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5. Multiplex knockout of trichome-regulating MYB duplicates in hybrid poplar using a single gRNA

Author

Bewg, William P, Harding, Scott A, Engle, Nancy L, Vaidya, Brajesh N, Zhou, Ran, Reeves, Jacob, Horn, Thomas W, Joshee, Nirmal, Jenkins, Jerry W, Shu, Shengqiang, Barry, Kerrie W, Yoshinaga, Yuko, Grimwood, Jane, Schmitz, Robert J, Schmutz, Jeremy, Tschaplinski, Timothy J, and Tsai, Chung-Jui

Subjects
Biological Sciences, Ecology, Biotechnology, Genetics, CRISPR-Cas Systems, Gene Editing, Populus, RNA, Guide, Kinetoplastida, Trichomes, Agricultural and Veterinary Sciences, Plant Biology & Botany, Plant biology
Abstract

As the focus for CRISPR/Cas-edited plants moves from proof-of-concept to real-world applications, precise gene manipulation will increasingly require concurrent multiplex editing for polygenic traits. A common approach for editing across multiple sites is to design one guide RNA (gRNA) per target; however, this complicates construct assembly and increases the possibility of off-target mutations. In this study, we utilized one gRNA to target MYB186, a known positive trichome regulator, as well as its paralogs MYB138 and MYB38 at a consensus site for mutagenesis in hybrid poplar (Populus tremula × P. alba INRA 717-1B4). Unexpected duplications of MYB186 and MYB138 resulted in eight alleles for the three targeted genes in the hybrid poplar. Deep sequencing and polymerase chain reaction analyses confirmed editing across all eight targets in nearly all of the resultant glabrous mutants, ranging from small indels to large genomic dropouts, with no off-target activity detected at four potential sites. This highlights the effectiveness of a single gRNA targeting conserved exonic regions for multiplex editing. Additionally, cuticular wax and whole-leaf analyses showed a complete absence of triterpenes in the trichomeless mutants, hinting at a previously undescribed role for the nonglandular trichomes of poplar.

Published
2022

8. Diagnostic Performance and Safety of Positron Emission Tomography with 18F-rhPSMA-7.3 in Patients with Newly Diagnosed Unfavourable Intermediate- to Very-high-risk Prostate Cancer: Results from a Phase 3, Prospective, Multicentre Study (LIGHTHOUSE)

Author

Allaf, Mohamad, Andriole, Gerald, Avery, Ryan J., Avril, Norbert, Barker, Helen, Belkoff, Laurence, Budäus, Lars, Cher, Michael L., Chisholm, Diane, Covington, Matthew F., Cox, Ian, Ferrandino, Michael, Fleming, Mark T., Franceschi, Dinko, Gardiner, Peter, Gartrell, Benjamin, Gauden, David, Hasa, Ergela, Hermsen, Rick, Horn, Thomas, Iranpour, Pooya, Jacene, Heather, Jayaratna, Isuru, Joshi, Shreyas S., Kay, Matthew, Kostakoglu, Lale, Kuo, Phillip, Lavely, William, Lokuta, Mary, Lowentritt, Benjamin, Miller, Matthew P., Nix, Jeffrey W., Ogan, Kenneth, Penny, Ross, Piert, Morand, Purysko, Andrei, Ravizzini, Gregory, Saltzstein, Daniel, Savir-Baruch, Bital, Siegel, Barry A., Steuber, Thomas, Twardowski, Przemyslaw, Uchio, Edward, Ulaner, Gary A., Wixom, Jenna M., Yoo, Don, Zukotynski, Katherine, Surasi, Devaki Shilpa, Eiber, Matthias, Maurer, Tobias, Preston, Mark A., Helfand, Brian T., Josephson, David, Tewari, Ashutosh K., Somford, Diederik M., Rais-Bahrami, Soroush, Koontz, Bridget F., Bostrom, Peter J., Chau, Albert, Davis, Phillip, Schuster, David M., and Chapin, Brian F.

Published
2023
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10. Role of Human 15-Lipoxygenase‑2 in the Biosynthesis of the Lipoxin Intermediate, 5S,15S-diHpETE, Implicated with the Altered Positional Specificity of Human 15-Lipoxygenase‑1

Author

Perry, Steven C, Horn, Thomas, Tourdot, Benjamin E, Yamaguchi, Adriana, Kalyanaraman, Chakrapani, Conrad, William S, Akinkugbe, Oluwayomi, Holinstat, Michael, Jacobson, Matthew P, and Holman, Theodore R

Subjects
Arachidonate 15-Lipoxygenase, Arachidonic Acid, Arachidonic Acids, Humans, Hydroxyeicosatetraenoic Acids, Lipoxins, Medicinal and Biomolecular Chemistry, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Biochemistry & Molecular Biology
Abstract

The oxylipins, 5S,12S-dihydroxy-6E,8Z,10E,14Z-eicosatetraenoic acid (5S,12S-diHETE) and 5S,15S-dihydroxy-6E,8Z,11Z,13E-eicosatetraenoic acid (5S,15S-diHETE), have been identified in cell exudates and have chemotactic activity toward eosinophils and neutrophils. Their biosynthesis has been proposed to occur by sequential oxidations of arachidonic acid (AA) by lipoxygenase enzymes, specifically through oxidation of AA by h5-LOX followed by h12-LOX, h15-LOX-1, or h15-LOX-2. In this work, h15-LOX-1 demonstrates altered positional specificity when reacting with 5S-HETE, producing 90% 5S,12S-diHETE, instead of 5S,15S-diHETE, with kinetics 5-fold greater than that of h12-LOX. This is consistent with previous work in which h15-LOX-1 reacts with 7S-HDHA, producing the noncanonical, DHA-derived, specialized pro-resolving mediator, 7S,14S-diHDHA. It is also determined that oxygenation of 5S-HETE by h15-LOX-2 produces 5S,15S-diHETE and its biosynthetic kcat/KM flux is 2-fold greater than that of h15-LOX-1, suggesting that h15-LOX-2 may have a greater role in lipoxin biosynthesis than previously thought. In addition, it is shown that oxygenation of 12S-HETE and 15S-HETE by h5-LOX is kinetically slow, suggesting that the first step in the in vitro biosynthesis of both 5S,12S-diHETE and 5S,15S-diHETE is the production of 5S-HETE.

Published
2020

11. Spatial Immunephenotypes of Distant Metastases but not Matched Primary Urothelial Carcinomas Predict Response to Immune Checkpoint Inhibition

Author

Erlmeier, Franziska, Klümper, Niklas, Landgraf, Laura, Strissel, Pamela L., Strick, Reiner, Sikic, Danijel, Taubert, Helge, Wach, Sven, Geppert, Carol I., Bahlinger, Veronika, Breyer, Johannes, Ritter, Manuel, Bolenz, Christian, Roghmann, Florian, Erben, Philipp, Schwamborn, Kristina, Wirtz, Ralph M., Horn, Thomas, Wullich, Bernd, Hölzel, Michael, Hartmann, Arndt, Gschwend, Jürgen E., Weichert, Wilko, and Eckstein, Markus

Published
2023
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12. Cohort Study of Oligorecurrent Prostate Cancer Patients: Oncological Outcomes of Patients Treated with Salvage Lymph Node Dissection via Prostate-specific Membrane Antigen–radioguided Surgery

Author

Knipper, Sophie, Mehdi Irai, Mehrdad, Simon, Ricarda, Koehler, Daniel, Rauscher, Isabel, Eiber, Matthias, van Leeuwen, Fijs W.B., van Leeuwen, Pim, de Barros, Hilda, van der Poel, Henk, Budäus, Lars, Steuber, Thomas, Graefen, Markus, Tennstedt, Pierre, Heck, Matthias M., Horn, Thomas, and Maurer, Tobias

Published
2023
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13. Enhanced In Vivo Delivery of Stem Cells using Microporous Annealed Particle Scaffolds.

Author

Koh, Jaekyung, Griffin, Donald R, Archang, Maani M, Feng, An-Chieh, Horn, Thomas, Margolis, Michael, Zalazar, David, Segura, Tatiana, Scumpia, Philip O, and Di Carlo, Dino

Subjects
Cells, Cultured, Stem Cells, Mesenchymal Stem Cells, Animals, Mice, Inbred C57BL, Mice, Fluorescent Antibody Technique, Tissue Engineering, Microfluidics, Tissue Scaffolds, hydrogel microparticles, injectable microporous scaffolds, microfluidics, stem cell delivery, tissue engineering, Stem Cell Research - Nonembryonic - Human, Biotechnology, Regenerative Medicine, Bioengineering, Stem Cell Research - Nonembryonic - Non-Human, Stem Cell Research, 5.2 Cellular and gene therapies, Development of treatments and therapeutic interventions, Generic health relevance, Musculoskeletal, Nanoscience & Nanotechnology
Abstract

Delivery to the proper tissue compartment is a major obstacle hampering the potential of cellular therapeutics for medical conditions. Delivery of cells within biomaterials may improve localization, but traditional and newer void-forming hydrogels must be made in advance with cells being added into the scaffold during the manufacturing process. Injectable, in situ cross-linking microporous scaffolds are recently developed that demonstrate a remarkable ability to provide a matrix for cellular proliferation and growth in vitro in three dimensions. The ability of these scaffolds to deliver cells in vivo is currently unknown. Herein, it is shown that mesenchymal stem cells (MSCs) can be co-injected locally with microparticle scaffolds assembled in situ immediately following injection. MSC delivery within a microporous scaffold enhances MSC retention subcutaneously when compared to cell delivery alone or delivery within traditional in situ cross-linked nanoporous hydrogels. After two weeks, endothelial cells forming blood vessels are recruited to the scaffold and cells retaining the MSC marker CD29 remain viable within the scaffold. These findings highlight the utility of this approach in achieving localized delivery of stem cells through an injectable porous matrix while limiting obstacles of introducing cells within the scaffold manufacturing process.

Published
2019

14. Landscape Physiognomy Influences Abundance of the Lone Star Tick, Amblyomma americanum (Ixodida: Ixodidae), in Ozark Forests

Author

Van Horn, Thomas R, Adalsteinsson, Solny A, Westby, Katie M, Biro, Elizabeth, Myers, Jonathan A, Spasojevic, Marko J, Walton, Maranda, and Medley, Kim A

Subjects
Veterinary Sciences, Agricultural, Veterinary and Food Sciences, Life on Land, Animals, Forests, Ixodidae, Larva, Missouri, Models, Biological, Nymph, Population Density, Amblyomma americanum, tick-borne disease, management, spatial epidemiology, Biological Sciences, Medical and Health Sciences, Tropical Medicine, Veterinary sciences, Microbiology, Medical microbiology
Abstract

The lone star tick, Amblyomma americanum Linnaeus (Ixodida: Ixodidae), is emerging as an important human disease vector in the United States. While some recent studies have modeled broad-scale (regional or county-level) distribution patterns of A. americanum, less is known about how local-scale habitat characteristics drive A. americanum abundance. Such local-scale information is vital to identify targets for tick population control measures within land management units. We investigated how habitat features predict host-seeking A. americanum adult and nymph abundance within a 12-ha oak-hickory forest plot in the Missouri Ozarks. We trapped ticks using CO2-baited traps at 40 evenly spaced locations for three 24-h periods during the summer of 2015, and we measured biotic and abiotic variables surrounding each location. Of 2,008 A. americanum captured, 1,009 were nymphs, and 999 were adults. We observed spatial heterogeneity in local tick abundance (min = 0 ticks, max = 112 ticks, mean = 16.7 ticks per trap night). Using generalized linear mixed models, we found that both nymphs and adults had greater abundance in valleys as well as on northern-facing aspects. Moreover, nymph abundance was negatively related to temperature variance, while adult abundance had a negative relationship with elevation. These results demonstrate that managers in this region may be able to predict local tick abundance through simple physiognomic factors and use these parameters for targeted management action.

Published
2018

16. Human 15-LOX-1 active site mutations alter inhibitor binding and decrease potency.

Author

Armstrong, Michelle, van Hoorebeke, Christopher, Horn, Thomas, Deschamps, Joshua, Freedman, J Cody, Kalyanaraman, Chakrapani, Jacobson, Matthew P, and Holman, Theodore

Subjects
Humans, Arachidonate 15-Lipoxygenase, Lipoxygenase Inhibitors, Mutagenesis, Site-Directed, Molecular Structure, Catalytic Domain, Structure-Activity Relationship, Dose-Response Relationship, Drug, Kinetics, Mutation, Models, Molecular, 15-Lipoxygenase-1, Docking, Human, Inhibitor, Mutagenesis, Stroke, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Medicinal and Biomolecular Chemistry, Organic Chemistry, Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry
Abstract

Human 15-lipoxygenase-1 (h15-LOX-1 or h12/15-LOX) reacts with polyunsaturated fatty acids and produces bioactive lipid derivatives that are implicated in many important human diseases. One such disease is stroke, which is the fifth leading cause of death and the first leading cause of disability in America. The discovery of h15-LOX-1 inhibitors could potentially lead to novel therapeutics in the treatment of stroke, however, little is known about the inhibitor/active site interaction. This study utilizes site-directed mutagenesis, guided in part by molecular modeling, to gain a better structural understanding of inhibitor interactions within the active site. We have generated eight mutants (R402L, R404L, F414I, F414W, E356Q, Q547L, L407A, I417A) of h15-LOX-1 to determine whether these active site residues interact with two h15-LOX-1 inhibitors, ML351 and an ML094 derivative, compound 18. IC50 values and steady-state inhibition kinetics were determined for the eight mutants, with four of the mutants affecting inhibitor potency relative to wild type h15-LOX-1 (F414I, F414W, E356Q and L407A). The data indicate that ML351 and compound 18, bind in a similar manner in the active site to an aromatic pocket close to F414 but have subtle differences in their specific binding modes. This information establishes the binding mode for ML094 and ML351 and will be leveraged to develop next-generation inhibitors.

Published
2016

17. Strict Regiospecificity of Human Epithelial 15-Lipoxygenase‑2 Delineates Its Transcellular Synthesis Potential

Author

Green, Abigail R, Barbour, Shannon, Horn, Thomas, Carlos, Jose, Raskatov, Jevgenij A, and Holman, Theodore R

Subjects
Organic Chemistry, Chemical Sciences, Arachidonate 15-Lipoxygenase, Catalysis, Humans, Hydroxyeicosatetraenoic Acids, Substrate Specificity, Medicinal and Biomolecular Chemistry, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medical biochemistry and metabolomics, Medicinal and biomolecular chemistry
Abstract

Lipoxins are an important class of lipid mediators that induce the resolution of inflammation and arise from transcellular exchange of arachidonic acid (AA)-derived lipoxygenase products. Human epithelial 15-lipoxygenase-2 (h15-LOX-2), the major lipoxygenase in macrophages, has exhibited strict regiospecificity, catalyzing only the hydroperoxidation of carbon 15 of AA. To determine the catalytic potential of h15-LOX-2 in transcellular synthesis events, we reacted it with the three lipoxygenase-derived monohydroperoxy-eicosatetraenoic acids (HPETE) in humans: 5-HPETE, 12-HPETE, and 15-HPETE. Only 5-HPETE was a substrate for h15-LOX-2, and the steady-state catalytic efficiency (kcat/Km) of this reaction was 31% of the kcat/Km of AA. The only major product of h15-LOX-2's reaction with 5-HPETE was the proposed lipoxin intermediate, 5,15-dihydroperoxy-eicosatetraenoic acid (5,15-diHPETE). However, h15-LOX-2 did not react further with 5,15-diHPETE to produce lipoxins. This result is consistent with the specificity of h15-LOX-2 despite the increased reactivity of 5,15-diHPETE. Density functional theory calculations determined that the radical, after abstracting the C10 hydrogen atom from 5,15-diHPETE, had an energy 5.4 kJ/mol lower than that of the same radical generated from AA, demonstrating the facility of 5,15-diHPETE to form lipoxins. Interestingly, h15-LOX-2 does react with 5S,6R-diHETE, forming LipoxinA4, indicating the gemdiol does not prohibit h15-LOX-2 reactivity. Taken together, these results demonstrate the strict regiospecificity of h15-LOX-2 that circumscribes its role in transcellular synthesis.

Published
2016

20. Baseline factors affecting closure of venous leg ulcers

Author

Andersen, Charles A., Anderson, Caesar A., Arenberger, Petr, Aschoff, Roland, Augustin, Matthias, Bakos, Noemi, Beele, Hilde, Bervoets, An, Cavorsi, Joseph, Cazzell, Shawn M., Cetkovska, Petra, Clements, J. Randolph, Cook, Emily A., Deck, Kenneth B., De Conninck, Arlette, Despatis, Marc A., Dhillon, Yadwinder S., Dissemond, Joachim, Dove, Cyaandi, Emmert, Steffen, Eming, Sabine, Ennis, William J., Enriquez, George L., Farber, Alik, Filipovska, Olga, Frykberg, Robert G., Gagnon, Joel J., Galiano, Robert, George, Tobias, Giacalone, Vincent, Gordon, Ian L., Grzela, Tomasz, Hajdu, Csaba, Hanft, Jason R., Homey, Bernhard, Hood, Douglas B., Horn, Thomas, Jimenez, Juan C., Juenger, Michael, Keast, David H., Kemeny, Lajos, Kim, Paul J., Kirsner, Robert S., Kotala, Marek, Lantis, John C., II, Lauf, Laszlo, Lavery, Lawrence, Lawall, Holger, Lawrence, Peter F., Malka, Marcin, Marston, William A., Matejkova, Astrid, Mayer, Perry V., Mikosinski, Jacek, Molyneaux, Michael M., Moore, Michael F., Mostow, Eliot N., Motley, Travis A., Nemes, Edina, Pavlasova, Vera, Quist, Sven, Remenyik, Eva, Reyzelman, Alexander M., Rez, Rita, Rock, Paul B., Ruzicka, Thomas, Rybak, Zbigniew, Shebetka, Karry Ann, Shimozaki, Kenneth K., Simka, Marian, Stuecker, Markus, Stuchlik, David, Swiercz, Pawel, Tassone, John, Jr., Twardowska-Saucha, Krystyna, Van Gils, Carl, Vanscheidt, Wolfgang, Varkonyi, Istvan, Vartivarian, Mher, Vasku, Vladimir, Vayser, Dean, Walters, Jodi, Weichenthal, Michael, Wu, Stephanie C.S., Zenilman, Jonathan M., Zimolova, Radka, Zubilewicz, Tomasz, Galiano, Robert D., Eming, Sabine A., Cargill, D. Innes, Dickerson, Jaime E., Jr., and Slade, Herbert B.

Published
2017
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22. Treatment of carcinoma in situ of the urinary bladder with an alpha-emitter immunoconjugate targeting the epidermal growth factor receptor: a pilot study

Author

Autenrieth, Michael E., Seidl, Christof, Bruchertseifer, Frank, Horn, Thomas, Kurtz, Florian, Feuerecker, Benedikt, D’Alessandria, Calogero, Pfob, Christian, Nekolla, Stephan, Apostolidis, Christos, Mirzadeh, Saed, Gschwend, Jürgen E., Schwaiger, Markus, Scheidhauer, Klemens, and Morgenstern, Alfred

Published
2018
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26. NIH Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: II. The 2014 Pathology Working Group Report

Author

Shulman, Howard M., Cardona, Diana M., Greenson, Joel K., Hingorani, Sangeeta, Horn, Thomas, Huber, Elisabeth, Kreft, Andreas, Longerich, Thomas, Morton, Thomas, Myerson, David, Prieto, Victor G., Rosenberg, Avi, Treister, Nathaniel, Washington, Kay, Ziemer, Mirjana, Pavletic, Steven Z., Lee, Stephanie J., Flowers, Mary E.D., Schultz, Kirk R., Jagasia, Madan, Martin, Paul J., Vogelsang, Georgia B., and Kleiner, David E.

Published
2015
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47. Positive Predictive Factors for Urogenital Injuries in Severely Injured Patients with Pelvic and Spinal Fractures: Introducing the UPPS Scoring System.

Author

Mair, Olivia Anna, Himmler, Maren, Brunnemer, Suna, Faymonville, Christoph, Honeck, Patrick, Horn, Thomas, Biberthaler, Peter, and Hanschen, Marc

Subjects
VERTEBRAL fractures, PELVIC fractures, MOTORCYCLING injuries, SPINAL injuries, PELVIC bones, INTENSIVE care units, UROLOGICAL surgery, HELMETS
Abstract

Background and Objectives: Although urogenital injuries are common in severely injured patients, their diagnosis is often delayed. Predicting genitourinary injuries (GUI), especially in the immediate stages post injury, remains a challenge. This study aims to evaluate and determine positive predictive factors for the presence of GUI in polytrauma patients. Subsequently, these factors shall be used to develop an easy-to-use scoring system, deployable directly in the emergency setting. Materials and Methods: This study evaluates all severely injured patients with an Injury Severity Score (ISS) ≥ 16 admitted to the emergency departments of two German university hospitals between 2016 and 2020. These patients were retrospectively scanned for injuries of the thoracic and/or lumbar spine and/or the pelvic girdle. Demographic data was analyzed alongside trauma mechanism, type of injuries, mortality, length of hospital stays, surgeries, laboratory results, and urological treatment. Subgroup analysis was performed to compare patients with and without GUIs using t-tests. Conducting a binary logistic regression model, the significant factors were combined to create a scoring system, which was further analyzed for accuracy. Results: In total, 413 patients with an average ISS of 33.8 ± 15.0 were identified, and 47 patients (11.4%) sustained urogenital injuries with an average Abbreviated Injury Scale (AIS) score of 2.3 ± 1.1 (range: 1–5). The severity of the pelvic girdle injury correlated with the presence of urogenital injuries (p = 0.002), while there was no correlation with spinal injuries. Moreover, most GUIs resulted from motorcycle accidents (p < 0.001) and 87.2% of these patients were male. Patients with GUI were significantly more likely to show macrohematuria (p < 0.001) on admission and were more severely injured overall (ISS > 34). There was no significant difference in the length of intensive care unit (ICU) stay, the days until discharge, or death rates. Conclusions: Factors or circumstances which reliably predict the presence of GUI were found to include the male sex, a motorcycle accident, high severity of pelvic girdle fractures, macrohematuria on admission to the emergency department, and an ISS > 34. With these findings, we introduce the 'Urotrauma in Polytrauma patients with Pelvic and/or Spinal injuries' (UPPS) score for easier prediction of GUI in the emergency setting. [ABSTRACT FROM AUTHOR]

Published
2022
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