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A rank 18 Waring decomposition of sM_〈 3〉 with 432 symmetries [article]

Austin Conner
2017 arXiv   pre-print
I present an explicit rank 18 Waring decomposition of sM_〈 3〉 and describe its symmetry group.  ...  I present a Waring decomposition of sM 3 and describe its particularly large symmetry group, which I hope will lead to generalizations to larger n.  ...  Z 2 3 ⋊ SL(2, F 3 ) ≤ G ≤ H ≤ Z 2 3 ⋊ SL(2, The Waring decomposition presented here was derived from a numerical decomposition given in [10] .  ... 
arXiv:1711.05796v1 fatcat:bxm7cetpz5hwfogv4ghdztpmcy

Trusts and Trustees

Austin Wakeman Scott, Jairus Ware Perry
1930 Harvard Law Review  
By Jairus Ware Perry. Two volumes. Seventh edition by Raymond C. Baldes. Boston: Little, Brown & Co. 1929. pp. clxxi, 1729. $20.00. The remarkable thing about Mr.  ... 
doi:10.2307/1330761 fatcat:gmug2akqjfc4xh4bjsiu6t2hqa

Continuous Habitable Zones: Using Bayesian Methods to Prioritize Characterization of Potentially Habitable Worlds [article]

Austin Ware, Patrick Young, Amanda Truitt, Alexander Spacek
2022 arXiv   pre-print
The likelihood that a star has metallicity Z k and mass M k if a given radius is not in the CHZ 2 is given by Ware et al.  ...  For candidates with mass measurements, we adopt the upper mass limit Ware et al. derived from the planetary mass-radius relation for rocky cores from Zeng et al. (2016) , M = R 1.37 .  ... 
arXiv:2203.06259v1 fatcat:2624rcfbyjcqnghixpogtxupxm

An evaluation of the indoor air quality in bars before and after a smoking ban in Austin, Texas

Michael S Waring, Jeffrey A Siegel
2006 Journal of Exposure Science and Environmental Epidemiology  
These results suggest that the smoking ban has effectively improved indoor air quality in Austin bars without an associated decrease in occupancy.  ...  This study assessed differences in the indoor air quality and occupancy levels in seventeen bars due to a city-wide smoking ban that took effect on September 1, 2005 in Austin, Texas, USA.  ...  of an enclosed area in which smoking is prohibited (Austin HHSD, 2006) .  ... 
doi:10.1038/sj.jes.7500513 pmid:16804559 fatcat:c2vfdcufajfyxcmqfdrbif3mgu

Elevation of Plasma Cell-Free Hemoglobin in Pulmonary Arterial Hypertension

Evan L. Brittain, David R. Janz, Eric D. Austin, Julie A. Bastarache, Lisa A. Wheeler, Lorraine B. Ware, Anna R. Hemnes
2014 Chest  
Drs Brittain, Janz, Austin, Bastarache, and Ware and Ms Wheeler have reported that no potential confl icts of interest exist with any companies/organizations whose products or services may be discussed  ...  Statistical analyses were performed using SPSS 20 soft ware (IBM ). Results We measured CFH in 200 patients with PAH, 29 patients with PVH, 19 healthy subjects, and 16 UMCs.  ... 
doi:10.1378/chest.14-0809 pmid:24945582 pmcid:PMC4251612 fatcat:aaxjaqemivgxlje3zyxtelbkca

Loss of anti-contractile effect of perivascular adipose tissue in offspring of obese rats

K E Zaborska, M Wareing, G Edwards, C Austin
2016 International Journal of Obesity  
RATIONALE: Maternal obesity pre-programmes offspring to develop obesity and associated cardiovascular disease. Perivascular adipose tissue (PVAT) exerts an anti-contractile effect on the vasculature, which is reduced in hypertension and obesity. OBJECTIVE: The objective of this study was to determine whether maternal obesity pre-programmes offspring to develop PVAT dysfunction in later life. METHODS: Female Sprague-Dawley rats were fed a diet containing 10% (control) or 45% fat (high fat diet,
more » ... FD) for 12 weeks prior to mating and during pregnancy and lactation. Male offspring were killed at 12 or 24 weeks of age and tension in PVAT-intact or -denuded mesenteric artery segments was measured isometrically. Concentration-response curves were constructed to U46619 and norepinephrine. RESULTS: Only 24-week-old HFD offspring were hypertensive (P o 0.0001), although the anti-contractile effect of PVAT was lost in vessels from HFD offspring of each age. Inhibition of nitric oxide (NO) synthase with 100 μM L-NMMA attenuated the anti-contractile effect of PVAT and increased contractility of PVAT-denuded arteries (P o 0.05, Po 0.0001). The increase in contraction was smaller in PVAT-intact than PVAT-denuded vessels from 12-week-old HFD offspring, suggesting decreased PVAT-derived NO and release of a contractile factor (Po 0.07). An additional, NO-independent effect of PVAT was evident only in norepinephrine-contracted vessels. Activation of AMP-activated kinase (with 10 μM A769662) was anti-contractile in PVAT-denuded (P o0.0001) and -intact (P o 0.01) vessels and was due solely to NO in controls; the AMPK effect was similar in HFD offspring vessels (P o0.001 and P o 0.01, respectively) but was partially NO-independent. CONCLUSIONS: The diminished anti-contractile effects of PVAT in offspring of HFD dams are primarily due to release of a PVAT-derived contractile factor and reduced NO bioavailability.
doi:10.1038/ijo.2016.62 pmid:27102050 pmcid:PMC4973217 fatcat:k7egoikit5grlia5qfbo2ks24a

Loss of anti-contractile effect of perivascular adipose tissue in offspring of obese rats

K E Zaborska, M Wareing, G Edwards, C Austin
2017 International Journal of Obesity  
RATIONALE: Maternal obesity pre-programmes offspring to develop obesity and associated cardiovascular disease. Perivascular adipose tissue (PVAT) exerts an anti-contractile effect on the vasculature, which is reduced in hypertension and obesity. OBJECTIVE: The objective of this study was to determine whether maternal obesity pre-programmes offspring to develop PVAT dysfunction in later life. METHODS: Female Sprague-Dawley rats were fed a diet containing 10% (control) or 45% fat (high fat diet,
more » ... FD) for 12 weeks prior to mating and during pregnancy and lactation. Male offspring were killed at 12 or 24 weeks of age and tension in PVAT-intact or -denuded mesenteric artery segments was measured isometrically. Concentration-response curves were constructed to U46619 and norepinephrine. RESULTS: Only 24-week-old HFD offspring were hypertensive (P o 0.0001), although the anti-contractile effect of PVAT was lost in vessels from HFD offspring of each age. Inhibition of nitric oxide (NO) synthase with 100 μM L-NMMA attenuated the anti-contractile effect of PVAT and increased contractility of PVAT-denuded arteries (P o 0.05, Po 0.0001). The increase in contraction was smaller in PVAT-intact than PVAT-denuded vessels from 12-week-old HFD offspring, suggesting decreased PVAT-derived NO and release of a contractile factor (Po 0.07). An additional, NO-independent effect of PVAT was evident only in norepinephrine-contracted vessels. Activation of AMP-activated kinase (with 10 μM A769662) was anti-contractile in PVAT-denuded (P o0.0001) and -intact (P o 0.01) vessels and was due solely to NO in controls; the AMPK effect was similar in HFD offspring vessels (P o0.001 and P o 0.01, respectively) but was partially NO-independent. CONCLUSIONS: The diminished anti-contractile effects of PVAT in offspring of HFD dams are primarily due to release of a PVAT-derived contractile factor and reduced NO bioavailability.
doi:10.1038/ijo.2017.17 pmid:28358003 fatcat:wpennjpe4rcfjjw5n6lwqfhk2q

202 AMPK Activation Partially Restores the Anti-Contractile Effect of Perivascular Adipose Tissue in Female Offspring of Obese Rats

Karolina Zaborska, Gillian Edwards, Clare Austin, Mark Wareing
2016 Heart  
Focal adhesions (FA) are dynamic transmembrane protein complexes serving as mediators of signalling between the extracellular matrix (ECM) and the actin cytoskeleton (CK). Remodelling of FAs and the CK play key roles in some of the pathological functions of vascular smooth muscle cells (VSMC) such as proliferation, migration and contraction. Focal adhesion proteins (FAPs), constituents of FAs, indirectly dictate some VSMC functions. The FAPs, paxillin, Hic-5 and vinculinâC ¼ ™s presence within
more » ... As is well established in VSMCs, however, their behaviour in response to biomechanical and vasoconstrictor stimuli are not. Endogenous vasoconstrictors such as Endothelin-1 (ET-1) and Noradrenaline (NA), alongside changes in ECM have individually promoted changes in the VSMC CK and FA arrangement. To contextualise these cytoskeletal changes and their consequences on vascular function, more information is needed about FAP localisation and CK arrangement in response to vasoactive stimulation alongside ECM changes. Aims To investigate actin CK remodelling and the localisation of Hic-5, vinculin and paxillin in response to changes in substrate composition and contractile stimulation. Methods Rat VSMCS (RVSMCs) were cultured on glass or type I collagen-coated glass and were stimulated with 15μM NA, 100 nM ET-1 or remained unstimulated. Cells were stained for actin filaments and either Hic-5, vinculin or paxillin. Changes in CK arrangement were visually assessed. The punctate regions of FAPs were quantified using image analysis software. Results When cultured on glass, Hic-5 and paxillin occupied punctate regions within RVSMC; vinculin was diffusely spread throughout the cell. The punctate regions were principally localised to the ends of actin stress fibres. Compared to unstimulated RVSMCs (punctate region mean area, 1.043μm²), NA caused a reduction in paxillin punctate region area of RVSMCs cultured on both glass (0.5548μm²; P < 0.0001) and collagen (0.7060μm²; P < 0.001). NA also induced cytosolic dissemination of Hic-5 without affecting punctate region area. Vinculin localisation did not change in response to NA ET-1 or collagen. ET-1 did not induce changes in paxillin or Hic-5 localisation or CK arrangement. RVSMCs cultured on glass showed a peripheral arrangement of the CK within the cell compared to those cultured on collagen, irrespective of stimulation. Conclusion The study demonstrates that NA selectively regulates FAP localisation for paxillin and Hic-5, but not vinculin. As ET-1 does not regulate FAP localisation; these results indicate that individual FA remodelling is agonist specific within VSMCs. Furthermore, ECM composition is vital in CK reorganisation in a manner independent of NA-induced FA remodelling. Accordingly, actin CK and FA reorganisation in response to altered ECM composition or vasoconstrictors may contribute to vascular remodelling in cardiovascular disease. Introduction Maternal obesity programmes offspring to develop obesity and associated cardiovascular disease. Perivascular adipose tissue (PVAT) exerts an anti-contractile effect in healthy blood vessels; an effect lost in male offspring of obese dams. However, the mechanism by which maternal obesity programmes PVAT dysfunction in offspring remains unknown. Methods Six week old female Sprague-Dawley rats were fed a control (10% fat) or 45% fat obesogenic diet (HFD) for 12 weeks before mating; during pregnancy and lactation. At weaning, female offspring were provided with the control diet until sacrifice at either 12 (12 wo) or 24 (24 wo) weeks of age. PVAT-denuded mesenteric arteries from pups, with or without exogenous PVAT, were mounted on a wire myograph and concentration-response curves were constructed to thromboxane A 2 receptor agonist U46619 (10 nM-3 mM) ± 10 mM A769662, an activator of AMP-activated protein kinase (AMPK) ± glucosamine (an O-GlcNAcylator). Western blotting was used to asses protein expression in PVAT stimulated with or without glucosamine. Results Body weight, insulin levels and blood pressure were increased in HFD dams and their 12wo and 24 wo offspring compared to age-matched controls. Without PVAT, vessel contractions to U46619 were reduced in 12 wo offspring of HFD dams, effects mimicked in control arteries by pre-incubation with 10 mM glucosamine. PVAT from control, but not from HFD offspring, exerted an anti-contractile effect on the corresponding PVAT-denuded arteries at both ages. Pre-incubation of control PVAT with glucosamine diminished the anticontractile effect at both ages. PVAT from HFD offspring preincubated with glucosamine had no effect on PVAT-denuded vessels but simultaneous AMPK activation within PVAT partially restored anti-contractile capability at both ages. Protein O-GlcNAcylation expression was increased in HFD PVAT and control PVAT incubated with glucosamine, whereas AMPK expression was decreased. Conclusions The enhanced protein O-GlcNAcylation and decreased AMPK expression in HFD PVAT may underlie the reduced anti-contractile effect of PVAT in female offspring of obese dams. Nevertheless, simultaneous AMPK activation within HFD PVAT partially restored the anti-contractile effects of PVAT.
doi:10.1136/heartjnl-2016-309890.202 fatcat:dds7dd5wkze2dlyjztytrqff7y

The Role of O-GlcNAcylation in Perivascular Adipose Tissue Dysfunction of Offspring of High-Fat Diet-Fed Rats

Karolina E. Zaborska, Gillian Edwards, Clare Austin, Mark Wareing
2017 Journal of Vascular Research  
decreased AMPK activity and expression in HFDO PVAT, although phosphorylated eNOS expression was only reduced in that from males. The loss of anticontractile effect of HFDO PVAT is likely to result from increased O-GlcNAcylation, which decreased AMPK activity and, in males, decreased NO bioavailability. Abstract Perivascular adipose tissue (PVAT), which reduces vascular contractility, is dysfunctional in the male offspring of rats fed a high-fat diet (HFD), partially due to a reduced NO
more » ... ability. O-GlcNAcylation of eNOS decreases its activity, thus we investigated the role of O-GlcNAcylation in the prenatal programming of PVAT dysfunction. Female Sprague-Dawley rats were fed either a control (10% fat) or an obesogenic HFD (45% fat) diet for 12 weeks prior to mating, and throughout pregnancy and lactation. Offspring were weaned onto the control diet and were killed at 12 and 24 weeks of age. Mesenteric arteries from the 12-week-old offspring of HFD dams (HFDO) contracted less to U46619; these effects were mimicked by glucosamine in control arteries. PVAT from 12-and 24-week-old controls, but not from HFDO, exerted an anticontractile effect. Glucosamine attenuated the anticontractile effect of PVAT in the vessels from controls but not from HFDO. AMP-activated protein kinase (AMPK) activation (with A769662) partially restored an anticontractile effect in glucosamine-treated controls and HFDO PVAT. Glucosamine 80 soconstrictor agents. Endothelial dysfunction is associated with obesity [12, 13] and is clearly linked to decreased nitric oxide (NO) bioavailability [7, 14] . Interestingly, endothelial dysfunction also occurs in the offspring of dams fed an obesogenic diet during their pregnancy [15] . Obesity-linked hypertension is proposed to be associated with loss of perivascular adipose tissue (PVAT) function [16] . Most blood vessels are surrounded by PVAT [17] , an endocrine organ which secrets numerous bioactive proteins (adipokines) [18] that modulate vascular function. The predominantly anticontractile effect of PVAT in healthy subjects results from the release of PVAT-derived relaxant factors, including NO [19] , which more than offset the effects of PVAT-derived contractile factors. Obesity is associated with a diminished PVAT anticontractile effect and decreased endothelium-dependent vasodilation [20] [21] [22] . Impaired adipokine production, inflammation, and oxidative stress have been proposed to be responsible for the reduced anticontractile effect of PVAT observed in obesity [21, 22] . Our group has previously demonstrated that this anticontractile effect of PVAT is lost in the male offspring of rats that have been fed a high-fat diet (HFD dams) [23] . Protein O-GlcNAcylation is a dynamic, reversible process that attaches the O-linked β-N-acetylglucosamine (O-GlcNAc) to serine/threonine residues of proteins. Under normal conditions, 2-5% of glucose that is taken up by cells enters the hexosamine biosynthetic pathway in which glucose is utilised by glutamine fructose-6-phosphate amidotransferase to uridine diphosphate N -acetylglucosamine. Glycosyltransferase then mediates the attachment of the O-GlcNAc to serine/threonine residues of target proteins. Hyperglycaemia and hyperinsulinemia increase protein O-GlcNAcylation, which has been suggested to mediate the adverse effects of insulin resistance and diabetes on vascular function [24] . We have previously found that the plasma insulin levels are elevated in the male offspring of obese dams [23] , which would suggest that protein O-GlcNAcylation might be increased in these animals. O-GlcNAcylation of eNOS is known to decrease its activity [25] and leads to impaired NO-mediated arterial dilation [26] , and we have previously shown that the anticontractile effect of PVAT is lost in male offspring of HFD dams due to reduced NO bioavailability [23] . AMP-activated protein kinase (AMPK) is an energy sensor involved in the regulation of glucose, lipid, and protein metabolism [27] , and in obesity dysregulation of these processes is associated with reduced AMPK activity [28] . In the vasculature, AMPK phosphorylates and acti-
doi:10.1159/000458422 pmid:28376507 pmcid:PMC5569708 fatcat:jcawionzazastkt4acw4vog2gq

A network-based telemetry architecture developed for the Martha's Vineyard Coastal Observatory

T.C. Austin, J.B. Edson, W.R. McGillis, M. Purcell, R.A. Petitt, M.K. McElroy, C.W. Grant, J. Ware, S.K. Hurst
2002 IEEE Journal of Oceanic Engineering  
Underwater observatories with real-time data and virtually unlimited power transmission capabilities compared to traditional oceanographic moorings are beginning to provide scientists with continuous access to the coastal and open ocean. However, for any coastal observatory to serve as a cost-effective system for the collection of long-term scientific and environmental data, it must have a simple, upgradeable power and telemetry system and an instrument interface that is compatible with
more » ... standards. It must be designed for extended environmental exposure and ease of service to avoid high maintenance costs. Most importantly, the observatory must be accessible to all potential users, including students, scientists, engineers, and policy makers. This strategy was applied to the design of the Martha's Vineyard Coastal Observatory on the south shore of the island of Martha's Vineyard. The new facility, and in particular its system architecture, as developed by the Woods Hole Oceanographic Institution with support from the National Science Foundation, are described.
doi:10.1109/joe.2002.1002477 fatcat:yv4dzxbjtffgtgcok7arpe3ppq

An integrated comparative physiology and molecular approach pinpoints mediators of breath-hold capacity in dolphins [article]

Ashley M Blawas, Kathryn E Ware, Emma Schmaltz, Jake Spruance, Austin S Allen, Nicole West, Nicolas Devos, David L Corcoran, Douglas P Nowacek, William C Eward, Andreas Fahlman, Jason A Somarelli
2021 bioRxiv   pre-print
Ischemic events, such as ischemic heart disease and ischemic stroke, are the number one cause of death globally. Ischemia prevents blood, carrying essential nutrients and oxygen, from reaching the tissues leading to cell death, tissue death, and eventual organ failure. While humans are relatively intolerant to these ischemic events, other species, such as marine mammals, have evolved remarkable tolerance to chronic ischemia/reperfusion during diving. Here we capitalized on the unique
more » ... of bottlenose dolphins (Tursiops truncatus) as a comparative model of ischemic stress and hypoxia tolerance to identify molecular features associated with breath-holding. Using RNA-Seq we observed time-dependent upregulation of the arachidonate 5-lipoxygenase (ALOX5) gene during breath-holding. Consistent with the RNA-Seq data, we also observed increased ALOX5 enzymatic activity in the serum of dolphins undergoing breath-holds. ALOX5 has previously been shown to be activated during hypoxia in rodent models, and its metabolites, leukotrienes, induce vasoconstriction. The upregulation of ALOX5 occurred within the estimated aerobic dive limit of the species, suggesting that ALOX5 enzymatic activity may promote tolerance to ischemic stress through sustained vasoconstriction in dolphins during diving. These observations pinpoint a potential molecular mechanism by which dolphins, and perhaps other marine mammals, have adapted to the prolonged breath-holds associated with diving.
doi:10.1101/2021.01.20.425775 fatcat:w44jhoeiwfcvtk6sovj54mdiqa

Utility of point‐of‐care lung ultrasound for monitoring cardiogenic pulmonary edema in dogs

Shane D. Murphy, Jessica L. Ward, Austin K. Viall, Melissa A. Tropf, Rebecca L. Walton, Jennifer L. Fowler, Wendy A. Ware, Teresa C. DeFrancesco
2020 Journal of Veterinary Internal Medicine  
Point-of-care lung ultrasound (LUS) is an effective tool to diagnose left-sided congestive heart failure (L-CHF) in dogs via detection of ultrasound artifacts (B-lines) caused by increased lung water. To determine whether LUS can be used to monitor resolution of cardiogenic pulmonary edema in dogs, and to compare LUS to other indicators of L-CHF control. Twenty-five client-owned dogs hospitalized for treatment of first-onset L-CHF. Protocolized LUS, thoracic radiographs (TXR), and plasma
more » ... nal pro-B-type natriuretic peptide were performed at hospital admission, hospital discharge, and recheck examinations. Lung ultrasound findings were compared between timepoints and to other clinical measures of L-CHF. From time of hospital admission to discharge (mean 19.6 hours), median number of LUS sites strongly positive for B-lines (>3 B-lines per site) decreased from 5 (range, 1-8) to 1 (range, 0-5; P < .001), and median total B-line score decreased from 37 (range, 6-74) to 5 (range, 0-32; P = .002). Lung ultrasound indices remained improved at first recheck (P < .001). Number of strong positive sites correlated positively with respiratory rate (r = 0.52, P = .008) and TXR edema score (r = 0.51, P = .009) at hospital admission. Patterns of edema resolution differed between LUS and TXR, with cranial quadrants showing more significant reduction in B-lines compared to TXR edema score (80% vs 29% reduction, respectively; P = .003). Lung ultrasound could be a useful tool for monitoring resolution of pulmonary edema in dogs with L-CHF.
doi:10.1111/jvim.15990 pmid:33270302 fatcat:qsh27tbdqbb6ph66olzqo3nyuy

BIMG-12. [18F]FLUCICLOVINE PET TO DISTINGUISH PSEUDOPROGRESSION FROM TUMOR PROGRESSION IN POST-TREATMENT GLIOBLASTOMA

Ali Nabavizadeh, Robert Doot, Anthony Young, MacLean Nasrallah, Jeffrey Ware, Erin Schubert, Fraser Henderson, Austin Pantel, Arati Desai, Stephen Bagley, Donald O'Rourke, Steven Brem
2020 Neuro-Oncology Advances  
PURPOSE Differentiation of true tumor progression from pseudoprogression (PsP) is a major unmet need in patients with glioblastoma (GBM). [18F]Fluciclovine is a synthetic amino acid PET radiotracer that is FDA approved in the setting of biochemical recurrence in prostate cancer. The aim of this study was to assess the value of [18F]Fluciclovine PET in differentiation of true tumor progression and PsP in post-treatment of glioblastoma. METHODS 15 patients with GBM with new contrast-enhancing
more » ... ons or lesions showing increased enhancement (&gt;25% increase) on standard MRI after completion of radiation underwent 60-minutes dynamic [18F]Fluciclovine PET imaging. Patients subsequently (within 1 week) underwent resection of the enhancing lesion and the tumor percentage vs treatment-related changes were quantified on histopathology. Patients were considered true tumor progression if tumor represented ≥ 50% of the resected specimen and considered PsP if treatment-related changes represented ≥70% of the resected specimen. Summed 30- to 40-minute post-injection PET images were used to measure SUVpeak, SUVmax, and 50% threshold SUVmean. RESULTS 10 patients with true tumor progression and 5 patients with PsP were included. Patients who demonstrated true tumor progression had significantly higher SUVpeak compared to patients with PsP (5.3±1.4 vs 3.1± 0.9, p=0.002, AUC=0.92, p&lt;0.0001). SUVpeak cut-off of 3.5 provided 100% sensitivity, 80% specificity and 93% accuracy for differentiation of true tumor progression from PsP. There was a moderate to strong correlation between SUVpeak and tumor percentage on histopathology (Rho= 0.68, p=0.004). Alternative SUV measures had similar performance. DISCUSSION Our preliminary results indicated that [18F]Fluciclovine PET imaging can accurately differentiate true tumor progression from PsP. Further studies are required to confirm these promising early results and determine the optimal criteria for interpreting [18F]Fluciclovine PET to distinguish PsP from true tumor progression.
doi:10.1093/noajnl/vdab024.011 fatcat:wqnmk7x7tvhbzaebubygvq4rfq

Acute simvastatin increases endothelial nitric oxide synthase phosphorylation via AMP-activated protein kinase and reduces contractility of isolated rat mesenteric resistance arteries

Luciana V. Rossoni, Mark Wareing, Camilla F. Wenceslau, Mahmood Al-Abri, Chris Cobb, Clare Austin
2011 Clinical Science  
Rossoni, Mark Wareing, Camilla F. Wenceslau, Mahmood Al-Abri and Chris Cobb. The study was directed by Clare Austin. .  ... 
doi:10.1042/cs20110259 pmid:21671887 pmcid:PMC3174052 fatcat:dgq4gslgirajdb7urwarvxnybm

E-cadherin represses anoikis resistance in sarcomas through both signaling and mechanical mechanisms [article]

Mohit Kumar Jolly, Kathryn E Ware, Shengnan Xu, Shivee Gilja, Samantha Shetler, Yanjun Yang, Xueyang Wang, Garland Austin, Alexander J Hish, Suzanne Bartholf DeWitt, Jason T George, R. Timothy Kreulen (+9 others)
2018 bioRxiv   pre-print
E-cadherin, an epithelial-specific cell-cell adhesion molecule, plays multiple roles in maintaining adherens junctions, regulating migration and invasion, and mediating intracellular signaling. Downregulation of E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT) and correlates with poor prognosis in multiple carcinomas. Conversely, upregulation of E-cadherin is prognostic for improved survival in sarcomas. Yet, despite the prognostic benefit of E-cadherin expression in sarcoma,
more » ... the mechanistic significance of E-cadherin in sarcomas remains poorly understood. Here, by combining mathematical models with wet-bench experiments, we identify the core regulatory networks mediated by E-cadherin in sarcomas, and decipher their functional consequences. Unlike in carcinomas, E-cadherin overexpression in sarcomas does not induce a mesenchymal-epithelial transition (MET). However, E-cadherin acts to reduce both anchorage-independent growth and spheroid formation of sarcoma cells. Ectopic E-cadherin expression acts to downregulate phosphorylated CREB (p-CREB) and the transcription factor, TBX2, to inhibit anoikis resistance. RNAi-mediated knockdown of TBX2 phenocopies the effect of E-cadherin on p-CREB levels and restores anoikis sensitivity to sarcoma cells. Beyond its signaling role, E-cadherin expression in sarcoma cells can also strengthen cell-cell adhesion and restricts spheroid growth through mechanical action. Together, our results demonstrate that E-cadherin inhibits sarcoma aggressiveness by inducing anoikis and restricting colony growth.
doi:10.1101/347815 fatcat:zkzx3uze5bhq7b2ctuns4rekdu
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