Biology subjects

Adams, J. A.

Publications and source records attributed to Adams, J. A..

3 recordsLinked to original sources

bioRxiv2024

The protease ADAMTS5 controls ovarian cancer cell invasion, downstream of Rab25.

Ovarian cancer is the 3rd most common gynaecological malignancy worldwide, with a 5-year survival rate of less than 30% in the presence of metastasis. Metastatic progression is characterised by extensive remodelling of the extracellular matrix, primarily mediated by secreted matrix metalloproteinases, including members of the a disintegrin and metalloprotease with thrombospondin motif (ADAMTS) family. In particular, ADAMTS5 has been reported to be upregulated in ovarian malignant tumours compared to borderline and benign lesions, suggesting it might play a role in metastatic progression. Furthermore, it has been suggested that Rab25, a small GTPase of the Ras family, might upregulate ADAMTS5 expression in ovarian cancer cells. Here we demonstrated that Rab25 promotes ADAMTS5 expression, through the activation of the NF-{kappa}B signalling pathway. Furthermore, ADAMTS5 was necessary and sufficient to stimulate ovarian cancer cell migration through complex fibroblast-secreted matrices, while ADAMTS5 inhibition prevented ovarian cancer spheroid invasion in 3D systems. Finally, in ovarian cancer patients high ADAMTS5 expression correlated with poor prognosis. Altogether, these data identify ADAMTS5 as a novel regulator of ovarian cancer cell migration and invasion, suggesting it might represent a novel therapeutic target to prevent ovarian metastasis.

cancer biology↗

bioRxiv2018

Whole Body Periodic Acceleration Improves Survival and Microvascular Leak in a Murine Endotoxin Model

Sepsis is a life threatening condition which produces multi-organ dysfunction with profound circulatory and cellular derangements. Administration of E.Coli endotoxin (LPS) produces systemic inflammatory effects of sepsis including disruption of endothelial barrier, and if severe enough death. Whole body periodic acceleration (pGz) is the headward-footward motion of the body. pGz has been shown to induce pulsatile shear stress to the endothelium, thereby releasing vascular and cardio protective mediators. The purpose of this study was to determine whether or not pGz performed as a pre-treatment or post-treatment strategy improves survival in a lethal murine endotoxin model.\n\nThis study was designed as a prospective randomized controlled study in mice. pGz was performed in mice as pre-treatment (pGz-LPS, 3 days prior to LPS), post-treatment (LPS-pGz, 30 min after LPS) strategies or Control (LPS-CONT), in a lethal murine model of endotoxemia. Endotoxemia was induced with intraperitoneal injection of E.Coli (40mg/kg). In a separate group of mice, a nonspecific nitric oxide synthase inhibitor (L-NAME) was provided in their drinking water and pGz-LPS and LPS-pGz performed to determine the effect of nitric oxide (NO) inhibition on survival. In another subset of mice, micro vascular leakage was determined. Behavioral scoring around the clock was performed in all mice at 30 min intervals after LPS administration, until 48 hrs. survival or death. LPS induced 100% mortality in LPS-CONT animals by 30 hrs. In contrast, survival to 48 hrs. occurred in 60% of pGz-LPS and 80% of LPS-pGz. L-NAME abolished the survival effects of pGz. Microvascular leakage was markedly reduced in both pre and post pGz treated animals and was associated with increased TIE2 and p-TIE2. In a murine model of lethal endotoxemia, pGz performed as a pre or post treatment strategy significantly improved survival, and markedly reduced microvascular leakage. The effect was modulated, in part, by NO since a non-selective inhibitor of NO abolished the pGz survival effect.

physiology↗

bioRxiv2017

Guiding the design of bacterial signaling interactions using a coevolutionary landscape

The selection of amino acid identities that encode new interactions between two-component signaling (TCS) proteins remains a significant challenge. Recent work constructed a co-evolutionary landscape that can be used to select mutations to maintain signal transfer interactions between partner TCS proteins without introducing signal transfer between non-partners (crosstalk). A bigger challenge is to introduce mutations between non-natural partner TCS proteins using the landscape to enhance, suppress, or have a neutral effect on their basal signal transfer rates. This study focuses on the selection of mutations to a response regulator (RR) from Bacilus subtilis and its effect on phosphotransfer with a histidine kinase (HK) from Escherichia Coli. Twelve single-point mutations of the RR protein are selected from the landscape and experimentally expressed to directly test the theoretical predictions on the effect of signal transfer. Differential Scanning Calorimetry is used to monitor any protein stability effects caused by the mutations, which could be detrimental to proper protein function. Of these proteins, seven mutants successfully perturb phosphoryl transfer activity in the computationally predicted manner between the TCS proteins. Furthermore, brute-force exhaustive mutagenesis approaches indicate that only 1% of mutations result in enhanced activity. In comparison, of the six mutations predicted to enhance phosphotransfer, two mutations exhibit a significant enhancement while two mutations are comparable to the wild-type. Thus co-evolutionary landscape theory offers significant improvement over traditional large-scale mutational studies in the efficiency of selecting mutations for protein engineering and design.

bioinformatics↗