LysR-type transcriptional regulators (LTTRs) are emerging as key circuit components in regulating microbial stress responses and are implicated in modulating oxidative stress in the human opportunistic pathogen Pseudomonas aeruginosa. The oxidative stress response encapsulates several strategies to overcome the deleterious effects of reactive oxygen species. However, many of the regulatory components and associated molecular mechanisms underpinning this key adaptive response remain to be characterised. Comparative analysis of publically available transcriptomic datasets led to the identification of a novel LTTR, PA2206, whose expression was altered in response to a range of host signals in addition to oxidative stress. PA2206 was found to be required for tolerance to H2O2 in vitro and lethality in vivo in the Zebrafish embryo model of infection. Transcriptomic analysis in the presence of H2O2 showed that PA2206 altered the expression of 58 genes, including a large repertoire of oxidative stress and iron responsive genes, independent of the master regulator of oxidative stress, OxyR. Contrary to the classic mechanism of LysR regulation, PA2206 did not autoregulate its own expression and did not influence expression of adjacent or divergently transcribed genes. The PA2214-15 operon was identified as a direct target of PA2206 with truncated promoter fragments revealing binding to the 5-ATTGCCTGGGGTTAT-3 LysR box adjacent to the predicted -35 region. PA2206 also interacted with the pvdS promoter suggesting a global dimension to the PA2206 regulon, and suggests PA2206 is an important regulatory component of P. aeruginosa adaptation during oxidative stress.
A non-classical LysR-type transcriptional regulator PA2206 is required for an effective oxidative stress response in Pseudomonas aeruginosa.
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View SamplesATFS-1 has been shown to regulate transcription of mitochondrial chaperone genes such as mtHsp70/hsp-6 and hsp-60 in response to mitocondrial stress. To identify the entire ATFS-1-mediated response, we compared the transcript profiles from wild-type and atfs-1(tm4525) worms raised in the absence and presence of mitochondrial stress.
Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation.
Specimen part
View SamplesWe previously identified a number of genes which were differentially expressed during mitochondrial stress in an ATFS-1-dependent manner using an atfs-1 loss-of-function mutant allele . To complement the findings from our previous microarray, we compared the transcript profiles from wild-type and atfs-1(et18) gain-of-function worms (which have constitutively active ATFS-1) in the absence of mitochondrial stress.
Maintenance and propagation of a deleterious mitochondrial genome by the mitochondrial unfolded protein response.
Specimen part
View SamplesZIP-3 has been shown to repress the mitochondrial-UPR response. To identify genes repressed by ZIP-3, we compared transcript profiles from wildtype, atfs-1(tm4919) and zip-3(gk3164) worms raised on control RNAi or spg-7 RNAi Overall design: RNA samples were prepared from wild-type(wt) and zip-3(gk3164)(mutant) worms fed either control RNAi or spg-7 RNAi. Worms were synchronized by bleaching, raised on NGM plates seeded with control RNAi or spg-7 RNAi till L4 stage and then harvested. Each experiment was performed in triplicate indicated as 1,2 and 3.
Mitochondrial UPR repression during <i>Pseudomonas aeruginosa</i> infection requires the bZIP protein ZIP-3.
Specimen part, Subject
View SamplesZIP-3 has been shown to repress the mitochondrial-UPR genes and immune response during P. aeruginosa infection. To identify genes repressed by ZIP-3, we compared transcript profiles from wildtype and zip-3(gk3164) worms raised on P. aeruginosa or E. coli. Overall design: RNA samples were prepared from wild-type(wt) and zip-3(gk3164)(mutant) worms fed either E. coli or P. aeruginosa. Worms were synchronized by bleaching, starved on empty NGM plates for 48h, transferred to E. coli or P. aeruginosa seeded NGM plates for 18h and then harvested. Each experiment was performed in triplicate indicated as 1,2 and 3.
Mitochondrial UPR repression during <i>Pseudomonas aeruginosa</i> infection requires the bZIP protein ZIP-3.
Specimen part, Subject
View SamplesTo determine the effect on gene expression of intratumoral injection of the Toll-like receptor agonist CpG1826. MC38 colon cancer cells were injected subcutaneously into C57BL/6 mice and allowed to establish until ~40 mm2.
Toll-Like Receptor Triggering and T-Cell Costimulation Induce Potent Antitumor Immunity in Mice.
Specimen part
View SamplesReceptor tyrosine kinases MET and EGFR are critically involved in initiation of liver regeneration. Other cytokines and signaling molecules also help in the early part of the process. Regeneration employs effective redundancy schemes to compensate for missing signals. Elimination of any single signaling pathway only delays but does not abolish the process. Our present study, however, shows that combined systemic elimination of MET and EGFR signaling abolishes liver regeneration, prevents restoration of liver mass and leads to liver decompensation. Our results demonstrate that liver function is dependent on synchronous availability of signaling from these two pathways. The study shows that MET and EGFR separately control many non-overlapping signaling endpoints, allowing for compensation when only one of the signals is blocked. The combined elimination of the signals however was not tolerated. The results provide critical new information on interactive MET and EGFR signaling and the contribution of their combined absence to regeneration arrest and liver decompensation.
Combined systemic elimination of MET and epidermal growth factor receptor signaling completely abolishes liver regeneration and leads to liver decompensation.
Specimen part, Time
View SamplesBackground: Antimalarials have anticancer potential. Results: We have systematically tested five distinct antimalaria drugs in a panel of cancer cell lines. Conclusion: Three antimalarial classes display potent antiproliferative activity, and their potency is correlated with cancer cell gene expression patterns. Significance: We confirm and extend anticancer potential of these antimalarials and we discuss their therapeutic potential based on clinical data.
Anticancer properties of distinct antimalarial drug classes.
Sex, Age, Cell line
View SamplesCharacterisation of the tumor extrinsic (immune-mediated) mechanisms by which panobinostat and trastuzumab can collaboratively promote tumor-associated NK cell infiltration to eradicate trastuzumab-refractory HER2+ tumors Overall design: RNA sequencing was performed on established whole AU565(pv) HER2+ human breast tumors, harvested from SCID mice 2-days post treatment initiation with vehicle (PBS/D5W), panobinostat (15mg/kg/day), trastuzumab (10mg/kg day 1) or both drugs in combination. Each treatment group comprised of 4 mice.
HDAC Inhibitor Panobinostat Engages Host Innate Immune Defenses to Promote the Tumoricidal Effects of Trastuzumab in HER2<sup>+</sup> Tumors.
Specimen part, Cell line, Subject
View SamplesIL-6, a proinflammtory cytokine produced by antigen presenting cells and non-hematopoietic cells in response to external stimuli, acts as an important bridge between the innate and adaptive immune responses. IL-6 together with IL-4 can promote Th2 polarization, while in combination with TGFbeta mediates Th17 differentiation. We examined early changes in gene expression in mouse CD4+ T cells induced by IL-6.
The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells.
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