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81.
Nirogi RV Deshpande AD Kambhampati R Badange RK Kota L Daulatabad AV Shinde AK Ahmad I Kandikere V Jayarajan P Dubey PK 《Bioorganic & medicinal chemistry letters》2011,21(1):346-349
N1-Arylsulfonyl-3-piperazinyl indole derivatives were designed and identified as a novel class of 5-HT6 receptors ligands. All the compounds have high affinity and antagonist activity towards 5-HT6 receptor. The compound 7a (Ki = 3.4 nM, functional assay IC50 = 310 nM) shows enhanced cognitive effect when tested in NORT and Morris water maze models. Synthesis, SAR and PK profile of these novel compounds constitute the subject matter of this Letter. 相似文献
82.
83.
84.
Mutations in both gp120 and gp41 Are Responsible for the Broad Neutralization Resistance of Variant Human Immunodeficiency Virus Type 1 MN to Antibodies Directed at V3 and Non-V3 Epitopes 总被引:2,自引:6,他引:2 下载免费PDF全文
Eun Ju Park Luba K. Vujcic Rita Anand Theodore S. Theodore Gerald V. Quinnan Jr. 《Journal of virology》1998,72(9):7099-7107
The escape of human immunodeficiency virus type 1 from effects of neutralizing antibodies was studied by using neutralization-resistant (NR) variants generated by growing the neutralization-sensitive (NS) wild-type MN virus in the presence of human serum with neutralizing antibodies, more than 99% of which were directed at the V3 region of gp120. The variants obtained had broad neutralization resistance to human sera, without limitation with respect to the V3 specificity of the sera. The molecular basis for the resistance was evaluated with molecularly cloned viruses, as well as with pseudoviruses expressing envelope glycoproteins of the NS and NR phenotypes. Nucleotide sequence analyses comparing NS and NR clones revealed a number of polymorphisms, including six in the V1/V2 region, two in C4/V5 of gp120, three in the leucine zipper (LZ) domain of gp41, and two in the second external putative α-helix region of gp41. A series of chimeras from NS and NR env genes was constructed, and each was presented on pseudoviruses to locate the domain(s) which conferred the phenotypic changes. The neutralization phenotypes of the chimeric clones were found to be dependent on mutations in both the C4/V5 region of gp120 and the LZ region of gp41. Additionally, interaction between mutations in gp120 and gp41 was demonstrated in that a chimeric env gene consisting of a gp120 coding sequence from an NS clone and a gp41 sequence from an NR clone yielded a pseudovirus with minimal infectivity. The possible significance of predicted amino acid changes in these domains is discussed. The results indicate that polyvalent antibodies predominantly directed against V3 can induce NR through selection for mutations that alter interactions of other domains in the envelope complex. 相似文献
85.
Anand Bery Felix Leung Christopher R Smith Eleftherios P Diamandis Vathany Kulasingam 《Clinical proteomics》2014,11(1):13
Background
Conventional proteomic approaches have thus far been unable to identify novel serum biomarkers for ovarian cancer that are more sensitive and specific than the current clinically used marker, CA-125. Because endogenous peptides are smaller and may enter the circulation more easily than proteins, a focus on the low-molecular-weight region may reveal novel biomarkers with enhanced sensitivity and specificity. In this study, we deciphered the peptidome of ascites fluid from 3 ovarian cancer patients and 3 benign individuals (ascites fluid from patients with liver cirrhosis).Results
Following ultrafiltration of the ascites fluids to remove larger proteins, each filtrate was subjected to solid phase extraction and fractionated using strong cation exchange chromatography. The resultant fractions were analyzed using an Orbitrap mass spectrometer. We identified over 2000 unique endogenous peptides derived from 259 proteins. We then catalogued over 777 peptides that were found only in ovarian cancer ascites. Our list of peptides found in ovarian cancer specimens includes fragments derived from the proteins vitronectin, transketolase and haptoglobin.Conclusions
Peptidomics may uncover previously undiscovered disease-specific endogenous peptides that warrant further investigation as biomarkers for ovarian cancer. 相似文献86.
The recent establishment of induced pluripotent stem (iPS) cells promises the development of autologous cell therapies for degenerative diseases, without the ethical concerns associated with human embryonic stem (ES) cells. Initially, iPS cells were generated by retroviral transduction of somatic cells with core reprogramming genes. To avoid potential genotoxic effects associated with retroviral transfection, more recently, alternative non-viral gene transfer approaches were developed. Before a potential clinical application of iPS cell-derived therapies can be planned, it must be ensured that the reprogramming to pluripotency is not associated with genome mutagenesis or epigenetic aberrations. This may include direct effects of the reprogramming method or “off-target” effects associated with the reprogramming or the culture conditions. Thus, a rigorous safety testing of iPS or iPS-derived cells is imperative, including long-term studies in model animals. This will include not only rodents but also larger mammalian model species to allow for assessing long-term stability of the transplanted cells, functional integration into the host tissue, and freedom from undifferentiated iPS cells. Determination of the necessary cell dose is also critical; it is assumed that a minimum of 1 billion transplantable cells is required to achieve a therapeutic effect. This will request medium to long-term in vitro cultivation and dozens of cell divisions, bearing the risk of accumulating replication errors. Here, we review the clinical potential of human iPS cells and evaluate which are the most suitable approaches to overcome or minimize risks associated with the application of iPS cell-derived cell therapies. 相似文献
87.
Neer K. Singh Saurabh Anand Aditi Jain Sandip Das 《Plant Molecular Biology Reporter》2017,35(2):237-251
Comparative genomics-based synteny analysis has proved to be an effective strategy to understand evolution of genomic regions spanning a single gene (micro-unit) to large segments encompassing hundreds of kilobases to megabases. Brassicaceae is in a unique position to contribute to understanding genome and trait evolution through comparative genomics because whole genome sequences from as many as nine species have been completed and are available for analysis. In the present work, we compared genomic loci surrounding the KCS17-KCS18 cluster across these nine genomes. KCS18 or FAE 1 gene encodes beta-ketoacyl synthase, (β-KCS) a membrane-bound enzyme that catalyses the key rate-limiting step during synthesis of VLCFAs such as erucic acid (C22) present in seed oil in Brassicaceae by elongating carbon chain from C18 to C22; knowledge on role of KCS17 in plant development is however lacking. Synteny across the genomic segments harbouring FAE1 showed variable levels of gene retention ranging between 26% (Arabidopsis thaliana and Brassica napus C03) and 89% (between A. thaliana and Brassica rapa A01), and gene density ranged between 1 gene/2.86 kb and 1 gene/4.88 kb. Interestingly, in diploid Brassica species, FAE1 was retained in only one of the sub-genomes in spite of the presence of three sub-genomes created as a result of genome triplication; in contrast, FAE1 was present at three loci, with four copies in Camellina sativa which is also known to have experienced a recent genome triplication revealing contrasting fates upon duplication. The organization of KCS17 and KCS18 as head-to-tail cluster was conserved across most of the species, except the C genome containing Brassicas, namely B. oleracea and B. napus, where disruptions because of other genes were observed. Even in the conserved blocks, the distance between KCS17 and KCS18 varied; the functional implication of the organization of KCS17-KCS18 as a cluster vis-à-vis fatty acid biosynthesis needs to be dissected, as the cis-regulatory region is expected to be present in the intergenic space. Phylogenetic analysis of KCS gene family along with KCS17-KCS18 from members of Brassicaceae reveals their ancestral relationship with KCS8-KCS9 block. Further comparative functional analysis between KCS8, KCS9, KCS16, KCS17 and KCS18 across evolutionary time-scale will be required to understand the conservation or diversification of roles of these members of KCS family in fatty acid biosynthesis during course of evolution. 相似文献
88.
Lin L Braunewell KH Gundelfinger ED Anand R 《Biochemical and biophysical research communications》2002,296(4):827-832
Visinin-like protein-1 (VILIP-1), a myristoylated calcium sensor protein with three EF-hand motifs, modulates adenylyl cyclase activity. It translocates to membranes when a postulated "calcium-myristoyl switch" is triggered by calcium-binding to expose its sequestered myristoyl moiety. We investigated the contributions of the EF-hand motifs to the translocation of VILIP-1 to membranes and to the modulation of adenylyl cyclase activity. Mutation of residues crucial for binding calcium within each one of the EF-hand motifs indicated that they all contributed to binding calcium. Simultaneous mutations of all of the three EF-hand motifs completely abolished VILIP-1's ability to bind calcium, attenuated but did not eliminate its modulation of adenylyl cyclase activity, and abolished its calcium-dependence for association with cellular membranes. These results show that the calcium-binding EF-hand motifs of VILIP-1 do not have an essential role in modulating adenylyl cyclase activity but instead have a structural role in activating the "calcium-myristoyl switch" of VILIP-1. 相似文献
89.
Park JJ Anand S Zhao Y Matsumura Y Sakoda Y Kuramasu A Strome SE Chen L Tamada K 《Cancer immunology, immunotherapy : CII》2012,61(2):203-214
Genetic engineering of tumor cells to express immune-stimulatory molecules, including cytokines and co-stimulatory ligands,
is a promising approach to generate highly efficient cancer vaccines. The co-signaling molecule, LIGHT, is particularly well
suited for use in vaccine development as it delivers a potent co-stimulatory signal through the Herpes virus entry mediator
(HVEM) receptor on T cells and facilitates tumor-specific T cell immunity. However, because LIGHT binds two additional receptors,
lymphotoxin β receptor and Decoy receptor 3, there are significant concerns that tumor-associated LIGHT results in both unexpected
adverse events and interference with the ability of the vaccine to enhance antitumor immunity. In order to overcome these
problems, we generated tumor cells expressing the single-chain variable fragment (scFv) of anti-HVEM agonistic mAb on the
cell surface. Tumor cells expressing anti-HVEM scFv induce a potent proliferation and cytokine production of co-cultured T
cells. Inoculation of anti-HVEM scFv-expressing tumor results in a spontaneous tumor regression in CD4+ and CD8+ T cell-dependent
fashion, associated with the induction of tumor-specific long-term memory. Stimulation of HVEM and 4-1BB co-stimulatory signals
by anti-HVEM scFv-expressing tumor vaccine combined with anti-4-1BB mAb shows synergistic effects which achieve regression
of pre-established tumor and T cell memory specific to parental tumor. Taken in concert, our data suggest that genetic engineering
of tumor cells to selectively potentiate the HVEM signaling pathway is a promising antitumor vaccine therapy. 相似文献
90.
The role of forest plantations in biodiversity conservation has gained more attention in recent years. However, most work on evaluating the diversity of forest plantations focuses only on one spatial scale; thus, we examined the effects of sampling scale on diversity in forest plantations. We designed a hierarchical sampling strategy to collect data on woody species diversity in planted pine (Pinus tabuliformis Carr.), planted larch (Larix principis-rupprechtii Mayr.), and natural secondary deciduous broadleaf forests in a mountainous region of Beijing, China. Additive diversity partition analysis showed that, compared to natural forests, the planted pine forests had a different woody species diversity partitioning pattern at multi-scales (except the Simpson diversity in the regeneration layer), while the larch plantations did not show multi-scale diversity partitioning patterns that were obviously different from those in the natural secondary broadleaf forest. Compare to the natural secondary broadleaf forests, the effects of planted pine forests on woody species diversity are dependent on the sampling scale and layers selected for analysis. Diversity in the planted larch forest, however, was not significantly different from that in the natural forest for all diversity components at all sampling levels. Our work demonstrated that the species selected for afforestation and the sampling scales selected for data analysis alter the conclusions on the levels of diversity supported by plantations. We suggest that a wide range of scales should be considered in the evaluation of the role of forest plantations on biodiversity conservation. 相似文献