112 results on '"Wagh K"'
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2. CNNs and Melanoma: The Perfect Pair for Accurate and Timely Cancer Staging
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Wagh, K. S., primary, Chordia, Anuj, additional, Deshmukh, Unnati, additional, Kadde, Miraj, additional, and Mahashabde, Bhargavi, additional
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- 2023
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3. The Link between Integrability, Level Crossings, and Exact Solution in Quantum Models
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Owusu, H. K., Wagh, K., and Yuzbashyan, E. A.
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Condensed Matter - Statistical Mechanics - Abstract
We investigate the connection between energy level crossings in integrable systems and their integrability, i.e. the existence of a set of non-trivial integrals of motion. In particular, we consider a general quantum Hamiltonian linear in the coupling u, H(u) = T + uV, and require that it has the maximum possible number of nontrivial commuting partners also linear in u. We demonstrate how this commutation requirement alone leads to: (1) an exact solution for the energy spectrum and (2) level crossings, which are always present in these Hamiltonians in violation of the Wigner-von Neumann non-crossing rule. Moreover, we construct these Hamiltonians explicitly by resolving the above commutation requirement and show their equivalence to a sector of Gaudin magnets (central spin Hamiltonians). In contrast, fewer than the maximum number of conservation laws does not guarantee level crossings., Comment: 33 pages, 10 figures, minor typos corrected, reference added, model generalized beyond real symmetric to Hermitian operators
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- 2008
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4. Les Houches 'Physics at TeV Colliders 2005' Beyond the Standard Model working group: summary report
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Allanach, B. C., Grojean, C., Skands, P., Accomando, E., Azuelos, G., Baer, H., Balazs, C., Belanger, G., Benakli, K., Boudjema, F., Brelier, B., Bunichev, V., Cacciapaglia, G., Carena, M., Choudhury, D., Delsart, P. -A., De Sanctis, U., Desch, K., Dobrescu, B. A., Dudko, L., Kacimi, M. El, Ellwanger, U., Ferrag, S., Finch, A., Franke, F., Fraas, H., Freitas, A., Gambino, P., Ghodbane, N., Godbole, R. M., Goujdami, D., Gris, Ph., Guasch, J., Guchait, M., Hahn, T., Heinemeyer, S., Hektor, A., Hesselbach, S., Hollik, W., Hugonie, C., Hurth, T., Idarraga, J., Jinnouchi, O., Kalinowski, J., Kneur, J. -L., Kraml, S., Kadastik, M., Kannike, K., Lafaye, R., Landsberg, G., Lari, T., Lee, J. S., Lykken, J., Mahmoudi, F., Mangano, M., Menon, A., Miller, D. J., Millet, T., Milstene, C., Montesano, S., Moortgat, F., Moortgat-Pick, G., Moretti, S., Morrissey, D. E., Muanza, S., Muhlleitner, M. M., Muntel, M., Nowak, H., Ohl, T., Penaranda, S., Perelstein, M., Perez, E., Perries, S., Peskin, M., Petzoldt, J., Pilaftsis, A., Plehn, T., Polesello, G., Pompos, A., Porod, W., Przysiezniak, H., Pukhov, A., Raidal, M., Rainwater, D., Raklev, A. R., Rathsman, J., Reuter, J., Richardson, P., Rindani, S. D., Rolbiecki, K., Rzehak, H., Schumacher, M., Schumann, S., Semenov, A., Serin, L., Servant, G., Shepherd-Themistocleous, C. H., Sherstnev, S., Silvestrini, L., Singh, R. K., Slavich, P., Spira, M., Sopczak, A., Sridhar, K., Tompkins, L., Troncon, C., Tsuno, S., Wagh, K., Wagner, C. E. M., Weiglein, G., Wienemann, P., Zerwas, D., and Zhukov, V.
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High Energy Physics - Phenomenology - Abstract
The work contained herein constitutes a report of the "Beyond the Standard Model'' working group for the Workshop "Physics at TeV Colliders", Les Houches, France, 2-20 May, 2005. We present reviews of current topics as well as original research carried out for the workshop. Supersymmetric and non-supersymmetric models are studied, as well as computational tools designed in order to facilitate their phenomenology., Comment: 269 pages, 165 figures. Web page of the workshop (with links to the talks): http://lappweb.in2p3.fr/conferences/LesHouches/Houches2005/
- Published
- 2006
5. An Operative Approach for Effective Segmentation of Retinal Blood Vessels Based on Multilevel DNN
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Gupta, Sachin, Puthillath, Beena, Sharma, Meenakshi, Wagh, K. S., and Wagh, Sharmila K.
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Cerebral vascular issues ,CAD ,AV ratio ,Neovascularization - Abstract
Vision is obstructed by issues with the retina's blood vessels. Given the rise in patients with visual problems, the frequency of periodic eye exams has increased. Decreasing numbers of ophthalmologists make the screening procedure challenging. Thus, for this field, automated computer-aided diagnostics are required. Over the past few decades, research has advanced to the point that it can now distinguish the different types of illnesses that affect vessels. Risky retinal vessels confirm the occurrence of CAD, DR hypertension, cerebral vascular issues, and stroke. A significant stage of DR called neovascularization involves the growth of many blood vessels without the bifurcation pattern and stiffness and minimal blood loss injuries. Arteriovenous junctions and vesicle width help to identify hypertensive retinopathy in patients. Retinal telangiectasia is a macular condition that affects the retina. The small blood vessels close to the fovea get enlarged or leak blood due to infection. The AV ratio and intersection also provide information on several vessel-related diseases. The suggested DNN is compared to traditional segmentation methods quantitatively and is found to have superior SN while still maintaining respectable SP and Acc. In addition, the area under the curve (AUC) is determined to verify accurate vascular segmentation from the retina. An improved post processing method will aid in accurate binary segmentation and preserve delicate blood vessel structures.
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- 2023
6. Exploring novel adversarial attack strategies on android systems
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Pandey, H., primary, Mankar, A., additional, Wagaj, V., additional, Bit, A., additional, and Wagh, K. S., additional
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- 2021
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7. Drape estimation vs. visual assessment for estimating postpartum hemorrhage
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Patel, A., Goudar, S.S., Geller, S.E., Kodkany, B.S., Edlavitch, S.A., Wagh, K., Patted, S.S., Naik, V.A., Moss, N., and Derman, R.J.
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- 2006
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8. FORMULATION AND EVALUATION OF THEOPHYLLINE FLOATING MATRIX TABLET: 1308
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WAGH, K, PATIL, S, MAHAJAN, V, and BAVISKAR, D
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- 2011
9. HIV-1 diversity considerations for clinical studies of passively transferred broadly neutralising antibodies
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Wagh, K., primary, Stephenson, K., additional, Barouch, D., additional, and Korber, B., additional
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- 2019
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10. IMPACT OF DIGITALIZATION OF ECONOMY IN THE INDIAN CONTEXT.
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RAJEEV, SANKAR and WAGH, K. K.
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TRADE regulation , *BUSINESS communication , *DIGITAL technology , *ECONOMIC models , *CONSUMPTION (Economics) , *DIGITIZATION - Published
- 2021
11. Content Based Video Retrieval
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Wagh K. D and Dr. Kharat M. U.
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- 2016
12. To Control Mobile Web Services Access Using Fuzzy Logic
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Wagh, K. S., primary
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- 2019
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13. A Survey: Data Leakage Detection Techniques
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Wagh, K. S., primary
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- 2018
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14. Formulation and Evaluation of Fluconazole Gel by using Synthetic Polymer
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Dhandore, S. G., primary and Wagh, K. B., primary
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- 2018
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15. ESBL encoding third-generation cephalosporin resistance observed in bloodstream infection in India.
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Patil, S., Wagh, K., Lopes, B., Liu, S., and Wen, F.
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- 2023
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16. Forskolin: upcoming antiglaucoma molecule
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Patil, P., Surana, S., Wagh, V., and Wagh, K.
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Dietary supplements ,Ophthalmic drugs ,Diterpenes ,Ethnic, cultural, racial issues/studies ,Social sciences ,Women's issues/gender studies - Abstract
Byline: P. Patil, S. Surana, V. Wagh, K. Wagh Forskolin is the first pharmaceutical drug and product derived from a plant to be approved in India by the DCGI in [...]
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- 2012
17. Secret Sharing Based Securing Online Banking Transactions
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Wagh K. S
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Business ,Computer security ,computer.software_genre ,computer ,Secret sharing - Published
- 2016
18. The link between integrability, level crossings and exact solution in quantum models
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Owusu, H K, primary, Wagh, K, additional, and Yuzbashyan, E A, additional
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- 2008
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19. Equilibration problem for the generalized Langevin equation
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Dhar, A., primary and Wagh, K., additional
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- 2007
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20. Corrigendum to “Drape estimation vs. visual assessment for estimating postpartum hemorrhage” [International Journal of Gynecology & Obstetrics 93 (2006) 220-224]
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Patel, A., primary, Goudar, S.S., additional, Geller, S.E., additional, Kodkany, B.S., additional, Edlavitch, S.A., additional, Wagh, K., additional, Patted, S.S., additional, Naik, V.A., additional, Moss, N., additional, and Derman, R.J., additional
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- 2006
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21. Forskolin: Upcoming antiglaucoma molecule.
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Wagh, V. D., Patil, P. N., Surana, S. J., and Wagh, K. V.
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DRUG approval ,MEDICINAL plants ,GLAUCOMA ,ULCERS ,ANIMAL experimentation ,DRUG storage - Abstract
Forskolin is the first pharmaceutical drug and product derived from a plant to be approved in India by the DCGI in 2006. Forskolin (7beta-acetoxy-8, 13-epoxy-1a, 6β, 9a-trihydroxy-labd-14-en-11-one) is a diterpenoid isolated from plant Coleus forskohlii (Lamiaceae). It is a lipid-soluble compound that can penetrate cell membranes and stimulates the enzyme adenylate cyclase which, in turn, stimulates ciliary epithelium to activate cyclic adenosine monophosphate, which decreases intraocular pressure (IOP) by reducing aqueous humor inflow. The topical application of forskolin is capable of reducing IOP in rabbits, monkeys, and humans. In its drug interactions, forskolin may act synergistically with epinephrine, ephedrine and pseudoephedrine. Whereas the effects of anti-clotting medications like warfarin, clopidogre, aspirin, anoxaparin, etc., may be enhanced by forskolin. Forskolin is contraindicated in the medications for people with ulcers as forskolin may increase acid level. Forskolin has a very good shelf-life of five years. Recently, its Ophthalmic inserts and in situ gels for sustained and delayed-release drug delivery systems were tested in New Zealand Albino Rabbits for its antiglaucoma efficacy. This drug review explains Forskolin as a drug, its antiglaucoma potential and recent findings of forskolin as an antiglaucoma agent. The literature search method used for this review was different databases and search engines like PubMed, International Pharmaceutical Abstracts, Google, Medicinal and Aromatic Plants (MAPA). [ABSTRACT FROM AUTHOR]
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- 2012
22. Corrigendum to “Drape estimation vs. visual assessment for estimating postpartum hemorrhage” [International Journal of Gynecology and Obstetrics 93 (2006) 220–224]
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Patel, A., Goudar, S.S., Geller, S.E., Kodkany, B.S., Edlavitch, S.A., Wagh, K., Patted, S.S., Naik, V.A., Moss, N., and Derman, R.J.
- Published
- 2006
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23. Les Houches physics at TeV colliders 2005 beyond the standard model working group: Summary report
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Allanach, Benjamin C., Grojean, Christophe, Skands, Peter Z., Accomando, E., Azuelos, Georges, Baer, H., Balazs, Csaba, Belanger, G., Benakli, Karim, Boudjema, Fawzi, Brelier, B., Bunichev, V., Cacciapaglia, Giacomo, Carena, Marcela, Choudhury, D., Delsart, Pierre-Antoine, Sanctis, U., Desch, Klaus, Dobrescu, Bogdan A., Dudko, Lev V., El Kacimi, M., Ellwanger, Ulrich, Ferrag, S., Finch, A., Franke, F., Fraas, H., Freitas, A., Gambino, Paolo, Ghodbane, Nabil, Godbole, R. M., Goujdami, D., Gris, Ph, Guasch, Jaume Inglada, Guchait, M., Hahn, Thomas, Heinemeyer, Sven, Hektor, A., Hesselbach, Stefan, Hollik, W., Hugonie, Cyril, Hurth, T., Idarraga, J., Jinnouchi, Osamu, Kalinowski, J., Kneur, J. L., Sabine Kraml, Kadastik, M., Kannike, K., Lafaye, R., Landsberg, Greg L., Lari, T., Lee, Jae Sik, Lykken, J., Mahmoudi, F., Mangano, Michelangelo L., Menon, Arjun, Miller, D. J., Millet, T., Milstene, Caroline, Montesano, S., Moortgat, F., Moortgat-Pick, Gudrid A., Moretti, Stefano, Morrissey, David Edgar, Muanza, S., Muhlleitner, M. M., Muntel, M., Kluge, Hannelies, Ohl, Thorsten, Penaranda, Siannah, Perelstein, M., Perez, E., Perries, S., Peskin, Michael E., Petzoldt, J., Pilaftsis, Apostolos, Plehn, Tilman, Polesello, G., Pompos, A., Porod, Werner, Przysiezniak, H., Pukhov, A., Raidal, Martti, Rainwater, David Landry, Raklev, Are R., Rathsman, Johan, Reuter, Juergen, Richardson, Peter, Rindani, Saurabh D., Rolbiecki, K., Rzehak, H., Schumacher, M., Schumann, S., Semenov, A., Serin, L., Servant, Geraldine, Shepherd-Themistocleous, Claire H., Sherstnev, S., Silvestrini, Luca, Singh, R. K., Slavich, Pietro, Spira, Michael, Sopczak, A., Sridhar, K., Tompkins, Lauren Alexandra, Troncon, Clara, Tsuno, S., Wagh, K., Wagner, Carlos E. M., Weiglein, Georg, Wienemann, P., Zerwas, D., and Zhukov, V.
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High Energy Physics::Phenomenology ,Particle Physics - Phenomenology - Abstract
The work contained herein constitutes a report of the Beyond the Standard Model'' working group for the Workshop Physics at TeV Colliders, Les Houches, France, 2-20 May, 2005. We present reviews of current topics as well as original research carried out for the workshop. Supersymmetric and non-supersymmetric models are studied, as well as computational tools designed in order to facilitate their phenomenology.
24. Improving web link mining using semantic similarity measurement
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Wagh, K. and Satish Kolhe
25. Mechanical regulation of lymphocyte activation and function.
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Pathni A, Wagh K, Rey-Suarez I, and Upadhyaya A
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- Humans, Animals, Lymphocytes immunology, Lymphocytes metabolism, Cytoskeleton metabolism, Mechanotransduction, Cellular, Lymphocyte Activation immunology
- Abstract
Mechanosensing, or how cells sense and respond to the physical environment, is crucial for many aspects of biological function, ranging from cell movement during development to cancer metastasis, the immune response and gene expression driving cell fate determination. Relevant physical stimuli include the stiffness of the extracellular matrix, contractile forces, shear flows in blood vessels, complex topography of the cellular microenvironment and membrane protein mobility. Although mechanosensing has been more widely studied in non-immune cells, it has become increasingly clear that physical cues profoundly affect the signaling function of cells of the immune system. In this Review, we summarize recent studies on mechanical regulation of immune cells, specifically lymphocytes, and explore how the force-generating cytoskeletal machinery might mediate mechanosensing. We discuss general principles governing mechanical regulation of lymphocyte function, spanning from the molecular scale of receptor activation to cellular responses to mechanical stimuli., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)
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- 2024
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26. Viral Envelope Evolution in Simian-HIV-Infected Neonate and Adult-Dam Pairs of Rhesus Macaques.
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Giorgi EE, Li H, Hora B, Shaw GM, Wagh K, and Williams WB
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- Animals, Genetic Variation, Animals, Newborn, HIV Antibodies immunology, HIV Antibodies blood, Viral Envelope Proteins genetics, Viral Envelope Proteins immunology, HIV Infections virology, Macaca mulatta, Simian Immunodeficiency Virus genetics, Simian Immunodeficiency Virus immunology, Simian Acquired Immunodeficiency Syndrome virology, Phylogeny, HIV-1 genetics, HIV-1 immunology, HIV-1 classification, Antibodies, Neutralizing immunology, Antibodies, Neutralizing blood, Evolution, Molecular
- Abstract
We recently demonstrated that Simian-HIV (SHIV)-infected neonate rhesus macaques (RMs) generated heterologous HIV-1 neutralizing antibodies (NAbs) with broadly-NAb (bNAb) characteristics at a higher frequency compared with their corresponding dam. Here, we characterized genetic diversity in Env sequences from four neonate or adult/dam RM pairs: in two pairs, neonate and dam RMs made heterologous HIV-1 NAbs; in one pair, neither the neonate nor the dam made heterologous HIV-1 NAbs; and in another pair, only the neonate made heterologous HIV-1 NAbs. Phylogenetic and sequence diversity analyses of longitudinal Envs revealed that a higher genetic diversity, within the host and away from the infecting SHIV strain, was correlated with heterologous HIV-1 NAb development. We identified 22 Env variable sites, of which 9 were associated with heterologous HIV-1 NAb development; 3/9 sites had mutations previously linked to HIV-1 Env bNAb development. These data suggested that viral diversity drives heterologous HIV-1 NAb development, and the faster accumulation of viral diversity in neonate RMs may be a potential mechanism underlying bNAb induction in pediatric populations. Moreover, these data may inform candidate Env immunogens to guide precursor B cells to bNAb status via vaccination by the Env-based selection of bNAb lineage members with the appropriate mutations associated with neutralization breadth.
- Published
- 2024
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27. Vaccine induction of heterologous HIV-1-neutralizing antibody B cell lineages in humans.
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Williams WB, Alam SM, Ofek G, Erdmann N, Montefiori DC, Seaman MS, Wagh K, Korber B, Edwards RJ, Mansouri K, Eaton A, Cain DW, Martin M, Hwang J, Arus-Altuz A, Lu X, Cai F, Jamieson N, Parks R, Barr M, Foulger A, Anasti K, Patel P, Sammour S, Parsons RJ, Huang X, Lindenberger J, Fetics S, Janowska K, Niyongabo A, Janus BM, Astavans A, Fox CB, Mohanty I, Evangelous T, Chen Y, Berry M, Kirshner H, Van Itallie E, Saunders KO, Wiehe K, Cohen KW, McElrath MJ, Corey L, Acharya P, Walsh SR, Baden LR, and Haynes BF
- Subjects
- Humans, HIV Infections immunology, HIV Infections virology, Cell Lineage, Liposomes, env Gene Products, Human Immunodeficiency Virus immunology, Mutation, HIV Envelope Protein gp41 immunology, AIDS Vaccines immunology, HIV-1 immunology, Antibodies, Neutralizing immunology, B-Lymphocytes immunology, HIV Antibodies immunology
- Abstract
A critical roadblock to HIV vaccine development is the inability to induce B cell lineages of broadly neutralizing antibodies (bnAbs) in humans. In people living with HIV-1, bnAbs take years to develop. The HVTN 133 clinical trial studied a peptide/liposome immunogen targeting B cell lineages of HIV-1 envelope (Env) membrane-proximal external region (MPER) bnAbs (NCT03934541). Here, we report MPER peptide-liposome induction of polyclonal HIV-1 B cell lineages of mature bnAbs and their precursors, the most potent of which neutralized 15% of global tier 2 HIV-1 strains and 35% of clade B strains with lineage initiation after the second immunization. Neutralization was enhanced by vaccine selection of improbable mutations that increased antibody binding to gp41 and lipids. This study demonstrates proof of concept for rapid vaccine induction of human B cell lineages with heterologous neutralizing activity and selection of antibody improbable mutations and outlines a path for successful HIV-1 vaccine development., Competing Interests: Declaration of interests B.F.H. and S.M.A. have US patents 9402917, 9402893, 9717789, and 10588960 and US patent application 63/540482. B.F.H., S.M.A., and B.K. have US patent 10076567. B.F.H. and K.O.S. have patent applications PCT/US2023/077677 and PCT/US2023/077686. C.B.F. has patents on PEGylated liposomes., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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28. A global update on the status of prevention of folic acid-preventable spina bifida and anencephaly in year 2022.
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Wagh K, Kancherla V, Dorsey A, Pachón H, and Oakley GP Jr
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- Humans, Female, Global Health, Prevalence, Pregnancy, Flour, Edible Grain, Folic Acid therapeutic use, Food, Fortified, Anencephaly prevention & control, Anencephaly epidemiology, Spinal Dysraphism prevention & control, Spinal Dysraphism epidemiology
- Abstract
Background: Mandatory fortification of staple foods with folic acid is an effective public health strategy to prevent folic acid-preventable spina bifida and anencephaly (FAP SBA). We estimated the global proportion of FAP SBA prevented through mandatory folic acid fortification of cereal grains (i.e., wheat flour, maize flour, and rice)., Methods: We used year 2022 data from the Food Fortification Initiative to identify countries (n = 69) with mandatory fortification of grains that includes folic acid. Sixty-eight countries were eligible for analysis with complete data. Proportion of FAP SBA prevention was modeled assuming >150 mcg/day of folic acid fortification protects against FAP SBA, reducing post-fortification prevalence to a lowest achievable level of 0.5 cases per 1000 births., Results: Our analysis found that a total of 63,520 cases of FAP SBA were prevented in the year 2022 in 68 countries implementing mandatory folic acid fortification of grains with folic acid. This translated to a 23.7% prevention of all possible FAP SBA prevention globally. An excess of 204,430 cases of FAPSBA still occurred in over 100 countries where mandatory staple food fortification with folic acid is not implemented., Conclusion: Our study showed that only a quarter of all FAP SBA cases were averted through mandatory folic acid fortification in the year 2022; many countries are not implementing the policy, resulting in a large proportion of FAP SBA cases that can be prevented. Fortification will help countries with achieving 2030 Sustainable Development Goals on neonatal- and under-five mortality, disability, stillbirths, and elective terminations prevention, from FAP SBA., (© 2024 Wiley Periodicals LLC.)
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- 2024
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29. HIResist: a database of HIV-1 resistance to broadly neutralizing antibodies.
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Misra M, Jeffy J, Liao C, Pickthorn S, Wagh K, and Herschhorn A
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- Humans, Broadly Neutralizing Antibodies, HIV Antibodies, Antibodies, Neutralizing, env Gene Products, Human Immunodeficiency Virus, Epitopes, HIV Infections, HIV-1
- Abstract
Motivation: Changing the course of the human immunodeficiency virus type I (HIV-1) pandemic is a high public health priority with approximately 39 million people currently living with HIV-1 (PLWH) and about 1.5 million new infections annually worldwide. Broadly neutralizing antibodies (bnAbs) typically target highly conserved sites on the HIV-1 envelope glycoproteins (Envs), which mediate viral entry, and block the infection of diverse HIV-1 strains. But different mechanisms of HIV-1 resistance to bnAbs prevent robust application of bnAbs for therapeutic and preventive interventions., Results: Here we report the development of a new database that provides data and computational tools to aid the discovery of resistant features and may assist in analysis of HIV-1 resistance to bnAbs. Bioinformatic tools allow identification of specific patterns in Env sequences of resistant strains and development of strategies to elucidate the mechanisms of HIV-1 escape; comparison of resistant and sensitive HIV-1 strains for each bnAb; identification of resistance and sensitivity signatures associated with specific bnAbs or groups of bnAbs; and visualization of antibody pairs on cross-sensitivity plots. The database has been designed with a particular focus on user-friendly and interactive interface. Our database is a valuable resource for the scientific community and provides opportunities to investigate patterns of HIV-1 resistance and to develop new approaches aimed to overcome HIV-1 resistance to bnAbs., Availability and Implementation: HIResist is freely available at https://hiresist.ahc.umn.edu/., (© The Author(s) 2024. Published by Oxford University Press.)
- Published
- 2024
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30. Engineering immunogens that select for specific mutations in HIV broadly neutralizing antibodies.
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Henderson R, Anasti K, Manne K, Stalls V, Saunders C, Bililign Y, Williams A, Bubphamala P, Montani M, Kachhap S, Li J, Jaing C, Newman A, Cain D, Lu X, Venkatayogi S, Berry M, Wagh K, Korber B, Saunders KO, Tian M, Alt F, Wiehe K, Acharya P, Alam SM, and Haynes BF
- Abstract
Vaccine development targeting rapidly evolving pathogens such as HIV-1 requires induction of broadly neutralizing antibodies (bnAbs) with conserved paratopes and mutations, and, in some cases, the same Ig-heavy chains. The current trial-and-error search for immunogen modifications that improve selection for specific bnAb mutations is imprecise. To precisely engineer bnAb boosting immunogens, we used molecular dynamics simulations to examine encounter states that form when antibodies collide with the HIV-1 Envelope (Env). By mapping how bnAbs use encounter states to find their bound states, we identified Env mutations that were predicted to select for specific antibody mutations in two HIV-1 bnAb B cell lineages. The Env mutations encoded antibody affinity gains and selected for desired antibody mutations in vivo . These results demonstrate proof-of-concept that Env immunogens can be designed to directly select for specific antibody mutations at residue-level precision by vaccination, thus demonstrating the feasibility of sequential bnAb-inducing HIV-1 vaccine design., Competing Interests: Declaration of Interests The authors declare the following competing interests: A patent application covering HIV-1 Envelope modifications based on this study has been submitted by Duke University. The authors declare no other competing interests.
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- 2023
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31. Neutralization escape by SARS-CoV-2 Omicron subvariant BA.2.86.
- Author
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Lasrado N, Collier AY, Hachmann NP, Miller J, Rowe M, Schonberg ED, Rodrigues SL, LaPiana A, Patio RC, Anand T, Fisher J, Mazurek CR, Guan R, Wagh K, Theiler J, Korber BT, and Barouch DH
- Subjects
- Humans, SARS-CoV-2 genetics, Antibodies, Neutralizing, Immunization, Secondary, Antibodies, Viral, COVID-19
- Abstract
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variant BA.2.86 has over 30 mutations in spike compared with BA.2 and XBB.1.5, which raised the possibility that BA.2.86 might evade neutralizing antibodies (NAbs) induced by vaccination or infection. In this study, we show that NAb titers are substantially lower to BA.2.86 compared with BA.2 but are similar or slightly higher than to other current circulating variants, including XBB.1.5, EG.5.1, and FL.1.5.1. Moreover, NAb titers against all these variants were higher in vaccinated individuals with a history of XBB.1.5 infection compared with vaccinated individuals with no history of XBB.1.5 infection, suggesting the potential utility of the monovalent XBB.1.5 mRNA boosters., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dan Barouch reports financial support was provided by National Cancer Institute. Dan Barouch reports financial support was provided by Massachusetts Consortium on Pathogen Readiness. Dan Barouch reports financial support was provided by Ragon Institute., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
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32. Transcription Factor Dynamics: One Molecule at a Time.
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Wagh K, Stavreva DA, Upadhyaya A, and Hager GL
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- Chromatin genetics, Regulatory Sequences, Nucleic Acid, Transcription Factors genetics, Transcription Factors metabolism, Gene Expression Regulation
- Abstract
Cells must tightly regulate their gene expression programs and yet rapidly respond to acute biochemical and biophysical cues within their environment. This information is transmitted to the nucleus through various signaling cascades, culminating in the activation or repression of target genes. Transcription factors (TFs) are key mediators of these signals, binding to specific regulatory elements within chromatin. While live-cell imaging has conclusively proven that TF-chromatin interactions are highly dynamic, how such transient interactions can have long-term impacts on developmental trajectories and disease progression is still largely unclear. In this review, we summarize our current understanding of the dynamic nature of TF functions, starting with a historical overview of early live-cell experiments. We highlight key factors that govern TF dynamics and how TF dynamics, in turn, affect downstream transcriptional bursting. Finally, we conclude with open challenges and emerging technologies that will further our understanding of transcriptional regulation.
- Published
- 2023
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33. Mutational basis of serum cross-neutralization profiles elicited by infection or vaccination with SARS-CoV-2 variants.
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Wagh K, Shen X, Theiler J, Girard B, Marshall JC, Montefiori DC, and Korber B
- Abstract
A series of SARS-CoV-2 variants emerged during the pandemic under selection for neutralization resistance. Convalescent and vaccinated sera show consistently different cross-neutralization profiles depending on infecting or vaccine variants. To understand the basis of this heterogeneity, we modeled serum cross-neutralization titers for 165 sera after infection or vaccination with historically prominent lineages tested against 18 variant pseudoviruses. Cross-neutralization profiles were well captured by models incorporating autologous neutralizing titers and combinations of specific shared and differing mutations between the infecting/vaccine variants and pseudoviruses. Infecting/vaccine variant-specific models identified mutations that significantly impacted cross-neutralization and quantified their relative contributions. Unified models that explained cross-neutralization profiles across all infecting and vaccine variants provided accurate predictions of holdout neutralization data comprising untested variants as infecting or vaccine variants, and as test pseudoviruses. Finally, comparative modeling of 2-dose versus 3-dose mRNA-1273 vaccine data revealed that the third dose overcame key resistance mutations to improve neutralization breadth., Highlights: Modeled SARS-CoV-2 cross-neutralization using mutations at key sitesIdentified resistance mutations and quantified relative impactAccurately predicted holdout variant and convalescent/vaccine sera neutralizationShowed that the third dose of mRNA-1273 vaccination overcomes resistance mutations.
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- 2023
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34. Divide and conquer: broadly neutralizing antibody combinations for improved HIV-1 viral coverage.
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Wagh K and Seaman MS
- Subjects
- Humans, Broadly Neutralizing Antibodies pharmacology, HIV Antibodies, Antibodies, Neutralizing therapeutic use, HIV Infections drug therapy, HIV Infections prevention & control, HIV-1
- Abstract
Purpose of Review: Successful HIV-1 prevention and therapy will require broad and potent coverage of within-host and global viral diversity. Broadly neutralizing antibody (bNAb) combination and multispecific therapeutics provide an opportunity to meet this challenge due to the complementary activity of individual antibody components. Here, we review the principles and applications of this concept., Recent Findings: The Antibody Mediated Prevention (AMP) trials have demonstrated the high bar for neutralization potency and breadth that bNAb-mediated prevention modalities will need to achieve to have a meaningful impact on the HIV-1 epidemic. Additional clinical studies have recently shown that an even higher bar may be required for therapeutic inhibition of the diverse within-host quasispecies present in viremic and aviremic people with HIV-1 (PWH). We discuss how the complementarity of bNAbs in terms of neutralization profiles, resistance mutations and coverage of within-host quasispecies may overcome these stringent requirements and lead to effective bNAb combination or multispecific antibody based prophylactic and therapeutic strategies., Summary: The design of next-generation bNAb-based combination or multispecific therapeutics for the prevention and/or treatment of HIV-1 infection will need to leverage the complementarity of component bNAbs to maximize the potency and breadth that will be required for clinical success., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)
- Published
- 2023
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35. The Glucocorticoid Receptor is Required for Efficient Aldosterone-Induced Transcription by the Mineralocorticoid Receptor.
- Author
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Johnson TA, Fettweis G, Wagh K, Almeida-Prieto B, Krishnamurthy M, Upadhyaya A, Hager GL, and Alvarez de la Rosa D
- Abstract
The glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) have distinct, yet overlapping physiological and pathophysiological functions. There are indications that both receptors interact functionally and physically, but the precise role of this interdependence is poorly understood. Here, we analyzed the impact of GR co-expression on MR genome-wide chromatin binding and transcriptional responses to aldosterone and glucocorticoids, both physiological ligands of this receptor. Our data show that GR co-expression alters MR genome-wide binding to consensus DNA sequences in a locus- and ligand-specific way. MR binding to consensus DNA sequences is affected by GR. Transcriptional responses of MR in the absence of GR are weak and show poor correlation with chromatin binding. In contrast, co-expression of GR potentiates MR-mediated transcription, particularly in response to aldosterone. Finally, single-molecule tracking of MR suggests that the presence of GR contributes to productive binding of MR/aldosterone complexes to chromatin. Together, our data indicate that co-expression of GR potentiates aldosterone-mediated MR transcriptional activity, even in the absence of glucocorticoids., Competing Interests: Competing Interest Statement: The authors have nothing to disclose.
- Published
- 2023
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36. Dynamic switching of transcriptional regulators between two distinct low-mobility chromatin states.
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Wagh K, Stavreva DA, Jensen RAM, Paakinaho V, Fettweis G, Schiltz RL, Wüstner D, Mandrup S, Presman DM, Upadhyaya A, and Hager GL
- Subjects
- Animals, Machine Learning, Protein Domains, Single Molecule Imaging, Mammals, Chromatin genetics, Histones genetics
- Abstract
How chromatin dynamics relate to transcriptional activity remains poorly understood. Using single-molecule tracking, coupled with machine learning, we show that histone H2B and multiple chromatin-bound transcriptional regulators display two distinct low-mobility states. Ligand activation results in a marked increase in the propensity of steroid receptors to bind in the lowest-mobility state. Mutational analysis revealed that interactions with chromatin in the lowest-mobility state require an intact DNA binding domain and oligomerization domains. These states are not spatially separated as previously believed, but individual H2B and bound-TF molecules can dynamically switch between them on time scales of seconds. Single bound-TF molecules with different mobilities exhibit different dwell time distributions, suggesting that the mobility of TFs is intimately coupled with their binding dynamics. Together, our results identify two unique and distinct low-mobility states that appear to represent common pathways for transcription activation in mammalian cells.
- Published
- 2023
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37. Structural basis for breadth development in the HIV-1 V3-glycan targeting DH270 antibody clonal lineage.
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Henderson R, Zhou Y, Stalls V, Wiehe K, Saunders KO, Wagh K, Anasti K, Barr M, Parks R, Alam SM, Korber B, Haynes BF, Bartesaghi A, and Acharya P
- Subjects
- Humans, Antibodies, Neutralizing, HIV Antibodies, Polysaccharides, HIV Infections prevention & control, HIV-1 genetics
- Abstract
Antibody affinity maturation enables adaptive immune responses to a wide range of pathogens. In some individuals broadly neutralizing antibodies develop to recognize rapidly mutating pathogens with extensive sequence diversity. Vaccine design for pathogens such as HIV-1 and influenza has therefore focused on recapitulating the natural affinity maturation process. Here, we determine structures of antibodies in complex with HIV-1 Envelope for all observed members and ancestral states of the broadly neutralizing HIV-1 V3-glycan targeting DH270 antibody clonal B cell lineage. These structures track the development of neutralization breadth from the unmutated common ancestor and define affinity maturation at high spatial resolution. By elucidating contacts mediated by key mutations at different stages of antibody development we identified sites on the epitope-paratope interface that are the focus of affinity optimization. Thus, our results identify bottlenecks on the path to natural affinity maturation and reveal solutions for these that will inform immunogen design aimed at eliciting a broadly neutralizing immune response by vaccination., (© 2023. The Author(s).)
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- 2023
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38. SARS-CoV-2 variant transition dynamics are associated with vaccination rates, number of co-circulating variants, and convalescent immunity.
- Author
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Beesley LJ, Moran KR, Wagh K, Castro LA, Theiler J, Yoon H, Fischer W, Hengartner NW, Korber B, and Del Valle SY
- Subjects
- Humans, Pandemics, Retrospective Studies, SARS-CoV-2 genetics, COVID-19 epidemiology, COVID-19 prevention & control
- Abstract
Background: Throughout the COVID-19 pandemic, the SARS-CoV-2 virus has continued to evolve, with new variants outcompeting existing variants and often leading to different dynamics of disease spread., Methods: In this paper, we performed a retrospective analysis using longitudinal sequencing data to characterize differences in the speed, calendar timing, and magnitude of 16 SARS-CoV-2 variant waves/transitions for 230 countries and sub-country regions, between October 2020 and January 2023. We then clustered geographic locations in terms of their variant behavior across several Omicron variants, allowing us to identify groups of locations exhibiting similar variant transitions. Finally, we explored relationships between heterogeneity in these variant waves and time-varying factors, including vaccination status of the population, governmental policy, and the number of variants in simultaneous competition., Findings: This work demonstrates associations between the behavior of an emerging variant and the number of co-circulating variants as well as the demographic context of the population. We also observed an association between high vaccination rates and variant transition dynamics prior to the Mu and Delta variant transitions., Interpretation: These results suggest the behavior of an emergent variant may be sensitive to the immunologic and demographic context of its location. Additionally, this work represents the most comprehensive characterization of variant transitions globally to date., Funding: Laboratory Directed Research and Development (LDRD), Los Alamos National Laboratory., Competing Interests: Declaration of interests Dr. Theiler received a Bill and Melinda Gates Foundation Grant for bioinformatic analysis unrelated to the present work. The authors have no other conflicts of interest to report., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2023
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39. Author Correction: Strategies for HIV-1 vaccines that induce broadly neutralizing antibodies.
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Haynes BF, Wiehe K, Borrow P, Saunders KO, Korber B, Wagh K, McMichael AJ, Kelsoe G, Hahn BH, Alt F, and Shaw GM
- Published
- 2023
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40. Strategies for HIV-1 vaccines that induce broadly neutralizing antibodies.
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Haynes BF, Wiehe K, Borrow P, Saunders KO, Korber B, Wagh K, McMichael AJ, Kelsoe G, Hahn BH, Alt F, and Shaw GM
- Subjects
- Humans, Broadly Neutralizing Antibodies, HIV Antibodies, Antibodies, Neutralizing, Antigens, Viral, HIV-1, AIDS Vaccines, HIV Infections
- Abstract
After nearly four decades of research, a safe and effective HIV-1 vaccine remains elusive. There are many reasons why the development of a potent and durable HIV-1 vaccine is challenging, including the extraordinary genetic diversity of HIV-1 and its complex mechanisms of immune evasion. HIV-1 envelope glycoproteins are poorly recognized by the immune system, which means that potent broadly neutralizing antibodies (bnAbs) are only infrequently induced in the setting of HIV-1 infection or through vaccination. Thus, the biology of HIV-1-host interactions necessitates novel strategies for vaccine development to be designed to activate and expand rare bnAb-producing B cell lineages and to select for the acquisition of critical improbable bnAb mutations. Here we discuss strategies for the induction of potent and broad HIV-1 bnAbs and outline the steps that may be necessary for ultimate success., (© 2022. Springer Nature Limited.)
- Published
- 2023
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41. A Germline-Targeting Chimpanzee SIV Envelope Glycoprotein Elicits a New Class of V2-Apex Directed Cross-Neutralizing Antibodies.
- Author
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Bibollet-Ruche F, Russell RM, Ding W, Liu W, Li Y, Wagh K, Wrapp D, Habib R, Skelly AN, Roark RS, Sherrill-Mix S, Wang S, Rando J, Lindemuth E, Cruickshank K, Park Y, Baum R, Carey JW, Connell AJ, Li H, Giorgi EE, Song GS, Ding S, Finzi A, Newman A, Hernandez GE, Machiele E, Cain DW, Mansouri K, Lewis MG, Montefiori DC, Wiehe KJ, Alam SM, Teng IT, Kwong PD, Andrabi R, Verkoczy L, Burton DR, Korber BT, Saunders KO, Haynes BF, Edwards RJ, Shaw GM, and Hahn BH
- Subjects
- Humans, Animals, Mice, Broadly Neutralizing Antibodies, HIV Antibodies, Pan troglodytes metabolism, Macaca mulatta, Antibodies, Neutralizing, Epitopes, Glycoproteins, env Gene Products, Human Immunodeficiency Virus, HIV Infections, HIV-1
- Abstract
HIV-1 and its SIV precursors share a broadly neutralizing antibody (bNAb) epitope in variable loop 2 (V2) at the envelope glycoprotein (Env) trimer apex. Here, we tested the immunogenicity of germ line-targeting versions of a chimpanzee SIV (SIVcpz) Env in human V2-apex bNAb heavy-chain precursor-expressing knock-in mice and as chimeric simian-chimpanzee immunodeficiency viruses (SCIVs) in rhesus macaques (RMs). Trimer immunization of knock-in mice induced V2-directed NAbs, indicating activation of V2-apex bNAb precursor-expressing mouse B cells. SCIV infection of RMs elicited high-titer viremia, potent autologous tier 2 neutralizing antibodies, and rapid sequence escape in the canonical V2-apex epitope. Six of seven animals also developed low-titer heterologous plasma breadth that mapped to the V2-apex. Antibody cloning from two of these animals identified multiple expanded lineages with long heavy chain third complementarity determining regions that cross-neutralized as many as 7 of 19 primary HIV-1 strains, but with low potency. Negative stain electron microscopy (NSEM) of members of the two most cross-reactive lineages confirmed V2 targeting but identified an angle of approach distinct from prototypical V2-apex bNAbs, with antibody binding either requiring or inducing an occluded-open trimer. Probing with conformation-sensitive, nonneutralizing antibodies revealed that SCIV-expressed, but not wild-type SIVcpz Envs, as well as a subset of primary HIV-1 Envs, preferentially adopted a more open trimeric state. These results reveal the existence of a cryptic V2 epitope that is exposed in occluded-open SIVcpz and HIV-1 Env trimers and elicits cross-neutralizing responses of limited breadth and potency. IMPORTANCE An effective HIV-1 vaccination strategy will need to stimulate rare precursor B cells of multiple bNAb lineages and affinity mature them along desired pathways. Here, we searched for V2-apex germ line-targeting Envs among a large set of diverse primate lentiviruses and identified minimally modified versions of one chimpanzee SIV Env that bound several human V2-apex bNAb precursors and stimulated one of these in a V2-apex bNAb precursor-expressing knock-in mouse. We also generated chimeric simian-chimpanzee immunodeficiency viruses and showed that they elicit low-titer V2-directed heterologous plasma breadth in six of seven infected rhesus macaques. Characterization of this antibody response identified a new class of weakly cross-reactive neutralizing antibodies that target the V2-apex, but only in occluded-open Env trimers. The existence of this cryptic epitope, which in some Env backgrounds is immunodominant, needs to be considered in immunogen design.
- Published
- 2023
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42. A global update on the status of prevention of folic acid-preventable spina bifida and anencephaly in year 2020: 30-Year anniversary of gaining knowledge about folic acid's prevention potential for neural tube defects.
- Author
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Kancherla V, Wagh K, Priyadarshini P, Pachón H, and Oakley GP Jr
- Subjects
- Pregnancy, Child, Female, Humans, Folic Acid, Flour, Anniversaries and Special Events, Food, Fortified, Triticum, Anencephaly epidemiology, Anencephaly prevention & control, Spinal Dysraphism epidemiology, Spinal Dysraphism prevention & control, Neural Tube Defects prevention & control
- Abstract
Background: Spina bifida and anencephaly are major neural tube defects largely preventable through maternal periconceptional intake of folic acid. We estimated the global proportion of folic acid-preventable spina bifida and anencephaly (FAP SBA) prevented through mandatory folic acid fortification of cereal grains, including wheat flour, maize flour, and rice, at the end of year 2020, a time point marking the 30th anniversary of the publication of landmark British Medical Research Council (MRC) study providing unequivocal knowledge on folic acid's FAP SBA prevention potential., Methods: The Food Fortification Initiative database was used to identify countries with mandatory fortification policies with folic acid added to cereal grains. We examined the status of FAP SBA prevention assuming mandatory folic acid fortification at 200 mcg/day of folic acid protects against FAP SBA and reduces their prevalence to a minimum achievable rate of 0.5 cases/1000 live births., Results: Our analysis showed that 61,680 FAP SBA cases were prevented in the year 2020 through mandatory folic acid fortification of cereal grains in 58 countries, translating to 22% prevention of total possible FAP SBA prevention globally. Many countries in Africa, Asia, and Europe are yet to implement fortification. In 2020, 30 years after the MRC study was published, 218,270 preventable FAP SBA cases still occurred globally., Conclusion: Global prevention efforts for FAP SBA are inadequate even after three decades of knowledge on their prevention. Universal mandatory fortification of staples should be urgently implemented to prevent thousands of FAP SBA and associated elective terminations, stillbirths, and child mortality., (© 2022 Wiley Periodicals LLC.)
- Published
- 2022
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43. Immunogenicity and protective efficacy of a rhesus adenoviral vaccine targeting conserved COVID-19 replication transcription complex.
- Author
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Dagotto G, Ventura JD, Martinez DR, Anioke T, Chung BS, Siamatu M, Barrett J, Miller J, Schäfer A, Yu J, Tostanoski LH, Wagh K, Baric RS, Korber B, and Barouch DH
- Abstract
The COVID-19 pandemic marks the third coronavirus pandemic this century (SARS-CoV-1, MERS, SARS-CoV-2), emphasizing the need to identify and evaluate conserved immunogens for a pan-sarbecovirus vaccine. Here we investigate the potential utility of a T-cell vaccine strategy targeting conserved regions of the sarbecovirus proteome. We identified the most conserved regions of the sarbecovirus proteome as portions of the RNA-dependent RNA polymerase (RdRp) and Helicase proteins, both of which are part of the coronavirus replication transcription complex (RTC). Fitness constraints suggest that as SARS-CoV-2 continues to evolve these regions may better preserve cross-reactive potential of T-cell responses than Spike, Nucleocapsid, or Membrane proteins. We sought to determine if vaccine-elicited T-cell responses to the highly conserved regions of the RTC would reduce viral loads following challenge with SARS-CoV-2 in mice using a rhesus adenovirus serotype 52 (RhAd52) vector. The RhAd52.CoV.Consv vaccine generated robust cellular immunity in mice and led to significant reductions in viral loads in the nasal turbinates following challenge with a mouse-adapted SARS-CoV-2. These data suggest the potential utility of T-cell targeting of conserved regions for a pan-sarbecovirus vaccine., (© 2022. The Author(s).)
- Published
- 2022
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44. A tug of war between filament treadmilling and myosin induced contractility generates actin rings.
- Author
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Ni Q, Wagh K, Pathni A, Ni H, Vashisht V, Upadhyaya A, and Papoian GA
- Subjects
- Cytoskeleton metabolism, Myosins metabolism, Actin Cytoskeleton metabolism, Actins metabolism, Actomyosin metabolism
- Abstract
In most eukaryotic cells, actin filaments assemble into a shell-like actin cortex under the plasma membrane, controlling cellular morphology, mechanics, and signaling. The actin cortex is highly polymorphic, adopting diverse forms such as the ring-like structures found in podosomes, axonal rings, and immune synapses. The biophysical principles that underlie the formation of actin rings and cortices remain unknown. Using a molecular simulation platform called MEDYAN, we discovered that varying the filament treadmilling rate and myosin concentration induces a finite size phase transition in actomyosin network structures. We found that actomyosin networks condense into clusters at low treadmilling rates or high myosin concentrations but form ring-like or cortex-like structures at high treadmilling rates and low myosin concentrations. This mechanism is supported by our corroborating experiments on live T cells, which exhibit ring-like actin networks upon activation by stimulatory antibody. Upon disruption of filament treadmilling or enhancement of myosin activity, the pre-existing actin rings are disrupted into actin clusters or collapse towards the network center respectively. Our analyses suggest that the ring-like actin structure is a preferred state of low mechanical energy, which is, importantly, only reachable at sufficiently high treadmilling rates., Competing Interests: QN, KW, AP, HN, VV, AU, GP No competing interests declared, (© 2022, Ni et al.)
- Published
- 2022
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45. Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial.
- Author
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Julg B, Stephenson KE, Wagh K, Tan SC, Zash R, Walsh S, Ansel J, Kanjilal D, Nkolola J, Walker-Sperling VEK, Ophel J, Yanosick K, Borducchi EN, Maxfield L, Abbink P, Peter L, Yates NL, Wesley MS, Hassell T, Gelderblom HC, deCamp A, Mayer BT, Sato A, Gerber MW, Giorgi EE, Gama L, Koup RA, Mascola JR, Monczor A, Lupo S, Rolle CP, Arduino R, DeJesus E, Tomaras GD, Seaman MS, Korber B, and Barouch DH
- Subjects
- Adult, Antibodies, Monoclonal adverse effects, Antibodies, Neutralizing, Antiviral Agents therapeutic use, Broadly Neutralizing Antibodies, HIV Antibodies, Humans, Viremia drug therapy, HIV Infections, HIV Seropositivity, HIV-1
- Abstract
HIV-1 therapy with single or dual broadly neutralizing antibodies (bNAbs) has shown viral escape, indicating that at least a triple bNAb therapy may be needed for robust suppression of viremia. We performed a two-part study consisting of a single-center, randomized, double-blind, dose-escalation, placebo-controlled first-in-human trial of the HIV-1 V2-glycan-specific antibody PGDM1400 alone or in combination with the V3-glycan-specific antibody PGT121 in 24 adults without HIV in part 1, as well as a multi-center, open-label trial of the combination of PGDM1400, PGT121 and the CD4-binding-site antibody VRC07-523LS in five viremic adults living with HIV not on antiretroviral therapy (ART) in part 2 ( NCT03205917 ). The primary endpoints were safety, tolerability and pharmacokinetics for both parts and antiviral activity among viremic adults living with HIV and not on ART for part 2 of the study. The secondary endpoints were changes in CD4
+ T cell counts and development of HIV-1 sequence variations associated with PGDM1400, PGT121 and VRC07-523LS resistance in part 2. Intravenously administered PGDM1400 was safe and well-tolerated at doses up to 30 mg kg-1 and when given in combination with PGT121 and VRC07-523LS. A single intravenous infusion of 20 mg kg-1 of each of the three antibodies reduced plasma HIV RNA levels in viremic individuals by a maximum mean of 2.04 log10 copies per ml; however, viral rebound occurred in all participants within a median of 20 days after nadir. Rebound viruses demonstrated partial to complete resistance to PGDM1400 and PGT121 in vitro, whereas susceptibility to VRC07-523LS was preserved. Viral rebound occurred despite mean VRC07-523LS serum concentrations of 93 µg ml-1 . The trial met the pre-specified endpoints. Our data suggest that future bNAb combinations likely need to achieve broad antiviral activity, while also maintaining high serum concentrations, to mediate viral control., (© 2022. The Author(s).)- Published
- 2022
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46. mRNA-encoded HIV-1 Env trimer ferritin nanoparticles induce monoclonal antibodies that neutralize heterologous HIV-1 isolates in mice.
- Author
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Mu Z, Wiehe K, Saunders KO, Henderson R, Cain DW, Parks R, Martik D, Mansouri K, Edwards RJ, Newman A, Lu X, Xia SM, Eaton A, Bonsignori M, Montefiori D, Han Q, Venkatayogi S, Evangelous T, Wang Y, Rountree W, Korber B, Wagh K, Tam Y, Barbosa C, Alam SM, Williams WB, Tian M, Alt FW, Pardi N, Weissman D, and Haynes BF
- Subjects
- Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, COVID-19 Vaccines, Epitopes, Ferritins genetics, HIV Antibodies, Humans, Liposomes, Mice, RNA, Messenger, env Gene Products, Human Immunodeficiency Virus genetics, AIDS Vaccines, COVID-19, HIV-1, Nanoparticles
- Abstract
The success of nucleoside-modified mRNAs in lipid nanoparticles (mRNA-LNP) as COVID-19 vaccines heralded a new era of vaccine development. For HIV-1, multivalent envelope (Env) trimer protein nanoparticles are superior immunogens compared with trimers alone for priming of broadly neutralizing antibody (bnAb) B cell lineages. The successful expression of complex multivalent nanoparticle immunogens with mRNAs has not been demonstrated. Here, we show that mRNAs can encode antigenic Env trimers on ferritin nanoparticles that initiate bnAb precursor B cell expansion and induce serum autologous tier 2 neutralizing activity in bnAb precursor V
H + VL knock-in mice. Next-generation sequencing demonstrates acquisition of critical mutations, and monoclonal antibodies that neutralize heterologous HIV-1 isolates are isolated. Thus, mRNA-LNP can encode complex immunogens and may be of use in design of germline-targeting and sequential boosting immunogens for HIV-1 vaccine development., Competing Interests: Declaration of interests B.F.H., K.O.S., and K.W. have patent applications on some of the concepts and immunogens discussed in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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47. Editorial: Novel Concepts in Using Broadly Neutralizing Antibodies for HIV-1 Treatment and Prevention.
- Author
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Wagh K, van Gils MJ, Gristick H, and Schommers P
- Subjects
- Animals, HIV-1, Humans, Broadly Neutralizing Antibodies therapeutic use, HIV Infections therapy
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2021
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48. Phase separation in transcription factor dynamics and chromatin organization.
- Author
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Wagh K, Garcia DA, and Upadhyaya A
- Subjects
- Chromatin, Gene Expression, Gene Expression Regulation, Biomolecular Condensates, Transcription Factors
- Abstract
Studies over the past decade have highlighted the key role of liquid-liquid phase separation in cellular organization and function. Dynamic compartmentalization of transcription factors and coactivators by such phase-separated condensates regulates the assembly of transcriptional machinery at genomic loci. Although rapid advances in microscopy have demonstrated the ubiquity of such condensates, a rigorous characterization of the physics of phase separation in transcription remains to be carried out. In this review, we discuss theoretical and experimental evidence for biomolecular condensates as dynamic regulators of transcription. Looking beyond, we highlight functional consequences for transcription factor dynamics and gene expression and discuss potential pitfalls of misclassifying biomolecular condensates as liquid droplets in the absence of a rigorous physical description., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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49. Engineering well-expressed, V2-immunofocusing HIV-1 envelope glycoprotein membrane trimers for use in heterologous prime-boost vaccine regimens.
- Author
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Crooks ET, Almanza F, D'Addabbo A, Duggan E, Zhang J, Wagh K, Mou H, Allen JD, Thomas A, Osawa K, Korber BT, Tsybovsky Y, Cale E, Nolan J, Crispin M, Verkoczy LK, and Binley JM
- Subjects
- Broadly Neutralizing Antibodies immunology, Epitopes immunology, HIV Antibodies immunology, Humans, AIDS Vaccines immunology, HIV Envelope Protein gp120 immunology, HIV Envelope Protein gp41 immunology, HIV-1 immunology
- Abstract
HIV-1 vaccine immunofocusing strategies may be able to induce broadly-reactive neutralizing antibodies (NAbs). Here, we engineered a panel of diverse, membrane-resident native HIV-1 trimers vulnerable to two broad targets-the V2 apex and fusion peptide (FP). Selection criteria included i) high expression and ii) infectious function, so that trimer neutralization sensitivity can be profiled in pseudovirus (PV) assays. Initially, we boosted the expression of 17 candidate trimers by truncating gp41 and introducing a gp120-gp41 SOS disulfide to prevent gp120 shedding. "Repairs" were made to fill glycan holes and eliminate other strain-specific aberrations. A new neutralization assay allowed PV infection when our standard assay was insufficient. Trimers with exposed V3 loops, a target of non-NAbs, were discarded. To try to increase V2-sensitivity, we removed clashing glycans and modified the C-strand. Notably, a D167N mutation improved V2-sensitivity in several cases. Glycopeptide analysis of JR-FL trimers revealed near complete sequon occupation and that filling the N197 glycan hole was well-tolerated. In contrast, sequon optimization and inserting/removing glycans at other positions frequently had global "ripple" effects on glycan maturation and sequon occupation throughout the gp120 outer domain and gp41. V2 MAb CH01 selectively bound to trimers with small high mannose glycans near the base of the V1 loop, thereby avoiding clashes. Knocking in a rare N49 glycan was found to perturb gp41 glycans, increasing FP NAb sensitivity-and sometimes improving expression. Finally, a biophysical analysis of VLPs revealed that i) ~25% of particles bear Env spikes, ii) spontaneous particle budding is high and only increases 4-fold upon Gag transfection, and iii) Env+ particles express ~30-40 spikes. Taken together, we identified 7 diverse trimers with a range of sensitivities to two targets to allow rigorous testing of immunofocusing vaccine concepts., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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50. Safety, pharmacokinetics and antiviral activity of PGT121, a broadly neutralizing monoclonal antibody against HIV-1: a randomized, placebo-controlled, phase 1 clinical trial.
- Author
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Stephenson KE, Julg B, Tan CS, Zash R, Walsh SR, Rolle CP, Monczor AN, Lupo S, Gelderblom HC, Ansel JL, Kanjilal DG, Maxfield LF, Nkolola J, Borducchi EN, Abbink P, Liu J, Peter L, Chandrashekar A, Nityanandam R, Lin Z, Setaro A, Sapiente J, Chen Z, Sunner L, Cassidy T, Bennett C, Sato A, Mayer B, Perelson AS, deCamp A, Priddy FH, Wagh K, Giorgi EE, Yates NL, Arduino RC, DeJesus E, Tomaras GD, Seaman MS, Korber B, and Barouch DH
- Subjects
- Adult, Antiretroviral Therapy, Highly Active, Antiviral Agents immunology, Antiviral Agents pharmacokinetics, Broadly Neutralizing Antibodies immunology, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes virology, Double-Blind Method, Female, HIV Envelope Protein gp120 antagonists & inhibitors, HIV Envelope Protein gp120 immunology, HIV Infections genetics, HIV Infections pathology, HIV Infections virology, HIV-1 pathogenicity, Humans, Male, Middle Aged, Peptide Fragments antagonists & inhibitors, Peptide Fragments immunology, Placebos, Viral Load drug effects, Viral Load immunology, Young Adult, Antiviral Agents administration & dosage, Broadly Neutralizing Antibodies administration & dosage, HIV Infections drug therapy, HIV-1 drug effects
- Abstract
Human immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg kg
-1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30 mg kg-1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4+ T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48 participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade 3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4+ T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77 log in viremic participants, with a viral load nadir at a median of 8.5 days. Two individuals with low baseline viral loads experienced ART-free viral suppression for ≥168 days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load., (© 2021. The Author(s).)- Published
- 2021
- Full Text
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