Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1144996 | ENA |
REPOSITORIES: ENA
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Project description:Transcription factors play a key role in the development of a number of cancers, and therapeutically targeting them has remained a challenge. In prostate cancer, the ETS transcription factor ERG is recurrently rearranged and likely plays a critical role in prostate oncogenesis. Here we identified a series of peptides from a phage-display library that interact specifically with the DNA binding domain of ERG. The interactive interface was mapped to 9-residues in the 3rd helix of the ETS domain that is critical for ERG transcriptional activity. The peptides were found to efficiently disrupt ERG-mediated protein-protein interactions, transcription, DNA damage, and cell invasion, as well as attenuate ERG recruitment to target gene loci. Furthermore, a retroinverso peptidomimetic version of the peptide sequence suppressed tumor growth, intravasation, and metastasis in vivo. Taken together, our results demonstrate that transcription factors have specific residues important for protein-protein interactions and disrupting those critical interactions may be an effective therapeutic strategy. Examination of ERG in VCaP cells with respect to peptidomimetics treatment
2014-07-15 | E-GEOD-58939 | biostudies-arrayexpress
Project description:Virulent bacteriophages (or phages) are viruses that specifically infect and lyse a bacterial host. When multiple phages co-infect a bacterial host, the extent of lysis, dynamics of bacteria-phage and phage-phage interactions are expected to vary. The objective of this study is to identify the factors influencing the interaction of two virulent phages with different Pseudomonas aeruginosa growth states (planktonic, an infected epithelial cell line, and biofilm) by measuring the bacterial time-kill and individual phage replication kinetics. A single administration of phages effectively reduced P. aeruginosa viability in planktonic conditions and infected human lung cell cultures, but phage-resistant variants subsequently emerged. In static biofilms, the phage combination displayed initial inhibition of biofilm dispersal, but sustained control was achieved only by combining phages and meropenem antibiotic. In contrast, adherent biofilms showed tolerance to phage and/or meropenem, suggesting a spatiotemporal variation in the phage-bacterial interaction. The kinetics of adsorption of each phage to P. aeruginosa during single- or co-administration were comparable. However, the phage with the shorter lysis time depleted bacterial resources early and selected a specific nucleotide polymorphism that conferred a competitive disadvantage and cross-resistance to the second phage. The extent and strength of this phage-phage competition and genetic loci conferring phage resistance, are, however, P. aeruginosa genotype dependent. Nevertheless, adding phages sequentially resulted in their unimpeded replication with no significant increase in bacterial host lysis. These results highlight the interrelatedness of phage-phage competition, phage resistance and specific bacterial growth state (planktonic/biofilm) in shaping the interplay among P. aeruginosa and virulent phages.
2024-07-17 | GSE271537 | GEO
Project description:Antibiotic use can lead to expansion of multi-drug resistant pathobionts within the gut microbiome that can cause life-threatening infections. Selective alternatives to conventional antibiotics are in dire need. Here, we describe a Klebsiella PhageBank that enables the rapid design of antimicrobial bacteriophage cocktails to treat multi-drug resistant Klebsiella pneumoniae. Using a transposon library in carbapenem-resistant K. pneumoniae, we identified host factors required for phage infection in major Klebsiella phage families. Leveraging the diversity of the PhageBank and experimental evolution strategies, we formulated combinations of phages that minimize the occurrence of phage resistance in vitro. Optimized bacteriophage cocktails selectively suppressed the burden of multi-drug resistant K. pneumoniae in the mouse gut microbiome and drove bacterial populations to lose key virulence factors that act as phage receptors. Further, phage-mediated diversification of bacterial populations in the gut enabled co-evolution of phage variants with higher virulence and a broader host range. Altogether, the Klebsiella PhageBank represents a roadmap for both phage researchers and clinicians to enable phage therapy against a critical multidrug-resistant human pathogen.
2024-10-01 | GSE272297 | GEO
Project description:The emergence of carbapenem-resistant Acinetobacter baumannii has been increasingly reported, leading to more challenges in treating its infections. With the development of phage therapy and phage-antibiotic combinations, it is possible to improve the treatment of bacterial infections. In the present study, a vB_AbaP_WU2001 (vWU2001 for short) phage-specific CRAB was isolated and the genome size is 40,792 bp in length. The novel phage vWU2001 belongs to the Autographiviridae family and the order Caudovirales. Shotgun proteomics identified 289 proteins. The broad host range phage vWU2001 displayed a high adsorption rate, short latent period, large burst size and good stability. The phage could reduce preformed biofilms and inhibit biofilm formation. The combination of phage vWU2001 and colistin had significantly higher bacterial growth inhibition activity than that of phage, or colistin alone. The efficacy of the combined treatment was also evaluated in Galleria mellonella. The evaluation of its therapeutic potential revealed that the combination of phage and colistin showed a significantly greater increase in G. mellonella survival and clearance of bacterial number compared to that of phage or colistin alone, indicating that the combination was synergistic against CRAB. The results demonstrated that phage vWU2001 has the potential to be developed as an antibacterial agent.
2021-09-04 | PXD028206 | JPOST Repository
Project description:Shotgun (bottom-up) approach has been widely applied in large-scale proteomics studies. The inherent shortages of shotgun approach lie in that the generated peptides often overwhelm the analytical capacity of current LC-MS/MS systems and that abundant proteins often hamper the identification of proteins in low abundance for highly complex samples. To reduce the sample complexity and relieve the problems caused by abundant proteins, herein we introduce a modified selective proteomics approach, termed ENCHANT, for enzyme and chemical assisted N-terminal blocked peptides analysis. Modified from our previous Nα-acetylome approach, ENCHANT aims to analyze three kinds of peptides, acetylated protein N-termini, N-terminal glutamine and N-terminal cysteine containing peptides. Application of ENCHANT to HeLa cells allowed to identify 3,375 proteins, 19.6% more than that by conventional shotgun approach. More importantly, ENCHANT demonstrated an excellent complementarity to conventional shotgun approach with the overlap of 34.5%. In terms of quantification using data independent acquisition (DIA) technology, ENCHANT resulted in 23.9% more quantified proteins than conventional shotgun approach with the overlap of 27.6%. Therefore, our results strongly suggest that ENCHANT is a promising selective proteomics approach complementary to conventional shotgun approach in both qualitative and quantitative proteomics studies.
2017-11-30 | PXD007863 | Pride
Project description:Robust analysis of both protein N- and C-termini can reveal novel N- and C-degrons that modify protein stability and shape the eukaryotic proteome. Herein, we designed a workflow, termed LysargiNase-assisted Analysis of Protein N- and C-Terminome (NAPT) by sequential and selective separating N- and C-termini on strong cation exchange chromatography (SCX). Taking advantage of N-terminal peptides’ reduced charge states at pH 2.7 and C-terminal peptides’ enhanced charge states at pH 8.5, an adequate shift of pH during SCX fractionation could easily lead to sequential elution of N-terminal, internal, and C-terminal peptides. Combining NAPT with multiple enzymatic digestion strategies, we identified 2458 human protein N-termini and 3056 human protein C-termini from Hela cell line. As N-terminal peptides generally bear two less positive charges than internal peptides at pH 2.7 after LysargiNase digestion, leaving one-positive-charge tolerance for histidine-containing N-terminal peptides, and C-terminal peptides were separated at pH 8.5 where histidine was neutrally charged, NAPT workflow showed minimal bias against histidine residues and excellent complementarity compared to its sister, the SAPT workflow, which adopted trypsin as protease. Taken together, 4285 protein N-termini and 4170 protein C-termini were identified by NAPT and SAPT, representing the largest human protein C-termini and the second largest human protein N-termini dataset so far, demonstrating their valuable potential in terminomic studies. Furthermore, we systematically analyzed sequences of identified protein termini and validated that their behavior obeyed several degron pathways.
2022-04-11 | PXD030791 |
Project description:We analyzed RNA-Seq data of two Staphylococcus aureus strains, Newman and SH1000, infected by Kayvirus phage K. Staphylococcus virus K is used in the phage therapy, its genome is 148 kb long consisting of dsDNA with long terminal repeats, and encodes 233 ORFs and 4 tRNAs. The sampling times 0, 2, 5, 10, 20, and 30 minutes after infection were chosen based on the growth characteristics of the phage K at the two S. aureus strains. From the RNA-Seq data we determined transcriptional profile of the phage K and its hosts, which allowed us to identify differentially expressed genes, ncRNAs, and promotor and terminator sites. Transcription of the phage K genes starts immediately after the infection of bacterial cells and we found a gradual take-over by phage K transcripts in the infected cells. The temporal transcriptional profile of phage K was similar in both strains and the relative expression of phage K genes shows three distinct transcript types – early, middle, and late based on the time they reach maximum expression. The bacterial response to phage K infection is similar to the general stress response. It includes the upregulation of nucleotide, amino acid and energy synthesis and transporter genes and the downregulation of transcription factors. The expression of particular virulence genes involved in adhesion and immune system evasion as well as prophage integrases were marginally affected. This work unveils the versatile nature of phage K infection leading to its broad host range
2022-03-23 | GSE190637 | GEO