Cellular inhibitor of apoptosis 1 (cIAP-1) degradation by caspase 8 during TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis.

TNF-related apoptosis-inducing ligand (TRAIL) is a potential chemotherapeutic agent with high selectivity for malignant cells. Many tumors, however, are resistant to TRAIL cytotoxicity. Although cellular inhibitors of apoptosis 1 and 2 (cIAP-1 and -2) are often over-expressed in cancers, their role in mediating TRAIL resistance remains unclear. Here, we demonstrate that TRAIL-induced apoptosis of liver cancer cells is associated with degradation of cIAP-1 and X-linked IAP (XIAP), whereas cIAP-2 remains unchanged. Lower concentrations of TRAIL causing minimal or no apoptosis do not alter cIAP-1 or XIAP protein levels. Silencing of cIAP-1 expression, but not XIAP or cIAP-2, as well as co-treatment with a second mitochondrial activator of caspases (SMAC) mimetic (which results in rapid depletion of cIAP-1), sensitizes the cells to TRAIL. TRAIL-induced loss of cIAP-1 and XIAP requires caspase activity. In particular, caspase 8 knockdown stabilizes both cIAP-1 and XIAP, while caspase 9 knockdown prevents XIAP, but not cIAP-1 degradation. Cell-free experiments confirmed cIAP-1 is a substrate for caspase 8, with likely multiple cleavage sites. These results suggest that TRAIL-mediated apoptosis proceeds through caspase 8-dependent degradation of cIAP-1. Targeted depletion of cIAP-1 by SMAC mimetics in conjunction with TRAIL may be beneficial for the treatment of human hepatobiliary malignancies

Dimension reduction for systems with slow relaxation

We develop reduced, stochastic models for high dimensional, dissipative dynamical systems that relax very slowly to equilibrium and can encode long term memory. We present a variety of empirical and first principles approaches for model reduction, and build a mathematical framework for analyzing the reduced models. We introduce the notions of universal and asymptotic filters to characterize `optimal' model reductions for sloppy linear models. We illustrate our methods by applying them to the practically important problem of modeling evaporation in oil spills.Comment: 48 Pages, 13 figures. Paper dedicated to the memory of Leo Kadanof

Experimental study of a R290 variable geometry ejector

Ejectors are classified as fluid-dynamics controlled devices where the "component-scale"performances are imposed by the local-scale fluid dynamic phenomena. For this reason, ejector performances (measured by the pressure-entrainment ratio coordinate of the critical point) are determined by the connection of operation conditions, working fluid and geometrical parameters. Given such a connection, variable geometry ejector represents a promising solution to increase the flexibility of ejector-based systems. The present study aims to extend knowledge on variable geometry systems, evaluating the local and global performances of the R290 ejector equipped with a spindle. The prototype ejector was installed at the R290 vapour compression test rig adapted and modified for the required experimental campaign. The test campaign considered global parameter measurements, such as the pressure and the temperature at inlets and outlet ports together with the mass flow rates at both inlet nozzles, and the local pressure drop measurements inside the ejector. In addition, the experimental data were gathered for different spindle positions starting from fully open position the spindle position limited by the mass flow rate inside the test rig with the step of 1.0 mm

A smac mimetic reduces TNF related apoptosis inducing ligand (TRAIL)-induced invasion and metastasis of cholangiocarcinoma cells.

UNLABELLED: Cholangiocarcinoma (CCA) cells paradoxically express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a death ligand that, failing to kill CCA cells, instead promotes their tumorigenicity and especially the metastatic behaviors of cell migration and invasion. Second mitochondria-derived activator of caspase (smac) mimetics are promising cancer therapeutic agents that enhance proapoptotic death receptor signaling by causing cellular degradation of inhibitor of apoptosis (IAP) proteins. Our aim was to examine the in vitro and in vivo effects of the smac mimetic JP1584 in CCA. Despite JP1584-mediated loss of cellular inhibitor of apoptosis-1 (cIAP-1) and cIAP-2, TRAIL failed to induce apoptosis in KMCH-1, TFK-1, and BDEneu CCA cells; a finding consistent with a downstream block in death signaling. Because cIAP-1 and cIAP-2 also promote nuclear factor kappa B (NF-kappaB) activation by the canonical pathway, the effect of JP1584 on this signaling pathway was examined. Treatment with JP1584 inhibited TRAIL-induced NF-kappaB activation as well as TRAIL-mediated up-regulation of the NF-kappaB target gene, matrix metalloproteinase 7 (MMP7). JP1584 also reduced TRAIL-mediated CCA cell migration and invasion in vitro. Finally, in a syngeneic rat orthotopic CCA model, JP1584 administration reduced MMP7 messenger RNA levels and extrahepatic metastases. CONCLUSION: : Although the smac mimetic JP1584 does not sensitize cells to apoptosis, it reduces TRAIL-induced CCA cell metastatic behavior. These data support the emerging concept that IAPs are prometastatic and represent targets for antimetastatic therapies

Death receptor 5 signaling promotes hepatocyte lipoapoptosis.

Nonalcoholic steatohepatitis is characterized by hepatic steatosis, elevated levels of circulating free fatty acids (FFA), endoplasmic reticulum (ER) stress, and hepatocyte lipoapoptosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor 5 (DR5) is significantly elevated in patients with nonalcoholic steatohepatitis, and steatotic hepatocytes demonstrate increased sensitivity to TRAIL-mediated cell death. Nonetheless, a role for TRAIL and/or DR5 in mediating lipoapoptotic pathways is unexplored. Here, we examined the contribution of DR5 death signaling to lipoapoptosis by free fatty acids. The toxic saturated free fatty acid palmitate induces an increase in DR5 mRNA and protein expression in Huh-7 human hepatoma cells leading to DR5 localization into lipid rafts, cell surface receptor clustering with subsequent recruitment of the initiator caspase-8, and ultimately cellular demise. Lipoapoptosis by palmitate was not inhibited by a soluble human recombinant DR5-Fc chimera protein suggesting that DR5 cytotoxic signaling is ligand-independent. Hepatocytes from murine TRAIL receptor knock-out mice (DR(-/-)) displayed reduced palmitate-mediated lipotoxicity. Likewise, knockdown of DR5 or caspase-8 expression by shRNA technology attenuated palmitate-induced Bax activation and apoptosis in Huh-7 cells, without altering induction of ER stress markers. Similar observations were verified in other cell models. Finally, knockdown of CHOP, an ER stress-mediated transcription factor, reduced DR5 up-regulation and DR5-mediated caspase-8 activation upon palmitate treatment. Collectively, these results suggest that ER stress-induced CHOP activation by palmitate transcriptionally up-regulates DR5, likely resulting in ligand-independent cytotoxic signaling by this death receptor

Floating oil-covered debris from Deepwater Horizon : identification and application

Author Posting. © IOP Publishing, 2012. This article is posted here by permission of IOP Publishing. Re-use is limited to non-commercial purposes. The definitive version was published in Environmental Research Letters 7 (2012): 015301, doi:10.1088/1748-9326/7/1/015301.The discovery of oiled and non-oiled honeycomb material in the Gulf of Mexico surface waters and along coastal beaches shortly after the explosion of Deepwater Horizon sparked debate about its origin and the oil covering it. We show that the unknown pieces of oiled and non-oiled honeycomb material collected in the Gulf of Mexico were pieces of the riser pipe buoyancy module of Deepwater Horizon. Biomarker ratios confirmed that the oil had originated from the Macondo oil well and had undergone significant weathering. Using the National Oceanic and Atmospheric Administration's records of the oil spill trajectory at the sea surface, we show that the honeycomb material preceded the front edge of the uncertainty of the oil slick trajectory by several kilometers. We conclude that the observation of debris fields deriving from damaged marine materials may be incorporated into emergency response efforts and forecasting of coastal impacts during future offshore oil spills, and ground truthing predicative models.This research was supported by NSF grant OCE-1043976 to CR

The United States' next generation of atmospheric composition and coastal ecosystem measurements : NASA's Geostationary Coastal and Air Pollution Events (GEO-CAPE) Mission

Author Posting. © American Meteorological Society, 2012. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Bulletin of the American Meteorological Society 93 (2012): 1547–1566, doi:10.1175/BAMS-D-11-00201.1.The Geostationary Coastal and Air Pollution Events (GEO-CAPE) mission was recommended by the National Research Council's (NRC's) Earth Science Decadal Survey to measure tropospheric trace gases and aerosols and coastal ocean phytoplankton, water quality, and biogeochemistry from geostationary orbit, providing continuous observations within the field of view. To fulfill the mandate and address the challenge put forth by the NRC, two GEO-CAPE Science Working Groups (SWGs), representing the atmospheric composition and ocean color disciplines, have developed realistic science objectives using input drawn from several community workshops. The GEO-CAPE mission will take advantage of this revolutionary advance in temporal frequency for both of these disciplines. Multiple observations per day are required to explore the physical, chemical, and dynamical processes that determine tropospheric composition and air quality over spatial scales ranging from urban to continental, and over temporal scales ranging from diurnal to seasonal. Likewise, high-frequency satellite observations are critical to studying and quantifying biological, chemical, and physical processes within the coastal ocean. These observations are to be achieved from a vantage point near 95°–100°W, providing a complete view of North America as well as the adjacent oceans. The SWGs have also endorsed the concept of phased implementation using commercial satellites to reduce mission risk and cost. GEO-CAPE will join the global constellation of geostationary atmospheric chemistry and coastal ocean color sensors planned to be in orbit in the 2020 time frame.Funding for GEO-CAPE definition activities is provided by the Earth Science Division of the National Aeronautics and Space Administration.2013-04-0

Dynamics of live oil droplets and natural gas bubbles in deep water

Explaining the dynamics of gas-saturated live petroleum in deep water remains a challenge. Recently, Pesch et al. (Environ. Eng. Sci. 2018, 35, 289−299) reported laboratory experiments on methane-saturated oil droplets under emulated deep-water conditions, providing an opportunity to elucidate the underlying dynamical processes. We explain these observations with the Texas A&M Oil spill/Outfall Calculator (TAMOC), which models the pressure-, temperature-, and composition-dependent interactions between: oil-gas phase transfer; aqueous dissolution; and densities and volumes of liquid oil droplets, gas bubbles, and two-phase droplet-bubble pairs. TAMOC reveals that aqueous dissolution removed >95% of the methane from ~3.5-mm live oil droplets within 14.5 min, prior to gas bubble formation, during the experiments of Pesch et al. Additional simulations indicate that aqueous dissolution, fluid density changes, and gas-oil phase transitions (ebullition, condensation) may all contribute to the fates of live oil and gas in deep water, depending on the release conditions. Illustrative model scenarios suggest that 5-mm diameter gas bubbles released at <470 m water depth can transport methane, ethane, and propane to the water surface. Ethane and propane can reach the water surface from much deeper releases of 5-mm diameter live oil droplets, during which ebullition occurs at water depths of <70 m

Severity of current depression and remission status are associated with structural connectome alterations in major depressive disorder

Major depressive disorder (MDD) is associated to affected brain wiring. Little is known whether these changes are stable over time and hence might represent a biological predisposition, or whether these are state markers of current disease severity and recovery after a depressive episode. Human white matter network ("connectome") analysis via network science is a suitable tool to investigate the association between affected brain connectivity and MDD. This study examines structural connectome topology in 464 MDD patients (mean age: 36.6 years) and 432 healthy controls (35.6 years). MDD patients were stratified categorially by current disease status (acute vs. partial remission vs. full remission) based on DSM-IV criteria. Current symptom severity was assessed continuously via the Hamilton Depression Rating Scale (HAMD). Connectome matrices were created via a combination of T1-weighted magnetic resonance imaging (MRI) and tractography methods based on diffusion-weighted imaging. Global tract-based metrics were not found to show significant differences between disease status groups, suggesting conserved global brain connectivity in MDD. In contrast, reduced global fractional anisotropy (FA) was observed specifically in acute depressed patients compared to fully remitted patients and healthy controls. Within the MDD patients, FA in a subnetwork including frontal, temporal, insular, and parietal nodes was negatively associated with HAMD, an effect remaining when correcting for lifetime disease severity. Therefore, our findings provide new evidence of MDD to be associated with structural, yet dynamic, state-dependent connectome alterations, which covary with current disease severity and remission status after a depressive episode

Brain structural correlates of insomnia severity in 1053 individuals with major depressive disorder : results from the ENIGMA MDD Working Group

It has been difficult to find robust brain structural correlates of the overall severity of major depressive disorder (MDD). We hypothesized that specific symptoms may better reveal correlates and investigated this for the severity of insomnia, both a key symptom and a modifiable major risk factor of MDD. Cortical thickness, surface area and subcortical volumes were assessed from T1-weighted brain magnetic resonance imaging (MRI) scans of 1053 MDD patients (age range 13-79 years) from 15 cohorts within the ENIGMA MDD Working Group. Insomnia severity was measured by summing the insomnia items of the Hamilton Depression Rating Scale (HDRS). Symptom specificity was evaluated with correlates of overall depression severity. Disease specificity was evaluated in two independent samples comprising 2108 healthy controls, and in 260 clinical controls with bipolar disorder. Results showed that MDD patients with more severe insomnia had a smaller cortical surface area, mostly driven by the right insula, left inferior frontal gyrus pars triangularis, left frontal pole, right superior parietal cortex, right medial orbitofrontal cortex, and right supramarginal gyrus. Associations were specific for insomnia severity, and were not found for overall depression severity. Associations were also specific to MDD; healthy controls and clinical controls showed differential insomnia severity association profiles. The findings indicate that MDD patients with more severe insomnia show smaller surfaces in several frontoparietal cortical areas. While explained variance remains small, symptom-specific associations could bring us closer to clues on underlying biological phenomena of MDD