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461.
AbstractKlebsiella pneumoniae (K. pneumoniae) is a Gram-negative opportunistic pathogen commonly associated with hospital-acquired infections that are often resistant even to antibiotics. Heptosyltransferase (HEP) belongs to the family of glycosyltransferase-B (GT-B) and plays an important in the synthesis of lipopolysaccharides (LPS) essential for the formation of bacterial cell membrane. HEP-III participates in the transfer of heptose sugar to the outer surface of bacteria to synthesize LPS. LPS truncation increases the bacterial sensitivity to hydrophobic antibiotics and detergents, making the HEP as a novel drug target. In the present study, we report the 3D homology model of K. pneumoniae HEP-III and its structure validation. Active site was identified based on similarities with known structures using Dali server, and structure-based pharmacophore model was developed for the active site substrate ADP. The generated pharmacophore model was used as a 3D search query for virtual screening of the ASINEX database. The hit compounds were further filtered based on fit value, molecular docking, docking scores, molecular dynamics (MD) simulations of HEP-III complexed with hit molecules, followed by binding free energy calculations using Molecular Mechanics-Poisson–Boltzmann Surface Area (MM-PBSA). The insights obtained in this work provide the rationale for design of novel inhibitors targeting K. pneumoniae HEP-III and the mechanistic aspects of their binding. Communicated by Ramaswamy H. Sarma 相似文献
462.
Rajiv Kumar Neetu Singh Shalini Gautam Om Prakash Singh Kamlesh Gidwani Madhukar Rai David Sacks Shyam Sundar Susanne Nylén 《PLoS neglected tropical diseases》2014,8(10)
Visceral leishmaniasis (VL) is associated with increased circulating levels of multiple pro-inflammatory cytokines and chemokines, including IL-12, IFNγ, and TNFα, and elevated expression of IFNγ mRNA in lesional tissue such as the spleen and bone marrow. However, an immunological feature of VL patients is that their peripheral blood mononuclear cells (PBMCs) typically fail to respond to stimulation with leishmanial antigen. Unexpectedly, it was recently shown that Leishmania specific IFNγ, can readily be detected when a whole blood stimulation assay (WBA) is used. We sought to define the conditions that permit whole blood cells to respond to antigen stimulation, and clarify the biological role of the IFNγ found to be released by cells from VL patients. CD4+ T cells were found to be crucial for and the main source of the IFNγ production in Leishmania stimulated whole blood (WB) cultures. Complement, antibodies and red blood cells present in whole blood do not play a significant role in the IFNγ response. The IFNγ production was reduced by blockade of human leukocyte antigen (HLA)-DR, indicating that the response to leishmanial antigens observed in WB of active VL patients is a classical HLA- T cell receptor (TCR) driven reaction. Most importantly, blockade of IFNγ in ex-vivo splenic aspirate cultures demonstrated that despite the progressive nature of their disease, the endogenous IFNγ produced in patients with active VL serves to limit parasite growth. 相似文献
463.
T. E. Sheeja P. R. Anju R. S. Shalini S. Siju K. Dhanya B. Krishnamoorthy 《Physiology and Molecular Biology of Plants》2013,19(2):245-250
Knema andamanica is a red-listed endemic medicinal species of Myristicaceae restricted to Andaman and Nicobar (A&N) Islands, India. This species is used in tribal medicines and has immense bioprospective potential. With a view to generate suitable genomic markers for classification and identification, we have generated RAPD, SCAR and conserved 18S rDNA markers from K. andamanica. A unique 585 bp fragment, that distinguished it from seven other related species of Myristicaceae was first amplified using the random primer OPE 06 and converted to SCAR marker (GenBank accession # JN228256). The conserved sequences of 18S rDNA loci from K. andamanica were also amplified and sequenced (GenBank accession #JN228265). The sequence revealed deviations including 18 variable regions and 15 indels that were unique to K. andamanica. These markers can help in definite identification of K. andamanica even at the juvenile stages. 相似文献
464.
465.
Entamoeba histolytica (E. histolytica) is an etiological agent of human amoebic colitis, and it causes a high level of morbidity and mortality worldwide, particularly in developing countries. Ca2+ plays a pivotal role in amoebic pathogenesis, and Ca2+-binding proteins (CaBPs) of E. histolytica appear to be a major determinant in this process. E. histolytica has 27-EF-hand containing CaBPs, suggesting that this organism has complex Ca2+ signaling cascade. E. histolytica CaBPs share (29–47%) sequence identity with ubiquitous Ca2+-binding protein calmodulin (CaM); however, they do not show any significant structural similarity, indicating lack of a typical CaM in this organism. Structurally, these CaBPs are very diverse among themselves, and perhaps such diversity allows them to recognize different cellular targets, thereby enabling them to perform a range of cellular functions. The presence of such varied signaling molecules helps parasites to invade host cells and advance in disease progression. In the past two decades, tremendous progress has been made in understanding the structure of E. histolytica CaBPs by using the X-ray or NMR method. To gain greater insight into the structural and functional diversity of these amoebic CaBPs, we analyzed and compiled all the available literature. Most of the CaBPs has about 150 amino acids with 4-EF hand or EF-hand-like sequences, similar to CaM. In a few cases, all the EF-hand motifs are not capable of binding Ca2+, suggesting them to be pseudo EF-hand motifs. The CaBPs perform diverse cellular signaling that includes cytoskeleton remodeling, phagocytosis, cell proliferation, migration of trophozoites, and GTPase activity. Overall, the structural and functional diversity of E. histolytica CaBPs compiled here may offer a basis to develop an efficient drug to counter its pathogenesis. 相似文献
466.
Gaikwad Shubham B. More Pavankumar R. Sonawane Sachin K. Arya Shalini S. 《International journal of peptide research and therapeutics》2021,27(4):2671-2684
International Journal of Peptide Research and Therapeutics - India ranks second in the harvesting and production of fish. The discard of fish is near about 20–40% of total fish weight.... 相似文献
467.
Alex Perálvarez-Marín Laura Mateos Shalini Singh Neus Visa Astrid Gräslund 《Biophysical journal》2009,97(1):277-285
Several biophysical techniques have been used to determine differences in the aggregation profile (i.e., the secondary structure, aggregation propensity, dynamics, and morphology of amyloid structures) and the effects on cell viability of three variants of the amyloid β peptide involved in Alzheimer's disease. We focused our study on the Glu22 residue, comparing the effects of freshly prepared samples and samples aged for at least 20 days. In the aged samples, a high propensity for aggregation and β-sheet secondary structure appears when residue 22 is capable of establishing polar (Glu22 in wild-type) or hydrophobic (Val22 in E22V) interactions. The Arctic variant (E22G) presents a mixture of mostly disordered and α-helix structures (with low β-sheet contribution). Analysis of transmission electron micrographs and atomic force microscopy images of the peptide variants after aging showed significant quantitative and qualitative differences in the morphology of the formed aggregates. The effect on human neuroblastoma cells of these Aβ12-28 variants does not correlate with the amount of β-sheet of the aggregates. In samples allowed to age, the native sequence was found to have an insignificant effect on cell viability, whereas the Arctic variant (E22G), the E22V variant, and the slightly-aggregating control (F19G-F20G) had more prominent effects. 相似文献
468.
Maria Angela Franceschini David A Boas Anna Zourabian Solomon G Diamond Shalini Nadgir David W Lin John B Moore Sergio Fantini 《Journal of applied physiology》2002,92(1):372-384
We present a noninvasive method to measure the venous oxygen saturation (Sv(O(2))) in tissues using near-infrared spectroscopy (NIRS). This method is based on the respiration-induced oscillations of the near-infrared absorption in tissues, and we call it spiroximetry (the prefix spiro means respiration). We have tested this method in three piglets (hind leg) and in eight human subjects (vastus medialis and vastus lateralis muscles). In the piglet study, we compared our NIRS measurements of the Sv(O(2)) (Sv(O(2))-NIRS(resp)) with the Sv(O(2)) of blood samples. Sv(O(2))-NIRS(resp) and Sv(O(2)) of blood samples agreed well over the whole range of Sv(O(2)) considered (20-95%). The two measurements showed an average difference of 1.0% and a standard deviation of the difference of 5.8%. In the human study, we found a good agreement between Sv(O(2))-NIRS(resp) and the Sv(O(2)) values measured with the NIRS venous occlusion method. Finally, in a preliminary test involving muscle exercise, Sv(O(2))-NIRS(resp) showed an expected postexercise decrease from the initial baseline value and a subsequent recovery to baseline. 相似文献