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Padmaja N. Kulkarni A. Huntley Blair Tarunendu Ghose Molly Mammen 《Cancer immunology, immunotherapy : CII》1985,19(3):211-214
Summary Methotrexate (MTX) was first conjugated to antibovine serum albumin IgG (antiBSA) or its F(ab)2 fragment to define conditions for retention of drug and antibody activity. With identical drug: protein molar ratios, incorporation in the F(ab)2 fragment was lower than in intact antiBSA, an observation consistent with analysis of the number of lysine residues (22 in F(ab)2 compared to 40 in antiBSA). In either case, up to approximately 10 mol MTX could be incorporated per mol protein, with recovery of 70% of the protein. At an incorporation ratio of 6 mol MTX per mol protein, MTX-antiBSA retained 100% of antibody activity and MTX-F(ab)2antiBSA retained 75%. MTX-antiBSA and MTX-F(ab)2antiBSA were equally potent in vitro inhibitors of dihydrofolate reductase. Conjugates prepared from antiEL4 IgG (AELG) and from F(ab)2AELG significantly increased survival in EL4 lymphoma-bearing mice compared with mice receiving equal amounts (5 mg MTX/kg) of free MTX, MTX linked to the F(ab)2 fragment of normal rabbit IgG, or a simple mixture of MTX and F(ab)2AELG. MTX-AELG at this dose level produced longer survival than MTX-F(ab)2AELG (0.005
2AELG MTX linked to the F(ab)2 fragment of AELG - MTX-F(ab)2antiBSA MTX linked to the F(ab)2 fragment of antiBSA - MTX-F(ab)2NRG MTX linked to the F(ab)2 fragment of NRG - MTX-NRG MTX linked to NRG - NHS N-hydroxysuccinimide - NRG normal rabbit IgG - PBS 0.01 M sodium phosphate (pH 7.1) containing 0.45 M sodium chloride - TAA tumor-associated antigen - t1/2 half-life 相似文献
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Flax secoisolariciresinol diglucoside (SDG) lignan is a natural phytoestrogen for which a positive role in metabolic diseases is emerging. Until recently however, much less was known about SDG and its monoglucoside (SMG) biosynthesis. Lately, flax UGT74S1 was identified and characterized as an enzyme sequentially glucosylating secoisolariciresinol (SECO) into SMG and SDG when expressed in yeast. However, the amino acids critical for UGT74S1 glucosyltransferase activity were unknown. A 3D structural modeling and docking, site-directed mutagenesis of five amino acids in the plant secondary product glycosyltransferase (PSPG) motif, and enzyme assays were conducted. UGT74S1 appeared to be structurally similar to the Arabidopsis thaliana UGT72B1 model. The ligand docking predicted Ser357 and Trp355 as binding to the phosphate and hydroxyl groups of UDP-glucose, whereas Cys335, Gln337 and Trp355 were predicted to bind the 7-OH, 2-OCH3 and 17-OCH3 of SECO. Site-directed mutagenesis of Cys335, Gln337, His352, Trp355 and Ser357, and enzyme assays revealed an alteration of these binding sites and a significant reduction of UGT74S1 glucosyltransferase catalytic activity towards SECO and UDP-glucose in all mutants. A complete abolition of UGT74S1 activity was observed when Trp355 was substituted to Ala355 and Gly355 or when changing His352 to Asp352, and an altered metabolite profile was observed in Cys335Ala, Gln337Ala, and Ser357Ala mutants. This study provided for the first time evidence that Trp355 and His352 are critical for UGT74S1’s glucosylation activity toward SECO and suggested the possibility for SMG production in vitro. 相似文献
5.
Sanghamitra Adak Sambit Datta Somnath Bhattacharya Tapas Kumar Ghose Arun Lahiri Majumder 《Physiology and Molecular Biology of Plants》2020,26(4):669-682
Study of genetic diversity in crop plants is essential for the selection of appropriate germplasm for crop improvement. As salinity posses a serious environmental challenge to rice production globally and especially in India, it is imperative that the study of large collections of germplasms be undertaken to search for salt tolerant stocks. In the present study, 64 indica germplasms were collected from different agro-climatic zones of West Bengal, India, from the Himalayan foothills in the northern part down to the southern saline belt of the state keeping in view the soil characteristics and other edaphic factors prevailing in the region. Salt tolerance parameters were used to screen the large set of germplasms in terms of root-shoot length, fresh-dry weight, chlorophyll content, Na+/K+ ratio and germination potential in presence of salt. Standard evaluation score or SES was calculated to find out tolerant to sensitive cultivar. Twenty-one SSR markers, some associated with the Saltol QTL and others being candidate gene based SSR (cgSSR) were used to study the polymorphism of collected germplasm. A wide diversity was detected among the collected germplasms at the phenotypic as well as molecular level. Of the 21 SSR markers, 15 markers were found to be polymorphic with 88 alleles. Based on phenotypic and biochemical results, 21 genotypes were identified as salinity tolerant, whereas 40 genotypes turned out to be salt susceptible. The present study shows that apart from the established salt tolerant lines, several other landraces like Bonkanta, Morisal, Ghiosh, Patni may be the source of salt tolerant donor in future breeding programs. 相似文献
6.
Melissa Holstein Jessica Hung Hasin Feroz Swarnim Ranjan Cheng Du Sanchayita Ghose Zheng Jian Li 《Biotechnology and bioengineering》2020,117(11):3591-3606
To achieve the high protein concentrations required for subcutaneous administration of biologic therapeutics, numerous manufacturing process challenges are often encountered. From an operational perspective, high protein concentrations result in highly viscous solutions, which can cause pressure increases during ultrafiltration. This can also lead to low flux during ultrafiltration and sterile filtration, resulting in long processing times. In addition, there is a greater risk of product loss from the hold-up volumes during filtration operations. From a formulation perspective, higher protein concentrations present the risk of higher aggregation rates as the closer proximity of the constituent species results in stronger attractive intermolecular interactions and higher frequency of self-association events. There are also challenges in achieving pH and excipient concentration targets in the ultrafiltration/diafiltration (UF/DF) step due to volume exclusion and Donnan equilibrium effects, which are exacerbated at higher protein concentrations. This paper highlights strategies to address these challenges, including the use of viscosity-lowering excipients, appropriate selection of UF/DF cassettes with modified membranes and/or improved flow channel design, and increased understanding of pH and excipient behavior during UF/DF. Additional considerations for high-concentration drug substance manufacturing, such as appearance attributes, stability, and freezing and handling are also discussed. These strategies can be employed to overcome the manufacturing process challenges and streamline process development efforts for high-concentration drug substance manufacturing. 相似文献
7.
Andrea Piserchio Pravin A. Nair Stewart Shuman Ranajeet Ghose 《Biomolecular NMR assignments》2009,3(1):77-80
Chlorella virus DNA ligase (ChVLig) is a minimal (298-amino acid) pluripotent ATP-dependent ligase composed of three structural
modules—a nucleotidyltransferase domain, an OB domain, and a β-hairpin latch—that forms a circumferential clamp around nicked
DNA. ChVLig provides an instructive model to understand the chemical and conformational steps of nick repair. Here we report
the assignment of backbone 13C, 15N, 1HN resonances of this 34.2 kDa protein, the first for a DNA ligase in full-length form. 相似文献
8.
Matthew J. Cooper Nathan J. Cox Eric I. Zimmerman Brian J. Dewar James S. Duncan Martin C. Whittle Thien A. Nguyen Lauren S. Jones Sreerupa Ghose Roy David M. Smalley Pei Fen Kuan Kristy L. Richards Richard I. Christopherson Jian Jin Stephen V. Frye Gary L. Johnson Albert S. Baldwin Lee M. Graves 《PloS one》2013,8(6)
Protein kinases play key roles in oncogenic signaling and are a major focus in the development of targeted cancer therapies. Imatinib, a BCR-Abl tyrosine kinase inhibitor, is a successful front-line treatment for chronic myelogenous leukemia (CML). However, resistance to imatinib may be acquired by BCR-Abl mutations or hyperactivation of Src family kinases such as Lyn. We have used multiplexed kinase inhibitor beads (MIBs) and quantitative mass spectrometry (MS) to compare kinase expression and activity in an imatinib-resistant (MYL-R) and -sensitive (MYL) cell model of CML. Using MIB/MS, expression and activity changes of over 150 kinases were quantitatively measured from various protein kinase families. Statistical analysis of experimental replicates assigned significance to 35 of these kinases, referred to as the MYL-R kinome profile. MIB/MS and immunoblotting confirmed the over-expression and activation of Lyn in MYL-R cells and identified additional kinases with increased (MEK, ERK, IKKα, PKCβ, NEK9) or decreased (Abl, Kit, JNK, ATM, Yes) abundance or activity. Inhibiting Lyn with dasatinib or by shRNA-mediated knockdown reduced the phosphorylation of MEK and IKKα. Because MYL-R cells showed elevated NF-κB signaling relative to MYL cells, as demonstrated by increased IκBα and IL-6 mRNA expression, we tested the effects of an IKK inhibitor (BAY 65-1942). MIB/MS and immunoblotting revealed that BAY 65-1942 increased MEK/ERK signaling and that this increase was prevented by co-treatment with a MEK inhibitor (AZD6244). Furthermore, the combined inhibition of MEK and IKKα resulted in reduced IL-6 mRNA expression, synergistic loss of cell viability and increased apoptosis. Thus, MIB/MS analysis identified MEK and IKKα as important downstream targets of Lyn, suggesting that co-targeting these kinases may provide a unique strategy to inhibit Lyn-dependent imatinib-resistant CML. These results demonstrate the utility of MIB/MS as a tool to identify dysregulated kinases and to interrogate kinome dynamics as cells respond to targeted kinase inhibition. 相似文献
9.
Photosynthesis and water efflux were measured in different PAR and stomatal conductance in members of Avicenniaceae and Rhizophoraceae.
Trend of leaf temperature with irradiance and its effect on photosynthesis were also estimated. In most of the studied species,
photosynthesis and stomatal conductance followed similar trends with increase in irradiance. The rate of net photosynthesis
and stomatal conductance were higher in members of Avicenniaceae than in Rhizophoraceae. In Avicenniaceae, the optimum PAR
for maximum photosynthesis ranged between 1340–1685 (μmol m-2s-1, which was also higher than that of Rhizophoraceae (840-1557 μmol m-2s-1). Almost in all the studied taxa, transpiration and stomatal conductance followed similar trends and reached the maximal
peaks at the same PAR value. The range of breakeven leaf temperature was almost the same in both the families (34-36°C in
Avicenniaceae and 33.5-36.3°C in Rhizophoraceae), beyond which assimilation rate declined. 相似文献
10.
B Samanta G Mez? K P Das A C Ghose F Hudecz P C Sen 《The journal of peptide research》2005,65(4):445-449
Protein kinase (PK) A catalytic (PKAcat) subunit was purified to homogeneity from bovine lens using a 100-kDa cut-off membrane filtration followed by different chromatographic procedures. The molecular weight of PKAcat was found to be 41 kDa. The kinase phosphorylates histone IIIs and other synthetic modified peptides of VRKRTLRRL with different amino acid environment. The extent of phosphorylation depends not only on the presence of Ser or Thr (phosphorylating residues) but also on other surrounding amino acid residues. Although some peptides compete in phosphorylating histone, they are not very significant. The result suggests that the extent of phosphorylation depends on the amino acid residue(s) surrounding phosphorylable residue(s) on the peptide. 相似文献