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121.
122.
Margaret L. Wong Jason Murphy Edmund Harrington Carrie M. Gower Rishi K. Jain Markus Schirle Jason R. Thomas 《Proteome science》2017,15(1):17
Background
Identifying selective kinase inhibitors remains a major challenge. The design of bivalent inhibitors provides a rational strategy for accessing potent and selective inhibitors. While bivalent kinase inhibitors have been successfully designed, no comprehensive assessment of affinity and selectivity for a series of bivalent inhibitors has been performed. Here, we present an evaluation of the structure activity relationship for bivalent kinase inhibitors targeting ABL1.Methods
Various SNAPtag constructs bearing different specificity ligands were expressed in vitro. Bivalent inhibitor formation was accomplished by synthesizing individual ATP-competitive kinase inhibitors containing a SNAPtag targeting moiety, enabling the spontaneous self-assembly of the bivalent inhibitor. Assembled bivalent inhibitors were incubated with K562 lysates, and then subjected to affinity enrichment using various ATP-competitive inhibitors immobilized to sepharose beads. Resulting eluents were analyzed using Tandem Mass Tag (TMT) labeling and two-dimensional liquid chromatography-tandem mass spectrometry (2D–LC-MS/MS). Relative binding affinity of the bivalent inhibitor was determined by calculating the concentration at which 50% of a given kinase remained bound to the affinity matrix.Results
The profiling of three parental ATP-competitive inhibitors and nine SNAPtag conjugates led to the identification of 349 kinase proteins. In all cases, the bivalent inhibitors exhibited enhanced binding affinity and selectivity for ABL1 when compared to the parental compound conjugated to SNAPtag alone. While the rank order of binding affinity could be predicted by considering the binding affinities of the individual specificity ligands, the resulting affinity of the assembled bivalent inhibitor was not predictable. The results from this study suggest that as the potency of the ATP-competitive ligand increases, the contribution of the specificity ligand towards the overall binding affinity of the bivalent inhibitor decreases. However, the affinity of the specificity components in its interaction with the target is essential for achieving selectivity.Conclusion
Through comprehensive chemical proteomic profiling, this work provides the first insight into the influence of ATP-competitive and specificity ligands binding to their intended target on a proteome-wide scale. The resulting data suggest a subtle interplay between the ATP-competitive and specificity ligands that cannot be accounted for by considering the specificity or affinity of the individual components alone.123.
Kumar Kundan Raina Susheel Kumar Sultan Sheikh M. 《Journal of plant biochemistry and biotechnology.》2020,29(4):700-714
Journal of Plant Biochemistry and Biotechnology - Plants, being sessile in nature have developed refined mechanisms to rapidly sense changing environment and protect themselves from environmental... 相似文献
124.
Salmonella spp. have been shown to cause apoptosis of various host cell types as a part of their infection process. However, the induction of apoptosis remains to be looked into under the different host environments including acidic stress experienced by the pathogen. In order to simulate the in vivo acidic conditions, we studied the potential of S. typhi and its protein expressed under in vitro acidic conditions to induce apoptosis in macrophages. Murine macrophages were isolated and interacted with serovar Typhi and its acid stress protein for different time periods. The assessment of nucleosomal DNA, and nuclear staining with H-33342 dye and flow cytometry indicated the occurrence of characteristic features of apoptosis. Analysis of data revealed that S. typhi caused apoptotic cell death in 61% of macrophages whereas stress-induced protein alone accounted for apoptotic cell death in 45% of macrophages. The present study, for the first time demonstrates the potential of stress-induced outermembrane component of S. typhi to induce apoptosis. Identification of such factors may offer new insights for understanding the pathophysiology of the disease during the host-pathogen interactions. 相似文献
125.
Diarrheagenic E. coli strains contribute to water related diseases in urban and rural environment in developing and developed world. E. coli pathotype and pathogenicity varies due to complex multifactorial mechanism involving a large number of virulence factors. Rapid assessment of the virulence pattern of E. coli isolates is possible by Real-Time PCR probes like TaqMan. For designing TaqMan probes and primers for multiplex PCR selected E. coli gene sequences: stx1, stx2, hlyA, chuA, eae, lacZ, lamB and fimA were retrieved from NCBI's GenBank database. The alignment of the multiple sequences and analysis of conserved sequences was carried out using ClustalW and BLAST programs. The primers and Taqmen probes were designed using Beacon Designer software version 2.1 for two multiplexed PCR assays. In silico PCR simulation of these assays showed PCR products for stx2 (248bp) stx1 (102 bp), lacZ (228bp) and lamB (86 bp) in multiplex #1 and eae (200bp), chuA (147 bp), hlyA (141bp) and fimA (79 bp) in multiplex #2, respectively. These multiplexed PCR amplification products and probes can be used to identify and confirm presence of O157:H7/ H7-, O157:H43/45 and O26:H-/H11 serotypes. In conclusion, multiplex Real-Time Polymerase Chain Reaction oligomers and TaqMan probes designed and validated in silico will be helpful in management of water quality and outbreaks, by improving specificity and minimizing time needed for in vitro verification work. 相似文献
126.
Kalajzic I Staal A Yang WP Wu Y Johnson SE Feyen JH Krueger W Maye P Yu F Zhao Y Kuo L Gupta RR Achenie LE Wang HW Shin DG Rowe DW 《The Journal of biological chemistry》2005,280(26):24618-24626
The inherent heterogeneity of bone cells complicates the interpretation of microarray studies designed to identify genes highly associated with osteoblast differentiation. To overcome this problem, we have utilized Col1a1 promoter-green fluorescent protein transgenic mouse lines to isolate bone cells at distinct stages of osteoprogenitor maturation. Comparison of gene expression patterns from unsorted or isolated sorted bone cell populations at days 7 and 17 of calvarial cultures revealed an increased specificity regarding which genes are selectively expressed in a subset of bone cell types during differentiation. Furthermore, distinctly different patterns of gene expression associated with major signaling pathways (Igf1, Bmp, and Wnt) were observed at different levels of maturation. Some of our data differ from current models of osteoprogenitor cell differentiation and emphasize components of the pathways that were not revealed in studies based on a total cell population. Thus, applying methods to generate more homogeneous populations of cells at a defined level of cellular differentiation from a primary osteogenic culture is feasible and leads to a novel interpretation of the gene expression associated with increasing levels of osteoprogenitor maturation. 相似文献
127.
The PCR-based genome walking method has been commonly used to isolate upstream regions from known cDNA sequences. The limitation of this technique is based on the location of the restriction site upstream to the gene-specific primer in the genome; hence, different restriction enzymes have to be used to isolate larger upstream fragments. In this paper, we present the advantageous use of partial and size-selected DNA as templates for genome walking, in isolating larger upstream fragments. We have successfully tested this approach to isolate larger upstream fragments using the FailSafe PCR System. Use of partial digestion and size selection can provide better chances in obtaining larger flanking regions of known DNA sequence, when compared to use of total digested DNA. 相似文献
128.
Salmonella faces a variety of stresses including acid and heat, in the natural environment whether in the gastrointestinal tract of mammalian host or in the external environment during transmission where survival and multiplication is a priority for the pathogen. In the present study, Salmonella enterica serovar Typhi was grown under acid (inorganic and organic) as well as heat stress and the outermembrane protein (OMP) profiles were compared. A 55 kDa OMP was found to be expressed with high intensity under the selected stress conditions in comparison to normal conditions. The protein expressed under acidic stress reacted with antibodies raised against heat shock protein indicating the similarity of atleast some of the epitopes. In vivo immunogenicity (reactivity with typhoid patient sera) revealed that the 55kDa protein under each stress condition was reactive with 83% of the typhoid sera. In the light of role of the stress induced proteins in pathogenesis of microbial infections and their immunogenic potential, these findings may be relevant for a better understanding of the host-microbe interactions and for future development of diagnostic and preventive strategies. 相似文献
129.
Ameena Jehaludi E. Kevin Heist M. Russell Giveans Rishi Anand 《Indian pacing and electrophysiology journal》2018,18(3):100-107
Background
Although a rare complication of catheter based ablation for atrial fibrillation (AF), atrioesophageal fistula (AEF) is a serious and fatal event [[1], [2], [3], [4], [5]]. Most reports of AEF are single cases or small case series.Objective
The purpose of this study was to perform a comprehensive literature search of all published atrioesophageal fistula following catheter ablation for AF in order to identify the mortality rates associated with therapeutic modalities and suggest the most definitive management in reducing mortality.Methods
A comprehensive literature review of reported observational cases of atrioesophageal fistula post catheter based ablation for atrial fibrillation was performed.Results
Sixty-five cases of AEF post atrial fibrillation ablation were reviewed. The mean age was 55 years old. 73.8% (48/65) of the identified cases occurred in males (p?<?0.001). Of the 65 cases, 13 underwent surgical radiofrequency ablation (RFA) and 52 underwent percutaneous RFA. Mortality resulted in 53.8% of those who underwent surgical RFA and in 55.8% of those who underwent percutaneous RFA (p?=?.888). The time range interval from procedure to onset of symptoms was 1–60 days. The most prevalent symptom, fever, occurred in 52 of the 65 cases, followed by neurological symptoms (n?=?44). CT of the chest (n?=?37), transthoracic echocardiogram (n?=?21), and CT of the head (n?=?18) were the preferred diagnostic modalities. Patients who underwent surgical correction with esophageal repair for treatment were more likely to survive, in comparison to patients who were treated with non-surgical interventions, such as antibiotic therapy, anticoagulation therapy or esophageal stenting. Of the total 34 patients who were treated surgically, 27 survived (79.4%). Of the total 31 patients who were treated non-surgically, only 2 survived (6.5%), reflecting significantly lower mortality with surgical versus non-surgical therapy (p?<?0.001).Conclusion
Atrioesophageal fistula is an uncommon but potentially fatal complication of atrial fibrillation ablation. Patients who underwent surgical repair were twelve times more likely to survive than those treated with stenting, antibiotic therapy or no intervention. Based on the observation that patients are 12 times more likely to survive an AEF with surgery than without, the authors believe that prompt surgical correction of AEF should be considered as standard of care when dealing with this dreaded complication. 相似文献130.