A Comparison of Online and In-Person Activity Engagement: The Case of Shopping and Eating Meals

You're viewing a past Journal from the Good Systems Grand Challenge team at The University of Texas at Austin from February 2020.Office of the VP for Researc

Structure and diversity trends at Fagus timberline in central Italy

Structure and diversity trends (β-diversity and species richness) across the Fagus sylvatica timberline in the central Apennines were investigated. Twenty-three belt transects were laid out across the upper forest line in the Simbruini Mountains. Number of species, plant cover, and height of different layers were recorded in each quadrat. The moving split-window method was used to detect ecological discontinuities across beech timberlines. We show how β-diversity changes along timberlines and we put forward some hypotheses about the possible dynamics of these transitions. Fourmodels resulted from the analysis of β-diversity trends: two β-diversity peaks indicated a transition where shrubs, mainly Juniperus communis ssp. alpina, (two high peaks) or beech scrub (two small peaks) formed a mantle that could allow forest expansion. One high β-diversity peak referred to an anthropo-zoogenic boundary maintained by disturbance, without the presence of a mantle. A little peak indicated a gradual transition at the upper potential timberline limit where beech forest had lost its typical floristical composition and structural characteristics

Phospholipase D inhibitors reduce human prostate cancer cell proliferation and colony formation

BACKGROUND: Phospholipases D1 and D2 (PLD1/2) hydrolyse cell membrane glycerophospholipids to generate phosphatidic acid, a signalling lipid, which regulates cell growth and cancer progression through effects on mTOR and PKB/Akt. PLD expression and/or activity is raised in breast, colorectal, gastric, kidney and thyroid carcinomas but its role in prostate cancer (PCa), the major cancer of men in the western world, is unclear. METHODS: PLD1 protein expression in cultured PNT2C2, PNT1A, P4E6, LNCaP, PC3, PC3M, VCaP, 22RV1 cell lines and patient-derived PCa cells was analysed by western blotting. PLD1 protein localisation in normal, benign prostatic hyperplasia (BPH), and castrate-resistant prostate cancer (CRPC) tissue sections and in a PCa tissue microarray (TMA) was examined by immunohistochemistry. PLD activity in PCa tissue was assayed using an Amplex Red method. The effect of PLD inhibitors on PCa cell viability was measured using MTS and colony forming assays. RESULTS: PLD1 protein expression was low in the luminal prostate cell lines (LNCaP, VCaP, 22RV1) compared with basal lines (PC3 and PC3M). PLD1 protein expression was elevated in BPH biopsy tissue relative to normal and PCa samples. In normal and BPH tissue, PLD1 was predominantly detected in basal cells as well in some stromal cells, rather than in luminal cells. In PCa tissue, luminal cells expressed PLD1. In a PCa TMA, the mean peroxidase intensity per DAB-stained Gleason 6 and 7 tissue section was significantly higher than in sections graded Gleason 9. In CRPC tissue, PLD1 was expressed prominently in the stromal compartment, in luminal cells in occasional glands and in an expanding population of cells that co-expressed chromogranin A and neurone-specific enolase. Levels of PLD activity in normal and PCa tissue samples were similar. A specific PLD1 inhibitor markedly reduced the survival of both prostate cell lines and patient-derived PCa cells compared with two dual PLD1/PLD2 inhibitors. Short-term exposure of PCa cells to the same specific PLD1 inhibitor significantly reduced colony formation. CONCLUSIONS: A new specific inhibitor of PLD1, which is well tolerated in mice, reduces PCa cell survival and thus has potential as a novel therapeutic agent to reduce prostate cancer progression. Increased PLD1 expression may contribute to the hyperplasia characteristic of BPH and in the progression of castrate-resistant PCa, where an expanding population of neuroendocrine-like cells express PLD1.British Journal of Cancer advance online publication, 14 November 2017; doi:10.1038/bjc.2017.391 www.bjcancer.com

Allostery: Abl kinase and TruBind? Back-scattering Interferometry

When abnormally expressed or controlled, kinase activity can cause cellular dysregulation and contribute to the onset of several diseases, including cancer. Based on the understanding of kinase malfunction, the discovery of small organic molecules to alter kinase function has culminated in the development of targeted cancer therapy. However, limited selectivity and the emergence of drug resistance remain fundamental challenges.<br>Most known kinase inhibitors are Type I inhibitors, ATP-competitive compounds such as dasatinib that bind to the ATP binding site. Type II inhibitors are compounds which bind partially in the ATP binding site and extend into an adjacent allosteric site that is present only in the inactive kinase conformation. Compared to Type I inhibitors, Type II inhibitors have been shown to possess advantageous pharmacological properties. As such, many Type II inhibitors currently on the market, such as imatinib, are very effective anti-cancer drugs.<br>Mutations resistant to Type I/II inhibitors are emerging at a rapid pace and often limit the success of targeted cancer therapies. At present, there are more than 50 mutation sites conferring different levels of imatinib resistance. Recently, a number of Type III inhibitors that function via allosteric modulation have demonstrated promise towards addressing mutation dependent drug resistance. As such, the need to identify and develop reversible inhibitors that are resistant to such mutations and bind with a high affinity is the focus of many research projects.<br>The binding affinity of Type I, II and III Bcr-Abl kinase inhibitors with wild type and four mutant Bcr-Abl kinases (H396P, M351T, Q252H, and T315I) were measured using TruBind? Back-Scattering Interferometry (BSI). BSI successfully demonstrated facile determination of equilibrium dissociation constants (Kd) for all systems, with a high degree of concordance with competition assay derived IC50 results. These results indicate that BSI binding studies both class I, II, and III kinase inhibitors can easily be performed, allowing for confirmation of target engagement as well as direct binding assessment of type II and III kinase inhibitors against inactive Bcr-Abl kinase. The latter makes BSI an attractive biophysical technique for the study of second and third generation kinase inhibitors to address the challenges of kinase inhibitor drug resistance

Binding Studies of Type I, II, and IV Kinase Inhibitors against Abl Kinase using Back-Scattering Interferometry MOA for allosteric inhibitors that overcome drug resistance

<p>When abnormally expressed or controlled, kinase activity can cause cellular dysregulation and contribute to the onset of several diseases, including cancer. Based on the understanding of kinase malfunction, the discovery of small organic molecules to alter kinase function has culminated in the development of targeted cancer therapy. However, limited selectivity and the emergence of drug resistance remain fundamental challenges. Most known kinase inhibitors are Type I inhibitors, ATP-competitive compounds such as dasatinib that bind to the ATP binding site. Type II inhibitors are compounds which bind partially in the ATP binding site and extend into an adjacent allosteric site that is present only in the inactive kinase conformation. Compared to Type I inhibitors, Type II inhibitors have been shown to possess advantageous pharmacological properties. As such, many Type II inhibitors currently on the market, such as imatinib, are very effective anti-cancer drugs. Mutations resistant to Type I/II inhibitors are emerging at a rapid pace and often limit the success of targeted cancer therapies. At present, there are more than 50 mutation sites conferring different levels of imatinib resistance. Recently, a number of Type IV inhibitors that function via allosteric modulation have demonstrated promise towards addressing mutation dependent drug resistance. As such, the need to identify and develop reversible inhibitors that are resistant to such mutations and bind with a high affinity is the focus of many research projects. The binding affinity of Type I, II and IV Bcr-Abl kinase inhibitors with wild type and four mutant Bcr-Abl kinases (H396P, M351T, Q252H, and T315I) were measured using TruBind? Back-Scattering Interferometry (BSI). BSI successfully demonstrated facile determination of equilibrium dissociation constants (Kd) for all systems, with a high degree of concordance with competition assay derived IC50 results. These results indicate that BSI binding studies both class I, II, and IIV kinase inhibitors can easily be performed, allowing for confirmation of target engagement as well as direct binding assessment of type II and IV kinase inhibitors against inactive Bcr-Abl kinase. The latter makes BSI an attractive biophysical technique for the study of second and third generation kinase inhibitors to address the challenges of kinase inhibitor drug resistance.</p

A Comparison of Online and In-Person Activity Engagement: The Case of Shopping and Eating Meals

You are viewing a publication by UT affiliates from the May 2020 Good System Network Digest.Office of the VP for Researc

Cell stress increases ATP release in NLRP3 inflammasome-mediated autoinflammatory diseases, resulting in cytokine imbalance

Item does not contain fulltextCell stress is implicated in triggering bouts of systemic inflammation in patients with autoinflammatory disorders. Blood monocytes from patients affected by NLRP3-mediated cryopyrin-associated periodic syndromes (CAPS) release greater amounts of IL-1beta than monocytes from unaffected subjects. Here we show that stress lowers the threshold of activation; blood monocytes from CAPS patients maintain the high levels of secreted IL-1beta (fivefold) and IL-18 (10-fold) when stimulated with 1,000-fold less LPS than that required for full IL-1beta secretion in control subjects. Unexpectedly, IL-1alpha secretion is increased 10-fold, indicating that inflammatory episodes in CAPS may not be entirely a result of IL-1beta but may also involve IL-1alpha. In CAPS monocytes, LPS induces the externalization of copious amounts of ATP (10-fold), which drive IL-1beta, IL-18, and IL-1alpha release via activation of the P2X purinoceptor 7. This enhanced ATP release appears to be the link between cell stress and increased cytokine secretion in CAPS. In the later phase after LPS stimulation, CAPS monocytes undergo oxidative stress, which impairs production of the anti-inflammatory IL-1 receptor antagonist (IL-1Ra). Remarkably, IL-1Ra secretion is fully restored by treatment with antioxidants. In two patients with the same NLRP3 mutation, but different disease severity, monocytes from the mildly affected patient exhibited more efficient redox response, lower ATP secretion, and more balanced cytokine production. Thus, the robustness of the individual antioxidant response increases the tolerance to stress and reduces the negative effect of the disease. Pharmacologic block of P2X purinoceptor 7 and improved stress tolerance may represent novel treatment strategies in stress-associated inflammatory diseases