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203 results on '"Schulze, Christopher"'

1. Decadal increases in carbon uptake offset by respiratory losses across northern permafrost ecosystems

Author

See, Craig R, Virkkala, Anna-Maria, Natali, Susan M, Rogers, Brendan M, Mauritz, Marguerite, Biasi, Christina, Bokhorst, Stef, Boike, Julia, Bret-Harte, M Syndonia, Celis, Gerardo, Chae, Namyi, Christensen, Torben R, Murner (Connon), Sara June, Dengel, Sigrid, Dolman, Han, Edgar, Colin W, Elberling, Bo, Emmerton, Craig A, Euskirchen, Eugénie S, Göckede, Mathias, Grelle, Achim, Heffernan, Liam, Helbig, Manuel, Holl, David, Humphreys, Elyn, Iwata, Hiroki, Järveoja, Järvi, Kobayashi, Hideki, Kochendorfer, John, Kolari, Pasi, Kotani, Ayumi, Kutzbach, Lars, Kwon, Min Jung, Lathrop, Emma R, López-Blanco, Efrén, Mammarella, Ivan, Marushchak, Maija E, Mastepanov, Mikhail, Matsuura, Yojiro, Merbold, Lutz, Meyer, Gesa, Minions, Christina, Nilsson, Mats B, Nojeim, Julia, Oberbauer, Steven F, Olefeldt, David, Park, Sang-Jong, Parmentier, Frans-Jan W, Peichl, Matthias, Peter, Darcy, Petrov, Roman, Poyatos, Rafael, Prokushkin, Anatoly S, Quinton, William, Rodenhizer, Heidi, Sachs, Torsten, Savage, Kathleen, Schulze, Christopher, Sjögersten, Sofie, Sonnentag, Oliver, St. Louis, Vincent L, Torn, Margaret S, Tuittila, Eeva-Stiina, Ueyama, Masahito, Varlagin, Andrej, Voigt, Carolina, Watts, Jennifer D, Zona, Donatella, Zyryanov, Viacheslav I, and Schuur, Edward AG

Subjects
Agricultural, Veterinary and Food Sciences, Biological Sciences, Ecology, Forestry Sciences, Atmospheric Sciences, Physical Geography and Environmental Geoscience, Environmental Science and Management
Abstract

Tundra and boreal ecosystems encompass the northern circumpolar permafrost region and are experiencing rapid environmental change with important implications for the global carbon (C) budget. We analysed multi-decadal time series containing 302 annual estimates of carbon dioxide (CO2) flux across 70 permafrost and non-permafrost ecosystems, and 672 estimates of summer CO2 flux across 181 ecosystems. We find an increase in the annual CO2 sink across non-permafrost ecosystems but not permafrost ecosystems, despite similar increases in summer uptake. Thus, recent non-growing-season CO2 losses have substantially impacted the CO2 balance of permafrost ecosystems. Furthermore, analysis of interannual variability reveals warmer summers amplify the C cycle (increase productivity and respiration) at putatively nitrogen-limited sites and at sites less reliant on summer precipitation for water use. Our findings suggest that water and nutrient availability will be important predictors of the C-cycle response of these ecosystems to future warming.

Published
2024

2. Upscaling Wetland Methane Emissions From the FLUXNET‐CH4 Eddy Covariance Network (UpCH4 v1.0): Model Development, Network Assessment, and Budget Comparison

Author

McNicol, Gavin, Fluet‐Chouinard, Etienne, Ouyang, Zutao, Knox, Sara, Zhang, Zhen, Aalto, Tuula, Bansal, Sheel, Chang, Kuang‐Yu, Chen, Min, Delwiche, Kyle, Feron, Sarah, Goeckede, Mathias, Liu, Jinxun, Malhotra, Avni, Melton, Joe R, Riley, William, Vargas, Rodrigo, Yuan, Kunxiaojia, Ying, Qing, Zhu, Qing, Alekseychik, Pavel, Aurela, Mika, Billesbach, David P, Campbell, David I, Chen, Jiquan, Chu, Housen, Desai, Ankur R, Euskirchen, Eugenie, Goodrich, Jordan, Griffis, Timothy, Helbig, Manuel, Hirano, Takashi, Iwata, Hiroki, Jurasinski, Gerald, King, John, Koebsch, Franziska, Kolka, Randall, Krauss, Ken, Lohila, Annalea, Mammarella, Ivan, Nilson, Mats, Noormets, Asko, Oechel, Walter, Peichl, Matthias, Sachs, Torsten, Sakabe, Ayaka, Schulze, Christopher, Sonnentag, Oliver, Sullivan, Ryan C, Tuittila, Eeva‐Stiina, Ueyama, Masahito, Vesala, Timo, Ward, Eric, Wille, Christian, Wong, Guan Xhuan, Zona, Donatella, Windham‐Myers, Lisamarie, Poulter, Benjamin, and Jackson, Robert B

Subjects
Earth Sciences, Atmospheric Sciences, Climate Action, Life on Land, Climate change science, Geology, Physical geography and environmental geoscience
Abstract

Wetlands are responsible for 20%–31% of global methane (CH4) emissions and account for a large source of uncertainty in the global CH4 budget. Data-driven upscaling of CH4 fluxes from eddy covariance measurements can provide new and independent bottom-up estimates of wetland CH4 emissions. Here, we develop a six-predictor random forest upscaling model (UpCH4), trained on 119 site-years of eddy covariance CH4 flux data from 43 freshwater wetland sites in the FLUXNET-CH4 Community Product. Network patterns in site-level annual means and mean seasonal cycles of CH4 fluxes were reproduced accurately in tundra, boreal, and temperate regions (Nash-Sutcliffe Efficiency ∼0.52–0.63 and 0.53). UpCH4 estimated annual global wetland CH4 emissions of 146 ± 43 TgCH4 y−1 for 2001–2018 which agrees closely with current bottom-up land surface models (102–181 TgCH4 y−1) and overlaps with top-down atmospheric inversion models (155–200 TgCH4 y−1). However, UpCH4 diverged from both types of models in the spatial pattern and seasonal dynamics of tropical wetland emissions. We conclude that upscaling of eddy covariance CH4 fluxes has the potential to produce realistic extra-tropical wetland CH4 emissions estimates which will improve with more flux data. To reduce uncertainty in upscaled estimates, researchers could prioritize new wetland flux sites along humid-to-arid tropical climate gradients, from major rainforest basins (Congo, Amazon, and SE Asia), into monsoon (Bangladesh and India) and savannah regions (African Sahel) and be paired with improved knowledge of wetland extent seasonal dynamics in these regions. The monthly wetland methane products gridded at 0.25° from UpCH4 are available via ORNL DAAC (https://doi.org/10.3334/ORNLDAAC/2253).

Published
2023

3. The ABCflux database: Arctic–boreal CO2 flux observations and ancillary information aggregated to monthly time steps across terrestrial ecosystems

Author

Virkkala, Anna-Maria, Natali, Susan M, Rogers, Brendan M, Watts, Jennifer D, Savage, Kathleen, Connon, Sara June, Mauritz, Marguerite, Schuur, Edward AG, Peter, Darcy, Minions, Christina, Nojeim, Julia, Commane, Roisin, Emmerton, Craig A, Goeckede, Mathias, Helbig, Manuel, Holl, David, Iwata, Hiroki, Kobayashi, Hideki, Kolari, Pasi, López-Blanco, Efrén, Marushchak, Maija E, Mastepanov, Mikhail, Merbold, Lutz, Parmentier, Frans-Jan W, Peichl, Matthias, Sachs, Torsten, Sonnentag, Oliver, Ueyama, Masahito, Voigt, Carolina, Aurela, Mika, Boike, Julia, Celis, Gerardo, Chae, Namyi, Christensen, Torben R, Bret-Harte, M Syndonia, Dengel, Sigrid, Dolman, Han, Edgar, Colin W, Elberling, Bo, Euskirchen, Eugenie, Grelle, Achim, Hatakka, Juha, Humphreys, Elyn, Järveoja, Järvi, Kotani, Ayumi, Kutzbach, Lars, Laurila, Tuomas, Lohila, Annalea, Mammarella, Ivan, Matsuura, Yojiro, Meyer, Gesa, Nilsson, Mats B, Oberbauer, Steven F, Park, Sang-Jong, Petrov, Roman, Prokushkin, Anatoly S, Schulze, Christopher, St. Louis, Vincent L, Tuittila, Eeva-Stiina, Tuovinen, Juha-Pekka, Quinton, William, Varlagin, Andrej, Zona, Donatella, and Zyryanov, Viacheslav I

Subjects
Earth Sciences, Physical Geography and Environmental Geoscience, Atmospheric Sciences, Geoinformatics, Geochemistry, Atmospheric sciences, Physical geography and environmental geoscience
Abstract

Past efforts to synthesize and quantify the magnitude and change in carbon dioxide (CO2) fluxes in terrestrial ecosystems across the rapidly warming Arctic-boreal zone (ABZ) have provided valuable information but were limited in their geographical and temporal coverage. Furthermore, these efforts have been based on data aggregated over varying time periods, often with only minimal site ancillary data, thus limiting their potential to be used in large-scale carbon budget assessments. To bridge these gaps, we developed a standardized monthly database of Arctic-boreal CO2 fluxes (ABCflux) that aggregates in situ measurements of terrestrial net ecosystem CO2 exchange and its derived partitioned component fluxes: gross primary productivity and ecosystem respiration. The data span from 1989 to 2020 with over 70 supporting variables that describe key site conditions (e.g., vegetation and disturbance type), micrometeorological and environmental measurements (e.g., air and soil temperatures), and flux measurement techniques. Here, we describe these variables, the spatial and temporal distribution of observations, the main strengths and limitations of the database, and the potential research opportunities it enables. In total, ABCflux includes 244 sites and 6309 monthly observations; 136 sites and 2217 monthly observations represent tundra, and 108 sites and 4092 observations represent the boreal biome. The database includes fluxes estimated with chamber (19% of the monthly observations), snow diffusion (3%) and eddy covariance (78%) techniques. The largest number of observations were collected during the climatological summer (June-August; 32%), and fewer observations were available for autumn (September-October; 25%), winter (December-February; 18%), and spring (March-May; 25%). ABCflux can be used in a wide array of empirical, remote sensing and modeling studies to improve understanding of the regional and temporal variability in CO2 fluxes and to better estimate the terrestrial ABZ CO2 budget. ABCflux is openly and freely available online (Virkkala et al., 2021b, 10.3334/ORNLDAAC/1934). Copyright:

Published
2022

4. Self-administered intranasal etripamil using a symptom-prompted, repeat-dose regimen for atrioventricular-nodal-dependent supraventricular tachycardia (RAPID): a multicentre, randomised trial

Author

Ip, James E, Jones, Alonzo, Sr, Stambler, Bruce S, Schleinkofer, David E, Winters, Stephen, Lam, Wilson, Goldstein, Robert, Dor, Isaac Dor, Talwar, Sandeep, O'Neill, Padraig G, Koren, Michael J, Beinart, Sean C, Ambati, Srivani, Mazer, Sean P, Kinn, Robert M, Roy, Karine, Manshadi, Ramin, Kuk, Richard, Verma, Aditya, Phelan, Timothy, Stoian, Alexandru A, Ellenbogen, Kenneth, Jayachandran, J Vijay, Connelly, Terence P, Daccarett, Marcos, Gandhi, Gaurang, Mittal, Suneet, Abdel-Wahab, Amir, Augostini, Ralph, Ip, John H, Sorrentino, Denise, Roux, Jean-Francois, Brar, Ramandeep, Khoo, Clarence, Bennett, Matthew, Lo, Eric, Coutu, Benoit, Sterns, Laurence, Greer, Gerald S, Gujja, Pradeep, Gianfagna, Robert A, Swarup, Vijendra, Sogade, Felix, Wilton, Stephen, Ruisi, Christopher, Barbera, Saverio, Banchs, Javier E., Korley, Victoria, Schulze, Christopher, Damle, Roger, Healey, Jeffrey Sean, Pandey, A Shekhar, Anderson, Jeffrey L, Venkatachalam, K L, Noseworthy, Peter, Mondésert, Blandine, Verma, Atul, Friars, Douglas G, Kambur, Thomas R, Lockwood, Evan, Meininger, Glenn, Olsovsky, Greg, Jones Sr, Alonzo, Greer, Gerald, Mehta, Rohit, Akbar, Saleem, Salman, Malik, Rama, Bhola, Arora, Ramesh, Shah, Dhirenkumar, Shah, Rakesh, Cammarata, Michael, Owens, Andrew, Ludington, Katherine, Wharton, Marcus, Bagheri, Michael, Khan, Mohammed, Carr, Kenneth Warren, Siddique, Sultan, Parvathaneni, Sunthosh, Devabhaktuni, Subodh, Mouhaffel, Assad, Mark, George, Di Biase, Luigi, Rangappa, Sunil, Morton, Jared, Yarmohammadi, Hirad, Karim, Amin, Martinez Fleites, Aldo, Nero, Thomas, Shafiq, Qaiser, Pandey, Shekhar, Khaykin, Yaariv, Joza, Jacqueline, Gosselin, Gilbert, Skanes, Allen, Vyselaar, John, Savard, Daniel, Heidbuchel, Hein, Xhaet, Olivier, Catez, Emmanuel, Vijgen, Johan, Godart, Pascal, Casado, Ruben, Mairesse, Georges, Rossenbacker, Tom, Haemers, Peter, Hoffer, Etienne, Hausman, Pierre, Vertes, Andras, Duray, Gabor, Szolnoki, Erzsebet, Csanadi, Zoltan, Lakatos, Ferenc, Alings, Marco, Dorman, Reinhart, Tuininga, Y S, Jansen, W, Velthuis, Sebastiaan, van Bemmel, B, Bech, Gerhard Jan Willem, Pisters, Ron, Valk, Suzanne, Romer, Tjeerd, Luermans, Justin, Beelen, Driek, van Eck, Martijn, Houtgraaf, Jaco, Vet, Thijs, Shellings, Dirk, Oosterhof, T, Miekus, Pawel, Bebenek, Waldemar, Bielecka-Dabrowa, Agata, Gniot, Jacek, Zmuda, Witold, Kasprzak, Michal, Balak, Wojciech, Ptaszynski, Pawel, Nowak, Jacek, Prokopczuk, Janusz, Przybylski, Andrzej, Wozniak-Skowerska, Iwona, Derejko, Pawel, Czarnecka, Danuta, Janas, Adam, Merino Llorens, Jose Luis, Tercedor, Luis, Iniguez Romo, Andres, Ruiz Granell, Ricardo, Gonzalez Juanatey, Jose Ramon, Pascual-Figal, Domingo, Martinez-Selles, Manuel, Anguera Camos, Ignacio, Ibanez Criado, Alicia, Matrinez Basterra, Javier, Izquierdo, Alvaro, Rivas Gandara, Nuria, Alegret Colome, Josep M, Perez Diez, Diego, Martínez Hervás, Miguel Ángel, Medina, Maria, Segura Saint-Gerons, Jose María, Pedrote Leal, Alonso, Fernandez Lozano, Ignacio, Quesada, Aurelio, Guerra Ramos, Jose, Sarrias, Axel, Ramos Maqueda, Javier, Mansourati, Jacques, Defaye, Pascal, Guedon-Moreau, Laurence, Milhem, Antoine, De Guillebon, Maxime, Chevalier, Philippe, Badoz, Marc, Kriatselis, Charalampos, Simonis, Gregor, Lewalter, Thorsten, Zarse, Markus, Wilke, Andreas, Kraemer, Fabian, Al-Zoebi, Ayham, Camm, A John, Dorian, Paul, Kowey, Peter R, Merino, Jose L, Piccini, Jonathan P, Pokorney, Sean D, Sager, Philip T, Wharton, J Marcus, Bharucha, David B, Plat, Francis, Shardonofsky, Silvia, and Chen, Michael

Published
2023
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5. Shp1 Loss Enhances Macrophage Effector Function and Promotes Anti-Tumor Immunity

Author

Myers, Darienne R, Abram, Clare L, Wildes, David, Belwafa, Amira, Welsh, Alia MN, Schulze, Christopher J, Choy, Tiffany J, Nguyen, Tram, Omaque, Neil, Hu, Yongmei, Singh, Mallika, Hansen, Rich, Goldsmith, Mark A, Quintana, Elsa, Smith, Jacqueline AM, and Lowell, Clifford A

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Immunization, Immunotherapy, Cancer, Vaccine Related, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Adaptive Immunity, Adenocarcinoma, Animals, Antigens, Differentiation, Breast Neoplasms, Colonic Neoplasms, Female, Humans, Immunity, Innate, Lymphocytes, Tumor-Infiltrating, Melanoma, Experimental, Mice, Inbred C57BL, Mice, Knockout, Phagocytosis, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Receptors, Immunologic, Signal Transduction, Skin Neoplasms, THP-1 Cells, Tumor Burden, Tumor Microenvironment, Tumor-Associated Macrophages, tyrosine phosphatase, phagocytosis, PTPN6, immuno-oncology, SIRP alpha, inflammation, SIRPα, Medical Microbiology, Biochemistry and cell biology, Genetics
Abstract

Shp1, encoded by the gene Ptpn6, is a protein tyrosine phosphatase that transduces inhibitory signals downstream of immunoreceptors in many immune cell types. Blocking Shp1 activity represents an exciting potential immunotherapeutic strategy for the treatment of cancer, as Shp1 inhibition would be predicted to unleash both innate and adaptive immunity against tumor cells. Antibodies blocking the interaction between CD47 on tumor cells and SIRPα on macrophages enhance macrophage phagocytosis, show efficacy in preclinical tumor models, and are being evaluated in the clinic. Here we found that Shp1 bound to phosphorylated peptide sequences derived from SIRPα and transduced the anti-phagocytic signal, as Shp1 loss in mouse bone marrow-derived macrophages increased phagocytosis of tumor cells in vitro. We also generated a novel mouse model to evaluate the impact of global, inducible Ptpn6 deletion on anti-tumor immunity. We found that inducible Shp1 loss drove an inflammatory disease in mice that was phenotypically similar to that seen when Ptpn6 is knocked out from birth. This indicates that acute perturbation of Shp1 in vivo could drive hyperactivation of immune cells, which could be therapeutically beneficial, though at the risk of potential toxicity. In this model, we found that Shp1 loss led to robust anti-tumor immunity against two immune-rich syngeneic tumor models that are moderately inflamed though not responsive to checkpoint inhibitors, MC38 and E0771. Shp1 loss did not promote anti-tumor activity in the non-inflamed B16F10 model. The observed activity in MC38 and E0771 tumors was likely due to effects of both innate and adaptive immune cells. Following Shp1 deletion, we observed increases in intratumoral myeloid cells in both models, which was more striking in E0771 tumors. E0771 tumors also contained an increased ratio of effector to regulatory T cells following Shp1 loss. This was not observed for MC38 tumors, though we did find increased levels of IFNγ, a cytokine produced by effector T cells, in these tumors. Overall, our preclinical data suggested that targeting Shp1 may be an attractive therapeutic strategy for boosting the immune response to cancer via a mechanism involving both innate and adaptive leukocytes.

Published
2020

6. ViZDoom: DRQN with Prioritized Experience Replay, Double-Q Learning, & Snapshot Ensembling

Author

Schulze, Christopher and Schulze, Marcus

Subjects
Computer Science - Artificial Intelligence
Abstract

ViZDoom is a robust, first-person shooter reinforcement learning environment, characterized by a significant degree of latent state information. In this paper, double-Q learning and prioritized experience replay methods are tested under a certain ViZDoom combat scenario using a competitive deep recurrent Q-network (DRQN) architecture. In addition, an ensembling technique known as snapshot ensembling is employed using a specific annealed learning rate to observe differences in ensembling efficacy under these two methods. Annealed learning rates are important in general to the training of deep neural network models, as they shake up the status-quo and counter a model's tending towards local optima. While both variants show performance exceeding those of built-in AI agents of the game, the known stabilizing effects of double-Q learning are illustrated, and priority experience replay is again validated in its usefulness by showing immediate results early on in agent development, with the caveat that value overestimation is accelerated in this case. In addition, some unique behaviors are observed to develop for priority experience replay (PER) and double-Q (DDQ) variants, and snapshot ensembling of both PER and DDQ proves a valuable method for improving performance of the ViZDoom Marine., Comment: 9 pages, 5 figures

Published
2018

8. RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers

Author

Nichols, Robert J, Haderk, Franziska, Stahlhut, Carlos, Schulze, Christopher J, Hemmati, Golzar, Wildes, David, Tzitzilonis, Christos, Mordec, Kasia, Marquez, Abby, Romero, Jason, Hsieh, Tientien, Zaman, Aubhishek, Olivas, Victor, McCoach, Caroline, Blakely, Collin M, Wang, Zhengping, Kiss, Gert, Koltun, Elena S, Gill, Adrian L, Singh, Mallika, Goldsmith, Mark A, Smith, Jacqueline AM, and Bivona, Trever G

Subjects
Biochemistry and Cell Biology, Biological Sciences, Rare Diseases, Cancer, Development of treatments and therapeutic interventions, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Aetiology, Animals, Antineoplastic Agents, Biomarkers, Tumor, Cell Line, Tumor, Enzyme Inhibitors, Extracellular Signal-Regulated MAP Kinases, Genetic Predisposition to Disease, Guanosine Triphosphate, HEK293 Cells, Humans, Mice, Inbred BALB C, Mice, Nude, Mitogen-Activated Protein Kinase Kinases, Mutation, Neoplasms, Neurofibromin 1, Phenotype, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins p21(ras), SOS1 Protein, Signal Transduction, Tumor Burden, Xenograft Model Antitumor Assays, raf Kinases, Medical and Health Sciences, Developmental Biology, Biochemistry and cell biology
Abstract

Oncogenic alterations in the RAS/RAF/MEK/ERK pathway drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAFV600E-driven cancers, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including non-V600E oncogenic BRAF, RAS GTPase-activating protein (GAP) NF1 (neurofibromin 1) loss and oncogenic KRAS. Here, we show that targeting the SHP2 phosphatase (encoded by PTPN11) with RMC-4550, a small-molecule allosteric inhibitor, is effective in human cancer models bearing RAS-GTP-dependent oncogenic BRAF (for example, class 3 BRAF mutants), NF1 loss or nucleotide-cycling oncogenic RAS (for example, KRASG12C). SHP2 inhibitor treatment decreases oncogenic RAS/RAF/MEK/ERK signalling and cancer growth by disrupting SOS1-mediated RAS-GTP loading. Our findings illuminate a critical function for SHP2 in promoting oncogenic RAS/MAPK pathway activation in cancers with RAS-GTP-dependent oncogenic BRAF, NF1 loss and nucleotide-cycling oncogenic KRAS. SHP2 inhibition is a promising molecular therapeutic strategy for patients with cancers bearing these oncogenic drivers.

Published
2018

9. ViZDoom: DRQN with Prioritized Experience Replay, Double-Q Learning and Snapshot Ensembling

Author

Schulze, Christopher, Schulze, Marcus, Kacprzyk, Janusz, Series Editor, Pal, Nikhil R., Advisory Editor, Bello Perez, Rafael, Advisory Editor, Corchado, Emilio S., Advisory Editor, Hagras, Hani, Advisory Editor, Kóczy, László T., Advisory Editor, Kreinovich, Vladik, Advisory Editor, Lin, Chin-Teng, Advisory Editor, Lu, Jie, Advisory Editor, Melin, Patricia, Advisory Editor, Nedjah, Nadia, Advisory Editor, Nguyen, Ngoc Thanh, Advisory Editor, Wang, Jun, Advisory Editor, Arai, Kohei, editor, Kapoor, Supriya, editor, and Bhatia, Rahul, editor

Published
2019
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11. The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites

Author

Yoo, Euna, Schulze, Christopher J., Stokes, Barbara H., Onguka, Ouma, Yeo, Tomas, Mok, Sachel, Gnädig, Nina F., Zhou, Yani, Kurita, Kenji, Foe, Ian T., Terrell, Stephanie M., Boucher, Michael J., Cieplak, Piotr, Kumpornsin, Krittikorn, Lee, Marcus C.S., Linington, Roger G., Long, Jonathan Z., Uhlemann, Anne-Catrin, Weerapana, Eranthie, Fidock, David A., and Bogyo, Matthew

Published
2020
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13. Design of Selective Substrates and Activity-Based Probes for Hydrolase Important for Pathogenesis 1 (HIP1) from Mycobacterium tuberculosis

Author

Lentz, Christian S, Ordonez, Alvaro A, Kasperkiewicz, Paulina, La Greca, Florencia, O’Donoghue, Anthony J, Schulze, Christopher J, Powers, James C, Craik, Charles S, Drag, Marcin, Jain, Sanjay K, and Bogyo, Matthew

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Tuberculosis, Infectious Diseases, Rare Diseases, Emerging Infectious Diseases, 2.1 Biological and endogenous factors, Aetiology, Infection, Good Health and Well Being, Animals, Antitubercular Agents, Bacterial Proteins, Drug Design, Enzyme Inhibitors, Humans, Kinetics, Molecular Structure, Mycobacterium tuberculosis, Serine Proteases, Substrate Specificity, hydrolase important for pathogenesis 1, protease, activity-based probe, fluorogenic substrate, substrate profiling, Medical microbiology
Abstract

Although serine proteases are important mediators of Mycobacterium tuberculosis (Mtb) virulence, there are currently no tools to selectively block or visualize members of this family of enzymes. Selective reporter substrates or activity-based probes (ABPs) could provide a means to monitor infection and response to therapy using imaging methods. Here, we use a combination of substrate selectivity profiling and focused screening to identify optimized reporter substrates and ABPs for the Mtb "Hydrolase important for pathogenesis 1" (Hip1) serine protease. Hip1 is a cell-envelope-associated enzyme with minimal homology to host proteases, making it an ideal target for probe development. We identified substituted 7-amino-4-chloro-3-(2-bromoethoxy)isocoumarins as irreversible inhibitor scaffolds. Furthermore, we used specificity data to generate selective reporter substrates and to further optimize a selective chloroisocoumarin inhibitor. These new reagents are potentially useful in delineating the roles of Hip1 during pathogenesis or as diagnostic imaging tools for specifically monitoring Mtb infections.

Published
2016

15. Genome-Directed Lead Discovery: Biosynthesis, Structure Elucidation, and Biological Evaluation of Two Families of Polyene Macrolactams against Trypanosoma brucei

Author

Schulze, Christopher J, Donia, Mohamed S, Siqueira-Neto, Jair L, Ray, Debalina, Raskatov, Jevgenij A, Green, Richard E, McKerrow, James H, Fischbach, Michael A, and Linington, Roger G

Subjects
Biological Sciences, Medicinal and Biomolecular Chemistry, Chemical Sciences, Human Genome, Rare Diseases, Biotechnology, Genetics, Vector-Borne Diseases, Infectious Diseases, 2.2 Factors relating to the physical environment, Aetiology, Infection, Good Health and Well Being, Animals, Antiprotozoal Agents, Drug Discovery, Drug Evaluation, Preclinical, Humans, Inhibitory Concentration 50, Lactams, Molecular Structure, Multigene Family, Polyenes, Trypanosoma brucei brucei, Organic Chemistry, Biological sciences, Chemical sciences
Abstract

Marine natural products are an important source of lead compounds against many pathogenic targets. Herein, we report the discovery of lobosamides A-C from a marine actinobacterium, Micromonospora sp., representing three new members of a small but growing family of bacterially produced polyene macrolactams. The lobosamides display growth inhibitory activity against the protozoan parasite Trypanosoma brucei (lobosamide A IC50 = 0.8 μM), the causative agent of human African trypanosomiasis (HAT). The biosynthetic gene cluster of the lobosamides was sequenced and suggests a conserved cluster organization among the 26-membered macrolactams. While determination of the relative and absolute configurations of many members of this family is lacking, the absolute configurations of the lobosamides were deduced using a combination of chemical modification, detailed spectroscopic analysis, and bioinformatics. We implemented a "molecules-to-genes-to-molecules" approach to determine the prevalence of similar clusters in other bacteria, which led to the discovery of two additional macrolactams, mirilactams A and B from Actinosynnema mirum. These additional analogs have allowed us to identify specific structure-activity relationships that contribute to the antitrypanosomal activity of this class. This approach illustrates the power of combining chemical analysis and genomics in the discovery and characterization of natural products as new lead compounds for neglected disease targets.

Published
2015

16. Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS

Author

Schulze, Christopher J., primary, Seamon, Kyle J., additional, Zhao, Yulei, additional, Yang, Yu C., additional, Cregg, Jim, additional, Kim, Dongsung, additional, Tomlinson, Aidan, additional, Choy, Tiffany J., additional, Wang, Zhican, additional, Sang, Ben, additional, Pourfarjam, Yasin, additional, Lucas, Jessica, additional, Cuevas-Navarro, Antonio, additional, Ayala-Santos, Carlos, additional, Vides, Alberto, additional, Li, Chuanchuan, additional, Marquez, Abby, additional, Zhong, Mengqi, additional, Vemulapalli, Vidyasiri, additional, Weller, Caroline, additional, Gould, Andrea, additional, Whalen, Daniel M., additional, Salvador, Anthony, additional, Milin, Anthony, additional, Saldajeno-Concar, Mae, additional, Dinglasan, Nuntana, additional, Chen, Anqi, additional, Evans, Jim, additional, Knox, John E., additional, Koltun, Elena S., additional, Singh, Mallika, additional, Nichols, Robert, additional, Wildes, David, additional, Gill, Adrian L., additional, Smith, Jacqueline A. M., additional, and Lito, Piro, additional

Published
2023
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17. A boreal forest model benchmarking dataset for North America: a case study with the Canadian Land Surface Scheme Including Biogeochemical Cycles (CLASSIC)

Author

Qu, Bo, primary, Roy, Alexandre, additional, Melton, Joe R, additional, Black, T Andrew, additional, Amiro, Brian, additional, Euskirchen, Eugénie S, additional, Ueyama, Masahito, additional, Kobayashi, Hideki, additional, Schulze, Christopher, additional, Gosselin, Gabriel Hould, additional, Cannon, Alex J, additional, Detto, Matteo, additional, and Sonnentag, Oliver, additional

Published
2023
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18. Self-administered intranasal etripamil using a symptom-prompted, repeat-dose regimen for atrioventricular-nodal-dependent supraventricular tachycardia (RAPID): a multicentre, randomised trial

Author

Stambler, Bruce S, primary, Camm, A John, additional, Alings, Marco, additional, Dorian, Paul, additional, Heidbuchel, Hein, additional, Houtgraaf, Jaco, additional, Kowey, Peter R, additional, Merino, Jose L, additional, Mondésert, Blandine, additional, Piccini, Jonathan P, additional, Pokorney, Sean D, additional, Sager, Philip T, additional, Verma, Atul, additional, Wharton, J Marcus, additional, Bharucha, David B, additional, Plat, Francis, additional, Shardonofsky, Silvia, additional, Chen, Michael, additional, Ip, James E, additional, Jones, Alonzo, additional, Stambler, Bruce S, additional, Schleinkofer, David E, additional, Winters, Stephen, additional, Lam, Wilson, additional, Goldstein, Robert, additional, Dor, Isaac Dor, additional, Talwar, Sandeep, additional, O'Neill, Padraig G, additional, Koren, Michael J, additional, Beinart, Sean C, additional, Ambati, Srivani, additional, Mazer, Sean P, additional, Kinn, Robert M, additional, Roy, Karine, additional, Manshadi, Ramin, additional, Kuk, Richard, additional, Verma, Aditya, additional, Phelan, Timothy, additional, Stoian, Alexandru A, additional, Ellenbogen, Kenneth, additional, Jayachandran, J Vijay, additional, Connelly, Terence P, additional, Daccarett, Marcos, additional, Gandhi, Gaurang, additional, Mittal, Suneet, additional, Abdel-Wahab, Amir, additional, Augostini, Ralph, additional, Ip, John H, additional, Sorrentino, Denise, additional, Roux, Jean-Francois, additional, Brar, Ramandeep, additional, Khoo, Clarence, additional, Bennett, Matthew, additional, Lo, Eric, additional, Coutu, Benoit, additional, Sterns, Laurence, additional, Greer, Gerald S, additional, Gujja, Pradeep, additional, Gianfagna, Robert A, additional, Swarup, Vijendra, additional, Sogade, Felix, additional, Wilton, Stephen, additional, Ruisi, Christopher, additional, Barbera, Saverio, additional, Banchs, Javier E., additional, Korley, Victoria, additional, Schulze, Christopher, additional, Damle, Roger, additional, Healey, Jeffrey Sean, additional, Pandey, A Shekhar, additional, Anderson, Jeffrey L, additional, Venkatachalam, K L, additional, Noseworthy, Peter, additional, Friars, Douglas G, additional, Kambur, Thomas R, additional, Lockwood, Evan, additional, Meininger, Glenn, additional, Olsovsky, Greg, additional, Jones Sr, Alonzo, additional, Greer, Gerald, additional, Mehta, Rohit, additional, Akbar, Saleem, additional, Salman, Malik, additional, Rama, Bhola, additional, Arora, Ramesh, additional, Shah, Dhirenkumar, additional, Shah, Rakesh, additional, Cammarata, Michael, additional, Owens, Andrew, additional, Ludington, Katherine, additional, Wharton, Marcus, additional, Bagheri, Michael, additional, Khan, Mohammed, additional, Carr, Kenneth Warren, additional, Siddique, Sultan, additional, Parvathaneni, Sunthosh, additional, Devabhaktuni, Subodh, additional, Mouhaffel, Assad, additional, Mark, George, additional, Di Biase, Luigi, additional, Rangappa, Sunil, additional, Morton, Jared, additional, Yarmohammadi, Hirad, additional, Karim, Amin, additional, Martinez Fleites, Aldo, additional, Nero, Thomas, additional, Shafiq, Qaiser, additional, Pandey, Shekhar, additional, Khaykin, Yaariv, additional, Joza, Jacqueline, additional, Gosselin, Gilbert, additional, Skanes, Allen, additional, Vyselaar, John, additional, Savard, Daniel, additional, Xhaet, Olivier, additional, Catez, Emmanuel, additional, Vijgen, Johan, additional, Godart, Pascal, additional, Casado, Ruben, additional, Mairesse, Georges, additional, Rossenbacker, Tom, additional, Haemers, Peter, additional, Hoffer, Etienne, additional, Hausman, Pierre, additional, Vertes, Andras, additional, Duray, Gabor, additional, Szolnoki, Erzsebet, additional, Csanadi, Zoltan, additional, Lakatos, Ferenc, additional, Dorman, Reinhart, additional, Tuininga, Y S, additional, Jansen, W, additional, Velthuis, Sebastiaan, additional, van Bemmel, B, additional, Bech, Gerhard Jan Willem, additional, Pisters, Ron, additional, Valk, Suzanne, additional, Romer, Tjeerd, additional, Luermans, Justin, additional, Beelen, Driek, additional, van Eck, Martijn, additional, Vet, Thijs, additional, Shellings, Dirk, additional, Oosterhof, T, additional, Miekus, Pawel, additional, Bebenek, Waldemar, additional, Bielecka-Dabrowa, Agata, additional, Gniot, Jacek, additional, Zmuda, Witold, additional, Kasprzak, Michal, additional, Balak, Wojciech, additional, Ptaszynski, Pawel, additional, Nowak, Jacek, additional, Prokopczuk, Janusz, additional, Przybylski, Andrzej, additional, Wozniak-Skowerska, Iwona, additional, Derejko, Pawel, additional, Czarnecka, Danuta, additional, Janas, Adam, additional, Merino Llorens, Jose Luis, additional, Tercedor, Luis, additional, Iniguez Romo, Andres, additional, Ruiz Granell, Ricardo, additional, Gonzalez Juanatey, Jose Ramon, additional, Pascual-Figal, Domingo, additional, Martinez-Selles, Manuel, additional, Anguera Camos, Ignacio, additional, Ibanez Criado, Alicia, additional, Matrinez Basterra, Javier, additional, Izquierdo, Alvaro, additional, Rivas Gandara, Nuria, additional, Alegret Colome, Josep M, additional, Perez Diez, Diego, additional, Martínez Hervás, Miguel Ángel, additional, Medina, Maria, additional, Segura Saint-Gerons, Jose María, additional, Pedrote Leal, Alonso, additional, Fernandez Lozano, Ignacio, additional, Quesada, Aurelio, additional, Guerra Ramos, Jose, additional, Sarrias, Axel, additional, Ramos Maqueda, Javier, additional, Mansourati, Jacques, additional, Defaye, Pascal, additional, Guedon-Moreau, Laurence, additional, Milhem, Antoine, additional, De Guillebon, Maxime, additional, Chevalier, Philippe, additional, Badoz, Marc, additional, Kriatselis, Charalampos, additional, Simonis, Gregor, additional, Lewalter, Thorsten, additional, Zarse, Markus, additional, Wilke, Andreas, additional, Kraemer, Fabian, additional, and Al-Zoebi, Ayham, additional

Published
2023
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20. Nitrous Oxide Fluxes in Permafrost Peatlands Remain Negligible After Wildfire and Thermokarst Disturbance

Author

Schulze, Christopher, Sonnentag, Oliver, Voigt, Carolina, Thompson, Lauren, van Delden, Lona, Heffernan, Liam, Hernandez‐Ramirez, Guillermo, Kuhn, McKenzie, Lin, Sisi, Olefeldt, David, Schulze, Christopher, Sonnentag, Oliver, Voigt, Carolina, Thompson, Lauren, van Delden, Lona, Heffernan, Liam, Hernandez‐Ramirez, Guillermo, Kuhn, McKenzie, Lin, Sisi, and Olefeldt, David

Abstract

The greenhouse gas (GHG) balance of boreal peatlands in permafrost regions will be affected by climate change through disturbances such as permafrost thaw and wildfire. Although the future GHG balance of boreal peatlands including ponds is dominated by the exchange of both carbon dioxide (CO2) and methane (CH4), disturbance impacts on fluxes of the potent GHG nitrous oxide (N2O) could contribute to shifts in the net radiative balance. Here, we measured monthly (April to October) fluxes of N2O, CH4, and CO2 from three sites located across the sporadic and discontinuous permafrost zones of western Canada. Undisturbed permafrost peat plateaus acted as N2O sinks (−0.025 mg N2O m−2 d−1), but N2O uptake was lower from burned plateaus (−0.003 mg N2O m−2 d−1) and higher following permafrost thaw in the thermokarst bogs (−0.054 mg N2O m−2 d−1). The thermokarst bogs had below-ambient N2O soil gas concentrations, suggesting that denitrification consumed atmospheric N2O during reduction to dinitrogen. Atmospheric uptake of N2O in peat plateaus and thermokarst bogs increased with soil temperature and soil moisture, suggesting sensitivity of N2O consumption to further climate change. Four of five peatland ponds acted as N2O sinks (−0.018 mg N2O m−2 d−1), with no influence of thermokarst expansion. One pond with high nitrate concentrations had high N2O emissions (0.30 mg N2O m−2 d−1). Overall, our study suggests that the future net radiative balance of boreal peatlands will be dominated by impacts of wildfire and permafrost thaw on CH4 and CO2 fluxes, while the influence from N2O is minor.

Published
2023

24. The ABCflux database: Arctic–boreal CO2 flux observations and ancillary information aggregated to monthly time steps across terrestrial ecosystems

Author

Virkkala​​​​​​​, Anna-Maria, Natali, Susan M., Rogers, Brendan M., Watts, Jennifer D., Savage, Kathleen, Connon, Sara June, Mauritz, Marguerite, Schuur, Edward A. G., Peter, Darcy, Minions, Christina, Nojeim, Julia, Commane, Roisin, Emmerton, Craig A., Goeckede, Mathias, Helbig, Manuel, Holl, David, Iwata, Hiroki, Kobayashi, Hideki, Kolari, Pasi, López-Blanco, Efrén, Marushchak, Maija E., Mastepanov, Mikhail, Merbold, Lutz, Parmentier, Frans-Jan W., Peichl, Matthias, Sachs, Torsten, Sonnentag, Oliver, Ueyama, Masahito, Voigt, Carolina, Aurela, Mika, Boike, Julia, Celis, Gerardo, Chae, Namyi, Christensen, Torben R., Bret-Harte, M. Syndonia, Dengel, Sigrid, Dolman, Han, Edgar, Colin W., Elberling, Bo, Euskirchen, Eugenie, Grelle, Achim, Hatakka, Juha, Humphreys, Elyn, Järveoja, Järvi, Kotani, Ayumi, Kutzbach, Lars, Laurila, Tuomas, Lohila, Annalea, Mammarella, Ivan, Matsuura, Yojiro, Meyer, Gesa, Nilsson, Mats B., Oberbauer, Steven F., Park, Sang-Jong, Petrov, Roman, Prokushkin, Anatoly S., Schulze, Christopher, St. Louis, Vincent L., Tuittila, Eeva-Stiina, Tuovinen, Juha-Pekka, Quinton, William, Varlagin, Andrej, Zona, Donatella, Zyryanov, Viacheslav I., Virkkala​​​​​​​, Anna-Maria, Natali, Susan M., Rogers, Brendan M., Watts, Jennifer D., Savage, Kathleen, Connon, Sara June, Mauritz, Marguerite, Schuur, Edward A. G., Peter, Darcy, Minions, Christina, Nojeim, Julia, Commane, Roisin, Emmerton, Craig A., Goeckede, Mathias, Helbig, Manuel, Holl, David, Iwata, Hiroki, Kobayashi, Hideki, Kolari, Pasi, López-Blanco, Efrén, Marushchak, Maija E., Mastepanov, Mikhail, Merbold, Lutz, Parmentier, Frans-Jan W., Peichl, Matthias, Sachs, Torsten, Sonnentag, Oliver, Ueyama, Masahito, Voigt, Carolina, Aurela, Mika, Boike, Julia, Celis, Gerardo, Chae, Namyi, Christensen, Torben R., Bret-Harte, M. Syndonia, Dengel, Sigrid, Dolman, Han, Edgar, Colin W., Elberling, Bo, Euskirchen, Eugenie, Grelle, Achim, Hatakka, Juha, Humphreys, Elyn, Järveoja, Järvi, Kotani, Ayumi, Kutzbach, Lars, Laurila, Tuomas, Lohila, Annalea, Mammarella, Ivan, Matsuura, Yojiro, Meyer, Gesa, Nilsson, Mats B., Oberbauer, Steven F., Park, Sang-Jong, Petrov, Roman, Prokushkin, Anatoly S., Schulze, Christopher, St. Louis, Vincent L., Tuittila, Eeva-Stiina, Tuovinen, Juha-Pekka, Quinton, William, Varlagin, Andrej, Zona, Donatella, and Zyryanov, Viacheslav I.

Abstract

Past efforts to synthesize and quantify the magnitude and change in carbon dioxide (CO2) fluxes in terrestrial ecosystems across the rapidly warming Arctic–boreal zone (ABZ) have provided valuable information but were limited in their geographical and temporal coverage. Furthermore, these efforts have been based on data aggregated over varying time periods, often with only minimal site ancillary data, thus limiting their potential to be used in large-scale carbon budget assessments. To bridge these gaps, we developed a standardized monthly database of Arctic–boreal CO2 fluxes (ABCflux) that aggregates in situ measurements of terrestrial net ecosystem CO2 exchange and its derived partitioned component fluxes: gross primary productivity and ecosystem respiration. The data span from 1989 to 2020 with over 70 supporting variables that describe key site conditions (e.g., vegetation and disturbance type), micrometeorological and environmental measurements (e.g., air and soil temperatures), and flux measurement techniques. Here, we describe these variables, the spatial and temporal distribution of observations, the main strengths and limitations of the database, and the potential research opportunities it enables. In total, ABCflux includes 244 sites and 6309 monthly observations; 136 sites and 2217 monthly observations represent tundra, and 108 sites and 4092 observations represent the boreal biome. The database includes fluxes estimated with chamber (19 % of the monthly observations), snow diffusion (3 %) and eddy covariance (78 %) techniques. The largest number of observations were collected during the climatological summer (June–August; 32 %), and fewer observations were available for autumn (September–October; 25 %), winter (December–February; 18 %), and spring (March–May; 25 %). ABCflux can be used in a wide array of empirical, remote sensing and modeling studies to improve understanding of the regional and temporal variability in CO2 fluxes and to better estimate th

Published
2022

25. The ABCflux database:Arctic-boreal CO2flux observations and ancillary information aggregated to monthly time steps across terrestrial ecosystems

Author

Virkkala, Anna Maria, Natali, Susan M., Rogers, Brendan M., Watts, Jennifer D., Savage, Kathleen, Connon, Sara June, Mauritz, Marguerite, Schuur, Edward A.G., Peter, Darcy, Minions, Christina, Nojeim, Julia, Commane, Roisin, Emmerton, Craig A., Goeckede, Mathias, Helbig, Manuel, Holl, David, Iwata, Hiroki, Kobayashi, Hideki, Kolari, Pasi, López-Blanco, Efrén, Marushchak, Maija E., Mastepanov, Mikhail, Merbold, Lutz, Parmentier, Frans Jan W., Peichl, Matthias, Sachs, Torsten, Sonnentag, Oliver, Ueyama, Masahito, Voigt, Carolina, Aurela, Mika, Boike, Julia, Celis, Gerardo, Chae, Namyi, Christensen, Torben R., Bret-Harte, M. Syndonia, Dengel, Sigrid, Dolman, Han, Edgar, Colin W., Elberling, Bo, Euskirchen, Eugenie, Grelle, Achim, Hatakka, Juha, Humphreys, Elyn, Järveoja, Järvi, Kotani, Ayumi, Kutzbach, Lars, Laurila, Tuomas, Lohila, Annalea, Mammarella, Ivan, Matsuura, Yojiro, Meyer, Gesa, Nilsson, Mats B., Oberbauer, Steven F., Park, Sang Jong, Petrov, Roman, Prokushkin, Anatoly S., Schulze, Christopher, St. Louis, Vincent L., Tuittila, Eeva Stiina, Tuovinen, Juha Pekka, Quinton, William, Varlagin, Andrej, Zona, Donatella, Zyryanov, Viacheslav I., Virkkala, Anna Maria, Natali, Susan M., Rogers, Brendan M., Watts, Jennifer D., Savage, Kathleen, Connon, Sara June, Mauritz, Marguerite, Schuur, Edward A.G., Peter, Darcy, Minions, Christina, Nojeim, Julia, Commane, Roisin, Emmerton, Craig A., Goeckede, Mathias, Helbig, Manuel, Holl, David, Iwata, Hiroki, Kobayashi, Hideki, Kolari, Pasi, López-Blanco, Efrén, Marushchak, Maija E., Mastepanov, Mikhail, Merbold, Lutz, Parmentier, Frans Jan W., Peichl, Matthias, Sachs, Torsten, Sonnentag, Oliver, Ueyama, Masahito, Voigt, Carolina, Aurela, Mika, Boike, Julia, Celis, Gerardo, Chae, Namyi, Christensen, Torben R., Bret-Harte, M. Syndonia, Dengel, Sigrid, Dolman, Han, Edgar, Colin W., Elberling, Bo, Euskirchen, Eugenie, Grelle, Achim, Hatakka, Juha, Humphreys, Elyn, Järveoja, Järvi, Kotani, Ayumi, Kutzbach, Lars, Laurila, Tuomas, Lohila, Annalea, Mammarella, Ivan, Matsuura, Yojiro, Meyer, Gesa, Nilsson, Mats B., Oberbauer, Steven F., Park, Sang Jong, Petrov, Roman, Prokushkin, Anatoly S., Schulze, Christopher, St. Louis, Vincent L., Tuittila, Eeva Stiina, Tuovinen, Juha Pekka, Quinton, William, Varlagin, Andrej, Zona, Donatella, and Zyryanov, Viacheslav I.

Abstract

Past efforts to synthesize and quantify the magnitude and change in carbon dioxide (CO2) fluxes in terrestrial ecosystems across the rapidly warming Arctic-boreal zone (ABZ) have provided valuable information but were limited in their geographical and temporal coverage. Furthermore, these efforts have been based on data aggregated over varying time periods, often with only minimal site ancillary data, thus limiting their potential to be used in large-scale carbon budget assessments. To bridge these gaps, we developed a standardized monthly database of Arctic-boreal CO2 fluxes (ABCflux) that aggregates in situ measurements of terrestrial net ecosystem CO2 exchange and its derived partitioned component fluxes: gross primary productivity and ecosystem respiration. The data span from 1989 to 2020 with over 70 supporting variables that describe key site conditions (e.g., vegetation and disturbance type), micrometeorological and environmental measurements (e.g., air and soil temperatures), and flux measurement techniques. Here, we describe these variables, the spatial and temporal distribution of observations, the main strengths and limitations of the database, and the potential research opportunities it enables. In total, ABCflux includes 244 sites and 6309 monthly observations; 136 sites and 2217 monthly observations represent tundra, and 108 sites and 4092 observations represent the boreal biome. The database includes fluxes estimated with chamber (19% of the monthly observations), snow diffusion (3%) and eddy covariance (78%) techniques. The largest number of observations were collected during the climatological summer (June-August; 32%), and fewer observations were available for autumn (September-October; 25%), winter (December-February; 18%), and spring (March-May; 25%). ABCflux can be used in a wide array of empirical, remote sensing and modeling studies to improve understanding of the regional and temporal variability in CO2 fluxes and to better estimate the te

Published
2022

28. Abstract 3598: A first-in-class tri-complex KRASG13C(ON) inhibitor validates therapeutic targeting of KRASG13Cand drives tumor regressions in preclinical models

Author

Schulze, Christopher J., primary, Cregg, Jim, additional, Seamon, Kyle J., additional, Yang, Yu Chi, additional, Wang, Zhican, additional, Garrenton, Lindsay S., additional, Bermingham, Alun, additional, Knox, John E., additional, Tomlinson, Aidan, additional, Chou, Kang-Jye, additional, Li, Shaoling, additional, Wildes, David P., additional, Singh, Mallika, additional, Koltun, Elena S., additional, Gill, Adrian L., additional, Nichols, Robert J., additional, and Smith, Jacqueline A., additional

Published
2022
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29. Effects of Warming, Wildfire, and Permafrost Thaw on Carbon Dioxide Fluxes from Boreal Peat Landscapes in northwestern Canada

Author

Schulze, Christopher, primary, Olefeldt, David, additional, Emmerton, Craig, additional, Harris, Lorna, additional, Kljun, Natascha, additional, Chasmer, Laura, additional, Hopkinson, Chris, additional, Detto, Matteo, additional, Helbig, Manuel, additional, Gosselin, Gabriel Hould, additional, and Sonnentag, Oliver, additional

Published
2022
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31. The ABCflux database: Arctic-Boreal CO2 flux observations and ancillary information aggregated to monthly time steps across terrestrial ecosystems

Author

Virkkala, Anna-Maria, primary, Natali, Susan M., additional, Rogers, Brendan M., additional, Watts, Jennifer D., additional, Savage, Kathleen, additional, Connon, Sara June, additional, Mauritz, Marguerite, additional, Schuur, Edward A. G., additional, Peter, Darcy, additional, Minions, Christina, additional, Nojeim, Julia, additional, Commane, Roisin, additional, Emmerton, Craig A., additional, Goeckede, Mathias, additional, Helbig, Manuel, additional, Holl, David, additional, Iwata, Hiroki, additional, Kobayashi, Hideki, additional, Kolari, Pasi, additional, López-Blanco, Efrén, additional, Marushchak, Maija E., additional, Mastepanov, Mikhail, additional, Merbold, Lutz, additional, Parmentier, Frans-Jan W., additional, Peichl, Matthias, additional, Sachs, Torsten, additional, Sonnentag, Oliver, additional, Ueyama, Masahito, additional, Voigt, Carolina, additional, Aurela, Mika, additional, Boike, Julia, additional, Celis, Gerardo, additional, Chae, Namyi, additional, Christensen, Torben R., additional, Bret-Harte, M. Syndonia, additional, Dengel, Sigrid, additional, Dolman, Han, additional, Edgar, Colin W., additional, Elberling, Bo, additional, Euskirchen, Eugenie, additional, Grelle, Achim, additional, Hatakka, Juha, additional, Humphreys, Elyn, additional, Järveoja, Järvi, additional, Kotani, Ayumi, additional, Kutzbach, Lars, additional, Laurila, Tuomas, additional, Lohila, Annalea, additional, Mammarella, Ivan, additional, Matsuura, Yojiro, additional, Meyer, Gesa, additional, Nilsson, Mats B., additional, Oberbauer, Steven F., additional, Park, Sang-Jong, additional, Petrov, Roman, additional, Prokushkin, Anatoly S., additional, Schulze, Christopher, additional, St.Louis, Vincent L., additional, Tuittila, Eeva-Stiina, additional, Tuovinen, Juha-Pekka, additional, Quinton, William, additional, Varlagin, Andrej, additional, Zona, Donatella, additional, and Zyryanov, Viacheslav I., additional

Published
2021
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32. Abstract 1261: A next generation tri-complex KRASG12C(ON) inhibitor directly targets the active, GTP-bound state of mutant RAS and may overcome resistance to KRASG12C(OFF) inhibition

Author

Nichols, Robert J., primary, Cregg, Jim, additional, Schulze, Christopher J., additional, Wang, Zhican, additional, Yang, Kevin, additional, Jiang, Jingjing, additional, Whalen, Daniel M., additional, Hansen, Rich, additional, Garrenton, Lindsay S., additional, Bermingham, Alun, additional, Knox, John E., additional, Choy, Tiffany, additional, Reyes, Denise, additional, Rios, Mayra, additional, Seamon, Kyle, additional, Longhi, Michael, additional, Chou, Kang-Jye, additional, Li, Shaoling, additional, Wildes, David P., additional, Singh, Mallika, additional, Koltun, Elena S., additional, Gill, Adrian L., additional, and Smith, Jacqueline A. M., additional

Published
2021
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34. KiDSafe - Implementierung einer neuen Versorgungsform zur Verbesserung der ambulanten Versorgung von Kindern und Jugendlichen mit Arzneimitteln durch Erhöhung der Arzneimitteltherapiesicherheit

Author

Toni, Irmgard, Moritz, Katrin, Schulze, Christopher, Schreeck, Filippa, Schwab, Matthias, Rascher, Wolfgang, Neubert, Antje, and KiDSafe Konsortium

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Hintergrund: Kinder und Jugendliche sind bei der Arzneimittelversorgung benachteiligt. Durch off-label Anwendungen, fehlende pädiatrische Darreichungsformen und komplexe Dosisberechnungen treten Medikationsfehler (MF) mit Schädigungspotenzial bis zu dreimal häufiger auf als bei Erwachsenen[zum vollständigen Text gelangen Sie über die oben angegebene URL], 19. Deutscher Kongress für Versorgungsforschung (DKVF)

Published
2020

35. Drug Utilisation and Off-Label Use on a German Neonatal Intensive Care Unit: A Retrospective Cohort Study and 10-Year Comparison

Author

Geißler, Carmen, Schulze, Christopher, Botzenhardt, Sebastian, Rascher, Wolfgang, and Neubert, Antje

Subjects
lcsh:Pharmacy and materia medica, NICU, health care facilities, manpower, and services, education, prescribing, lcsh:RS1-441, off-label use, ddc:610, European Paediatric Regulation, Article
Abstract

Pharmacotherapy of neonates is complex and marked to a large extent of off-label use. The implementation of the Paediatric Regulation (2007) gave hope for a change in the safety and efficacy for drugs used in neonatal intensive care units (NICU). This study investigates drug utilisation patterns and off-label use in a German neonatal intensive care unit (NICU) in 2014. A 12-months retrospective, observational cohort study was performed at the NICU of the University Children&rsquo, s Hospital Erlangen, Germany. Licensing status was determined using the Summary of Product Characteristics (SmPC). Results are compared with a similar study conducted 10 years earlier. The study included 204 patients (57.8% male) (2004: 183) and 2274 drug prescriptions were recorded (2004: 1978). The drugs that were mostly prescribed were drugs for the nervous system (2004: 22.6%, 2014: 26.9%) and anti-infectives for systemic use (2004: 26.0%, 2014: 24.9%), 34.3% (2004) and 39.2% (2014) of all prescriptions were off-label, 62.7% of all patients received at least one off-label or unlicensed drug (2004: 70%). For 13 drugs, the licensing status changed either from off-label to label (n = 9) or vice versa (n = 4). Overall, there was no significant change neither in terms of the drugs used nor regarding their licensing status. Further studies are needed to validate these findings in a European context.

Published
2020

36. The biophysical climate mitigation potential of boreal peatlands during the growing season

Author

Helbig, Manuel, Waddington, James M, Alekseychik, Pavel, Amiro, Brian, Aurela, Mika, Barr, Alan G, Black, T Andrew, Carey, Sean K, Chen, Jiquan, Chi, Jinshu, Desai, Ankur R, Dunn, Allison, Euskirchen, Eugenie S, Flanagan, Lawrence B, Friborg, Thomas, Garneau, Michelle, Grelle, Achim, Harder, Silvie, Heliasz, Michal, Humphreys, Elyn R, Ikawa, Hiroki, Isabelle, Pierre-Erik, Iwata, Hiroki, Jassal, Rachhpal, Korkiakoski, Mika, Kurbatova, Juliya, Kutzbach, Lars, Lapshina, Elena, Lindroth, Anders, Löfvenius, Mikaell Ottosson, Lohila, Annalea, Mammarella, Ivan, Marsh, Philip, Moore, Paul A, Maximov, Trofim, Nadeau, Daniel F, Nicholls, Erin M, Nilsson, Mats B, Ohta, Takeshi, Peichl, Matthias, Petrone, Richard M, Prokushkin, Anatoly, Quinton, William L, Roulet, Nigel, Runkle, Benjamin R K, Sonnentag, Oliver, Strachan, Ian B, Taillardat, Pierre, Tuittila, Eeva-Stiina, Tuovinen, Juha-Pekka, Turner, Jessica, Ueyama, Masahito, Varlagin, Andrej, Vesala, Timo, Wilmking, Martin, Zyrianov, Vyacheslav, Schulze, Christopher, Helbig, Manuel, Waddington, James M, Alekseychik, Pavel, Amiro, Brian, Aurela, Mika, Barr, Alan G, Black, T Andrew, Carey, Sean K, Chen, Jiquan, Chi, Jinshu, Desai, Ankur R, Dunn, Allison, Euskirchen, Eugenie S, Flanagan, Lawrence B, Friborg, Thomas, Garneau, Michelle, Grelle, Achim, Harder, Silvie, Heliasz, Michal, Humphreys, Elyn R, Ikawa, Hiroki, Isabelle, Pierre-Erik, Iwata, Hiroki, Jassal, Rachhpal, Korkiakoski, Mika, Kurbatova, Juliya, Kutzbach, Lars, Lapshina, Elena, Lindroth, Anders, Löfvenius, Mikaell Ottosson, Lohila, Annalea, Mammarella, Ivan, Marsh, Philip, Moore, Paul A, Maximov, Trofim, Nadeau, Daniel F, Nicholls, Erin M, Nilsson, Mats B, Ohta, Takeshi, Peichl, Matthias, Petrone, Richard M, Prokushkin, Anatoly, Quinton, William L, Roulet, Nigel, Runkle, Benjamin R K, Sonnentag, Oliver, Strachan, Ian B, Taillardat, Pierre, Tuittila, Eeva-Stiina, Tuovinen, Juha-Pekka, Turner, Jessica, Ueyama, Masahito, Varlagin, Andrej, Vesala, Timo, Wilmking, Martin, Zyrianov, Vyacheslav, and Schulze, Christopher

Abstract

Peatlands and forests cover large areas of the boreal biome and are critical for global climate regulation. They also regulate regional climate through heat and water vapour exchange with the atmosphere. Understanding how land-atmosphere interactions in peatlands differ from forests may therefore be crucial for modelling boreal climate system dynamics and for assessing climate benefits of peatland conservation and restoration. To assess the biophysical impacts of peatlands and forests on peak growing season air temperature and humidity, we analysed surface energy fluxes and albedo from 35 peatlands and 37 evergreen needleleaf forests—the dominant boreal forest type—and simulated air temperature and vapour pressure deficit (VPD) over hypothetical homogeneous peatland and forest landscapes. We ran an evapotranspiration model using land surface parameters derived from energy flux observations and coupled an analytical solution for the surface energy balance to an atmospheric boundary layer (ABL) model. We found that peatlands, compared to forests, are characterized by higher growing season albedo, lower aerodynamic conductance, and higher surface conductance for an equivalent VPD. This combination of peatland surface properties results in a ∼20% decrease in afternoon ABL height, a cooling (from 1.7 to 2.5 °C) in afternoon air temperatures, and a decrease in afternoon VPD (from 0.4 to 0.7 kPa) for peatland landscapes compared to forest landscapes. These biophysical climate impacts of peatlands are most pronounced at lower latitudes (∼45°N) and decrease toward the northern limit of the boreal biome (∼70°N). Thus, boreal peatlands have the potential to mitigate the effect of regional climate warming during the growing season. The biophysical climate mitigation potential of peatlands needs to be accounted for when projecting the future climate of the boreal biome, when assessing the climate benefits of conserving pristine boreal peatlands, and when restoring peatlands that

Published
2020

38. Increased SAR-CoV-2 shedding associated with reduced disease severity despite continually emerging genetic variants

Author

Tang, Cynthia Y., primary, Wang, Yang, additional, Gao, Cheng, additional, Smith, David R., additional, McElroy, Jane A., additional, Li, Tao, additional, Segovia, Karen, additional, Haynes, Tricia, additional, Hammer, Richard, additional, Sampson, Christopher, additional, Ritter, Detlef, additional, Schulze, Christopher, additional, Trotman, Robin, additional, Lidl, Grace M, additional, Webby, Richard, additional, Hang, Jun, additional, and Wan, Xiu-Feng, additional

Published
2021
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40. The biophysical climate mitigation potential of boreal peatlands during the growing season

Author

Helbig, Manuel, primary, Waddington, James M, additional, Alekseychik, Pavel, additional, Amiro, Brian, additional, Aurela, Mika, additional, Barr, Alan G, additional, Black, T Andrew, additional, Carey, Sean K, additional, Chen, Jiquan, additional, Chi, Jinshu, additional, Desai, Ankur R, additional, Dunn, Allison, additional, Euskirchen, Eugenie S, additional, Flanagan, Lawrence B, additional, Friborg, Thomas, additional, Garneau, Michelle, additional, Grelle, Achim, additional, Harder, Silvie, additional, Heliasz, Michal, additional, Humphreys, Elyn R, additional, Ikawa, Hiroki, additional, Isabelle, Pierre-Erik, additional, Iwata, Hiroki, additional, Jassal, Rachhpal, additional, Korkiakoski, Mika, additional, Kurbatova, Juliya, additional, Kutzbach, Lars, additional, Lapshina, Elena, additional, Lindroth, Anders, additional, Löfvenius, Mikaell Ottosson, additional, Lohila, Annalea, additional, Mammarella, Ivan, additional, Marsh, Philip, additional, Moore, Paul A, additional, Maximov, Trofim, additional, Nadeau, Daniel F, additional, Nicholls, Erin M, additional, Nilsson, Mats B, additional, Ohta, Takeshi, additional, Peichl, Matthias, additional, Petrone, Richard M, additional, Prokushkin, Anatoly, additional, Quinton, William L, additional, Roulet, Nigel, additional, Runkle, Benjamin R K, additional, Sonnentag, Oliver, additional, Strachan, Ian B, additional, Taillardat, Pierre, additional, Tuittila, Eeva-Stiina, additional, Tuovinen, Juha-Pekka, additional, Turner, Jessica, additional, Ueyama, Masahito, additional, Varlagin, Andrej, additional, Vesala, Timo, additional, Wilmking, Martin, additional, Zyrianov, Vyacheslav, additional, and Schulze, Christopher, additional

Published
2020
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41. Shp1 Loss Enhances Macrophage Effector Function and Promotes Anti-Tumor Immunity

Author

Myers, Darienne R., primary, Abram, Clare L., additional, Wildes, David, additional, Belwafa, Amira, additional, Welsh, Alia M. N., additional, Schulze, Christopher J., additional, Choy, Tiffany J., additional, Nguyen, Tram, additional, Omaque, Neil, additional, Hu, Yongmei, additional, Singh, Mallika, additional, Hansen, Rich, additional, Goldsmith, Mark A., additional, Quintana, Elsa, additional, Smith, Jacqueline A. M., additional, and Lowell, Clifford A., additional

Published
2020
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42. Abstract LB-113: Positioning a selective, bi-steric inhibitor of mTORC1 as a combination partner in RAS-driven cancers

Author

Yang, Yu Chi, primary, Schulze, Christopher, additional, Jiang, Jingjing, additional, Reyes, Denise F., additional, Choy, Tiffany, additional, Nguyen, Tram, additional, Wang, Zhican, additional, Lee, Dong, additional, Nichols, Robert J., additional, Wang, Zhengping, additional, Smith, Jacqueline A., additional, Kelsey, Steve M., additional, and Singh, Mallika, additional

Published
2020
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43. Allosteric Inhibition of SHP2 Stimulates Antitumor Immunity by Transforming the Immunosuppressive Environment

Author

Quintana, Elsa, primary, Schulze, Christopher J., additional, Myers, Darienne R., additional, Choy, Tiffany J., additional, Mordec, Kasia, additional, Wildes, David, additional, Shifrin, Nataliya Tobvis, additional, Belwafa, Amira, additional, Koltun, Elena S., additional, Gill, Adrian L., additional, Singh, Mallika, additional, Kelsey, Stephen, additional, Goldsmith, Mark A., additional, Nichols, Robert, additional, and Smith, Jacqueline A.M., additional

Published
2020
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44. A stepped-wedge randomized trial protocol of a community intervention for increasing lung screening through engaging primary care providers (I-STEP)

Author

Salazar, Ana S., primary, Sekhon, Subhjit, additional, Rohatgi, Karthik W., additional, Nuako, Akua, additional, Liu, Jingxia, additional, Harriss, Courtney, additional, Brennan, Ellen, additional, LaBeau, Dareld, additional, Abdalla, Ibrahim, additional, Schulze, Christopher, additional, Muenks, Jackie, additional, Overlot, Dave, additional, Higgins, Jeri Ann, additional, Jones, Linda S., additional, Swick, Colleen, additional, Goings, Stacia, additional, Badiu, Jennifer, additional, Walker, Justin, additional, Colditz, Graham A., additional, and James, Aimee S., additional

Published
2020
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45. Controls on Stable Methane Isotope Values in Northern Peatlands and Potential Shifts in Values Under Permafrost Thaw Scenarios

Author

Kuhn, McKenzie A., Varner, Ruth K., McCalley, Carmody K., Perryman, Clarice R., Aurela, Mika, Burke, Sophia A., Chanton, Jeffrey P., Crill, Patrick M., DelGreco, Jessica, Deng, Jia, Heffernan, Liam, Herrick, Christina, Hodgkins, Suzanne B., Jones, Cheristy P., Juutinen, Sari, Kane, Evan S., Lamit, Louis J., Larmola, Tuula, Lilleskov, Erik, Olefeldt, David, Palace, Michael W., Rich, Virginia I., Schulze, Christopher, Shorter, Joanne H., Sullivan, Franklin B., Sonnentag, Oliver, Turetsky, Merritt R., and Waldrop, Mark P.

Abstract

Northern peatlands are a globally significant source of methane (CH4), and emissions are projected to increase due to warming and permafrost loss. Understanding the microbial mechanisms behind patterns in CH4production in peatlands will be key to predicting annual emissions changes, with stable carbon isotopes (δ13C‐CH4) being a powerful tool for characterizing these drivers. Given that δ13C‐CH4is used in top‐down atmospheric inversion models to partition sources, our ability to model CH4production pathways and associated δ13C‐CH4values is critical. We sought to characterize the role of environmental conditions, including hydrologic and vegetation patterns associated with permafrost thaw, on δ13C‐CH4values from high‐latitude peatlands. We measured porewater and emitted CH4stable isotopes, pH, and vegetation composition from five boreal‐Arctic peatlands. Porewater δ13C‐CH4was strongly associated with peatland type, with δ13C enriched values obtained from more minerotrophic fens (−61.2 ± 9.1‰) compared to permafrost‐free bogs (−74.1 ± 9.4‰) and raised permafrost bogs (−81.6 ± 11.5‰). Variation in porewater δ13C‐CH4was best explained by sedge cover, CH4concentration, and the interactive effect of peatland type and pH (r2= 0.50, p< 0.001). Emitted δ13C‐CH4varied greatly but was positively correlated with porewater δ13C‐CH4. We calculated a mixed atmospheric δ13C‐CH4value for northern peatlands of −65.3 ± 7‰ and show that this value is more sensitive to landscape drying than wetting under permafrost thaw scenarios. Our results suggest northern peatland δ13C‐CH4values are likely to shift in the future which has important implications for source partitioning in atmospheric inversion models. Peatlands are abundant across the boreal‐Arctic landscape and are important sources of methane, a powerful greenhouse gas. The amount of methane emitted into the atmosphere depends on multiple factors including the organic material being decomposed and the microbial processes (“pathways”) that produce methane. The different pathways of methane production leave distinct fingerprints (“stable carbon isotopes”) on methane that provide information on how that methane was formed and help to trace methane in the atmosphere back to its ground source. We looked at how stable carbon isotopes change across five northern peatland locations and wanted to know what controls those changes. We found that stable carbon isotopes differ between bogs and fens and are further controlled by soil pH and the abundance of sedge vegetation present. We used this information to test how stable carbon isotopes from northern peatlands might change as the landscape becomes wetter or drier due to the impacts of climate change. We found that peatland stable carbon isotopes are most sensitive to potential landscape drying opposed to wetting which has important implications for improving methane emission models. Porewater δ13C‐CH4values of northern bogs and fens differ from each other and correlate with emitted δ13C‐CH4valuesIn addition to peatland type, vascular plant cover, pH, and CH4concentration help explain variation in porewater δ13C‐CH4valuesThe δ13C‐CH4value for northern peatlands is more sensitive to landscape drying than wetting under permafrost thaw scenarios Porewater δ13C‐CH4values of northern bogs and fens differ from each other and correlate with emitted δ13C‐CH4values In addition to peatland type, vascular plant cover, pH, and CH4concentration help explain variation in porewater δ13C‐CH4values The δ13C‐CH4value for northern peatlands is more sensitive to landscape drying than wetting under permafrost thaw scenarios

Published
2024
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46. Abstract PR10: Tri-complex inhibitors of the oncogenic, GTP-bound form of KRASG12C overcome RTK-mediated escape mechanisms and drive tumor regressions in vivo

Author

Schulze, Christopher J, primary, Bermingham, Alun, additional, Choy, Tiffany J, additional, Cregg, James J, additional, Kiss, Gert, additional, Marquez, Abby, additional, Reyes, Denise, additional, Saldajeno-Concar, Mae, additional, Weller, Caroline E, additional, Whalen, Daniel M, additional, Yang, Yu C, additional, Koltun, Elena S, additional, Nichols, Robert J, additional, Singh, Mallika, additional, Wildes, David, additional, Gill, Adrian L, additional, Hansen, Richard L, additional, Kelsey, Steve, additional, Goldsmith, Mark A, additional, and Smith, Jacqueline A.M., additional

Published
2019
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47. The antimalarial natural product salinipostin A identifies essential α/β serine hydrolases involved in lipid metabolism inP. falciparumparasites

Author

Yoo, Euna, primary, Schulze, Christopher J., additional, Stokes, Barbara H., additional, Onguka, Ouma, additional, Yeo, Tomas, additional, Mok, Sachel, additional, Gnädig, Nina F., additional, Zhou, Yani, additional, Kurita, Kenji, additional, Foe, Ian T., additional, Terrell, Stephanie M., additional, Boucher, Michael J., additional, Cieplak, Piotr, additional, Linington, Roger G., additional, Long, Jonathan Z., additional, Uhlemann, Anne-Catrin, additional, Weerapana, Eranthie, additional, Fidock, David A., additional, and Bogyo, Matthew, additional

Published
2019
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48. The Antimalarial Natural Product Salinipostin a Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. Falciparum Parasites

Author

Yoo, Euna, primary, Schulze, Christopher J., additional, Stokes, Barbara H., additional, Onguka, Ouma, additional, Yeo, Tomas, additional, Mok, Sachel, additional, Gnädig, Nina F., additional, Zhou, Yani, additional, Kurita, Kenji, additional, Foe, Ian T., additional, Terrell, Stephanie M., additional, Boucher, Michael J., additional, Cieplak, Piotr, additional, Linington, Roger G., additional, Long, Jonathan Z., additional, Uhlemann, Anne-Catrin, additional, Weerapana, Eranthie, additional, Fidock, David A., additional, and Bogyo, Matthew, additional

Published
2019
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49. RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers.

Author

Nichols, Robert, Nichols, Robert, Haderk, Franziska, Stahlhut, Carlos, Schulze, Christopher, Hemmati, Golzar, Wildes, David, Tzitzilonis, Christos, Mordec, Kasia, Marquez, Abby, Romero, Jason, Hsieh, Tientien, Zaman, Aubhishek, Olivas, Victor, McCoach, Caroline, Wang, Zhengping, Kiss, Gert, Koltun, Elena, Gill, Adrian, Singh, Mallika, Goldsmith, Mark, Smith, Jacqueline, Bivona, Trever, Blakely, Collin, Nichols, Robert, Nichols, Robert, Haderk, Franziska, Stahlhut, Carlos, Schulze, Christopher, Hemmati, Golzar, Wildes, David, Tzitzilonis, Christos, Mordec, Kasia, Marquez, Abby, Romero, Jason, Hsieh, Tientien, Zaman, Aubhishek, Olivas, Victor, McCoach, Caroline, Wang, Zhengping, Kiss, Gert, Koltun, Elena, Gill, Adrian, Singh, Mallika, Goldsmith, Mark, Smith, Jacqueline, Bivona, Trever, and Blakely, Collin

Abstract

Oncogenic alterations in the RAS/RAF/MEK/ERK pathway drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAFV600E-driven cancers, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including non-V600E oncogenic BRAF, RAS GTPase-activating protein (GAP) NF1 (neurofibromin 1) loss and oncogenic KRAS. Here, we show that targeting the SHP2 phosphatase (encoded by PTPN11) with RMC-4550, a small-molecule allosteric inhibitor, is effective in human cancer models bearing RAS-GTP-dependent oncogenic BRAF (for example, class 3 BRAF mutants), NF1 loss or nucleotide-cycling oncogenic RAS (for example, KRASG12C). SHP2 inhibitor treatment decreases oncogenic RAS/RAF/MEK/ERK signalling and cancer growth by disrupting SOS1-mediated RAS-GTP loading. Our findings illuminate a critical function for SHP2 in promoting oncogenic RAS/MAPK pathway activation in cancers with RAS-GTP-dependent oncogenic BRAF, NF1 loss and nucleotide-cycling oncogenic KRAS. SHP2 inhibition is a promising molecular therapeutic strategy for patients with cancers bearing these oncogenic drivers.

Published
2018

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