10 results on '"Gulati, Upma"'
Search Results
2. pH-Controlled Intramolecular Decarboxylative Cyclization of Biarylacetic Acids: Implication on Umpolung Reactivity of Aroyl Radicals.
- Author
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Laha JK, Gulati U, Saima, Schulte T, and Breugst M
- Subjects
- Acylation, Hydrogen-Ion Concentration, Cyclization
- Abstract
A simple approach for the intramolecular aroylation of electron-rich arenes under mild conditions has been developed. A pH-controlled polarity umpolung strategy can be used to synthesize different fluorenones, which are important building blocks for biological applications. Unlike previous acylation reactions involving nucleophilic aroyl radicals, this approach likely relies on in situ generated electrophilic aroyl radicals. Detailed mechanistic and computational investigations provide detailed insights into the reaction mechanism and support the hypothesis of a pH-mediated umpolung.
- Published
- 2022
- Full Text
- View/download PDF
3. Benzylic Methylene Functionalizations of Diarylmethanes.
- Author
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Gulati U, Gandhi R, and Laha JK
- Abstract
Diarylmethanes are cardinal scaffolds by virtue of their unique structural feature including the presence of a benzylic CH
2 group that can be easily functionalized to generate a variety of fascinating molecules holding immense importance in pharmaceutical, agrochemical, and material sciences. While the originally developed protocols for benzylic C-H functionalization in diarylmethanes employing base-mediated and metal-catalyzed strategies are still actively used, they are joined by a new array of metal-free conditions, offering milder and benign conditions. With the recent surge of interest towards the synthesis of functionalized diarylmethanes, numerous choices are now available for a synthetic organic chemist to transform the benzylic C-H bond to C-C or C-X bond offering the synthesis of any molecule of choice. This review highlights benzylic methylene (CH2 ) functionalizations of diaryl/heteroarylmethanes utilizing various base-mediated, transition-metal-catalyzed, and transition-metal free approaches for the synthesis of structurally diverse important organic molecules, often with a high chemo-, regio- and enantio-selectivity. This review also attempts to provide analysis of the scope and limitations, mechanistic understanding, and sustainability of the transformations., (© 2020 Wiley-VCH GmbH.)- Published
- 2020
- Full Text
- View/download PDF
4. Antibody quantity versus quality after influenza vaccination.
- Author
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Feng J, Gulati U, Zhang X, Keitel WA, Thompson DM, James JA, Thompson LF, and Air GM
- Subjects
- Aged, Antibodies, Neutralizing blood, Antibodies, Neutralizing immunology, Antibodies, Viral blood, Antigens, Viral immunology, Case-Control Studies, Enzyme-Linked Immunosorbent Assay, Epitopes immunology, Humans, Influenza A Virus, H3N2 Subtype immunology, Influenza, Human immunology, Lupus Erythematosus, Systemic immunology, Protein Folding, Vaccination, Antibodies, Viral immunology, Antibody Affinity, Influenza Vaccines immunology, Influenza, Human prevention & control
- Abstract
The correlates for protection against influenza infection are incompletely characterized. We have applied an ELISA strategy that distinguishes antibodies against native viral surface antigens (potentially neutralizing) from antibodies directed against internal and denatured viral proteins (not neutralizing) to three groups of vaccinated subjects: (1) participants in a study of repeated annual vaccination, (2) elderly subjects and (3) patients with Systemic Lupus Erythematosus compared to control subjects. Antibody increase after vaccination was inversely related to the level of pre-existing antibodies in all groups; most subjects had significant initial antibody levels and showed little increase in amount of antibody after vaccination, but the avidity of their serum antibodies tended to increase. Antibodies against denatured virus proteins varied with vaccine formulation; vaccines that are more recent have less total protein for the same amount of native hemagglutinin. We propose an index consisting of rank order of antibody level plus antibody avidity, both measured against native virus, plus hemagglutination-inhibition antibody titer, as a useful measure of immunity against influenza.
- Published
- 2009
- Full Text
- View/download PDF
5. Increased antibodies against unfolded viral antigens in the elderly after influenza vaccination.
- Author
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Gulati U, Keitel WA, and Air GM
- Subjects
- Aged, Aging immunology, Antibody Affinity, Cross Reactions, Dose-Response Relationship, Immunologic, Hemagglutination Inhibition Tests, Humans, Influenza A Virus, H1N1 Subtype immunology, Influenza B virus immunology, Influenza, Human, Protein Folding, Viral Proteins, Antibodies, Viral blood, Antigens, Viral immunology, Influenza A Virus, H3N2 Subtype immunology, Influenza Vaccines immunology
- Abstract
Objective: Our studies aimed to measure the quality of antibody response to influenza vaccines in the elderly. The frequency of significant rise in hemagglutination inhibition (HAI) titer in the elderly is low and although annual vaccination reduces morbidity and mortality, better correlates of vaccine efficacy in the elderly are needed., Methods: We measured the amount and avidity of serum antibodies against native H3N2 influenza glycoproteins or denatured virus (unfoldons) in pre- and post-vaccinated sera of 36 elderly subjects., Results: Eighty percent of subjects had high pre-immunization antibody levels and only 13% showed >or=2fold increase after vaccination, but 33% showed >or=2fold increase in avidity. With increasing dosage there was a significant increase in avidity against unfoldons with 50% of subjects showing >or=2fold increase at the highest dose. Elderly subjects given subunit vaccine showed higher reactivity with unfoldons (78% of native) than younger subjects studied earlier who were given inactivated whole virus vaccine (19% of native)., Conclusion: The clear inverse relationship between pre-immunization antibody levels and antibody increase after vaccination implies that a major reason for the low frequency of antibody responses in elderly subjects is simply because they have high pre-immunization antibody levels. Only low reactivity was observed with earlier viruses. The increased proportion and avidity of antibodies against unfoldons is of concern, as these are not protective, and vaccine developers need to be aware of the role of age or vaccine formulation in inducing anti-unfoldon antibodies.
- Published
- 2007
- Full Text
- View/download PDF
6. Receptor binding specificity of recent human H3N2 influenza viruses.
- Author
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Kumari K, Gulati S, Smith DF, Gulati U, Cummings RD, and Air GM
- Subjects
- Animals, Cell Line, Chickens, Cricetinae, Dogs, Erythrocytes virology, Hemagglutination, Viral, Hemagglutinin Glycoproteins, Influenza Virus genetics, Hemagglutinin Glycoproteins, Influenza Virus metabolism, Humans, Macaca mulatta, N-Acetylneuraminic Acid metabolism, Polysaccharides metabolism, Virus Assembly, Virus Internalization, Virus Replication, Influenza A Virus, H3N2 Subtype physiology, Receptors, Virus physiology, Virus Attachment
- Abstract
Background: Human influenza viruses are known to bind to sialic acid linked alpha2-6 to galactose, but the binding specificity beyond that linkage has not been systematically examined. H3N2 human influenza isolates lost binding to chicken red cells in the 1990s but viruses isolated since 2003 have re-acquired the ability to agglutinate chicken erythrocytes. We have investigated specificity of binding, changes in hemagglutinin sequence of the recent viruses and the role of sialic acid in productive infection., Results: Viruses that agglutinate, or do not agglutinate, chicken red cells show identical binding to a Glycan Array of 264 oligosaccharides, binding exclusively to a subset of alpha2-6-sialylsaccharides. We identified an amino acid change in hemagglutinin that seemed to correlate with chicken red cell binding but when tested by mutagenesis there was no effect. Recombinant hemagglutinins expressed on Sf-9 cells bound chicken red cells but the released recombinant baculoviruses agglutinated only human red cells. Similarly, an isolate that does not agglutinate chicken red cells show hemadsorption of chicken red cells to infected MDCK cells. We suggest that binding of chicken red cells to cell surface hemagglutinin but not to virions is due to a more favorable hemagglutinin density on the cell surface. We investigated whether a virus specific for alpha2-6 sialyloligosaccharides shows differential entry into cells that have varying proportions of alpha2-6 and alpha2-3 sialic acids, including human A549 and HeLa cells with high levels of alpha2-6 sialic acid, and CHO cells that have only alpha2-3 sialic acid. We found that the virus enters all cell types tested and synthesizes viral nucleoprotein, localized in the nucleus, and hemagglutinin, transported to the cell surface, but infectious progeny viruses were released only from MDCK cells., Conclusion: Agglutination of chicken red cells does not correlate with altered binding to any oligosaccharide on the Glycan Array, and may result from increased avidity due to density of hemagglutinin and not increased affinity. Absence of alpha2-6 sialic acid does not protect a cell from influenza infection and the presence of high levels of alpha2-6-sialic acids on a cell surface does not guarantee productive replication of a virus with alpha2-6 receptor specificity.
- Published
- 2007
- Full Text
- View/download PDF
7. An epidemiologically significant epitope of a 1998 human influenza virus neuraminidase forms a highly hydrated interface in the NA-antibody complex.
- Author
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Venkatramani L, Bochkareva E, Lee JT, Gulati U, Graeme Laver W, Bochkarev A, and Air GM
- Subjects
- Animals, Antibodies, Monoclonal chemistry, Antigens, Viral genetics, Antigens, Viral immunology, Crystallography, X-Ray, Epitopes immunology, Genetic Drift, Humans, Hydrogen Bonding, Immunoglobulin Fab Fragments chemistry, Influenza, Human immunology, Mice, Neuraminidase immunology, Protein Binding, Protein Structure, Tertiary, Surface Properties, Antibodies, Viral chemistry, Antigen-Antibody Complex chemistry, Epitopes chemistry, Influenza A Virus, H3N2 Subtype immunology, Influenza, Human epidemiology, Neuraminidase chemistry, Orthomyxoviridae enzymology, Orthomyxoviridae immunology, Water metabolism
- Abstract
The crystal structure of the complex between neuraminidase (NA) of influenza virus A/Memphis/31/98 (H3N2) and Fab of monoclonal antibody Mem5 has been determined at 2.1A resolution and shows a novel pattern of interactions compared to other NA-Fab structures. The interface buries a large area of 2400 A2 and the surfaces have high complementarity. However, the interface is also highly hydrated. There are 33 water molecules in the interface>or=95% buried from bulk solvent, but only 13 of these are isolated from other water molecules. The rest are involved in an intricate network of water-mediated hydrogen bonds throughout the interface, stabilizing the complex. Glu199 on NA, the most critical side-chain to the interaction as previously determined by escape mutant analysis and site-directed mutation, is located in a non-aqueous island. Glu199 and three other residues that contribute the major part of the antigen buried surface of the complex have mutated in human influenza viruses isolated after 1998, confirming that Mem5 identifies an epidemiologically important antigenic site. We conclude that antibody selection of NA variants is a significant component of recent antigenic drift in human H3N2 influenza viruses, supporting the idea that influenza vaccines should contain NA in addition to hemagglutinin.
- Published
- 2006
- Full Text
- View/download PDF
8. Mismatched hemagglutinin and neuraminidase specificities in recent human H3N2 influenza viruses.
- Author
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Gulati U, Wu W, Gulati S, Kumari K, Waner JL, and Air GM
- Subjects
- Animals, Humans, Species Specificity, Erythrocytes virology, Hemagglutinin Glycoproteins, Influenza Virus metabolism, Influenza A Virus, H3N2 Subtype, Influenza A virus metabolism, Neuraminidase metabolism
- Abstract
The hemagglutinin (HA) of influenza viruses initiates infection by binding to sialic acid on the cell surface via alpha2,6 (human) or alpha2,3 (avian) linkage. The influenza neuraminidase (NA) can cleave both alpha2,3- and alpha2,6-linked sialic acids, but all influenza NAs have a marked preference for the non-human alpha2,3 linkage. Recent H3N2 influenza viruses have lost the ability to agglutinate chicken red blood cells. To determine if changes in HA specificity or affinity correlate with NA specificity or activity, we examined red cell binding and elution of a series of H3N2 viruses. We found that the NA activity of many influenza viruses does not release binding by their HA. In some egg-adapted strains, lack of elution correlates with low levels of viral NA activity, and these elute rapidly when bacterial NA is added. However, a Fujian-like virus, A/Oklahoma/323/03, does not elute by its own NA or with Vibrio cholerae sialidase, and it binds to red cells pre-treated with V. cholerae sialidase. It elutes after addition of the broad specificity Micromonospora viridifaciens sialidase. Human glycophorin inhibits A/Oklahoma/323/03 hemagglutination 6-fold better than fetuin. We conclude that specific forms of sialic acid are used as receptor by recent human H3N2 influenza viruses, perhaps involving branched alpha2,6 sialic acid or alpha2,8 sialic acid structures on O-linked carbohydrates. The virus itself has no O-linked glycans, so even though the NA is not able to cleave receptors on cells, the viruses will not self-aggregate. It will be important to monitor efficacy of neuraminidase inhibitors in case there are NA-resistant receptors in the human respiratory tract that allow the viruses to be less dependent on NA activity.
- Published
- 2005
- Full Text
- View/download PDF
9. Amount and avidity of serum antibodies against native glycoproteins and denatured virus after repeated influenza whole-virus vaccination.
- Author
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Gulati U, Kumari K, Wu W, Keitel WA, and Air GM
- Subjects
- Adult, Antibodies, Viral blood, Antibody Affinity immunology, Antibody Specificity immunology, Glycoproteins immunology, Hemagglutination Inhibition Tests, Humans, Middle Aged, Vaccines, Inactivated immunology, Viral Proteins immunology, Influenza Vaccines immunology
- Abstract
There is still uncertainty on the correlates of protection by influenza vaccine. To determine the relationship between hemagglutination-inhibition (HI) titer and the specificity and avidity of serum antibodies, we analyzed serum from a longitudinal trial (1983-1987) of influenza vaccine efficacy [Keitel WA, Cate TR, Couch RB, Huggins LL, Hess KR. Efficacy of repeated annual immunization with inactivated influenza virus vaccines over a five year period. Vaccine 1997;15(10):1114-22 ]. We captured native virus particles with fetuin and separately measured relative antibody levels and avidities of antibodies against native glycoproteins and antibodies against denatured viral proteins. Most subjects had pre-existing antibodies against A/Victoria/75 and, although 70% had >two-fold increased antibodies against A/Philippines/82 after vaccination, only 30% showed increased antibodies to A/Victoria/75 indicating no dominance of original antigenic sin. There was variation in the levels of antibodies to unfolded antigens compared to native, but antibodies against denatured proteins never exceeded those against native virus. In some cases, the avidity increased without a significant increase in antibody concentration, which might explain why some vaccinees with low HI titer demonstrate adequate protection. We found that the negative correlation between pre-vaccination HI titer and the increase after vaccination is also seen when antibodies are measured directly, but that there is little relationship between HI titer and antibodies against native glycoproteins, either in amount or avidity. Our assay, which has also been adapted for recent influenza viruses that do not bind to fetuin, may be useful for vaccine evaluation.
- Published
- 2005
- Full Text
- View/download PDF
10. Antibody epitopes on the neuraminidase of a recent H3N2 influenza virus (A/Memphis/31/98).
- Author
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Gulati U, Hwang CC, Venkatramani L, Gulati S, Stray SJ, Lee JT, Laver WG, Bochkarev A, Zlotnick A, and Air GM
- Subjects
- Amino Acid Sequence, Animals, Antibodies, Monoclonal genetics, Antibodies, Viral genetics, Antigens, Viral genetics, Binding Sites genetics, Cross Reactions, Epitope Mapping, Epitopes genetics, Genes, Immunoglobulin, Genes, Viral, Humans, Immunoglobulin Fab Fragments genetics, Influenza A virus genetics, Mice, Models, Molecular, Molecular Sequence Data, Mutation, Neuraminidase chemistry, Neuraminidase genetics, Protein Conformation, Influenza A Virus, H3N2 Subtype, Influenza A virus enzymology, Influenza A virus immunology, Neuraminidase immunology
- Abstract
We have characterized monoclonal antibodies raised against the neuraminidase (NA) of a Sydney-like influenza virus (A/Memphis/31/98, H3N2) in a reassortant virus A/NWS/33(HA)-A/Mem/31/98(NA) (H1N2) and nine escape mutants selected by these monoclonal antibodies. Five of the antibodies use the same heavy chain VDJ genes and may not be independent. Another antibody, Mem5, uses the same V(H) and J genes with a different D gene and different isotype. Sequence changes in escape mutants selected by these antibodies occur in two loops of the NA, at amino acid 198, 199, 220, or 221. These amino acids are located on the opposite side of the NA monomer to the major epitopes found in N9 and early N2 NAs. Escape mutants with a change at 198 have reduced NA activity compared to the wild-type virus. Asp198 points toward the substrate binding pocket, and we had previously found that a site-directed mutation of this amino acid resulted in a loss of enzyme activity (M. R. Lentz, R. G. Webster, and G. M. Air, Biochemistry 26:5351-5358, 1987). Mutations at residue 199, 220, or 221 did not alter the NA activity significantly compared to that of wild-type NA. A 3.5-A structure of Mem5 Fab complexed with the Mem/98 NA shows that the Mem5 antibody binds at the sites of escape mutation selected by the other antibodies.
- Published
- 2002
- Full Text
- View/download PDF
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