Office: CHEM 405C
Current Fields of Interest:
Medicinal/Synthetic Bioorganic/Organic Chemistry and Drug Design: Discovery, design and synthesis of nucleoside/nucleotide and heterocyclic enzyme inhibitors with chemotherapeutic emphasis in the areas of antiviral, anticancer, antibiotic, and antiparasitic targets. Primary goals include development of potent inhibitors to shut down disease replication pathways through a combination of cross-disciplinary synthetic, biological screening, mechanistic, and structure-based drug design techniques.
The primary focus for the Seley-Radtke laboratories involves the design and synthesis of flexible nucleoside (“fleximers”) and nucleobases (“flex-bases) inhibitors as a powerful approach to overcome the development of resistance to currently used therapeutics. The fleximers are able retain full potency when faced with “escape mutations” in biologically critical enzymatic systems – the inherent flexibility of the inhibitors allows them to conformationally adjust to steric and electronic clashes encountered in the binding site, and to engage secondary amino acids not previously involved in the enzyme’s mechanism of action.
Potent activity has been reported for a series of “doubly flexible” acyclic nucleosides and their corresponding prodrugs against various viruses including coronaviruses such as SARS-1, MERS-CoV, and most recently SARS-CoV-2 and COVID. Importantly, the corresponding parent nucleosides, for example, Acyclovir, have shown no activity against any of those viruses. Not only does this observation provide strong impetus that the fleximer technology can be a powerful tool for developing more effective inhibitors, but also provides an important broad-spectrum approach that is critical to overcoming viral variants and new emerging strains. Other targets currently under investigation with both the acyclic, as well as various 2’-deoxy and ribose-based scaffolds, include filoviruses such as Ebola and Marburg, and flaviviruses such as tickborne encephalitis, Dengue and Yellow Fever, among other high priority neglected diseases.
In addition to viral targets, another project focuses on the use of nucleobases as anticancer agents. For example, the potent activity exhibited by gemcitabine, Ara-C and other related FDA-approved anticancer analogues, has led to numerous structural modifications designed to increase target specificity and potency. Following upon the recent observation that several nucleobase analogues including thiophene-expanded purines, as well as pyrrolo – and thienopyrimidines designed in our laboratories have exhibited selective and highly potent (sub-nanomolar) levels of activity against several key cancers including lung, colon, leukemia, renal, and triple negative breast cancers (among others), we have initiated a program to elucidate their mechanism of action, as well as to further study their highly promising activity in vitro and in vivo. These compounds have advanced to animal studies and as well as investigations to elucidate their mechanism of action.
All of the projects being pursued in the Seley-Radtke laboratories employ structure activity relationship (SAR) algorithms for the biological enhancement of lead compounds. Intimately related to the goals of the drug design projects, synthetic organic chemistry includes the discovery of unique strategies to solve design challenges using state of the art techniques for the construction of modified heterocycles, carbohydrates and carbocyclic moieties. In addition, we utilize a cross-disciplinary chemical biology approach in partnership with our various collaborators around the world to determine the effectiveness of the potential drug candidates, as well as to investigate enzyme fidelity with our unique analogues that possess strategic structural advantages for enhanced molecular recognition.
Publications (Last 3 Years)
- Khandazhinskaya, A.; Eletskaya, B.; Fateev, I.; Kharitonova, M.; Konstantinova, I.; Barai, V.; Azhaev, A.; Hyvonen, M.; Keinanen, T.; Kochetkov, S.; Seley-Radtke*, K.; Khomutov, A.; Matyugina, E. “Novel fleximer pyrazole-containing adenosine analogues: chemical and biotechnological synthesis” 2021, Org Biomol Chem, DOI: 10.1039/d1ob01069g.
- Eyer, L.; Svobodfa, P.; Balvan, J.; Vičar, T.; Raudenska, M.; Stefánik, M; Haviernik, J.; Huvarová, I.; Straková, P.; Hubálek, Z.; Seley-Radtke, K. L.; de Clercq, E.; Růžek, D. “Broad-spectrum antiviral activity of 3´-deoxy-3´-fluoroadenosine against emerging flaviviruses”, 2021, Antimicrob Agents Chemoth; 5:e01522-20.https://doi.org/10.1128/AAC.01522-20.
- Thames, J. E.; Waters III, C. D.; Valle, C.; Bassetto, M.; Aouadi, W.; Martin, B.; Falat, A.; Coutard, B.; Brancale, A.; Canard, B.; Decroly, E.; *Seley-Radtke, K. L. “Synthesis and Biological Evaluation of Novel Flexible Nucleoside Analogues that Inhibit Flavivirus Replication In Vitro” Bioorg Med Chem 2020, 28, 115713.
- Vichier-Guerre, S.; Ku, T.; Pochet, S.; Seley-Radtke, K. L.* “An expedient synthesis of flexible nucleosides through enzymatic glycosylation of proximal and distal fleximer bases”, ChemMedChem, 2020, 21, 1412-1417 (featured article and cover).
- Matugina, E. S.; Khandazhinskaya, A. L.; Kochetkov, S. N. *Seley-Radtke, K. L. “Synthesis of Pyrrole-Containing Heteroaromatic Compounds by Suzuki-Miyaura Cross-Coupling” Mendeleev Communications 2020, 30, 231-231.
- Yates, M. K.; Chatterjee, P.; Flint, M.; Arefeayne, Y.; Plavec, J.; Spiropoulou, C. F.; *Seley-Radtke, K. L.; “Probing the Effects of Pyrimidine Functional Group Switches on Acyclic Fleximer Analogues for Antiviral Activity” Molecules: Discovery, Design, Synthesis, and Application of Nucleoside/Nucleotides” 2019, 24, 3184-3197, doi.org/10.3390/molecules24173184.
- Khandazhinskaya, A. L.; Matyugina, E. S.; Solyev, P. N.; Wilkinson, M.; Buckheit, K. W.; Buckheit Jr., R. W.; Chernousova, L. N.; Smirnova, T. G.; Andreevskaya, S. N.; Kochetkov, S. N.; De Koning, H. P.; *Seley-Radtke, K. L. “Biological Investigations for a Series of Carbocyclic Nucleoside Analogues as Antibacterial Agents”, Molecules: Discovery, Design, Synthesis, and Application of Nucleoside/Nucleotides” 2019, 24(19), 3433-3448, doi:10.3390/molecules24193433.
- Cawrse, B. M.; Robinson, N. M.; Lee, N. C.; Wilson, G. M.; *Seley-Radtke, K L.; Structural and biological Investigations for a series of N-5 substituted pyrrolo[3,2-d]pyrimidines as potential anticancer therapeutics. Molecules: Bioactive Nucleosides and Nucleotides 2019, 24, 2656-68; doi:10.3390/molecules24142656.
- Ku, T.; Lopresti, N.; Shirley, M.; Mori, M.; Marchant, J.; Heng, X.; Botta, M.; Summers, M. F.; *Seley-Radtke, K. L. Synthesis of Distal and Proximal Fleximer Base Analogues and Evaluation in the Nucleocapsid Protein of HIV-1. Bioorganic Med Chem; 2019, 27, 2883-92.
- Yates, M. and *Seley-Radtke, K. L., “The evolution of nucleoside analogue antivirals: a review for chemists and non-chemists. Part II: complex modifications to the nucleoside scaffold” Antiviral Res. 2019, 162, 5-21. Highlighted article.
- Khandazhinskaya, A. L.; Alexandrova, L.A.; Matyugina, E. S.; Solyev, P. N.; Efremenkova, O. V.; Buckheit, K. W.; Garvey, M.; Buckheit Jr, R. W.; Chernousova, L. N.; Smirnova, T. G.; Andreevskaya, S. N.; Leonova, O. G.; Popenko, V. I.; Kochetkov, S. N.; *Seley-Radtke, K. L. “Novel 5’-Norcarbocyclic Pyrimidine Derivatives” as Antibacterial Agents, Molecules, 2018, 23, 3069-87.
- *Seley-Radtke, K. L. and Yates, M. “The evolution of nucleoside analogue antivirals: a review for chemists and non-chemists. Part I: early structural modifications to the nucleoside scaffold.” Antiviral Res. 2018, 154, 66-86. Highlighted article.
- Temburnikar, K.; *Seley-Radtke, K. L.; “Recent advances in synthetic approaches to C-nucleosides”, Beilstein J Org Chem 2018, 14, 772-785.
- *Seley-Radtke, K. L. “Flexibility – not just for Yoga!” Antiviral Chem Chemoth, 2018, 26, 1-12. Highlighted article.
- Eyer, L.; Nencka, R.; de Clercq, E.; Seley-Radtke, K.L.; Růžek, D. “Nucleoside analogues as a rich source of antiviral agents against arthropod-borne flaviviruses”, Antiviral Chem Chemother 2018, 26, 1-28.
- Cawrse, B.M.; Lapidus, R.S.; Cooper, B.; Choi, E. Y.; *Seley-Radtke, K.L.; “Antiproliferative Effects of Halogenated Pyrrolo[3,2-d]pyrimidines with Decreased Toxicity Via N5 Substitution.” ChemMedChem 2018, 13, 178-185.
Invited (Peer-reviewed) Book Chapters
1. Ku, T. C.; *Seley-Radtke, K. L. “Design and Synthesis of Fleximers. A Novel Class of
Structurally Diverse Nucleosides”, in “New Trends in Enzymatic and Chemical synthesis of
Nucleic Acid Derivatives”, Jesús Fernández-Lucas and María-José Camarasa Rius eds.
Wiley-VCH, Weinheim, Germany, 2019, Chapter 8, 195-255.
2. Zimmermann, S. C.; *Seley-Radtke, K. L. "Flexible nucleobase analogues. New tools for
nucleic acid discoveries", in RNA Technologies: DNA and RNA Chemical Biology in Science
and Medicine, V. A. Erdmann, W. T. Markiewicz and J. Barciszewski eds. Springer, NY, NY
2014, pp 149-165.
3. *Seley, K. L.; Mosley, S. L. "Purine Analogues and Their Role in Methylation and Cancer
Chemotherapy" in DNA Methylation and Cancer Therapy, Moshe Szyf, Ed. Landes
Bioscience, Georgetown, TX, 2004, Chapter 13, pp 178-186.
4. *Seley, K. L. "Tricyclic Nucleosides Revisited" in Recent Advances in Nucleosides:
Chemistry and Chemotherapy, pg. 299-326, C.K. Chu, Ed. Elsevier Science, 2002.
5. Schneller, S. W.; Seley, K. L.; Hegde, V. R.; Rajappan, V. P. "5′-Norcarbanucleosides in L-
Like Configurations" in Recent Advances in Nucleosides: Chemistry and Chemotherapy, pg.
291-297; C.K. Chu, Ed. Elsevier Science, 2002.
2021-present Wayne State University, NIH FIRST program, External Advisory Board member
2019-present Pennsylvania State University, NIH T32 Chemistry Biology Interface Graduate Training Program Advisory Board
2017 Distinguished Visiting Professor, Université d’Orléans, Orléans, France
2017-2018 University System of Maryland Regents’ Professor for Excellent in Research
2015-2018 UMBC Presidential Research Professor
2015-2016 Chair, University Faculty Promotion and Tenure Review Committee (UFRC)
2011-present Professor, Chemistry & Biochemistry, UMBC, & Joint UMB Biochemistry program
2010-present Auburn University COSAM Advisory Council member
2009-present UMBC Honors College Advisory Board member
2008-2010 UMBC Honors Program Faculty Fellow
2007-present NIH Chemistry Biology Interface Graduate Program, Director and mentor
2007-2008 UMBC President’s Commission on Women, Faculty representative
2005-present Program in Oncology, Greenebaum Cancer Center, Faculty Member
2005-present Auburn University Society of Women in Sciences & Mathematics Board Member
2004-2006 UMBC Graduate Summer Bridge Program, Founder & Inaugural Director
2003-present NIH/UMBC Meyerhoff Minority Graduate & Undergraduate Faculty mentor
2003-present NSF UMBC MARC U*STAR program, Faculty mentor
2003-2004 NSF UMBC EMBARC (REU) Program, Program Director
2003-2011 Associate Professor, Chemistry & Biochemistry, UMBC
1998-2003 Assistant Professor, Chemistry & Biochemistry, Georgia Institute of Technology
1997-98 Visiting Assistant Professor, Auburn University
1996-98 Postdoctoral Research Fellow, Auburn University
Other than Higher Education:
2022-present Editor in Chief, Annual Reports in Medicinal Chemistry (beginning Oct 2022)
2022-2024 President, International Society for Antiviral Research (ISAR)
2022-present Associate Editor, Science Advances/AAAS
2020-2022 President-elect, International Society for Antiviral Research
2021-present Scientific and Clinical Advisory Board, Antios Therapeutics
2021 Chair, NIH review panel, AIDC-B, July 22-23
2021 Chair, NIH review panel – Topics in Coronavirus Drug Discovery and Development [2021/05 ZRG1 AIDC-K (83)], March 31-April 1
2021 Louisiana Board of Regents Chemistry Enhancement review panel
2020-present Chair, ICAR Program committee, ISAR
2020-present CEO and President, Flexivir Biosciences LLC
2020-2023 Co-Chair, Gordon Research Conference on Nucleosides, Nucleotides & Oligonucleotides
2020 Chair, NIH review panel – Emergency Awards: Rapid Investigation of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Coronavirus Disease 2019 (COVID-19), July 17; Dec 28-29
2020 Co-Chair, NIH review panel – Antimicrobial Therapeutics and Resistance, March 19-20, July 8-9, Oct 11-12
2020-2022 Editorial Board, Annual Reports in Medicinal Chemistry
2020-present Advisory Board, American Council on Science and Health
2020 NIH Review panel: ZRG1 BCMB-A; NIH Transformative Research Awards, April 7
2019-present Gordon Research Conference Council, member
2018-2019 Co-Vice Chair, Gordon Research Conference on Nucleosides, Nucleotides & Oligonucleotides, June 23-29, 2019
2019-2023 Secretary, International Society of Nucleosides, Nucleotides & Nucleic Acids (IS3NA)
2019 NIH Review panel – Antimicrobial Therapeutics and Resistance – Co-Chair, March 25-26, June 3-4 and Nov 7-8, July 31 (Chair)
2019 Session Chair, Advances in Noncanonical Nucleic Acids, Rogaška Slatina, Slovenia, Oct 17-19.
2019 Session Chair, Gordon Research Conference on Nucleosides, Nucleotides & Oligonucleotides, June 23-29
2019 NIH ZRG1 IMM-R(50) U.S.-Brazil Collaborative Biomedical Research Program, ad hoc reviewer, July 16
2019 Session Chair, 32nd International Conference on Antiviral Research, Baltimore, May 12-15th, 2019.
2019 NIH Review panel – Antimicrobial Therapeutics and Resistance – Co-Chair, March 25-26, June 3-4, and Nov 7-8; July 31 (Chair)
2018 Session Chair, Advances in Noncanonical Nucleic Acids, Portorož, Slovenia, Oct 25-27.
2018 Session Chair and Co-organizer, XXIII International Roundtable on Nucleosides, Nucleotides & Nucleic Acids, San Diego, August 26-30
2018 Session Chair, 31st International Conference for Antiviral Research (ICAR), Porto, Portugal, June 11-15
2018 NIH Special Emphasis Panel – Antimicrobial Therapeutics and Resistance – ZRG1 IDM-Y (82) and 2018/05 ZRG1 IDM-T (07)S, March 28-29, June 28-29, Nov 15-16
2018 Session Chair, 7th European Workshop in Drug Synthesis, Siena, Italy, May 24
2018-present Section Editor, Molecules – Chemical Biology
2018 Special Collections Editor, “Advances in Antiviral Nucleoside Analogues and Their Prodrugs“, Antiviral Chemistry & Chemotherapy
2017 NIH Special Emphasis Panel – Antimicrobial Therapeutics and Resistance ZRG1 IDM-Y (82), Nov 2-3
2017 NIH/NCI ZCA1 SRBK NCI Clinical and Translational R21 & Omnibus R03 review panel, Vice Chair, June 13-14
2017-2018 Immediate Past President, International Society for Nucleosides, Nucleotides & Nucleic Acids (IS3NA)
2017-2018 Chair, Nominations Committee, IS3NA
2017-present Chair, The Chu Family Foundation awards, International Society of Antiviral Research (ISAR)
2017 Session Chair, Gordon Research Conference on Nucleosides, Nucleotides & Oligonucleotides, Salve Regina University, Newport, RI, June 25-30
2017 Session Chair, 30th International Conference on Antiviral Research, Atlanta, GA, May 21-25
2016-present Associate Editor, Antiviral Chemistry & Chemotherapy
2016 NIH/NIGMS ZGM1 TRN-Y, Maximizing Investigators Research Awards (MIRA) review panel, Nov 10-11
2016 NIH ZAI1-JRR-M-J3 Rapid Assessment of Zika Virus (ZIKV) Complications review panel, ad hoc member and vice chair, Oct 20
2016 NIH AIDS Discovery & Development of Therapeutics (ADDT) study section, ad hoc member, July 26
2016 NIH F04A-Y(20)L T31/T32 Fellowship study section, ad hoc member, July 13
2016 Session Chair, XXII International Roundtable on Nucleosides, Nucleotides & Nucleic Acids, Paris, France, July 18-21
2016 Session Chair, 6th European Workshop in Drug Synthesis, Siena, Italy, May 17
2016 Session Chair, 5th Antiviral Drugs Research & Development, San Diego, June 1
2016 Conference Committee, 29th International Conference on Antiviral Research, San Diego, CA
2016 Session Chair, 29th International Conference on Antiviral Research, San Diego, CA, April 19
2015-2016 President, International Society on Nucleosides, Nucleotides & Nucleic Acids (IS3NA)
2016-2018 Board of Directors, International Society for Antiviral Research (ISAR)
2016-present Chair, The Chu Family Women in Science Awards Committee, ISAR
2016-present Chair, The Chu Family Early Career Awards Committee, IS3NA
2015 NIH/NIGMS ZGM1 TRN-Y, Maximizing Investigators Research Awards (MIRA) review panel
2015-present Women in Science Scholarship Committee, ISAR
2015-present UMBC Meyerhoff Program Advisory Board
2015 NIH/NCI ZCA1 SRB-2 Drug Development & Targeting Special Emphasis Panel, Acting Chair
2015 Session Chair, 10th European Workshop in Drug Design, Siena, Italy, May 18-22
2105 Session Chair, 28th International Conference on Antiviral Research, Rome, Italy, May 11-15
2014 Session Chair, 21st International Roundtable on Nucleosides, Nucleotides & Nucleic Acids, August 24-28, Poznan, Poland
2014-present Program Committee, ISAR
2014 Broadening Experiences in Scientific Training, Advisory Board member, University of Notre Dame Ph.D. program
2014 Session Chair, National ACS Medicinal Chemistry Symposium, Charleston, SC, May 18, 2014
2014 Session Chair, 27th International Conference on Antiviral Research (ICAR), Raleigh, May 12-15
2014 NIH ZRG1 AARR-J PAR Panel: Sustained Release of Antivirals for Treatment or Prevention of HIV, Acting Chair
2013-present Women in Chemistry Committee, ISAR
2013-2016 Board of Directors, ISAR
2013 NIH/NCI ZCA1 SRLB-2 Exploratory/Developmental Research study section
2013-2014 Vice President, IS3NA
2013-2014 Co-organizer, National ACS Medicinal Chemistry Symposium, Charleston, SC, May 18-21, 2014
2013-2014 Session Chair, National ACS Medicinal Chemistry Symposium, Charleston, SC, May 18-21, 2014
2013-2017 Award Nomination & Selection Committee, ACS Medicinal Chemistry Division
2013 Session Chair, 26th ICAR, San Francisco, May 10-16
2012-2017 ISAR Poster Award Committee Chair
2012-present Editorial Board, Clinical Medicine Insights, Therapeutics
2012 Med Chem Session Chair, 244th National ACS meeting, Philadelphia, PA
2012 Session Chair, 4th European Workshop in Drug Synthesis, May 28, Siena, Italy
2012 Med Chem Session Chair, 243rd National ACS meeting, San Diego, CA
2012 NIH ZRG1 Member Conflict study section (ad hoc)
2011-2013 Editorial Board, Research and Reports in Medicinal Chemistry
2011 Med Chem Session Chair, 242nd National ACS meeting, Denver, CO.
2011 Session Chair, 8th European Workshop in Drug Design, May 22-28, Siena, Italy
2011-present Associate Editor, Current Protocols in Chemical Biology
2010-2014 NIH AIDS Discovery & Development of Therapeutics (ADDT) study section, member (Vice Chair – 2013-2014)
2010-2012 ACS Div. of Med. Chem. Long Range Planning Committee
2007-2012 Secretary, IS3NA
2010 Session Chair, 19th International Roundtable on Nucleosides, Nucleotides & Nucleic Acids, August 29-Sept 3, 2010, Lyon, France
2009 NSF Chemical Synthesis study section
2008-present NAS Jefferson Science Fellowship Selection Committee
2008-2012 Scientific Advisory Board, Deszyme Inc.
2008 Session Chair, 12th Indian Society of Chemists & Biologists Int. Conf. on “The Interface of Chemistry-Biology in Biomedical Research“, Pilani, India
2007-2016 U.S. Embassy, Moscow Russia, Senior Science Advisor
2007 Women in International Security (WIIS) workshop “Science, Technology and U.S. National Security: Engaging the Next Generation” invited panel member and discussion leader, Washington, DC
2006-present NAS Jefferson Science Fellow, U.S. Department of State
2005-2010 NIH/NIGMS Biomedical Research Training-A and-B study sections member
2005-present IS3NA, Membership (Chair), Publications & website committees
2005-present ISAR, Career Development Committee, Poster Awards Committee
2004-2008 Merck/AAAS Undergraduate Science Research Program (USRP) Selection Committee Member
2004 NIH Tropical Medicine & Parasitology Study Section member (ad hoc)
2004 Session Chair, International Roundtable on Nucleosides, Nucleotides and Nucleic Acids, Minneapolis, MN
2003 NIH Tropical Medicine & Parasitology Study Section member (ad hoc)
2003 Session Chair, Gordon Research Conference, Purines, Pyrimidines & Related Substances, Newport, RI
2002 NIH Bioorganic & Natural Products Study Section member (ad hoc)
2002 NIH BNZP Bioengineering Study Section member (ad hoc)
Honors, Awards, and Distinctions:
2021 Baltimore Sun’s 2021’s 25 Women to Watch
2020 International Society for Antiviral Research (ISAR) Antonín Holý Memorial Award
2017 USM Regents’ Faculty Award for Excellence in Research
2016 Maryland Chemist of the Year, American Chemical Society
2015-2018 UMBC Presidential Research Professor
2015 Outstanding Chemistry Alumni Award, University of South Florida
2011 Outstanding Faculty Member of the Year, UMBC Honors College students
2008-2010 Inaugural Faculty Fellow, UMBC Honors College Program
2006 NAS Jefferson Science Fellow, U.S. Department of State
2006 Distinguished Faculty Award, The National Society of Collegiate Scholars
2003 ACS PROGRESS Lectureship in Chemical Sciences Award
2002 “Class Of 1940 W. Howard Ector Outstanding Teacher” Georgia Institute of Technology ($10,000 prize)
1998 Outstanding Faculty Award, Cardinal Key Honor Society, Auburn University
1997 Sigma Xi Outstanding Dissertation, Auburn University
1997 Carolyn Taylor Carr Award, Auburn University
1992 American Association of University Women Scholarship, U. of South Florida
1992 Hugh Culverhouse Outstanding Graduate Student Award, U. of South Florida
- CHEM 299: Training in Experimental Chemistry (Cooperative Education)
- CHEM 351: Organic Chemistry I
- CHEM 351L: Organic Chemistry Laboratory I
- CHEM 352: Organic Chemistry II
- CHEM 352L: Organic Chemistry Laboratory II
- CHEM 399: Tutorial Projects in Chemistry
- CHEM 450: Chemistry of Heterocyclic Compounds
- CHEM 453: Organic Chemistry of Nucleic Acids
- CHEM 455: Introduction to Biomedicinal Chemistry
- CHEM 490: Special Topics in Chemistry – Organic Synthetic Methology
- CHEM 499: Undergraduate Research
- CHEM 600: Advanced Laboratory Projects
- CHEM 602: Introduction to Laboratory Research
- CHEM 650: Chemistry of Heterocyclic Compounds
- CHEM 653: Organic Chemistry of Nucleic Acids
- CHEM 654: Organic Synthetic Methodology
- CHEM 655: Introduction to Biomedicinal Chemistry
- CHEM 713: Biochemistry/Chemistry Seminar
- CHEM 715: Issues at the Chemistry/Biology Interface
- CHEM 898: Pre-Candidacy Doctoral Research
- CHEM 899: Doctoral Dissertation Research