Erioflorin stabilizes the tumor suppressor Pdcd4 by inhibiting its interaction with the E3-ligase β-TrCP1

Loss of the tumor suppressor Pdcd4 was reported for various tumor entities and proposed as a prognostic marker in tumorigenesis. We previously characterized decreased Pdcd4 protein stability in response to mitogenic stimuli, which resulted from p70S6K1-dependent protein phosphorylation, β-TrCP1-mediated ubiquitination, and proteasomal destruction. Following high-throughput screening of natural product extract libraries using a luciferase-based reporter assay to monitor phosphorylation-dependent proteasomal degradation of the tumor suppressor Pdcd4, we succeeded in showing that a crude extract from Eriophyllum lanatum stabilized Pdcd4 from TPA-induced degradation. Erioflorin was identified as the active component and inhibited not only degradation of the Pdcd4-luciferase-based reporter but also of endogenous Pdcd4 at low micromolar concentrations. Mechanistically, erioflorin interfered with the interaction between the E3-ubiquitin ligase β-TrCP1 and Pdcd4 in cell culture and in in vitro binding assays, consequently decreasing ubiquitination and degradation of Pdcd4. Interestingly, while erioflorin stabilized additional β-TrCP-targets (such as IκBα and β-catenin), it did not prevent the degradation of targets of other E3-ubiquitin ligases such as p21 (a Skp2-target) and HIF-1α (a pVHL-target), implying selectivity for β-TrCP. Moreover, erioflorin inhibited the tumor-associated activity of known Pdcd4- and IκBα-regulated αtranscription factors, that is, AP-1 and NF-κB, altered cell cycle progression and suppressed proliferation of various cancer cell lines. Our studies succeeded in identifying erioflorin as a novel Pdcd4 stabilizer that inhibits the interaction of Pdcd4 with the E3-ubiquitin ligase β-TrCP1. Inhibition of E3-ligase/target-protein interactions may offer the possibility to target degradation of specific proteins only as compared to general proteasome inhibition

Testing the proposed link between cosmic rays and cloud cover

A decrease in the globally averaged low level cloud cover, deduced from the ISCCP infra red data, as the cosmic ray intensity decreased during the solar cycle 22 was observed by two groups. The groups went on to hypothesise that the decrease in ionization due to cosmic rays causes the decrease in cloud cover, thereby explaining a large part of the presently observed global warming. We have examined this hypothesis to look for evidence to corroborate it. None has been found and so our conclusions are to doubt it. From the absence of corroborative evidence, we estimate that less than 23%, at the 95% confidence level, of the 11-year cycle change in the globally averaged cloud cover observed in solar cycle 22 is due to the change in the rate of ionization from the solar modulation of cosmic rays

Measurements of Smoke Characteristics in HVAC Ducts

Research paper published in the journal Fire Technology in 2001The characteristics of smoke traveling in an HVAC duct have been observed along with the response of selected duct smoke detectors. The simulated HVAC system consists of a 9 m long duct, 0.45 m in diameter. An exhaust fan is placed at one end of the duct and is capable of inducing airflow rates that range from 0 to 1.5 m 3 /s. The flow is controlled by means of a manual damper. On the upstream end of the duct there is a square exhaust hood approximately 2.2 m at the bottom and 0.3 m at the top. The bottom of the hood is approximately 2.5 m above the floor a shroud extends down to approximately 1.5 m above the floor. The test section, placed immediately downstream of the hood, is 3.5 m long duct with a square cross section of 0.4 m on a side. The instrumentation includes oxygen, carbon monoxide and carbon dioxide gas analyzers and a load cell to determine the energy release rate of the fires tested. The smoke within the duct is characterized by means of a laser light sheet and CCD camera, two white light source and photocell ensembles, a Pitot tube and an array of eight thermocouples placed on the vertical plane of symmetry. A smoke detector was placed at the downstream end of the test section. Two types of detectors were tested, ionization and photoelectric, with a single sampling probe geometry. The fires tested cover a wide range of fuels (propane, heptane, toluene, toluene/heptane mixture, shredded paper, polyurethane foam, wood cribs) with the peak energy release rates up to 800 kW. The smoke detector performance, temperature, flow field, smoke particle size and particle distributions are dependent on the fire characteristics and airflow through the duct. The different measurements could be scaled by means of the fire size and airflow rate but left a strong dependency on the fuel and burning characteristics (i.e. smoldering, flaming). The optical density and mass optical density are analyzed as metrics for characterizing smoke and smoke detector response. Detailed comparisons between the different metrics used are presented throughout this work. Clear evidence of stratification and aging of the smoke along the duct are also presented. The limitations of the present configuration and the need for a larger scale study are also discussed

A Vulnerability Assessment of Fish and Invertebrates to Climate Change on the Northeast U.S. Continental Shelf

Climate change and decadal variability are impacting marine fish and invertebrate species worldwide and these impacts will continue for the foreseeable future. Quantitative approaches have been developed to examine climate impacts on productivity, abundance, and distribution of various marine fish and invertebrate species. However, it is difficult to apply these approaches to large numbers of species owing to the lack of mechanistic understanding sufficient for quantitative analyses, as well as the lack of scientific infrastructure to support these more detailed studies. Vulnerability assessments provide a framework for evaluating climate impacts over a broad range of species with existing information. These methods combine the exposure of a species to a stressor (climate change and decadal variability) and the sensitivity of species to the stressor. These two components are then combined to estimate an overall vulnerability. Quantitative data are used when available, but qualitative information and expert opinion are used when quantitative data is lacking. Here we conduct a climate vulnerability assessment on 82 fish and invertebrate species in the Northeast U.S. Shelf including exploited, forage, and protected species. We define climate vulnerability as the extent to which abundance or productivity of a species in the region could be impacted by climate change and decadal variability. We find that the overall climate vulnerability is high to very high for approximately half the species assessed; diadromous and benthic invertebrate species exhibit the greatest vulnerability. In addition, the majority of species included in the assessment have a high potential for a change in distribution in response to projected changes in climate. Negative effects of climate change are expected for approximately half of the species assessed, but some species are expected to be positively affected (e.g., increase in productivity or move into the region). These results will inform research and management activities related to understanding and adapting marine fisheries management and conservation to climate change and decadal variability

Multimessenger Search for Sources of Gravitational Waves and High-Energy Neutrinos: Results for Initial LIGO-Virgo and IceCube

We report the results of a multimessenger search for coincident signals from the LIGO and Virgo gravitational-wave observatories and the partially completed IceCube high-energy neutrino detector, including periods of joint operation between 2007-2010. These include parts of the 2005-2007 run and the 2009-2010 run for LIGO-Virgo, and IceCube's observation periods with 22, 59 and 79 strings. We find no significant coincident events, and use the search results to derive upper limits on the rate of joint sources for a range of source emission parameters. For the optimistic assumption of gravitational-wave emission energy of $10^{-2}$\,M$_\odot$c$^2$ at $\sim 150$\,Hz with $\sim 60$\,ms duration, and high-energy neutrino emission of $10^{51}$\,erg comparable to the isotropic gamma-ray energy of gamma-ray bursts, we limit the source rate below $1.6 \times 10^{-2}$\,Mpc$^{-3}$yr$^{-1}$. We also examine how combining information from gravitational waves and neutrinos will aid discovery in the advanced gravitational-wave detector era

Study of Movement Speeds Down Stairs

The Study of Movement Speeds Down Stairs closely examines forty-three unique case studies on movement patterns down stairwells. These studies include observations made during evacuation drills, others made during normal usage, interviews with people after fire evacuations, recommendations made from compiled studies, and detailed results from laboratory studies. The methodology used in each study for calculating density and movement speed, when known, are also presented, and this book identifies an additional seventeen variables linked to altering movement speeds. The Study of Movement Speeds Down Stairs is intended for researchers as a reference guide for evaluating pedestrian evacuation dynamics down stairwells. Practitioners working in a related field may also find this book invaluable

Relationship between chemical and theoretical oxygen demand for specific classes of organic chemicals

This study examined the relationship between ThOD and COD For a database of 565 organic chemicals comprising 64 classes. A mixed beta-normal distribution was used to develop a statistically reliable method to estimate COD from ThOD for specific classes of organic chemicals. The data were divided into six groups; (1) well-correlated aromatic chemicals, (2) well-correlated non-aromatic chemicals, (3) potentially well-correlated aromatic chemicals, (4) potentially well-correlated non-aromatic chemicals, (5) other aromatic chemicals, (6) other non-aromatic chemicals. The results show there is 90% statistical confidence that COD will be within the range of: 0.96-1.0 x ThOD (mean equal to 0.98) for the chemical classes in group 1; 0.92-1.0 x ThOD (mean equal to 0.97) for the chemical classes in group 2; 0.80-1.0 x ThOD (mean equal to 0.93) for the chemical classes in group 3; 0.75-1.0 x ThOD (mean equal to 0.92) for the chemical classes in group 4. The COD for chemicals in groups 5 and 6 was either poorly correlated or could not be correlated because insufficient data were available. COD cannot be estimated from ThOD for the 43 chemical classes represented by the 288 chemicals in groups 5 and 6. Caution should be used in applying COD measurements to these chemical classes or to mixtures which consist primarily of chemicals contained in these chemical classes. In addition, a modification of the COD test may be required for individual chemicals contained in this poorly correlated group of chemical classes (e.g., modification for volatile chemicals, C.J.M. Wolff COD determination of volatile compounds