Guillain-Barré syndrome, emergency medicine, neurology
- Published
- 2018
16. Five Views of Christ in the Old Testament : Genre, Authorial Intent, and the Nature of Scripture
- Author
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Zondervan, Brian J. Tabb, Andrew M. King, Zondervan, Brian J. Tabb, and Andrew M. King
- Subjects
- Bible. Old Testament--Criticism, interpretation,, Typology (Theology), RELIGION / Biblical Criticism & Interpretation / O, RELIGION / Biblical Studies / Old Testament / Gene
- Abstract
The authors of the New Testament regularly quote and allude to Old Testament passages that point to the presence, person, and work of Jesus. Jesus himself claimed that Moses wrote about him (John 5:46). And on the road to Emmaus, Jesus instructed the disciples from'Moses and all the prophets'regarding himself (Luke 24:27).Though Christians affirm that the Old Testament bears witness to Christ, how the Old Testament writers did this is a matter of extensive debate. Furthermore, Christian biblical scholars also debate the degree to which contemporary interpreters of the Bible can follow the hermeneutics of the New Testament authors in using the Old Testament to point to the person and work of Jesus Christ.Five Views on Christ in the Old Testament is the first book to bring together in conversation the major views on how the Old Testament points to Christ. Contributors and views include:The First Testament Priority View (John Goldingay)The Christotelic View (Tremper Longman III)The Redemptive-Historical Christocentric View (Jason DeRouchie)The Reception-Centered Intertextual View (Havilah Dharamraj)The Premodern View (Craig Carter)Each contributor presents their preferred methodology, showing readers how their interpretive approach best explains the biblical data. Additionally, authors provide case studies of various Old Testament passages that equip readers to better compare the strengths and weaknesses of each of author's approaches. This essential resource will help readers learn practical steps to help them read the Old Testament more faithfully as it testifies to Jesus the Messiah.
- Published
- 2022
17. Social Identity and the Book of Amos
- Author
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Andrew M. King and Andrew M. King
- Subjects
- Group identity--Religious aspects, Jews--Identity--History, People of God
- Abstract
What, according to the Book of Amos, does it mean to be the people of God?In this book, Andrew M. King employs a Social Identity Approach (SIA), comprised of Social Identity Theory and Self-Categorization Theory, to explore the relationship between identity formation and the biblical text. Specifically, he examines the identity-forming strategies embedded in the Book of Amos. King begins by outlining the Social Identity Approach, especially its use in Hebrew Bible scholarship. Turning to the Book of Amos, he analyzes group dynamics and intergroup conflicts (national and interpersonal), as well as Amos's presentation of Israel's history and Israel's future. King provides extensive insight into the rhetorical strategies in Amos that shape the trans-temporal audience's sense of self. To live as the people of God, according to Amos, readers and hearers must adopt norms defined by a proper relationship to God that results in the proper treatment of others.
- Published
- 2021
18. The Law, The Prophets, and The Writings : Studies in Evangelical Old Testament Hermeneutics in Honor of Duane A. Garrett
- Author
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Andrew M King, Joshua M Philpot, William R Osborne, Andrew M King, Joshua M Philpot, and William R Osborne
- Abstract
The Old Testament is no ordinary text; it is a revelation of God's will, character, purpose, and plan, inspired by the Spirit of God. That same Spirit continues to work within God's people today as they read the Bible, even when the meaning is difficult to discern. In The Law, the Prophets, and the Writings, eighteen evangelical scholars analyze the Old Testament through a historical, literary, and theological hermeneutic, providing new insights into the meaning of the Scriptures. This festschrift in honor of Duane A. Garrett seeks to help Christians faithfully read and understand the Old Testament Scriptures.
- Published
- 2021
19. A Common Platform for Antibiotic Dereplication and Adjuvant Discovery
- Author
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Andrew C. Pawlowski, Gerard D. Wright, Gianfranco De Pascale, Andrew M. King, Kalinka Koteva, Arthur O. Sieron, and Georgina Cox
- Subjects
0301 basic medicine ,medicine.drug_class ,medicine.medical_treatment ,030106 microbiology ,Clinical Biochemistry ,Antibiotics ,Computational biology ,Biology ,Biochemistry ,03 medical and health sciences ,Antibiotic resistance ,Drug Resistance, Bacterial ,Drug Discovery ,medicine ,Molecular Biology ,Adjuvants, Pharmaceutic ,Pharmacology ,Bacteria ,Molecular Structure ,business.industry ,Antimicrobial ,Anti-Bacterial Agents ,High-Throughput Screening Assays ,Biotechnology ,Rapid identification ,030104 developmental biology ,Molecular Medicine ,Identification (biology) ,business ,Adjuvant - Abstract
Solving the antibiotic resistance crisis requires the discovery of new antimicrobial drugs and the preservation of existing ones. The discovery of inhibitors of antibiotic resistance, antibiotic adjuvants, is a proven example of the latter. A major difficulty in identifying new antibiotics is the frequent rediscovery of known compounds, necessitating laborious "dereplication" to identify novel chemical entities. We have developed an antibiotic resistance platform (ARP) that can be used for both the identification of antibiotic adjuvants and for antibiotic dereplication. The ARP is a cell-based array of mechanistically distinct individual resistance elements in an identical genetic background. In dereplication mode, we demonstrate the rapid identification, and thus discrimination, of common antibiotics. In adjuvant discovery mode, we show that the ARP can be harnessed in screens to identify inhibitors of resistance. The ARP is therefore a powerful tool that has broad application in confronting the resistance crisis.
- Published
- 2017
- Full Text
- View/download PDF
20. Did Jehu Destroy Baal from Israel? A Contextual Reading of Jehu's Revolt
- Author
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Andrew M. King
- Abstract
2 Kings 10:28 says unequivocally, “and so Jehu destroyed Baal from Israel.” This declaration has factored significantly into several reconstructions of Israelite religion in the 9th-8th centuries BCE. Some scholars argue that an established Baal cult was wholly absent from Israel following Jehu's purge. These scholars must then reinterpret the Baal polemics of Hos 2 as indicating something other than religious defection. This approach, however, misses important contextual data when considered within a broader ancient Near Eastern setting. This article argues that the Jehu narrative employs several stereotyped motifs present in Assyrian Royal Inscriptions (divine election, characterization of the enemy, chaos vs. order, exaggerated rhetoric and violence) as an understood means of legitimizing Jehu's reign. When these factors are identified, the rhetorical nature of the biblical author's language comes into focus. Thus, a face-value reading misses important textual indicators. Though Jehu dealt a major blow to the established Baal cult in the 9th century BCE, the language of the text accounts for its continuation.
- Published
- 2017
- Full Text
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21. Structural and Kinetic Characterization of Diazabicyclooctanes as Dual Inhibitors of Both Serine-β-Lactamases and Penicillin-Binding Proteins
- Author
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Gerard D. Wright, Eric Brouillette, J. Andrew N. Alexander, Marija Vuckovic, Eric D. Brown, Samarendra N. Maiti, Dustin T. King, Andrew M. King, Natalie C. J. Strynadka, Abdelhamid Asli, Shawn French, François Malouin, and Thomas R. Parr
- Subjects
0301 basic medicine ,Penicillin binding proteins ,Protein Conformation ,medicine.drug_class ,Avibactam ,030106 microbiology ,Antibiotics ,Microbial Sensitivity Tests ,Biology ,medicine.disease_cause ,Biochemistry ,Microbiology ,03 medical and health sciences ,chemistry.chemical_compound ,medicine ,Penicillin-Binding Proteins ,Escherichia coli ,Beta-Lactamase Inhibitors ,Drug discovery ,General Medicine ,Enterobacter ,biology.organism_classification ,Antimicrobial ,3. Good health ,Kinetics ,030104 developmental biology ,chemistry ,Molecular Medicine ,beta-Lactamase Inhibitors ,Azabicyclo Compounds - Abstract
Avibactam is a diazabicyclooctane β-lactamase inhibitor possessing outstanding but incomplete efficacy against multidrug-resistant Gram-negative pathogens in combination with β-lactam antibiotics. Significant pharmaceutical investment in generating derivatives of avibactam warrants a thorough characterization of their activity. We show here through structural and kinetic analysis that select diazabicyclooctane derivatives display effective but varied inhibition of two clinically important β-lactamases (CTX-M-15 and OXA-48). Furthermore, these derivatives exhibit considerable antimicrobial activity (MIC ≤ 2 μg/mL) against clinical isolates of Pseudomonas aeruginosa, Escherichia coli, and Enterobacter spp. Imaging of cell phenotype along with structural and biochemical experiments unambiguously demonstrate that this activity, in E. coli, is a result of targeting penicillin-binding protein 2. Our results suggest that structure-activity relationship studies for the purpose of drug discovery must consider both β-lactamases and penicillin-binding proteins as targets. We believe that this approach will yield next-generation combination or monotherapies with an expanded spectrum of activity against currently untreatable Gram-negative pathogens.
- Published
- 2016
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22. A Pressure Test to Make 10 Molecules in 90 Days: External Evaluation of Methods to Engineer Biology
- Author
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Min-Hyung Ryu, Anthony L. Forget, Ashty S. Karim, Robert Warden-Rothman, Quentin M. Dudley, Fang-Yuan Chang, Evangelos C. Tatsis, Michael C. Jewett, Sarah E. O'Connor, Carlos E. Rodríguez-López, Amar Ghodasara, Katelin Pratt, Marnix H. Medema, Raissa Eluere, Michael A. Fischbach, Arturo Casini, Cassandra Bristol, D. Benjamin Gordon, Amin Espah Borujeni, Jian Li, Christopher A. Voigt, Andrew M. King, Alexander Cristofaro, Yong-Chan Kwon, He Wang, Eric M. Young, and Rui Gan
- Subjects
0301 basic medicine ,Time Factors ,Bioinformatics ,Carbazoles ,Cyclohexane Monoterpenes ,Saccharomyces cerevisiae ,Biology ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Catalysis ,03 medical and health sciences ,Lactones ,Colloid and Surface Chemistry ,Bioinformatica ,Escherichia coli ,Pressure ,Life Science ,Production (economics) ,Furans ,Molecular Structure ,Chemistry ,Pacidamycin D ,Computational Biology ,General Chemistry ,Pyrimidine Nucleosides ,Streptomyces ,0104 chemical sciences ,Thiazoles ,030104 developmental biology ,Aminoglycosides ,Warhead ,Vincristine ,Monoterpenes ,Biochemical engineering ,EPS ,Enediynes ,Fatty Alcohols ,Genetic Engineering ,Peptides ,Pyrrolnitrin - Abstract
Centralized facilities for genetic engineering, or "biofoundries", offer the potential to design organisms to address emerging needs in medicine, agriculture, industry, and defense. The field has seen rapid advances in technology, but it is difficult to gauge current capabilities or identify gaps across projects. To this end, our foundry was assessed via a timed "pressure test", in which 3 months were given to build organisms to produce 10 molecules unknown to us in advance. By applying a diversity of new approaches, we produced the desired molecule or a closely related one for six out of 10 targets during the performance period and made advances toward production of the others as well. Specifically, we increased the titers of 1-hexadecanol, pyrrolnitrin, and pacidamycin D, found novel routes to the enediyne warhead underlying powerful antimicrobials, established a cell-free system for monoterpene production, produced an intermediate toward vincristine biosynthesis, and encoded 7802 individually retrievable pathways to 540 bisindoles in a DNA pool. Pathways to tetrahydrofuran and barbamide were designed and constructed, but toxicity or analytical tools inhibited further progress. In sum, we constructed 1.2 Mb DNA, built 215 strains spanning five species ( Saccharomyces cerevisiae, Escherichia coli, Streptomyces albidoflavus, Streptomyces coelicolor, and Streptomyces albovinaceus), established two cell-free systems, and performed 690 assays developed in-house for the molecules.
- Published
- 2018
23. A Brief Didactic Intervention to Improve Multiple-Choice Item- Writing Quality
- Author
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Jonathan S Jones, Andrew W Phillips, Andrew M King, Molly K Estes, Lauren W Conlon, and Kevin R Scott
- Subjects
Exam item writing ,lcsh:LC8-6691 ,lcsh:Special aspects of education ,multiple choice questions ,lcsh:L ,lcsh:Education - Abstract
Audience: Emergency Medicine Residents, Faculty Introduction: High stakes examinations encountered throughout medical education are often composed of single best answer multiple-choice questions (MCQs). Many guidelines for writing MCQs exist, but often item writers receive little to no formal training. Flawed exam items have been shown to have lower discrimination values, potentially introducing construct-irrelevant variance to examinations, reducing their validity.1–3 Long-term faculty development in the area of item writing has been shown to improve examination item quality, with a pilot study showing that a more brief intervention had the same impact on quality of written items.4–6 Furthermore, when learners have been engaged in item writing, they have found the exercise to be a beneficial learning experience, with one study demonstrating an improved performance on a summative assessment as a result of participating in item writing.7–10 Objectives: The primary objective of this training module is to provide emergency medicine residents the basic knowledge necessary to write high quality structured single-best answer examination items through a brief, independent study format. Method: The training module is a PowerPoint-based lecture with recorded voiceover, which is provided in mp4 format.
- Published
- 2018
- Full Text
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24. Zinc Chelation by a Small-Molecule Adjuvant Potentiates Meropenem Activity in Vivo against NDM-1-Producing Klebsiella pneumoniae
- Author
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Sebastian S. Gehrke, Sarah A. Reid-Yu, James F. Britten, Brian K. Coombes, Shannon B. Falconer, Gerard D. Wright, Eric D. Brown, Andrew M. King, and Wenliang Wang
- Subjects
medicine.drug_class ,Klebsiella pneumoniae ,medicine.medical_treatment ,Antibiotics ,Biology ,biology.organism_classification ,Meropenem ,In vitro ,3. Good health ,Microbiology ,Infectious Diseases ,In vivo ,Toxicity ,medicine ,Adjuvant ,Pathogen ,medicine.drug - Abstract
The widespread emergence of antibiotic drug resistance has resulted in a worldwide healthcare crisis. In particular, the extensive use of β-lactams, a highly effective class of antibiotics, has been a driver for pervasive β-lactam resistance. Among the most important resistance determinants are the metallo-β-lactamases (MBL), which are zinc-requiring enzymes that inactivate nearly all classes of β-lactams, including the last-resort carbapenem antibiotics. The urgent need for new compounds targeting MBL resistance mechanisms has been widely acknowledged; however, the development of certain types of compounds-namely metal chelators-is actively avoided due to host toxicity concerns. The work herein reports the identification of a series of zinc-selective spiro-indoline-thiadiazole analogues that, in vitro, potentiate β-lactam antibiotics against an MBL-carrying pathogen by withholding zinc availability. This study demonstrates the ability of one such analogue to inhibit NDM-1 in vitro and, using a mouse model of infection, shows that combination treatment of the respective analogue with meropenem results in a significant decrease in bacterial burden in contrast to animals that received antibiotic treatment alone. These results support the therapeutic potential of these chelators in overcoming antibiotic resistance.
- Published
- 2015
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25. Monotheism and Yahweh’s Appropriation of Baal
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Andrew M. King
- Published
- 2016
- Full Text
- View/download PDF
26. The Wiley Blackwell Companion to Ancient Israel
- Author
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Andrew M King
- Subjects
Linguistics and Language ,Archeology ,History ,Religious studies ,Environmental ethics ,Language and Linguistics ,Classics - Published
- 2016
- Full Text
- View/download PDF
27. Hosea. Two Horizons Old Testament Commentary
- Author
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Andrew M. King
- Published
- 2016
- Full Text
- View/download PDF
28. A molecular portrait of maternal sepsis from Byzantine Troy
- Author
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Shea N. Gardner, Hendrik N. Poinar, Gerard D. Wright, John Southon, Melanie Kuch, Jonathan E. Allen, Makoto Kuroda, Jacob Enk, Kengo Kato, Derek E. G. Briggs, Andrew Kitchen, Ana T. Duggan, Tatum D. Mortimer, Alison Devault, Henrike Kiesewetter, Caitlin S. Pepperell, Gino Fornaciari, William Aylward, G. Brian Golding, Edward C. Holmes, and Andrew M. King
- Subjects
0301 basic medicine ,Antibiotics ,medicine.disease_cause ,Pregnancy ,Gardnerella vaginalis ,Biology (General) ,Pregnancy Complications, Infectious ,Staphylococcus saprophyticus ,Microbiology and Infectious Disease ,biology ,Ancient DNA ,Fossils ,General Neuroscience ,General Medicine ,humanities ,Abscess ,chorioamnionitis ,Genomics and Evolutionary Biology ,Medicine ,Female ,DNA, Bacterial ,medicine.drug_class ,QH301-705.5 ,Science ,infectious disease ,030106 microbiology ,Short Report ,Genomics ,General Biochemistry, Genetics and Molecular Biology ,DNA sequencing ,Microbiology ,evolution ,evolutionary biology ,genomics ,human ,microbiology ,03 medical and health sciences ,medicine ,Humans ,Gram-Positive Bacterial Infections ,General Immunology and Microbiology ,biology.organism_classification ,030104 developmental biology ,Infectious disease (medical specialty) ,Microscopy, Electron, Scanning ,Other ,Bacteria - Abstract
Pregnancy complications are poorly represented in the archeological record, despite their importance in contemporary and ancient societies. While excavating a Byzantine cemetery in Troy, we discovered calcified abscesses among a woman’s remains. Scanning electron microscopy of the tissue revealed ‘ghost cells’, resulting from dystrophic calcification, which preserved ancient maternal, fetal and bacterial DNA of a severe infection, likely chorioamnionitis. Gardnerella vaginalis and Staphylococcus saprophyticus dominated the abscesses. Phylogenomic analyses of ancient, historical, and contemporary data showed that G. vaginalis Troy fell within contemporary genetic diversity, whereas S. saprophyticus Troy belongs to a lineage that does not appear to be commonly associated with human disease today. We speculate that the ecology of S. saprophyticus infection may have differed in the ancient world as a result of close contacts between humans and domesticated animals. These results highlight the complex and dynamic interactions with our microbial milieu that underlie severe maternal infections. DOI: http://dx.doi.org/10.7554/eLife.20983.001, eLife digest Why and how have some bacteria evolved to cause illness in humans? One way to study bacterial evolution is to search for ancient samples of bacteria and use DNA sequencing technology to investigate how modern bacteria have changed from their ancestors. Understanding the evolution process may help researchers to understand how some bacteria become resistant to the antibiotics designed to kill them. Complications that occur during pregnancy, including bacterial infections, have long been a major cause of death for women. Now, Devault, Mortimer et al. have been able to sequence the DNA of bacteria found in tissue collected from a woman buried 800 years ago in a cemetery in Troy. Some of the woman’s tissues had been well preserved because they had calcified (probably as the result of infection), which preserved their structure in a mineralized layer. Two mineralized “nodules” in the body appear to be the remains of abscesses. Some of the human DNA in the nodules came from a male, suggesting that the woman was pregnant with a boy and that the abscesses formed in placental tissue. Sequencing the DNA of the bacteria in the abscess allowed Devault, Mortimer et al. to diagnose the woman’s infection, which was caused by two types of bacteria. One species, called Gardnerella vaginalis, is found in modern pregnancy-related infections. The DNA of the ancient samples was similar to that of modern bacteria. The other bacteria species was an ancient form of Staphylococcus saprophyticus, a type of bacteria that causes urinary tract infections. However, the DNA of the ancient S. saprophyticus bacteria is quite different to that of the bacteria found in modern humans. Instead, their DNA sequence appears more similar to forms of the bacteria that infect currently livestock. As humans lived closely with their livestock at the time the woman lived, her infection may be due to a type of bacteria that passed easily between humans and animals. Overall, the results suggest that the disease-causing properties of bacteria can arise from a wide range of sources. In addition, Devault, Mortimer et al. have demonstrated that certain types of tissue found in archeological remains are a potential gold mine of information about the evolution of bacteria and other microbes found in the human body. DOI: http://dx.doi.org/10.7554/eLife.20983.002
- Published
- 2017
29. Identifying producers of antibacterial compounds by screening for antibiotic resistance
- Author
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Ricardo Medina, Peter Spanogiannopoulos, Andrew M. King, Gerard D. Wright, Wenliang Wang, Nicholas Waglechner, and Maulik N. Thaker
- Subjects
medicine.drug_class ,Antibiotics ,Drug Evaluation, Preclinical ,Biomedical Engineering ,Bioengineering ,Biology ,Applied Microbiology and Biotechnology ,Antibiotic resistance ,Vancomycin ,medicine ,Phylogeny ,business.industry ,Ansamycin ,Glycopeptides ,Reproducibility of Results ,Drug Resistance, Microbial ,Glycopeptide ,Biosynthetic enzyme ,Anti-Bacterial Agents ,Biosynthetic Pathways ,Biotechnology ,Actinobacteria ,Chemical diversity ,Molecular Medicine ,Rifampin ,business ,Biosynthetic genes - Abstract
Microbially derived natural products are major sources of antibiotics and other medicines, but discovering new antibiotic scaffolds and increasing the chemical diversity of existing ones are formidable challenges. We have designed a screen to exploit the self-protection mechanism of antibiotic producers to enrich microbial libraries for producers of selected antibiotic scaffolds. Using resistance as a discriminating criterion we increased the discovery rate of producers of both glycopeptide and ansamycin antibacterial compounds by several orders of magnitude in comparison with historical hit rates. Applying a phylogeny-based screening filter for biosynthetic genes enabled the binning of producers of distinct scaffolds and resulted in the discovery of a glycopeptide antibacterial compound, pekiskomycin, with an unusual peptide scaffold. This strategy provides a means to readily sample the chemical diversity available in microbes and offers an efficient strategy for rapid discovery of microbial natural products and their associated biosynthetic enzymes.
- Published
- 2013
- Full Text
- View/download PDF
30. The Comprehensive Antibiotic Resistance Database
- Author
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Gerard D. Wright, Jonathan S O'Brien, Patricia L. Taylor, Irene Tang, Marie Yan, Arlene D. Sutherland, Lindsay Kalan, Wenliang Wang, Andrew C. Pawlowski, Mariya Morar, Maulik N. Thaker, Kirandeep Bhullar, Gianfranco De Pascale, Michael R. Mulvey, Marc J. Canova, Nicholas Waglechner, Fazmin Nizam, Marisa A. Azad, Andrew M. King, Kalinka Koteva, Linda Ejim, Peter Spanogiannopoulos, Andrew G. McArthur, Laura J. V. Piddock, Alison J. Baylay, Austin Yan, and Tennison Yu
- Subjects
medicine.drug_class ,Ecology (disciplines) ,Antibiotics ,Genomics ,Computational biology ,Ontology (information science) ,Biology ,Genome ,User-Computer Interface ,Antibiotic resistance ,Anti-Infective Agents ,Mechanisms of Resistance ,Databases, Genetic ,medicine ,Pharmacology (medical) ,Pharmacology ,Internet ,Base Sequence ,business.industry ,Computational Biology ,Drug Resistance, Microbial ,Biotechnology ,Resistome ,Infectious Diseases ,Genes, Bacterial ,business ,Genome, Bacterial ,Antibiotic resistance genes - Abstract
The field of antibiotic drug discovery and the monitoring of new antibiotic resistance elements have yet to fully exploit the power of the genome revolution. Despite the fact that the first genomes sequenced of free living organisms were those of bacteria, there have been few specialized bioinformatic tools developed to mine the growing amount of genomic data associated with pathogens. In particular, there are few tools to study the genetics and genomics of antibiotic resistance and how it impacts bacterial populations, ecology, and the clinic. We have initiated development of such tools in the form of the Comprehensive Antibiotic Research Database (CARD; http://arpcard.mcmaster.ca ). The CARD integrates disparate molecular and sequence data, provides a unique organizing principle in the form of the Antibiotic Resistance Ontology (ARO), and can quickly identify putative antibiotic resistance genes in new unannotated genome sequences. This unique platform provides an informatic tool that bridges antibiotic resistance concerns in health care, agriculture, and the environment.
- Published
- 2013
- Full Text
- View/download PDF
31. Author response: A molecular portrait of maternal sepsis from Byzantine Troy
- Author
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Gerard D. Wright, Caitlin S. Pepperell, Makoto Kuroda, Edward C. Holmes, G. Brian Golding, Derek E. G. Briggs, Hendrik N. Poinar, Shea N. Gardner, Jonathan E. Allen, Melanie Kuch, Ana T. Duggan, Andrew M. King, Andrew Kitchen, Alison Devault, Tatum D. Mortimer, Jacob Enk, Kengo Kato, Henrike Kiesewetter, Gino Fornaciari, William Aylward, and John Southon
- Subjects
Sepsis ,Portrait ,media_common.quotation_subject ,medicine ,Art ,Ancient history ,medicine.disease ,Byzantine architecture ,media_common - Published
- 2016
- Full Text
- View/download PDF
32. Molecular Mechanism of Avibactam-Mediated β-Lactamase Inhibition
- Author
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Natalie C. J. Strynadka, Sarah M. Lal, Dustin T. King, Andrew M. King, and Gerard D. Wright
- Subjects
0303 health sciences ,030306 microbiology ,Stereochemistry ,Avibactam ,Mutant ,Kinetic analysis ,Biology ,3. Good health ,Serine ,03 medical and health sciences ,chemistry.chemical_compound ,Infectious Diseases ,chemistry ,Biochemistry ,Clavulanic acid ,Hydrolase ,medicine ,Molecular mechanism ,030304 developmental biology ,medicine.drug - Abstract
Emerging β-lactamase-mediated resistance is threatening the clinical utility of the single most prominent class of antibacterial agents used in medicine, the β-lactams. The diazabicyclooctane avibactam is able to inhibit a wider range of serine β-lactamases than has been previously observed with β-lactamase inhibitors such as the widely prescribed clavulanic acid. However, despite its broad-spectrum activity, variable levels of inhibition have been observed for molecular class D β-lactamases. In order to better understand the molecular basis and spectrum of inhibition by avibactam, we provide structural and mechanistic analysis of the compound in complex with important class A and D serine β-lactamases. Herein, we reveal the 1.7- and 2.0-Å-resolution crystal structures of avibactam covalently bound to class D β-lactamases OXA-10 and OXA-48. Furthermore, a kinetic analysis of key active-site mutants for class A β-lactamase CTX-M-15 allows us to propose a validated mechanism for avibactam-mediated β-lactamase inhibition including a unique role for S130, which acts as a general base. This study provides molecular insights that will aid in the design and development of avibactam-based chemotherapeutic agents effective against emerging drug-resistant microorganisms.
- Published
- 2016
33. Carbon fibre composite deformable mirrors: Developments at UCL
- Author
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Chris Yates, Chris Dorn, Richard Martin Dwan, David J. Brooks, Ian M. Richardson, Glyn Charles Dando, Glynn Evans, Sarah Kendrew, Andrew M. King, and Peter Doel
- Subjects
Materials science ,Optics ,business.industry ,Surface roughness ,Mechanical engineering ,Polishing ,Residual ,Adaptive optics ,business ,Optical telescope ,Deformable mirror ,Data modeling ,Grinding - Abstract
Adaptive optics performance is essential for achieving the demanding science goals set for the ground-based optical telescopes of the future - the so-called extremely large telescopes (ELTs). Research into novel technologies for lightweight and robust active and adaptive mirrors is crucial for ensuring this capability. Surface quality, form, and a high level of stability during operation are very important criteria for such mirrors. In 2004 we reported initial results from a project into the design and manufacture of a prototype carbon fibre reinforced polymer (CFRP) deformable mirror. This system has now been extensively characterised and tested, and results of dynamical testing and influence function measurements are discussed here. Manual grinding and polishing resulted in a residual form error of the order of 10 μ m P-V and a surface roughness of approximately 5 nm rms. A good agreement was observed between the modeling data and experimental results.
- Published
- 2016
34. Prototype carbon fiber composite deformable mirror
- Author
-
Peter Doel, David J. Brooks, Chris Yates, Sarah Kendrew, Andrew M. King, Chris Dorn, Glynn Evans, Richard Martin Dwan, and Ian M. Richardson
- Subjects
Carbon fiber reinforced polymer ,Computer science ,business.industry ,General Engineering ,Mechanical engineering ,Active optics ,Atomic and Molecular Physics, and Optics ,Finite element method ,Deformable mirror ,Characterization (materials science) ,Set (abstract data type) ,Optics ,Adaptive optics ,business ,Actuator - Abstract
Research into novel technologies for active and adaptive optics is essential to ensure the required performance for the demanding science goals set for next-generation astronomical observatories. Both in space and on the ground, the potential gain from ultralightweight and thermally stable deformable optics is high. Surface quality, form, and a high level of stability during operation are important criteria for such mirrors. In 2006 we reported our initial results of the design and manufacture of a prototype carbon fiber reinforced polymer (CFRP) deformable mirror, including a description of the mirror's assembly with a stiff backing structure and actuator array, and an extensive characterization of the system. Here we discuss results of dynamical testing and influence function measurements as well as details of the methodology. Influence function shapes showed reasonable agreement with the finite element analysis predictions, confirming the suitability of the finite element method as a design aid for precision optical systems. While problems remain with this technology, our results highlight some important issues and provide useful guidelines for further research. © 2007 Society of Photo-Optical Instrumentation Engineers.
- Published
- 2016
35. Total Synthesis of Aspergillomarasmine A and Related Compounds: A Sulfamidate Approach Enables Exploration of Structure-Activity Relationships
- Author
-
Kalinka Koteva, Alfredo Capretta, Silvia Albu, Andrew M. King, Gerard D. Wright, and Salma Al-Karmi
- Subjects
Stereochemistry ,Nanotechnology ,Microbial Sensitivity Tests ,Secondary metabolite ,010402 general chemistry ,01 natural sciences ,Catalysis ,beta-Lactamases ,chemistry.chemical_compound ,Structure-Activity Relationship ,Enterobacteriaceae ,Pseudomonas ,parasitic diseases ,medicine ,Enzyme Inhibitors ,chemistry.chemical_classification ,Aspartic Acid ,Acinetobacter ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Total synthesis ,Biological activity ,General Chemistry ,General Medicine ,Aspergillomarasmine A ,Amides ,0104 chemical sciences ,Anti-Bacterial Agents ,Enzyme ,chemistry ,medicine.drug - Abstract
The fungal secondary metabolite aspergillomarasmine A (AMA) has recently been identified as an inhibitor of metallo-β-lactamases NDM-1 and VIM-2. Described herein is an efficient and practical route to AMA and its related compounds by a sulfamidate approach. In addition, a series of derivatives has been prepared and tested for biological activity in an effort to explore preliminary structure activity relationships. While it was determined that natural LLL isomer of AMA remains the most effective inactivator of NDM-1 enzyme activity both in vitro and in cells, the structure is highly tolerant of the changes in the stereochemistry at positions 3, 6, and 9.
- Published
- 2016
36. ChemInform Abstract: Total Synthesis and Activity of the Metallo-β-lactamase Inhibitor Aspergillomarasmine A
- Author
-
Kalinka Koteva, Gerard D. Wright, Andrew M. King, and Alfredo Capretta
- Subjects
chemistry.chemical_classification ,Codrug ,Chemistry ,medicine.drug_class ,Antibiotics ,Total synthesis ,General Medicine ,Secondary metabolite ,Aspergillomarasmine A ,Serine ,chemistry.chemical_compound ,Enzyme ,Biochemistry ,Nucleophile ,medicine ,medicine.drug - Abstract
Resistance to β-lactam antibiotics is mediated primarily by enzymes that hydrolytically inactivate the drugs by one of two mechanisms: serine nucleophilic attack or metal-dependent activation of a water molecule. Serine β-lactamases are countered in the clinic by several codrugs that inhibit these enzymes, thereby rescuing antibiotic action. There are no equivalent inhibitors of metallo-β-lactamases in clinical use, but the fungal secondary metabolite aspergillomarasmine A has recently been identified as a potential candidate for such a codrug. Herein we report the synthesis of aspergillomarasmine A. The synthesis enabled confirmation of the stereochemical configuration of the compound and offers a route for the synthesis of derivatives in the future.
- Published
- 2016
- Full Text
- View/download PDF
37. Sympathomimetic Syndrome
- Author
-
Andrew M. King, Eric R. Malone, and Cynthia K. Aaron
- Published
- 2016
- Full Text
- View/download PDF
38. Total Synthesis and Activity of the Metallo-β-lactamase Inhibitor Aspergillomarasmine A
- Author
-
Alfredo Capretta, Gerard D. Wright, Andrew M. King, and Kalinka Koteva
- Subjects
0301 basic medicine ,medicine.drug_class ,Stereochemistry ,Antibiotics ,010402 general chemistry ,01 natural sciences ,Catalysis ,beta-Lactamases ,Serine ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,medicine ,Structure–activity relationship ,Beta-Lactamase Inhibitors ,chemistry.chemical_classification ,Aspartic Acid ,Codrug ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Total synthesis ,General Chemistry ,General Medicine ,Aspergillomarasmine A ,0104 chemical sciences ,3. Good health ,030104 developmental biology ,Enzyme ,Aspergillus ,chemistry ,Biochemistry ,beta-Lactamase Inhibitors - Abstract
Resistance to β-lactam antibiotics is mediated primarily by enzymes that hydrolytically inactivate the drugs by one of two mechanisms: serine nucleophilic attack or metal-dependent activation of a water molecule. Serine β-lactamases are countered in the clinic by several codrugs that inhibit these enzymes, thereby rescuing antibiotic action. There are no equivalent inhibitors of metallo-β-lactamases in clinical use, but the fungal secondary metabolite aspergillomarasmine A has recently been identified as a potential candidate for such a codrug. Herein we report the synthesis of aspergillomarasmine A. The synthesis enabled confirmation of the stereochemical configuration of the compound and offers a route for the synthesis of derivatives in the future.
- Published
- 2015
39. Cardiotoxicodynamics: Toxicity of Cardiovascular Xenobiotics
- Author
-
Nathan B, Menke, Steven J, Walsh, and Andrew M, King
- Subjects
Cardiotonic Agents ,Adrenergic beta-Antagonists ,Potassium Channel Blockers ,Action Potentials ,Humans ,Angiotensin-Converting Enzyme Inhibitors ,Arrhythmias, Cardiac ,Heart ,Anti-Arrhythmia Agents ,Sodium Channel Blockers ,Xenobiotics - Abstract
Maintaining adequate tissue perfusion depends on a variety of factors, all of which can be influenced by xenobiotics (substances foreign to the body, including pharmaceuticals, chemicals, and natural compounds). Volume status, systemic vascular resistance, myocardial contractility, and cardiac rhythm all play a significant role in ensuring hemodynamic stability and proper cardiovascular function. Direct effects on the nervous system, the vasculature, or the heart itself as well as indirect metabolic effects may play a significant role in the development of cardiotoxicity. This article is dedicated to discussion of the disruption of cardiovascular physiology by xenobiotics.
- Published
- 2015
40. Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance
- Author
-
Dustin T. King, Timothy R. Walsh, Sarah A. Reid-Yu, Wenliang Wang, Brian K. Coombes, Gerard D. Wright, Natalie C. J. Strynadka, Gianfranco De Pascale, and Andrew M. King
- Subjects
Carbapenem ,medicine.drug_class ,Klebsiella pneumoniae ,Cephalosporin ,Antibiotics ,Drug Evaluation, Preclinical ,Biology ,Meropenem ,beta-Lactam Resistance ,beta-Lactamases ,Microbiology ,Mice ,Antibiotic resistance ,Gram-Negative Bacteria ,polycyclic compounds ,medicine ,Animals ,Aspartic Acid ,Biological Products ,Multidisciplinary ,Drug Synergism ,biochemical phenomena, metabolism, and nutrition ,Acinetobacter ,bacterial infections and mycoses ,biology.organism_classification ,Virology ,3. Good health ,Anti-Bacterial Agents ,Penicillin ,Aspergillus ,Carbapenems ,bacteria ,Female ,Thienamycins ,beta-Lactamase Inhibitors ,medicine.drug - Abstract
The emergence and spread of carbapenem-resistant Gram-negative pathogens is a global public health problem. The acquisition of metallo-β-lactamases (MBLs) such as NDM-1 is a principle contributor to the emergence of carbapenem-resistant Gram-negative pathogens that threatens the use of penicillin, cephalosporin and carbapenem antibiotics to treat infections. To date, a clinical inhibitor of MBLs that could reverse resistance and re-sensitize resistant Gram-negative pathogens to carbapenems has not been found. Here we have identified a fungal natural product, aspergillomarasmine A (AMA), that is a rapid and potent inhibitor of the NDM-1 enzyme and another clinically relevant MBL, VIM-2. AMA also fully restored the activity of meropenem against Enterobacteriaceae, Acinetobacter spp. and Pseudomonas spp. possessing either VIM or NDM-type alleles. In mice infected with NDM-1-expressing Klebsiella pneumoniae, AMA efficiently restored meropenem activity, demonstrating that a combination of AMA and a carbapenem antibiotic has therapeutic potential to address the clinical challenge of MBL-positive carbapenem-resistant Gram-negative pathogens.
- Published
- 2014
41. PM10 levels in communities close to and away from opencast coal mining sites in Northeast England
- Author
-
Denise Howel, John Merefield, Andrew M King, Tanja Pless-Mulloli, and Ian Stone
- Subjects
Working hours ,Atmospheric Science ,Mining engineering ,business.industry ,Weather data ,Coal mining ,Environmental science ,Urban network ,Physical geography ,business ,General Environmental Science ,Arithmetic mean - Abstract
Concerns about levels of particulate matter of less than 10 μm (PM10) and their potential health effects have been raised by residents living near opencast coal mining sites in the UK. PM10 levels were measured by TEOM in 5 matched pairs of communities in northeast England, 5 near active opencast sites and 5 further away, to characterise the PM10 exposure of residents. 14 609 paired 30-min TEOM readings, and weather data were collected during 1996–97, over 6 weeks each in four pairs and for 24 weeks in one pair. Co-located samplers collected PM10 on an approximately weekly basis and samples were analysed using scanning electron microscopy with energy dispersive analysis (SEM-EDS). The patterns of PM10 levels over time were similar in Opencast and Control Communities and were mostly similar to readings from nearby automated urban network stations. This suggested regional influences on PM10 levels. The geometric mean PM10 was 17.0 μg m−3 in Opencast and 14.9 μg m−3 in Control Communities (arithmetic mean 22.1 μg m−3 in Opencast 18.2 μg m−3 in Control Communities): Opencast Communities thus had 14% higher PM10 levels than Control Communities on average. While the size distribution and proportion of shale particles indicated the opencast site as contributor to the PM10 load in adjacent communities, elevated PM10 levels in Opencast Communities were not positively linked with permitted working hours or wind direction being from the site to the community. No consistent relationship was found between PM10 levels and wind speed or day of the week.
- Published
- 2000
- Full Text
- View/download PDF
42. Time-resolved vibrationally mediated photodissociation of HNO3: Watching vibrational energy flow
- Author
-
F. Fleming Crim, Michael P. Gorman, Andrew M. King, and Dieter Bingemann
- Subjects
Quantitative Biology::Biomolecules ,Chemistry ,Overtone ,Photodissociation ,General Physics and Astronomy ,Photoexcitation ,Excited state ,Intramolecular force ,Physics::Atomic and Molecular Clusters ,Vibrational energy relaxation ,Physics::Chemical Physics ,Physical and Theoretical Chemistry ,Atomic physics ,Ultrashort pulse ,Excitation - Abstract
Ultrafast excitation of an O–H stretching vibrational followed by photodissociation of the energized molecules allows direct observation of the time for intramolecular energy redistribution in isolated nitric acid. We excite the first overtone of the O–H stretch vibration in HNO3 with a 100 fs laser pulse. A second, time-delayed pulse preferentially photodissociates molecules having vibrational excitation in modes orthogonal to the O–H stretch. The photodissociation yield increases as a function of time because energy flows out of the initially excited O–H bond into other more efficiently dissociated vibrations. The single exponential time constant for this intramolecular vibrational relaxation is 12 ps, consistent with moderate coupling of the O–H stretch to states close in energy.
- Published
- 1997
- Full Text
- View/download PDF
43. All the Boundaries of the Land: The Promised Land in Biblical thought in Light Of the Ancient Near East. By Nili Wazana. Winona Lake, IN: Eisenbrauns, 2013. Pp. xiv + 352. $59.50
- Author
-
Andrew M. King
- Subjects
Geography ,Middle East ,Religious studies ,Archaeology - Published
- 2016
- Full Text
- View/download PDF
44. PM10 particulate matter—The significance of ambient levels
- Author
-
Andrew M King and Stephen Dorling
- Subjects
Atmospheric Science ,Environmental chemistry ,Environmental science ,Particulates ,General Environmental Science - Published
- 1997
- Full Text
- View/download PDF
45. Performance of XIPS Electric Propulsion in On-orbit Station Keeping of the Boeing 702 Spacecraft
- Author
-
Manuel Martinez-Lavin, Dan M. Goebel, Thomas A. Bond, and Andrew M. King
- Subjects
Engineering ,Spacecraft ,Ion thruster ,Electrically powered spacecraft propulsion ,business.industry ,Communications satellite ,Orbit (dynamics) ,Propulsion ,Aerospace engineering ,business - Abstract
Five years after its initial launch and with over 70 units in use on 18 satellites, Xenon Ion Propulsion (XIPS) has become the premier technology for on-orbit station keeping of commercial communications satellites. The latest in XIPS technology, the 25 cm thruster, is used on the Boeing 702 satellites, which were first launched in December 1999. The Boeing 702 25 cm XIPS system uses nominally 4.5 kW of power for “high power” orbit raising and 2.2 kW of power for “low power” station keeping. The 25 cm XIPS system provides 100% of the in-orbit propulsion requirements for the 702 spacecraft, including drift, eccentricity and inclination control in addition to momentum dumping. The 25 cm XIPS systems have accumulated to date over 7000 hours of operation on five spacecraft with daily reproducible, reliable inorbit performance.
- Published
- 2002
- Full Text
- View/download PDF
46. Living near opencast coal mining sites and children's respiratory health
- Author
-
John Merefield, Ross Darnell, Ian Stone, Denise Howel, Jan Bessell, Andrew M King, and Tanja Pless-Mulloli
- Subjects
Male ,medicine.medical_specialty ,Matched-Pair Analysis ,Respiratory Tract Diseases ,Prevalence ,Residence Characteristics ,Wheeze ,Environmental health ,Air Pollution ,Epidemiology ,medicine ,Humans ,Respiratory sounds ,Particle Size ,Bronchitis ,Child ,Asthma ,Respiratory Sounds ,medicine.diagnostic_test ,business.industry ,Public health ,Incidence (epidemiology) ,Public Health, Environmental and Occupational Health ,Infant ,medicine.disease ,Coal Mining ,United Kingdom ,Socioeconomic Factors ,Case-Control Studies ,Child, Preschool ,Acute Disease ,Chronic Disease ,Papers ,Female ,medicine.symptom ,business - Abstract
OBJECTIVES—To answer the question whether living near opencast coal mining sites affects acute and chronic respiratory health. METHODS—All 4860 children aged 1-11 from five socioeconomically matched pairs of communities close to active opencast sites and control sites away from them were selected. Exposure was assessed by concentrations of particulate matter with aerodynamic diameter
- Published
- 2000
47. New Directions: TEOMs and the volatility of UK non-urban PM10: a regulatory dilemma
- Author
-
John Merefield, Ian Stone, Andrew M King, and Tanja Pless-Mulloli
- Subjects
Dilemma ,Atmospheric Science ,Operations research ,Financial economics ,Economics ,Volatility (finance) ,General Environmental Science - Published
- 2000
- Full Text
- View/download PDF
48. Comparisons of non-urban and urban network levels of particulate matter, and meteorological data
- Author
-
Stephen Dorling and Andrew M King
- Subjects
Fluid Flow and Transfer Processes ,Atmospheric Science ,Environmental Engineering ,Mechanical Engineering ,Environmental science ,Urban network ,Particulates ,Atmospheric sciences ,Pollution - Published
- 1998
- Full Text
- View/download PDF
49. Towards a practical implementation of X-ray ghost imaging with synchrotron light
- Author
-
Daniele Pelliccia, Margie P. Olbinado, Alexander Rack, Andrew M. Kingston, Glenn R. Myers, and David M. Paganin
- Subjects
X-ray imaging ,X-ray ghost imaging ,X-ray speckle ,coherence ,computational X-ray imaging ,hard X-rays ,point-spread function ,Crystallography ,QD901-999 - Abstract
An experimental procedure for transmission X-ray ghost imaging using synchrotron light is presented. Hard X-rays from an undulator were divided by a beamsplitter to produce two copies of a speckled incident beam. Both beams were simultaneously measured on an indirect pixellated detector and the intensity correlation between the two copies was used to retrieve the ghost image of samples placed in one of the two beams, without measuring the samples directly. Aiming at future practical uses of X-ray ghost imaging, the authors discuss details regarding data acquisition, image reconstruction strategies and measure the point-spread function of the ghost-imaging system. This approach may become relevant for applications of ghost imaging with X-ray sources such as undulators in storage rings, free-electron lasers and lower-coherence laboratory facilities.
- Published
- 2018
- Full Text
- View/download PDF
50. Transient electronic absorption of vibrationally excited CH[sub 2]I[sub 2]: Watching energy flow in solution
- Author
-
Andrew M. King, Dieter Bingemann, and F. Fleming Crim
- Subjects
Chemistry ,General Physics and Astronomy ,Molecular electronic transition ,symbols.namesake ,Franck–Condon principle ,Intramolecular force ,Excited state ,Attenuation coefficient ,Ultrafast laser spectroscopy ,symbols ,Vibrational energy relaxation ,Physics::Chemical Physics ,Physical and Theoretical Chemistry ,Atomic physics ,Excitation - Abstract
Transient electronic absorption of methylene iodide (CH2I2) in CCl4, CDCl3, and C6D6 after excitation of two quanta of C–H stretching vibration with a 100 fs laser pulse allows direct observation of the times for intramolecular vibrational relaxation and energy transfer to the solvent. Intramolecular energy redistribution populates vibrational states with larger Franck–Condon factors for the electronic transition, leading to an increased absorption of probe pulses in the wavelength range of 380–440 nm. A model based on the temperature dependence of the electronic absorption coefficient describes the transient absorption well for all wavelengths. In the model, the temperature rises and decays exponentially with time, reflecting the initial redistribution of energy within the excited molecule and the subsequent transfer of energy from the vibrationally excited molecule into the solvent. The intramolecular vibrational relaxation time for CH2I2 is essentially the same in the solvents CCl4 (10.8±1.5 ps) and CD...
- Published
- 2000
- Full Text
- View/download PDF
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