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3. Specimen collection is essential for modern science.

Author

Nachman, Michael, Beckman, Elizabeth, Bowie, Rauri, Cicero, Carla, Conroy, Chris, Hayes, Tyrone, Koo, Michelle, Lacey, Eileen, Martin, Christopher, McGuire, Jimmy, Patton, James, Spencer, Carol, Wake, Marvalee, Wang, Ian, Achmadi, Anang, Álvarez-Castañeda, Sergio, Andersen, Michael, Arroyave, Jairo, Austin, Christopher, Barker, F, Barrow, Lisa, Barrowclough, George, Bates, John, Bauer, Aaron, Bell, Kayce, Bell, Rayna, Bronson, Allison, Brown, Rafe, Burbrink, Frank, Burns, Kevin, Cadena, Carlos, Cannatella, David, Castoe, Todd, Chakrabarty, Prosanta, Colella, Jocelyn, Cook, Joseph, Cracraft, Joel, Davis, Drew, Davis Rabosky, Alison, DElía, Guillermo, Dumbacher, John, Dunnum, Jonathan, Edwards, Scott, Esselstyn, Jacob, Faivovich, Julián, Fjeldså, Jon, Flores-Villela, Oscar, Ford, Kassandra, Fuchs, Jérôme, Fujita, Matthew, Good, Jeffrey, Greenbaum, Eli, Greene, Harry, Hackett, Shannon, Hamidy, Amir, Hanken, James, Haryoko, Tri, Hawkins, Melissa, Heaney, Lawrence, Hillis, David, Hollingsworth, Bradford, Hornsby, Angela, Hosner, Peter, Irham, Mohammad, Jansa, Sharon, Jiménez, Rosa, Joseph, Leo, Kirchman, Jeremy, LaDuc, Travis, Leaché, Adam, Lessa, Enrique, López-Fernández, Hernán, Mason, Nicholas, McCormack, John, McMahan, Caleb, Moyle, Robert, Ojeda, Ricardo, Olson, Link, Kin Onn, Chan, Parenti, Lynne, Parra-Olea, Gabriela, Patterson, Bruce, Pauly, Gregory, Pavan, Silvia, Peterson, A, Poe, Steven, Rabosky, Daniel, Raxworthy, Christopher, Reddy, Sushma, Rico-Guevara, Alejandro, Riyanto, Awal, Rocha, Luiz, Ron, Santiago, Rovito, Sean, Rowe, Kevin, Rowley, Jodi, Ruane, Sara, Salazar-Valenzuela, David, Shultz, Allison, and Sidlauskas, Brian

Subjects
Animals, Museums, Specimen Handling, Natural History
Abstract

Natural history museums are vital repositories of specimens, samples and data that inform about the natural world; this Formal Comment revisits a Perspective that advocated for the adoption of compassionate collection practices, querying whether it will ever be possible to completely do away with whole animal specimen collection.

Published
2023

5. Developing Meaning for Mathematical Expressions

Author

Lannin, John K., Austin, Christopher, and Geary, David C.

Abstract

In this article, the authors describe the two interpretations of mathematical expressions, as a process and as a product. They begin with an initial discussion of Tall's (2013) interpretations of expressions and connect this to state standards. Next, they describe the different interpretations of algebraic expressions based on their work with middle and high school students. They conclude with an example of how they provided instruction that promotes a deep understanding of the interpretations of expressions.

Published
2023
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7. The National COVID Cohort Collaborative (N3C): Rationale, Design, Infrastructure, and Deployment

Author

Haendel, Melissa A, Chute, Christopher G, Bennett, Tellen D, Eichmann, David A, Guinney, Justin, Kibbe, Warren A, Payne, Philip RO, Pfaff, Emily R, Robinson, Peter N, Saltz, Joel H, Spratt, Heidi, Suver, Christine, Wilbanks, John, Wilcox, Adam B, Williams, Andrew E, Wu, Chunlei, Blacketer, Clair, Bradford, Robert L, Cimino, James J, Clark, Marshall, Colmenares, Evan W, Francis, Patricia A, Gabriel, Davera, Graves, Alexis, Hemadri, Raju, Hong, Stephanie S, Hripscak, George, Jiao, Dazhi, Klann, Jeffrey G, Kostka, Kristin, Lee, Adam M, Lehmann, Harold P, Lingrey, Lora, Miller, Robert T, Morris, Michele, Murphy, Shawn N, Natarajan, Karthik, Palchuk, Matvey B, Sheikh, Usman, Solbrig, Harold, Visweswaran, Shyam, Walden, Anita, Walters, Kellie M, Weber, Griffin M, Zhang, Xiaohan Tanner, Zhu, Richard L, Amor, Benjamin, Girvin, Andrew T, Manna, Amin, Qureshi, Nabeel, Kurilla, Michael G, Michael, Sam G, Portilla, Lili M, Rutter, Joni L, Austin, Christopher P, and Gersing, Ken R

Subjects
COVID-19, Computer Security, Data Analysis, Data Science, Ethics Committees, Research, Government Regulation, Humans, Information Dissemination, Intersectoral Collaboration, National Institutes of Health (U.S.), United States, N3C Consortium, EHR data, SARS-CoV-2, clinical data model harmonization, collaborative analytics, open science, Information and Computing Sciences, Engineering, Medical and Health Sciences, Medical Informatics
Abstract

ObjectiveCoronavirus disease 2019 (COVID-19) poses societal challenges that require expeditious data and knowledge sharing. Though organizational clinical data are abundant, these are largely inaccessible to outside researchers. Statistical, machine learning, and causal analyses are most successful with large-scale data beyond what is available in any given organization. Here, we introduce the National COVID Cohort Collaborative (N3C), an open science community focused on analyzing patient-level data from many centers.Materials and methodsThe Clinical and Translational Science Award Program and scientific community created N3C to overcome technical, regulatory, policy, and governance barriers to sharing and harmonizing individual-level clinical data. We developed solutions to extract, aggregate, and harmonize data across organizations and data models, and created a secure data enclave to enable efficient, transparent, and reproducible collaborative analytics.ResultsOrganized in inclusive workstreams, we created legal agreements and governance for organizations and researchers; data extraction scripts to identify and ingest positive, negative, and possible COVID-19 cases; a data quality assurance and harmonization pipeline to create a single harmonized dataset; population of the secure data enclave with data, machine learning, and statistical analytics tools; dissemination mechanisms; and a synthetic data pilot to democratize data access.ConclusionsThe N3C has demonstrated that a multisite collaborative learning health network can overcome barriers to rapidly build a scalable infrastructure incorporating multiorganizational clinical data for COVID-19 analytics. We expect this effort to save lives by enabling rapid collaboration among clinicians, researchers, and data scientists to identify treatments and specialized care and thereby reduce the immediate and long-term impacts of COVID-19.

Published
2021

8. Crossing Lydekker's Line: Northern Water Dragons (Tropicagama temporalis) Colonized the Mollucan Islands of Indonesia from New Guinea

Author

Karin, Benjamin R, Stubbs, Alexander L, Arifin, Umilaela, Iskandar, Djoko T, Arida, Evy, Austin, Christopher C, and McGuire, Jimmy A

Subjects
Biological Sciences, Ecology, Evolutionary Biology, Genetics, Agamidae, Biogeography, Lizard, Maluku, Phylogeography, Wallacea, Ecological Applications, Zoology
Abstract

Wallace's and Lydekker's Lines both describe important biogeographic barriers in the Indo-Australian Archipelago, with Wallace's Line demarcating the boundary of the Greater Sunda Shelf and Lydekker's Line indicating the edge of the Sahul continental shelf. Despite their similarities, Wallace's Line has been much more heavily studied than has Lydekker's Line, yet provides an interesting system for testing the source of fauna into eastern Wallacea. New collections of Northern Water Dragons, Tropicagama temporalis, from several islands in Maluku, eastern Indonesia now allow for an assessment of the phylogeography of the species and the ability to test if New Guinean or Australian populations served as the source for over-water dispersal across Lydekker's Line into Maluku. We collected specimens from remote islands in eastern Indonesia, sequenced the mitochondrial ND2 gene, and aligned the data to previously sequenced specimens on GenBank. We conducted several phylogenetic and divergence time analyses to investigate the source population and timing of dispersal. We found low genetic diversity among the islands in Maluku, and these samples showed little genetic divergence from New Guinea samples. The New Guinea and Maluku populations diverged less than 1 million years ago (Ma) and together diverged from the Australian population between 2.3 and 4.7 Ma. These results, along with patterns in other taxa, illustrated that, despite Australia's close geographic proximity to many of the islands in southeastern Indonesia, New Guinea has been the more frequent source of Wallacean fauna from Sahul.

Published
2020

9. Habitat preference modulates trans-oceanic dispersal in a terrestrial vertebrate.

Author

Blom, Mozes, Matzke, Nicholas, Bragg, Jason, Arida, Evy, Austin, Christopher, Backlin, Adam, Carretero, Miguel, Fisher, Robert, Glaw, Frank, Hathaway, Stacie, Iskandar, Djoko, Rittmeyer, Eric, Rocha, Sara, Sanchez, Mickaël, Stubbs, Alexander, Vences, Miguel, Moritz, Craig, Karin, Benjamin, Mcguire, Jimmy, and Reilly, Sean

Subjects
Cryptoblepharus, biogeography, exon capture, long-distance dispersal, Animal Distribution, Animals, Biological Evolution, Ecosystem, Lizards, Oceans and Seas, Phylogeny, Phylogeography, Population Dynamics
Abstract

The importance of long-distance dispersal (LDD) in shaping geographical distributions has been debated since the nineteenth century. In terrestrial vertebrates, LDD events across large water bodies are considered highly improbable, but organismal traits affecting dispersal capacity are generally not taken into account. Here, we focus on a recent lizard radiation and combine a summary-coalescent species tree based on 1225 exons with a probabilistic model that links dispersal capacity to an evolving trait, to investigate whether ecological specialization has influenced the probability of trans-oceanic dispersal. Cryptoblepharus species that occur in coastal habitats have on average dispersed 13 to 14 times more frequently than non-coastal species and coastal specialization has, therefore, led to an extraordinarily widespread distribution that includes multiple continents and distant island archipelagoes. Furthermore, their presence across the Pacific substantially predates the age of human colonization and we can explicitly reject the possibility that these patterns are solely shaped by human-mediated dispersal. Overall, by combining new analytical methods with a comprehensive phylogenomic dataset, we use a quantitative framework to show how coastal specialization can influence dispersal capacity and eventually shape geographical distributions at a macroevolutionary scale.

Published
2019

10. The Global academic research organization network: Data sharing to cure diseases and enable learning health systems.

Author

Fukushima, Masanori, Austin, Christopher, Sato, Norihiro, Maruyama, Tatsuya, Navarro, Eileen, Rocca, Mitra, Demotes, Jacques, Haendel, Melissa, Volchenboum, Samuel L, Cowperthwaite, Matthew, Silverstein, Jonathan C, Webb, Chris, Sim, Ida, Chase, Marianne, Speakman, John, Augustine, Erika, Ford, Daniel E, and Kush, Rebecca

Subjects
data sharing, global, harmonization, registry, standards
Abstract

Introduction:Global data sharing is essential. This is the premise of the Academic Research Organization (ARO) Council, which was initiated in Japan in 2013 and has since been expanding throughout Asia and into Europe and the United States. The volume of data is growing exponentially, providing not only challenges but also the clear opportunity to understand and treat diseases in ways not previously considered. Harnessing the knowledge within the data in a successful way can provide researchers and clinicians with new ideas for therapies while avoiding repeats of failed experiments. This knowledge transfer from research into clinical care is at the heart of a learning health system. Methods:The ARO Council wishes to form a worldwide complementary system for the benefit of all patients and investigators, catalyzing more efficient and innovative medical research processes. Thus, they have organized Global ARO Network Workshops to bring interested parties together, focusing on the aspects necessary to make such a global effort successful. One such workshop was held in Austin, Texas, in November 2017. Representatives from Japan, Taiwan, Singapore, Europe, and the United States reported on their efforts to encourage data sharing and to use research to inform care through learning health systems. Results:This experience report summarizes presentations and discussions at the Global ARO Network Workshop held in November 2017 in Austin, TX, with representatives from Japan, Korea, Singapore, Taiwan, Europe, and the United States. Themes and recommendations to progress their efforts are explored. Standardization and harmonization are at the heart of these discussions to enable data sharing. In addition, the transformation of clinical research processes through disruptive innovation, while ensuring integrity and ethics, will be key to achieving the ARO Council goal to overcome diseases such that people not only live longer but also are healthier and happier as they age. Conclusions:The achievement of global learning health systems will require further exploration, consensus-building, funding aligned with incentives for data sharing, standardization, harmonization, and actions that support global interests for the benefit of patients.

Published
2019

11. Quantifying amphibian range fragmentation in the southeastern United States

Author

Newman, Catherine E. and Austin, Christopher C.

Subjects
biogeography, conservation, ecological niche modeling, habitat fragmentation, landscape ecology, species distributions
Abstract

The southeastern United States is home to the highest amphibian species richness in North America. An often overlooked component of research on factors that drive amphibian geographic distributions is description of species range shape. Broad-scale range disjunction has implications for phylogeography, ecology, and conservation, but descriptions of fragmentation are usually based on subjective visual assessment of range maps. Here, we describe a method for objectively quantifying range fragmentation and use this method to describe the patterns of amphibian species range shapes in the Southeast. Species ranges varied widely in degree of fragmentation, from completely contiguous to highly fragmented, and degree of isolation of range fragments. Incorporating ecological niche models added information about fine-scale habitat fragmentation. Although 12 species had ranges with either high or moderate fragmentation, the only area where range fragments of more than two of the 12 species overlapped was the Appalachian Highlands, suggesting that range fragmentation in the Southeast is driven by multiple biogeographic processes.

Published
2019

12. Early Empiric Antibiotic Use in Patients Hospitalized With COVID-19: A Retrospective Cohort Study*

Author

Widere, J. Christian, Davis, Claire Leilani, Loomba, Johanna Jean, Bell, Taison D., Enfield, Kyle B., Barros, Andrew Julio, Amor, Benjamin, Bissell, Mark M., Bradwell, Katie Rebecca, Girvin, Andrew T., Manna, Amin, Qureshi, Nabeel, Chute, Christopher G., Pfaff, Emily R., Gabriel, Davera, Hong, Stephanie S., Kostka, Kristin, Lehmann, Harold P., Moffitt, Richard A., Morris, Michele, Palchuk, Matvey B., Zhang, Xiaohan Tanner, Zhu, Richard L., Austin, Christopher P., Gersing, Kenneth R., Bozzette, Samuel, Deacy, Mariam, Garbarini, Nicole, Kurilla, Michael G., Michael, Sam G., Rutter, Joni L., Temple-O’Connor, Meredith, Haendel, Melissa A., Bennett, Tellen D., Chute, Christopher G., Eichmann, David A., Guinney, Justin, Kibbe, Warren A., Liu, Hongfang, Payne, Philip R.O., Pfaff, Emily R., Robinson, Peter N., Saltz, Joel H., Spratt, Heidi, Starren, Justin, Suver, Christine, Wilcox, Adam B., Williams, Andrew E., Wu, Chunlei, Pfaff, Emily R., Amor, Benjamin, Bissell, Mark M., Clark, Marshall, Girvin, Andrew T., Hong, Stephanie S., Kostka, Kristin, Lee, Adam M., Miller, Robert T., Morris, Michele, Palchuk, Matvey B., Walters, Kellie M., Haendel, Melissa A., Chute, Christopher G., Gersing, Kenneth R., Walden, Anita, Walden, Anita, Chae, Yooree, Cook, Connor, Dest, Alexandra, Dietz, Racquel R., Dillon, Thomas, Francis, Patricia A., Fuentes, Rafael, Graves, Alexis, McMurry, Julie A., Neumann, Andrew J., O’Neil, Shawn T., Sheikh, Usman, Volz, Andréa M., Zampino, Elizabeth, Saltz, Mary Morrison, Suver, Christine, Chute, Christopher G., Haendel, Melissa A., McMurry, Julie A., Volz, Andréa M., Walden, Anita, Bramante, Carolyn, Harper, Jeremy Richard, Hernandez, Wenndy, Koraishy, Farrukh M, Mariona, Federico, Saha, Amit, and Vedula, Satyanarayana

Published
2023
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13. Assay Guidance Manual: Quantitative Biology and Pharmacology in Preclinical Drug Discovery

Author

Coussens, Nathan P, Sittampalam, G Sitta, Guha, Rajarshi, Brimacombe, Kyle, Grossman, Abigail, Chung, Thomas DY, Weidner, Jeffrey R, Riss, Terry, Trask, O Joseph, Auld, Douglas, Dahlin, Jayme L, Devanaryan, Viswanath, Foley, Timothy L, McGee, James, Kahl, Steven D, Kales, Stephen C, Arkin, Michelle, Baell, Jonathan, Bejcek, Bruce, Gal‐Edd, Neely, Glicksman, Marcie, Haas, Joseph V, Iversen, Philip W, Hoeppner, Marilu, Lathrop, Stacy, Sayers, Eric, Liu, Hanguan, Trawick, Bart, McVey, Julie, Lemmon, Vance P, Li, Zhuyin, McManus, Owen, Minor, Lisa, Napper, Andrew, Wildey, Mary Jo, Pacifici, Robert, Chin, William W, Xia, Menghang, Xu, Xin, Lal‐Nag, Madhu, Hall, Matthew D, Michael, Sam, Inglese, James, Simeonov, Anton, and Austin, Christopher P

Subjects
Orphan Drug, Rare Diseases, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Biological Assay, Drug Discovery, Geography, High-Throughput Screening Assays, Humans, Translational Research, Biomedical, Cardiorespiratory Medicine and Haematology, Oncology and Carcinogenesis, Other Medical and Health Sciences, General Clinical Medicine
Abstract

The Assay Guidance Manual (AGM) is an eBook of best practices for the design, development, and implementation of robust assays for early drug discovery. Initiated by pharmaceutical company scientists, the manual provides guidance for designing a "testing funnel" of assays to identify genuine hits using high-throughput screening (HTS) and advancing them through preclinical development. Combined with a workshop/tutorial component, the overall goal of the AGM is to provide a valuable resource for training translational scientists.

Published
2018

22. A call for global action for rare diseases in Africa

Author

Baynam, Gareth S., Groft, Stephen, van der Westhuizen, Francois H., Gassman, Safiyya D., du Plessis, Kelly, Coles, Emily P., Selebatso, Eda, Selebatso, Moses, Gaobinelwe, Boikobo, Selebatso, Tebogo, Joel, Dipesalema, Llera, Virginia A., Vorster, Barend C., Wuebbels, Barbara, Djoudalbaye, Benjamin, Austin, Christopher P., Kumuthini, Judit, Forman, John, Kaufmann, Petra, Chipeta, James, Gavhed, Désirée, Larsson, Annika, Stojiljkovic, Maja, Nordgren, Ann, Roldan, Emilio J. A., Taruscio, Domenica, Wong-Rieger, Durhane, Nowak, Kristen, Bilkey, Gemma A., Easteal, Simon, Bowdin, Sarah, Reichardt, Juergen K. V., Beltran, Sergi, Kosaki, Kenjiro, van Karnebeek, Clara D. M., Gong, Mengchun, Shuyang, Zhang, Mehrian-Shai, Ruty, Adams, David R., Puri, Ratna D., Zhang, Feng, Pachter, Nicholas, Muenke, Maximilian, Nellaker, Christoffer, Gahl, William A., Cederroth, Helene, Broley, Stephanie, Schoonen, Maryke, Boycott, Kym M., and Posada, Manuel

Published
2020
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23. Lessons from Toxicology: Developing a 21st-Century Paradigm for Medical Research

Author

Langley, Gill, Austin, Christopher P, Balapure, Anil K, Birnbaum, Linda S, Bucher, John R, Fentem, Julia, Fitzpatrick, Suzanne C, Fowle, John R, Kavlock, Robert J, Kitano, Hiroaki, Lidbury, Brett A, Muotri, Alysson R, Peng, Shuang-Qing, Sakharov, Dmitry, Seidle, Troy, Trez, Thales, Tonevitsky, Alexander, van de Stolpe, Anja, Whelan, Maurice, and Willett, Catherine

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Clinical Research, 5.9 Resources and infrastructure (treatment development), Development of treatments and therapeutic interventions, Generic health relevance, Good Health and Well Being, Animal Testing Alternatives, Biomedical Research, Computer Simulation, Drug Discovery, Genomics, Humans, Systems Biology, Toxicology, Environmental Sciences, Medical and Health Sciences, Biomedical and clinical sciences, Environmental sciences, Health sciences
Abstract

Biomedical developments in the 21st century provide an unprecedented opportunity to gain a dynamic systems-level and human-specific understanding of the causes and pathophysiologies of disease. This understanding is a vital need, in view of continuing failures in health research, drug discovery, and clinical translation. The full potential of advanced approaches may not be achieved within a 20th-century conceptual framework dominated by animal models. Novel technologies are being integrated into environmental health research and are also applicable to disease research, but these advances need a new medical research and drug discovery paradigm to gain maximal benefits. We suggest a new conceptual framework that repurposes the 21st-century transition underway in toxicology. Human disease should be conceived as resulting from integrated extrinsic and intrinsic causes, with research focused on modern human-specific models to understand disease pathways at multiple biological levels that are analogous to adverse outcome pathways in toxicology. Systems biology tools should be used to integrate and interpret data about disease causation and pathophysiology. Such an approach promises progress in overcoming the current roadblocks to understanding human disease and successful drug discovery and translation. A discourse should begin now to identify and consider the many challenges and questions that need to be solved.

Published
2015

24. The promise and peril of chemical probes

Author

Arrowsmith, Cheryl H, Audia, James E, Austin, Christopher, Baell, Jonathan, Bennett, Jonathan, Blagg, Julian, Bountra, Chas, Brennan, Paul E, Brown, Peter J, Bunnage, Mark E, Buser-Doepner, Carolyn, Campbell, Robert M, Carter, Adrian J, Cohen, Philip, Copeland, Robert A, Cravatt, Ben, Dahlin, Jayme L, Dhanak, Dashyant, Edwards, Aled M, Frederiksen, Mathias, Frye, Stephen V, Gray, Nathanael, Grimshaw, Charles E, Hepworth, David, Howe, Trevor, Huber, Kilian VM, Jin, Jian, Knapp, Stefan, Kotz, Joanne D, Kruger, Ryan G, Lowe, Derek, Mader, Mary M, Marsden, Brian, Mueller-Fahrnow, Anke, Müller, Susanne, O'Hagan, Ronan C, Overington, John P, Owen, Dafydd R, Rosenberg, Saul H, Ross, Ruth, Roth, Bryan, Schapira, Matthieu, Schreiber, Stuart L, Shoichet, Brian, Sundström, Michael, Superti-Furga, Giulio, Taunton, Jack, Toledo-Sherman, Leticia, Walpole, Chris, Walters, Michael A, Willson, Timothy M, Workman, Paul, Young, Robert N, and Zuercher, William J

Subjects
Generic health relevance, Biomedical Research, Humans, Information Dissemination, Intellectual Property, Internet, Molecular Probes, Molecular Weight, Sensitivity and Specificity, Small Molecule Libraries, Medicinal and Biomolecular Chemistry, Biochemistry and Cell Biology, Biochemistry & Molecular Biology
Abstract

Chemical probes are powerful reagents with increasing impacts on biomedical research. However, probes of poor quality or that are used incorrectly generate misleading results. To help address these shortcomings, we will create a community-driven wiki resource to improve quality and convey current best practice.

Published
2015

26. A Global Approach to Rare Diseases Research and Orphan Products Development: The International Rare Diseases Research Consortium (IRDiRC)

Author

Cutillo, Christine M., Austin, Christopher P., Groft, Stephen C., COHEN, IRUN R., Series editor, LAJTHA, ABEL, Series editor, LAMBRIS, JOHN D., Series editor, PAOLETTI, RODOLFO, Series editor, REZAEI, NIMA, Series editor, Posada de la Paz, Manuel, editor, Taruscio, Domenica, editor, and Groft, Stephen C., editor

Published
2017
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27. Improved Diagnosis and Care for Rare Diseases through Implementation of Precision Public Health Framework

Author

Baynam, Gareth, Bowman, Faye, Lister, Karla, Walker, Caroline E., Pachter, Nicholas, Goldblatt, Jack, Boycott, Kym M., Gahl, William A., Kosaki, Kenjiro, Adachi, Takeya, Ishii, Ken, Mahede, Trinity, McKenzie, Fiona, Townshend, Sharron, Slee, Jennie, Kiraly-Borri, Cathy, Vasudevan, Anand, Hawkins, Anne, Broley, Stephanie, Schofield, Lyn, Verhoef, Hedwig, Groza, Tudor, Zankl, Andreas, Robinson, Peter N., Haendel, Melissa, Brudno, Michael, Mattick, John S., Dinger, Marcel E., Roscioli, Tony, Cowley, Mark J., Olry, Annie, Hanauer, Marc, Alkuraya, Fowzan S., Taruscio, Domenica, Posada de la Paz, Manuel, Lochmüller, Hanns, Bushby, Kate, Thompson, Rachel, Hedley, Victoria, Lasko, Paul, Mina, Kym, Beilby, John, Tifft, Cynthia, Davis, Mark, Laing, Nigel G., Julkowska, Daria, Le Cam, Yann, Terry, Sharon F., Kaufmann, Petra, Eerola, Iiro, Norstedt, Irene, Rath, Ana, Suematsu, Makoto, Groft, Stephen C., Austin, Christopher P., Draghia-Akli, Ruxandra, Weeramanthri, Tarun S., Molster, Caron, Dawkins, Hugh J. S., COHEN, IRUN R., Series editor, LAJTHA, ABEL, Series editor, LAMBRIS, JOHN D., Series editor, PAOLETTI, RODOLFO, Series editor, REZAEI, NIMA, Series editor, Posada de la Paz, Manuel, editor, Taruscio, Domenica, editor, and Groft, Stephen C., editor

Published
2017
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30. A high-throughput screening assay for determining cellular levels of total tau protein.

Author

Dehdashti, Seameen, Zheng, Wei, Gever, Joel, Wilhelm, Robert, Nguyen, Dac-Trung, Sittampalam, Gurusingham, McKew, John, Austin, Christopher, and Prusiner, Stanley

Subjects
Alzheimer Disease, Animals, CHO Cells, Cell Culture Techniques, Cell Line, Tumor, Cricetinae, Cricetulus, Fibroblasts, High-Throughput Screening Assays, Humans, tau Proteins
Abstract

The microtubule-associated protein (MAP) tau has been implicated in the pathology of numerous neurodegenerative diseases. In the past decade, the hyperphosphorylated and aggregated states of tau protein have been important targets in the drug discovery field for the potential treatment of Alzheimers disease. Although several compounds have been reported to reduce the hyperphosphorylated state of tau or impact the stabilization of tau, their therapeutic activities are remain to be validated. Recently, reduction of total cellular tau protein has emerged as an alternate intervention point for drug development and a potential treatment of tauopathies. We have developed and optimized homogenous assays, using the AlphaLISA and HTRF assay technologies, for the quantification of total cellular tau protein levels in the SH-SY5Y neuroblastoma cell line. The signal-to-basal ratios were 375 and 5.3, and the Z factors were 0.67 and 0.60 for the AlphaLISA and HTRF tau assays, respectively. The clear advantages of these homogeneous tau assays over conventional total tau assays, such as ELISA and Western blot, are the elimination of plate wash steps and miniaturization of the assay into 1536-well plate format for the ultra-high-throughput screening of large compound libraries.

Published
2013

34. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

Author

Anastasiou, Dimitrios, Yu, Yimin, Israelsen, William J, Jiang, Jian-Kang, Boxer, Matthew B, Hong, Bum Soo, Tempel, Wolfram, Dimov, Svetoslav, Shen, Min, Jha, Abhishek, Yang, Hua, Mattaini, Katherine R, Metallo, Christian M, Fiske, Brian P, Courtney, Kevin D, Malstrom, Scott, Khan, Tahsin M, Kung, Charles, Skoumbourdis, Amanda P, Veith, Henrike, Southall, Noel, Walsh, Martin J, Brimacombe, Kyle R, Leister, William, Lunt, Sophia Y, Johnson, Zachary R, Yen, Katharine E, Kunii, Kaiko, Davidson, Shawn M, Christofk, Heather R, Austin, Christopher P, Inglese, James, Harris, Marian H, Asara, John M, Stephanopoulos, Gregory, Salituro, Francesco G, Jin, Shengfang, Dang, Lenny, Auld, Douglas S, Park, Hee-Won, Cantley, Lewis C, Thomas, Craig J, and Vander Heiden, Matthew G

Subjects
Biochemistry and Cell Biology, Biological Sciences, Cancer, Animals, Biopolymers, Blotting, Western, Cell Proliferation, Cell Transformation, Neoplastic, Enzyme Activators, Humans, Mice, Neoplasms, Pyruvate Kinase, Medicinal and Biomolecular Chemistry, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medicinal and biomolecular chemistry
Abstract

Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism.

Published
2012

36. Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1–2 trial

Author

Ory, Daniel S, Ottinger, Elizabeth A, Farhat, Nicole Yanjanin, King, Kelly A, Jiang, Xuntian, Weissfeld, Lisa, Berry-Kravis, Elizabeth, Davidson, Cristin D, Bianconi, Simona, Keener, Lee Ann, Rao, Ravichandran, Soldatos, Ariane, Sidhu, Rohini, Walters, Kimberly A, Xu, Xin, Thurm, Audrey, Solomon, Beth, Pavan, William J, Machielse, Bernardus N, Kao, Mark, Silber, Steven A, McKew, John C, Brewer, Carmen C, Vite, Charles H, Walkley, Steven U, Austin, Christopher P, and Porter, Forbes D

Published
2017
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37. A Role for the Melanocortin 4 Receptor in Sexual Function

Author

Martin, William J., Howard, Andrew D., Nargund, Ravi P., Austin, Christopher P., Guan, Xiaoming, Drisko, Jennifer, Cashen, Doreen, Sebhat, Iyassu, Patchett, Arthur A., Figueroa, David J., DiLella, Anthony G., Connolly, Brett M., Weinberg, David H., Tan, Carina P., Palyha, Oksana C., Pong, Sheng-Shung, MacNeil, Tanya, Rosenblum, Charles, Vongs, Aurawan, Tang, Rui, Yu, Hong, Sailer, Andreas W., Fong, Tung Ming, Huang, Cathy, Tota, Michael R., Chang, Ray S., Stearns, Ralph, Tamvakopoulos, Constantin, Christ, George, Drazen, Deborah L., Spar, Brian D., Nelson, Randy J., and MacIntyre, D. Euan

Published
2002

39. Identification and Characterization of a Second Melanin-Concentrating Hormone Receptor, MCH-2R

Author

Sailer, Andreas W., Sano, Hideki, Zeng, Zhizhen, McDonald, Terrence P., Pan, Jie, Pong, Sheng-Shung, Feighner, Scott D., Tan, Carina P., Fukami, Takehiro, Iwaasa, Hisashi, Hreniuk, Donna L., Morin, Nancy R., Sadowski, Sharon J., Ito, Makoto, Ito, Masahiko, Bansal, Alka, Ky, Betty, Figueroa, David J., Jiang, Qingping, Austin, Christopher P., MacNeil, Douglas J., Ishihara, Akane, Ihara, Masaki, Kanatani, Akio, Howard, Andrew D., and Liu, Qingyun

Published
2001

42. Contributors

Author

Austin, Christopher P., primary, Balls, Michael, additional, Blaauboer, Bas J., additional, Botham, Philip, additional, Burt, Tal, additional, Casey, Warren, additional, Červinka, Miroslav, additional, Cheng, Shujun, additional, Combes, Robert D., additional, Corvi, Raffaella, additional, Cronin, Mark T.D., additional, Curren, Rodger D., additional, De Angelis, Isabella, additional, Dehne, Eva-Maria, additional, Doe, John, additional, Eskes, Chantra, additional, Feigenbaum, Alexandre, additional, Forgacs, Zsolt, additional, Forsby, Anna, additional, France, Malcolm P., additional, Freeman Bain, Simon A., additional, Goldberg, Alan, additional, Gruber, Franz P., additional, Guillouzo, André, additional, Hartung, Thomas, additional, Heinonen, Tuula, additional, Hickman, James, additional, Hill, Erin H., additional, Imai, Koichi, additional, Kandarova, Helena, additional, Kavlock, Robert J., additional, Kenna, J Gerry, additional, Knudsen, Lisbeth E., additional, Kojima, Hajime, additional, Kolar, Roman, additional, Leist, Marcel, additional, Lidbury, Brett A., additional, Lowit, Anna, additional, Minor, Philip, additional, Pfaller, Walter, additional, Prieto, Pilar, additional, Ram, Rebecca, additional, Repetto, Guillermo, additional, Rogiers, Vera, additional, Roi, Annett J., additional, Rowan, Andrew, additional, Sakai, Yasuyuki, additional, Sesardic, Thea, additional, Shuler, Michael, additional, Śladowski, Dariusz, additional, Spielmann, Horst, additional, Stephens, Martin L., additional, Tähti, Hanna, additional, Tanaka, Noriho, additional, Testai, Emanuela, additional, Tice, Raymond R., additional, Trigwell, Susan, additional, Verfaillie, Catherine, additional, von Aulock, Sonja, additional, Worth, Andrew P., additional, Yoon, Miyoung, additional, and Zuang, Valérie, additional

Published
2019
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45. Receptor for Motilin Identified in the Human Gastrointestinal System

Author

Feighner, Scott D., Tan, Carina P., McKee, Karen Kulju, Palyha, Oksana C., Hreniuk, Donna L., Pong, Sheng-Shung, Austin, Christopher P., Figueroa, David, MacNeil, Douglas, Cascieri, Margaret A., Nargund, Ravi, Bakshi, Raman, Abramovitz, Mark, Stocco, Rino, Kargman, Stacia, O'Neill, Gary, Evans, Jilly, Patchett, Arthur A., Smith, Roy G., and Howard, Andrew D.

Published
1999

48. A Framework for Assessing Clinical Trial Site Readiness

Author

Buse, John B., primary, Austin, Christopher P., additional, Johnston, S. Claiborne, additional, Lewis-Hall, Freda, additional, March, Andrew N., additional, Shore, Carolyn K., additional, Tenaerts, Pamela, additional, and Rutter, Joni L., additional

Published
2023
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50. Basic science: Bedrock of progress

Author

Collins, Francis S., Anderson, James M., Austin, Christopher P., Battey, James F., Birnbaum, Linda S., Briggs, Josephine P., Clayton, Janine A., Cuthbert, Bruce, Eisinger, Robert W., Fauci, Anthony S., Gallin, John I., Gibbons, Gary H., Glass, Roger I., Gottesman, Michael M., Gray, Patricia A., Green, Eric D., Greider, Franziska B., Hodes, Richard, Hudson, Kathy L., Humphreys, Betsy, Katz, Stephen I., Koob, George F., Koroshetz, Walter J., Lauer, Michael S., Lorsch, Jon R., Lowy, Douglas R., McGowan, John J., Murray, David M., Nakamura, Richard, Norris, Andrea, Perez-Stable, Eliseo J., Pettigrew, Roderic I., Riley, William T., Rodgers, Griffin P., Sieving, Paul A., Somerman, Martha J., Spong, Catherine Y., Tabak, Lawrence A., Volkow, Nora D., and Wilder, Elizabeth L.

Published
2016

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