CL 316, 243 mediated reductions in blood glucose are enhanced in RIP140{sup −/−} mice independent of alterations in lipolysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peppler, Willem T.; Miotto, Paula M.; Holloway, Graham P.

The β-3 adrenergic agonist CL 316, 243 acutely lowers blood glucose through a mechanism thought to involve fatty-acid induced insulin release. The purpose of this study was to determine if ablation of the nuclear receptor, receptor-inactivating protein 140 (RIP140), altered this response. Here, we used a single injection of CL 316, 243 (1 mg/kg) and found that whole body RIP140{sup −/−} mice had a greater decline in blood glucose over 2 h. This occurred alongside increased hexokinase II (HKII) protein content in adipose tissue and skeletal muscle, but independent of changes in circulating insulin or indices of lipolysis. These data indicate thatmore » RIP140 has a unique role in the acute effect of β-3 adrenergic receptor activation using CL 316, 243.« less

Rip Current Velocity Structure in Drifter Trajectories and Numerical Simulations

NASA Astrophysics Data System (ADS)

Schmidt, W. E.; Slinn, D. N.

2008-12-01

Estimates of rip current velocity and cross-shore structure were made using surfzone drifters, bathymetric surveys, and rectified video images. Over 60 rip current trajectories were observed during a three year period at a Southern California beach in July 2000, 2001, and 2002. Incident wave heights (Hs) immediately offshore (~7 m depth) were obtained by initializing a refraction model with data from nearby directional wave buoys, and varied from 0.3 to 1.0 m. Tide levels varied over approximately 1 m and winds were light. Numerical simulations using the non-linear shallow water equations and modeled over measured bathymetry also produced similar flows and statistics. Time series of drifter position, sampled at 1 Hz, were first-differenced to produce velocity time series. Maximum observed velocities varied between 25 and 80 cm s-1, whereas model maximum velocities were lower by a factor 2 to 3. When velocity maxima were non-dimensionalized by respective trajectory mean velocity, both observed and modeled values varied between 1.5 and 3.5. Cross-shore location of rip current velocity maxima for both shore-normal and shore-oblique rip currents were strongly coincident with the surfzone edge (Xb), as determined by rectified video (observations) or breakpoint (model). Once outside of the surfzone, observed and modeled rip current velocities decreased to 10% of their peak values within 2 surfzone widths of the shoreline, a useful definition of rip current cross-shore extent.

Necroptosis is a key pathogenic event in human and experimental murine models of non-alcoholic steatohepatitis.

PubMed

Afonso, Marta B; Rodrigues, Pedro M; Carvalho, Tânia; Caridade, Marta; Borralho, Paula; Cortez-Pinto, Helena; Castro, Rui E; Rodrigues, Cecília M P

2015-10-01

Hepatocyte cell death, inflammation and oxidative stress constitute key pathogenic mechanisms underlying non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the role of necroptosis in human and experimental NAFLD and its association with tumour necrosis factor α (TNF-α) and oxidative stress. Serum markers of necrosis, liver receptor-interacting protein 3 (RIP3) and phosphorylated mixed lineage kinase domain-like (MLKL) were evaluated in control individuals and patients with NAFLD. C57BL/6 wild-type (WT) or RIP3-deficient (RIP3(-/-)) mice were fed a high-fat choline-deficient (HFCD) or methionine and choline-deficient (MCD) diet, with subsequent histological and biochemical analysis of hepatic damage. In primary murine hepatocytes, necroptosis and oxidative stress were also assessed after necrostatin-1 (Nec-1) treatment or RIP3 silencing. We show that circulating markers of necrosis and TNF-α, as well as liver RIP3 and MLKL phosphorylation were increased in NAFLD. Likewise, RIP3 and MLKL protein levels and TNF-α expression were increased in the liver of HFCD and MCD diet-fed mice. Moreover, RIP3 and MLKL sequestration in the insoluble protein fraction of NASH (non-alcoholic steatohepatitis) mice liver lysates represented an early event during stetatohepatitis progression. Functional studies in primary murine hepatocytes established the association between TNF-α-induced RIP3 expression, activation of necroptosis and oxidative stress. Strikingly, RIP3 deficiency attenuated MCD diet-induced liver injury, steatosis, inflammation, fibrosis and oxidative stress. In conclusion, necroptosis is increased in the liver of NAFLD patients and in experimental models of NASH. Further, TNF-α triggers RIP3-dependent oxidative stress during hepatocyte necroptosis. As such, targeting necroptosis appears to arrest or at least impair NAFLD progression. © 2015 Authors; published by Portland Press Limited.

Rip current evidence by hydrodynamic simulations, bathymetric surveys and UAV observation

NASA Astrophysics Data System (ADS)

Benassai, Guido; Aucelli, Pietro; Budillon, Giorgio; De Stefano, Massimo; Di Luccio, Diana; Di Paola, Gianluigi; Montella, Raffaele; Mucerino, Luigi; Sica, Mario; Pennetta, Micla

2017-09-01

The prediction of the formation, spacing and location of rip currents is a scientific challenge that can be achieved by means of different complementary methods. In this paper the analysis of numerical and experimental data, including RPAS (remotely piloted aircraft systems) observations, allowed us to detect the presence of rip currents and rip channels at the mouth of Sele River, in the Gulf of Salerno, southern Italy. The dataset used to analyze these phenomena consisted of two different bathymetric surveys, a detailed sediment analysis and a set of high-resolution wave numerical simulations, completed with Google EarthTM images and RPAS observations. The grain size trend analysis and the numerical simulations allowed us to identify the rip current occurrence, forced by topographically constrained channels incised on the seabed, which were compared with observations.

Degree of anisotropy as an automated indicator of rip channels in high resolution bathymetric models

NASA Astrophysics Data System (ADS)

Trimble, S. M.; Houser, C.; Bishop, M. P.

2017-12-01

A rip current is a concentrated seaward flow of water that forms in the surf zone of a beach as a result of alongshore variations in wave breaking. Rips can carry swimmers swiftly into deep water, and they are responsible for hundreds of fatal drownings and thousands of rescues worldwide each year. These currents form regularly alongside hard structures like piers and jetties, and can also form along sandy coasts when there is a three dimensional bar morphology. This latter rip type tends to be variable in strength and location, making them arguably the most dangerous to swimmers and most difficult to identify. These currents form in characteristic rip channels in surf zone bathymetry, in which the primary axis of self-similarity is oriented shore-normal. This paper demonstrates a new method for automating identification of such rip channels in bathymetric digital surface models (DSMs) using bathymetric data collected by various remote sensing methods. Degree of anisotropy is used to detect rip channels and distinguishes between sandbars, rip channels, and other beach features. This has implications for coastal geomorphology theory and safety practices. As technological advances increase access and accuracy of topobathy mapping methods in the surf zone, frequent nearshore bathymetric DSMs could be more easily captured and processed, then analyzed with this method to result in localized, automated, and frequent detection of rip channels. This could ultimately reduce rip-related fatalities worldwide (i) in present mitigation, by identifying the present location of rip channels, (ii) in forecasting, by tracking the channel's evolution through multiple DSMs, and (iii) in rip education by improving local lifeguard knowledge of the rip hazard. Although this paper on applies analysis of degree of anisotropy to the identification of rip channels, this parameter can be applied to multiple facets of barrier island morphological analysis.

Case Study of Rip Current Knowledge amongst Students Participating in a Study Abroad Program

ERIC Educational Resources Information Center

Houser, Chris; Brander, Robert; Brannstrom, Christian; Trimble, Sarah; Flaherty, Jane

2016-01-01

Rip currents are narrow seaward-flowing currents common on many global beaches and are capable of transporting even experienced swimmers a significant distance offshore, placing them at risk of needing rescue or drowning. In this respect, rips represent a significant hazard to beach users around the world and are recognized as a major health…

ROMI-RIP: Rough mill rip-first simulator. Forest Service general technical report (Final)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thomas, R.E.

1995-07-01

The ROugh Mill Rip-First Simulator (ROMI-RIP) is a computer software package that simulates the gang-ripping of lumber. ROMI-RIP was designed to closely simulate current machines and industrial practice. This simulator allows the user to perform `what if` analyses on various gang-rip-first rough mill operations with fixed, floating outer blade and all-movable blade arbors. ROMI-RIP accepts cutting bills with up to 300 different part sizes. Plots of processed boards are easily viewed or printed. Detailed summaries of processing steps (number of rips and crosscuts) and yields (single boards or entire board files) can also be viewed of printed. ROMI-RIP requires IBMmore » personal computers with 80286 of higher processors.« less

Mapping bathymetry and rip channels with WorldView2 multispectral data

NASA Astrophysics Data System (ADS)

Trimble, S. M.; Houser, C.

2014-12-01

Rip currents are a worldwide coastal hazard that have claimed 616 lives in Costa Rica since 2001 (~50/yr). Lifeguard staff, warning signs, and flag systems have been shown to reduce deaths at rip-prone beaches but are not a perfect system. At Playa Cocles, a popular beach destination along the Caribbean Coast of Costa Rica near Puerto Viejo, lifeguards post flags at the mouth of the 3 to 6 rip currents present each morning. In July 2014, these dangerous currents were measured with floating GPS drogues at speeds up to 3.1 m/s. The purpose of this study is to demonstrate the capability of the Digital Globe WorldView2 (WV2) multispectral satellite for identifying rip channels and mapping bathymetry in the surf zone (20m and less), because rips form at topographically low spots in the bathymetry as a result of feedback amongst waves, substrate, and antecedent bathymetry. WV2 was launched in 2009; it has a 1.1 day pass-over rate with 1.84m ground pixel resolution of 8 bands, including 'yellow' (585-625 nm) and 'coastal blue' (400-450 nm). Using one 25km2 image from 23 December 2009, during the "high season" of tourism, a bathymetric map of Playa Cocles is created and measured for accuracy. Results of the study will assist the Comisión Nacional de Emergencias de Costa Rica and the town of Puerto Viejo by creating a rip current hazard evaluation and prediction system for the rip-prone beach of Playa Cocles. This creation methodology may be repeated for any following dates or other locations in Costa Rica (or anywhere on the globe captured by WV2). Future work will build on this research to determine rip current strength, location, and seasonality from a combination of WV2 satellite information and field data.

Mapping and Mitigating the International Rip Current Health Hazard

NASA Astrophysics Data System (ADS)

Trimble, S. M.; Houser, C.

2016-12-01

Rip currents are concentrated seaward flows of water originating in the surf zones of beaches. Rips cause hundreds of international drownings each year. Calculating exact numbers is barred by logistical difficulties in obtaining accurate incident reports, but annual rip current fatalities are estimated at 100, 53 and 21 in the United States (US), Costa Rica, and Australia respectively. Notably, Australia's lifeguards rescue 17,600 swimmers from rips each year. This project addresses the geophysical, social, and systematic causes of fatalities in hopes of decreasing the global number of rip-related deaths. We demonstrate a novel method for mapping bathymetry in the surf zone (20m deep or less), specifically within rip channels (topographic low spots in the nearshore that result from feedback amongst waves, substrate, and antecedent bathymetry). We calculate bathymetry using 8-band multispectral imagery from the Digital Globe WorldView2 (WV2) satellite and field measurements of depth, generating maps of the changing nearshore at two embayed, rip-prone beaches: Playa Cocles, Costa Rica, and Bondi Beach, Australia. WV2 has a 1.1 day pass-over rate with 1.84m ground pixel resolution of 8 bands, including `yellow' (585-625 nm) and `coastal blue' (400-450 nm). Methods are tested for consistency amongst dates and locations. Previous research shows drownings result from a combination of the physical environment with personal and group behaviors; for this reason we build on rip-detection by evaluating tourists' and locals' knowledge and understanding of their beach's rip behavior. By combining the geomorphologic maps developed from WV2 with interview data, we evaluate how the physical environment dictates the exposure of certain swimmers. Controls include rip channel location, beach access points, and environmental factors favored by swimmers. The project serves as an evaluation of the landscape's creation of a physical feature that becomes a hazard when vulnerable humans swim into it. Results are meant to inform policy makers so that they may implement the methods: developing frequent nearshore maps to observe rip channel behavior, designing beach access controls informed by morphology, posting informative signs in ideal locations, and funding lifeguard programs.

Three-dimensional transient rip currents: Bathymetric excitation of low-frequency intrinsic variability

NASA Astrophysics Data System (ADS)

Uchiyama, Yusuke; McWilliams, James C.; Akan, Cigdem

2017-07-01

The ROMS-WEC model [Uchiyama et al., 2010] based on an Eulerian wave-averaged vortex-force asymptotic theory of McWilliams et al. (2004) is applied to analyze 3-D transient wave-driven rip currents and associated intrinsic very low-frequency (VLF) variability in the surf zone on a surveyed bathymetry under spatiotemporally uniform offshore incident waves. The 3-D rip currents are substantially depth-dependent due to the vertical recirculation, composed of pairs of counter-rotating longitudinal overturning roll cells that promote surface convergence. The vortex force plays an important role in vorticity budget, preconditioning overall vorticity reduction. These rip currents are intrinsically unstable and contribute about 70% to kinetic energy (KE) as eddy kinetic energy (EKE), consistent with observations. The dominant fluctuation period fits the VLF band, at about 18 min. The current effect on waves (CEW) alters not only the mean rip structure, but also the associated turbulence as the modified cross-shore EKE profile with considerable accentuation in the inner surf zone. Increased alongshore bathymetric variability proportionally intensifies KE and intrinsic EKE, whereas it reduces the VLF period. With a guide of a pseudo 2D model, we reveal that vortex tilting effect due to the horizontal vorticity inherent in the 3-D rip currents promotes collapse of the 3-D eddies through an enhanced forward kinetic energy cascade, leading to short-lived, laterally-stretched 3-D eddies resulting in elongated filaments that decay more quickly than coherent, long-lived, circular 2-D eddies.

Operational prediction of rip currents using numerical model and nearshore bathymetry from video images

NASA Astrophysics Data System (ADS)

Sembiring, L.; Van Ormondt, M.; Van Dongeren, A. R.; Roelvink, J. A.

2017-07-01

Rip currents are one of the most dangerous coastal hazards for swimmers. In order to minimize the risk, a coastal operational-process based-model system can be utilized in order to provide forecast of nearshore waves and currents that may endanger beach goers. In this paper, an operational model for rip current prediction by utilizing nearshore bathymetry obtained from video image technique is demonstrated. For the nearshore scale model, XBeach1 is used with which tidal currents, wave induced currents (including the effect of the wave groups) can be simulated simultaneously. Up-to-date bathymetry will be obtained using video images technique, cBathy 2. The system will be tested for the Egmond aan Zee beach, located in the northern part of the Dutch coastline. This paper will test the applicability of bathymetry obtained from video technique to be used as input for the numerical modelling system by comparing simulation results using surveyed bathymetry and model results using video bathymetry. Results show that the video technique is able to produce bathymetry converging towards the ground truth observations. This bathymetry validation will be followed by an example of operational forecasting type of simulation on predicting rip currents. Rip currents flow fields simulated over measured and modeled bathymetries are compared in order to assess the performance of the proposed forecast system.

Detailed Characterization of Nearshore Processes During NCEX

NASA Astrophysics Data System (ADS)

Holland, K.; Kaihatu, J. M.; Plant, N.

2004-12-01

Recent technology advances have allowed the coupling of remote sensing methods with advanced wave and circulation models to yield detailed characterizations of nearshore processes. This methodology was demonstrated as part of the Nearshore Canyon EXperiment (NCEX) in La Jolla, CA during Fall 2003. An array of high-resolution, color digital cameras was installed to monitor an alongshore distance of nearly 2 km out to depths of 25 m. This digital imagery was analyzed over the three-month period through an automated process to produce hourly estimates of wave period, wave direction, breaker height, shoreline position, sandbar location, and bathymetry at numerous locations during daylight hours. Interesting wave propagation patterns in the vicinity of the canyons were observed. In addition, directional wave spectra and swash / surf flow velocities were estimated using more computationally intensive methods. These measurements were used to provide forcing and boundary conditions for the Delft3D wave and circulation model, giving additional estimates of nearshore processes such as dissipation and rip currents. An optimal approach for coupling these remotely sensed observations to the numerical model was selected to yield accurate, but also timely characterizations. This involved assimilation of directional spectral estimates near the offshore boundary to mimic forcing conditions achieved under traditional approaches involving nested domains. Measurements of breaker heights and flow speeds were also used to adaptively tune model parameters to provide enhanced accuracy. Comparisons of model predictions and video observations show significant correlation. As compared to nesting within larger-scale and coarser resolution models, the advantages of providing boundary conditions data using remote sensing is much improved resolution and fidelity. For example, rip current development was both modeled and observed. These results indicate that this approach to data-model coupling is tenable and may be useful in near-real-time characterizations required by many applied scenarios.

Development and Utilization of Regional Oceanic Modeling System (ROMS). Delicacy, Imprecision, and Uncertainty of Oceanic Simulations: An Investigation with the Regional Oceanic Modeling System (ROMS). Submesoscale Flows and Mixing in the Ocean Surface Layer Using the Regional Oceanic Modeling System (ROMS). Eddy Effects in General Circulation, Spanning Mean Currents, Mesoscale Eddies, and Topographic Generation, including Submesoscale Nests

DTIC Science & Technology

2012-09-30

unbalanced motions is likely to occur. Due to an rapidly expanding set of investigation on oceanic flows at submesoscales, it is increasingly clear...Uchiyama, E. M. Lane, J. M. Restrepo, & J. C. McWilliams, 2011: A vortex force analysis of the interaction of rip currents and gravity waves. J. Geophys...particular topographic features, the torque is pervasively positive (cyclonic) along the Stream, in opposition to the anticyclonic wind curl in the

Rip currents, mega-cusps, and eroding dunes

USGS Publications Warehouse

Thornton, E.B.; MacMahan, J.; Sallenger, A.H.

2007-01-01

Dune erosion is shown to occur at the embayment of beach mega-cusps O(200 m alongshore) that are associated with rip currents. The beach is the narrowest at the embayment of the mega-cusps allowing the swash of large storm waves coincident with high tides to reach the toe of the dune, to undercut the dune and to cause dune erosion. Field measurements of dune, beach, and rip current morphology are acquired along an 18 km shoreline in southern Monterey Bay, California. This section of the bay consists of a sandy shoreline backed by extensive dunes, rising to heights exceeding 40 m. There is a large increase in wave height going from small wave heights in the shadow of a headland, to the center of the bay where convergence of waves owing to refraction over the Monterey Bay submarine canyon results in larger wave heights. The large alongshore gradient in wave height results in a concomitant alongshore gradient in morphodynamic scale. The strongly refracted waves and narrow bay aperture result in near normal wave incidence, resulting in well-developed, persistent rip currents along the entire shoreline. The alongshore variations of the cuspate shoreline are found significantly correlated with the alongshore variations in rip spacing at 95% confidence. The alongshore variations of the volume of dune erosion are found significantly correlated with alongshore variations of the cuspate shoreline at 95% confidence. Therefore, it is concluded the mega-cusps are associated with rip currents and that the location of dune erosion is associated with the embayment of the mega-cusp.

Development and evaluation of an intervention to reduce rip current related beach drowning.

PubMed

Hatfield, Julie; Williamson, Ann; Sherker, Shauna; Brander, Rob; Hayen, Andrew

2012-05-01

The objective of this research was to evaluate a campaign to improve beachgoer recognition of calm-looking rip currents, known to contribute to surf drowning. Posters, postcards, and brochures conveying the message "Don't get sucked in by the rip" were distributed in an intervention area. Beachgoers were interviewed in this and a similar control area one year before and immediately after the intervention (respective response rates: 69.9% and 82.3%), Consenting respondents were sent follow-up questionnaires after approximately 6 months and 55% responded. In the intervention area, 28.8% of post-intervention, and 57.2% of follow-up respondents, had seen our campaign. At post-intervention, intervention respondents demonstrated improvement (relative to baseline) in intentions to swim away from a calm-looking rip, ability and confidence in identifying a rip, intention never to swim at unpatrolled beaches, and responses to being caught in a rip, compared to the control respondents. Similar improvements were observed post-intervention for respondents in the intervention area who had seen our campaign (relative to those who had not), and at 6 month follow-up for intervention respondents (relative to control respondents). The relatively brief print-based campaign was effective in warning beachgoers about calm-looking rips. Copyright © 2011 Elsevier Ltd. All rights reserved.

RIP3: a molecular switch for necrosis and inflammation

PubMed Central

Moriwaki, Kenta; Chan, Francis Ka-Ming

2013-01-01

The receptor-interacting protein kinase 3 (RIP3/RIPK3) has emerged as a critical regulator of programmed necrosis/necroptosis, an inflammatory form of cell death with important functions in pathogen-induced and sterile inflammation. RIP3 activation is tightly regulated by phosphorylation, ubiquitination, and caspase-mediated cleavage. These post-translational modifications coordinately regulate the assembly of a macromolecular signaling complex termed the necrosome. Recently, several reports indicate that RIP3 can promote inflammation independent of its pronecrotic activity. Here, we review our current understanding of the mechanisms that drive RIP3-dependent necrosis and its role in different inflammatory diseases. PMID:23913919

The Plant Ribosome-Inactivating Proteins Play Important Roles in Defense against Pathogens and Insect Pest Attacks

PubMed Central

Zhu, Feng; Zhou, Yang-Kai; Ji, Zhao-Lin; Chen, Xiao-Ren

2018-01-01

Ribosome-inactivating proteins (RIPs) are toxic N-glycosidases that depurinate eukaryotic and prokaryotic rRNAs, thereby arresting protein synthesis during translation. RIPs are widely found in various plant species and within different tissues. It is demonstrated in vitro and in transgenic plants that RIPs have been connected to defense by antifungal, antibacterial, antiviral, and insecticidal activities. However, the mechanism of these effects is still not completely clear. There are a number of reviews of RIPs. However, there are no reviews on the biological functions of RIPs in defense against pathogens and insect pests. Therefore, in this report, we focused on the effect of RIPs from plants in defense against pathogens and insect pest attacks. First, we summarize the three different types of RIPs based on their physical properties. RIPs are generally distributed in plants. Then, we discuss the distribution of RIPs that are found in various plant species and in fungi, bacteria, algae, and animals. Various RIPs have shown unique bioactive properties including antibacterial, antifungal, antiviral, and insecticidal activity. Finally, we divided the discussion into the biological roles of RIPs in defense against bacteria, fungi, viruses, and insects. This review is focused on the role of plant RIPs in defense against bacteria, fungi, viruses, and insect attacks. The role of plant RIPs in defense against pathogens and insects is being comprehended currently. Future study utilizing transgenic technology approaches to study the mechanisms of RIPs will undoubtedly generate a better comprehending of the role of plant RIPs in defense against pathogens and insects. Discovering additional crosstalk mechanisms between RIPs and phytohormones or reactive oxygen species (ROS) against pathogen and insect infections will be a significant subject in the field of biotic stress study. These studies are helpful in revealing significance of genetic control that can be beneficial to engineer crops tolerance to biotic stress. PMID:29479367

Methodology for prediction of rip currents using a three-dimensional numerical, coupled, wave current model

USGS Publications Warehouse

Voulgaris, George; Kumar, Nirnimesh; Warner, John C.; Leatherman, Stephen; Fletemeyer, John

2011-01-01

Rip current currents constitute one of the most common hazards in the nearshore that threaten the lives of the unaware public that makes recreational use of the coastal zone. Society responds to this danger through a number of measures that include: (a) the deployment of trained lifeguards; (b) public education related to the hidden hazards of the nearshore; and (c) establishment of warning systems.

Comparing a quasi-3D to a full 3D nearshore circulation model: SHORECIRC and ROMS

USGS Publications Warehouse

Haas, Kevin A.; Warner, John C.

2009-01-01

Predictions of nearshore and surf zone processes are important for determining coastal circulation, impacts of storms, navigation, and recreational safety. Numerical modeling of these systems facilitates advancements in our understanding of coastal changes and can provide predictive capabilities for resource managers. There exists many nearshore coastal circulation models, however they are mostly limited or typically only applied as depth integrated models. SHORECIRC is an established surf zone circulation model that is quasi-3D to allow the effect of the variability in the vertical structure of the currents while maintaining the computational advantage of a 2DH model. Here we compare SHORECIRC to ROMS, a fully 3D ocean circulation model which now includes a three dimensional formulation for the wave-driven flows. We compare the models with three different test applications for: (i) spectral waves approaching a plane beach with an oblique angle of incidence; (ii) monochromatic waves driving longshore currents in a laboratory basin; and (iii) monochromatic waves on a barred beach with rip channels in a laboratory basin. Results identify that the models are very similar for the depth integrated flows and qualitatively consistent for the vertically varying components. The differences are primarily the result of the vertically varying radiation stress utilized by ROMS and the utilization of long wave theory for the radiation stress formulation in vertical varying momentum balance by SHORECIRC. The quasi-3D model is faster, however the applicability of the fully 3D model allows it to extend over a broader range of processes, temporal, and spatial scales.

Comparing a quasi-3D to a full 3D nearshore circulation model: SHORECIRC and ROMS

USGS Publications Warehouse

Haas, K.A.; Warner, J.C.

2009-01-01

Predictions of nearshore and surf zone processes are important for determining coastal circulation, impacts of storms, navigation, and recreational safety. Numerical modeling of these systems facilitates advancements in our understanding of coastal changes and can provide predictive capabilities for resource managers. There exists many nearshore coastal circulation models, however they are mostly limited or typically only applied as depth integrated models. SHORECIRC is an established surf zone circulation model that is quasi-3D to allow the effect of the variability in the vertical structure of the currents while maintaining the computational advantage of a 2DH model. Here we compare SHORECIRC to ROMS, a fully 3D ocean circulation model which now includes a three dimensional formulation for the wave-driven flows. We compare the models with three different test applications for: (i) spectral waves approaching a plane beach with an oblique angle of incidence; (ii) monochromatic waves driving longshore currents in a laboratory basin; and (iii) monochromatic waves on a barred beach with rip channels in a laboratory basin. Results identify that the models are very similar for the depth integrated flows and qualitatively consistent for the vertically varying components. The differences are primarily the result of the vertically varying radiation stress utilized by ROMS and the utilization of long wave theory for the radiation stress formulation in vertical varying momentum balance by SHORECIRC. The quasi-3D model is faster, however the applicability of the fully 3D model allows it to extend over a broader range of processes, temporal, and spatial scales. ?? 2008 Elsevier Ltd.

Mapping bathymetry in an active surf zone with the WorldView2 multispectral satellite

NASA Astrophysics Data System (ADS)

Trimble, S. M.; Houser, C.; Brander, R.; Chirico, P.

2015-12-01

Rip currents are strong, narrow seaward flows of water that originate in the surf zones of many global beaches. They are related to hundreds of international drownings each year, but exact numbers are difficult to calculate due to logistical difficulties in obtaining accurate incident reports. Annual average rip current fatalities are estimated to be ~100, 53 and 21 in the United States (US), Costa Rica, and Australia respectively. Current warning systems (e.g. National Weather Service) do not account for fine resolution nearshore bathymetry because it is difficult to capture. The method shown here could provide frequent, high resolution maps of nearshore bathymetry at a scale required for improved rip prediction and warning. This study demonstrates a method for mapping bathymetry in the surf zone (20m deep and less), specifically within rip channels, because rips form at topographically low spots in the bathymetry as a result of feedback amongst waves, substrate, and antecedent bathymetry. The methods employ the Digital Globe WorldView2 (WV2) multispectral satellite and field measurements of depth to generate maps of the changing bathymetry at two embayed, rip-prone beaches: Playa Cocles, Puerto Viejo de Talamanca, Costa Rica, and Bondi Beach, Sydney, Australia. WV2 has a 1.1 day pass-over rate with 1.84m ground pixel resolution of 8 bands, including 'yellow' (585-625 nm) and 'coastal blue' (400-450 nm). The data is used to classify bottom type and to map depth to the return in multiple bands. The methodology is tested at each site for algorithm consistency between dates, and again for applicability between sites.

Ribosome-inactivating proteins

PubMed Central

Walsh, Matthew J; Dodd, Jennifer E; Hautbergue, Guillaume M

2013-01-01

Ribosome-inactivating proteins (RIPs) were first isolated over a century ago and have been shown to be catalytic toxins that irreversibly inactivate protein synthesis. Elucidation of atomic structures and molecular mechanism has revealed these proteins to be a diverse group subdivided into two classes. RIPs have been shown to exhibit RNA N-glycosidase activity and depurinate the 28S rRNA of the eukaryotic 60S ribosomal subunit. In this review, we compare archetypal RIP family members with other potent toxins that abolish protein synthesis: the fungal ribotoxins which directly cleave the 28S rRNA and the newly discovered Burkholderia lethal factor 1 (BLF1). BLF1 presents additional challenges to the current classification system since, like the ribotoxins, it does not possess RNA N-glycosidase activity but does irreversibly inactivate ribosomes. We further discuss whether the RIP classification should be broadened to include toxins achieving irreversible ribosome inactivation with similar turnovers to RIPs, but through different enzymatic mechanisms. PMID:24071927

Implementation and modification of a three-dimensional radiation stress formulation for surf zone and rip-current applications

USGS Publications Warehouse

Kumar, N.; Voulgaris, G.; Warner, John C.

2011-01-01

Regional Ocean Modeling System (ROMS v 3.0), a three-dimensional numerical ocean model, was previously enhanced for shallow water applications by including wave-induced radiation stress forcing provided through coupling to wave propagation models (SWAN, REF/DIF). This enhancement made it suitable for surf zone applications as demonstrated using examples of obliquely incident waves on a planar beach and rip current formation in longshore bar trough morphology (Haas and Warner, 2009). In this contribution, we present an update to the coupled model which implements a wave roller model and also a modified method of the radiation stress term based on Mellor (2008, 2011a,b,in press) that includes a vertical distribution which better simulates non-conservative (i.e., wave breaking) processes and appears to be more appropriate for sigma coordinates in very shallow waters where wave breaking conditions dominate. The improvements of the modified model are shown through simulations of several cases that include: (a) obliquely incident spectral waves on a planar beach; (b) obliquely incident spectral waves on a natural barred beach (DUCK'94 experiment); (c) alongshore variable offshore wave forcing on a planar beach; (d) alongshore varying bathymetry with constant offshore wave forcing; and (e) nearshore barred morphology with rip-channels. Quantitative and qualitative comparisons to previous analytical, numerical, laboratory studies and field measurements show that the modified model replicates surf zone recirculation patterns (onshore drift at the surface and undertow at the bottom) more accurately than previous formulations based on radiation stress (Haas and Warner, 2009). The results of the model and test cases are further explored for identifying the forces operating in rip current development and the potential implication for sediment transport and rip channel development. Also, model analysis showed that rip current strength is higher when waves approach at angles of 5?? to 10?? in comparison to normally incident waves. ?? 2011 Elsevier B.V.

Ribosome-inactivating proteins: potent poisons and molecular tools.

PubMed

Walsh, Matthew J; Dodd, Jennifer E; Hautbergue, Guillaume M

2013-11-15

Ribosome-inactivating proteins (RIPs) were first isolated over a century ago and have been shown to be catalytic toxins that irreversibly inactivate protein synthesis. Elucidation of atomic structures and molecular mechanism has revealed these proteins to be a diverse group subdivided into two classes. RIPs have been shown to exhibit RNA N-glycosidase activity and depurinate the 28S rRNA of the eukaryotic 60S ribosomal subunit. In this review, we compare archetypal RIP family members with other potent toxins that abolish protein synthesis: the fungal ribotoxins which directly cleave the 28S rRNA and the newly discovered Burkholderia lethal factor 1 (BLF1). BLF1 presents additional challenges to the current classification system since, like the ribotoxins, it does not possess RNA N-glycosidase activity but does irreversibly inactivate ribosomes. We further discuss whether the RIP classification should be broadened to include toxins achieving irreversible ribosome inactivation with similar turnovers to RIPs, but through different enzymatic mechanisms.

Does Switching to Reduced Ignition Propensity Cigarettes Alter Smoking Behavior or Exposure to Tobacco Smoke Constituents?

PubMed Central

Rees, Vaughan W.; Norton, Kaila J.; Cummings, K. Michael; Connolly, Gregory N.; Alpert, Hillel R.; Sjödin, Andreas; Romanoff, Lovisa; Li, Zheng; June, Kristie M.; Giovino, Gary A.

2010-01-01

Introduction: Since 2004, several jurisdictions have mandated that cigarettes show reduced ignition propensity (RIP) in laboratory testing. RIP cigarettes may limit fires caused by smoldering cigarettes, reducing fire-related deaths and injury. However, some evidence suggests that RIP cigarettes emit more carbon monoxide and polycyclic aromatic hydrocarbons, and smokers may alter their smoking patterns in response to RIP cigarettes. Both of these could increase smokers’ exposures to harmful constituents in cigarettes. Methods: An 18-day switching study with a comparison group was conducted in Boston, MA (N = 77), and Buffalo, NY (N = 83), in 2006–2007. Current daily smokers completed 4 laboratory visits and two 48-hr field data collections. After a 4-day baseline, Boston participants switched to RIP cigarettes for 14 days, whereas Buffalo participants smoked RIP cigarettes throughout. Outcome measures included cigarettes smoked per day; smoking topography; salivary cotinine; breath CO; and hydroxylated metabolites of pyrene, naphthalene, phenanthrene, and fluorene. Because the groups differed demographically, analyses adjusted for race, age, and sex. Results: We observed no significant changes in smoking topography or CO exposure among participants who switched to RIP cigarettes. Cigarette use decreased significantly in the switched group (37.7 cigarettes/48 hr vs. 32.6 cigarettes/48 hr, p = .031), while hydroxyphenanthrenes increased significantly (555 ng/g creatinine vs. 669 ng/g creatinine, p = .007). No other biomarkers were significantly affected. Discussion: Small increases in exposure to phenanthrene among smokers who switched to RIP versions were observed, while other exposures and smoking topography were not significantly affected. Toxicological implications of these findings are unclear. These findings should be weighed against the potential public health benefits of adopting RIP design standards for cigarette products. PMID:20805292

Rethinking the design of the furniture rough mill

Treesearch

Charles J. Gatchell; Charles J. Gatchell

1987-01-01

This paper discusses the crosscut-first rough mill with emphasis on the effects of lumber quality, cutting bills, and operator efficiency on yields. Adding a gang-rip-first option is recommended, which will use more of the lower grades of lumber while meeting the needs of the furniture and cabinet industries. Current research that indicates why gang ripping to glueline...

ROMI 4.0: Rough mill simulator 4.0 users manual

Treesearch

R. Edward Thomas; Timo Grueneberg; Urs Buehlmann

2015-01-01

The Rough MIll simulator (ROMI Version 4.0) is a computer software package for personal computers (PCs) that simulates current industrial practices for rip-first, chop-first, and rip and chop-first lumber processing. This guide shows how to set up the software; design, implement, and execute simulations; and examine the results. ROMI 4.0 accepts cutting bills with as...

CYLD Deubiquitinates RIP1 in the TNFα-Induced Necrosome to Facilitate Kinase Activation and Programmed Necrosis

PubMed Central

Moquin, David M.; McQuade, Thomas; Chan, Francis Ka-Ming

2013-01-01

Background Necroptosis/programmed necrosis is initiated by a macro-molecular protein complex termed the necrosome. Receptor interacting protein kinase 1 (RIPK1/RIP1) and RIP3 are key components of the necrosome. TNFα is a prototypic inducer of necrosome activation, and it is widely believed that deubiquitination of RIP1 at the TNFR-1 signaling complex precedes transition of RIP1 into the cytosol where it forms the RIP1-RIP3 necrosome. Cylindromatosis (CYLD) is believed to promote programmed necrosis by facilitating RIP1 deubiquitination at this membrane receptor complex. Methodology/Principal Findings We demonstrate that RIP1 is indeed the primary target of CYLD in TNFα-induced programmed necrosis. We observed that CYLD does not regulate RIP1 ubiquitination at the TNF receptor. TNF and zVAD-induced programmed necrosis was highly attenuated in CYLD-/- cells. However, in the presence of cycloheximide or SMAC mimetics, programmed necrosis was only moderately reduced in CYLD-/- cells. Under the latter conditions, RIP1-RIP3 necrosome formation is only delayed, but not abolished in CYLD-/- cells. We further demonstrate that RIP1 within the NP-40 insoluble necrosome is ubiquitinated and that CYLD regulates RIP1 ubiquitination in this compartment. Hence, RIP1 ubiquitination in this late-forming complex is greatly increased in CYLD-/- cells. Increased RIP1 ubiquitination impairs RIP1 and RIP3 phosphorylation, a signature of kinase activation. Conclusions/Significance Our results show that CYLD regulates RIP1 ubiquitination in the TNFα-induced necrosome, but not in the TNFR-1 signaling complex. In cells sensitized to programmed necrosis with SMAC mimetics, CYLD is not essential for necrosome assembly. Since SMAC mimetics induces the loss of the E3 ligases cIAP1 and cIAP2, reduced RIP1 ubiquitination could lead to reduced requirement for CYLD to remove ubiquitin chains from RIP1 in the TNFR-1 complex. As increased RIP1 ubiquitination in the necrosome correlates with impaired RIP1 and RIP3 phosphorylation and function, these results suggest that CYLD controls RIP1 kinase activity during necrosome assembly. PMID:24098568

A GPU accelerated PDF transparency engine

NASA Astrophysics Data System (ADS)

Recker, John; Lin, I.-Jong; Tastl, Ingeborg

2011-01-01

As commercial printing presses become faster, cheaper and more efficient, so too must the Raster Image Processors (RIP) that prepare data for them to print. Digital press RIPs, however, have been challenged to on the one hand meet the ever increasing print performance of the latest digital presses, and on the other hand process increasingly complex documents with transparent layers and embedded ICC profiles. This paper explores the challenges encountered when implementing a GPU accelerated driver for the open source Ghostscript Adobe PostScript and PDF language interpreter targeted at accelerating PDF transparency for high speed commercial presses. It further describes our solution, including an image memory manager for tiling input and output images and documents, a PDF compatible multiple image layer blending engine, and a GPU accelerated ICC v4 compatible color transformation engine. The result, we believe, is the foundation for a scalable, efficient, distributed RIP system that can meet current and future RIP requirements for a wide range of commercial digital presses.

Impact of reduced ignition propensity cigarette regulation on consumer smoking behavior and quit intentions: evidence from 6 waves (2004–11) of the ITC Four Country Survey

PubMed Central

2013-01-01

Background Although on the decline, smoking-related fires remain a leading cause of fire death in the United States and United Kingdom and account for over 10% of fire-related deaths worldwide. This has prompted lawmakers to enact legislation requiring manufacturers to implement reduced ignition propensity (RIP) safety standards for cigarettes. The current research evaluates how implementation of RIP safety standards in different countries influenced smokers’ perceptions of cigarette self-extinguishment, frequency of extinguishment, and the impact on consumer smoking behaviors, including cigarettes smoked per day and planning to quit. Methods Participants for this research come from Waves 3 through 8 of the International Tobacco Control (ITC) Four Country Survey conducted longitudinally from 2004 through 2011 in the United States, United Kingdom, Australia, and Canada. Results Perceptions of cigarette self-extinguishment and frequency of extinguishment increased concurrently with an increase in the prevalence of RIP safety standards for cigarettes. Presence of RIP safety standards was also associated with a greater intention to quit smoking, but was not associated with the number of cigarettes smoked per day. Intention to quit was higher among those who were more likely to report that their cigarettes self-extinguish sometimes and often, but we found no evidence of an interaction between frequency of extinguishment and RIP safety standards on quit intentions. Conclusions Overall, because these standards largely do not influence consumer smoking behavior, RIP implementation may significantly reduce the number of cigarette-related fires and the associated death and damages. Further research should assess how implementation of RIP safety standards has influenced smoking-related fire incidence, deaths, and other costs associated with smoking-related fires. PMID:24359292

Impact of reduced ignition propensity cigarette regulation on consumer smoking behavior and quit intentions: evidence from 6 waves (2004-11) of the ITC Four Country Survey.

PubMed

Adkison, Sarah E; O'Connor, Richard J; Borland, Ron; Yong, Hua-Hie; Cummings, K Michael; Hammond, David; Fong, Geoffrey T

2013-12-21

Although on the decline, smoking-related fires remain a leading cause of fire death in the United States and United Kingdom and account for over 10% of fire-related deaths worldwide. This has prompted lawmakers to enact legislation requiring manufacturers to implement reduced ignition propensity (RIP) safety standards for cigarettes. The current research evaluates how implementation of RIP safety standards in different countries influenced smokers' perceptions of cigarette self-extinguishment, frequency of extinguishment, and the impact on consumer smoking behaviors, including cigarettes smoked per day and planning to quit. Participants for this research come from Waves 3 through 8 of the International Tobacco Control (ITC) Four Country Survey conducted longitudinally from 2004 through 2011 in the United States, United Kingdom, Australia, and Canada. Perceptions of cigarette self-extinguishment and frequency of extinguishment increased concurrently with an increase in the prevalence of RIP safety standards for cigarettes. Presence of RIP safety standards was also associated with a greater intention to quit smoking, but was not associated with the number of cigarettes smoked per day. Intention to quit was higher among those who were more likely to report that their cigarettes self-extinguish sometimes and often, but we found no evidence of an interaction between frequency of extinguishment and RIP safety standards on quit intentions. Overall, because these standards largely do not influence consumer smoking behavior, RIP implementation may significantly reduce the number of cigarette-related fires and the associated death and damages. Further research should assess how implementation of RIP safety standards has influenced smoking-related fire incidence, deaths, and other costs associated with smoking-related fires.

RIP1 Inhibition Rescues from LPS-Induced RIP3-Mediated Programmed Cell Death, Distributed Energy Metabolism and Spatial Memory Impairment.

PubMed

Nikseresht, Sara; Khodagholi, Fariba; Nategh, Mohsen; Dargahi, Leila

2015-10-01

Receptor interacting protein 1 (RIP1) has a critical role in initiation of programmed necrosis or necroptosis. RIP1 in a close collaboration with RIP3 not only mediates necroptosis but also is involved in apoptosis and inflammatory signaling. However, the interpretation of the distinct function of RIP1 and RIP3 is complicated. Herein, we demonstrated that RIP1 inhibition in the context of LPS-induced neuroinflammation decreases RIP3 expression. Concomitant administration of Nec-1, specific inhibitor of RIP1, with LPS also attenuated the activating effect of RIP3 on metabolic enzymes, glutamate-ammonia ligase and glutamate dehydrogenase as bioenergetic determinants, in hippocampal and cortical cells. RIP1 inhibition possessed an anti-inflammatory effect and improved the antioxidant capacity against LPS. Interestingly, and opposed to some reports that necroptosis inhibition sensitizes cells to apoptosis, our results showed that RIP1 inhibition attenuates apoptotic cell death in response to LPS. The survival of neuronal function was also confirmed by measuring spontaneous alternations of rats in Y-maze. In conclusion, effects of RIP1 inhibition on RIP3 and cell death provide new approaches to ameliorate neuroinflammation and relative disorders.

Functional conservation and innovation of amphioxus RIP1-mediated signaling in cell fate determination.

PubMed

Li, Jun; Yuan, Shaochun; Qi, Lin; Huang, Shengfeng; Huang, Guangrui; Yang, Manyi; Xu, Liqun; Li, Yuxin; Zhang, Renwei; Yu, Yingcai; Chen, Shangwu; Xu, Anlong

2011-10-15

Recently, receptor interacting protein (RIP)-1 has been recognized as an intracellular sensor at the crossroads of apoptosis, necroptosis, and cell survival. To reveal when this crucial molecule originated and how its function in integrating stress signals evolved, in this study we report on two RIP1 homologs in Chinese amphioxus (Branchiostoma belcheri tsingtauense), designated B. belcheri tsingtauense RIP1a and B. belcheri tsingtauense RIP1b. Phylogenetic analysis indicates that they are generated by domain recombination and lineage-specific duplication. Similar to human RIP1, both B. belcheri tsingtauense RIP1a and B. belcheri tsingtauense RIP1b activate NF-κB in a kinase activity-independent manner and induce apoptosis through the Fas-associated death domain protein-caspase cascade. Moreover, we found that the natural point mutation of Q to I in the RIP homotypic interaction motif of B. belcheri tsingtauense RIP1a provides negative feedback for amphioxus RIP1-mediated signaling. Thus, our study not only suggests that RIP1 has emerged as a molecular switch in triggering cell death or survival in a basal chordate, but also adds new insights into the regulation mechanisms of RIP1-related signaling, providing a novel perspective on human diseases mediated by RIP1.

Ralstonia solanacearum novel E3 ubiquitin ligase (NEL) effectors RipAW and RipAR suppress pattern-triggered immunity in plants.

PubMed

Nakano, Masahito; Oda, Kenji; Mukaihara, Takafumi

2017-07-01

Ralstonia solanacearum is the causal agent of bacterial wilt in solanaceous crops. This pathogen injects more than 70 effector proteins into host plant cells via the Hrp type III secretion system to cause a successful infection. However, the function of these effectors in plant cells, especially in the suppression of plant immunity, remains largely unknown. In this study, we characterized two Ralstonia solanacearum effectors, RipAW and RipAR, which share homology with the IpaH family of effectors from animal and plant pathogenic bacteria, that have a novel E3 ubiquitin ligase (NEL) domain. Recombinant RipAW and RipAR show E3 ubiquitin ligase activity in vitro. RipAW and RipAR localized to the cytoplasm of plant cells and significantly suppressed pattern-triggered immunity (PTI) responses such as the production of reactive oxygen species and the expression of defence-related genes when expressed in leaves of Nicotiana benthamiana. Mutation in the conserved cysteine residue in the NEL domain of RipAW completely abolished the E3 ubiquitin ligase activity in vitro and the ability to suppress PTI responses in plant leaves. These results indicate that RipAW suppresses plant PTI responses through the E3 ubiquitin ligase activity. Unlike other members of the IpaH family of effectors, RipAW and RipAR had no leucine-rich repeat motifs in their amino acid sequences. A conserved C-terminal region of RipAW is indispensable for PTI suppression. Transgenic Arabidopsis plants expressing RipAW and RipAR showed increased disease susceptibility, suggesting that RipAW and RipAR contribute to bacterial virulence in plants.

Receptor-interacting protein kinase 3-mediated programmed cell necrosis in rats subjected to focal cerebral ischemia-reperfusion injury.

PubMed

Dong, Yanru; Bao, Cuifen; Yu, Jingwei; Liu, Xia

2016-07-01

In the current study, the activation of tumor necrosis factor-α receptor 1 (TNFR1) and receptor-interacting protein kinase 3 (RIP3) were investigated following cerebral ischemia-reperfusion injury (CIRI). Healthy SD rats were randomly divided into 3 groups: Sham operation group, model group and inhibitor group. The model group and inhibitor group were further divided into 4 subgroups of 6, 12, 24 and 72 h following CIRI. Using right middle cerebral artery embolization, the CIRI model was generated. To confirm that the CIRI model was established, neurological scores, TTC staining and brain water content measurements were conducted. Immunohistochemistry and western blotting were conducted to investigate the expression of TNFR1 and RIP3 in the cerebral cortex. It was observed that nerve cell necrosis occurred following 6 h of CIRI. The appearance of necrotic cells was gradually increased with increasing CIRI duration. TNFR1 and RIP3 were positively expressed following 6 h of CIRI. With increasing durations of CIRI, the protein expression levels of TNFR1 and RIP3 were significantly increased. Pre‑administration with Z-VAD-FMK (zVAD) significantly increased the protein level of RIP3, however, had no effect on the levels of TNFR1, and was accompanied by a reduction in necrosis. In conclusion, RIP3‑mediated cell necrosis was enhanced by caspase blockade zVAD and the function of zVAD was independent of TNFR1 signaling following IR.

Depletion of the Receptor-Interacting Protein Kinase 3 (RIP3) Decreases Photoreceptor Cell Death During the Early Stages of Ocular Murine Cytomegalovirus Infection.

PubMed

Xu, Jinxian; Mo, Juan; Liu, Xinglou; Marshall, Brendan; Atherton, Sally S; Dong, Zheng; Smith, Sylvia; Zhang, Ming

2018-05-01

The purpose of this study was to determine if the receptor-interacting protein kinase 3 (RIP3) plays a significant role in innate immune responses and death of bystander retinal neurons during murine cytomegalovirus (MCMV) retinal infection, by comparing the innate immune response and cell death in RIP3-depleted mice (Rip3-/-) and Rip3+/+ control mice. Rip3-/- and Rip3+/+ mice were immunosuppressed (IS) and inoculated with MCMV via the supraciliary route. Virus-injected and mock-injected control eyes were removed at days 4, 7, and 10 post infection (p.i.) and markers of innate immunity and cell death were analyzed. Compared to Rip3+/+ mice, significantly more MCMV was recovered and more MCMV-infected RPE cells were observed in injected eyes of Rip3-/- mice at days 4 and 7 p.i. In contrast, fewer TUNEL-stained photoreceptors were observed in Rip3-/- eyes than in Rip3+/+ eyes at these times. Electron microscopy showed that significantly more apoptotic photoreceptor cells were present in Rip3+/+ mice than in Rip3-/- mice. Immunohistochemistry showed that the majority of TUNEL-stained photoreceptors died via mitochondrial flavoprotein apoptosis-inducing factor (AIF)-mediated, caspase 3-independent apoptosis. The majority of RIP3-expressing cells in infected eyes were RPE cells, microglia/macrophages, and glia, whereas retinal neurons contained much lower amounts of RIP3. Western blots showed significantly higher levels of activated nuclear factor-κB and caspase 1 were present in Rip3+/+ eyes compared to Rip3-/- eyes. Our results suggest that RIP3 enhances innate immune responses against ocular MCMV infection via activation of the inflammasome and nuclear factor-κB, which also leads to inflammation and death of bystander cells by multiple pathways including apoptosis and necroptosis.

Depletion of the Receptor-Interacting Protein Kinase 3 (RIP3) Decreases Photoreceptor Cell Death During the Early Stages of Ocular Murine Cytomegalovirus Infection

PubMed Central

Xu, Jinxian; Mo, Juan; Liu, Xinglou; Marshall, Brendan; Atherton, Sally S.; Dong, Zheng; Smith, Sylvia

2018-01-01

Purpose The purpose of this study was to determine if the receptor-interacting protein kinase 3 (RIP3) plays a significant role in innate immune responses and death of bystander retinal neurons during murine cytomegalovirus (MCMV) retinal infection, by comparing the innate immune response and cell death in RIP3-depleted mice (Rip3−/−) and Rip3+/+ control mice. Methods Rip3−/− and Rip3+/+ mice were immunosuppressed (IS) and inoculated with MCMV via the supraciliary route. Virus-injected and mock-injected control eyes were removed at days 4, 7, and 10 post infection (p.i.) and markers of innate immunity and cell death were analyzed. Results Compared to Rip3+/+ mice, significantly more MCMV was recovered and more MCMV-infected RPE cells were observed in injected eyes of Rip3−/− mice at days 4 and 7 p.i. In contrast, fewer TUNEL-stained photoreceptors were observed in Rip3−/− eyes than in Rip3+/+ eyes at these times. Electron microscopy showed that significantly more apoptotic photoreceptor cells were present in Rip3+/+ mice than in Rip3−/− mice. Immunohistochemistry showed that the majority of TUNEL-stained photoreceptors died via mitochondrial flavoprotein apoptosis-inducing factor (AIF)-mediated, caspase 3–independent apoptosis. The majority of RIP3-expressing cells in infected eyes were RPE cells, microglia/macrophages, and glia, whereas retinal neurons contained much lower amounts of RIP3. Western blots showed significantly higher levels of activated nuclear factor–κB and caspase 1 were present in Rip3+/+ eyes compared to Rip3−/− eyes. Conclusions Our results suggest that RIP3 enhances innate immune responses against ocular MCMV infection via activation of the inflammasome and nuclear factor–κB, which also leads to inflammation and death of bystander cells by multiple pathways including apoptosis and necroptosis.

Receptor-interacting protein kinases modulate noise-induced sensory hair cell death

PubMed Central

Zheng, H-W; Chen, J; Sha, S-H

2014-01-01

Receptor-interacting protein (RIP) kinases promote the induction of necrotic cell death pathways. Here we investigated signaling pathways in outer hair cells (OHCs) of adult male CBA/J mice exposed to noise that causes permanent threshold shifts, with a particular focus on RIP kinase-regulated necroptosis. One hour after noise exposure, nuclei of OHCs in the basal region of the cochlea displayed both apoptotic and necrotic features. RIP1 and RIP3 protein levels increased and caspase-8 was activated. Treatment with pan-caspase inhibitor ZVAD blocked the activation of caspase-8 and reduced the number of apoptotic nuclei, while increasing levels of RIP1, RIP3, and necrotic OHCs. Conversely, treatment with necrosis inhibitor necrostatin-1 (Nec-1) or RIP3 siRNA (siRIP3) diminished noise-induced increases in RIP1 and RIP3, and decreased necrotic OHC nuclei. This treatment also increased the number of apoptotic nuclei without increasing activation of caspase-8. Consistent with the elevation of levels of RIP1 and RIP3, noise-induced active AMPKα levels increased with ZVAD treatment, but decreased with Nec-1 and siRIP3 treatment. Furthermore, treatment with siRIP3 did not alter the activation of caspase-8, but instead increased activation of caspase-9 and promoted endonuclease G translocation into OHC nuclei. Finally, auditory brainstem response functional measurements and morphological assessment of OHCs showed that ZVAD treatment reduces noise-induced deficits. This protective function is potentiated when combined with siRIP3 treatment. In conclusion, noise-induced OHC apoptosis and necrosis are modulated by caspases and RIP kinases, respectively. Inhibition of either pathway shifts the prevalence of OHC death to the alternative pathway. PMID:24874734

Analysis of Ribosome Inactivating Protein (RIP): A Bioinformatics Approach

NASA Astrophysics Data System (ADS)

Jothi, G. Edward Gnana; Majilla, G. Sahaya Jose; Subhashini, D.; Deivasigamani, B.

2012-10-01

In spite of the medical advances in recent years, the world is in need of different sources to encounter certain health issues.Ribosome Inactivating Proteins (RIPs) were found to be one among them. In order to get easy access about RIPs, there is a need to analyse RIPs towards constructing a database on RIPs. Also, multiple sequence alignment was done towards screening for homologues of significant RIPs from rare sources against RIPs from easily available sources in terms of similarity. Protein sequences were retrieved from SWISS-PROT and are further analysed using pair wise and multiple sequence alignment.Analysis shows that, 151 RIPs have been characterized to date. Amongst them, there are 87 type I, 37 type II, 1 type III and 25 unknown RIPs. The sequence length information of various RIPs about the availability of full or partial sequence was also found. The multiple sequence alignment of 37 type I RIP using the online server Multalin, indicates the presence of 20 conserved residues. Pairwise alignment and multiple sequence alignment of certain selected RIPs in two groups namely Group I and Group II were carried out and the consensus level was found to be 98%, 98% and 90% respectively.

Rapid Inhibition Profiling in Bacillus subtilis to Identify the Mechanism of Action of New Antimicrobials.

PubMed

Lamsa, Anne; Lopez-Garrido, Javier; Quach, Diana; Riley, Eammon P; Pogliano, Joe; Pogliano, Kit

2016-08-19

Increasing antimicrobial resistance has become a major public health crisis. New antimicrobials with novel mechanisms of action (MOA) are desperately needed. We previously developed a method, bacterial cytological profiling (BCP), which utilizes fluorescence microscopy to rapidly identify the MOA of antimicrobial compounds. BCP is based upon our discovery that cells treated with antibiotics affecting different metabolic pathways generate different cytological signatures, providing quantitative information that can be used to determine a compound's MOA. Here, we describe a system, rapid inhibition profiling (RIP), for creating cytological profiles of new antibiotic targets for which there are currently no chemical inhibitors. RIP consists of the fast, inducible degradation of a target protein followed by BCP. We demonstrate that degrading essential proteins in the major metabolic pathways for DNA replication, transcription, fatty acid biosynthesis, and peptidoglycan biogenesis in Bacillus subtilis rapidly produces cytological profiles closely matching that of antimicrobials targeting the same pathways. Additionally, RIP and antibiotics targeting different steps in fatty acid biosynthesis can be differentiated from each other. We utilize RIP and BCP to show that the antibacterial MOA of four nonsteroidal anti-inflammatory antibiotics differs from that proposed based on in vitro data. RIP is a versatile method that will extend our knowledge of phenotypes associated with inactivating essential bacterial enzymes and thereby allow for screening for molecules that inhibit novel essential targets.

Classical and quantum cosmology of the little rip abrupt event

NASA Astrophysics Data System (ADS)

Albarran, Imanol; Bouhmadi-López, Mariam; Kiefer, Claus; Marto, João; Vargas Moniz, Paulo

2016-09-01

We analyze from a classical and quantum point of view the behavior of the Universe close to a little rip, which can be interpreted as a big rip sent towards the infinite future. Like a big rip singularity, a little rip implies the destruction of all bounded structures in the Universe and is thus an event where quantum effects could be important. We present here a new phantom scalar field model for the little rip. The quantum analysis is performed in quantum geometrodynamics, with the Wheeler-DeWitt equation as its central equation. We find that the little rip can be avoided in the sense of the DeWitt criterion, that is, by having a vanishing wave function at the place of the little rip. Therefore our analysis completes the answer to the question: can quantum cosmology smoothen or avoid the divergent behavior genuinely caused by phantom matter? We show that this can indeed happen for the little rip, similar to the avoidance of a big rip and a little sibling of the big rip.

Virus inhibition of RIP3-dependent necrosis.

PubMed

Upton, Jason W; Kaiser, William J; Mocarski, Edward S

2010-04-22

Viral infection activates cytokine expression and triggers cell death, the modulation of which is important for successful pathogenesis. Necroptosis is a form of programmed necrosis dependent on two related RIP homotypic interaction motif (RHIM)-containing signaling adaptors, receptor-interacting protein kinases (RIP) 1 and 3. We find that murine cytomegalovirus infection induces RIP3-dependent necrosis. Whereas RIP3 kinase activity and RHIM-dependent interactions control virus-associated necrosis, virus-induced death proceeds independently of RIP1 and is therefore distinct from TNFalpha-dependent necroptosis. Viral M45-encoded inhibitor of RIP activation (vIRA) targets RIP3 during infection and disrupts RIP3-RIP1 interactions characteristic of TNFalpha-induced necroptosis, thereby suppressing both death pathways. Importantly, attenuation of vIRA mutant virus in wild-type mice is normalized in RIP3-deficient mice. Thus, vIRA function validates necrosis as central to host defense against viral infections and highlights the benefit of multiple virus-encoded cell-death suppressors that inhibit not only apoptotic, but also necrotic mechanisms of virus clearance. Copyright 2010 Elsevier Inc. All rights reserved.

RIP2: A novel player in the regulation of keratinocyte proliferation and cutaneous wound repair?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adams, Stephanie; Valchanova, Ralitsa S.; Munz, Barbara, E-mail: barbara.munz@charite.de

2010-03-10

We could recently demonstrate an important role of receptor interacting protein 4 (RIP4) in the regulation of keratinocyte differentiation. Now, we analyzed a potential role of the RIP4 homolog RIP2 in keratinocytes. Specifically, we demonstrate here that rip2 expression is induced by scratch-wounding and after the induction of differentiation in these cells. Furthermore, serum growth factors and cytokines can induce rip2, with TNF-{alpha}-dependent induction being dependent on p38 MAPK. In addition, we demonstrate that scratch-induced upregulation of rip2 expression is completely blocked by the steroid dexamethasone. Since we also show that RIP2 is an important player in the regulation ofmore » keratinocyte proliferation, these data suggest that inhibition of rip2 upregulation after wounding might contribute to the reduced and delayed wound re-epithelialization phenotype seen in glucocorticoid-treated patients.« less

"I didn't know her, but…": parasocial mourning of mediated deaths on Facebook RIP pages

NASA Astrophysics Data System (ADS)

Klastrup, Lisbeth

2015-04-01

This article examines the use of six Danish "Rest in Peace" or (RIP) memorial pages. The article focuses on the relation between news media and RIP page use, in relation to general communicative practices on these pages. Based on an analysis of press coverage of the deaths of six young people and a close analysis of 1,015 comments extracted from the RIP pages created to memorialize them, it is shown that their deaths attracted considerable media attention, as did the RIP pages themselves. Comment activity seem to reflect the news stories in the way the commenters refer to the context of death and the emotional distress they experience, but mainly comments on the RIP pages are conventional expressions of sympathy and "RIP" wishes. The article concludes that public RIP pages might be understood as virtual spontaneous shrines, affording an emerging practice of "RIP-ing."

Extensive Evolution of Cereal Ribosome-Inactivating Proteins Translates into Unique Structural Features, Activation Mechanisms, and Physiological Roles

PubMed Central

De Zaeytijd, Jeroen; Van Damme, Els J. M.

2017-01-01

Ribosome-inactivating proteins (RIPs) are a class of cytotoxic enzymes that can depurinate rRNAs thereby inhibiting protein translation. Although these proteins have also been detected in bacteria, fungi, and even some insects, they are especially prevalent in the plant kingdom. This review focuses on the RIPs from cereals. Studies on the taxonomical distribution and evolution of plant RIPs suggest that cereal RIPs have evolved at an enhanced rate giving rise to a large and heterogeneous RIP gene family. Furthermore, several cereal RIP genes are characterized by a unique domain architecture and the lack of a signal peptide. This advanced evolution of cereal RIPs translates into distinct structures, activation mechanisms, and physiological roles. Several cereal RIPs are characterized by activation mechanisms that include the proteolytic removal of internal peptides from the N-glycosidase domain, a feature not documented for non-cereal RIPs. Besides their role in defense against pathogenic fungi or herbivorous insects, cereal RIPs are also involved in endogenous functions such as adaptation to abiotic stress, storage, induction of senescence, and reprogramming of the translational machinery. The unique properties of cereal RIPs are discussed in this review paper. PMID:28353660

Inhibition of HSP90α protects cultured neurons from oxygen-glucose deprivation induced necroptosis by decreasing RIP3 expression.

PubMed

Wang, Zhen; Guo, Li-Min; Wang, Yong; Zhou, Hong-Kang; Wang, Shu-Chao; Chen, Dan; Huang, Ju-Fang; Xiong, Kun

2018-06-01

Heat shock protein 90α (HSP90α) maintains cell stabilization and regulates cell death, respectively. Recent studies have shown that HSP90α is involved in receptor interacting protein 3 (RIP3)-mediated necroptosis in HT29 cells. It is known that oxygen and glucose deprivation (OGD) can induce necroptosis, which is regulated by RIP3 in neurons. However, it is still unclear whether HSP90α participates in the process of OGD-induced necroptosis in cultured neurons via the regulation of RIP3. Our study found that necroptosis occurs in primary cultured cortical neurons and PC-12 cells following exposure to OGD insult. Additionally, the expression of RIP3/p-RIP3, MLKL/p-MLKL, and the RIP1/RIP3 complex (necrosome) significantly increased following OGD, as measured through immunofluorescence (IF) staining, Western blotting (WB), and immunoprecipitation (IP) assay. Additionally, data from computer simulations and IP assays showed that HSP90α interacts with RIP3. In addition, HSP90α was overexpressed following OGD in cultured neurons, as measured through WB and IF staining. Inhibition of HSP90α in cultured neurons, using the specific inhibitor, geldanamycin (GA), and siRNA/shRNA of HSP90α, protected cultured neurons from necrosis. Our study showed that the inhibitor of HSP90α, GA, rescued cultured neurons not only by decreasing the expression of total RIP3/MLKL, but also by decreasing the expression of p-RIP3/p-MLKL and the RIP1/RIP3 necrosome. In this study, we reveal that inhibition of HSP90α protects primary cultured cortical neurons and PC-12 cells from OGD-induced necroptosis through the modulation of RIP3 expression. © 2017 Wiley Periodicals, Inc.

Characterization of a New HIV-1 CRF01_AE/ CRF07_BC recombinant virus in Tianjin, China.

PubMed

Zhou, Zhehua; Ma, Ping; Feng, Yi; Ou, Weidong; Qian, Jing; Gao, Liying; Zhang, Defa; Shao, Yiming; Wei, Min

2018-05-04

Human immunodeficiency virus (HIV) is notorious for its rapid evolving since its transmissions from money to human. Currently, HIV contains multiple subtypes, circulating recombinant forms (CRFs) and unique recombinant forms (URFs). Here, from an HIV-positive mother and her child in Tianjin, China, we identified a novel HIV-1 second-generation recombinant virus (TJ20170316 and TJ20170317) between CRF01_AE and CRF07_BC. Near full-length genomes were obtained from both samples, and they shared very close sequences, except some point mutations. Phylogenetic analyses of the near full-length genomes showed that they consist of CRF01_AE backbone and part CRF07_BC sequences. Recombinant Identification Program (RIP) and Simplot software identified four breakpoints in gag, pol, vif, tat genes in TJ20170316, totally different from other reported CRFs and URFs. The emergence of such URF in Tianjin, China, highlights the complexity of HIV-1 epidemic and more measures should be taken to prevent HIV transmissions.

Stroma-induced Jagged1 expression drives PC3 prostate cancer cell migration; disparate effects of RIP-generated proteolytic fragments on cell behaviour and Notch signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Delury, Craig, E-mail: c.delury@lancaster.ac.uk; Hart, Claire, E-mail: claire.hart@manchester.ac.uk; Brown, Mick, E-mail: michael.brown@ics.manchester.ac.uk

The Notch ligand Jagged1 is subject to regulated intramembrane proteolysis (RIP) which yields a soluble ectodomain (sJag) and a soluble Jagged1 intracellular domain (JICD). The full-length Jagged1 protein enhances prostate cancer (PCa) cell proliferation and is highly expressed in metastatic cells. However, little is known regarding the mechanisms by which Jagged1 or its RIP-generated fragments might promote PCa bone metastasis. In the current study we show that bone marrow stroma (BMS) induces Jagged1 expression in bone metastatic prostate cancer PC3 cells and that this enhanced expression is mechanistically linked to the promotion of cell migration. We also show that RIP-generatedmore » Jagged1 fragments exert disparate effects on PC3 cell behaviour and Notch signaling. In conclusion, the expression of both the full-length ligand and its RIP-generated fragments must be considered in tandem when attempting to regulate Jagged1 as a possible PCa therapy. - Highlights: • Bone marrow stroma induces Jagged1 expression in prostate cancer (PCa) PC3 cells. • This enhanced expression of full-length Jagged1 is required for PC3 cell migration. • Proteolytic fragments of Jagged1 exert disparate effects on PC3 cell behaviour. • Effects of fragments on cell behaviour do not correlate with Notch signaling. • Effects of Jagged1 and its fragments on PCa metastasis likely to be complex.« less

TALE-Like Effectors Are an Ancestral Feature of the Ralstonia solanacearum Species Complex and Converge in DNA Targeting Specificity.

PubMed

Schandry, Niklas; de Lange, Orlando; Prior, Philippe; Lahaye, Thomas

2016-01-01

Ralstonia solanacearum, a species complex of bacterial plant pathogens divided into four monophyletic phylotypes, causes plant diseases in tropical climates around the world. Some strains exhibit a broad host range on solanaceous hosts, while others are highly host-specific as for example some banana-pathogenic strains. Previous studies showed that transcription activator-like (TAL) effectors from Ralstonia, termed RipTALs, are capable of activating reporter genes in planta, if these are preceded by a matching effector binding element (EBE). RipTALs target DNA via their central repeat domain (CRD), where one repeat pairs with one DNA-base of the given EBE. The repeat variable diresidue dictates base repeat specificity in a predictable fashion, known as the TALE code. In this work, we analyze RipTALs across all phylotypes of the Ralstonia solanacearum species complex. We find that RipTALs are prevalent in phylotypes I and IV but absent from most phylotype III and II strains (10/12, 8/14, 1/24, and 1/5 strains contained a RipTAL, respectively). RipTALs originating from strains of the same phylotype show high levels of sequence similarity (>98%) in the N-terminal and C-terminal regions, while RipTALs isolated from different phylotypes show 47-91% sequence similarity in those regions, giving rise to four RipTAL classes. We show that, despite sequence divergence, the base preference for guanine, mediated by the N-terminal region, is conserved across RipTALs of all classes. Using the number and order of repeats found in the CRD, we functionally sub-classify RipTALs, introduce a new simple nomenclature, and predict matching EBEs for all seven distinct RipTALs identified. We experimentally study RipTAL EBEs and uncover that some RipTALs are able to target the EBEs of other RipTALs, referred to as cross-reactivity. In particular, RipTALs from strains with a broad host range on solanaceous hosts cross-react on each other's EBEs. Investigation of sequence divergence between RipTAL repeats allows for a reconstruction of repeat array biogenesis, for example through slipped strand mispairing or gene conversion. Using these studies we show how RipTALs of broad host range strains evolved convergently toward a shared target sequence. Finally, we discuss the differences between TALE-likes of plant pathogens in the context of disease ecology.

Predicting radiocaesium sorption characteristics with soil chemical properties for Japanese soils.

PubMed

Uematsu, Shinichiro; Smolders, Erik; Sweeck, Lieve; Wannijn, Jean; Van Hees, May; Vandenhove, Hildegarde

2015-08-15

The high variability of the soil-to-plant transfer factor of radiocaesium (RCs) compels a detailed analysis of the radiocaesium interception potential (RIP) of soil, which is one of the specific factors ruling the RCs transfer. The range of the RIP values for agricultural soils in the Fukushima accident affected area has not yet been fully surveyed. Here, the RIP and other major soil chemical properties were characterised for 51 representative topsoils collected in the vicinity of the Fukushima contaminated area. The RIP ranged a factor of 50 among the soils and RIP values were lower for Andosols compared to other soils, suggesting a role of soil mineralogy. Correlation analysis revealed that the RIP was most strongly and negatively correlated to soil organic matter content and oxalate extractable aluminium. The RIP correlated weakly but positively to soil clay content. The slope of the correlation between RIP and clay content showed that the RIP per unit clay was only 4.8 mmol g(-1) clay, about threefold lower than that for clays of European soils, suggesting more amorphous minerals and less micaceous minerals in the clay fraction of Japanese soils. The negative correlation between RIP and soil organic matter may indicate that organic matter can mask highly selective sorption sites to RCs. Multiple regression analysis with soil organic matter and cation exchange capacity explained the soil RIP (R(2)=0.64), allowing us to map soil RIP based on existing soil map information. Copyright © 2015 Elsevier B.V. All rights reserved.

The transcriptional co-factor RIP140 regulates mammary gland development by promoting the generation of key mitogenic signals.

PubMed

Nautiyal, Jaya; Steel, Jennifer H; Mane, Meritxell Rosell; Oduwole, Olayiwola; Poliandri, Ariel; Alexi, Xanthippi; Wood, Nicholas; Poutanen, Matti; Zwart, Wilbert; Stingl, John; Parker, Malcolm G

2013-03-01

Nuclear receptor interacting protein (Nrip1), also known as RIP140, is a co-regulator for nuclear receptors that plays an essential role in ovulation by regulating the expression of the epidermal growth factor-like family of growth factors. Although several studies indicate a role for RIP140 in breast cancer, its role in the development of the mammary gland is unclear. By using RIP140-null and RIP140 transgenic mice, we demonstrate that RIP140 is an essential factor for normal mammary gland development and that it functions by mediating oestrogen signalling. RIP140-null mice exhibit minimal ductal elongation with no side-branching, whereas RIP140-overexpressing mice show increased cell proliferation and ductal branching with age. Tissue recombination experiments demonstrate that RIP140 expression is required in both the mammary epithelial and stromal compartments for ductal elongation during puberty and that loss of RIP140 leads to a catastrophic loss of the mammary epithelium, whereas RIP140 overexpression augments the mammary basal cell population and shifts the progenitor/differentiated cell balance within the luminal cell compartment towards the progenitors. For the first time, we present a genome-wide global view of oestrogen receptor-α (ERα) binding events in the developing mammary gland, which unravels 881 ERα binding sites. Unbiased evaluation of several ERα binding sites for RIP140 co-occupancy reveals selectivity and demonstrates that RIP140 acts as a co-regulator with ERα to regulate directly the expression of amphiregulin (Areg), the progesterone receptor (Pgr) and signal transducer and activator of transcription 5a (Stat5a), factors that influence key mitogenic pathways that regulate normal mammary gland development.

Necroptosis in health and diseases.

PubMed

Zhou, Wen; Yuan, Junying

2014-11-01

Necroptosis is a form of regulated necrosis that can be activated by ligands of death receptors and stimuli that induce the expression of death receptor ligands under apoptotic deficient conditions. Activation of necroptosis by ligands of death receptors requires the kinase activity of RIP1, which mediates the activation of RIP3 and MLKL, two critical downstream mediators of necroptosis. Blocking the kinase activity of RIP1, a key druggable target in the necroptosis pathway, by necrostatins inhibits the activation of necroptosis and allows cell survival and proliferation in the presence of death receptor ligands. The activation of necroptosis is modulated by different forms of ubiquitination, including K63, linear and K48 ubiquitination, as well as phosphorylation of RIP1, RIP3 and MLKL. Necroptosis is suppressed by caspase-8/FADD-mediated apoptosis. Deficiency in caspase-8 and FADD leads to embryonic lethality, tissue degeneration and inflammation which can be suppressed by inhibition of RIP1 kinase and RIP3. On the other hand, the lack of RIP3 kinase activity leads to early embryonic lethality which can be suppressed by the loss of caspase-8, suggesting that although the kinase activity of RIP3 is involved in mediating necroptosis, the basal activity of RIP3 kinase may be required for suppressing caspase-8 mediated apoptosis. Necroptosis as well as RIP1- and RIP3-mediated inflammatory response have been implicated in mediating multiple human diseases including TNF-mediated hypothermia and systemic inflammation, ischemic reperfusion injury, neurodegeneration, Gaucher's disease, progressive atherosclerotic lesions, etc. Targeting RIP1 kinase may provide therapeutic benefits for the treatment of human diseases characterized by necrosis and inflammation. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Population-wide sampling of retrotransposon insertion polymorphisms using deep sequencing and efficient detection.

PubMed

Yu, Qichao; Zhang, Wei; Zhang, Xiaolong; Zeng, Yongli; Wang, Yeming; Wang, Yanhui; Xu, Liqin; Huang, Xiaoyun; Li, Nannan; Zhou, Xinlan; Lu, Jie; Guo, Xiaosen; Li, Guibo; Hou, Yong; Liu, Shiping; Li, Bo

2017-09-01

Active retrotransposons play important roles during evolution and continue to shape our genomes today, especially in genetic polymorphisms underlying a diverse set of diseases. However, studies of human retrotransposon insertion polymorphisms (RIPs) based on whole-genome deep sequencing at the population level have not been sufficiently undertaken, despite the obvious need for a thorough characterization of RIPs in the general population. Herein, we present a novel and efficient computational tool called Specific Insertions Detector (SID) for the detection of non-reference RIPs. We demonstrate that SID is suitable for high-depth whole-genome sequencing data using paired-end reads obtained from simulated and real datasets. We construct a comprehensive RIP database using a large population of 90 Han Chinese individuals with a mean ×68 depth per individual. In total, we identify 9342 recent RIPs, and 8433 of these RIPs are novel compared with dbRIP, including 5826 Alu, 2169 long interspersed nuclear element 1 (L1), 383 SVA, and 55 long terminal repeats. Among the 9342 RIPs, 4828 were located in gene regions and 5 were located in protein-coding regions. We demonstrate that RIPs can, in principle, be an informative resource to perform population evolution and phylogenetic analyses. Taking the demographic effects into account, we identify a weak negative selection on SVA and L1 but an approximately neutral selection for Alu elements based on the frequency spectrum of RIPs. SID is a powerful open-source program for the detection of non-reference RIPs. We built a non-reference RIP dataset that greatly enhanced the diversity of RIPs detected in the general population, and it should be invaluable to researchers interested in many aspects of human evolution, genetics, and disease. As a proof of concept, we demonstrate that the RIPs can be used as biomarkers in a similar way as single nucleotide polymorphisms. © The Authors 2017. Published by Oxford University Press.

RIP2 Is a Critical Regulator for NLRs Signaling and MHC Antigen Presentation but Not for MAPK and PI3K/Akt Pathways.

PubMed

Wu, Xiao Man; Chen, Wen Qin; Hu, Yi Wei; Cao, Lu; Nie, Pin; Chang, Ming Xian

2018-01-01

RIP2 is an adaptor protein which is essential for the activation of NF-κB and NOD1- and NOD2-dependent signaling. Although NOD-RIP2 axis conservatively existed in the teleost, the function of RIP2 was only reported in zebrafish, goldfish, and rainbow trout in vitro . Very little is known about the role and mechanisms of piscine NOD-RIP2 axis in vivo . Our previous study showed the protective role of zebrafish NOD1 in larval survival through CD44a-mediated activation of PI3K-Akt signaling. In this study, we examined whether RIP2 was required for larval survival with or without pathogen infection, and determined the signaling pathways modulated by RIP2. Based on our previous report and the present study, our data demonstrated that NOD1-RIP2 axis was important for larval survival in the early ontogenesis. Similar to NOD1, RIP2 deficiency significantly affected immune system processes. The significantly enriched pathways were mainly involved in immune system, such as "Antigen processing and presentation" and "NOD-like receptor signaling pathway" and so on. Furthermore, both transcriptome analysis and qRT-PCR revealed that RIP2 was a critical regulator for expression of NLRs (NOD-like receptors) and those genes involved in MHC antigen presentation. Different from NOD1, the present study showed that NOD1, but not RIP2 deficiency significantly impaired protein levels of MAPK pathways. Although RIP2 deficiency also significantly impaired the expression of CD44a, the downstream signaling of CD44a-Lck-PI3K-Akt pathway remained unchanged. Collectively, our works highlight the similarity and discrepancy of NOD1 and RIP2 in the regulation of immune signaling pathways in the zebrafish early ontogenesis, and confirm the crucial role of RIP2 in NLRs signaling and MHC antigen presentation, but not for MAPK and PI3K/Akt pathways.

Biochemical, Structural and Molecular Dynamics Analyses of the Potential Virulence Factor RipA from Yersinia pestis

PubMed Central

Torres, Rodrigo; Swift, Robert V.; Chim, Nicholas; Wheatley, Nicole; Lan, Benson; Atwood, Brian R.; Pujol, Céline; Sankaran, Banu; Bliska, James B.; Amaro, Rommie E.; Goulding, Celia W.

2011-01-01

Human diseases are attributed in part to the ability of pathogens to evade the eukaryotic immune systems. A subset of these pathogens has developed mechanisms to survive in human macrophages. Yersinia pestis, the causative agent of the bubonic plague, is a predominately extracellular pathogen with the ability to survive and replicate intracellularly. A previous study has shown that a novel rip (required for intracellular proliferation) operon (ripA, ripB and ripC) is essential for replication and survival of Y. pestis in postactivated macrophages, by playing a role in lowering macrophage-produced nitric oxide (NO) levels. A bioinformatics analysis indicates that the rip operon is conserved among a distally related subset of macrophage-residing pathogens, including Burkholderia and Salmonella species, and suggests that this previously uncharacterized pathway is also required for intracellular survival of these pathogens. The focus of this study is ripA, which encodes for a protein highly homologous to 4-hydroxybutyrate-CoA transferase; however, biochemical analysis suggests that RipA functions as a butyryl-CoA transferase. The 1.9 Å X-ray crystal structure reveals that RipA belongs to the class of Family I CoA transferases and exhibits a unique tetrameric state. Molecular dynamics simulations are consistent with RipA tetramer formation and suggest a possible gating mechanism for CoA binding mediated by Val227. Together, our structural characterization and molecular dynamic simulations offer insights into acyl-CoA specificity within the active site binding pocket, and support biochemical results that RipA is a butyryl-CoA transferase. We hypothesize that the end product of the rip operon is butyrate, a known anti-inflammatory, which has been shown to lower NO levels in macrophages. Thus, the results of this molecular study of Y. pestis RipA provide a structural platform for rational inhibitor design, which may lead to a greater understanding of the role of RipA in this unique virulence pathway. PMID:21966419

Structural snapshots along the reaction pathway of Yersinia pestis RipA, a putative butyryl-CoA transferase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Torres, Rodrigo; Lan, Benson; Latif, Yama

2014-04-01

The crystal structures of Y. pestis RipA mutants were determined to provide insights into the CoA transferase reaction pathway. Yersinia pestis, the causative agent of bubonic plague, is able to survive in both extracellular and intracellular environments within the human host, although its intracellular survival within macrophages is poorly understood. A novel Y. pestis three-gene rip (required for intracellular proliferation) operon, and in particular ripA, has been shown to be essential for survival and replication in interferon γ-induced macrophages. RipA was previously characterized as a putative butyryl-CoA transferase proposed to yield butyrate, a known anti-inflammatory shown to lower macrophage-produced NOmore » levels. RipA belongs to the family I CoA transferases, which share structural homology, a conserved catalytic glutamate which forms a covalent CoA-thioester intermediate and a flexible loop adjacent to the active site known as the G(V/I)G loop. Here, functional and structural analyses of several RipA mutants are presented in an effort to dissect the CoA transferase mechanism of RipA. In particular, E61V, M31G and F60M RipA mutants show increased butyryl-CoA transferase activities when compared with wild-type RipA. Furthermore, the X-ray crystal structures of E61V, M31G and F60M RipA mutants, when compared with the wild-type RipA structure, reveal important conformational changes orchestrated by a conserved acyl-group binding-pocket phenylalanine, Phe85, and the G(V/I)G loop. Binary structures of M31G RipA and F60M RipA with two distinct CoA substrate conformations are also presented. Taken together, these data provide CoA transferase reaction snapshots of an open apo RipA, a closed glutamyl-anhydride intermediate and an open CoA-thioester intermediate. Furthermore, biochemical analyses support essential roles for both the catalytic glutamate and the flexible G(V/I)G loop along the reaction pathway, although further research is required to fully understand the function of the acyl-group binding pocket in substrate specificity.« less

Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases

PubMed Central

Thapa, Roshan J.; Nogusa, Shoko; Chen, Peirong; Maki, Jenny L.; Lerro, Anthony; Andrake, Mark; Rall, Glenn F.; Degterev, Alexei; Balachandran, Siddharth

2013-01-01

Interferons (IFNs) are cytokines with powerful immunomodulatory and antiviral properties, but less is known about how they induce cell death. Here, we show that both type I (α/β) and type II (γ) IFNs induce precipitous receptor-interacting protein (RIP)1/RIP3 kinase-mediated necrosis when the adaptor protein Fas-associated death domain (FADD) is lost or disabled by phosphorylation, or when caspases (e.g., caspase 8) are inactivated. IFN-induced necrosis proceeds via progressive assembly of a RIP1–RIP3 “necrosome” complex that requires Jak1/STAT1-dependent transcription, but does not need the kinase activity of RIP1. Instead, IFNs transcriptionally activate the RNA-responsive protein kinase PKR, which then interacts with RIP1 to initiate necrosome formation and trigger necrosis. Although IFNs are powerful activators of necrosis when FADD is absent, these cytokines are likely not the dominant inducers of RIP kinase-driven embryonic lethality in FADD-deficient mice. We also identify phosphorylation on serine 191 as a mechanism that disables FADD and collaborates with caspase inactivation to allow IFN-activated necrosis. Collectively, these findings outline a mechanism of IFN-induced RIP kinase-dependent necrotic cell death and identify FADD and caspases as negative regulators of this process. PMID:23898178

Genome-wide screening of Oryza sativa ssp. japonica and indica reveals a complex family of proteins with ribosome-inactivating protein domains.

PubMed

Wytynck, Pieter; Rougé, Pierre; Van Damme, Els J M

2017-11-01

Ribosome-inactivating proteins (RIPs) are cytotoxic enzymes capable of halting protein synthesis by irreversible modification of ribosomes. Although RIPs are widespread they are not ubiquitous in the plant kingdom. The physiological importance of RIPs is not fully elucidated, but evidence suggests a role in the protection of the plant against biotic and abiotic stresses. Searches in the rice genome revealed a large and highly complex family of proteins with a RIP domain. A comparative analysis retrieved 38 RIP sequences from the genome sequence of Oryza sativa subspecies japonica and 34 sequences from the subspecies indica. The RIP sequences are scattered over different chromosomes but are mostly found on the third chromosome. The phylogenetic tree revealed the pairwise clustering of RIPs from japonica and indica. Molecular modeling and sequence analysis yielded information on the catalytic site of the enzyme, and suggested that a large part of RIP domains probably possess N-glycosidase activity. Several RIPs are differentially expressed in plant tissues and in response to specific abiotic stresses. This study provides an overview of RIP motifs in rice and will help to understand their biological role(s) and evolutionary relationships. Copyright © 2017 Elsevier Ltd. All rights reserved.

TNF Signaling through RIP1 Kinase Enhances SN38-Induced Death in Colon Adenocarcinoma.

PubMed

Cabal-Hierro, Lucia; O'Dwyer, Peter J

2017-04-01

Elucidation of TNF-directed mechanisms for cell death induction and maintenance of tumor growth has revealed a role for receptor-interacting protein kinases 1 and 3 (RIPK1/RIP1 and RIPK3/RIP3), components of the necrosome complex, as determinants of cell fate. Here, the participation of TNF signaling was analyzed with regard to the cytotoxic action of different DNA-damaging agents in a panel of colon cancer cells. While most of these cell lines were insensitive to TNF, combination with these drugs increased sensitivity by inducing cell death and DNA damage, especially in the case of the topoisomerase inhibitor SN38. Changes in levels of RIP1 and RIP3 occurred following monotherapy with SN38 or in combination with TNF. Downregulation of RIP1 resulted in increased resistance to SN38, implying a requirement for RIP1 in mediating cytotoxicity through the TNF/TNFR signaling pathway. Downregulation of RIP1 in a xenograft model impaired tumor growth inhibition from SN38 treatment, suggesting the potential of RIP1 to determine the clinical outcome of irinotecan treatment. These results indicate that TNF plays a key role in determining the cytotoxic effectiveness of SN38 in colorectal cancer and suggests a re-evaluation of TNF-based interventions to enhance therapeutic efficacy. Implications: The capacity of RIP1 to influence drug sensitivity suggests RIP1 may have biomarker potential. Mol Cancer Res; 15(4); 395-404. ©2017 AACR . ©2017 American Association for Cancer Research.

Suppressing Receptor-Interacting Protein 140: a New Sight for Salidroside to Treat Cerebral Ischemia.

PubMed

Chen, Tong; Ma, Zhanqiang; Zhu, Lingpeng; Jiang, Wenjiao; Wei, Tingting; Zhou, Rui; Luo, Fen; Zhang, Kai; Fu, Qiang; Ma, Chunhua; Yan, Tianhua

2016-11-01

The purpose of the current study was to detect the effect of salidroside (Sal) on cerebral ischemia and explore its potential mechanism. Middle cerebral artery occlusion (MCAO) was performed to investigate the effects of Sal on cerebral ischemia. The rats were randomly divided into five groups: sham group, vehicle group, clopidogrel (7.5 mg/kg) group, Sal (20 mg/kg) group, and Sal (40 mg/kg) group. SH-SY5Y cells were exposed to ischemia-reperfusion (I/R) injury to verify the protective effect of Sal in vitro. We also built the stable receptor-interacting protein 140 (RIP140)-overexpressing SH-SY5Y cells. The results showed that Sal significantly reduces brain infarct size and cerebral edema. Sal could effectively decrease the levels of interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in serum of the MCAO rats and supernatant of I/R-induced SH-SY5Y cells. Immunohistochemical and Western blot results demonstrated that Sal inhibited RIP140-mediated inflammation and apoptosis in the MCAO rats and SH-SY5Y cells. In addition, we further confirmed that RIP140/NF-κB signaling plays a crucial role by evaluating the protein expression in RIP140-overexpressing SH-SY5Y cells. Our findings suggested that Sal could be used as an effective neuroprotective agent for cerebral ischemia due to its significant effect on preventing neuronal cell injury after cerebral ischemia both in vivo and in vitro by the inhibitions of RIP140-mediated inflammation and apoptosis.

RIP1 and RIP3 complex regulates radiation-induced programmed necrosis in glioblastoma.

PubMed

Das, Arabinda; McDonald, Daniel G; Dixon-Mah, Yaenette N; Jacqmin, Dustin J; Samant, Vikram N; Vandergrift, William A; Lindhorst, Scott M; Cachia, David; Varma, Abhay K; Vanek, Kenneth N; Banik, Naren L; Jenrette, Joseph M; Raizer, Jeffery J; Giglio, Pierre; Patel, Sunil J

2016-06-01

Radiation-induced necrosis (RN) is a relatively common side effect of radiation therapy for glioblastoma. However, the molecular mechanisms involved and the ways RN mechanisms differ from regulated cell death (apoptosis) are not well understood. Here, we compare the molecular mechanism of cell death (apoptosis or necrosis) of C6 glioma cells in both in vitro and in vivo (C6 othotopically allograft) models in response to low and high doses of X-ray radiation. Lower radiation doses were used to induce apoptosis, while high-dose levels were chosen to induce radiation necrosis. Our results demonstrate that active caspase-8 in this complex I induces apoptosis in response to low-dose radiation and inhibits necrosis by cleaving RIP1 and RI. When activation of caspase-8 was reduced at high doses of X-ray radiation, the RIP1/RIP3 necrosome complex II is formed. These complexes induce necrosis through the caspase-3-independent pathway mediated by calpain, cathepsin B/D, and apoptosis-inducing factor (AIF). AIF has a dual role in apoptosis and necrosis. At high doses, AIF promotes chromatinolysis and necrosis by interacting with histone H2AX. In addition, NF-κB, STAT-3, and HIF-1 play a crucial role in radiation-induced inflammatory responses embedded in a complex inflammatory network. Analysis of inflammatory markers in matched plasma and cerebrospinal fluid (CSF) isolated from in vivo specimens demonstrated the upregulation of chemokines and cytokines during the necrosis phase. Using RIP1/RIP3 kinase specific inhibitors (Nec-1, GSK'872), we also establish that the RIP1-RIP3 complex regulates programmed necrosis after either high-dose radiation or TNF-α-induced necrosis requires RIP1 and RIP3 kinases. Overall, our data shed new light on the relationship between RIP1/RIP3-mediated programmed necrosis and AIF-mediated caspase-independent programmed necrosis in glioblastoma.

The effects and regulatory mechanism of RIP3 on RGC-5 necroptosis following elevated hydrostatic pressure.

PubMed

Shang, Lei; Ding, Wei; Li, Na; Liao, Lvshuang; Chen, Dan; Huang, Jufang; Xiong, Kun

2017-02-06

Necroptosis is a type of regulated cell death that has been implicated in various diseases. Receptor-interacting protein 3 (RIP3), a member of the RIP family, is an important mediator of the necroptotic pathway. Cleavage of RIP3 at Asp328 by caspase-8 abolishes the kinase activity of RIP3, which is critical for necroptosis. Moreover, RIP3 is significantly upregulated during the early stages of acute high intra-ocular pressure and oxygen glucose deprivation. In this study, the effects of RIP3 during elevated hydrostatic pressure (EHP) were investigated and the possible mechanism through which caspase-8 regulated RIP3 cleavage was explored. Flow cytometry analysis revealed that the number of EHP-induced necrotic retinal ganglion cell 5 (RGC-5) cells was reduced after RIP3-knockdown. Furthermore, malondialdehyde (MDA) levels and glycogen phosphorylase (PYGL) activity in normal RGC-5 cells were much higher than those in RIP3-knockdown cells after EHP. EHP-induced RGC-5 necrosis was significantly reduced after treatment with butylated hydroxyanisole (BHA), a reactive oxygen species (ROS) scavenger. MDA levels and PYGL activity were lower in normal RGC-5 cells than those in cells with caspase-8 inhibition after EHP. Western blot analysis demonstrated that the RIP3 cleavage product was upregulated in cells with caspase-8 inhibition. Additionally, flow cytometry analysis revealed that the number of EHP-induced necrotic RGC-5 cells was increased after caspase-8 inhibition. Our results suggested that RGC-5 necroptosis following EHP was mediated by RIP3 through induction of PYGL activity and subsequent ROS accumulation. Thus, caspase-8 may participate in the regulation of RGC-5 necroptosis via RIP3 cleavage. © The Author 2016. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Proteasome inhibitor PS-341 limits macrophage necroptosis by promoting cIAPs-mediated inhibition of RIP1 and RIP3 activation.

PubMed

Zhang, Yuchen; Cheng, Junjun; Zhang, Junmeng; Wu, Xiaofan; Chen, Fang; Ren, Xuejun; Wang, Yunlong; Li, Quan; Li, Yu

2016-09-02

Apoptotic and necrotic macrophages have long been known for their existence in atherosclerotic lesions. However, the mechanisms underlying the choice of their death pattern have not been fully elucidated. Here, we report the effects of PS-341, a potent and specific proteasome inhibitor, on the cell death of primary bone marrow-derived macrophages (BMDMs) in vitro. The results showed that PS-341 could not induce macrophage apoptosis or promote TNF-induced macrophage apoptosis, on the other hand, PS-341 could significantly inhibit macrophage necroptosis induced by TNF and pan-caspase inhibitor z-VAD treatment. Remarkably, high-dose of PS-341 showed similar inhibitory effects on macrophage necroptosis comparable to that of kinase inhibition of RIP1 through specific inhibitor Nec-1 or inhibition of RIP3 via specific genetical ablation. Furthermore, the degradation of cellular inhibitor of apoptosis proteins (cIAPs) was suppressed by PS-341, which could antagonize the activation of RIP1 kinase via post-translational mechanism. Further evidences demonstrated reduced levels of both RIP1 and RIP 3 upon PS-341 treatment, concomitantly, a more strong association of RIP1 with cIAPs and less with RIP3 was found following PS-341 treatment, these findings suggested that PS-341 may disrupt the formation of RIP1-RIP3 complex (necrosome) through stabilizing cIAPs. Collectively, our results indicated that the proteasome-mediated degradation of cIAPs could be inhibited by PS-341 and followed by limited RIP1 and RIP3 kinase activities, which were indispensable for necroptosis, thus eliciting a significant necroptosis rescue in BMDMs in vitro. Overall, our study has identified a new role of PS-341 in the cell death of BMDMs and provided a novel insight into the atherosclerotic inflammation caused by proteasome-mediated macrophage necroptosis. Copyright © 2016 Elsevier Inc. All rights reserved.

Necroptosis may be a novel mechanism for cardiomyocyte death in acute myocarditis.

PubMed

Zhou, Fei; Jiang, Xuejun; Teng, Lin; Yang, Jun; Ding, Jiawang; He, Chao

2018-05-01

In this study, we investigated the roles of RIP1/RIP3 mediated cardiomyocyte necroptosis in CVB3-induced acute myocarditis. Serum concentrations of creatinine kinase (CK), CK-MB, and cardiac troponin I were detected using a Hitachi Automatic Biochemical Analyzer in a mouse model of acute VMC. Histological changes in cardiac tissue were observed by light microscope and expression levels of RIP1/RIP3 in the cardiac tissue were detected via Western blot and immunohistochemistry. The data showed that RIP1/RIP3 was highly expressed in cardiomyocytes in the acute VMC mouse model and that the necroptosis pathway specific blocker, Nec-1, dramatically reduced the myocardial damage by downregulating the expression of RIP1/RIP3. These findings provide evidence that necroptosis plays a significant role in cardiomyocyte death and it is a major pathway for cell death in acute VMC. Blocking the necroptosis pathway may serve as a new therapeutic option for the treatment of acute viral myocarditis.

Blue Light Action on Mitochondria Leads to Cell Death by Necroptosis.

PubMed

Del Olmo-Aguado, Susana; Núñez-Álvarez, Claudia; Osborne, Neville N

2016-09-01

Blue light impinging on the many mitochondria associated with retinal ganglion cells (RGCs) in situ has the potential of eliciting necroptosis through an action on RIP1/RIP3 to stimulate RGC death in diseases like glaucoma and diabetic retinopathy. Cells in culture die when exposed to blue light. The death process is mitochondria-dependent and is known to involve a decrease in the production of ATP, a generation of ROS, the activation of poly-(ADP-ribose) polymerase, the stimulation of apoptosis-inducing factor (AIF) as well as the up-regulation of heme-oxygenase-1 (HO-1). Our present results show that blue light-induced activation of AIF is not directly linked with the stimulation of RIP1/RIP3. Down-regulation of RIP1/RIP3 did not influence AIF. AIF activation therefore appears to enhance the rate of necroptosis by a direct action on DNA breakdown, the end stage of necroptosis. This implies that silencing of AIF mRNA may provide a degree of protection to blue light insult. Also, necrostatin-1 attenuated an increased turnover of HO-1 mRNA caused by blue light to suggest an indirect inhibition of necroptosis, caused by the action of necrostatin-1 on RIP1/RIP3 to reduce oxidative stress. This is supported by the finding that gene silencing of RIP1 and RIP3 has no effect on HO-1. We therefore conclude that inhibitors of RIP kinase might be more specific than necrostatin-1 as a neuroprotective agent to blunt solely necroptosis caused by blue light.

New ribosome-inactivating proteins with polynucleotide:adenosine glycosidase and antiviral activities from Basella rubra L. and bougainvillea spectabilis Willd.

PubMed

Bolognesi, A; Polito, L; Olivieri, F; Valbonesi, P; Barbieri, L; Battelli, M G; Carusi, M V; Benvenuto, E; Del Vecchio Blanco, F; Di Maro, A; Parente, A; Di Loreto, M; Stirpe, F

1997-12-01

New single-chain (type 1) ribosome-inactivating proteins (RIPs) were isolated from the seeds of Basella rubra L. (two proteins) and from the leaves of Bougainvillea spectabilis Willd. (one protein). These RIPs inhibit protein synthesis both in a cell-free system, with an IC50 (concentration causing 50% inhibition) in the 10(-10) M range, and by various cell lines, with IC50S in the 10(-8)-10(-6) M range. All three RIPs released adenine not only from rat liver ribosomes but also from Escherichia coli rRNA, polyadenylic acid, herring sperm DNA, and artichoke mottled crinkle virus (AMCV) genomic RNA, thus being polynucleotide:adenosine glycosidases. The proteins from Basella rubra had toxicity to mice similar to that of most type 1 RIPs (Barbieri et al., 1993, Biochim Biophys Acta 1154: 237-282) with an LD50 (concentration that is 50% lethal) < or = 8 mg.kg-1 body weight, whilst the RIP from Bougainvillea spectabilis had an LD50 > 32 mg.kg-1. The N-terminal sequence of the two RIPs from Basella rubra had 80-93% identity, whereas it differed from the sequence of the RIP from Bougainvillea spectabilis. When tested with antibodies against various RIPs, the RIPs from Basella gave some cross-reactivity with sera against dianthin 32, and weak cross-reactivity with momordin I and momorcochin-S, whilst the RIP from Bougainvillea did not cross-react with any antiserum tested. An RIP from Basella rubra and one from Bougainvillea spectabilis were tested for antiviral activity, and both inhibited infection of Nicotiana benthamiana by AMCV.

Respiratory monitoring by inductive plethysmography in unrestrained subjects using position sensor-adjusted calibration.

PubMed

Brüllmann, Gregor; Fritsch, Karsten; Thurnheer, Robert; Bloch, Konrad E

2010-01-01

Portable respiratory inductive plethysmography (RIP) is promising for noninvasive monitoring of breathing patterns in unrestrained subjects. However, its use has been hampered by requiring recalibration after changes in body position. To facilitate RIP application in unrestrained subjects, we developed a technique for adjustment of RIP calibration using position sensor feedback. Five healthy subjects and 12 patients with lung disease were monitored by portable RIP with sensors incorporated within a body garment. Unrestrained individuals were studied during 40-60 min while supine, sitting and upright/walking. Position was changed repeatedly every 5-10 min. Initial qualitative diagnostic calibration followed by volume scaling in absolute units during 20 breaths in different positions by flow meter provided position-specific volume-motion coefficients for RIP. These were applied during subsequent monitoring in corresponding positions according to feedback from 4 accelerometers placed at the chest and thigh. Accuracy of RIP was evaluated by face mask pneumotachography. Position sensor feedback allowed accurate adjustment of RIP calibration during repeated position changes in subjects and patients as reflected in a minor mean difference (bias) in breath-by-breath tidal volumes estimated by RIP and flow meter of 0.02 liters (not significant) and limits of agreement (+/-2 SD) of +/-19% (2,917 comparisons). An average of 10 breaths improved precision of RIP (limits of agreement +/-14%). RIP calibration incorporating position sensor feedback greatly enhances the application of RIP as a valuable, unobtrusive tool to investigate respiratory physiology and ventilatory limitation in unrestrained healthy subjects and patients with lung disease during everyday activities including position changes. Copyright 2009 S. Karger AG, Basel.

Validation of Polyvinylidene Fluoride Impedance Sensor for Respiratory Event Classification during Polysomnography in Children.

PubMed

Griffiths, Anne G; Patwari, Pallavi P; Loghmanee, Darius A; Balog, Matthew J; Trosman, Irina; Sheldon, Stephen H

2017-02-15

Polysomnography is the gold standard for diagnosis and characterization of severity of sleep-disordered breathing. Accuracy and reliability of the technology used are critical to the integrity of the study's interpretation. Strict criteria for obstructive sleep apnea in children are lacking and diagnosis often requires consideration of frequency of respiratory events in addition to other measures. Current American Academy of Sleep Medicine recommendations for pediatric patients includes use of respiratory inductance plethysmography (RIP) belts, whereas polyvinylidene fluoride (PVDF) belts are currently only acceptable for use in adults. We hypothesized that PVDF belts would be equally effective as RIP belts for detection of respiratory effort and events in children. Children ages 2-17 y were recruited from a large pediatric tertiary referral center after obtaining consent for participation. Fifty subjects were recruited (average age, 7.8 y). Clinically relevant limits of agreement were predetermined to be a difference in total count of obstructive or central apneas or hypopneas of ± 5 events. Scoring of respiratory events was not significantly different by belt type based on Bland-Altman plots of total apnea-hypopnea index and obstructive apneas. Obstructive hypopneas scoring ranged beyond our clinical limit of agreement. Findings in obese subjects were consistent with the larger sample with the exception of an increase in outliers. Artifact amount was comparable (RIP 10.9% ± 22.5% and PVDF 10.5% ± 19.5%). Based on these findings, PVDF belts appear to be as effective as RIP belts in detection of respiratory effort and events in children. A commentary on this article appears in this issue on page 159. © 2017 American Academy of Sleep Medicine

Targeting ricin to the ribosome.

PubMed

May, Kerrie L; Yan, Qing; Tumer, Nilgun E

2013-07-01

The plant toxin ricin is highly toxic for mammalian cells and is of concern for bioterrorism. Ricin belongs to a family of functionally related toxins, collectively referred to as ribosome inactivating proteins (RIPs), which disable ribosomes and halt protein synthesis. Currently there are no specific antidotes against ricin or related RIPs. The catalytic subunit of ricin is an N-glycosidase that depurinates a universally conserved adenine residue within the sarcin/ricin loop (SRL) of the 28S rRNA. This depurination activity inhibits translation and its biochemistry has been intensively studied. Yet, recent developments paint a more complex picture of toxicity, with ribosomal proteins and cellular signaling pathways contributing to the potency of ricin. In particular, several studies have now established the importance of the ribosomal stalk structure in facilitating the depurination activity and ribosome specificity of ricin and other RIPs. This review highlights recent developments defining toxin-ribosome interactions and examines the significance of these interactions for toxicity and therapeutic intervention. Copyright © 2013 Elsevier Ltd. All rights reserved.

Runway Safety Monitor Algorithm for Runway Incursion Detection and Alerting

NASA Technical Reports Server (NTRS)

Green, David F., Jr.; Jones, Denise R. (Technical Monitor)

2002-01-01

The Runway Safety Monitor (RSM) is an algorithm for runway incursion detection and alerting that was developed in support of NASA's Runway Incursion Prevention System (RIPS) research conducted under the NASA Aviation Safety Program's Synthetic Vision System element. The RSM algorithm provides pilots with enhanced situational awareness and warnings of runway incursions in sufficient time to take evasive action and avoid accidents during landings, takeoffs, or taxiing on the runway. The RSM currently runs as a component of the NASA Integrated Display System, an experimental avionics software system for terminal area and surface operations. However, the RSM algorithm can be implemented as a separate program to run on any aircraft with traffic data link capability. The report documents the RSM software and describes in detail how RSM performs runway incursion detection and alerting functions for NASA RIPS. The report also describes the RIPS flight tests conducted at the Dallas-Ft Worth International Airport (DFW) during September and October of 2000, and the RSM performance results and lessons learned from those flight tests.

Effects of beach morphology and waves on onshore larval transport

NASA Astrophysics Data System (ADS)

Fujimura, A.; Reniers, A.; Paris, C. B.; Shanks, A.; MacMahan, J.; Morgan, S.

2015-12-01

Larvae of intertidal species grow offshore, and migrate back to the shore when they are ready to settle on their adult substrates. In order to reach the habitat, they must cross the surf zone, which is characterized as a semi-permeable barrier. This is accomplished through physical forcing (i.e., waves and current) as well as their own behavior. Two possible scenarios of onshore larval transport are proposed: Negatively buoyant larvae stay in the bottom boundary layer because of turbulence-dependent sinking behavior, and are carried toward the shore by streaming of the bottom boundary layer; positively buoyant larvae move to the shore during onshore wind events, and sink to the bottom once they encounter high turbulence (i.e., surf zone edge), where they are carried by the bottom current toward the shore (Fujimura et al. 2014). Our biophysical Lagrangian particle tracking model helps to explain how beach morphology and wave conditions affect larval distribution patterns and abundance. Model results and field observations show that larval abundance in the surf zone is higher at mildly sloped, rip-channeled beaches than at steep pocket beaches. Beach attributes are broken up to examine which and how beach configuration factors affect larval abundance. Modeling with alongshore uniform beaches with variable slopes reveal that larval populations in the surf zone are negatively correlated with beach steepness. Alongshore variability enhances onshore larval transport because of increased cross-shore water exchange by rip currents. Wave groups produce transient rip currents and enhance cross-shore exchange. Effects of other wave components, such as wave height and breaking wave rollers are also considered.

NWS Offshore Marine Forecasts by Zone

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Beach Hazards Rip Currents Hypothermia Hurricanes Thunderstorms Lightning Coastal Flooding Tsunamis 406 page is also available in a text version. Similar webpages for Coastal/Great Lakes Forecasts by Zone

Coastal/Great Lakes Forecasts by Zone

Science.gov Websites

Hazards Rip Currents Hypothermia Hurricanes Thunderstorms Lightning Coastal Flooding Tsunamis 406 EPIRB's Coastal/Great Lakes Forecasts by Zone >>Click on the area of interest below<< Coastal and

Protein synthesis inhibition activity by strawberry tissue protein extracts during plant life cycle and under biotic and abiotic stresses.

PubMed

Polito, Letizia; Bortolotti, Massimo; Mercatelli, Daniele; Mancuso, Rossella; Baruzzi, Gianluca; Faedi, Walther; Bolognesi, Andrea

2013-07-25

Ribosome-inactivating proteins (RIPs), enzymes that are widely distributed in the plant kingdom, inhibit protein synthesis by depurinating rRNA and many other polynucleotidic substrates. Although RIPs show antiviral, antifungal, and insecticidal activities, their biological and physiological roles are not completely understood. Additionally, it has been described that RIP expression is augmented under stressful conditions. In this study, we evaluated protein synthesis inhibition activity in partially purified basic proteins (hereafter referred to as RIP activity) from tissue extracts of Fragaria × ananassa (strawberry) cultivars with low (Dora) and high (Record) tolerance to root pathogens and fructification stress. Association between the presence of RIP activity and the crop management (organic or integrated soil), growth stage (quiescence, flowering, and fructification), and exogenous stress (drought) were investigated. RIP activity was found in every tissue tested (roots, rhizomes, leaves, buds, flowers, and fruits) and under each tested condition. However, significant differences in RIP distribution were observed depending on the soil and growth stage, and an increase in RIP activity was found in the leaves of drought-stressed plants. These results suggest that RIP expression and activity could represent a response mechanism against biotic and abiotic stresses and could be a useful tool in selecting stress-resistant strawberry genotypes.

Type 1 ribosome-inactivating proteins depurinate plant 25S rRNA without species specificity.

PubMed Central

Prestle, J; Schönfelder, M; Adam, G; Mundry, K W

1992-01-01

Four different type 1 ribosome-inactivating proteins (RIPs) with RNA N-glycosidase activity were tested for their ability to attack the large rRNA of plant ribosomes derived from tobacco plants, as well as from the plant species from which the particular RIP had been isolated. Incubation of tobacco ribosomes with RIPs isolated from either Phytolacca americana L. (pokeweed), Dianthus barbatus L. (carnation), Spinacia oleracea L. (spinach) or Chenopodium amaranthicolor Coste and Reyn. (chenopodium) rendered the 25S rRNA sensitive to aniline-catalyzed hydrolysis, generating a single rRNA-fragment of about 350 nucleotides. The same fragment was generated when rRNAs from pokeweed, carnation, spinach or chenopodium ribosomes were aniline-treated without any deliberate treatment of the ribosomes with the respective RIP. This indicated that ribosomes from all RIP-producing plants were already inactivated by their own RIPs during preparation. These results demonstrate that plant ribosomes are generally susceptible to RIP attack, including modification by their own RIPs. Direct sequencing of the newly generated fragments revealed that a single N-glycosidic bond at an adenosine residue within the highly conserved sequence 5'-AGUACGAGAGGA-3' was cleaved by all of the RIPs investigated, a situation also found in animal, yeast and Escherichia coli ribosomes. Images PMID:1620614

RIP1-HAT1-SIRT Complex Identification and Targeting in Treatment and Prevention of Cancer.

PubMed

Carafa, Vincenzo; Nebbioso, Angela; Cuomo, Francesca; Rotili, Dante; Cobellis, Gilda; Bontempo, Paola; Baldi, Alfonso; Spugnini, Enrico P; Citro, Gennaro; Chambery, Angela; Russo, Rosita; Ruvo, Menotti; Ciana, Paolo; Maravigna, Luca; Shaik, Jani; Radaelli, Enrico; De Antonellis, Pasquale; Tarantino, Domenico; Pirolli, Adele; Ragno, Rino; Zollo, Massimo; Stunnenberg, Hendrik G; Mai, Antonello; Altucci, Lucia

2018-03-13

Purpose: Alteration in cell death is a hallmark of cancer. A functional role regulating survival, apoptosis, and necroptosis has been attributed to RIP1/3 complexes. Experimental Design: We have investigated the role of RIP1 and the effects of MC2494 in cell death induction, using different methods as flow cytometry, transcriptome analysis, immunoprecipitation, enzymatic assays, transfections, mutagenesis, and in vivo studies with different mice models. Results: Here, we show that RIP1 is highly expressed in cancer, and we define a novel RIP1/3-SIRT1/2-HAT1/4 complex. Mass spectrometry identified five acetylations in the kinase and death domain of RIP1. The novel characterized pan-SIRT inhibitor, MC2494, increases RIP1 acetylation at two additional sites in the death domain. Mutagenesis of the acetylated lysine decreases RIP1-dependent cell death, suggesting a role for acetylation of the RIP1 complex in cell death modulation. Accordingly, MC2494 displays tumor-selective potential in vitro , in leukemic blasts ex vivo, and in vivo in both xenograft and allograft cancer models. Mechanistically, MC2494 induces bona fide tumor-restricted acetylated RIP1/caspase-8-mediated apoptosis. Excitingly, MC2494 displays tumor-preventive activity by blocking 7,12-dimethylbenz(α)anthracene-induced mammary gland hyperproliferation in vivo Conclusions: These preventive features might prove useful in patients who may benefit from a recurrence-preventive approach with low toxicity during follow-up phases and in cases of established cancer predisposition. Thus, targeting the newly identified RIP1 complex may represent an attractive novel paradigm in cancer treatment and prevention. Clin Cancer Res; 1-15. ©2018 AACR. ©2018 American Association for Cancer Research.

Activation of necroptosis in human and experimental cholestasis.

PubMed

Afonso, Marta B; Rodrigues, Pedro M; Simão, André L; Ofengeim, Dimitry; Carvalho, Tânia; Amaral, Joana D; Gaspar, Maria M; Cortez-Pinto, Helena; Castro, Rui E; Yuan, Junying; Rodrigues, Cecília M P

2016-09-29

Cholestasis encompasses liver injury and inflammation. Necroptosis, a necrotic cell death pathway regulated by receptor-interacting protein (RIP) 3, may mediate cell death and inflammation in the liver. We aimed to investigate the role of necroptosis in mediating deleterious processes associated with cholestatic liver disease. Hallmarks of necroptosis were evaluated in liver biopsies of primary biliary cholangitis (PBC) patients and in wild-type and RIP3-deficient (RIP3 -/- ) mice subjected to common bile duct ligation (BDL). The functional link between RIP3, heme oxygenase-1 (HO-1) and antioxidant response was investigated in vivo after BDL and in vitro. We demonstrate increased RIP3 expression and mixed lineage kinase domain-like protein (MLKL) phosphorylation in liver samples of human PBC patients, coincident with thioflavin T labeling, suggesting activation of necroptosis. BDL resulted in evident hallmarks of necroptosis, concomitant with progressive bile duct hyperplasia, multifocal necrosis, fibrosis and inflammation. MLKL phosphorylation was increased and insoluble aggregates of RIP3, MLKL and RIP1 formed in BLD liver tissue samples. Furthermore, RIP3 deficiency blocked BDL-induced necroinflammation at 3 and 14 days post-BDL. Serum hepatic enzymes, fibrogenic liver gene expression and oxidative stress decreased in RIP3 -/- mice at 3 days after BDL. However, at 14 days, cholestasis aggravated and fibrosis was not halted. RIP3 deficiency further associated with increased hepatic expression of HO-1 and accumulation of iron in BDL mice. The functional link between HO-1 activity and bile acid toxicity was established in RIP3-deficient primary hepatocytes. Necroptosis is triggered in PBC patients and mediates hepatic necroinflammation in BDL-induced acute cholestasis. Targeting necroptosis may represent a therapeutic strategy for acute cholestasis, although complementary approaches may be required to control progression of chronic cholestatic liver disease.

Receptor interacting protein 3-induced RGC-5 cell necroptosis following oxygen glucose deprivation.

PubMed

Ding, Wei; Shang, Lei; Huang, Ju-Fang; Li, Na; Chen, Dan; Xue, Li-Xiang; Xiong, Kun

2015-08-04

Necroptosis is a type of regulated form of cell death that has been implicated in the pathogenesis of various diseases. Receptor-interacting protein 3 (RIP3), a member of the RIP family of proteins, has been reported as an important necroptotic pathway mediator in regulating a variety of human diseases, such as myocardial ischemia, inflammatory bowel disease, and ischemic brain injury. Our previous study showed that RIP3 was expressed in rat retinal ganglion cells (RGCs), where it was significantly upregulated during the early stage of acute high intraocular pressure. Furthermore, RIP3 expression was co-localized with propidium iodide (PI)-positive staining (necrotic cells). These results suggested that RIP3 up-regulation might be involved in the necrosis of injured RGCs. In this study, we aimed to reveal the possible involvement of RIP3 in oxygen glucose deprivation (OGD)-induced retinal ganglion cell-5 (RGC-5) necroptosis. RGC-5 cells were cultured in Dulbecco's-modified essential medium and necroptosis was induced by 8 h OGD. PI staining and flow cytometry were performed to detect RGC-5 necrosis. RIP3 expression was detected by western blot and flow cytometry was used to detect the effect of RIP3 on RGC-5 necroptosis following OGD in rip3 knockdown cells. Malondialdehyde (MDA) lipid peroxidation assay was performed to determine the degree of oxidative stress. PI staining showed that necrosis was present in the early stage of OGD-induced RGC-5 cell death. The presence of RGC-5 necroptosis after OGD was detected by flow cytometry using necrostatin-1, a necroptosis inhibitor. Western blot demonstrated that RIP3 up-regulation may be involved in RGC-5 necroptosis. Flow cytometry revealed that the number of OGD-induced necrotic RGC-5 cells was reduced after rip3 knockdown. Furthermore, MDA levels in the normal RGC-5 cells were much higher than in the rip3-knockdown cells after OGD. Our findings suggest that RGC-5 cell necroptosis following OGD is mediated by a RIP3-induced increase in oxidative stress.

Cytosolic calcium mediates RIP1/RIP3 complex-dependent necroptosis through JNK activation and mitochondrial ROS production in human colon cancer cells.

PubMed

Sun, Wen; Wu, Xiaxia; Gao, Hongwei; Yu, Jie; Zhao, Wenwen; Lu, Jin-Jian; Wang, Jinhua; Du, Guanhua; Chen, Xiuping

2017-07-01

Necroptosis is a form of programmed necrosis mediated by signaling complexes with receptor-interacting protein 1 (RIP1) and RIP3 kinases as the main mediators. However, the underlying execution pathways of this phenomenon have yet to be elucidated in detail. In this study, a RIP1/RIP3 complex was formed in 2-methoxy-6-acetyl-7-methyljuglone (MAM)-treated HCT116 and HT29 colon cancer cells. With this formation, mitochondrial reactive oxygen species (ROS) levels increased, mitochondrial depolarization occurred, and ATP concentrations decreased. This process was identified as necroptosis. This finding was confirmed by experiments showing that MAM-induced cell death was attenuated by the pharmacological or genetic blockage of necroptosis signaling, including RIP1 inhibitor necrostatin-1s (Nec-1s) and siRNA-mediated gene silencing of RIP1 and RIP3, but was unaffected by caspase inhibitor z-vad-fmk or necrosis inhibitor 2-(1H-Indol-3-yl)-3-pentylamino-maleimide (IM54). Transmission electron microscopy (TEM) analysis further revealed the ultrastructural features of MAM-induced necroptosis. MAM-induced RIP1/RIP3 complex triggered necroptosis through cytosolic calcium (Ca 2+ ) accumulation and sustained c-Jun N-terminal kinase (JNK) activation. Both calcium chelator BAPTA-AM and JNK inhibitor SP600125 could attenuate necroptotic features, including mitochondrial ROS elevation, mitochondrial depolarization, and ATP depletion. 2-thenoyltrifluoroacetone (TTFA), which is a mitochondrial complex II inhibitor, was found to effectively reverse both MAM induced mitochondrial ROS generation and cell death, indicating the complex II was the ROS-producing site. The essential role of mitochondrial ROS was confirmed by the protective effect of overexpression of manganese superoxide dismutase (MnSOD). MAM-induced necroptosis was independent of TNFα, p53, MLKL, and lysosomal membrane permeabilization. In summary, our study demonstrated that RIP1/RIP3 complex-triggered cytosolic calcium accumulation is a critical mediator in MAM-induced necroptosis through sustained JNK activation and mitochondrial ROS production. Our study also provided new insights into the molecular regulation of necroptosis in human colon cancer cells. Copyright © 2017 Elsevier Inc. All rights reserved.

RIP1 regulates TNF-α-mediated lymphangiogenesis and lymphatic metastasis in gallbladder cancer by modulating the NF-κB-VEGF-C pathway

PubMed Central

Lin, Bin; Hong, Hai-Jie; Zhu, Si-Yuan; Jiang, Lei; Wang, Xiao-Qian; Tang, Nan-Hong; She, Fei-Fei; Chen, Yan-Ling

2018-01-01

Background Tumor necrosis factor alpha (TNF-α) enhances lymphangiogenesis in gallbladder carcinoma (GBC) via activation of nuclear factor (NF-κB)-dependent vascular endothelial growth factor-C (VEGF-C). Receptor-interacting protein 1 (RIP1) is a multifunctional protein in the TNF-α signaling pathway and is highly expressed in GBC. However, whether RIP1 participates in the signaling pathway of TNF-α-mediated VEGF-C expression that enhances lymphangiogenesis in GBC remains unclear. Methods The RIP1 protein levels in the GBC-SD and NOZ cells upon stimulation with increasing concentrations of TNF-α as indicated was examined using Western blot. Lentiviral RIP1 shRNA and siIκBα were constructed and transduced respectively them into NOZ and GBC-SD cells, and then PcDNA3.1-RIP1 vectors was transduced into siRIP1 cell lines to reverse RIP1 expression. The protein expression of RIP1, inhibitor of NF-κB alpha (IκBα), p-IκBα, TAK1, NF-κB essential modulator were examined through immunoblotting or immunoprecipitation. Moreover, VEGF-C mRNA levels were measured by quantitative real-time polymerase chain reaction, VEGF-C protein levels were measured by immunoblotting and enzyme-linked immunosorbent assay, and VEGF-C promoter and NF-κB activities were quantified using a dual luciferase reporter assay. The association of NF-κB with the VEGF-C promoter was analysed by chromatin immunoprecipitation assay. A three-dimensional coculture method and orthotopic transplantation nude mice model were used to evaluate lymphatic tube-forming and metastasis ability in GBC cells. The expression of RIP1 protein, TNF-α protein and lymphatic vessels in human GBC tissues was examined by immunohistochemistry, and the dependence between RIP1 protein with TNF-α protein and lymphatic vessel density was analysed. Results TNF-α dose- and time-dependently increased RIP1 protein expression in the GBC-SD and NOZ cells of GBC, and the strongest effect was observed with a concentration of 50 ng/ml. RIP1 is fundamental for TNF-α-mediated NF-κB activation in GBC cells and can regulate TNF-α-mediated VEGF-C expression at the protein and transcriptional levels through the NF-κB pathway. RIP1 can regulate TNF-α-mediated lymphatic tube formation and metastasis in GBC cells both in vitro and vivo. The average optical density of RIP1 was linearly related to that of TNF-α protein and the lymphatic vessel density in GBC tissues. Conclusion We conclude that RIP1 regulates TNF-α-mediated lymphangiogenesis and lymph node metastasis in GBC by modulating the NF-κB-VEGF-C pathway. PMID:29844685

RIP1 regulates TNF-α-mediated lymphangiogenesis and lymphatic metastasis in gallbladder cancer by modulating the NF-κB-VEGF-C pathway.

PubMed

Li, Cheng-Zong; Jiang, Xiao-Jie; Lin, Bin; Hong, Hai-Jie; Zhu, Si-Yuan; Jiang, Lei; Wang, Xiao-Qian; Tang, Nan-Hong; She, Fei-Fei; Chen, Yan-Ling

2018-01-01

Tumor necrosis factor alpha (TNF-α) enhances lymphangiogenesis in gallbladder carcinoma (GBC) via activation of nuclear factor (NF-κB)-dependent vascular endothelial growth factor-C (VEGF-C). Receptor-interacting protein 1 (RIP1) is a multifunctional protein in the TNF-α signaling pathway and is highly expressed in GBC. However, whether RIP1 participates in the signaling pathway of TNF-α-mediated VEGF-C expression that enhances lymphangiogenesis in GBC remains unclear. The RIP1 protein levels in the GBC-SD and NOZ cells upon stimulation with increasing concentrations of TNF-α as indicated was examined using Western blot. Lentiviral RIP1 shRNA and siIκBα were constructed and transduced respectively them into NOZ and GBC-SD cells, and then PcDNA3.1-RIP1 vectors was transduced into siRIP1 cell lines to reverse RIP1 expression. The protein expression of RIP1, inhibitor of NF-κB alpha (IκBα), p-IκBα, TAK1, NF-κB essential modulator were examined through immunoblotting or immunoprecipitation. Moreover, VEGF-C mRNA levels were measured by quantitative real-time polymerase chain reaction, VEGF-C protein levels were measured by immunoblotting and enzyme-linked immunosorbent assay, and VEGF-C promoter and NF-κB activities were quantified using a dual luciferase reporter assay. The association of NF-κB with the VEGF-C promoter was analysed by chromatin immunoprecipitation assay. A three-dimensional coculture method and orthotopic transplantation nude mice model were used to evaluate lymphatic tube-forming and metastasis ability in GBC cells. The expression of RIP1 protein, TNF-α protein and lymphatic vessels in human GBC tissues was examined by immunohistochemistry, and the dependence between RIP1 protein with TNF-α protein and lymphatic vessel density was analysed. TNF-α dose- and time-dependently increased RIP1 protein expression in the GBC-SD and NOZ cells of GBC, and the strongest effect was observed with a concentration of 50 ng/ml. RIP1 is fundamental for TNF-α-mediated NF-κB activation in GBC cells and can regulate TNF-α-mediated VEGF-C expression at the protein and transcriptional levels through the NF-κB pathway. RIP1 can regulate TNF-α-mediated lymphatic tube formation and metastasis in GBC cells both in vitro and vivo. The average optical density of RIP1 was linearly related to that of TNF-α protein and the lymphatic vessel density in GBC tissues. We conclude that RIP1 regulates TNF-α-mediated lymphangiogenesis and lymph node metastasis in GBC by modulating the NF-κB-VEGF-C pathway.

Rip Current Media Event

Science.gov Websites

All NOAA ABOUT About NWS Organization Strategic Plan For NWS Employees International National Centers water. Don't before a victim trying to help someone. if a lifeguard is not present, yell instructions on

Validation of the ROMI-RIP rough mill simulator

Treesearch

Edward R. Thomas; Urs Buehlmann

2002-01-01

The USDA Forest Service's ROMI-RIP rough mill rip-first simulation program is a popular tool for analyzing rough mill conditions, determining more efficient rough mill practices, and finding optimal lumber board cut-up patterns. However, until now, the results generated by ROMI-RIP have not been rigorously compared to those of an actual rough mill. Validating the...

Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense

PubMed Central

Wang, Xing; Li, Yun; Liu, Shan; Yu, Xiaoliang; Li, Lin; Shi, Cuilin; He, Wenhui; Li, Jun; Xu, Lei; Hu, Zhilin; Yu, Lu; Yang, Zhongxu; Chen, Qin; Ge, Lin; Zhang, Zili; Zhou, Biqi; Jiang, Xuejun; Chen, She; He, Sudan

2014-01-01

The receptor-interacting kinase-3 (RIP3) and its downstream substrate mixed lineage kinase domain-like protein (MLKL) have emerged as the key cellular components in programmed necrotic cell death. Receptors for the cytokines of tumor necrosis factor (TNF) family and Toll-like receptors (TLR) 3 and 4 are able to activate RIP3 through receptor-interacting kinase-1 and Toll/IL-1 receptor domain-containing adapter inducing IFN-β, respectively. This form of cell death has been implicated in the host-defense system. However, the molecular mechanisms that drive the activation of RIP3 by a variety of pathogens, other than the above-mentioned receptors, are largely unknown. Here, we report that human herpes simplex virus 1 (HSV-1) infection triggers RIP3-dependent necrosis. This process requires MLKL but is independent of TNF receptor, TLR3, cylindromatosis, and host RIP homotypic interaction motif-containing protein DNA-dependent activator of IFN regulatory factor. After HSV-1 infection, the viral ribonucleotide reductase large subunit (ICP6) interacts with RIP3. The formation of the ICP6–RIP3 complex requires the RHIM domains of both proteins. An HSV-1 ICP6 deletion mutant failed to cause effective necrosis of HSV-1–infected cells. Furthermore, ectopic expression of ICP6, but not RHIM mutant ICP6, directly activated RIP3/MLKL-mediated necrosis. Mice lacking RIP3 exhibited severely impaired control of HSV-1 replication and pathogenesis. Therefore, this study reveals a previously uncharacterized host antipathogen mechanism. PMID:25316792

Potential for yield improvement in combined rip-first and crosscut-first rough mill processing

Treesearch

Ed Thomas; Urs Buehlmann

2016-01-01

Traditionally, lumber cutting systems in rough mills have either first ripped lumber into wide strips and then crosscut the resulting strips into component lengths (rip-first), or first crosscut the lumber into component lengths, then ripped the segments to the required widths (crosscut-first). Each method has its advantages and disadvantages. Crosscut-first typically...

A 16-year evaluation of effects of ripping on shortleaf pine on a Missouri ozarks site

Treesearch

David Gwaze; Carl Hauser; Mark Johanson

2006-01-01

A shortleaf pine (Pinus echinata Mill.) ripping study was established by the Missouri Department of Conservation in March 1988 at the Logan Creek Conservation Area. The objective of the study was to evaluate the effects of ripping on survival, height, diameter, volume, crown spread, and free-to-grow status of planted shortleaf pine seedlings. Ripping...

MeRIP-PF: An Easy-to-use Pipeline for High-resolution Peak-finding in MeRIP-Seq Data

PubMed Central

Li, Yuli; Song, Shuhui; Li, Cuiping; Yu, Jun

2013-01-01

RNA modifications, especially methylation of the N6 position of adenosine (A)—m6A, represent an emerging research frontier in RNA biology. With the rapid development of high-throughput sequencing technology, in-depth study of m6A distribution and function relevance becomes feasible. However, a robust method to effectively identify m6A-modified regions has not been available yet. Here, we present a novel high-efficiency and user-friendly analysis pipeline called MeRIP-PF for the signal identification of MeRIP-Seq data in reference to controls. MeRIP-PF provides a statistical P-value for each identified m6A region based on the difference of read distribution when compared to the controls and also calculates false discovery rate (FDR) as a cut off to differentiate reliable m6A regions from the background. Furthermore, MeRIP-PF also achieves gene annotation of m6A signals or peaks and produce outputs in both XLS and graphical format, which are useful for further study. MeRIP-PF is implemented in Perl and is freely available at http://software.big.ac.cn/MeRIP-PF.html. PMID:23434047

Structural Study of the RIPoptosome Core Reveals a Helical Assembly for Kinase Recruitment

PubMed Central

2015-01-01

Receptor interaction protein kinase 1 (RIP1) is a molecular cell-fate switch. RIP1, together with Fas-associated protein with death domain (FADD) and caspase-8, forms the RIPoptosome that activates apoptosis. RIP1 also associates with RIP3 to form the necrosome that triggers necroptosis. The RIPoptosome assembles through interactions between the death domains (DDs) of RIP1 and FADD and between death effector domains (DEDs) of FADD and caspase-8. In this study, we analyzed the overall structure of the RIP1 DD/FADD DD complex, the core of the RIPoptosome, by negative-stain electron microscopy and modeling. The results show that RIP1 DD and FADD DD form a stable complex in vitro similar to the previously described Fas DD/FADD DD complex, suggesting that the RIPoptosome and the Fas death-inducing signaling complex share a common assembly mechanism. Both complexes adopt a helical conformation that requires type I, II, and III interactions between the death domains. PMID:25119434

Cylindromatosis mediates neuronal cell death in vitro and in vivo.

PubMed

Ganjam, Goutham K; Terpolilli, Nicole Angela; Diemert, Sebastian; Eisenbach, Ina; Hoffmann, Lena; Reuther, Christina; Herden, Christiane; Roth, Joachim; Plesnila, Nikolaus; Culmsee, Carsten

2018-01-19

The tumor-suppressor cylindromatosis (CYLD) is a deubiquitinating enzyme and key regulator of cell proliferation and inflammation. A genome-wide siRNA screen linked CYLD to receptor interacting protein-1 (RIP1) kinase-mediated necroptosis; however, the exact mechanisms of CYLD-mediated cell death remain unknown. Therefore, we investigated the precise role of CYLD in models of neuronal cell death in vitro and evaluated whether CYLD deletion affects brain injury in vivo. In vitro, downregulation of CYLD increased RIP1 ubiquitination, prevented RIP1/RIP3 complex formation, and protected neuronal cells from oxidative death. Similar protective effects were achieved by siRNA silencing of RIP1 or RIP3 or by pharmacological inhibition of RIP1 with necrostatin-1. In vivo, CYLD knockout mice were protected from trauma-induced brain damage compared to wild-type littermate controls. These findings unravel the mechanisms of CYLD-mediated cell death signaling in damaged neurons in vitro and suggest a cell death-mediating role of CYLD in vivo.

Implementation of the vortex force formalism in the coupled ocean-atmosphere-wave-sediment transport (COAWST) modeling system for inner shelf and surf zone applications

NASA Astrophysics Data System (ADS)

Kumar, Nirnimesh; Voulgaris, George; Warner, John C.; Olabarrieta, Maitane

The coupled ocean-atmosphere-wave-sediment transport modeling system (COAWST) enables simulations that integrate oceanic, atmospheric, wave and morphological processes in the coastal ocean. Within the modeling system, the three-dimensional ocean circulation module (ROMS) is coupled with the wave generation and propagation model (SWAN) to allow full integration of the effect of waves on circulation and vice versa. The existing wave-current coupling component utilizes a depth dependent radiation stress approach. In here we present a new approach that uses the vortex force formalism. The formulation adopted and the various parameterizations used in the model as well as their numerical implementation are presented in detail. The performance of the new system is examined through the presentation of four test cases. These include obliquely incident waves on a synthetic planar beach and a natural barred beach (DUCK' 94); normal incident waves on a nearshore barred morphology with rip channels; and wave-induced mean flows outside the surf zone at the Martha's Vineyard Coastal Observatory (MVCO). Model results from the planar beach case show good agreement with depth-averaged analytical solutions and with theoretical flow structures. Simulation results for the DUCK' 94 experiment agree closely with measured profiles of cross-shore and longshore velocity data from Garcez Faria et al. (1998, 2000). Diagnostic simulations showed that the nonlinear processes of wave roller generation and wave-induced mixing are important for the accurate simulation of surf zone flows. It is further recommended that a more realistic approach for determining the contribution of wave rollers and breaking induced turbulent mixing can be formulated using non-dimensional parameters which are functions of local wave parameters and the beach slope. Dominant terms in the cross-shore momentum balance are found to be the quasi-static pressure gradient and breaking acceleration. In the alongshore direction, bottom stress, breaking acceleration, horizontal advection and horizontal vortex forces dominate the momentum balance. The simulation results for the bar/rip channel morphology case clearly show the ability of the modeling system to reproduce horizontal and vertical circulation patterns similar to those found in laboratory studies and to numerical simulations using the radiation stress representation. The vortex force term is found to be more important at locations where strong flow vorticity interacts with the wave-induced Stokes flow field. Outside the surf zone, the three-dimensional model simulations of wave-induced flows for non-breaking waves closely agree with flow observations from MVCO, with the vertical structure of the simulated flow varying as a function of the vertical viscosity as demonstrated by Lentz et al. (2008).

Ralstonia solanacearum Type III Effector RipAY Is a Glutathione-Degrading Enzyme That Is Activated by Plant Cytosolic Thioredoxins and Suppresses Plant Immunity.

PubMed

Mukaihara, Takafumi; Hatanaka, Tadashi; Nakano, Masahito; Oda, Kenji

2016-04-12

The plant pathogen Ralstonia solanacearum uses a large repertoire of type III effector proteins to succeed in infection. To clarify the function of effector proteins in host eukaryote cells, we expressed effectors in yeast cells and identified seven effector proteins that interfere with yeast growth. One of the effector proteins, RipAY, was found to share homology with the ChaC family proteins that function as γ-glutamyl cyclotransferases, which degrade glutathione (GSH), a tripeptide that plays important roles in the plant immune system. RipAY significantly inhibited yeast growth and simultaneously induced rapid GSH depletion when expressed in yeast cells. The in vitro GSH degradation activity of RipAY is specifically activated by eukaryotic factors in the yeast and plant extracts. Biochemical purification of the yeast protein identified that RipAY is activated by thioredoxin TRX2. On the other hand, RipAY was not activated by bacterial thioredoxins. Interestingly, RipAY was activated by plant h-type thioredoxins that exist in large amounts in the plant cytosol, but not by chloroplastic m-, f-, x-, y- and z-type thioredoxins, in a thiol-independent manner. The transient expression of RipAY decreased the GSH level in plant cells and affected the flg22-triggered production of reactive oxygen species (ROS) and expression of pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) marker genes in Nicotiana benthamiana leaves. These results indicate that RipAY is activated by host cytosolic thioredoxins and degrades GSH specifically in plant cells to suppress plant immunity. Ralstonia solanacearum is the causal agent of bacterial wilt disease of plants. This pathogen injects virulence effector proteins into host cells to suppress disease resistance responses of plants. In this article, we report a biochemical activity of R. solanacearum effector protein RipAY. RipAY can degrade GSH, a tripeptide that plays important roles in the plant immune system, with its γ-glutamyl cyclotransferase activity. The high GSH degradation activity of RipAY is considered to be a good weapon for this bacterium to suppress plant immunity. However, GSH also plays important roles in bacterial tolerance to various stresses and growth. Interestingly, RipAY has an excellent safety mechanism to prevent unwanted firing of its enzyme activity in bacterial cells because RipAY is specifically activated by host eukaryotic thioredoxins. This study also reveals a novel host plant protein acting as a molecular switch for effector activation. Copyright © 2016 Mukaihara et al.

The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression.

PubMed

Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Giao Ly, Nancy Ngoc; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Barilla, Rocky; Daley, Donnele; Greco, Stephanie H; Torres-Hernandez, Alejandro; Pergamo, Matthew; Ochi, Atsuo; Zambirinis, Constantinos P; Pansari, Mridul; Rendon, Mauricio; Tippens, Daniel; Hundeyin, Mautin; Mani, Vishnu R; Hajdu, Cristina; Engle, Dannielle; Miller, George

2016-04-14

Neoplastic pancreatic epithelial cells are believed to die through caspase 8-dependent apoptotic cell death, and chemotherapy is thought to promote tumour apoptosis. Conversely, cancer cells often disrupt apoptosis to survive. Another type of programmed cell death is necroptosis (programmed necrosis), but its role in pancreatic ductal adenocarcinoma (PDA) is unclear. There are many potential inducers of necroptosis in PDA, including ligation of tumour necrosis factor receptor 1 (TNFR1), CD95, TNF-related apoptosis-inducing ligand (TRAIL) receptors, Toll-like receptors, reactive oxygen species, and chemotherapeutic drugs. Here we report that the principal components of the necrosome, receptor-interacting protein (RIP)1 and RIP3, are highly expressed in PDA and are further upregulated by the chemotherapy drug gemcitabine. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo deletion of RIP3 or inhibition of RIP1 protected against oncogenic progression in mice and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumour microenvironment associated with intact RIP1/RIP3 signalling depended in part on necroptosis-induced expression of the chemokine attractant CXCL1, and CXCL1 blockade protected against PDA. Moreover, cytoplasmic SAP130 (a subunit of the histone deacetylase complex) was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle--its cognate receptor--was upregulated in tumour-infiltrating myeloid cells. Ligation of Mincle by SAP130 promoted oncogenesis, whereas deletion of Mincle protected against oncogenesis and phenocopied the immunogenic reprogramming of the tumour microenvironment that was induced by RIP3 deletion. Cellular depletion suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects when RIP3 or Mincle is deleted. Accordingly, T cells, which are not protective against PDA progression in mice with intact RIP3 or Mincle signalling, are reprogrammed into indispensable mediators of anti-tumour immunity in the absence of RIP3 or Mincle. Our work describes parallel networks of necroptosis-induced CXCL1 and Mincle signalling that promote macrophage-induced adaptive immune suppression and thereby enable PDA progression.

The Necrosome Promotes Pancreas Oncogenesis via CXCL1 and Mincle Induced Immune Suppression

PubMed Central

Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Giao Ly, Nancy Ngoc; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Barilla, Rocky; Daley, Donnele; Greco, Stephanie H.; Torres-Hernandez, Alejandro; Pergamo, Matthew; Ochi, Atsuo; Zambirinis, Constantinos P.; Pansari, Mridul; Rendon, Mauricio; Tippens, Daniel; Hundeyin, Mautin; Mani, Vishnu R.; Hajdu, Cristina; Engle, Dannielle; Miller, George

2016-01-01

Neoplastic pancreatic epithelial cells are widely believed to die via Caspase 8-dependant apoptotic cell death and chemotherapy is thought to further promote tumor apoptosis1. Conversely, disruption of apoptosis is a basic modality cancer cells exploit for survival2,3. However, the role of necroptosis, or programmed necrosis, in pancreatic ductal adenocarcinoma (PDA) is uncertain. There are a multitude of potential inducers of necroptosis in PDA including ligation of TNFR1, CD95, TRAIL receptors, Toll-like receptors, ROS, and Chemotherapeutics4,5. Here we report that the principal components of the necrosome, RIP1 and RIP3, are highly expressed in PDA and are further upregulated by chemotherapy. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo RIP3 deletion or RIP1 inhibition was protective against oncogenic progression and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumor microenvironment (TME) associated with intact RIP1/RIP3 signaling was in-part contingent on necroptosis-induced CXCL1 expression whereas CXCL1 blockade was protective against PDA. Moreover, we found that cytoplasmic SAP130 was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle – its cognate receptor – was upregulated in tumor-infiltrating myeloid cells. Mincle ligation by SAP130 promoted oncogenesis whereas Mincle deletion was protective and phenocopied the immunogenic reprogramming of the TME characteristic of RIP3 deletion. Cellular depletion experiments suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects in the context of RIP3 or Mincle deletion. As such, T cells which are dispensable to PDA progression in hosts with intact RIP3 or Mincle signaling become reprogrammed into indispensable mediators of anti-tumor immunity in absence of RIP3 or Mincle. Our work describes parallel networks of necroptosis-induced CXCL1 and Mincle signaling which critically promote macrophage-induced adaptive immune suppression enabling PDA progression. PMID:27049944

Herpes Simplex Virus 1 (HSV-1) and HSV-2 Mediate Species-Specific Modulations of Programmed Necrosis through the Viral Ribonucleotide Reductase Large Subunit R1

PubMed Central

Yu, Xiaoliang; Li, Yun; Chen, Qin; Su, Chenhe; Zhang, Zili; Yang, Chengkui; Hu, Zhilin; Hou, Jue; Zhou, Jinying; Gong, Ling; Jiang, Xuejun

2015-01-01

ABSTRACT Receptor-interacting protein kinase 3 (RIP3) and its substrate mixed-lineage kinase domain-like protein (MLKL) are core regulators of programmed necrosis. The elimination of pathogen-infected cells by programmed necrosis acts as an important host defense mechanism. Here, we report that human herpes simplex virus 1 (HSV-1) and HSV-2 had opposite impacts on programmed necrosis in human cells versus their impacts in mouse cells. Similar to HSV-1, HSV-2 infection triggered programmed necrosis in mouse cells. However, neither HSV-1 nor HSV-2 infection was able to induce programmed necrosis in human cells. Moreover, HSV-1 or HSV-2 infection in human cells blocked tumor necrosis factor (TNF)-induced necrosis by preventing the induction of an RIP1/RIP3 necrosome. The HSV ribonucleotide reductase large subunit R1 was sufficient to suppress TNF-induced necrosis, and its RIP homotypic interaction motif (RHIM) domain was required to disrupt the RIP1/RIP3 complex in human cells. Therefore, this study provides evidence that HSV has likely evolved strategies to evade the host defense mechanism of programmed necrosis in human cells. IMPORTANCE This study demonstrated that infection with HSV-1 and HSV-2 blocked TNF-induced necrosis in human cells while these viruses directly activated programmed necrosis in mouse cells. Expression of HSV R1 suppressed TNF-induced necrosis of human cells. The RHIM domain of R1 was essential for its association with human RIP3 and RIP1, leading to disruption of the RIP1/RIP3 complex. This study provides new insights into the species-specific modulation of programmed necrosis by HSV. PMID:26559832

Herpes Simplex Virus 1 (HSV-1) and HSV-2 Mediate Species-Specific Modulations of Programmed Necrosis through the Viral Ribonucleotide Reductase Large Subunit R1.

PubMed

Yu, Xiaoliang; Li, Yun; Chen, Qin; Su, Chenhe; Zhang, Zili; Yang, Chengkui; Hu, Zhilin; Hou, Jue; Zhou, Jinying; Gong, Ling; Jiang, Xuejun; Zheng, Chunfu; He, Sudan

2016-01-15

Receptor-interacting protein kinase 3 (RIP3) and its substrate mixed-lineage kinase domain-like protein (MLKL) are core regulators of programmed necrosis. The elimination of pathogen-infected cells by programmed necrosis acts as an important host defense mechanism. Here, we report that human herpes simplex virus 1 (HSV-1) and HSV-2 had opposite impacts on programmed necrosis in human cells versus their impacts in mouse cells. Similar to HSV-1, HSV-2 infection triggered programmed necrosis in mouse cells. However, neither HSV-1 nor HSV-2 infection was able to induce programmed necrosis in human cells. Moreover, HSV-1 or HSV-2 infection in human cells blocked tumor necrosis factor (TNF)-induced necrosis by preventing the induction of an RIP1/RIP3 necrosome. The HSV ribonucleotide reductase large subunit R1 was sufficient to suppress TNF-induced necrosis, and its RIP homotypic interaction motif (RHIM) domain was required to disrupt the RIP1/RIP3 complex in human cells. Therefore, this study provides evidence that HSV has likely evolved strategies to evade the host defense mechanism of programmed necrosis in human cells. This study demonstrated that infection with HSV-1 and HSV-2 blocked TNF-induced necrosis in human cells while these viruses directly activated programmed necrosis in mouse cells. Expression of HSV R1 suppressed TNF-induced necrosis of human cells. The RHIM domain of R1 was essential for its association with human RIP3 and RIP1, leading to disruption of the RIP1/RIP3 complex. This study provides new insights into the species-specific modulation of programmed necrosis by HSV. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Coupled RipCAS-DFLOW (CoRD) Software and Data Management System for Reproducible Floodplain Vegetation Succession Modeling

NASA Astrophysics Data System (ADS)

Turner, M. A.; Miller, S.; Gregory, A.; Cadol, D. D.; Stone, M. C.; Sheneman, L.

2016-12-01

We present the Coupled RipCAS-DFLOW (CoRD) modeling system created to encapsulate the workflow to analyze the effects of stream flooding on vegetation succession. CoRD provides an intuitive command-line and web interface to run DFLOW and RipCAS in succession over many years automatically, which is a challenge because, for our application, DFLOW must be run on a supercomputing cluster via the PBS job scheduler. RipCAS is a vegetation succession model, and DFLOW is a 2D open channel flow model. Data adaptors have been developed to seamlessly connect DFLOW output data to be RipCAS inputs, and vice-versa. CoRD provides automated statistical analysis and visualization, plus automatic syncing of input and output files and model run metadata to the hydrological data management system HydroShare using its excellent Python REST client. This combination of technologies and data management techniques allows the results to be shared with collaborators and eventually published. Perhaps most importantly, it allows results to be easily reproduced via either the command-line or web user interface. This system is a result of collaboration between software developers and hydrologists participating in the Western Consortium for Watershed Analysis, Visualization, and Exploration (WC-WAVE). Because of the computing-intensive nature of this particular workflow, including automating job submission/monitoring and data adaptors, software engineering expertise is required. However, the hydrologists provide the software developers with a purpose and ensure a useful, intuitive tool is developed. Our hydrologists contribute software, too: RipCAS was developed from scratch by hydrologists on the team as a specialized, open-source version of the Computer Aided Simulation Model for Instream Flow and Riparia (CASiMiR) vegetation model; our hydrologists running DFLOW provided numerous examples and help with the supercomputing system. This project is written in Python, a popular language in the geosciences and a good beginner programming language, and is completely open source. It can be accessed at https://github.com/VirtualWatershed/CoRD with documentation available at http://virtualwatershed.github.io/CoRD. These facts enable continued development and use beyond the involvement of the current authors.

MeRIP-PF: an easy-to-use pipeline for high-resolution peak-finding in MeRIP-Seq data.

PubMed

Li, Yuli; Song, Shuhui; Li, Cuiping; Yu, Jun

2013-02-01

RNA modifications, especially methylation of the N(6) position of adenosine (A)-m(6)A, represent an emerging research frontier in RNA biology. With the rapid development of high-throughput sequencing technology, in-depth study of m(6)A distribution and function relevance becomes feasible. However, a robust method to effectively identify m(6)A-modified regions has not been available yet. Here, we present a novel high-efficiency and user-friendly analysis pipeline called MeRIP-PF for the signal identification of MeRIP-Seq data in reference to controls. MeRIP-PF provides a statistical P-value for each identified m(6)A region based on the difference of read distribution when compared to the controls and also calculates false discovery rate (FDR) as a cut off to differentiate reliable m(6)A regions from the background. Furthermore, MeRIP-PF also achieves gene annotation of m(6)A signals or peaks and produce outputs in both XLS and graphical format, which are useful for further study. MeRIP-PF is implemented in Perl and is freely available at http://software.big.ac.cn/MeRIP-PF.html. Copyright © 2013. Production and hosting by Elsevier Ltd.

RIP3-dependent necrosis induced inflammation exacerbates atherosclerosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meng, Lingjun, E-mail: menglingjun@nibs.ac.cn; National Institute of Biological Sciences, Beijing 102206; Jin, Wei

Atherothrombotic vascular disease is already the leading cause of mortality worldwide. Atherosclerosis shares features with diseases caused by chronic inflammation. More attention should concentrates on the innate immunity effect atherosclerosis progress. RIP3 (receptor-interacting protein kinase 3) act through the transcription factor named Nr4a3 (Nuclear orphan receptors) to regulate cytokine production. Deletion RIP3 decreases IL-1α production. Injection of anti-IL-1α antibody protects against the progress of atherosclerosis in ApoE −/− mice. RIP3 as a molecular switch in necrosis, controls macrophage necrotic death caused inflammation. Inhibiting necrosis will certainly reduce atherosclerosis through limit inflammation. Necrotic cell death caused systemic inflammation exacerbated cardiovascular disease. Inhibitionmore » of necrosis may yield novel therapeutic targets for treatment in years to come. - Highlights: • RIP3 regulate the Nr4a3 to control cytokine production. • Deletion RIP3 decreases IL-1a production. • Injection anti-IL-1a antibody protects against the progress of atherosclerosis. • RIP3 controls macrophage necrotic dead caused inflammation.« less

Short-crested waves in the surf zone

NASA Astrophysics Data System (ADS)

Wei, Zhangping; Dalrymple, Robert A.; Xu, Munan; Garnier, Roland; Derakhti, Morteza

2017-05-01

This study investigates short-crested waves in the surf zone by using the mesh-free Smoothed Particle Hydrodynamics model, GPUSPH. The short-crested waves are created by generating intersecting wave trains in a numerical wave basin with a beach. We first validate the numerical model for short-crested waves by comparison with large-scale laboratory measurements. Then short-crested wave breaking over a planar beach is studied comprehensively. We observe rip currents as discussed in Dalrymple (1975) and undertow created by synchronous intersecting waves. The wave breaking of the short-crested wavefield created by the nonlinear superposition of intersecting waves and wave-current interaction result in the formation of isolated breakers at the ends of breaking wave crests. Wave amplitude diffraction at these isolated breakers gives rise to an increase in the alongshore wave number in the inner surf zone. Moreover, 3-D vortices and multiple circulation cells with a rotation frequency much lower than the incident wave frequency are observed across the outer surf zone to the beach. Finally, we investigate vertical vorticity generation under short-crested wave breaking and find that breaking of short-crested waves generates vorticity as pointed out by Peregrine (1998). Vorticity generation is not only observed under short-crested waves with a limited number of wave components but also under directional wave spectra.

Necroptosis: an alternative cell death program defending against cancer

PubMed Central

Chen, Dongshi; Yu, Jian; Zhang, Lin

2016-01-01

One of the hallmarks of cancer is resistance to programmed cell death, which maintains the survival of cells en route to oncogenic transformation and underlies therapeutic resistance. Recent studies demonstrate that programmed cell death is not confined to caspase-dependent apoptosis, but includes necroptosis, a form of necrotic death governed by Receptor-Interacting Protein 1 (RIP1), RIP3, and Mixed Lineage Kinase Domain-Like (MLKL). Necroptosis serves as a critical cell-killing mechanism in response to severe stress and blocked apoptosis, and can be induced by inflammatory cytokines or chemotherapeutic drugs. Genetic or epigenetic alterations of necroptosis regulators such as RIP3 and cylindromatosis (CYLD), are frequently found in human tumors. Unlike apoptosis, necroptosis elicits a more robust immune response that may function as a defensive mechanism by eliminating tumor-causing mutations and viruses. Furthermore, several classes of anticancer agents currently under clinical development, such as SMAC and BH3 mimetics, can promote necroptosis in addition to apoptosis. A more complete understanding of the interplay among necroptosis, apoptosis, and other cell death modalities is critical for developing new therapeutic strategies to enhance killing of tumor cells. PMID:26968619

Towards estimation of respiratory muscle effort with respiratory inductance plethysmography signals and complementary ensemble empirical mode decomposition.

PubMed

Chen, Ya-Chen; Hsiao, Tzu-Chien

2018-07-01

Respiratory inductance plethysmography (RIP) sensor is an inexpensive, non-invasive, easy-to-use transducer for collecting respiratory movement data. Studies have reported that the RIP signal's amplitude and frequency can be used to discriminate respiratory diseases. However, with the conventional approach of RIP data analysis, respiratory muscle effort cannot be estimated. In this paper, the estimation of the respiratory muscle effort through RIP signal was proposed. A complementary ensemble empirical mode decomposition method was used, to extract hidden signals from the RIP signals based on the frequency bands of the activities of different respiratory muscles. To validate the proposed method, an experiment to collect subjects' RIP signal under thoracic breathing (TB) and abdominal breathing (AB) was conducted. The experimental results for both the TB and AB indicate that the proposed method can be used to loosely estimate the activities of thoracic muscles, abdominal muscles, and diaphragm. Graphical abstract ᅟ.

Genomic Variation, Host Range, and Infection Kinetics of Closely Related Cyanopodoviruses from New England Coastal Waters

NASA Astrophysics Data System (ADS)

Veglia, A. J.; Milford, C. R.; Marston, M.

2016-02-01

Viruses infecting marine Synechococcus are abundant in coastal marine environments and influence the community composition and abundance of their cyanobacterial hosts. In this study, we focused on the cyanopodoviruses which have smaller genomes and narrower host ranges relative to cyanomyoviruses. While previous studies have compared the genomes of diverse podoviruses, here we analyzed the genomic variation, host ranges, and infection kinetics of podoviruses within the same OTU. The genomes of fifty-five podoviral isolates from the coastal waters of New England were fully sequenced. Based on DNA polymerase gene sequences, these isolates fall into five discrete OTUs (termed RIP - Rhode Island Podovirus). Although all the isolates belonging to the same RIP have very similar DNA polymerase gene sequences (>98% sequence identity), differences in genome content, particularly in regions associated with tail fiber genes, were observed among isolates in the same RIP. Host range tests reveal variation both across and within RIPs. Notably within RIP1, isolates that had similar tail fiber regions also had similar host ranges. Isolates belonging to RIP4 do not contain the host-derived psbA photosynthesis gene, while isolates in the other four RIPs do possess a psbA gene. Nevertheless, infection kinetic experiments suggest that the latent period and burst size for RIP4 isolates are similar to RIP1 isolates. We are continuing to investigate the correlations among genome content, host range, and infection kinetics of isolates belonging to the same OTU. Our results to date suggest that there is substantial genomic variation within an OTU and that this variation likely influences cyanopodoviral - host interactions.

Taking Wave Prediction to New Levels: Wavewatch 3

DTIC Science & Technology

2016-01-01

features such as surf and rip currents , conditions that affect special operations, amphibious assaults, and logistics over the shore. Changes in...The Navy’s current version of WAVEWATCH Ill features the capability of operating with gridded domains of multiple resolution simultaneously, ranging...Netherlands. Its current form, WAVEWATCH Ill, was developed at NOAA’s National Center for Environmental Prediction. The model is free and open source

Detection of Necroptosis in Ligand-Mediated and Hypoxia-Induced Injury of Hepatocytes Using a Novel Optic Probe Detecting Receptor-Interacting Protein (RIP)1/RIP3 Binding.

PubMed

Haga, Sanae; Kanno, Akira; Ozawa, Takeaki; Morita, Naoki; Asano, Mami; Ozaki, Michitaka

2017-07-21

Liver injury is often observed in various pathological conditions including posthepatectomy state and cancer chemotherapy. It occurs mainly as a consequence of the combined necrotic and apoptotic types of cell death. In order to study liver/hepatocyte injury by necrotic type of cell death, we studied signal-regulated necrosis (necroptosis) by newly developing an optic probe detecting receptor-interacting protein (RIP)1/RIP3 binding, an essential process for necroptosis induction. In the mouse hepatocyte cell line, TIB-73 cells, TNF-a/cycloheximide (T/C) induced RIP1/3 binding only when caspase activity was suppressed by z-VAD-fmk (zVAD), a caspase-specific inhibitor. T/C/zVADinduced RIP1/3-binding was inhibited by necrostatin-1 (Nec-1), an allosteric inhibitor of RIP1. The reduced cell survival by T/C/zVAD was improved by Nec-1. These facts indicate that T/C induces necroptosis of hepatocytes when apoptotic pathway is inhibited/unavailable. FasL also induced cell death which was only partially inhibited by zVAD, indicating the possible involvement of necroptosis other than apoptosis. FasL activated caspase-3 and, similarly, induced RIP1/3-binding when caspases were inactivated. Interestingly, FasL-induced RIP1/3 binding was significantly suppressed by the antioxidants, Trolox and N-acetyl cysteine (NAC), suggesting the involvement of reactive oxygen species (ROS) in FasL-induced necroptotic cellular processes. H₂O₂, by itself, induced RIP1/3 binding that was suppressed by Nec-1, but not by zVAD. Hypoxia induced RIP1/3 binding after reoxygenation, which was suppressed by Nec-1 or by the antioxidants. Cell death induced by hypoxia/reoxygenation (H/R) was also improved by Nec-1. Similar to H₂O₂, H/R did not require caspase inhibition for RIP1/3 binding, suggesting the involvement of a caspase-independent mechanism for non-ligand induced and/or redox-mediated necroptosis. These data indicate that ROS induce necroptosis, and mediate the FasL- and hypoxia-induced necroptosis via a molecular mechanism that differs from a conventional caspase-dependent pathway. In conclusion, necroptosis is potentially involved in liver/hepatocyte injury induced by oxidative stress and FasL, other than apoptosis.

Controlling multiple manipulators using RIPS

NASA Technical Reports Server (NTRS)

Wang, Yulun; Jordan, Steve; Mangaser, Amante; Butner, Steve

1989-01-01

A prototype of the RIPS architecture (Robotic Instruction Processing System) was developed. A two arm robot control experiment is underway to characterize the architecture as well as research multi-arm control. This experiment uses two manipulators to cooperatively position an object. The location of the object is specified by the host computer's mouse. Consequently, real time kinematics and dynamics are necessary. The RIPS architecture is specialized so that it can satisfy these real time constraints. The two arm experimental set-up is discussed. A major part of this work is the continued development of a good programming environment for RIPS. The C++ language is employed and favorable results exist in the targeting of this language to the RIPS hardware.

Effects of preprocessing 1 Common and 2A Common red oak lumber on gang-rip-first rough-mill dimension part yields

Treesearch

Charles J. Gatchell; R. Edward Thomas; Elizabeth S. Walker

1999-01-01

Using the ROMI-RIP simulator we examined the implications of preprocessing for gang-rip-first rough mills. Rip-first rough mills can improve yield and throughput by preprocessing 1 Common and 2A Common hardwood lumber. This can be achieved by using a chop saw to separate poorer quality board segments from better ones and remove waste areas with little or no yield. This...

Molecular basis for repression of liver X receptor-mediated gene transcription by receptor-interacting protein 140

PubMed Central

Jakobsson, Tomas; Osman, Waffa; Gustafsson, Jan-Åke; Zilliacus, Johanna; Wärnmark, Anette

2007-01-01

Similarities in physiological roles of LXR (liver X receptors) and co-repressor RIP140 (receptor-interacting protein 140) in regulating energy homoeostasis and lipid and glucose metabolism suggest that the effects of LXR could at least partly be mediated by recruitment of the co-repressor RIP140. In the present study, we have elucidated the molecular basis for regulation of LXR transcriptional activity by RIP140. LXR is evenly localized in the nucleus and neither the N-terminal domain nor the LBD (ligand-binding domain) is necessary for nuclear localization. Both LXR subtypes, LXRα and LXRβ, interact with RIP140 and co-localize in diffuse large nuclear domains. Interaction and co-localization are dependent on the LBD of the receptor. The C-terminal domain of RIP140 is sufficient for full repressive effect. None of the C-terminal NR (nuclear receptor)-boxes is required for the co-repressor activity, whereas the NR-box-like motif as well as additional elements in the C-terminal region are required for full repressive function. The C-terminal NR-box-like motif is necessary for interaction with LXRβ, whereas additional elements are needed for strong interaction with LXRα. In conclusion, our results suggest that co-repression of LXR activity by RIP140 involves an atypical binding mode of RIP140 and a repression element in the RIP140 C-terminus. PMID:17391100

A novel Ras-interacting protein required for chemotaxis and cyclic adenosine monophosphate signal relay in Dictyostelium.

PubMed

Lee, S; Parent, C A; Insall, R; Firtel, R A

1999-09-01

We have identified a novel Ras-interacting protein from Dictyostelium, RIP3, whose function is required for both chemotaxis and the synthesis and relay of the cyclic AMP (cAMP) chemoattractant signal. rip3 null cells are unable to aggregate and lack receptor activation of adenylyl cyclase but are able, in response to cAMP, to induce aggregation-stage, postaggregative, and cell-type-specific gene expression in suspension culture. In addition, rip3 null cells are unable to properly polarize in a cAMP gradient and chemotaxis is highly impaired. We demonstrate that cAMP stimulation of guanylyl cyclase, which is required for chemotaxis, is reduced approximately 60% in rip3 null cells. This reduced activation of guanylyl cyclase may account, in part, for the defect in chemotaxis. When cells are pulsed with cAMP for 5 h to mimic the endogenous cAMP oscillations that occur in wild-type strains, the cells will form aggregates, most of which, however, arrest at the mound stage. Unlike the response seen in wild-type strains, the rip3 null cell aggregates that form under these experimental conditions are very small, which is probably due to the rip3 null cell chemotaxis defect. Many of the phenotypes of the rip3 null cell, including the inability to activate adenylyl cyclase in response to cAMP and defects in chemotaxis, are very similar to those of strains carrying a disruption of the gene encoding the putative Ras exchange factor AleA. We demonstrate that aleA null cells also exhibit a defect in cAMP-mediated activation of guanylyl cyclase similar to that of rip3 null cells. A double-knockout mutant (rip3/aleA null cells) exhibits a further reduction in receptor activation of guanylyl cyclase, and these cells display almost no cell polarization or movement in cAMP gradients. As RIP3 preferentially interacts with an activated form of the Dictyostelium Ras protein RasG, which itself is important for cell movement, we propose that RIP3 and AleA are components of a Ras-regulated pathway involved in integrating chemotaxis and signal relay pathways that are essential for aggregation.

Receptor Interacting Protein 3-Mediated Necroptosis Promotes Lipopolysaccharide-Induced Inflammation and Acute Respiratory Distress Syndrome in Mice.

PubMed

Wang, Linlin; Wang, Tingting; Li, Haobo; Liu, Qing; Zhang, Zhongjun; Xie, Wanli; Feng, Yinglu; Socorburam, Tumenjavkhlan; Wu, Gui; Xia, Zhengyuan; Wu, Qingping

2016-01-01

Necrosis amplifies inflammation and plays important roles in acute respiratory distress syndrome (ARDS). Necroptosis is a newly identified programmed necrosis that is mediated by receptor interacting protein 3 (RIP3). However, the potential involvement and impact of necroptosis in lipopolysaccharide (LPS)-induced ARDS remains unknown. We therefore explored the role and mechanism of RIP3-mediated necroptosis in LPS-induced ARDS. Mice were instilled with increasing doses of LPS intratracheally to induce different degrees of ARDS. Lung tissues were harvested for histological and TUNEL staining and western blot for RIP3, p-RIP3, X-linked inhibitor of apoptosis protein (XIAP), mixed lineage kinase domain-like protein (MLKL), total and cleaved caspases-3/8. Then, wild-type and RIP3 knock-out mice were induced ARDS with 30 mg/kg LPS. Pulmonary cellular necrosis was labeled by the propidium Iodide (PI) staining. Levels of TNF-a, Interleukin (IL)-1β, IL-6, IL-1α, IL-10 and HMGB1, tissue myeloperoxidase (MPO) activity, neutrophil counts and total protein concentration were measured. Results showed that in high dose LPS (30mg/kg and 40mg/kg) -induced severe ARDS, RIP3 protein was increased significantly, accompanied by increases of p-RIP3 and MLKL, while in low dose LPS (10mg/kg and 20mg/kg) -induced mild ARDS, apoptosis was remarkably increased. In LPS-induced severe ARDS, RIP3 knock-out alleviated the hypothermia symptom, increased survival rate and ameliorated the lung tissue injury RIP3 depletion also attenuated LPS-induced increase in IL-1α/β, IL-6 and HMGB1 release, decreased tissue MPO activity, and reduced neutrophil influx and total protein concentration in BALF in severe ARDS. Further, RIP3 depletion reduced the necrotic cells in the lung and decreased the expression of MLKL, but had no impact on cleaved caspase-3 in LPS-induced ARDS. It is concluded that RIP3-mediated necroptosis is a major mechanism of enhanced inflammation and lung tissue injury in high dose LPS- induced severe ARDS in mice.

Receptor Interacting Protein 3-Mediated Necroptosis Promotes Lipopolysaccharide-Induced Inflammation and Acute Respiratory Distress Syndrome in Mice

PubMed Central

Li, Haobo; Liu, Qing; Zhang, Zhongjun; Xie, Wanli; Feng, Yinglu; Socorburam, Tumenjavkhlan; Wu, Gui; Xia, Zhengyuan; Wu, Qingping

2016-01-01

Necrosis amplifies inflammation and plays important roles in acute respiratory distress syndrome (ARDS). Necroptosis is a newly identified programmed necrosis that is mediated by receptor interacting protein 3 (RIP3). However, the potential involvement and impact of necroptosis in lipopolysaccharide (LPS)-induced ARDS remains unknown. We therefore explored the role and mechanism of RIP3-mediated necroptosis in LPS-induced ARDS. Mice were instilled with increasing doses of LPS intratracheally to induce different degrees of ARDS. Lung tissues were harvested for histological and TUNEL staining and western blot for RIP3, p-RIP3, X-linked inhibitor of apoptosis protein (XIAP), mixed lineage kinase domain-like protein (MLKL), total and cleaved caspases-3/8. Then, wild-type and RIP3 knock-out mice were induced ARDS with 30 mg/kg LPS. Pulmonary cellular necrosis was labeled by the propidium Iodide (PI) staining. Levels of TNF-a, Interleukin (IL)-1β, IL-6, IL-1α, IL-10 and HMGB1, tissue myeloperoxidase (MPO) activity, neutrophil counts and total protein concentration were measured. Results showed that in high dose LPS (30mg/kg and 40mg/kg) -induced severe ARDS, RIP3 protein was increased significantly, accompanied by increases of p-RIP3 and MLKL, while in low dose LPS (10mg/kg and 20mg/kg) -induced mild ARDS, apoptosis was remarkably increased. In LPS-induced severe ARDS, RIP3 knock-out alleviated the hypothermia symptom, increased survival rate and ameliorated the lung tissue injury RIP3 depletion also attenuated LPS-induced increase in IL-1α/β, IL-6 and HMGB1 release, decreased tissue MPO activity, and reduced neutrophil influx and total protein concentration in BALF in severe ARDS. Further, RIP3 depletion reduced the necrotic cells in the lung and decreased the expression of MLKL, but had no impact on cleaved caspase-3 in LPS-induced ARDS. It is concluded that RIP3-mediated necroptosis is a major mechanism of enhanced inflammation and lung tissue injury in high dose LPS- induced severe ARDS in mice. PMID:27195494

Necrosulfonamide Attenuates Spinal Cord Injury via Necroptosis Inhibition.

PubMed

Wang, Yongxiang; Wang, Jingcheng; Wang, Hua; Feng, Xinmin; Tao, Yuping; Yang, Jiandong; Cai, Jun

2018-06-01

Spinal cord injury (SCI) is a serious trauma without efficient treatment currently. Necroptosis can be blocked post injury by special inhibitors. This study is to investigate the effects, mechanism, and potential benefit of necrosulfonamide (NSA) for SCI therapy. Pathologic condition was detected using hematoxylin-eosin staining on injured spinal cord and other major organs. Necroptosis-related factors-RIP1, RIP3, and MLKL-were detected using Western blot. Detections on mitochondrial functions such as adenosine triphosphate generation and activities of superoxide dismutase and caspase-3 were also performed. Finally, ethologic performance was detected using a 21-point open-field locomotion test. Reduced lesions and protected neurons were found in the injured spinal cord after treatment with NSA using hematoxylin-eosin staining for pathologic detection. No obvious toxicity on rat liver, kidney, heart, and spleen was detected. Rather than RIP1 and RIP3, MLKL was significantly inhibited by the NSA using Western blot detection. Adenosine triphosphate generation was obviously decreased post injury but slightly increased after the NSA treatment, especially 24 hours post injury. No significant changes were found on activities of superoxide dismutase and caspase-3 after the treatment of NSA. Ethologic performance was significantly improved using a 21-point, open-field locomotion test. Our research indicates NSA attenuates the spinal cord injury via necroptosis inhibition. It might be a potential and safe chemical benefit for SCI therapy. To our knowledge, this is the first study on the effects of NSA as treatment of traumatic SCI. Copyright © 2018 Elsevier Inc. All rights reserved.

CELF1 preferentially binds to exon-intron boundary and regulates alternative splicing in HeLa cells.

PubMed

Xia, Heng; Chen, Dong; Wu, Qijia; Wu, Gang; Zhou, Yanhong; Zhang, Yi; Zhang, Libin

2017-09-01

The current RIP-seq approach has been developed for the identification of genome-wide interaction between RNA binding protein (RBP) and the bound RNA transcripts, but still rarely for identifying its binding sites. In this study, we performed RIP-seq experiments in HeLa cells using a monoclonal antibody against CELF1. Mapping of the RIP-seq reads showed a biased distribution at the 3'UTR and intronic regions. A total of 15,285 and 1384 CELF1-specific sense and antisense peaks were identified using the ABLIRC software tool. Our bioinformatics analyses revealed that 5' and 3' splice site motifs and GU-rich motifs were highly enriched in the CELF1-bound peaks. Furthermore, transcriptome analyses revealed that alternative splicing was globally regulated by CELF1 in HeLa cells. For example, the inclusion of exon 16 of LMO7 gene, a marker gene of breast cancer, is positively regulated by CELF1. Taken together, we have shown that RIP-seq data can be used to decipher RBP binding sites and reveal an unexpected landscape of the genome-wide CELF1-RNA interactions in HeLa cells. In addition, we found that CELF1 globally regulates the alternative splicing by binding the exon-intron boundary in HeLa cells, which will deepen our understanding of the regulatory roles of CELF1 in the pre-mRNA splicing process. Copyright © 2017 Elsevier B.V. All rights reserved.

NOD1CARD Might Be Using Multiple Interfaces for RIP2-Mediated CARD-CARD Interaction: Insights from Molecular Dynamics Simulation

PubMed Central

Pradhan, Sukanta Kumar; De, Sachinandan

2017-01-01

The nucleotide-binding and oligomerization domain (NOD)-containing protein 1 (NOD1) plays the pivotal role in host-pathogen interface of innate immunity and triggers immune signalling pathways for the maturation and release of pro-inflammatory cytokines. Upon the recognition of iE-DAP, NOD1 self-oligomerizes in an ATP-dependent fashion and interacts with adaptor molecule receptor-interacting protein 2 (RIP2) for the propagation of innate immune signalling and initiation of pro-inflammatory immune responses. This interaction (mediated by NOD1 and RIP2) helps in transmitting the downstream signals for the activation of NF-κB signalling pathway, and has been arbitrated by respective caspase-recruitment domains (CARDs). The so-called CARD-CARD interaction still remained contradictory due to inconsistent results. Henceforth, to understand the mode and the nature of the interaction, structural bioinformatics approaches were employed. MD simulation of modelled 1:1 heterodimeric complexes revealed that the type-Ia interface of NOD1CARD and the type-Ib interface of RIP2CARD might be the suitable interfaces for the said interaction. Moreover, we perceived three dynamically stable heterotrimeric complexes with an NOD1:RIP2 ratio of 1:2 (two numbers) and 2:1. Out of which, in the first trimeric complex, a type-I NOD1-RIP2 heterodimer was found interacting with an RIP2CARD using their type-IIa and IIIa interfaces. However, in the second and third heterotrimer, we observed type-I homodimers of NOD1 and RIP2 CARDs were interacting individually with RIP2CARD and NOD1CARD (in type-II and type-III interface), respectively. Overall, this study provides structural and dynamic insights into the NOD1-RIP2 oligomer formation, which will be crucial in understanding the molecular basis of NOD1-mediated CARD-CARD interaction in higher and lower eukaryotes. PMID:28114344

NEMO Inhibits Programmed Necrosis in an NFκB-Independent Manner by Restraining RIP1

PubMed Central

Legarda, Diana; Ting, Adrian T.

2012-01-01

TNF can trigger two opposing responses: cell survival and cell death. TNFR1 activates caspases that orchestrate apoptosis but some cell types switch to a necrotic death when treated with caspase inhibitors. Several genes that are required to orchestrate cell death by programmed necrosis have been identified, such as the kinase RIP1, but very little is known about the inhibitory signals that keep this necrotic cell death pathway in check. We demonstrate that T cells lacking the regulatory subunit of IKK, NFκB essential modifier (NEMO), are hypersensitive to programmed necrosis when stimulated with TNF in the presence of caspase inhibitors. Surprisingly, this pro-survival activity of NEMO is independent of NFκB-mediated gene transcription. Instead, NEMO inhibits necrosis by binding to ubiquitinated RIP1 to restrain RIP1 from engaging the necrotic death pathway. In the absence of NEMO, or if ubiquitination of RIP1 is blocked, necrosis ensues when caspases are blocked. These results indicate that recruitment of NEMO to ubiquitinated RIP1 is a key step in the TNFR1 signaling pathway that determines whether RIP1 triggers a necrotic death response. PMID:22848449

Suppression of RIP3-dependent Necroptosis by Human Cytomegalovirus

PubMed Central

Omoto, Shinya; Guo, Hongyan; Talekar, Ganesh R.; Roback, Linda; Kaiser, William J.; Mocarski, Edward S.

2015-01-01

Necroptosis is an alternate programmed cell death pathway that is unleashed by caspase-8 compromise and mediated by receptor-interacting protein kinase 3 (RIP3). Murine cytomegalovirus (CMV) and herpes simplex virus (HSV) encode caspase-8 inhibitors that prevent apoptosis together with competitors of RIP homotypic interaction motif (RHIM)-dependent signal transduction to interrupt the necroptosis. Here, we show that pro-necrotic murine CMV M45 mutant virus drives virus-induced necroptosis during nonproductive infection of RIP3-expressing human fibroblasts, whereas WT virus does not. Thus, M45-encoded RHIM competitor, viral inhibitor of RIP activation, sustains viability of human cells like it is known to function in infected mouse cells. Importantly, human CMV is shown to block necroptosis induced by either TNF or M45 mutant murine CMV in RIP3-expressing human cells. Human CMV blocks TNF-induced necroptosis after RIP3 activation and phosphorylation of the mixed lineage kinase domain-like (MLKL) pseudokinase. An early, IE1-regulated viral gene product acts on a necroptosis step that follows MLKL phosphorylation prior to membrane leakage. This suppression strategy is distinct from RHIM signaling competition by murine CMV or HSV and interrupts an execution process that has not yet been fully elaborated. PMID:25778401

Changes in nuclear receptor corepressor RIP140 do not influence mitochondrial content in the cortex.

PubMed

Herbst, Eric A F; Bonen, Arend; Holloway, Graham P

2015-10-01

Changes in nuclear receptor interacting protein 140 (RIP140) influences mitochondrial content in skeletal muscle; however, the translation of these findings to the brain has not been investigated. The present study examined the impact of overexpressing and ablating RIP140 on mitochondrial content in muscle and the cortex through examining mRNA, mtDNA, and mitochondrial protein content. Our results show that changes in RIP140 expression significantly alters markers of mitochondrial content in skeletal muscle but not the brain.

Does loop quantum cosmology replace the big rip singularity by a non-singular bounce?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haro, Jaume de, E-mail: jaime.haro@upc.edu

It is stated that holonomy corrections in loop quantum cosmology introduce a modification in Friedmann's equation which prevent the big rip singularity. Recently in [1] it has been proved that this modified Friedmann equation is obtained in an inconsistent way, what means that the results deduced from it, in particular the big rip singularity avoidance, are not justified. The problem is that holonomy corrections modify the gravitational part of the Hamiltonian of the system leading, after Legendre's transformation, to a non covariant Lagrangian which is in contradiction with one of the main principles of General Relativity. A more consistent waymore » to deal with the big rip singularity avoidance is to disregard modification in the gravitational part of the Hamiltonian, and only consider inverse volume effects [2]. In this case we will see that, not like the big bang singularity, the big rip singularity survives in loop quantum cosmology. Another way to deal with the big rip avoidance is to take into account geometric quantum effects given by the the Wheeler-De Witt equation. In that case, even though the wave packets spread, the expectation values satisfy the same equations as their classical analogues. Then, following the viewpoint adopted in loop quantum cosmology, one can conclude that the big rip singularity survives when one takes into account these quantum effects. However, the spreading of the wave packets prevents the recover of the semiclassical time, and thus, one might conclude that the classical evolution of the universe come to and end before the big rip is reached. This is not conclusive because. as we will see, it always exists other external times that allows us to define the classical and quantum evolution of the universe up to the big rip singularity.« less

Elevated expression of the metabolic regulator receptor-interacting protein 140 results in cardiac hypertrophy and impaired cardiac function.

PubMed

Fritah, Asmaà; Steel, Jennifer H; Nichol, Donna; Parker, Nadeene; Williams, Sharron; Price, Anthony; Strauss, Leena; Ryder, Timothy A; Mobberley, Margaret A; Poutanen, Matti; Parker, Malcolm; White, Roger

2010-06-01

Receptor-interacting protein 140 (RIP140) is a ligand-dependent cofactor for nuclear receptors that regulate networks of genes involved in cellular processes, including metabolism. An important role for RIP140 in metabolic control has been identified in RIP140 null mice, whose phenotypes include derepression of genes involved in energy mobilization or catabolism in adipocytes and a switch to more oxidative fibres in skeletal muscle. We hypothesized that ubiquitous expression of RIP140 would suppress metabolic processes, leading to defects in development or cellular function. The primary effect of exogenous expression of RIP140 mRNA (real-time PCR) and protein (western blotting) in transgenic mice is impaired postnatal heart function. There was rapid onset of cardiac hypertrophy and ventricular fibrosis, detected microscopically, in male RIP140 transgenic mice from 4 weeks of age, resulting in 25% mortality by 5 months. RIP140 exogenous expression in the heart leads to decreased mitochondria state III and state IV membrane potential and oxygen consumption. Quantitative PCR showed more than 50% reduced expression of genes involved in mitochondrial activity and fatty acid metabolism, including mitochondrial transcription factor A, cytochrome oxidase VIIa, cytochrome XII, CD36, medium-chain acyl dehydrogenase, and fatty acid transport protein, many of which are known targets for nuclear receptors, including peroxisome proliferator-activated receptors PPARalpha and PPARdelta and oestrogen-related receptors ERRalpha and ERRgamma. This study demonstrates that RIP140 is an important cofactor in postnatal cardiac function and that inhibition of the action of RIP140 may provide a model system to investigate specific interventions designed to prevent or delay the onset of cardiac disease.

RIP4 is a target of multiple signal transduction pathways in keratinocytes: Implications for epidermal differentiation and cutaneous wound repair

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adams, Stephanie; Munz, Barbara, E-mail: barbara.munz@charite.de

2010-01-01

Receptor interacting protein 4 (RIP4) is an important regulator of epidermal morphogenesis during embryonic development. We could previously show that expression of the rip4 gene is strongly downregulated in cutaneous wound repair, which might be initiated by a broad variety of growth factors and cytokines. Here, we demonstrate that in keratinocytes, rip4 expression is controlled by a multitude of different signal transduction pathways, such as the p38 mitogen-activated protein kinase (MAPK) and the nuclear factor kappa B (NF-{kappa}B) cascade, in a unique and specific manner. Furthermore, we show that the steroid dexamethasone abolishes the physiological rip4 downregulation after injury andmore » might thus contribute to the phenotype of reduced and delayed wound reepithelialization seen in glucocorticoid-treated patients. As a whole, our data indicate that rip4 expression is regulated in a complex manner, which might have therapeutic implications.« less

RapidRIP quantifies the intracellular metabolome of 7 industrial strains of E. coli.

PubMed

McCloskey, Douglas; Xu, Julia; Schrübbers, Lars; Christensen, Hanne B; Herrgård, Markus J

2018-04-25

Fast metabolite quantification methods are required for high throughput screening of microbial strains obtained by combinatorial or evolutionary engineering approaches. In this study, a rapid RIP-LC-MS/MS (RapidRIP) method for high-throughput quantitative metabolomics was developed and validated that was capable of quantifying 102 metabolites from central, amino acid, energy, nucleotide, and cofactor metabolism in less than 5 minutes. The method was shown to have comparable sensitivity and resolving capability as compared to a full length RIP-LC-MS/MS method (FullRIP). The RapidRIP method was used to quantify the metabolome of seven industrial strains of E. coli revealing significant differences in glycolytic, pentose phosphate, TCA cycle, amino acid, and energy and cofactor metabolites were found. These differences translated to statistically and biologically significant differences in thermodynamics of biochemical reactions between strains that could have implications when choosing a host for bioprocessing. Copyright © 2018. Published by Elsevier Inc.

MyRIP interaction with MyoVa on secretory granules is controlled by the cAMP-PKA pathway.

PubMed

Brozzi, Flora; Lajus, Sophie; Diraison, Frederique; Rajatileka, Shavanthi; Hayward, Katy; Regazzi, Romano; Molnár, Elek; Váradi, Anikó

2012-11-01

Myosin- and Rab-interacting protein (MyRIP), which belongs to the protein kinase A (PKA)-anchoring family, is implicated in hormone secretion. However, its mechanism of action is not fully elucidated. Here we investigate the role of MyRIP in myosin Va (MyoVa)-dependent secretory granule (SG) transport and secretion in pancreatic beta cells. These cells solely express the brain isoform of MyoVa (BR-MyoVa), which is a key motor protein in SG transport. In vitro pull-down, coimmunoprecipitation, and colocalization studies revealed that MyRIP does not interact with BR-MyoVa in glucose-stimulated pancreatic beta cells, suggesting that, contrary to previous notions, MyRIP does not link this motor protein to SGs. Glucose-stimulated insulin secretion is augmented by incretin hormones, which increase cAMP levels and leads to MyRIP phosphorylation, its interaction with BR-MyoVa, and phosphorylation of the BR-MyoVa receptor rabphilin-3A (Rph-3A). Rph-3A phosphorylation on Ser-234 was inhibited by small interfering RNA knockdown of MyRIP, which also reduced cAMP-mediated hormone secretion. Demonstrating the importance of this phosphorylation, nonphosphorylatable and phosphomimic Rph-3A mutants significantly altered hormone release when PKA was activated. These data suggest that MyRIP only forms a functional protein complex with BR-MyoVa on SGs when cAMP is elevated and under this condition facilitates phosphorylation of SG-associated proteins, which in turn can enhance secretion.

Quantitative phosphoproteomic analysis of RIP3-dependent protein phosphorylation in the course of TNF-induced necroptosis.

PubMed

Zhong, Chuan-Qi; Li, Yuanyue; Yang, Daowei; Zhang, Na; Xu, Xiaozheng; Wu, Yaying; Chen, Jinan; Han, Jiahuai

2014-03-01

Tumor necrosis factor (TNF) induced cell death in murine fibrosarcoma L929 cells is a model system in studying programed necrosis (also known as necroptosis). Receptor interacting protein 3 (RIP3), a serine-threonine kinase, is known to play an essential role in TNF-induced necroptosis; however, the phosphorylation events initiated by RIP3 activation in necroptotic process is still largely unknown. Here, we performed a quantitative MS based analysis to compare TNF-induced changes in the global phosphoproteome of wild-type (RIP3(+/+) ) and RIP3-knockdown L929 cells at different time points after TNF treatment. A total of 8058 phosphopeptides spanning 6892 phosphorylation sites in 2762 proteins were identified in the three experiments, in which cells were treated with TNF for 0.5, 2, and 4 h. By comparing the phosphorylation sites in wild-type and RIP3-knockdown L929 cells, 174, 167, and 177 distinct phosphorylation sites were revealed to be dependent on RIP3 at the 0.5, 2, and 4 h time points after TNF treatment, respectively. Notably, most of them were not detected in a previous phosphoproteomic analysis of RIP3-dependent phosphorylation in lipopolysaccharide-stimulated peritoneal macrophages and TNF-treated murine embryonic fibroblasts (MEFs), suggesting that the data presented in this report are highly relevant to the study of TNF-induced necroptosis of L929 cells. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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Decreasing Mattress Ripping Using Forced Practice.

ERIC Educational Resources Information Center

Bluestone, Michael A.

A deaf, profoundly retarded institutionalized 20-year-old, who engaged in mattress ripping, was required to participate in forced practice behavioral training. Repeatedly physically guided through ripping mattresses, he was given the aversive consequence of a squirt of tabasco sauce solution. After 5 weeks of intensive behavioral training and a 3…

The sequence and structure of snake gourd (Trichosanthes anguina) seed lectin, a three-chain nontoxic homologue of type II RIPs.

PubMed

Sharma, Alok; Pohlentz, Gottfried; Bobbili, Kishore Babu; Jeyaprakash, A Arockia; Chandran, Thyageshwar; Mormann, Michael; Swamy, Musti J; Vijayan, M

2013-08-01

The sequence and structure of snake gourd seed lectin (SGSL), a nontoxic homologue of type II ribosome-inactivating proteins (RIPs), have been determined by mass spectrometry and X-ray crystallography, respectively. As in type II RIPs, the molecule consists of a lectin chain made up of two β-trefoil domains. The catalytic chain, which is connected through a disulfide bridge to the lectin chain in type II RIPs, is cleaved into two in SGSL. However, the integrity of the three-dimensional structure of the catalytic component of the molecule is preserved. This is the first time that a three-chain RIP or RIP homologue has been observed. A thorough examination of the sequence and structure of the protein and of its interactions with the bound methyl-α-galactose indicate that the nontoxicity of SGSL results from a combination of changes in the catalytic and the carbohydrate-binding sites. Detailed analyses of the sequences of type II RIPs of known structure and their homologues with unknown structure provide valuable insights into the evolution of this class of proteins. They also indicate some variability in carbohydrate-binding sites, which appears to contribute to the different levels of toxicity exhibited by lectins from various sources.

Efficient, Glucose Responsive, and Islet-Specific Transgene Expression by a Modified Rat Insulin Promoter

PubMed Central

Chai, Renjie; Chen, Shuyuan; Ding, Jiahuan; Grayburn, Paul A

2009-01-01

This study was done to improve efficiency and islet specificity of the rat insulin promoter (RIP). Various rat insulin promoter lengths were prepared and tested in vitro to drive luciferase reporter gene expression in INS1-cells, alpha-cells, acinar cells, ductal cells, and fibroblasts. The CMV promoter was used as a positive control. In addition, the DsRed reporter gene was administered in vivo to rat pancreas by ultrasound-targeted microbubble destruction (UTMD). Confocal microscopy was used to detect the presence and distribution of DsRed within the pancreas after UTMD. A modified RIP3.1 promoter, which includes portions of the insulin gene after its transcription start site is 5-fold more active in INS-1 cells than the full length RIP promoter or the CMV promoter. RIP3.1 is regulated by glucose level and various islet transcription factors in vitro, and exhibits activity in alpha-cells, but not exocrine cells. In vivo delivery of RIP3.1-DsRed resulted in expression of DsRed protein in beta-cells, and to a lesser extent alpha cells under normal glucose conditions. No DsRed signal was present in exocrine pancreas under RIP3.1. A modified rat insulin promoter, RIP3.1, efficiently and specifically directs gene expression to endocrine pancreas. PMID:19727136

A Novel Ras-interacting Protein Required for Chemotaxis and Cyclic Adenosine Monophosphate Signal Relay in Dictyostelium

PubMed Central

Lee, Susan; Parent, Carole A.; Insall, Robert; Firtel, Richard A.

1999-01-01

We have identified a novel Ras-interacting protein from Dictyostelium, RIP3, whose function is required for both chemotaxis and the synthesis and relay of the cyclic AMP (cAMP) chemoattractant signal. rip3 null cells are unable to aggregate and lack receptor activation of adenylyl cyclase but are able, in response to cAMP, to induce aggregation-stage, postaggregative, and cell-type-specific gene expression in suspension culture. In addition, rip3 null cells are unable to properly polarize in a cAMP gradient and chemotaxis is highly impaired. We demonstrate that cAMP stimulation of guanylyl cyclase, which is required for chemotaxis, is reduced ∼60% in rip3 null cells. This reduced activation of guanylyl cyclase may account, in part, for the defect in chemotaxis. When cells are pulsed with cAMP for 5 h to mimic the endogenous cAMP oscillations that occur in wild-type strains, the cells will form aggregates, most of which, however, arrest at the mound stage. Unlike the response seen in wild-type strains, the rip3 null cell aggregates that form under these experimental conditions are very small, which is probably due to the rip3 null cell chemotaxis defect. Many of the phenotypes of the rip3 null cell, including the inability to activate adenylyl cyclase in response to cAMP and defects in chemotaxis, are very similar to those of strains carrying a disruption of the gene encoding the putative Ras exchange factor AleA. We demonstrate that aleA null cells also exhibit a defect in cAMP-mediated activation of guanylyl cyclase similar to that of rip3 null cells. A double-knockout mutant (rip3/aleA null cells) exhibits a further reduction in receptor activation of guanylyl cyclase, and these cells display almost no cell polarization or movement in cAMP gradients. As RIP3 preferentially interacts with an activated form of the Dictyostelium Ras protein RasG, which itself is important for cell movement, we propose that RIP3 and AleA are components of a Ras-regulated pathway involved in integrating chemotaxis and signal relay pathways that are essential for aggregation. PMID:10473630

Necroptosis: an alternative cell death program defending against cancer.

PubMed

Chen, Dongshi; Yu, Jian; Zhang, Lin

2016-04-01

One of the hallmarks of cancer is resistance to programmed cell death, which maintains the survival of cells en route to oncogenic transformation and underlies therapeutic resistance. Recent studies demonstrate that programmed cell death is not confined to caspase-dependent apoptosis, but includes necroptosis, a form of necrotic death governed by Receptor-Interacting Protein 1 (RIP1), RIP3, and Mixed Lineage Kinase Domain-Like (MLKL) protein. Necroptosis serves as a critical cell-killing mechanism in response to severe stress and blocked apoptosis, and can be induced by inflammatory cytokines or chemotherapeutic drugs. Genetic or epigenetic alterations of necroptosis regulators such as RIP3 and cylindromatosis (CYLD), are frequently found in human tumors. Unlike apoptosis, necroptosis elicits a more robust immune response that may function as a defensive mechanism by eliminating tumor-causing mutations and viruses. Furthermore, several classes of anticancer agents currently under clinical development, such as SMAC and BH3 mimetics, can promote necroptosis in addition to apoptosis. A more complete understanding of the interplay among necroptosis, apoptosis, and other cell death modalities is critical for developing new therapeutic strategies to enhance killing of tumor cells. Copyright © 2016 Elsevier B.V. All rights reserved.

Muddy and dolomitic rip-up clasts in Triassic fluvial sandstones: Origin and impact on potential reservoir properties (Argana Basin, Morocco)

NASA Astrophysics Data System (ADS)

Henares, Saturnina; Arribas, Jose; Cultrone, Giuseppe; Viseras, Cesar

2016-06-01

The significance of rip-up clasts as sandstone framework grains is frequently neglected in the literature being considered as accessory components in bulk sandstone composition. However, this study highlights the great value of muddy and dolomitic rip-up clast occurrence as: (a) information source about low preservation potential from floodplain deposits and (b) key element controlling host sandstone diagenetic evolution and thus ultimate reservoir quality. High-resolution petrographic analysis on Triassic fluvial sandstones from Argana Basin (T6 and T7/T8 units) highlights the significance of different types of rip-up clasts as intrabasinal framework components of continental sediments from arid climates. On the basis of their composition and ductility, three main types are distinguished: (a) muddy rip-up clasts, (b) dolomitic muddy rip-up clasts and (c) dolomite crystalline rip-up clasts. Spatial distribution of different types is strongly facies-related according to grain size. Origin of rip-up clasts is related to erosion of coeval phreatic dolocretes, in different development stages, and associated muddy floodplain sediments. Cloudy cores with abundant inclusions and clear outer rims of dolomite crystals suggest a first replacive and a subsequent displacive growth, respectively. Dolomite crystals are almost stoichiometric. This composition is very similar to that of early sandstone dolomite cement, supporting phreatic dolocretes as dolomite origin in both situations. Sandstone diagenesis is dominated by mechanical compaction and dolomite cementation. A direct correlation exists between: (1) muddy rip-up clast abundance and early reduction of primary porosity by compaction with irreversible loss of intergranular volume (IGV); and (2) occurrence of dolomitic rip-up clasts and dolomite cement nucleation in host sandstone, occluding adjacent pores but preserving IGV. Both processes affect reservoir quality by generation of vertical and 3D fluid flow baffles and barriers that compartmentalize the reservoir. These findings may provide quantitative useful data for the better understanding of reservoir quality in analogous hydrocarbon-bearing basins such as the Bay of Fundy, Nova Scotia (Canada).

Coastal Warning Display Program

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! Boating Safety Beach Hazards Rip Currents Hypothermia Hurricanes Thunderstorms Lightning Coastal Flooding Tsunamis 406 EPIRB's National Weather Service Marine Forecasts COASTAL WARNING DISPLAY PROGRAM Marine COASTAL WARNING DISPLAY PROGRAM As of February 15, 1989, the National Weather Service retired its Coastal

Pancreatic β-cell overexpression of the glucagon receptor gene results in enhanced β-cell function and mass

PubMed Central

Gelling, Richard W.; Vuguin, Patricia M.; Du, Xiu Quan; Cui, Lingguang; Rømer, John; Pederson, Raymond A.; Leiser, Margarita; Sørensen, Heidi; Holst, Jens J.; Fledelius, Christian; Johansen, Peter B.; Fleischer, Norman; McIntosh, Christopher H. S.; Nishimura, Erica; Charron, Maureen J.

2009-01-01

In addition to its primary role in regulating glucose production from the liver, glucagon has many other actions, reflected by the wide tissue distribution of the glucagon receptor (Gcgr). To investigate the role of glucagon in the regulation of insulin secretion and whole body glucose homeostasis in vivo, we generated mice overexpressing the Gcgr specifically on pancreatic β-cells (RIP-Gcgr). In vivo and in vitro insulin secretion in response to glucagon and glucose was increased 1.7- to 3.9-fold in RIP-Gcgr mice compared with controls. Consistent with the observed increase in insulin release in response to glucagon and glucose, the glucose excursion resulting from both a glucagon challenge and intraperitoneal glucose tolerance test (IPGTT) was significantly reduced in RIP-Gcgr mice compared with controls. However, RIP-Gcgr mice display similar glucose responses to an insulin challenge. β-Cell mass and pancreatic insulin content were also increased (20 and 50%, respectively) in RIP-Gcgr mice compared with controls. When fed a high-fat diet (HFD), both control and RIP-Gcgr mice developed similar degrees of obesity and insulin resistance. However, the severity of both fasting hyperglycemia and impaired glucose tolerance (IGT) were reduced in RIP-Gcgr mice compared with controls. Furthermore, the insulin response of RIP-Gcgr mice to an IPGTT was twice that of controls when fed the HFD. These data indicate that increased pancreatic β-cell expression of the Gcgr increased insulin secretion, pancreatic insulin content, β-cell mass, and, when mice were fed a HFD, partially protected against hyperglycemia and IGT. PMID:19602585

Oxidative stress induced necroptosis activation is involved in the pathogenesis of hyperoxic acute lung injury.

PubMed

Han, C H; Guan, Z B; Zhang, P X; Fang, H L; Li, L; Zhang, H M; Zhou, F J; Mao, Y F; Liu, W W

2018-01-15

Necroptosis has been found to be involved in the pathogenesis of some lung diseases, but its role in hyperoxic acute lung injury (HALI) is still unclear. This study aimed to investigate contribution of necroptosis to the pathogenesis of HALI induced by hyperbaric hyperoxia exposure in a rat model. Rats were divided into control group, HALI group, Nec-1 (necroptosis inhibitor) group and edaravone group. Rats were exposed to pure oxygen at 250 kPa for 6 h to induce HALI. At 30 min before hyperoxia exposure, rats were intraperitoneally injected with Nec-1 or edaravone, and sacrificed at 24 h after hyperoxia exposure. Lung injury was evaluated by histology, lung water to dry ratio (W/D) and bronchoalveolar lavage fluid (BALF) biochemistry; the serum and plasma oxidative stress, expression of RIP1, RIP3 and MLKL, and interaction between RIP1 and RIP3 were determined. Results showed hyperoxia exposure significantly caused damage to lung and increased necroptotic cells and the expression of RIP1, RIP3 and MLKL. Edaravone pre-treatment not only inhibited the oxidative stress in HALI, but also reduced necroptotic cells, decreased the expression of RIP1, RIP3 and MLKL and improved lung pathology. Nec-1 pretreatment inhibited necroptosis and improved lung pathology, but had little influence on oxidative stress. This study suggests hyperoxia exposure induces oxidative stress may activate necroptosis, involving in the pathology of HALI, and strategies targeting necroptosis may become promising treatments for HALI. Copyright © 2017. Published by Elsevier Inc.

Hyperglycemic Conditions Prime Cells for RIP1-dependent Necroptosis*

PubMed Central

LaRocca, Timothy J.; Sosunov, Sergey A.; Shakerley, Nicole L.; Ten, Vadim S.; Ratner, Adam J.

2016-01-01

Necroptosis is a RIP1-dependent programmed cell death (PCD) pathway that is distinct from apoptosis. Downstream effector pathways of necroptosis include formation of advanced glycation end products (AGEs) and reactive oxygen species (ROS), both of which depend on glycolysis. This suggests that increased cellular glucose may prime necroptosis. Here we show that exposure to hyperglycemic levels of glucose enhances necroptosis in primary red blood cells (RBCs), Jurkat T cells, and U937 monocytes. Pharmacologic or siRNA inhibition of RIP1 prevented the enhanced death, confirming it as RIP1-dependent necroptosis. Hyperglycemic enhancement of necroptosis depends upon glycolysis with AGEs and ROS playing a role. Total levels of RIP1, RIP3, and mixed lineage kinase domain-like (MLKL) proteins were increased following treatment with high levels of glucose in Jurkat and U937 cells and was not due to transcriptional regulation. The observed increase in RIP1, RIP3, and MLKL protein levels suggests a potential positive feedback mechanism in nucleated cell types. Enhanced PCD due to hyperglycemia was specific to necroptosis as extrinsic apoptosis was inhibited by exposure to high levels of glucose. Hyperglycemia resulted in increased infarct size in a mouse model of brain hypoxia-ischemia injury. The increased infarct size was prevented by treatment with nec-1s, strongly suggesting that increased necroptosis accounts for exacerbation of this injury in conditions of hyperglycemia. This work reveals that hyperglycemia represents a condition in which cells are extraordinarily susceptible to necroptosis, that local glucose levels alter the balance of PCD pathways, and that clinically relevant outcomes may depend on glucose-mediated effects on PCD. PMID:27129772

Computer optimization of cutting yield from multiple ripped boards

Treesearch

A.R. Stern; K.A. McDonald

1978-01-01

RIPYLD is a computer program that optimizes the cutting yield from multiple-ripped boards. Decisions are based on automatically collected defect information, cutting bill requirements, and sawing variables. The yield of clear cuttings from a board is calculated for every possible permutation of specified rip widths and both the maximum and minimum percent yield...

Requirement of FADD, NEMO, and BAX/BAK for Aberrant Mitochondrial Function in Tumor Necrosis Factor Alpha-Induced Necrosis▿

PubMed Central

Irrinki, Krishna M.; Mallilankaraman, Karthik; Thapa, Roshan J.; Chandramoorthy, Harish C.; Smith, Frank J.; Jog, Neelakshi R.; Gandhirajan, Rajesh Kumar; Kelsen, Steven G.; Houser, Steven R.; May, Michael J.; Balachandran, Siddharth; Madesh, Muniswamy

2011-01-01

Necroptosis represents a form of alternative programmed cell death that is dependent on the kinase RIP1. RIP1-dependent necroptotic death manifests as increased reactive oxygen species (ROS) production in mitochondria and is accompanied by loss of ATP biogenesis and eventual dissipation of mitochondrial membrane potential. Here, we show that tumor necrosis factor alpha (TNF-α)-induced necroptosis requires the adaptor proteins FADD and NEMO. FADD was found to mediate formation of the TNF-α-induced pronecrotic RIP1-RIP3 kinase complex, whereas the IκB Kinase (IKK) subunit NEMO appears to function downstream of RIP1-RIP3. Interestingly, loss of RelA potentiated TNF-α-dependent necroptosis, indicating that NEMO regulates necroptosis independently of NF-κB. Using both pharmacologic and genetic approaches, we demonstrate that the overexpression of antioxidants alleviates ROS elevation and necroptosis. Finally, elimination of BAX and BAK or overexpression of Bcl-xL protects cells from necroptosis at a later step. These findings provide evidence that mitochondria play an amplifying role in inflammation-induced necroptosis. PMID:21746883

Runway Incursion Prevention System Testing at the Wallops Flight Facility

NASA Technical Reports Server (NTRS)

Jones, Denise R.

2005-01-01

A Runway Incursion Prevention System (RIPS) integrated with a Synthetic Vision System concept (SVS) was tested at the Reno/Tahoe International Airport (RNO) and Wallops Flight Facility (WAL) in the summer of 2004. RIPS provides enhanced surface situational awareness and alerts of runway conflicts in order to prevent runway incidents while also improving operational capability. A series of test runs was conducted using a Gulfstream-V (G-V) aircraft as the test platform and a NASA test aircraft and a NASA test van as incurring traffic. The purpose of the study, from the RIPS perspective, was to evaluate the RIPS airborne incursion detection algorithms and associated alerting and airport surface display concepts, focusing on crossing runway incursion scenarios. This paper gives an overview of the RIPS, WAL flight test activities, and WAL test results.

Role of necroptosis in autophagy signaling during hepatic ischemia and reperfusion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hong, Jeong-Min; Kim, Seok-Joo; Lee, Sun-Mee, E-ma

Ischemia and reperfusion (I/R) is a complex phenomenon involving massive inflammation and cell death. Necroptosis refers to a newly described cell death as “programmed necrosis” that is controlled by receptor-interacting protein kinase (RIP) 1 and RIP3, which is involved in the pathogenesis of several inflammatory diseases. Autophagy is an essential cytoprotective system that is rapidly activated in response to various stimuli and involves crosstalk between different modes of cell death and inflammation. In this study, we investigated pattern changes in necroptosis and its role in autophagy signaling during hepatic I/R. Male C57BL/6 mice were subjected to 60 min of ischemiamore » followed by 3 h reperfusion. Necrostatin-1 (Nec-1, a necroptosis inhibitor; 1.65 mg/kg) was administered intraperitoneally 5 min before reperfusion. Hepatic I/R significantly increased the level of RIP3, phosphorylated RIP1 and RIP3 protein expression, and RIP1/RIP3 necrosome formation, which were attenuated by Nec-1. I/R also significantly increased serum levels of alanine aminotransferase, tumor necrosis factor-α, and interleukin-6, which were attenuated by Nec-1. Meanwhile, hepatic I/R activated autophagy and mitophagy, as evidenced by increased LC3-II, PINK1, and Parkin, and decreased sequestosome 1/p62 protein expression. Nec-1 attenuated these changes and attenuated the increased levels of autophagy-related protein (ATG) 3, ATG7, Rab7, and cathepsin B protein expression during hepatic I/R. Moreover, hepatic I/R activated the extracellular signal-regulated kinase (ERK) pathway, and Nec-1 attenuated this increase. Taken together, our findings suggest that necroptosis contributes to hepatic damage during I/R, which induces autophagy via ERK activation. - Highlights: • Hepatic I/R induces RIP1/RIP3-dependent necroptosis. • Necroptosis contributes to hepatic I/R injury. • Necroptosis activates autophagic flux via ERK activation during hepatic I/R.« less

Cathepsins limit macrophage necroptosis through cleavage of Rip1 kinase.

PubMed

McComb, Scott; Shutinoski, Bojan; Thurston, Susan; Cessford, Erin; Kumar, Kriti; Sad, Subash

2014-06-15

It has recently been shown that programmed necrosis, necroptosis, may play a key role in the development of inflammation. Deciphering the regulation of this pathway within immune cells may therefore have implications in pathology associated with inflammatory diseases. We show that treatment of macrophages with the pan caspase inhibitor (zVAD-FMK) results in both increased phosphorylation and decreased cleavage of receptor interacting protein kinase-1 (Rip1), leading to necroptosis that is dependent on autocrine TNF signaling. Stimulation of cells with TLR agonists such as LPS in the presence of zVAD-FMK also induced Rip1-phosphorylation via a TNFR-independent mechanism. Further examination of Rip1 expression under these stimulatory conditions revealed a regulatory cleavage of Rip1 in macrophages that is not apparently attributable to caspase-8. Instead, we provide novel evidence that cysteine family cathepsins, which are highly abundant in myeloid cells, can also cleave Rip1 kinase. Using small interfering RNA knockdown, specific cathepsin inhibitors, and cell-free cleavage assays, we demonstrate that cysteine cathepsins B and S can directly cleave Rip1. Finally, we demonstrate that only through combined inhibition of cathepsins and caspase-8 could a potent induction of macrophage necroptosis be achieved. These data reveal a novel mechanism of regulation of necroptosis by cathepsins within macrophage cells. Copyright © 2014 by The American Association of Immunologists, Inc.

RIP1-mediated mitochondrial dysfunction and ROS production contributed to tumor necrosis factor alpha-induced L929 cell necroptosis and autophagy.

PubMed

Ye, Yuan-Chao; Wang, Hong-Ju; Yu, Lu; Tashiro, Shin-Ichi; Onodera, Satoshi; Ikejima, Takashi

2012-12-01

Tumor necrosis factor alpha (TNFα) induces necroptosis and autophagy; however, the detailed molecular mechanism is not fully understood. In this study, we found that TNFα administration caused mitochondrial dysfunction and reactive oxygen species (ROS) production, which led to necroptosis and autophagy in murine fibrosarcoma L929 cells. Notably, the RIP1 (serine-threonine kinase receptor-interacting protein 1, a main adaptor protein of necroptosis) specific inhibitor necrostatin-1 (Nec-1) recovered mitochondrial dysfunction and ROS production due to TNFα administration. Moreover, pan-caspase inhibitor z-VAD-fmk (zVAD) increased RIP1 expression and exacerbated TNFα-induced mitochondrial dysfunction and ROS production, indicating that RIP1 led to mitochondrial dysfunction and ROS production. In addition, cytochrome c release from mitochondria was accompanied with TNFα administration, and Nec-1 blocked the release of cytochrome c upon TNFα administration, while zVAD enhanced the release. These further suggested that RIP1 induced mitochondrial dysfunction accompanied with cytochrome c release. Furthermore, autophagy inhibitor 3-methyladenine (3MA) did not affect RIP1 expression as well as mitochondrial dysfunction and ROS production. Together with our previous publication that autophagy was a downstream consequence of necroptosis, we concluded that TNFα induced mitochondrial dysfunction accompanied with ROS production and cytochrome c release via RIP1, leading to necroptosis and resulting autophagic cell death. Copyright © 2012 Elsevier B.V. All rights reserved.

A Role for Tubular Necroptosis in Cisplatin-Induced AKI

PubMed Central

Xu, Yanfang; Ma, Huabin; Shao, Jing; Wu, Jianfeng; Zhou, Linying; Zhang, Zhirong; Wang, Yuze; Huang, Zhe; Ren, Junming; Liu, Suhuan; Chen, Xiangmei

2015-01-01

Cell death and inflammation in the proximal tubules are the hallmarks of cisplatin-induced AKI, but the mechanisms underlying these effects have not been fully elucidated. Here, we investigated whether necroptosis, a type of programmed necrosis, has a role in cisplatin-induced AKI. We found that inhibition of any of the core components of the necroptotic pathway—receptor-interacting protein 1 (RIP1), RIP3, or mixed lineage kinase domain-like protein (MLKL)—by gene knockout or a chemical inhibitor diminished cisplatin-induced proximal tubule damage in mice. Similar results were obtained in cultured proximal tubular cells. Furthermore, necroptosis of cultured cells could be induced by cisplatin or by a combination of cytokines (TNF-α, TNF-related weak inducer of apoptosis, and IFN-γ) that were upregulated in proximal tubules of cisplatin-treated mice. However, cisplatin induced an increase in RIP1 and RIP3 expression in cultured tubular cells in the absence of cytokine release. Correspondingly, overexpression of RIP1 or RIP3 enhanced cisplatin-induced necroptosis in vitro. Notably, inflammatory cytokine upregulation in cisplatin-treated mice was partially diminished in RIP3- or MLKL-deficient mice, suggesting a positive feedback loop involving these genes and inflammatory cytokines that promotes necroptosis progression. Thus, our data demonstrate that necroptosis is a major mechanism of proximal tubular cell death in cisplatin-induced nephrotoxic AKI. PMID:25788533

ROMI-3: Rough-Mill Simulator Version 3.0: User's Guide

Treesearch

Joel M. Weiss; R. Edward Thomas; R. Edward Thomas

2005-01-01

ROMI-3 Rough-Mill Simulator is a software package that simulates current industrial practices for rip-first and chop-first lumber processing. This guide shows the user how to set up and examine the results of simulations of current or proposed mill practices. ROMI-3 accepts cutting bills with as many as 600 combined solid and/or panel part sizes. Plots of processed...

NWS Marine Contacts

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! Boating Safety Beach Hazards Rip Currents Hypothermia Hurricanes Thunderstorms Lightning Coastal Flooding , Verification Richard May 301-427-9378 301-713-1520 FAX richard.may@noaa.gov Coastal Weather, Great Lakes, Ice operational nature relating to near shore and coastal forecasts, contact your local National Weather Service

USCG VHF Voice

Science.gov Websites

! Boating Safety Beach Hazards Rip Currents Hypothermia Hurricanes Thunderstorms Lightning Coastal Flooding frequency) The U.S. Coast Guard broadcasts coastal forecasts and storm Warnings of interest to the mariner coverage of coastal U.S., Great Lakes, Hawaii, and populated Alaska coastline. Typical coverage is 20

The phytopathogenic virulent effector protein RipI induces apoptosis in budding yeast Saccharomyces cerevisiae.

PubMed

Deng, Meng-Ying; Sun, Yun-Hao; Li, Pai; Fu, Bei; Shen, Dong; Lu, Yong-Jun

2016-10-01

Virulent protein toxins secreted by the bacterial pathogens can cause cytotoxicity by various molecular mechanisms to combat host cell defense. On the other hand, these proteins can also be used as probes to investigate the defense pathway of host innate immunity. Ralstonia solanacearum, one of the most virulent bacterial phytopathogens, translocates more than 70 effector proteins via type III secretion system during infection. Here, we characterized the cytotoxicity of effector RipI in budding yeast Saccharomyce scerevisiae, an alternative host model. We found that over-expression of RipI resulted in severe growth defect and arginine (R) 117 within the predicted integrase motif was required for inhibition of yeast growth. The phenotype of death manifested the hallmarks of apoptosis. Our data also revealed that RipI-induced apoptosis was independent of Yca1 and mitochondria-mediated apoptotic pathways because Δyca1 and Δaif1 were both sensitive to RipI as compared with the wild type. We further demonstrated that RipI was localized in the yeast nucleus and the N-terminal 1-174aa was required for the localization. High-throughput RNA sequencing analysis showed that upon RipI over-expression, 101 unigenes of yeast ribosome presented lower expression level, and 42 GO classes related to the nucleus or recombination were enriched with differential expression levels. Taken together, our data showed that a nuclear-targeting effector RipI triggers yeast apoptosis, potentially dependent on its integrase function. Our results also provided an alternative strategy to dissect the signaling pathway of cytotoxicity induced by the protein toxins. Copyright © 2016 Elsevier Ltd. All rights reserved.

Eleostearic acid induces RIP1-mediated atypical apoptosis in a kinase-independent manner via ERK phosphorylation, ROS generation and mitochondrial dysfunction

PubMed Central

Obitsu, S; Sakata, K; Teshima, R; Kondo, K

2013-01-01

RIP1 is a serine/threonine kinase, which is involved in apoptosis and necroptosis. In apoptosis, caspase-8 and FADD have an important role. On the other hand, RIP3 is a key molecule in necroptosis. Recently, we reported that eleostearic acid (ESA) elicits caspase-3- and PARP-1-independent cell death, although ESA-treated cells mediate typical apoptotic morphology such as chromatin condensation, plasma membrane blebbing and apoptotic body formation. The activation of caspases, Bax and PARP-1, the cleavage of AIF and the phosphorylation of histone H2AX, all of which are characteristics of typical apoptosis, do not occur in ESA-treated cells. However, the underlying mechanism remains unclear. To clarify the signaling pathways in ESA-mediated apoptosis, we investigated the functions of RIP1, MEK, ERK, as well as AIF. Using an extensive study based on molecular biology, we identified the alternative role of RIP1 in ESA-mediated apoptosis. ESA mediates RIP1-dependent apoptosis in a kinase independent manner. ESA activates serine/threonine phosphatases such as calcineurin, which induces RIP1 dephosphorylation, thereby ERK pathway is activated. Consequently, localization of AIF and ERK in the nucleus, ROS generation and ATP reduction in mitochondria are induced to disrupt mitochondrial cristae, which leads to cell death. Necrostatin (Nec)-1 blocked MEK/ERK phosphorylation and ESA-mediated apoptosis. Nec-1 inactive form (Nec1i) also impaired ESA-mediated apoptosis. Nec1 blocked the interaction of MEK with ERK upon ESA stimulation. Together, these findings provide a new finding that ERK and kinase-independent RIP1 proteins are implicated in atypical ESA-mediated apoptosis. PMID:23788031

Hyperglycemic Conditions Prime Cells for RIP1-dependent Necroptosis.

PubMed

LaRocca, Timothy J; Sosunov, Sergey A; Shakerley, Nicole L; Ten, Vadim S; Ratner, Adam J

2016-06-24

Necroptosis is a RIP1-dependent programmed cell death (PCD) pathway that is distinct from apoptosis. Downstream effector pathways of necroptosis include formation of advanced glycation end products (AGEs) and reactive oxygen species (ROS), both of which depend on glycolysis. This suggests that increased cellular glucose may prime necroptosis. Here we show that exposure to hyperglycemic levels of glucose enhances necroptosis in primary red blood cells (RBCs), Jurkat T cells, and U937 monocytes. Pharmacologic or siRNA inhibition of RIP1 prevented the enhanced death, confirming it as RIP1-dependent necroptosis. Hyperglycemic enhancement of necroptosis depends upon glycolysis with AGEs and ROS playing a role. Total levels of RIP1, RIP3, and mixed lineage kinase domain-like (MLKL) proteins were increased following treatment with high levels of glucose in Jurkat and U937 cells and was not due to transcriptional regulation. The observed increase in RIP1, RIP3, and MLKL protein levels suggests a potential positive feedback mechanism in nucleated cell types. Enhanced PCD due to hyperglycemia was specific to necroptosis as extrinsic apoptosis was inhibited by exposure to high levels of glucose. Hyperglycemia resulted in increased infarct size in a mouse model of brain hypoxia-ischemia injury. The increased infarct size was prevented by treatment with nec-1s, strongly suggesting that increased necroptosis accounts for exacerbation of this injury in conditions of hyperglycemia. This work reveals that hyperglycemia represents a condition in which cells are extraordinarily susceptible to necroptosis, that local glucose levels alter the balance of PCD pathways, and that clinically relevant outcomes may depend on glucose-mediated effects on PCD. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Cardioprotection of ischaemic preconditioning is associated with inhibition of translocation of MLKL within the plasma membrane.

PubMed

Szobi, Adrián; Farkašová-Ledvényiová, Veronika; Lichý, Martin; Muráriková, Martina; Čarnická, Slávka; Ravingerová, Tatiana; Adameová, Adriana

2018-06-19

Necroptosis, a form of cell loss involving the RIP1-RIP3-MLKL axis, has been identified in cardiac pathologies while its inhibition is cardioprotective. We investigated whether the improvement of heart function because of ischaemic preconditioning is associated with mitigation of necroptotic signaling, and these effects were compared with a pharmacological antinecroptotic approach targeting RIP1. Langendorff-perfused rat hearts were subjected to ischaemic preconditioning with or without a RIP1 inhibitor (Nec-1s). Necroptotic signaling and the assessment of oxidative damage and a putative involvement of CaMKII in this process were analysed in whole tissue and subcellular fractions. Ischaemic preconditioning, Nec-1s and their combination improved postischaemic heart function recovery and reduced infarct size to a similar degree what was in line with the prevention of MLKL oligomerization and translocation to the membrane. On the other hand, membrane peroxidation and apoptosis were unchanged by either approach. Ischaemic preconditioning failed to ameliorate ischaemia-reperfusion-induced increase in RIP1 and RIP3 while pSer229-RIP3 levels were reduced only by Nec-1s. In spite of the additive phosphorylation of CaMKII and PLN because of ditherapy, the postischaemic contractile force and relaxation was comparably improved in all the intervention groups while antiarrhythmic effects were observed in the ischaemic preconditioning group only. Necroptosis inhibition seems to be involved in cardioprotection of ischaemic preconditioning and is comparable but not intensified by an anti-RIP1 agent. Changes in oxidative stress nor CaMKII signaling are unlikely to explain the beneficial effects. © 2018 Comenius University in Bratislava, Faculty of Pharmacy. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Activation of hypothalamic RIP-Cre neurons promotes beiging of WAT via sympathetic nervous system.

PubMed

Wang, Baile; Li, Ang; Li, Xiaomu; Ho, Philip Wl; Wu, Donghai; Wang, Xiaoqi; Liu, Zhuohao; Wu, Kelvin Kl; Yau, Sonata Sy; Xu, Aimin; Cheng, Kenneth Ky

2018-04-01

Activation of brown adipose tissue (BAT) and beige fat by cold increases energy expenditure. Although their activation is known to be differentially regulated in part by hypothalamus, the underlying neural pathways and populations remain poorly characterized. Here, we show that activation of rat-insulin-promoter-Cre (RIP-Cre) neurons in ventromedial hypothalamus (VMH) preferentially promotes recruitment of beige fat via a selective control of sympathetic nervous system (SNS) outflow to subcutaneous white adipose tissue (sWAT), but has no effect on BAT Genetic ablation of APPL2 in RIP-Cre neurons diminishes beiging in sWAT without affecting BAT, leading to cold intolerance and obesity in mice. Such defects are reversed by activation of RIP-Cre neurons, inactivation of VMH AMPK, or treatment with a β3-adrenergic receptor agonist. Hypothalamic APPL2 enhances neuronal activation in VMH RIP-Cre neurons and raphe pallidus, thereby eliciting SNS outflow to sWAT and subsequent beiging. These data suggest that beige fat can be selectively activated by VMH RIP-Cre neurons, in which the APPL2-AMPK signaling axis is crucial for this defending mechanism to cold and obesity. © 2018 The Authors.

NATIONAL WEATHER SERVICE MARINE PRODUCTS VIA INTERNET

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! Boating Safety Beach Hazards Rip Currents Hypothermia Hurricanes Thunderstorms Lightning Coastal Flooding Text Forecasts and Products. For convenience, High Seas, Offshore and Coastal marine forecasts are available via the Internet for most U.S. coastal areas. Gridded forecast data for offshore and high seas

NOAA TELEPHONE RECORDINGS

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! Boating Safety Beach Hazards Rip Currents Hypothermia Hurricanes Thunderstorms Lightning Coastal Flooding . Mariners can now hear the latest coastal and offshore weather observations using Dial-A-Buoy. Dial-A-Buoy wind and wave measurements taken within the last hour at 65 buoy and 54 Coastal-Marine Automated

National Weather Service Marine Forecasts - FAQ

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! Boating Safety Beach Hazards Rip Currents Hypothermia Hurricanes Thunderstorms Lightning Coastal Flooding marine coastal areas may be found in Appendix B of the National Ocean Service's Coast Pilot's, volumes 1 Advisory (SCA): An advisory issued by coastal and Great Lakes Weather Forecast Offices (WFO) for areas

NATIONAL WEATHER SERVICE MARINE PRODUCTS VIA NOAA WEATHER RADIO

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! Boating Safety Beach Hazards Rip Currents Hypothermia Hurricanes Thunderstorms Lightning Coastal Flooding Radio network provides voice broadcasts of local and coastal marine forecasts on a continuous cycle. The forecasts are produced by local National Weather Service Forecast Offices. Coastal stations also broadcast

Genetic transformation of Neurospora tetrasperma, demonstration of repeat-induced point mutation (RIP) in self-crosses and a screen for recessive RIP-defective mutants.

PubMed Central

Bhat, Ashwin; Tamuli, Ranjan; Kasbekar, Durgadas P

2004-01-01

The pseudohomothallic fungus Neurospora tetrasperma is naturally resistant to the antibiotic hygromycin. We discovered that mutation of its erg-3 (sterol C-14 reductase) gene confers a hygromycin-sensitive phenotype that can be used to select transformants on hygromycin medium by complementation with the N. crassa erg-3+ and bacterial hph genes. Cotransformation of hph with PCR-amplified DNA of other genes enabled us to construct strains duplicated for the amplified DNA. Using transformation we constructed self-fertile strains that were homoallelic for an ectopic erg-3+ transgene and a mutant erg-3 allele at the endogenous locus. Self-crosses of these strains yielded erg-3 mutant ascospores that produced colonies with the characteristic morphology on Vogel's sorbose agar described previously for erg-3 mutants of N. crassa. The mutants were generated by repeat-induced point mutation (RIP), a genome defense process that causes numerous G:C to A:T mutations in duplicated DNA sequences. Homozygosity for novel recessive RIP-deficient mutations was signaled by self-crosses of erg-3-duplication strains that fail to produce erg-3 mutant progeny. Using this assay we isolated a UV-induced mutant with a putative partial RIP defect. RIP-induced mutants were isolated in rid-1 and sad-1, which are essential genes, respectively, for RIP and another genome defense mechanism called meiotic silencing by unpaired DNA. PMID:15280231

3RIP Evaluation of the Performance of the Search System Using a Realtime Simulation Technique.

ERIC Educational Resources Information Center

Lofstrom, Mats

This report describes a real-time simulation experiment to evaluate the performance of the search and editing system 3RIP, an interactive system written in the language BLISS on a DEC-10 computer. The test vehicle, preliminary test runs, and capacity test are detailed, and the following conclusions are reported: (1) 3RIP performs well up to the…

Performance review of the ROMI-RIP rough mill simulator

Treesearch

Edward Thomas; Urs Buehlmann

2003-01-01

The USDA Forest Service's ROMI-RIP version 2.0 (RR2) rough mill rip-first simulation program was validated in a recent study. The validation study found that when RR2 was set to search for optimum yield without considering actual rough mill strip solutions, it produced yields that were as much as 7 percent higher (71.1% versus 64.0%) than the actual rough mill....

Assessment of upper tropospheric and stratospheric water vapor and ozone in reanalyses as part of S-RIP

NASA Astrophysics Data System (ADS)

Davis, Sean M.; Hegglin, Michaela I.; Fujiwara, Masatomo; Dragani, Rossana; Harada, Yayoi; Kobayashi, Chiaki; Long, Craig; Manney, Gloria L.; Nash, Eric R.; Potter, Gerald L.; Tegtmeier, Susann; Wang, Tao; Wargan, Krzysztof; Wright, Jonathon S.

2017-10-01

Reanalysis data sets are widely used to understand atmospheric processes and past variability, and are often used to stand in as "observations" for comparisons with climate model output. Because of the central role of water vapor (WV) and ozone (O3) in climate change, it is important to understand how accurately and consistently these species are represented in existing global reanalyses. In this paper, we present the results of WV and O3 intercomparisons that have been performed as part of the SPARC (Stratosphere-troposphere Processes and their Role in Climate) Reanalysis Intercomparison Project (S-RIP). The comparisons cover a range of timescales and evaluate both inter-reanalysis and observation-reanalysis differences. We also provide a systematic documentation of the treatment of WV and O3 in current reanalyses to aid future research and guide the interpretation of differences amongst reanalysis fields.The assimilation of total column ozone (TCO) observations in newer reanalyses results in realistic representations of TCO in reanalyses except when data coverage is lacking, such as during polar night. The vertical distribution of ozone is also relatively well represented in the stratosphere in reanalyses, particularly given the relatively weak constraints on ozone vertical structure provided by most assimilated observations and the simplistic representations of ozone photochemical processes in most of the reanalysis forecast models. However, significant biases in the vertical distribution of ozone are found in the upper troposphere and lower stratosphere in all reanalyses.In contrast to O3, reanalysis estimates of stratospheric WV are not directly constrained by assimilated data. Observations of atmospheric humidity are typically used only in the troposphere, below a specified vertical level at or near the tropopause. The fidelity of reanalysis stratospheric WV products is therefore mainly dependent on the reanalyses' representation of the physical drivers that influence stratospheric WV, such as temperatures in the tropical tropopause layer, methane oxidation, and the stratospheric overturning circulation. The lack of assimilated observations and known deficiencies in the representation of stratospheric transport in reanalyses result in much poorer agreement amongst observational and reanalysis estimates of stratospheric WV. Hence, stratospheric WV products from the current generation of reanalyses should generally not be used in scientific studies.

Runway Incursion Prevention System Simulation Evaluation

NASA Technical Reports Server (NTRS)

Jones, Denise R.

2002-01-01

A Runway Incursion Prevention System (RIPS) was evaluated in a full mission simulation study at the NASA Langley Research center in March 2002. RIPS integrates airborne and ground-based technologies to provide (1) enhanced surface situational awareness to avoid blunders and (2) alerts of runway conflicts in order to prevent runway incidents while also improving operational capability. A series of test runs was conducted in a high fidelity simulator. The purpose of the study was to evaluate the RIPS airborne incursion detection algorithms and associated alerting and airport surface display concepts. Eight commercial airline crews participated as test subjects completing 467 test runs. This paper gives an overview of the RIPS, simulation study, and test results.

Concept-Development of a Structure Supported Membrane for Deployable Space Applications - From Nature to Manufacture and Testing

NASA Technical Reports Server (NTRS)

Zander, Martin; Belvin, W. K.

2012-01-01

Current space applications of membrane structures include large area solar power arrays, solar sails, antennas, and numerous other large aperture devices like the solar shades of the new James Webb Space Telescope. These expandable structural systems, deployed in-orbit to achieve the desired geometry, are used to collect, reflect and/or transmit electromagnetic radiation. This work, a feasibility study supporting a diploma thesis, describes the systematic process for developing a biologically inspired concept for a structure supported (integrated) membrane, that features a rip stop principle, makes self-deployment possible and is part of an ultra-light weight space application. Novel manufacturing of membrane prototypes and test results are presented for the rip-stop concepts. Test data showed that the new membrane concept has a higher tear resistance than neat film of equivalent mass.

RIP3 attenuates the pancreatic damage induced by deletion of ATG7.

PubMed

Zhou, Xiaodong; Xie, Li; Xia, Leizhou; Bergmann, Frank; Büchler, Markus W; Kroemer, Guido; Hackert, Thilo; Fortunato, Franco

2017-07-13

Invalidation of pancreatic autophagy entails pancreatic atrophy, endocrine and exocrine insufficiency and pancreatitis. The aim of this study was to investigate whether depletion of Rip3, which is involved in necroptotic signaling, may attenuate the pancreatic atrophy and pancreatitis resulting from autophagy inhibition. Autophagy and necroptosis signaling were evaluated in mice lacking expression of Rip3 in all organs and Atg7 in the pancreas. Acinar cell death, inflammation and fibrosis were evaluated by using of a compendium of immunofluorescence methods and immunoblots. Mice deficient for pancreatic Atg7 developed acute pancreatitis, which progressed to chronic pancreatitis. This phenotype reduces autophagy, increase apoptosis and necroptosis, inflammation and fibrosis, as well as premature death of the animals. Knockout of Rip3 exacerbated the apoptotic death of acinar cells, increased tissue damage, reduced macrophage infiltration and further accelerated the death of the mice with Atg7-deficient pancreas. The pancreatic degeneration induced by autophagy inhibition was exacerbated by Rip3 deletion.

PUMA amplifies necroptosis signaling by activating cytosolic DNA sensors

PubMed Central

Tong, Jingshan; Yang, Liheng; Wei, Liang; Stolz, Donna B.; Yu, Jian; Zhang, Jianke; Zhang, Lin

2018-01-01

Necroptosis, a form of regulated necrotic cell death, is governed by RIP1/RIP3-mediated activation of MLKL. However, the signaling process leading to necroptotic death remains to be elucidated. In this study, we found that PUMA, a proapoptotic BH3-only Bcl-2 family member, is transcriptionally activated in an RIP3/MLKL-dependent manner following induction of necroptosis. The induction of PUMA, which is mediated by autocrine TNF-α and enhanced NF-κB activity, contributes to necroptotic death in RIP3-expressing cells with caspases inhibited. On induction, PUMA promotes the cytosolic release of mitochondrial DNA and activation of the DNA sensors DAI/Zbp1 and STING, leading to enhanced RIP3 and MLKL phosphorylation in a positive feedback loop. Furthermore, deletion of PUMA partially rescues necroptosis-mediated developmental defects in FADD-deficient embryos. Collectively, our results reveal a signal amplification mechanism mediated by PUMA and cytosolic DNA sensors that is involved in TNF-driven necroptotic death in vitro and in vivo. PMID:29581256

Fish community structure in natural and engineered habitats in the Kansas River

USGS Publications Warehouse

White, K.; Gerken, J.; Paukert, Craig P.; Makinster, Andrew S.

2010-01-01

We investigated fish assemblage structure in engineered (rip-rap) and natural habitats (log jams and mud banks) in the Kansas River USA to determine if natural structures had higher abundance and diversity of fishes at a local spatial scale. A total of 439 randomly selected sites were boat electrofished from May to August 2005 and 2006. Mean species diversity and richness were significantly higher in rip-rap than log jams and mud banks. Mean relative abundance (CPUE; number of fish collected per hour electrofishing) of six of the 15 most common fishes (>1% of total catch) were most abundant in rip-rap, two were most abundant in log jams, and none in mud banks. Rip-rap had the highest relative abundance of fluvial specialist and macrohabitat generalists, whereas mean CPUE of fluvial dependents was highest in log jams. Although a discriminant function analysis indicated that nine size classes (eight species) discriminated among three habitat types, the high misclassification rate (38%) suggested a high degree of fish assemblage overlap among the habitats. Although previous work has suggested that engineered structures (rip-rap) and urbanization are linked to reduced biotic diversity or reduced growth of fish species, our results suggest that at a local scale rip-rap may not have the same negative impacts on fish assemblages.

Fish community structure in natural and engineered habitats in the Kansas river

USGS Publications Warehouse

White, K.; Gerken, J.; Paukert, C.; Makinster, A.

2010-01-01

We investigated fish assemblage structure in engineered (rip-rap) and natural habitats (log jams and mud banks) in the Kansas River USA to determine if natural structures had higher abundance and diversity of fishes at a local spatial scale. A total of 439 randomly selected sites were boat electrofished from May to August 2005 and 2006. Mean species diversity and richness were significantly higher in rip-rap than log jams and mud banks. Mean relative abundance (CPUE; number of fish collected per hour electrofishing) of six of the 15 most common fishes (>1% of total catch) were most abundant in rip-rap, two were most abundant in log jams, and none in mud banks. Rip-rap had the highest relative abundance of fluvial specialist and macrohabitat generalists, whereas mean CPUE of fluvial dependents was highest in log jams. Although a discriminant function analysis indicated that nine size classes (eight species) discriminated among three habitat types, the high misclassification rate (38%) suggested a high degree of fish assemblage overlap among the habitats. Although previous work has suggested that engineered structures (rip-rap) and urbanization are linked to reduced biotic diversity or reduced growth of fish species, our results suggest that at a local scale rip-rap may not have the same negative impacts on fish assemblages.

Synthesis, characterization and cytotoxic evaluation of inclusion complexes between Riparin A and β-cyclodextrin

NASA Astrophysics Data System (ADS)

Araújo, Éverton José Ferreira de; Silva, Oskar Almeida; Rezende-Júnior, Luís Mário; Sousa, Ian Jhemes Oliveira; Araújo, Danielle Yasmin Moura Lopes de; Carvalho, Rusbene Bruno Fonseca de; Pereira, Sean Telles; Gutierrez, Stanley Juan Chavez; Ferreira, Paulo Michel Pinheiro; Lima, Francisco das Chagas Alves

2017-08-01

This study performed a physicochemical characterization of the inclusion complex generated between Riparin A and β-cyclodextrin (Rip A/β-CD) and compared the cytotoxic potential of the incorporated Rip A upon Artemia salina larvae. Samples were analyzed by phase solubility diagram, dissolution profile, differential scanning calorimetry, X-ray diffraction, infrared spectroscopy, proton nuclear magnetic resonance, scanning electron microscopy and artemicidal action. Riparin A/β-cyclodextrin complexes presented increased water solubility, AL type solubility diagram and Kst constant of 373 L/mol. Thermal analysis demonstrated reduction of the melt peak of complexed Rip A at 116.2 °C. Infrared spectroscopy confirmed generation of inclusion complexes, 1H NMR pointed out the interaction with H-3 of β-CD cavities, alterations in the crystalline natures of Rip A when incorporated within β-CD were observed and inclusion complexes presented higher cytotoxic on A. salina nauplii, with CL50 value of 117.2 (84.9-161.8) μg/mL. So, Rip A was incorporated into β-CDs with high efficiency and water solubility of Rip A was improved. Such solubility was corroborated by cytotoxic evaluation and these outcomes support the improvement of biological properties for complexes between Riparin A/β-cyclodextrin.

Risk Reduction and Soil Ecosystem Restoration in an Active Oil Producing Area in an Ecologically Sensitive Setting

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kerry L. Sublette; Greg Thoma; Kathleen Duncan

2006-01-01

The empowerment of small independent oil and gas producers to solve their own remediation problems will result in greater environmental compliance and more effective protection of the environment as well as making small producers more self-reliant. In Chapter 1 we report on the effectiveness of a low-cost method of remediation of a combined spill of crude oil and brine in the Tallgrass Prairie Preserve in Osage County, OK. Specifically, we have used hay and fertilizer as amendments for remediation of both the oil and the brine. No gypsum was used. Three spills of crude oil plus produced water brine weremore » treated with combinations of ripping, fertilizers and hay, and a downslope interception trench in an effort to demonstrate an inexpensive, easily implemented, and effective remediation plan. There was no statistically significant effect of treatment on the biodegradation of crude oil. However, TPH reduction clearly proceeded in the presence of brine contamination. The average TPH half-life considering all impacted sites was 267 days. The combination of hay addition, ripping, and a downslope interception trench was superior to hay addition with ripping, or ripping plus an interception trench in terms of rates of sodium and chloride leaching from the impacted sites. Reductions in salt inventories (36 months) were 73% in the site with hay addition, ripping and an interception trench, 40% in the site with hay addition and ripping only, and < 3% in the site with ripping and an interception trench.« less

Immunotoxins Constructed with Ribosome-Inactivating Proteins and their Enhancers: A Lethal Cocktail with Tumor Specific Efficacy

PubMed Central

Gilabert-Oriol, Roger; Weng, Alexander; von Mallinckrodt, Benedicta; Melzig, Matthias F; Fuchs, Hendrik; Thakur, Mayank

2014-01-01

The term ribosome-inactivating protein (RIP) is used to denominate proteins mostly of plant origin, which have N-glycosidase enzymatic activity leading to a complete destruction of the ribosomal function. The discovery of the RIPs was almost a century ago, but their usage has seen transition only in the last four decades. With the advent of antibody therapy, the RIPs have been a subject of extensive research especially in targeted tumor therapies, which is the primary focus of this review. In the present work we enumerate 250 RIPs, which have been identified so far. An attempt has been made to identify all the RIPs that have been used for the construction of immunotoxins, which are conjugates or fusion proteins of an antibody or ligand with a toxin. The data from 1960 onwards is reviewed in this paper and an extensive list of more than 450 immunotoxins is reported. The clinical reach of tumor-targeted toxins has been identified and detailed in the work as well. While there is a lot of potential that RIPs embrace for targeted tumor therapies, the success in preclinical and clinical evaluations has been limited mainly because of their inability to escape the endo/lysosomal degradation. Various strategies that can increase the efficacy and lower the required dose for targeted toxins have been compiled in this article. It is plausible that with the advancements in platform technologies or improved endosomal escape the usage of tumor targeted RIPs would see the daylight of clinical success. PMID:25341935

The Expression of Dectin-1, Irak1 and Rip2 During the Host Response to Aspergillus fumigatus.

PubMed

Liu, Jinguo; Yu, Lin; Chen, Cuicui; Zhou, Jian; Gong, Xin; Li, Dandan; Hou, Dongni; Song, Yuanlin; Shao, Changzhou

2018-04-01

C-type lectin receptors (CLRs), Toll-like receptors (TLRs), and Nod-like receptors (NLRs) have the ability to recognize Aspergillus fumigatus (A. fumigates) and induce innate immune response. Dectin-1 is a well-described CLR, while interleukin-1 receptor-associated kinase 1 (Irak1) and receptor-interacting protein 2 (Rip2) are pivotal adaptor proteins of TLRs and NLRs signaling pathways, respectively. Our primary aim is to elucidate whether Dectin-1 regulates the expression of Irak1 and Rip2, and confirm that CLRs, TLRs, and NLRs pathways act synergistically in response to A. fumigatus infection. Pulmonary infection mouse models were established. Myeloid cells were differentiated in cell culture and examined by inverted microscopy, flow cytometry, and scanning electron microscopy. The relative mRNA levels were determined by qRT-PCR. The protein expression levels were determined by immunohistochemistry and Western blot. The expression of Dectin-1, Irak1, Rip2, and phosphorylation level of nuclear factor (NF)-κB p65 were induced by conidia in immunocompetent mice, while their expression and phosphorylation level were inhibited in immunocompromised mice after the administration of conidia. Conidia increased the expression of Dectin-1, Irak1, and Rip2 in myeloid cells, while Dectin-1 silencing significantly reduced their expression. Our findings demonstrate that Dectin-1, Irak1, and Rip2 are involved in response to A. fumigatus infection. Dectin-1 modulates the expression of Irak1 and Rip2. Additionally, these three signaling pathways are interconnected, and CLRs pathway plays a dominant role against A. fumigatus invasion.

Isolation and characterization of an RIP (ribosome-inactivating protein)-like protein from tobacco with dual enzymatic activity.

PubMed

Sharma, Neelam; Park, Sang-Wook; Vepachedu, Ramarao; Barbieri, Luigi; Ciani, Marialibera; Stirpe, Fiorenzo; Savary, Brett J; Vivanco, Jorge M

2004-01-01

Ribosome-inactivating proteins (RIPs) are N-glycosidases that remove a specific adenine from the sarcin/ricin loop of the large rRNA, thus arresting protein synthesis at the translocation step. In the present study, a protein termed tobacco RIP (TRIP) was isolated from tobacco (Nicotiana tabacum) leaves and purified using ion exchange and gel filtration chromatography in combination with yeast ribosome depurination assays. TRIP has a molecular mass of 26 kD as evidenced by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and showed strong N-glycosidase activity as manifested by the depurination of yeast rRNA. Purified TRIP showed immunoreactivity with antibodies of RIPs from Mirabilis expansa. TRIP released fewer amounts of adenine residues from ribosomal (Artemia sp. and rat ribosomes) and non-ribosomal substrates (herring sperm DNA, rRNA, and tRNA) compared with other RIPs. TRIP inhibited translation in wheat (Triticum aestivum) germ more efficiently than in rabbit reticulocytes, showing an IC50 at 30 ng in the former system. Antimicrobial assays using highly purified TRIP (50 microg mL(-1)) conducted against various fungi and bacterial pathogens showed the strongest inhibitory activity against Trichoderma reesei and Pseudomonas solancearum. A 15-amino acid internal polypeptide sequence of TRIP was identical with the internal sequences of the iron-superoxide dismutase (Fe-SOD) from wild tobacco (Nicotiana plumbaginifolia), Arabidopsis, and potato (Solanum tuberosum). Purified TRIP showed SOD activity, and Escherichia coli Fe-SOD was observed to have RIP activity too. Thus, TRIP may be considered a dual activity enzyme showing RIP-like activity and Fe-SOD characteristics.

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish.

PubMed

Viringipurampeer, I A; Shan, X; Gregory-Evans, K; Zhang, J P; Mohammadi, Z; Gregory-Evans, C Y

2014-05-01

Achromatopsia is a progressive autosomal recessive retinal disease characterized by early loss of cone photoreceptors and later rod photoreceptor loss. In most cases, mutations have been identified in CNGA3, CNGB3, GNAT2, PDE6C or PDE6H genes. Owing to this genetic heterogeneity, mutation-independent therapeutic schemes aimed at preventing cone cell death are very attractive treatment strategies. In pde6c(w59) mutant zebrafish, cone photoreceptors expressed high levels of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3) kinases, key regulators of necroptotic cell death. In contrast, rod photoreceptor cells were alternatively immunopositive for caspase-3 indicating activation of caspase-dependent apoptosis in these cells. Morpholino gene knockdown of rip3 in pde6c(w59) embryos rescued the dying cone photoreceptors by inhibiting the formation of reactive oxygen species and by inhibiting second-order neuron remodelling in the inner retina. In rip3 morphant larvae, visual function was restored in the cones by upregulation of the rod phosphodiesterase genes (pde6a and pde6b), compensating for the lack of cone pde6c suggesting that cones are able to adapt to their local environment. Furthermore, we demonstrated through pharmacological inhibition of RIP1 and RIP3 activity that cone cell death was also delayed. Collectively, these results demonstrate that the underlying mechanism of cone cell death in the pde6c(w59) mutant retina is through necroptosis, whereas rod photoreceptor bystander death occurs through a caspase-dependent mechanism. This suggests that targeting the RIP kinase signalling pathway could be an effective therapeutic intervention in retinal degeneration patients. As bystander cell death is an important feature of many retinal diseases, combinatorial approaches targeting different cell death pathways may evolve as an important general principle in treatment.

Fish oil-derived lipid emulsion induces RIP1-dependent and caspase 8-licensed necroptosis in IEC-6 cells through overproduction of reactive oxygen species.

PubMed

Yan, Jun-Kai; Yan, Wei-Hui; Cai, Wei

2018-06-23

Excessive cell death of enterocytes has been demonstrated to be partially associated with the intravenously-administrated lipid emulsions (LEs) during parenteral nutrition (PN) support. However, as a new generation of LE, the effect of fish oil-derived lipid emulsion (FOLE) on the death of enterocytes remains elusive. Intestinal epithelial cells (IEC-6 cell line) were treated with FOLE (0.25-1%) for 24 h. Cell survival was measured by CCK-8 assay, and morphological changes were monitored by time-lapse live cell imaging. The expression of receptor-interacting protein 1/3 (RIP1/3) and caspase 8 was assessed by westernblot, and the formation of necrosome (characterized by the assembly of RIP1/3 complex along with the dissociation of caspase 8) was examined by immunoprecipitation. Additionally, the production of intracellular reactive oxygen species (ROS) was detected by using a ROS detection kit with an oxidation-sensitive probe (DCFH-DA). FOLE dose-dependently induced non-apoptotic, but programmed necroctic cell death (necroptosis) within 4-8 h after treatment. The assembly of RIP1/3 complex along with the dissociation of caspase 8 from RIP1 was observed in FOLE-treated cells. Moreover, FOLE-induced cell death was significantly alleviated by inhibiting RIP1, and was further aggravated by inhibiting caspase 8. In addition, prior to cell death the accumulation of intracellular ROS was significantly increased in FOLE-treated cells (increased by approximately 5-fold versus control, p < 0.001), which could be attenuated by inhibiting RIP1 (decreased by approximately 35% versus FOLE, p < 0.05). FOLE induces RIP1-dependent and caspase 8-licensed necroptosis through overproduction of ROS in vitro. Our findings may provide novel insights into the clinical applications of FOLE during PN support.

Hyperglycemia potentiates a shift from apoptosis to RIP1-dependent necroptosis.

PubMed

McCaig, William D; Patel, Payal S; Sosunov, Sergey A; Shakerley, Nicole L; Smiraglia, Tori A; Craft, Miranda M; Walker, Katharine M; Deragon, Matthew A; Ten, Vadim S; LaRocca, Timothy J

2018-01-01

Apoptosis and necroptosis are the primary modes of eukaryotic cell death, with apoptosis being non-inflammatory while necroptosis is highly inflammatory. We previously demonstrated that, once activated, necroptosis is enhanced by hyperglycemia in several cell types. Here, we determine if hyperglycemia affects apoptosis similarly. We show that hyperglycemia does not enhance extrinsic apoptosis but potentiates a shift to RIP1-dependent necroptosis. This is due to increased levels and activity of RIP1, RIP3, and MLKL, as well as decreased levels and activity of executioner caspases under hyperglycemic conditions following stimulation of apoptosis. Cell death under hyperglycemic conditions was classified as necroptosis via measurement of markers and involvement of RIP1, RIP3, and MLKL. The shift to necroptosis was driven by RIP1, as mutation of this gene using CRISPR-Cas9 caused cell death to revert to apoptosis under hyperglycemic conditions. The shift of apoptosis to necroptosis depended on glycolysis and production of mitochondrial ROS. Importantly, the shift in PCD was observed in primary human T cells. Levels of RIP1 and MLKL increased, while executioner caspases and PARP1 cleavage decreased, in cerebral tissue from hyperglycemic neonatal mice that underwent hypoxia-ischemia (HI) brain injury, suggesting that this cell death shift occurs in vivo . This is significant as it demonstrates a shift from non-inflammatory to inflammatory cell death which may explain the exacerbation of neonatal HI-brain injury during hyperglycemia. These results are distinct from our previous findings where hyperglycemia enhanced necroptosis under conditions where apoptosis was inhibited artificially. Here we demonstrate a shift from apoptosis to necroptosis under hyperglycemic conditions while both pathways are fully active. Therefore, while our previous work documented that intensity of necroptosis is responsive to glucose, this work sheds light on the molecular balance between apoptosis and necroptosis and identifies hyperglycemia as a condition that pushes cells to undergo necroptosis despite the initial activation of apoptosis.

[Programmed necrosis and necroptosis - molecular mechanisms].

PubMed

Giżycka, Agata; Chorostowska-Wynimko, Joanna

2015-12-16

Programmed necrosis has been proven vital for organism development and homeostasis maintenance. Its regulatory effects on functional activity of the immune system, as well as on pathways regulating the death mechanisms in cells with diminished apoptotic activity, including malignant cells, have been confirmed. There is also increasing evidence indicating necrosis involvement in many human pathologies. Contrary to previous beliefs, necrosis is not only a passive, pathological, gene-independent process. However, the current knowledge regarding molecular regulation of programmed necrosis is scarce. In part this is due to the multiplicity and complexity of signaling pathways involved in programmed necrosis, as well as the absence of specific cellular markers identifying this process, but also the ambiguous and imprecise international terminology. This review presents the current state of the art on molecular mechanisms of programmed necrosis. In particular, its specific and frequent form, necroptosis, is discussed. The role of RIP1 and RIP3 kinases in this process is presented, as well as the diverse pathways induced by ligation of tumor necrosis factor α, to its receptor, TNFR1, i.e. cell survival, apoptosis or necroptosis.

A Load-Sharing Rip-Stop Fixation Construct for Arthroscopic Rotator Cuff Repair

PubMed Central

Denard, Patrick J.; Burkhart, Stephen S.

2012-01-01

Despite advancements in arthroscopic rotator cuff repair techniques, achieving tendon-to-bone healing can be difficult in the setting of poor-quality tendon. Moreover, medial tendon tears or tears with lateral tendon loss may preclude standard techniques. Rip-stop suture configurations have been shown to improve load to failure compared with simple or mattress stitch patterns and may be particularly valuable in these settings. The purpose of this report is to describe a technical modification of a rip-stop rotator cuff repair that combines the advantages of a rip-stop suture (by providing resistance to tissue cutout) and a double row of load-sharing suture anchors (minimizing the load per anchor and therefore the load per suture within each anchor). PMID:23766972

Pearl millet [Pennisetum glaucum (L.) R. Br.] consensus linkage map constructed using four RIL mapping populations and newly developed EST-SSRs.

PubMed

Rajaram, Vengaldas; Nepolean, Thirunavukkarasu; Senthilvel, Senapathy; Varshney, Rajeev K; Vadez, Vincent; Srivastava, Rakesh K; Shah, Trushar M; Supriya, Ambawat; Kumar, Sushil; Ramana Kumari, Basava; Bhanuprakash, Amindala; Narasu, Mangamoori Lakshmi; Riera-Lizarazu, Oscar; Hash, Charles Thomas

2013-03-09

Pearl millet [Pennisetum glaucum (L.) R. Br.] is a widely cultivated drought- and high-temperature tolerant C4 cereal grown under dryland, rainfed and irrigated conditions in drought-prone regions of the tropics and sub-tropics of Africa, South Asia and the Americas. It is considered an orphan crop with relatively few genomic and genetic resources. This study was undertaken to increase the EST-based microsatellite marker and genetic resources for this crop to facilitate marker-assisted breeding. Newly developed EST-SSR markers (99), along with previously mapped EST-SSR (17), genomic SSR (53) and STS (2) markers, were used to construct linkage maps of four F7 recombinant inbred populations (RIP) based on crosses ICMB 841-P3 × 863B-P2 (RIP A), H 77/833-2 × PRLT 2/89-33 (RIP B), 81B-P6 × ICMP 451-P8 (RIP C) and PT 732B-P2 × P1449-2-P1 (RIP D). Mapped loci numbers were greatest for RIP A (104), followed by RIP B (78), RIP C (64) and RIP D (59). Total map lengths (Haldane) were 615 cM, 690 cM, 428 cM and 276 cM, respectively. A total of 176 loci detected by 171 primer pairs were mapped among the four crosses. A consensus map of 174 loci (899 cM) detected by 169 primer pairs was constructed using MergeMap to integrate the individual linkage maps. Locus order in the consensus map was well conserved for nearly all linkage groups. Eighty-nine EST-SSR marker loci from this consensus map had significant BLAST hits (top hits with e-value ≤ 1E-10) on the genome sequences of rice, foxtail millet, sorghum, maize and Brachypodium with 35, 88, 58, 48 and 38 loci, respectively. The consensus map developed in the present study contains the largest set of mapped SSRs reported to date for pearl millet, and represents a major consolidation of existing pearl millet genetic mapping information. This study increased numbers of mapped pearl millet SSR markers by >50%, filling important gaps in previously published SSR-based linkage maps for this species and will greatly facilitate SSR-based QTL mapping and applied marker-assisted selection programs.

Variability of the soil-to-plant radiocaesium transfer factor for Japanese soils predicted with soil and plant properties.

PubMed

Uematsu, Shinichiro; Vandenhove, Hildegarde; Sweeck, Lieve; Van Hees, May; Wannijn, Jean; Smolders, Erik

2016-03-01

Food chain contamination with radiocaesium (RCs) in the aftermath of the Fukushima accident calls for an analysis of the specific factors that control the RCs transfer. Here, soil-to-plant transfer factors (TF) of RCs for grass were predicted from the potassium concentration in soil solution (mK) and the Radiocaesium Interception Potential (RIP) of the soil using existing mechanistic models. The mK and RIP were (a) either measured for 37 topsoils collected from the Fukushima accident affected area or (b) predicted from the soil clay content and the soil exchangeable potassium content using the models that had been calibrated for European soils. An average ammonium concentration was used throughout in the prediction. The measured RIP ranged 14-fold and measured mK varied 37-fold among the soils. The measured RIP was lower than the RIP predicted from the soil clay content likely due to the lower content of weathered micas in the clay fraction of Japanese soils. Also the measured mK was lower than that predicted. As a result, the predicted TFs relying on the measured RIP and mK were, on average, about 22-fold larger than the TFs predicted using the European calibrated models. The geometric mean of the measured TFs for grass in the affected area (N = 82) was in the middle of both. The TFs were poorly related to soil classification classes, likely because soil fertility (mK) was obscuring the effects of the soil classification related to the soil mineralogy (RIP). This study suggests that, on average, Japanese soils are more vulnerable than European soils at equal soil clay and exchangeable K content. The affected regions will be targeted for refined model validation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Ebulin-RP, a novel member of the Ebulin gene family with low cytotoxicity as a result of deficient sugar binding domains.

PubMed

Iglesias, Rosario; Ferreras, J Miguel; Di Maro, Antimo; Citores, Lucía

2018-03-01

Sambucus ebulus is a rich source of ribosome-inactivating proteins (RIPs) and RIP-related lectins generated from multiple genes. These proteins differ in their structure, enzymatic activity and sugar binding specificity. We have purified and characterized ebulin-RP from S. ebulus leaves and determined the amino acid sequence by cDNA cloning. Cytotoxicity was studied in a variety of cancer cells and a comparative study of the ability of ebulin-RP to bind sugars using "in vitro" and "in silico" approaches was performed. Ebulin-RP is a novel heterodimeric type 2 RIP present in S. ebulus leaves together with the type 2 RIP ebulin l, which displayed rRNA N-glycosidase activity but unlike ebulin l, lacked functional sugar binding domains. As a consequence of changes in its B-chain, ebulin-RP displayed lower cytotoxicity than ebulin l towards cancer cells and induced apoptosis as the predominant pattern of cell death. Ebulin-RP is a novel member of the ebulin gene family with low cytotoxicity as a result of deficient sugar binding domains. Type 2 RIP genes from Sambucus have evolved to render proteins with different sugar affinities that may be related to different biological activities and could result in an advantage for the plant. The ebulin family of RIPs and lectins can serve as a good model for studying the evolutionary process which may have occurred in RIPs. The lack of cytotoxicity of ebulin-RP makes it a good candidate as a toxic moiety in the construction of immunotoxins and conjugates directed against specific targets. Copyright © 2017 Elsevier B.V. All rights reserved.

Ablative Hypofractionated Radiation Therapy Enhances Non-Small Cell Lung Cancer Cell Killing via Preferential Stimulation of Necroptosis In Vitro and In Vivo.

PubMed

Wang, Huan-Huan; Wu, Zhi-Qiang; Qian, Dong; Zaorsky, Nicholas G; Qiu, Ming-Han; Cheng, Jing-Jing; Jiang, Chao; Wang, Juan; Zeng, Xian-Liang; Liu, Chun-Lei; Tian, Li-Jun; Ying, Guo-Guang; Meng, Mao-Bin; Hao, Xi-Shan; Yuan, Zhi-Yong

2018-05-01

To investigate how necroptosis (ie, programmed necrosis) is involved in killing of non-small cell lung cancer (NSCLC) after ablative hypofractionated radiation therapy (HFRT). Deoxyribonucleic acid damage, DNA repair, and the death form of NSCLC cells were assessed after radiation therapy. The overexpression and silencing of receptor-interacting protein kinases 3 (RIP3, a key protein involved activation of necroptosis)-stable NSCLC cell lines were successfully constructed. The form of cell death, the number and area of colonies, and the regulatory proteins of necroptosis were characterized after radiation therapy in vitro. Finally, NSCLC xenografts and patient specimens were used to examine involvement of necroptosis after ablative HFRT in vivo. Radiation therapy induced expected DNA damage and repair of NSCLC cell lines, but ablative HFRT at ≥10 Gy per fraction preferentially stimulated necroptosis in NSCLC cells and xenografts with high RIP3 expression, as characterized by induction and activation of RIP3 and mixed-lineage kinase domain-like protein and release of immune-activating chemokine high-mobility group box 1. In contrast, RNA interference of RIP3 attenuated ablative HFRT-induced necroptosis and activation of its regulatory proteins. Among central early-stage NSCLC patients receiving stereotactic body radiation therapy, high expression of RIP3 was associated with improved local control and progression-free survival (all P < .05). Ablative HFRT at ≥10 Gy per fraction enhances killing of NSCLC with high RIP3 expression via preferential stimulation of necroptosis. RIP3 may serve as a useful biomarker to predict favorable response to stereotactic body radiation therapy. Copyright © 2018 Elsevier Inc. All rights reserved.

Introduction to the SPARC Reanalysis Intercomparison Project (S-RIP) and overview of the reanalysis systems

NASA Astrophysics Data System (ADS)

Fujiwara, Masatomo; Wright, Jonathon S.; Manney, Gloria L.; Gray, Lesley J.; Anstey, James; Birner, Thomas; Davis, Sean; Gerber, Edwin P.; Harvey, V. Lynn; Hegglin, Michaela I.; Homeyer, Cameron R.; Knox, John A.; Krüger, Kirstin; Lambert, Alyn; Long, Craig S.; Martineau, Patrick; Molod, Andrea; Monge-Sanz, Beatriz M.; Santee, Michelle L.; Tegtmeier, Susann; Chabrillat, Simon; Tan, David G. H.; Jackson, David R.; Polavarapu, Saroja; Compo, Gilbert P.; Dragani, Rossana; Ebisuzaki, Wesley; Harada, Yayoi; Kobayashi, Chiaki; McCarty, Will; Onogi, Kazutoshi; Pawson, Steven; Simmons, Adrian; Wargan, Krzysztof; Whitaker, Jeffrey S.; Zou, Cheng-Zhi

2017-01-01

The climate research community uses atmospheric reanalysis data sets to understand a wide range of processes and variability in the atmosphere, yet different reanalyses may give very different results for the same diagnostics. The Stratosphere-troposphere Processes And their Role in Climate (SPARC) Reanalysis Intercomparison Project (S-RIP) is a coordinated activity to compare reanalysis data sets using a variety of key diagnostics. The objectives of this project are to identify differences among reanalyses and understand their underlying causes, to provide guidance on appropriate usage of various reanalysis products in scientific studies, particularly those of relevance to SPARC, and to contribute to future improvements in the reanalysis products by establishing collaborative links between reanalysis centres and data users. The project focuses predominantly on differences among reanalyses, although studies that include operational analyses and studies comparing reanalyses with observations are also included when appropriate. The emphasis is on diagnostics of the upper troposphere, stratosphere, and lower mesosphere. This paper summarizes the motivation and goals of the S-RIP activity and extensively reviews key technical aspects of the reanalysis data sets that are the focus of this activity. The special issue The SPARC Reanalysis Intercomparison Project (S-RIP) in this journal serves to collect research with relevance to the S-RIP in preparation for the publication of the planned two (interim and full) S-RIP reports.

Drug dealers' rational choices on which customers to rip-off.

PubMed

Jacques, Scott; Allen, Andrea; Wright, Richard

2014-03-01

Drug dealers are infamous for overcharging customers and handing over less than owed. One reason rip-offs frequently occur is blackmarket participants have limited access to formal means of dispute resolution and, as such, are attractive prey. Yet drug dealers do not cheat every customer. Though this is implicitly understood in the literature, sparse theoretical attention has been given to which customers are ripped-off and why. To address that lacuna, this paper uses the rationality perspective to analyze qualitative data obtained in interviews with 25 unincarcerated drug sellers operating in disadvantaged neighborhoods of St. Louis, Missouri. We find that dealers typically rip-off six types of customers: persons who are strangers, first-time or irregular customers; do not have sufficient money on hand to make a purchase; are uninformed about going market rates; are deemed unlikely to retaliate; are offensive; or are addicted to drugs. Dealers target these groups due to perceiving them as unlikely to be repeat business; not worth the hassle of doing business with; unlikely to realize they are being ripped-off; in the wrong and thus deserving of payback; and, unwilling to retaliate or take their money elsewhere. Our findings are discussed in relation to their practical implications, including the importance of giving blackmarket participants greater access to law, and how customers may prevent being ripped-off. Copyright © 2013 Elsevier B.V. All rights reserved.

ITCH directly K63-ubiquitinates the NOD2 binding protein, RIP2, to influence inflammatory signaling pathways

PubMed Central

Tao, MingFang; Scacheri, Peter C.; Marinis, Jill M.; Harhaj, Edward W.; Matesic, Lydia E.; Abbott, Derek W.

2009-01-01

Background: The inability to coordinate the signaling pathways that lead to proper cytokine responses characterizes the pathogenesis of inflammatory diseases such as Crohn's Disease. The Crohn's Disease susceptibility protein, NOD2, helps coordinate cytokine responses upon intracellular exposure to bacteria, and this signal coordination by NOD2 is accomplished, in part, through K63-linked polyubiquitin chains that create binding surfaces for the scaffolding of signaling complexes. Results: In this work, we show that the NOD2 signaling partner, RIP2, is directly K63 polyubiquitinated by ITCH, an E3 ubiquitin ligase which when lost genetically, causes widespread inflammatory disease at mucosal surfaces. We show that ITCH is responsible for RIP2 polyubiquitination in response to infection with listeria monocytogenes. We further show that NOD2 can bind polyubiquitinated RIP2, and while ITCH E3 ligase activity is required for optimal NOD2:RIP2-induced p38 and JNK activation, ITCH inhibits NOD2:RIP2-induced NFκB activation. This effect can be seen independently at the whole genome level by microarray analysis of MDP-treated Itch−/− primary macrophages. Conclusions: These findings suggest that ITCH helps regulate NOD2-dependent signal transduction pathways and as such, may be involved in the pathogenesis of NOD2-mediated inflammatory disease. PMID:19592251

Expression of nuclear receptor interacting proteins TIF-1, SUG-1, receptor interacting protein 140, and corepressor SMRT in tamoxifen-resistant breast cancer.

PubMed

Chan, C M; Lykkesfeldt, A E; Parker, M G; Dowsett, M

1999-11-01

Regulation of gene transcription as a consequence of steroid receptor-DNA interaction is mediated via nuclear receptor interacting proteins (RIPs), including coactivator or corepressor proteins, which interact with both the receptor and components of the basic transcriptional unit and vary between cell types. The aim of this study was to test the hypothesis that resistance of some breast carcinomas to tamoxifen was associated with inappropriate expression of some of these RIPs. Using Northern analysis, we observed no significant difference between the amount of either TIF-1 or SUG-1 mRNA expressed in parental MCF-7 and MCF-7 tamoxifen-resistant cell lines. However, the expression of RIP140 mRNA was lower in the resistant cell line and in the presence of estradiol, the level of RIP140 mRNA was higher in the resistant cells but not in the parental cells. In a cohort of 19 tamoxifen-resistant breast tumor samples, there was no significant difference in the level of the RIP140 and TIF-1 and corepressor SMRT mRNA compared with tamoxifen-treated tumors (n = 6) or untreated tumors (n = 21). However, SUG-1 mRNA was lower in resistant breast tumors. These data provide no support for increased expression of these RIPs or decreased expression of corepressor SMRT for being a mechanism for resistance of breast tumors to tamoxifen.

RIP3 AND pMLKL promote necroptosis-induced inflammation and alter membrane permeability in intestinal epithelial cells.

PubMed

Negroni, Anna; Colantoni, Eleonora; Pierdomenico, Maria; Palone, Francesca; Costanzo, Manuela; Oliva, Salvatore; Tiberti, Antonio; Cucchiara, Salvatore; Stronati, Laura

2017-11-01

Necroptosis is an inflammatory form of programmed cell death requiring receptor-interacting protein kinase 3 (RIP3) and mixed lineage kinase domain-like protein (MLKL). The aim of this study is to examine in depth in vitro and ex vivo the contribution of necroptosis to intestinal inflammation. In vitro: we used an intestinal cell line, HCT116RIP3, produced in our laboratory and overexpressing RIP3. Ex vivo: intestinal mucosal biopsies were taken from patients with inflammatory bowel disease (IBD) (20 with Crohn's disease; 20 with ulcerative colitis) and from 20 controls. RIP3-induced necroptosis triggers MLKL activation, increases cytokine/alarmin expression (IL-8, IL-1β, IL-33, HMGB1), NF-kBp65 translocation and NALP3 inflammasome assembly. It also affects membrane permeability by altering cell-cell junctional proteins (E-cadherin, Occludin, Zonulin-1). Targeting necroptosis through Necrostatin-1 significantly reduces intestinal inflammation in vitro and in cultured intestinal explants from IBD. We show for the first time in vitro and ex vivo that RIP3-driven necroptosis seriously affects intestinal inflammation by increasing pMLKL, activating different cytokines and alarmins, and altering epithelial permeability. The inhibition of necroptosis causes a significant decrease of all these effects. These data strongly support the view that targeting necroptosis may represent a promising new option for the treatment of inflammatory enteropathies. Copyright © 2017. Published by Elsevier Ltd.

The role of RIP3 mediated necroptosis in ouabain-induced spiral ganglion neurons injuries.

PubMed

Wang, Xi; Wang, Ye; Ding, Zhong-jia; Yue, Bo; Zhang, Peng-zhi; Chen, Xiao-dong; Chen, Xin; Chen, Jun; Chen, Fu-quan; Chen, Yang; Wang, Ren-feng; Mi, Wen-juan; Lin, Ying; Wang, Jie; Qiu, Jian-hua

2014-08-22

Spiral ganglion neuron (SGN) injury is a generally accepted precursor of auditory neuropathy. Receptor-interacting protein 3 (RIP3) has been reported as an important necroptosis pathway mediator that can be blocked by necrostatin-1 (Nec-1). In our study, we sought to identify whether necroptosis participated in SGN injury. Ouabain was applied to establish an SGN injury model. We measured the auditory brain-stem response (ABR) threshold shift as an indicator of the auditory conditions. Positive β3-tubulin immunofluorescence staining indicated the surviving SGNs. RIP3 expression was evaluated using immunofluorescence, quantitative real-time polymerase chain reaction and western blot. SGN injury promoted an increase in RIP3 expression that could be suppressed by application of the necroptosis inhibitor Nec-1. A decreased ABR threshold shift and increased SGN density were observed when Nec-1 was administered with apoptosis inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD). These results demonstrated that necroptosis is an indispensable pathway separately from apoptosis leading to SGN death pathway, in which RIP3 plays an important role. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

The little sibling of the big rip singularity

NASA Astrophysics Data System (ADS)

Bouhmadi-López, Mariam; Errahmani, Ahmed; Martín-Moruno, Prado; Ouali, Taoufik; Tavakoli, Yaser

2015-07-01

In this paper, we present a new cosmological event, which we named the little sibling of the big rip. This event is much smoother than the big rip singularity. When the little sibling of the big rip is reached, the Hubble rate and the scale factor blow up, but the cosmic derivative of the Hubble rate does not. This abrupt event takes place at an infinite cosmic time where the scalar curvature explodes. We show that a doomsday à la little sibling of the big rip is compatible with an accelerating universe, indeed at present it would mimic perfectly a ΛCDM scenario. It turns out that, even though the event seems to be harmless as it takes place in the infinite future, the bound structures in the universe would be unavoidably destroyed on a finite cosmic time from now. The model can be motivated by considering that the weak energy condition should not be strongly violated in our universe, and it could give us some hints about the status of recently formulated nonlinear energy conditions.

Mice Lacking RIP3 Kinase are not Protected from Acute Radiation Syndrome.

PubMed

Castle, Katherine D; Daniel, Andrea R; Moding, Everett J; Luo, Lixia; Lee, Chang-Lung; Kirsch, David G

2018-06-01

Exposure to high doses of ionizing radiation can cause lethal injury to normal tissue, thus inducing acute radiation syndrome. Acute radiation syndrome is caused by depletion of bone marrow cells (hematopoietic syndrome) and irreparable damage to the epithelial cells in the gastrointestinal tract (gastrointestinal syndrome). Although radiation initiates apoptosis in the hematopoietic and gastrointestinal compartments within the first few hours after exposure, alternative mechanisms of cell death may contribute to injury in these radiosensitive tissues. In this study, we utilized mice lacking a critical regulator of necroptosis, receptor interacting protein 3 (RIP3) kinase, to characterize the role of RIP3 in normal tissue toxicity after irradiation. Our results suggest that RIP3-mediated signaling is not a critical driver of acute radiation syndrome.

RNA-binding Protein Immunoprecipitation (RIP) to Examine AUF1 Binding to Senescence-Associated Secretory Phenotype (SASP) Factor mRNA

PubMed Central

Alspach, Elise; Stewart, Sheila A.

2016-01-01

Immunoprecipitation and subsequent isolation of nucleic acids allows for the investigation of protein:nucleic acid interactions. RNA-binding protein immunoprecipitation (RIP) is used for the analysis of protein interactions with mRNA. Combining RIP with quantitative real-time PCR (qRT-PCR) further enhances the RIP technique by allowing for the quantitative assessment of RNA-binding protein interactions with their target mRNAs, and how these interactions change in different cellular settings. Here, we describe the immunoprecipitation of the RNA-binding protein AUF1 with several different factors associated with the senescence-associated secretory phenotype (SASP) (Alspach and Stewart, 2013), specifically IL6 and IL8. This protocol was originally published in Alspach et al. (2014). PMID:27453911

HIV-1 early and late diagnosis in the Emilia Romagna Region (Italy): a three year study.

PubMed

Musumeci, Giuseppina; Magnani, Giacomo; Bon, Isabella; Longo, Serena; Bertoldi, Alessia; Degli Antoni, Anna Maria; Rossi, Maria Rita; Ruggeri, Alessandro; Sambri, Vittorio; Semprini, Simona; Sighinolfi, Laura; Ursitti, Maria Alessandra; Zerbini, Alessandro; Colangeli, Vincenzo; Calza, Leonardo; Finarelli, Alba Carola; Massimiliani, Erika; Re, Maria Carla

2016-10-01

It is crucial to establish the timing of infection and distinguish between early and long-lasting HIV-1 infections not only for partner notification and epidemiological surveillance, but also to offer early drug treatment and contain the spread of infection. This study analyzed serum and/or plasma samples with a first positive HIV antibody/antigen result coming from different Medical Centers in the Emilia Romagna Region, North East Italy, using the avidity assay, Western Blotting, RNA viral load, CD4 cell counts and genotyping assay. From May 2013 to May 2016, we certified 845 new HIV-1 infections, 18.7% of which were classified on the basis of avidity index as recent infections and 81.3% as long-lasting infections, with an estimated conversion time exceeding six months at the time of study. Western Blotting showed reactivity to only one or two HIV-1 proteins in recently infected patients (RIPs), while a complete pattern to gag, env and pol proteins was observed in most long-lasting infected patients (LLIPs). The median age, gender, nationality and risk transmission factors were comparable in RIPs and LLIPs. Phylogenetic analysis performed in available plasma disclosed B strains, non-B subtypes and circulating recombinant forms (CRFs) in both groups of patients, with a major presence of CRFs in non-Italian HIV subjects. The large number of patients unaware of their HIV status makes it crucial to discover hidden epidemics and implement appropriate targeted public health interventions.

Activation of concurrent apoptosis and necroptosis by SMAC mimetics for the treatment of refractory and relapsed ALL.

PubMed

McComb, Scott; Aguadé-Gorgorió, Júlia; Harder, Lena; Marovca, Blerim; Cario, Gunnar; Eckert, Cornelia; Schrappe, Martin; Stanulla, Martin; von Stackelberg, Arend; Bourquin, Jean-Pierre; Bornhauser, Beat C

2016-05-18

More precise treatment strategies are urgently needed to decrease toxicity and improve outcomes for treatment-refractory leukemia. We used ex vivo drug response profiling of high-risk, relapsed, or refractory acute lymphoblastic leukemia (ALL) cases and identified a subset with exquisite sensitivity to small-molecule mimetics of the second mitochondria-derived activator of caspases (SMAC) protein. Potent ex vivo activity of the SMAC mimetic (SM) birinapant correlated with marked in vivo antileukemic effects, as indicated by delayed engraftment, decreased leukemia burden, and prolonged survival of xenografted mice. Antileukemic activity was dependent on simultaneous execution of apoptosis and necroptosis, as demonstrated by functional genomic dissection with a multicolored lentiCRISPR approach to simultaneously disrupt multiple genes in patient-derived ALL. SM specifically targeted receptor-interacting protein kinase 1 (RIP1)-dependent death, and CRISPR-mediated disruption of RIP1 completely blocked SM-induced death yet had no impact on the response to standard antileukemic agents. Thus, SM compounds such as birinapant circumvent escape from apoptosis in leukemia by activating a potent dual RIP1-dependent apoptotic and necroptotic cell death, which is not exploited by current therapy. Ex vivo drug activity profiling could provide important functional diagnostic information to identify patients who may benefit from targeted treatment with birinapant in early clinical trials. Copyright © 2016, American Association for the Advancement of Science.

Scientific governance and the process for exposure scenario development in REACH.

PubMed

Money, Chris D; Van Hemmen, Joop J; Vermeire, Theo G

2007-12-01

The primary process established by the European Commission to address the science needed to define key REACH concepts and to help rationally implement REACH's ambitions is enshrined in a series of activities known as the REACH Implementation Projects (RIPs). These are projects that aim to define the methodology that could be used, and present the basis for guidance on the actual principles and procedures that may be (are proposed to be) followed in the development of the required documentation that ensures the safe use of chemicals. In order to develop soundly based and equitable regulation, it is necessary that science governance using established and accepted scientific principles must take a leading role. The extent to which such governance is embraced will be determined by many factors, but notably the process adopted to enable scientific discussion to take place. This article addresses the issues of science as they have impacted on the exemplification of the Exposure Scenario concept under REACH. The current RIP activities have created a non-adversarial process in which the key stakeholders are able to discuss the key REACH challenges. But the RIP activities will be finalised before REACH comes into force. A suitable mechanism should perhaps now be identified to ensure that this positive spirit of scientific discussion and collaboration can continue to benefit REACH and those that it serves well into the future.

Effects of Body Orientation and Retinal Image Pitch on the Perception of Gravity-Referenced Eye Level (GREL)

NASA Technical Reports Server (NTRS)

Cohen, Malcolm M.; Guzy, Larry T.; Wade, Charles E. (Technical Monitor)

1994-01-01

It has been asserted that the pitch orientation of a visual array and of an observer's body jointly determine the perception of GREL. The current study formally tests this assertion over an extended range with multiple combinations of visual and body pitch orientations. Ten subjects were individually secured in a Circolectric bed surrounded by a room (pitchroom) with walls that could be pitched at various angles with respect to gravity. The bed and the walls of the room were independently adjusted to each of five positions relative to gravitational vertical: -15, -7.5, 0, +7.5, and +15 degrees, yielding 25 combinations of body x room pitch angles, and retinal image pitch (RIP) conditions ranging from -30 to +30 degrees. Each subject set a target to apparent GREL while viewing it against a background of two electroluminescent strips on the outer edges of the far wall of the room. As determined by ANOVA, the orientation of the room, and its interaction with that of the observer, significantly altered GREL (p less than 0.01). Regression analysis showed that GREL was best described as a linear summation of the weighted independent contributions from a body-referenced mechanism (B) and a visual mechanism given by the orientation of the background array on the retina (RIP). The equation for this relationship is: GREL = .74 (B) +.64 (RIP) - 1.42; r-squared = .994.

Reducing the age range of tsunami deposits by 14C dating of rip-up clasts

NASA Astrophysics Data System (ADS)

Ishizawa, Takashi; Goto, Kazuhisa; Yokoyama, Yusuke; Miyairi, Yosuke; Sawada, Chikako; Takada, Keita

2018-02-01

Erosion by tsunami waves represents an important issue when determining the age of a tsunami deposit, because the age is usually estimated using dating of sediments above and below the deposit. Dating of material within the tsunami deposit, if suitable material is obtainable, can be used to further constrain its age. Eroded sediments are sometimes incorporated within the tsunami deposits as rip-up clasts, which might therefore be used as minimum age dating material. However, the single calibrated 14C age often shows a wide age range because of fluctuations in the calibration curve. Therefore, it remains uncertain whether rip-up clast measurements are useful to constrain the depositional age of tsunami deposits, or not. In this study, we carried out high-resolution 14C dating of tsunami deposits, including rip-up clasts of peat, in Rikuzentakata, northeastern Japan, where numerous rip-up clasts were observed within a tsunami deposit. Sediments above and below the tsunami deposit and a 5 cm large rip-up clast were dated sequentially. Comparison of these dating results with the calibration curve revealed that the clast was inverted. Its age was better constrained based on the stratigraphic order, and we infer that the clast corresponds to approximately 100 years of sedimentation. The oldest age of the clast was consistent with the age of the peat immediately below the tsunami deposit, suggesting that surface sediments probably formed the rip-up clast at the time of the tsunami. Thus, the dating of the rip-up clast was useful to further constrain the depositional age of the tsunami deposit, as we narrowed the tsunami deposit age range by approximately 100 years. Results show that ignoring tsunami-related erosion might lead to overestimation of the tsunami deposit age. For this reason, an appropriate dating site, which is less affected by minor tsunami-related erosion with regards to the paleo-topography, should be explored. We therefore propose a more effective sampling strategy for better age estimation of tsunami deposits.

Simultaneous induction of apoptosis and necroptosis by Tanshinone IIA in human hepatocellular carcinoma HepG2 cells.

PubMed

Lin, C-Y; Chang, T-W; Hsieh, W-H; Hung, M-C; Lin, I-H; Lai, S-C; Tzeng, Y-J

Tanshinone IIA (Tan IIA), a constituent of the traditional medicinal plant Salvia miltiorrhiza BUNGE, has been reported to possess anticancer activity through induction of apoptosis in many cancer cells. Surprisingly, the present study finds that Tan IIA simultaneously causes apoptosis and necroptosis in human hepatocellular carcinoma HepG2 cells. We further find that apoptosis can be converted to necroptosis by pan-caspase inhibitor Z-VAD-fmk, and the two death modes can be blocked by necroptotic inhibitor necrostatin-1. The underlying mechanisms are revealed by analysis of the signaling molecules using western blotting. In control cells, FLICE inhibitory protein in short form (FLIP S ) is expressed in relatively high levels and binds to caspase 8 in ripoptosome, which supposedly sustains cell survival. However, in Tan IIA-treated cells, FLIP S is down-regulated and may thus cause homodimer formation of cleaved caspase 8, cleavage of receptor-interacting serine/threonine-protein kinases 1, 3 (RIP1, RIP3), and mixed-lineage kinase domain-like (MLKL), in turn leads to cell apoptosis. In parallel, Tan IIA causes necroptosis by forming a suggested necrosomal complex composed of RIP1/RIP3. Regarding the inhibitors, z-VAD-fmk diminishes the cleaved caspase 8, RIP1, RIP3, and MLKL induced by Tan IIA, and reconstructs the ripoptosome complex, which marks cells moving from apoptosis to necroptosis. Nec-1 recovers the Tan IIA down-regulated FLIP S , consequently causes FLIP S to form heterodimer with caspase 8 and thus block apoptosis. Meanwhile, cleaved forms of RIP1 and RIP3 were observed preventing necroptosis. Intriguingly, the cytotoxicity of tumor necrosis factor-related apoptosis-inducing ligand to HepG2 cells is enhanced by Tan IIA in a pilot study, which may be attributed to low FLIP S levels induced by Tan IIA. In short, Tan IIA simultaneously induces both Nec-1 inhibition and FLIP S regulation-mediated apoptosis/necroptosis, which has not been previously documented. Moreover, the involvement of the cleavage type of MLKL in executing necroptosis warrants further investigation.

RIP1 maintains DNA integrity and cell proliferation by regulating PGC-1α-mediated mitochondrial oxidative phosphorylation and glycolysis.

PubMed

Chen, W; Wang, Q; Bai, L; Chen, W; Wang, X; Tellez, C S; Leng, S; Padilla, M T; Nyunoya, T; Belinsky, S A; Lin, Y

2014-07-01

Aerobic glycolysis or the Warburg effect contributes to cancer cell proliferation; however, how this glucose metabolism pathway is precisely regulated remains elusive. Here we show that receptor-interacting protein 1 (RIP1), a cell death and survival signaling factor, regulates mitochondrial oxidative phosphorylation and aerobic glycolysis. Loss of RIP1 in lung cancer cells suppressed peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression, impairing mitochondrial oxidative phosphorylation and accelerating glycolysis, resulting in spontaneous DNA damage and p53-mediated cell proliferation inhibition. Thus, although aerobic glycolysis within a certain range favors cancer cell proliferation, excessive glycolysis causes cytostasis. Our data suggest that maintenance of glycolysis by RIP1 is pivotal to cancer cell energy homeostasis and DNA integrity and may be exploited for use in anticancer therapy.

Enzymatic specificity of three ribosome-inactivating proteins against fungal ribosomes, and correlation with antifungal activity.

PubMed

Park, Sang-Wook; Stevens, Noah M; Vivanco, Jorge M

2002-12-01

Ribosome-inactivating proteins (RIPs) are enzymes that cleave a specific adenine base from the highly conserved sarcin/ricin (S/R) loop of the large ribosomal RNA, thus arresting protein synthesis at the translocation step. In the present study, we employed three RIPs to dissect the antifungal activity of RIPs as plant defense proteins. We measured the catalytic activity of RAT (the catalytic A-chain of ricin from Ricinus communis L.), saporin-S6 (from Saponaria officinalis L.), and ME (RIP from Mirabilis expansa R&P) against intact ribosomal substrates isolated from various pathogenic fungi. We further determined the enzymatic specificity of these three RIPs against fungal ribosomes, from Rhizoctonia solani Kuhn, Alternaria solani Sorauer, Trichoderma reesei Simmons and Candida albicans Berkhout, and correlated the data with antifungal activity. RAT showed the strongest toxicity against all tested fungal ribosomes, except for the ribosomes isolated from C. albicans, which were most susceptible to saporin. RAT and saporin showed higher enzymatic activity than ME against ribosomes from all of the fungal species assayed, but did not show detectable antifungal activity. In contrast, ME showed substantial inhibitory activity against fungal growth. Using N-hydroxysuccinimide-fluorescein labeling of RIPs and fluorescence microscopy, we determined that ME was targeted to the surface of fungal cells and transferred into the cells. Thus, ME caused ribosome depurination and subsequent fungal mortality. In contrast, saporin did not interact with fungal cells, correlating with its lack of antifungal activity.

Dual Inhibition of Rip2 and IRAK1/4 Regulates IL-1β and IL-6 in Sarcoidosis Alveolar Macrophages and Peripheral Blood Mononuclear Cells

PubMed Central

Talreja, Jaya; Talwar, Harvinder; Ahmad, Nisar; Rastogi, Ruchi; Samavati, Lobelia

2016-01-01

Sarcoidosis is a multisystem granulomatous disease of unknown etiology that primarily affects the lungs. Our previous work indicates that activation of p38 plays a pivotal role in sarcoidosis inflammatory response. Therefore, we investigated the upstream kinase responsible for activation of p38 in sarcoidosis alveolar macrophages (AMs) and peripheral mononuclear cells (PBMCs). We identified that sustained p38 phosphorylation in sarcoidosis AMs and PBMCs is associated with active MKK4 but not with MKK3/6. Additionally, we found that sarcoidosis AMs exhibit a higher expression of IRAK1, IRAK-M and Rip2. Surprisingly, ex vivo treatment of sarcoidosis AMs or PBMCs with IRAK1/4 inhibitor led to a significant increase in IL-1β mRNA expression both spontaneously and in response to TLR2 ligand. However, a combination of Rip2 and IRAK-1/4 inhibitors significantly decreased both IL-1β and IL-6 production in sarcoidosis PBMCs and moderately in AMs. Importantly, a combination of Rip2 and IRAK-1/4 inhibitors led to decreased IFN-γ and IL-6, and decreased percentage of activated CD4+CD25+ cells in PBMCs. These data suggest that in sarcoidosis both pathways, namely IRAK and Rip2 are deregulated. Targeted modulation of Rip2 and IRAK pathways may prove to be a novel treatment for sarcoidosis. PMID:27402699

Identification of RIP-II toxins by affinity enrichment, enzymatic digestion and LC-MS.

PubMed

Fredriksson, Sten-Åke; Artursson, Elisabet; Bergström, Tomas; Östin, Anders; Nilsson, Calle; Åstot, Crister

2015-01-20

Type 2 ribosome-inactivating protein toxins (RIP-II toxins) were enriched and purified prior to enzymatic digestion and LC-MS analysis. The enrichment of the RIP-II family of plant proteins, such as ricin, abrin, viscumin, and volkensin was based on their affinity for galactosyl moieties. A macroporous chromatographic material was modified with a galactose-terminated substituent and packed into miniaturized columns that were used in a chromatographic system to achieve up to 1000-fold toxin enrichment. The galactose affinity of the RIP-II proteins enabled their selective enrichment from water, beverages, and extracts of powder and wipe samples. The enriched fractions were digested with trypsin and RIP-II peptides were identified based on accurate mass LC-MS data. Their identities were unambiguously confirmed by LC-MS/MS product ion scans of peptides unique to each of the toxins. The LC-MS detection limit achieved for ricin target peptides was 10 amol and the corresponding detection limit for the full method was 10 fmol/mL (0.6 ng/mL). The affinity enrichment method was applied to samples from a forensic investigation into a case involving the illegal production of ricin and abrin toxins.

Prevention of autoimmune diabetes and islet allograft rejection by beta cell expression of XIAP: Insight into possible mechanisms of local immunomodulation.

PubMed

Obach, Mercè; Hosseini-Tabatabaei, Azadeh; Montane, Joel; Wind, Katarina; Soukhatcheva, Galina; Dai, Derek; Priatel, John J; Orban, Paul C; Verchere, C Bruce

2018-06-05

Overexpression of the X-linked inhibitor of apoptosis (XIAP) prevents islet allograft rejection. We constructed an adeno-associated virus expressing XIAP driven by the rat insulin promoter (dsAAV8-RIP-XIAP) for long-term beta-cell gene expression in vivo. Pancreatic delivery of dsAAV8-RIP-XIAP prevented autoimmune diabetes in 70% of non-obese diabetic (NOD) mice, associated with decreased insulitis. Islets from Balb/c mice transduced with dsAAV8-RIP-XIAP were protected following transplantation into streptozotocin (STZ)-diabetic Bl/6 recipients, associated with decreased graft infiltration. Interestingly, dsAAV8-RIP-XIAP transduction induced expression of lactate dehydrogenase (LDHA) and monocarboxylate transporter 1 (MCT1), two genes normally suppressed in beta cells and involved in production and release of lactate, a metabolite known to suppress local immune responses. Transduction of Balb/c islets with AAV8-RIP-LDHA-MCT1 tended to prolong allograft survival following transplant into STZ-diabetic Bl/6 recipients. These findings suggest that XIAP has therapeutic potential in autoimmune diabetes and raise the possibility that local lactate production may play a role in XIAP-mediated immunomodulation. Copyright © 2018. Published by Elsevier B.V.

Lysine Methylation of Nuclear Co-repressor Receptor Interacting Protein 140

PubMed Central

Huq, MD Mostaqul; Ha, Sung Gil; Barcelona, Helene; Wei, Li-Na

2009-01-01

Receptor interacting protein 140 (RIP140) undergoes extensive posttranslational modifications (PTMs), including phosphorylation, acetylation, arginine methylation, and pyridoxylation. PTMs affect its sub-cellular distribution, protein-protein interaction, and biological activity in adipocyte differentiation. Arginine methylation on Arg240, Arg650, and Arg948 suppresses the repressive activity of RIP140. Here we find that endogenous RIP140 in differentiated 3T3-L1 cells is also modified by lysine methylation. Three lysine residues, Lys591, Lys653, and Lys757 are mapped as potential methylation sites by mass spectrometry. Site-directed mutagenesis study shows that lysine methylation enhances its gene repressive activity. Mutation of lysine methylation sites enhances arginine methylation, while mutation on arginine methylation sites has little effect on its lysine methylation, suggesting a relationship between lysine methylation and arginine methylation. Kinetic analysis of PTMs of endogenous RIP140 in differentiated 3T3-L1 cells demonstrates sequential modifications on RIP140, initiated from constitutive lysine methylation, followed by increased arginine methylation later in differentiation. This study reveals a potential hierarchy of modifications, at least for lysine and arginine methylation, which bi-directionally regulate the functionality of a non-histone protein. PMID:19216533

Akt Regulates TNFα Synthesis Downstream of RIP1 Kinase Activation during Necroptosis

PubMed Central

McNamara, Colleen R.; Ahuja, Ruchita; Osafo-Addo, Awo D.; Barrows, Douglas; Kettenbach, Arminja; Skidan, Igor; Teng, Xin; Cuny, Gregory D.; Gerber, Scott; Degterev, Alexei

2013-01-01

Necroptosis is a regulated form of necrotic cell death that has been implicated in the pathogenesis of various diseases including intestinal inflammation and systemic inflammatory response syndrome (SIRS). In this work, we investigated the signaling mechanisms controlled by the necroptosis mediator receptor interacting protein-1 (RIP1) kinase. We show that Akt kinase activity is critical for necroptosis in L929 cells and plays a key role in TNFα production. During necroptosis, Akt is activated in a RIP1 dependent fashion through its phosphorylation on Thr308. In L929 cells, this activation requires independent signaling inputs from both growth factors and RIP1. Akt controls necroptosis through downstream targeting of mammalian Target of Rapamycin complex 1 (mTORC1). Akt activity, mediated in part through mTORC1, links RIP1 to JNK activation and autocrine production of TNFα. In other cell types, such as mouse lung fibroblasts and macrophages, Akt exhibited control over necroptosis-associated TNFα production without contributing to cell death. Overall, our results provide new insights into the mechanism of necroptosis and the role of Akt kinase in both cell death and inflammatory regulation. PMID:23469174

Therapeutic Benefit of Selective Inhibition of p110α PI3-Kinase in Pancreatic Neuroendocrine Tumors.

PubMed

Soler, Adriana; Figueiredo, Ana M; Castel, Pau; Martin, Laura; Monelli, Erika; Angulo-Urarte, Ana; Milà-Guasch, Maria; Viñals, Francesc; Baselga, Jose; Casanovas, Oriol; Graupera, Mariona

2016-12-01

Mutations in the PI3K pathway occur in 16% of patients with pancreatic neuroendocrine tumors (PanNETs), which suggests that these tumors are an exciting setting for PI3K/AKT/mTOR pharmacologic intervention. Everolimus, an mTOR inhibitor, is being used to treat patients with advanced PanNETs. However, resistance to mTOR-targeted therapy is emerging partially due to the loss of mTOR-dependent feedback inhibition of AKT. In contrast, the response to PI3K inhibitors in PanNETs is unknown. In the current study, we assessed the frequency of PI3K pathway activation in human PanNETs and in RIP1-Tag2 mice, a preclinical tumor model of PanNETs, and we investigated the therapeutic efficacy of inhibiting PI3K in RIP1-Tag2 mice using a combination of pan (GDC-0941) and p110α-selective (GDC-0326) inhibitors and isoform-specific PI3K kinase-dead-mutant mice. Human and mouse PanNETs showed enhanced pAKT, pPRAS40, and pS6 positivity compared with normal tissue. Although treatment of RIP1-Tag2 mice with GDC-0941 led to reduced tumor growth with no impact on tumor vessels, the selective inactivation of the p110α PI3K isoform, either genetically or pharmacologically, reduced tumor growth as well as vascular area. Furthermore, GDC-0326 reduced the incidence of liver and lymph node metastasis compared with vehicle-treated mice. We also demonstrated that tumor and stromal cells are implicated in the antitumor activity of GDC-0326 in RIP1-Tag2 tumors. Our data provide a rationale for p110α-selective intervention in PanNETs and unravel a new function of this kinase in cancer biology through its role in promoting metastasis. Clin Cancer Res; 22(23); 5805-17. ©2016 AACR. ©2016 American Association for Cancer Research.

Rips, Currents and Snags: Investigating the Delivery of Educational Goals for Young Australians in the Region of Gippsland, Victoria

ERIC Educational Resources Information Center

Lynch, Timothy

2012-01-01

Monash University (Gippsland campus) is situated in Churchill, Latrobe Valley, located in central Gippsland, eastern Victoria. A large percentage of the Gippsland region comprises of a socio-economically disadvantaged population (Figure 1). In Semester One, 2011 as part of the Bachelor of Primary Education course at Monash, it was decided that a…

A hierarchical model for clustering m(6)A methylation peaks in MeRIP-seq data.

PubMed

Cui, Xiaodong; Meng, Jia; Zhang, Shaowu; Rao, Manjeet K; Chen, Yidong; Huang, Yufei

2016-08-22

The recent advent of the state-of-art high throughput sequencing technology, known as Methylated RNA Immunoprecipitation combined with RNA sequencing (MeRIP-seq) revolutionizes the area of mRNA epigenetics and enables the biologists and biomedical researchers to have a global view of N (6)-Methyladenosine (m(6)A) on transcriptome. Yet there is a significant need for new computation tools for processing and analysing MeRIP-Seq data to gain a further insight into the function and m(6)A mRNA methylation. We developed a novel algorithm and an open source R package ( http://compgenomics.utsa.edu/metcluster ) for uncovering the potential types of m(6)A methylation by clustering the degree of m(6)A methylation peaks in MeRIP-Seq data. This algorithm utilizes a hierarchical graphical model to model the reads account variance and the underlying clusters of the methylation peaks. Rigorous statistical inference is performed to estimate the model parameter and detect the number of clusters. MeTCluster is evaluated on both simulated and real MeRIP-seq datasets and the results demonstrate its high accuracy in characterizing the clusters of methylation peaks. Our algorithm was applied to two different sets of real MeRIP-seq datasets and reveals a novel pattern that methylation peaks with less peak enrichment tend to clustered in the 5' end of both in both mRNAs and lncRNAs, whereas those with higher peak enrichment are more likely to be distributed in CDS and towards the 3'end of mRNAs and lncRNAs. This result might suggest that m(6)A's functions could be location specific. In this paper, a novel hierarchical graphical model based algorithm was developed for clustering the enrichment of methylation peaks in MeRIP-seq data. MeTCluster is written in R and is publicly available.

Evaluation of soil manipulation to prepare engineered earthen waste covers for revegetation

DOE PAGES

Waugh, W. Joseph; Benson, Craig H.; Albright, William H.; ...

2015-10-21

Seven ripping treatments designed to improve soil physical conditions for revegetation were compared on a test pad simulating an earthen cover for a waste disposal cell. The field test was part of study of methods to convert compacted-soil waste covers into evapotranspiration covers. The test pad consisted of a compacted layer of fine-textured soil simulating a barrier protection layer overlain by a gravelly sand bedding layer and a cobble armor layer. Treatments included combinations of soil-ripping implements (conventional shank [CS], wing-tipped shank [WTS], and parabolic oscillating shank with wings [POS]), ripping depths, and number of passes. Dimensions, dry density, moisturemore » content, and particle size distribution of disturbance zones were determined in two trenches excavated across rip rows. The goal was to create a root-zone dry density between 1.2 and 1.6 Mg m-3 and a seedbed soil texture ranging from clay loam to sandy loam with low rock content. All treatments created V-shaped disturbance zones as measured on trench faces. Disturbance zone size was most influenced by ripping depth. Winged implements created larger disturbance zones. All treatments lifted fines into the bedding layer, moved gravel and cobble down into the fine-textured protection layer, and thereby disrupted the capillary barrier at the interface. Changes in dry density within disturbance zones were comparable for the CS and WTS treatments but were highly variable among POS treatments. Water content increased in the bedding layer and decreased in the protection layer after ripping. The POS at 1.2-m depth and two passes created the largest zone with a low dry density (1.24 Mg m-3) and the most favorable seedbed soil texture (gravely silt loam). Furthermore, ripping also created large soil aggregates and voids in the protection layer that may produce preferential flow paths and reduce water storage capacity.« less

RipA, a Cytoplasmic Membrane Protein Conserved among Francisella Species, Is Required for Intracellular Survival▿

PubMed Central

Fuller, James R.; Craven, Robin R.; Hall, Joshua D.; Kijek, Todd M.; Taft-Benz, Sharon; Kawula, Thomas H.

2008-01-01

Francisella tularensis is a highly virulent bacterial pathogen that invades and replicates within numerous host cell types, including macrophages and epithelial cells. In an effort to better understand this process, we screened a transposon insertion library of the F. tularensis live vaccine strain (LVS) for mutant strains that invaded but failed to replicate within alveolar epithelial cell lines. One such strain isolated from this screen contained an insertion in the gene FTL_1914, which is conserved among all sequenced Francisella species yet lacks significant homology to any gene with known function. A deletion strain lacking FTL_1914 was constructed. This strain did not replicate in either epithelial or macrophage-like cells, and intracellular replication was restored by the wild-type allele in trans. Based on the deletion mutant phenotype, FTL_1914 was termed ripA (required for intracellular proliferation, factor A). Following uptake by J774.A1 cells, F. tularensis LVS ΔripA colocalized with LAMP-1 then escaped the phagosome at the same rate and frequency as wild-type LVS-infected cells. Electron micrographs of the F. tularensis LVS ΔripA mutant demonstrated the reentry of the mutant bacteria into double membrane vacuoles characteristic of autophagosomes in a process that was not dependent on replication. The F. tularensis LVS ΔripA mutant was significantly impaired in its ability to persist in the lung and in its capacity to disseminate and colonize the liver and spleen in a mouse model of pulmonary tularemia. The RipA protein was expressed during growth in laboratory media and localized to the cytoplasmic membrane. Thus, RipA is a cytoplasmic membrane protein conserved among Francisella species that is required for intracellular replication within the host cell cytoplasm as well as disease progression, dissemination, and virulence. PMID:18765722

Genipin protects d-galactosamine and lipopolysaccharide-induced hepatic injury through suppression of the necroptosis-mediated inflammasome signaling.

PubMed

Seo, Min-Jong; Hong, Jeong-Min; Kim, Seok-Joo; Lee, Sun-Mee

2017-10-05

Acute liver failure (ALF) is a life-threatening syndrome resulting from massive inflammation and hepatocyte death. Necroptosis, a programmed cell death controlled by receptor-interacting protein kinase (RIP) 1 and RIP3, has been shown to play an important role in regulating inflammation via crosstalk between other intracellular signaling. The inflammasome is a major intracellular multiprotein that induces inflammatory responses by mediating immune cell infiltration, thus potentiating injury. Genipin, a major active compound of the gardenia fruit, exhibits anti-inflammatory, antioxidant, and anti-apoptotic properties. This study investigated the hepatoprotective mechanisms of genipin on d-galactosamine (GalN) and lipopolysaccharide (LPS)-induced ALF, particularly focusing on interaction between necroptosis and inflammasome. Mice were given an intraperitoneal injection of genipin (25, 50, and 100mg/kg) or necrostatin-1 (Nec-1, a necroptosis inhibitor; 1.8mg/kg) 1h prior to GalN (800mg/kg)/LPS (40μg/kg) injection and were killed 3h after GalN/LPS injection. Genipin improved the survival rate and attenuated increases in serum aminotransferase activities and inflammatory cytokines after GalN/LPS injection. Genipin reduced GalN/LPS-induced increases in RIP3, phosphorylated RIP1 and RIP3 protein expression, and RIP1/RIP3 necrosome complex, similar to the effects of Nec-1. GalN/LPS significantly increased serum levels of high-mobility group box 1 and interleukin (IL)-33, which were attenuated by genipin and Nec-1. Moreover, similar to Nec-1, genipin attenuated GalN/LPS-induced increases in the protein expression levels of NLRP3, ASC, and caspase-1, inflammasome components, and levels of liver and serum IL-1β. Taken together, our findings suggest that genipin ameliorates GalN/LPS-induced hepatocellular damage by suppressing necroptosis-mediated inflammasome signaling. Copyright © 2017 Elsevier B.V. All rights reserved.

Ribosome-Inactivating Proteins: From Plant Defense to Tumor Attack

PubMed Central

de Virgilio, Maddalena; Lombardi, Alessio; Caliandro, Rocco; Fabbrini, Maria Serena

2010-01-01

Ribosome-inactivating proteins (RIPs) are EC3.2.32.22 N-glycosidases that recognize a universally conserved stem-loop structure in 23S/25S/28S rRNA, depurinating a single adenine (A4324 in rat) and irreversibly blocking protein translation, leading finally to cell death of intoxicated mammalian cells. Ricin, the plant RIP prototype that comprises a catalytic A subunit linked to a galactose-binding lectin B subunit to allow cell surface binding and toxin entry in most mammalian cells, shows a potency in the picomolar range. The most promising way to exploit plant RIPs as weapons against cancer cells is either by designing molecules in which the toxic domains are linked to selective tumor targeting domains or directly delivered as suicide genes for cancer gene therapy. Here, we will provide a comprehensive picture of plant RIPs and discuss successful designs and features of chimeric molecules having therapeutic potential. PMID:22069572

Discovery of a quorum-sensing inhibitor of drug-resistant staphylococcal infections by structure-based virtual screening.

PubMed

Kiran, Madanahally D; Adikesavan, Nallini Vijayarangan; Cirioni, Oscar; Giacometti, Andrea; Silvestri, Carmela; Scalise, Giorgio; Ghiselli, Roberto; Saba, Vittorio; Orlando, Fiorenza; Shoham, Menachem; Balaban, Naomi

2008-05-01

Staphylococci are a major health threat because of increasing resistance to antibiotics. An alternative to antibiotic treatment is preventing virulence by inhibition of bacterial cell-to-cell communication using the quorum-sensing inhibitor RNAIII-inhibiting peptide (RIP). In this work, we identified 2',5-di-O-galloyl-d-hamamelose (hamamelitannin) as a nonpeptide analog of RIP by virtual screening of a RIP-based pharmacophore against a database of commercially available small-molecule compounds. Hamamelitannin is a natural product found in the bark of Hamamelis virginiana (witch hazel), and it has no effect on staphylococcal growth in vitro; but like RIP, it does inhibit the quorum-sensing regulator RNAIII. In a rat graft model, hamamelitannin prevented device-associated infections in vivo, including infections caused by methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis strains. These findings suggest that hamamelitannin may be used as a suppressor to staphylococcal infections.

Expression of the NH2-Terminal Fragment of RasGAP in Pancreatic β-Cells Increases Their Resistance to Stresses and Protects Mice From Diabetes

PubMed Central

Yang, Jiang-Yan; Walicki, Jöel; Jaccard, Evrim; Dubuis, Gilles; Bulat, Natasa; Hornung, Jean-Pierre; Thorens, Bernard; Widmann, Christian

2009-01-01

OBJECTIVE Our laboratory has previously established in vitro that a caspase-generated RasGAP NH2-terminal moiety, called fragment N, potently protects cells, including insulinomas, from apoptotic stress. We aimed to determine whether fragment N can increase the resistance of pancreatic β-cells in a physiological setting. RESEARCH DESIGN AND METHODS A mouse line, called rat insulin promoter (RIP)-N, was generated that bears a transgene containing the rat insulin promoter followed by the cDNA-encoding fragment N. The histology, functionality, and resistance to stress of RIP-N islets were then assessed. RESULTS Pancreatic β-cells of RIP-N mice express fragment N, activate Akt, and block nuclear factor κB activity without affecting islet cell proliferation or the morphology and cellular composition of islets. Intraperitoneal glucose tolerance tests revealed that RIP-N mice control their glycemia similarly as wild-type mice throughout their lifespan. Moreover, islets isolated from RIP-N mice showed normal glucose-induced insulin secretory capacities. They, however, displayed increased resistance to apoptosis induced by a series of stresses including inflammatory cytokines, fatty acids, and hyperglycemia. RIP-N mice were also protected from multiple low-dose streptozotocin-induced diabetes, and this was associated with reduced in vivo β-cell apoptosis. CONCLUSIONS Fragment N efficiently increases the overall resistance of β-cells to noxious stimuli without interfering with the physiological functions of the cells. Fragment N and the pathway it regulates represent, therefore, a potential target for the development of antidiabetes tools. PMID:19696184

A Chimeric Peptide Composed of a Dermaseptin Derivative and an RNA III-Inhibiting Peptide Prevents Graft-Associated Infections by Antibiotic-Resistant Staphylococci

PubMed Central

Balaban, Naomi; Gov, Yael; Giacometti, Andrea; Cirioni, Oscar; Ghiselli, Roberto; Mocchegiani, Federico; Orlando, Fiorenza; D'Amato, Giuseppina; Saba, Vittorio; Scalise, Giorgio; Bernes, Sabina; Mor, Amram

2004-01-01

Staphylococcal bacteria are a prevalent cause of infections associated with foreign bodies and indwelling medical devices. Bacteria are capable of escaping antibiotic treatment through encapsulation into biofilms. RNA III-inhibiting peptide (RIP) is a heptapeptide that inhibits staphylococcal biofilm formation by obstructing quorum-sensing mechanisms. K4-S4(1-13)a is a 13-residue dermaseptin derivative (DD13) believed to kill bacteria via membrane disruption. We tested each of these peptides as well as a hybrid construct, DD13-RIP, for their ability to inhibit bacterial proliferation and suppress quorum sensing in vitro and for their efficacy in preventing staphylococcal infection in a rat graft infection model with methicillin-resistant Staphylococcus aureus (MRSA) or S. epidermidis (MRSE). In vitro, proliferation assays demonstrated that RIP had no inhibitory effect, while DD13-RIP and DD13 were equally effective, and that the chimeric peptide but not DD13 was slightly more effective than RIP in inhibiting RNA III synthesis, a regulatory RNA molecule important for staphylococcal pathogenesis. In vivo, the three peptides reduced graft-associated bacterial load in a dose-dependent manner, but the hybrid peptide was most potent in totally preventing staphylococcal infections at the lowest dose. In addition, each of the peptides acted synergistically with antibiotics. The data indicate that RIP and DD13 act in synergy by attacking bacteria simultaneously by two different mechanisms. Such a chimeric peptide may be useful for coating medical devices to prevent drug-resistant staphylococcal infections. PMID:15215107

Future singularities and teleparallelism in loop quantum cosmology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bamba, Kazuharu; Haro, Jaume de; Odintsov, Sergei D., E-mail: bamba@kmi.nagoya-u.ac.jp, E-mail: jaime.haro@upc.edu, E-mail: odintsov@ieec.uab.es

2013-02-01

We demonstrate how holonomy corrections in loop quantum cosmology (LQC) prevent the Big Rip singularity by introducing a quadratic modification in terms of the energy density ρ in the Friedmann equation in the Friedmann-Lemaître-Robertson-Walker (FLRW) space-time in a consistent and useful way. In addition, we investigate whether other kind of singularities like Type II,III and IV singularities survive or are avoided in LQC when the universe is filled by a barotropic fluid with the state equation P = −ρ−f(ρ), where P is the pressure and f(ρ) a function of ρ. It is shown that the Little Rip cosmology does notmore » happen in LQC. Nevertheless, the occurrence of the Pseudo-Rip cosmology, in which the phantom universe approaches the de Sitter one asymptotically, is established, and the corresponding example is presented. It is interesting that the disintegration of bound structures in the Pseudo-Rip cosmology in LQC always takes more time than that in Einstein cosmology. Our investigation on future singularities is generalized to that in modified teleparallel gravity, where LQC and Brane Cosmology in the Randall-Sundrum scenario are the best examples. It is remarkable that F(T) gravity may lead to all the kinds of future singularities including Little Rip.« less

Necrosome core machinery: MLKL.

PubMed

Zhang, Jing; Yang, Yu; He, Wenyan; Sun, Liming

2016-06-01

In the study of regulated cell death, the rapidly expanding field of regulated necrosis, in particular necroptosis, has been drawing much attention. The signaling of necroptosis represents a sophisticated form of a death pathway. Anti-caspase mechanisms (e.g., using inhibitors of caspases, or genetic ablation of caspase-8) switch cell fate from apoptosis to necroptosis. The initial extracellular death signals regulate RIP1 and RIP3 kinase activation. The RIP3-associated death complex assembly is necessary and sufficient to initiate necroptosis. MLKL was initially identified as an essential mediator of RIP1/RIP3 kinase-initiated necroptosis. Recent studies on the signal transduction using chemical tools and biomarkers support the idea that MLKL is able to make more functional sense for the core machinery of the necroptosis death complex, called the necrosome, to connect to the necroptosis execution. The experimental data available now have pointed that the activated MLKL forms membrane-disrupting pores causing membrane leakage, which extends the prototypical concept of morphological and biochemical events following necroptosis happening in vivo. The key role of MLKL in necroptosis signaling thus sheds light on the logic underlying this unique "membrane-explosive" cell death pathway. In this review, we provide the general concepts and strategies that underlie signal transduction of this form of cell death, and then focus specifically on the role of MLKL in necroptosis.

In vivo levels of S-adenosylmethionine modulate C:G to T:A mutations associated with repeat-induced point mutation in Neurospora crassa.

PubMed

Rosa, Alberto Luis; Folco, Hernán Diego; Mautino, Mario Ricardo

2004-04-14

In Neurospora crassa, the mutagenic process termed repeat-induced point mutation (RIP) inactivates duplicated DNA sequences during the sexual cycle by the introduction of C:G to T:A transition mutations. In this work, we have used a collection of N. crassa strains exhibiting a wide range of cellular levels of S-adenosylmethionine (AdoMet), the universal donor of methyl groups, to explore whether frequencies of RIP are dependent on the cellular levels of this metabolite. Mutant strains met-7 and eth-1 carry mutations in genes of the AdoMet pathway and have low levels of AdoMet. Wild type strains with high levels of AdoMet were constructed by introducing a chimeric transgene of the AdoMet synthetase (AdoMet-S) gene fused to the constitutive promoter trpC from Aspergillus nidulans. Crosses of these strains against tester duplications of the pan-2 and am genes showed that frequencies of RIP, as well as the total number of C:G to T:A transition mutations found in randomly selected am(RIP) alleles, are inversely correlated to the cellular level of AdoMet. These results indicate that AdoMet modulates the biochemical pathway leading to RIP.

Role for RIP1 in mediating necroptosis in experimental intracerebral hemorrhage model both in vivo and in vitro.

PubMed

Shen, Haitao; Liu, Chenglin; Zhang, Dongping; Yao, Xiyang; Zhang, Kai; Li, Haiying; Chen, Gang

2017-03-02

Cell death is a hallmark of second brain injury after intracerebral hemorrhage (ICH); however, the mechanism still has not been fully illustrated. In this study, we explored whether necroptosis, a type of regulated necrosis, has an essential role in brain injury after ICH. We found that inhibiting receptor-interacting protein 1 (RIP1) - a core element of the necroptotic pathway - by a specific chemical inhibitor or genetic knockdown attenuated brain injury in a rat model of ICH. Furthermore, necroptosis of cultured neurons could be induced by conditioned medium from microglia stimulated with oxygen hemoglobin, and this effect could be inhibited by TNF-α inhibitor, indicating that TNF-α secreted from activated microglia is an important factor in inducing necroptosis of neurons. Undoubtedly, overexpression of RIP1 increased conditioned medium-induced necroptosis in vitro, but this effect was partially diminished in mutation of serine kinase phosphorylation site of RIP1, showing that phosphorylation of RIP1 is the essential molecular mechanism of necroptosis, which was activated in the in vitro model of ICH. Collectively, our investigation identified that necroptosis is an important mechanism of cell death in brain injury after ICH, and inhibition of necroptosis may be a potential therapeutic intervention of ICH.

Mitochondrial Protein PGAM5 Regulates Mitophagic Protection against Cell Necroptosis.

PubMed

Lu, Wei; Sun, Junhui; Yoon, Jeong Seon; Zhang, Yan; Zheng, Lixin; Murphy, Elizabeth; Mattson, Mark P; Lenardo, Michael J

2016-01-01

Necroptosis as a molecular program, rather than simply incidental cell death, was established by elucidating the roles of receptor interacting protein (RIP) kinases 1 and 3, along with their downstream partner, mixed lineage kinase-like domain protein (MLKL). Previous studies suggested that phosphoglycerate mutase family member 5 (PGAM5), a mitochondrial protein that associates with RIP1/RIP3/MLKL complex, promotes necroptosis. We have generated mice deficient in the pgam5 gene and surprisingly found PGAM5-deficiency exacerbated rather than reduced necroptosis in response to multiple in vitro and in vivo necroptotic stimuli, including ischemic reperfusion injury (I/R) in the heart and brain. Electron microscopy, biochemical, and confocal analysis revealed that PGAM5 is indispensable for the process of PINK1 dependent mitophagy which antagonizes necroptosis. The loss of PGAM5/PINK1 mediated mitophagy causes the accumulation of abnormal mitochondria, leading to the overproduction of reactive oxygen species (ROS) that worsen necroptosis. Our results revise the former proposal that PGAM5 acts downstream of RIP1/RIP3 to mediate necroptosis. Instead, PGAM5 protects cells from necroptosis by independently promoting mitophagy. PGAM5 promotion of mitophagy may represent a therapeutic target for stroke, myocardial infarction and other diseases caused by oxidative damage and necroptosis.

Role for RIP1 in mediating necroptosis in experimental intracerebral hemorrhage model both in vivo and in vitro

PubMed Central

Shen, Haitao; Liu, Chenglin; Zhang, Dongping; Yao, Xiyang; Zhang, Kai; Li, Haiying; Chen, Gang

2017-01-01

Cell death is a hallmark of second brain injury after intracerebral hemorrhage (ICH); however, the mechanism still has not been fully illustrated. In this study, we explored whether necroptosis, a type of regulated necrosis, has an essential role in brain injury after ICH. We found that inhibiting receptor-interacting protein 1 (RIP1) – a core element of the necroptotic pathway – by a specific chemical inhibitor or genetic knockdown attenuated brain injury in a rat model of ICH. Furthermore, necroptosis of cultured neurons could be induced by conditioned medium from microglia stimulated with oxygen hemoglobin, and this effect could be inhibited by TNF-α inhibitor, indicating that TNF-α secreted from activated microglia is an important factor in inducing necroptosis of neurons. Undoubtedly, overexpression of RIP1 increased conditioned medium-induced necroptosis in vitro, but this effect was partially diminished in mutation of serine kinase phosphorylation site of RIP1, showing that phosphorylation of RIP1 is the essential molecular mechanism of necroptosis, which was activated in the in vitro model of ICH. Collectively, our investigation identified that necroptosis is an important mechanism of cell death in brain injury after ICH, and inhibition of necroptosis may be a potential therapeutic intervention of ICH. PMID:28252651

Toll-like Receptor-mediated Down-regulation of the Deubiquitinase Cylindromatosis (CYLD) Protects Macrophages from Necroptosis in Wild-derived Mice*

PubMed Central

Schworer, Stephen A.; Smirnova, Irina I.; Kurbatova, Irina; Bagina, Uliana; Churova, Maria; Fowler, Trent; Roy, Ananda L.; Degterev, Alexei; Poltorak, Alexander

2014-01-01

Pathogen recognition by the innate immune system initiates the production of proinflammatory cytokines but can also lead to programmed host cell death. Necroptosis, a caspase-independent cell death pathway, can contribute to the host defense against pathogens or cause damage to host tissues. Receptor-interacting protein (RIP1) is a serine/threonine kinase that integrates inflammatory and necroptotic responses. To investigate the mechanisms of RIP1-mediated activation of immune cells, we established a genetic screen on the basis of RIP1-mediated necroptosis in wild-derived MOLF/EiJ mice, which diverged from classical laboratory mice over a million years ago. When compared with C57BL/6, MOLF/EiJ macrophages were resistant to RIP1-mediated necroptosis induced by Toll-like receptors. Using a forward genetic approach in a backcross panel of mice, we identified cylindromatosis (CYLD), a deubiquitinase known to act directly on RIP1 and promote necroptosis in TNF receptor signaling, as the gene conferring the trait. We demonstrate that CYLD is required for Toll-like receptor-induced necroptosis and describe a novel mechanism by which CYLD is down-regulated at the transcriptional level in MOLF/EiJ macrophages to confer protection from necroptosis. PMID:24706750

Investigation of environmental change pattern in Japan. Utilization of LANDSAT-2 data for fisheries

NASA Technical Reports Server (NTRS)

Maruyasu, T.; Watanabe, T. (Principal Investigator)

1977-01-01

The author has identified the following significant results. MSS data provided extensive and simultaneous information about marine environmental conditions, such as the shift of the Kuroshio, fall and rise of coastal water mass, distribution of water masses, locations of vortex and current rips, exchanges of water between embayment and open ocean effluent rivers, fertility of plankton, red tide, pollution, etc.

Dark energy and fate of the Universe

NASA Astrophysics Data System (ADS)

Li, XiaoDong; Wang, Shuang; Huang, QingGuo; Zhang, Xin; Li, Miao

2012-07-01

We explore the ultimate fate of the Universe by using a divergence-free parametrization for dark energy w( z)= w 0+ w a [ln(2 + z) / (1 + z) - ln 2]. Unlike the Chevallier-Polarski-Linder parametrization, this parametrization has well behaved, bounded behavior for both high redshifts and negative redshifts, and thus can genuinely cover many theoretical dark energy models. After constraining the parameter space of this parametrization by using the current cosmological observations, we find that, at the 95.4% confidence level, our Universe can still exist at least 16.7 Gyr before it ends in a big rip. Moreover, for the phantom energy dominated Universe, we find that a gravitationally bound system will be destroyed at a time {{t ˜eq Psqrt {2| {1 + 3w( - 1)} |} } {/ {{t ˜eq Psqrt {2| {1 + 3w( - 1)} |} } {[ {6π | {1 + w( - 1)} |} ]}}} . } {[ {6π | {1 + w( - 1)} |} ]}}, where P is the period of a circular orbit around this system, before the big rip.

Cancer therapy in the necroptosis era

PubMed Central

Su, Z; Yang, Z; Xie, L; DeWitt, J P; Chen, Y

2016-01-01

Necroptosis is a caspase-independent form of regulated cell death executed by the receptor-interacting protein kinase 1 (RIP1), RIP3, and mixed lineage kinase domain-like protein (MLKL). Recently, necroptosis-based cancer therapy has been proposed to be a novel strategy for antitumor treatment. However, a big controversy exists on whether this type of therapy is feasible or just a conceptual model. Proponents believe that because necroptosis and apoptosis use distinct molecular pathways, triggering necroptosis could be an alternative way to eradicate apoptosis-resistant cancer cells. This hypothesis has been preliminarily validated by recent studies. However, some skeptics doubt this strategy because of the intrinsic or acquired defects of necroptotic machinery observed in many cancer cells. Moreover, two other concerns are whether or not necroptosis inducers are selective in killing cancer cells without disturbing the normal cells and whether it will lead to inflammatory diseases. In this review, we summarize current studies surrounding this controversy on necroptosis-based antitumor research and discuss the advantages, potential issues, and countermeasures of this novel therapy. PMID:26915291

Antinociceptive activity of Riparin II from Aniba riparia: Further elucidation of the possible mechanisms.

PubMed

Rodrigues de Carvalho, Alyne Mara; Vasconcelos, Leonardo Freire; Moura Rocha, Nayrton Flávio; Vasconcelos Rios, Emiliano Ricardo; Dias, Marília Leite; Maria de França Fonteles, Marta; Gaspar, Danielle Macêdo; Barbosa Filho, José Maria; Chavez Gutierrez, Stanley Juan; Florenço de Sousa, Francisca Cléa

2018-05-01

Riparin II (RipII) has an anti-inflammatory activity potentially due its ability to decrease TNF-α and IL-1β production and its histamine antagonism. The objective of this study was to evaluate the role of RipII in the pain process and the possible antinociceptive mechanisms involved, using classic models of nociception. Male Swiss mice were used in the assays. Determinate the acute toxicity according to the OECD 425 test guideline. The models used were the acetic acid-, formalin-, hot plate and glutamate-induced nociception. For evaluation of antinociceptive effect, the involvement of TRPV1, TRPA1, TRPM8, ASICS, Bradykinin, PKC and PKA were performed using the paw licking using agonists. The acute toxicity study did not detect any clinical signs or changes in behavior or mortality. RipII, administered orally (25 and 50 mg/kg) caused a reduction of nociception induced by acetic acid, formalin (on the second phase) and glutamate. In the investigation of antinociceptive mechanism, we used capsaicin (2.2 μg/paw), cinnamaldehyde (10 nmol/paw), menthol (1.2 μmol/paw), ASICS (2% acetic acid, pH 1.98) and bradykinin (10 μg/paw). The results showed that TRPV1, TRPA1, TRPM8, ASICS and bradykinin play a role in the antinociceptive effect of RipII. The results also showed that PKA is involved too. These data demonstrate that RipII has a low or not toxicity and produced an important antinociceptive effect through mechanisms that probably involve an interaction, at least in part, TRPV1, TRPA1, TRPM8, ASICS, bradykinin and PKA participate in the RipII's antinociceptive effect. Copyright © 2018 Elsevier B.V. All rights reserved.

Respiratory Inductance Plethysmography Improved Diagnostic Sensitivity and Specificity of Obstructive Sleep Apnea.

PubMed

Kogan, Dmitriy; Jain, Arad; Kimbro, Shawn; Gutierrez, Guillermo; Jain, Vivek

2016-08-01

Respiratory inductance plethysmography (RIP) is a tool used during a polysomnogram (PSG), which serves as a surrogate of respiratory effort and can help detect inspiratory air-flow limitation. We hypothesize that RIP can improve the sensitivity and specificity of scoring hypopneas when compared with both the recommended and acceptable criteria of the American Academy of Sleep Medicine. We retrospectively analyzed a cohort of 12 subjects who had no obstructive sleep apnea (OSA) or mild OSA on PSG when scored by the American Academy of Sleep Medicine acceptable criteria for hypopneas but had high clinical suspicion for a diagnosis of OSA. These subjects were rescored using the American Academy of Sleep Medicine recommended criteria as well as RIP. Hypopnea was scored when there was a 50% decrease in the amplitude of the RIP sum channel (which combined input from chest and abdominal belts). OSA was diagnosed if the subjects had >5 respiratory events/h of sleep. The subject's response to CPAP was assessed by using a short questionnaire called the post-PSG sleep assessment. which evaluated subjective sleep quality. A positive response was considered an improvement in the post-PSG sleep assessment score after CPAP use. When scored using the American Academy of Sleep Medicine acceptable criteria, 10 subjects had a negative study, and 2 subjects had mild OSA for a sensitivity of 11% and specificity of 50%. When scored using the recommended criteria, 10 subjects had OSA, and 2 were negative, for a sensitivity of 78% and specificity of 70%. By RIP scoring, all 12 subjects had >5 respiratory events/h for a sensitivity of 100% and specificity of 75%. This small retrospective pilot study showed improved sensitivity and specificity when scoring hypopneas by RIP sum channel. Copyright © 2016 by Daedalus Enterprises.

Identification of RIP1 as a critical mediator of Smac mimetic-mediated sensitization of glioblastoma cells for Drozitumab-induced apoptosis.

PubMed

Cristofanon, S; Abhari, B A; Krueger, M; Tchoghandjian, A; Momma, S; Calaminus, C; Vucic, D; Pichler, B J; Fulda, S

2015-04-16

This study aims at evaluating the combination of the tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL)-receptor 2 (TRAIL-R2)-specific antibody Drozitumab and the Smac mimetic BV6 in preclinical glioblastoma models. To this end, the effect of BV6 and/or Drozitumab on apoptosis induction and signaling pathways was analyzed in glioblastoma cell lines, primary glioblastoma cultures and glioblastoma stem-like cells. Here, we report that BV6 and Drozitumab synergistically induce apoptosis and reduce colony formation in several glioblastoma cell lines (combination index<0.1). Also, BV6 profoundly enhances Drozitumab-induced apoptosis in primary glioblastoma cultures and glioblastoma stem-like cells. Importantly, BV6 cooperates with Drozitumab to suppress tumor growth in two glioblastoma in vivo models including an orthotopic, intracranial mouse model, underlining the clinical relevance of these findings. Mechanistic studies reveal that BV6 and Drozitumab act in concert to trigger the formation of a cytosolic receptor-interacting protein (RIP) 1/Fas-associated via death domain (FADD)/caspase-8-containing complex and subsequent activation of caspase-8 and -3. BV6- and Drozitumab-induced apoptosis is blocked by the caspase inhibitor zVAD.fmk, pointing to caspase-dependent apoptosis. RNA interference-mediated silencing of RIP1 almost completely abolishes the BV6-conferred sensitization to Drozitumab-induced apoptosis, indicating that the synergism critically depends on RIP1 expression. In contrast, both necrostatin-1, a RIP1 kinase inhibitor, and Enbrel, a TNFα-blocking antibody, do not interfere with BV6/Drozitumab-induced apoptosis, demonstrating that apoptosis occurs independently of RIP1 kinase activity or an autocrine TNFα loop. In conclusion, the rational combination of BV6 and Drozitumab presents a promising approach to trigger apoptosis in glioblastoma, which warrants further investigation.

Mixed lineage kinase domain-like protein induces RGC-5 necroptosis following elevated hydrostatic pressure.

PubMed

Liao, Lvshuang; Shang, Lei; Li, Na; Wang, Shuchao; Wang, Mi; Huang, Yanxia; Chen, Dan; Huang, Jufang; Xiong, Kun

2017-10-01

Receptor-interacting protein 3 (RIP3) is an essential component of the necroptosis signaling pathway. Phosphorylation of its downstream target, mixed lineage kinase domain-like protein (MLKL), has been proposed to induce necroptosis by initiating Ca2+ influx. Our previous studies have shown that RGC-5 retinal ganglion cells undergo RIP3-mediated necroptosis following elevated hydrostatic pressure (EHP). However, the molecular mechanism underlying necroptosis induction downstream of RIP3 is still not well understood. Here, we investigated the effects of MLKL during EHP-induced necroptosis, and primarily explored the relationship between MLKL and Ca2+ influx. Immunofluorescence staining showed that the expression of MLKL was increased 12 h after EHP. Western blot analysis demonstrated that the phosphorylated and unphosphorylated forms of both RIP3 and MLKL were up-regulated 12 h after EHP, while inhibition of RIP3 by GSK'872 decreased the expression of phosphorylated MLKL at the same stage. Propidium iodide staining, lactate dehydrogenase release assays, flow cytometry, and electron microscopy revealed the increased necrosis of RGC-5 cells 12 h after EHP, which coincided with elevated cytosolic Ca2+ concentrations. Depletion of extracellular Ca2+ and siRNA-mediated silencing of MLKL significantly reduced EHP-induced necrosis. Both MLKL-specific siRNA and GSK'872 treatment diminished Ca2+ influx. Thus, our findings suggest that MLKL may be the key mediator of necroptosis downstream of RIP3 phosphorylation and may be involved in increasing intracellular Ca2+ concentrations in EHP-induced RGC-5 necroptosis. © The Author 2017. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Upregulation of PSMB4 is Associated with the Necroptosis after Spinal Cord Injury.

PubMed

Wu, Chunshuai; Chen, Jiajia; Liu, Yonghua; Zhang, Jinlong; Ding, Wensen; Wang, Song; Bao, Guofeng; Xu, Guanhua; Sun, Yuyu; Wang, Lingling; Chen, Limin; Gu, Haiyan; Cui, Baihong; Cui, Zhiming

2016-11-01

Spinal cord injury (SCI) is one of the most common and severe complications in spine injury. It is difficult to prevent cell necroptosis and promote the survival of residual neurons after SCI. Proteasome beta-4 subunit (PSMB4) is the first proteasomal subunit with oncogenic properties promoting cancer cell survival and tumor growth in vivo, and our previous study showed that PSMB4 is significantly associated with neuronal apoptosis in neuroinflammation. However, PSMB4 function in the necroptosis after SCI is unkown. RIP3, a key regulatory factor of necroptosis, correlates with the induction of necroptosis in various types of cells and signaling pathway. Upregulation of the RIP3 expression may play a role as a novel molecular mechanism in secondary neural tissue damage following SCI. In this study, we established an acute spinal cord contusion injury model in adult rats to investigate the potential role of PSMB4 during the pathological process of SCI. We found PSMB4 expression was significantly up-regulated 3 days after injury by western blot and immunohistochemical staining. Double immunofluorescent staining indicated obvious changes of PSMB4 expression occurred in neurons. Significant up-regulation of PSMB4 expression was observed in Rip3 positive neurons at 3 days after SCI, which indicated that PSMB4 might play a vital role in the regulation of Rip3. Overexpress and knockdown PSMB4 could intervene the RIP3 and Mixed lineage kinase domain-like protein (MLKL) pathway in Tumor necrosis factor-α (TNF-α) induced necroptosis cell model. Based on our experimental data, we boldly conclude that PSMB4 is associated with RIP3 involved necroptosis after SCI.

Sorafenib inhibits therapeutic induction of necroptosis in acute leukemia cells.

PubMed

Feldmann, Friederike; Schenk, Barbara; Martens, Sofie; Vandenabeele, Peter; Fulda, Simone

2017-09-15

Induction of necroptosis has emerged as an alternative approach to trigger programmed cell death, in particular in apoptosis-resistant cancer cells. Recent evidence suggests that kinase inhibitors targeting oncogenic B-RAF can also affect Receptor-interacting serine/threonine-protein kinase (RIP)1 and RIP3. Sorafenib, a multi-targeting kinase inhibitor with activity against B-RAF, is used for the treatment of acute leukemia. In the present study, we therefore investigated whether Sorafenib interferes with therapeutic induction of necroptosis in acute leukemia. Here, we report that Sorafenib inhibits necroptotic signaling and cell death in two models of necroptosis in acute leukemia. Sorafenib significantly reduces Second mitochondria-derived activator of caspases (Smac) mimetic-induced necroptosis in apoptosis-resistant acute myeloid leukemia (AML) cells as well as Smac mimetic/Tumor Necrosis Factor (TNF)α-induced necroptosis in FADD-deficient acute lymphoblastic leukemia (ALL) cells. Sub- to low micromolar concentrations of Sorafenib corresponding to its plasma levels reported in cancer patients are sufficient to inhibit necroptosis, emphasizing the clinical relevance of our findings. Furthermore, Sorafenib blocks Smac mimetic-mediated phosphorylation of mixed-lineage kinase domain-like protein (MLKL) that marks its activation, indicating that Sorafenib targets components upstream of MLKL such as RIP1 and RIP3. Intriguingly, Sorafenib reduces the Smac mimetic/TNFα-stimulated interaction of RIP1 with RIP3 and MLKL, demonstrating that it interferes with the assembly of the necrosome complex. Importantly, Sorafenib significantly protects primary, patient-derived AML blasts from Smac mimetic-induced necroptosis. By demonstrating that Sorafenib limits the anti-leukemic activity of necroptosis-inducing drugs in acute leukemia cells, our study has important implications for the use of Sorafenib in the treatment of acute leukemia.

Pore-Forming Toxins Induce Macrophage Necroptosis during Acute Bacterial Pneumonia.

PubMed

González-Juarbe, Norberto; Gilley, Ryan Paul; Hinojosa, Cecilia Anahí; Bradley, Kelley Margaret; Kamei, Akinobu; Gao, Geli; Dube, Peter Herman; Bergman, Molly Ann; Orihuela, Carlos Javier

2015-12-01

Necroptosis is a highly pro-inflammatory mode of cell death regulated by RIP (or RIPK)1 and RIP3 kinases and mediated by the effector MLKL. We report that diverse bacterial pathogens that produce a pore-forming toxin (PFT) induce necroptosis of macrophages and this can be blocked for protection against Serratia marcescens hemorrhagic pneumonia. Following challenge with S. marcescens, Staphylococcus aureus, Streptococcus pneumoniae, Listeria monocytogenes, uropathogenic Escherichia coli (UPEC), and purified recombinant pneumolysin, macrophages pretreated with inhibitors of RIP1, RIP3, and MLKL were protected against death. Alveolar macrophages in MLKL KO mice were also protected during S. marcescens pneumonia. Inhibition of caspases had no impact on macrophage death and caspase-1 and -3/7 were determined to be inactive following challenge despite the detection of IL-1β in supernatants. Bone marrow-derived macrophages from RIP3 KO, but not caspase-1/11 KO or caspase-3 KO mice, were resistant to PFT-induced death. We explored the mechanisms for PFT-induced necroptosis and determined that loss of ion homeostasis at the plasma membrane, mitochondrial damage, ATP depletion, and the generation of reactive oxygen species were together responsible. Treatment of mice with necrostatin-5, an inhibitor of RIP1; GW806742X, an inhibitor of MLKL; and necrostatin-5 along with co-enzyme Q10 (N5/C10), which enhances ATP production; reduced the severity of S. marcescens pneumonia in a mouse intratracheal challenge model. N5/C10 protected alveolar macrophages, reduced bacterial burden, and lessened hemorrhage in the lungs. We conclude that necroptosis is the major cell death pathway evoked by PFTs in macrophages and the necroptosis pathway can be targeted for disease intervention.

Pore-Forming Toxins Induce Macrophage Necroptosis during Acute Bacterial Pneumonia

PubMed Central

González-Juarbe, Norberto; Gilley, Ryan Paul; Hinojosa, Cecilia Anahí; Bradley, Kelley Margaret; Kamei, Akinobu; Gao, Geli; Dube, Peter Herman; Bergman, Molly Ann; Orihuela, Carlos Javier

2015-01-01

Necroptosis is a highly pro-inflammatory mode of cell death regulated by RIP (or RIPK)1 and RIP3 kinases and mediated by the effector MLKL. We report that diverse bacterial pathogens that produce a pore-forming toxin (PFT) induce necroptosis of macrophages and this can be blocked for protection against Serratia marcescens hemorrhagic pneumonia. Following challenge with S. marcescens, Staphylococcus aureus, Streptococcus pneumoniae, Listeria monocytogenes, uropathogenic Escherichia coli (UPEC), and purified recombinant pneumolysin, macrophages pretreated with inhibitors of RIP1, RIP3, and MLKL were protected against death. Alveolar macrophages in MLKL KO mice were also protected during S. marcescens pneumonia. Inhibition of caspases had no impact on macrophage death and caspase-1 and -3/7 were determined to be inactive following challenge despite the detection of IL-1β in supernatants. Bone marrow-derived macrophages from RIP3 KO, but not caspase-1/11 KO or caspase-3 KO mice, were resistant to PFT-induced death. We explored the mechanisms for PFT-induced necroptosis and determined that loss of ion homeostasis at the plasma membrane, mitochondrial damage, ATP depletion, and the generation of reactive oxygen species were together responsible. Treatment of mice with necrostatin-5, an inhibitor of RIP1; GW806742X, an inhibitor of MLKL; and necrostatin-5 along with co-enzyme Q10 (N5/C10), which enhances ATP production; reduced the severity of S. marcescens pneumonia in a mouse intratracheal challenge model. N5/C10 protected alveolar macrophages, reduced bacterial burden, and lessened hemorrhage in the lungs. We conclude that necroptosis is the major cell death pathway evoked by PFTs in macrophages and the necroptosis pathway can be targeted for disease intervention. PMID:26659062

Dispersal of fine sediment in nearshore coastal waters

USGS Publications Warehouse

Warrick, Jonathan A.

2013-01-01

Fine sediment (silt and clay) plays an important role in the physical, ecological, and environmental conditions of coastal systems, yet little is known about the dispersal and fate of fine sediment across coastal margin settings outside of river mouths. Here I provide simple physical scaling and detailed monitoring of a beach nourishment project near Imperial Beach, California, with a high portion of fines (40% silt and clay by weight). These results provide insights into the pathways and residence times of fine sediment transport across a wave-dominated coastal margin. Monitoring of the project used physical, optical, acoustic, and remote sensing techniques to track the fine portion of the nourishment sediment. The initial transport of fine sediment from the beach was influenced strongly by longshore currents of the surf zone that were established in response to the approach angles of the waves. The mean residence time of fine sediment in the surf zone—once it was suspended—was approximately 1 hour, and rapid decreases in surf zone fine sediment concentrations along the beach resulted from mixing and offshore transport in turbid rip heads. For example, during a day with oblique wave directions and surf zone longshore currents of approximately 25 cm/s, the offshore losses of fine sediment in rips resulted in a 95% reduction in alongshore surf zone fine sediment flux within 1 km of the nourishment site. However, because of the direct placement of nourishment sediment on the beach, fine suspended-sediment concentrations in the swash zone remained elevated for several days after nourishment, while fine sediment was winnowed from the beach. Once offshore of the surf zone, fine sediment settled downward in the water column and was observed to transport along and across the inner shelf. Vertically sheared currents influenced the directions and rates of fine sediment transport on the shelf. Sedimentation of fine sediment was greatest on the seafloor directly offshore of the nourishment site. However, a mass balance of sediment suggests that the majority of the fine sediment moved far away (over 2 km) from the nourishment site or to water depths greater than 10 m, where fine sediment represents a substantial portion of the bed material. Thus, the fate of fine sediment in nearshore waters was influenced strongly by wave conditions, surf zone and rip current transport, and the vertical density and flow conditions of coastal waters.

14 CFR 31.57 - Rip cords.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 1 2013-01-01 2013-01-01 false Rip cords. 31.57 Section 31.57 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS... emergency deflation, it must be designed and installed to preclude entanglement. (b) The force required to...

14 CFR 31.57 - Rip cords.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 1 2012-01-01 2012-01-01 false Rip cords. 31.57 Section 31.57 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS... emergency deflation, it must be designed and installed to preclude entanglement. (b) The force required to...

14 CFR 31.57 - Rip cords.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Rip cords. 31.57 Section 31.57 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS... emergency deflation, it must be designed and installed to preclude entanglement. (b) The force required to...

14 CFR 31.57 - Rip cords.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Rip cords. 31.57 Section 31.57 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS... emergency deflation, it must be designed and installed to preclude entanglement. (b) The force required to...

14 CFR 31.57 - Rip cords.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Rip cords. 31.57 Section 31.57 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS... emergency deflation, it must be designed and installed to preclude entanglement. (b) The force required to...

Positioning System Accuracy Assessment for the Runway Incursion Prevention System Flight Test at the Dallas/Ft. Worth International Airport

NASA Technical Reports Server (NTRS)

Quach, Cuong C.

2004-01-01

NASA/Langley Research Center collaborated with the Federal Aviation Administration (FAA) to test a Runway Incursion Prevention System (RIPS) at the Dallas Fort Worth International Airport (DFW) in October 2000. The RIPS combines airborne and ground sensor data with various cockpit displays to improve pilots' awareness of traffic conditions on the airport surface. The systems tested at DFW involved surface radar and data systems that gather and send surface traffic information to a research aircraft outfitted with the RIPS software, cockpit displays, and data link transceivers. The data sent to the airborne systems contained identification and GPS location of traffic. This information was compared with the own-ship location from airborne GPS receivers to generate incursion alerts. A total of 93 test tracks were flown while operating RIPS. This report compares the accuracy of the airborne GPS systems that gave the own-ship position of the research aircraft for the 93 test tracks.

Nondestructive measurement of an optical fiber refractive-index profile by a transmitted-light differential interference contact microscope.

PubMed

Liu, Zhongyao; Dong, Xiaoman; Chen, Qianghua; Yin, Chunyong; Xu, Yuxian; Zheng, Yingjun

2004-03-01

A novel transmitted-light differential interference contrast (DIC) system is used for nondestructive measurement of the refractive-index profile (RIP) of an optical fiber. By means of this system the phase of a measured light beam can be modulated with an analyzer, and the phase distribution of a fiber is obtained by calculation of the various interference patterns. The measurement theory and structure and some typical applications of this system are demonstrated. The results of measuring RIPs in graded-index fiber are presented. Both the experimental results and theoretical analysis show that the system takes the advantage of high index resolution and of sufficient measurement accuracy for measuring the refractive index of the optical fiber. The system has strong ability to overcome environmental disturbance because of its common-path design. Moreover, one can use the system to measure the RIP along the fiber axis and acquire an image of the three-dimensional RIP of the fiber.

RIP-ET: A riparian evapotranspiration package for MODFLOW-2005

USGS Publications Warehouse

Maddock, Thomas; Baird, Kathryn J.; Hanson, R.T.; Schmid, Wolfgang; Ajami, Hoori

2012-01-01

A new evapotranspiration package for the U.S. Geological Survey's groundwater-flow model, MODFLOW, is documented. The Riparian Evapotranspiration Package (RIP-ET) provides flexibility in simulating riparian and wetland transpiration not provided by the Evapotranspiration (EVT) or Segmented Function Evapotranspiration (ETS1) Packages for MODFLOW 2005. This report describes how the RIP-ET package was conceptualized and provides input instructions, listings and explanations of the source code, and an example. Traditional approaches to modeling evapotranspiration (ET) processes assume a piecewise linear relationship between ET flux and hydraulic head. The RIP-ET replaces this traditional relationship with a segmented, nonlinear dimensionless curve that reflects the eco-physiology of riparian and wetland ecosystems. Evapotranspiration losses from these ecosystems are dependent not only on hydraulic head, but on the plant types present. User-defined plant functional groups (PFGs) are used to elucidate the interaction between plant transpiration and groundwater conditions. Five generalized plant functional groups based on transpiration rates, plant rooting depth, and water tolerance ranges are presented: obligate wetland, shallow-rooted riparian, deep-rooted riparian, transitional riparian and bare ground/open water. Plant functional groups can be further divided into subgroups (PFSGs) based on plant size, density or other characteristics. The RIP-ET allows for partial habitat coverage and mixtures of plant functional subgroups to be present in a single model cell. RIP-ET also distinguishes between plant transpiration and bare-ground evaporation. Habitat areas are designated by polygons; each polygon can contain a mixture of PFSGs and bare ground, and is assigned a surface elevation. This process requires a determination of fractional coverage for each of the plant functional subgroups present in a polygon to account for the mixture of coverage types and resulting transpiration. The fractional cover within a cell has two components: (1) the polygonal fraction of active habitat (excluding area of bare ground, dead trees, or brush) in a cell, and (2) fraction of plant type area or bare ground area in a polygon. RIP-ET determines the transpiration rate for each plant functional group and evaporation from bare ground/open water in a cell, the total ET in the cell, and the total ET rate over the region of simulation.

Refractive index profiles of Ge-doped optical fibers with nanometer spatial resolution using atomic force microscopy.

PubMed

Pace, P; Huntington, Shane; Lyytikäinen, K; Roberts, A; Love, J

2004-04-05

We show a quantitative connection between Refractive Index Profiles (RIP) and measurements made by an Atomic Force Microscope (AFM). Germanium doped fibers were chemically etched in hydrofluoric acid solution (HF) and the wet etching characteristics of germanium were studied using an AFM. The AFM profiles were compared to both a concentration profile of the preform determined using a Scanning Electron Microscope (SEM) and a RIP of the fiber measured using a commercial profiling instrument, and were found to be in excellent agreement. It is now possible to calculate the RIP of a germanium doped fiber directly from an AFM profile.

NASA Runway Incursion Prevention System (RIPS) Dallas-Fort Worth Demonstration Performance Analysis

NASA Technical Reports Server (NTRS)

Cassell, Rick; Evers, Carl; Esche, Jeff; Sleep, Benjamin; Jones, Denise R. (Technical Monitor)

2002-01-01

NASA's Aviation Safety Program Synthetic Vision System project conducted a Runway Incursion Prevention System (RIPS) flight test at the Dallas-Fort Worth International Airport in October 2000. The RIPS research system includes advanced displays, airport surveillance system, data links, positioning system, and alerting algorithms to provide pilots with enhanced situational awareness, supplemental guidance cues, a real-time display of traffic information, and warnings of runway incursions. This report describes the aircraft and ground based runway incursion alerting systems and traffic positioning systems (Automatic Dependent Surveillance - Broadcast (ADS-B) and Traffic Information Service - Broadcast (TIS-B)). A performance analysis of these systems is also presented.

Exploring Transmedia: The Rip-Mix-Learn Classroom

ERIC Educational Resources Information Center

Benedict, Lucille A.; Champlin, David T.; Pence, Harry E.

2013-01-01

Google Docs was used to create the rip-mix-learn (RML) classroom in two, first-year undergraduate introductory chemistry and biology courses, a second-semester introductory chemistry course, and an upper-level developmental biology course. This "transmedia" approach assigned students to create sets of collaborative lecture notes into…

Research on ribosome-inactivating proteins from angiospermae to gymnospermae and cryptogamia

PubMed Central

Liu, Wang-Yi

2017-01-01

Ribosome-inactivating Proteins (RIPs) are a group of cytotoxin proteins that usually contain a RNA N-glycosidase domain, which irreversibly inactivates ribosome, thus inhibiting protein synthesis. During the past 14 years (1990-2004), the studies conducted in our laboratory had been focusing on the structure and enzymatic mechanism of several PIPs. Herein, we briefly described a summary of the studies conducted mainly in our laboratory on RIPs from angiospermae to gymnospermae and cryptogamia as follows. (1) Cinnamomin is a novel type II RIP isolated from mature seeds of camphor tree. Like ricin, it specifically removes the adenine at A4324 in rat liver 28S rRNA. We systematically studied this low-toxic RIP in term of its enzymatic mechanism, the primary and crystal structure and the nucleotide sequence of its gene, the genetic expression, and its physiological role in the seed cell and the toxicity to human cancer cells and insect larvae. The cleavage of supercoiled double-stranded DNA was its intrinsic property of cinnamomin A-chain, its N- and C-terminal regions were found to be required for deadenylation of rRNA and also necessary for deadenylation of supercoiled double-stranded circular DNA. These results strongly excluded the possibility that cleavage of supercoiled DNA was due to nuclease contamination. (2) Trichosanthin, an abortifacient protein, was purified from the Chinese medicinal herb, Tian-hua-fen, obtained from root tubers of Chinese trichosanthes plant. We proved that trichosanthin was a RNA N-glycosidase, inactivating eukaryotic ribosome by hydrolyzing the N-C glycosidic bond of the adenose at site 4324 in rat 28S rRNA, and inhibited protein synthesis in vitro. (3) A unique Biota orientalis RNase (RNase Bo) was extracted from the mature seeds of the cypress cypress tree (Oriental arborvita), which was gymnospermae plant. It cleaved only a specific phosphodiester bond between C4453 and A4454 of 28S RNA in rat ribosomes, producing a small RNA-fragment (S-fragment), thus inhibiting protein synthesis and belonging to RNase-like RIP, similar to α-sarcin, a special RIP. (4) Lamjapin, the first RIP purified from kelp, the marine cryptogamia algal plant, was shown to be the first single-chained RNA N-glycosidase from marine plant to date. It hydrolyzed rat ribosomal 28S RNA to produce meanly a rather smaller RNA, shorter than the diagnostic R-fragment under the restricted condition. The significance of existence of type I RIP in the lower marine algal plant was briefly discussed. PMID:29312524

The dimerization of the yeast cytochrome bc1 complex is an early event and is independent of Rip1.

PubMed

Conte, Annalea; Papa, Benedetta; Ferramosca, Alessandra; Zara, Vincenzo

2015-05-01

In Saccharomyces cerevisiae the mature cytochrome bc1 complex exists as an obligate homo-dimer in which each monomer consists of ten distinct protein subunits inserted into or bound to the inner mitochondrial membrane. Among them, the Rieske iron-sulfur protein (Rip1), besides its catalytic role in electron transfer, may be implicated in the bc1 complex dimerization. Indeed, Rip1 has the globular domain containing the catalytic center in one monomer while the transmembrane helix interacts with the adjacent monomer. In addition, the lack of Rip1 leads to the accumulation of an immature bc1 intermediate, only loosely associated with cytochrome c oxidase. In this study we have investigated the biogenesis of the yeast cytochrome bc1 complex using epitope tagged proteins to purify native assembly intermediates. We showed that the dimerization process is an early event during bc1 complex biogenesis and that the presence of Rip1, differently from previous proposals, is not essential for this process. We also investigated the multi-step model of bc1 assembly thereby lending further support to the existence of bona fide subcomplexes during bc1 maturation in the inner mitochondrial membrane. Finally, a new model of cytochrome bc1 complex assembly, in which distinct intermediates sequentially interact during bc1 maturation, has been proposed. Copyright © 2015 Elsevier B.V. All rights reserved.

Temporal Pattern and Crosstalk of Necroptosis Markers with Autophagy and Apoptosis Associated Proteins in Ischemic Hippocampus.

PubMed

Ryan, Fari; Khodagholi, Fariba; Dargahi, Leila; Minai-Tehrani, Dariush; Ahmadiani, Abolhassan

2018-01-08

Necroptosis, a novel type of programmed cell death, has been recently implicated as a possible mechanism for cerebral ischemia-reperfusion (I/R) injury. We herein studied time-dependent changes of necroptosis markers along with apoptosis- and autophagy-associated proteins in rat hippocampus at 1, 3, 6, 12, 24, and 48 h after global cerebral I/R injury. Furthermore, to determine the cross talk between autophagy and necroptosis, we examined the effects of pretreatment with bafilomycin-A1 (Baf-A1), as a late-stage autophagy inhibitor, on necroptosis. Highest levels of receptor-interacting protein 1 and 3 (RIP1 and RIP3), as key mediators of necroptosis, were observed at 24 h after reperfusion. Alongside, activity of glutamate dehydrogenase (GLUD1), downstream enzyme of RIP3, was increased. Peak time of necroptosis was subsequent to caspase-3-dependent cell death that peaked at 12 h of reperfusion but concurrent with autophagy. Administration of Baf-A1 could attenuate necroptosis, verified by decrease in RIP1 and RIP3 protein levels, as well as GLUD1 activity. However, there was no significant change in caspase-3-dependent cell death. Taken together, our results highlight that global cerebral I/R activates necroptosis that could be triggered by autophagy and interacts reversely with caspase-3-dependent apoptosis.

Learning Styles versus the Rip Van Winkle Syndrome.

ERIC Educational Resources Information Center

Orsak, Lana

1990-01-01

Rip Van Winkle would not recognize Corsicana (Texas) High School since its curriculum coordinator began implementing learning styles techniques in various pilot programs. Lecturing to rows of bored students has been replaced by students' active involvement in group activities, listening centers, and tactile/kinesthetic exercises on the floor or at…

Caspase Inhibition Prevents Tumor Necrosis Factor-α-Induced Apoptosis and Promotes Necrotic Cell Death in Mouse Hepatocytes in Vivo and in Vitro.

PubMed

Ni, Hong-Min; McGill, Mitchell R; Chao, Xiaojuan; Woolbright, Benjamin L; Jaeschke, Hartmut; Ding, Wen-Xing

2016-10-01

How different cell death modes and cell survival pathways cross talk remains elusive. We determined the interrelation of apoptosis, necrosis, and autophagy in tumor necrosis factor (TNF)-α/actinomycin D (ActD) and lipopolysaccharide/D-galactosamine (GalN)-induced hepatotoxicity in vitro and in vivo. We found that TNF-α/ActD-induced apoptosis was completely blocked by a general caspase inhibitor ZVAD-fmk at 24 hours but hepatocytes still died by necrosis at 48 hours. Inhibition of caspases also protected mice against lipopolysaccharide/GalN-induced apoptosis and liver injury at the early time point, but this protection was diminished after prolonged treatment by switching apoptosis to necrosis. Inhibition of receptor-interacting protein kinase (RIP)1 by necrostatin 1 partially inhibited TNF-α/ZVAD-induced necrosis in primary hepatocytes. Pharmacologic inhibition of autophagy or genetic deletion of Atg5 in hepatocytes did not protect against TNF-α/ActD/ZVAD-induced necrosis. Moreover, pharmacologic inhibition of RIP1 or genetic deletion of RIP3 failed to protect and even exacerbated liver injury after mice were treated with lipopolysaccharide/GalN and a pan-caspase inhibitor. In conclusion, our results suggest that different cell death mode and cell survival pathways are closely integrated during TNF-α-induced liver injury when both caspases and NF-κB are blocked. Moreover, results from our study also raised concerns about the safety of currently ongoing clinical trials that use caspase inhibitors. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Engineering a switch-on peptide to ricin A chain for increasing its specificity towards HIV-infected cells.

PubMed

Au, Ka-Yee; Wang, Rui-Rui; Wong, Yuen-Ting; Wong, Kam-Bo; Zheng, Yong-Tang; Shaw, Pang-Chui

2014-03-01

Ricin is a type II ribosome-inactivating protein (RIP) that potently inactivates eukaryotic ribosomes by removing a specific adenine residue at the conserved α-sarcin/ricin loop of 28S ribosomal RNA (rRNA). Here, we try to increase the specificity of the enzymatically active ricin A chain (RTA) towards human immunodeficiency virus type 1 (HIV-1) by adding a loop with HIV protease recognition site to RTA. HIV-specific RTA variants were constructed by inserting a peptide with HIV-protease recognition site either internally or at the C-terminal region of wild type RTA. Cleavability of variants by viral protease was tested in vitro and in HIV-infected cells. The production of viral p24 antigen and syncytium in the presence of C-terminal variants was measured to examine the anti-HIV activities of the variants. C-terminal RTA variants were specifically cleaved by HIV-1 protease both in vitro and in HIV-infected cells. Upon proteolysis, the processed variants showed enhanced antiviral effect with low cytotoxicity towards uninfected cells. RTA variants with HIV protease recognition sequence engineered at the C-terminus were cleaved and the products mediated specific inhibitory effect towards HIV replication. Current cocktail treatment of HIV infection fails to eradicate the virus from patients. Here we illustrate the feasibility of targeting an RIP towards HIV-infected cells by incorporation of HIV protease cleavage sequence. This approach may be generalized to other RIPs and is promising in drug design for combating HIV. Copyright © 2013 Elsevier B.V. All rights reserved.

Simulator Evaluation of Runway Incursion Prevention Technology for General Aviation Operations

NASA Technical Reports Server (NTRS)

Jones, Denise R.; Prinzel, Lawrence J., III

2011-01-01

A Runway Incursion Prevention System (RIPS) has been designed under previous research to enhance airport surface operations situation awareness and provide cockpit alerts of potential runway conflict, during transport aircraft category operations, in order to prevent runway incidents while also improving operations capability. This study investigated an adaptation of RIPS for low-end general aviation operations using a fixed-based simulator at the National Aeronautics and Space Administration (NASA) Langley Research Center (LaRC). The purpose of the study was to evaluate modified RIPS aircraft-based incursion detection algorithms and associated alerting and airport surface display concepts for low-end general aviation operations. This paper gives an overview of the system, simulation study, and test results.

Application of remote sensing for fishery resource assessment and monitoring. [analysis of fish catch relative to water rips

NASA Technical Reports Server (NTRS)

Savastano, K. J. (Principal Investigator)

1974-01-01

The author has identified the following significant results. A plot was drawn of the dolphin catch and the water discontinuities observed in the aerial photography. This plot was similar in format to the one made earlier on the white marlin catch relative to the water rips. Neither plot substantiates (as far as white marlin and dolphin are concerned) an opinion held by fishermen that better fishing may be found in the vicinity of the rips. Remotely inferred values for sea surface temperature, chlorophyll-a and turbidity were substituted for sea truth measurements in prediction models developed in previous analysis. Model performance, using the new values, was disappointing.

Structural basis of death domain signaling in the p75 neurotrophin receptor

PubMed Central

Lin, Zhi; Tann, Jason Y; Goh, Eddy TH; Kelly, Claire; Lim, Kim Buay; Gao, Jian Fang; Ibanez, Carlos F

2015-01-01

Death domains (DDs) mediate assembly of oligomeric complexes for activation of downstream signaling pathways through incompletely understood mechanisms. Here we report structures of complexes formed by the DD of p75 neurotrophin receptor (p75NTR) with RhoGDI, for activation of the RhoA pathway, with caspase recruitment domain (CARD) of RIP2 kinase, for activation of the NF-kB pathway, and with itself, revealing how DD dimerization controls access of intracellular effectors to the receptor. RIP2 CARD and RhoGDI bind to p75NTR DD at partially overlapping epitopes with over 100-fold difference in affinity, revealing the mechanism by which RIP2 recruitment displaces RhoGDI upon ligand binding. The p75NTR DD forms non-covalent, low-affinity symmetric dimers in solution. The dimer interface overlaps with RIP2 CARD but not RhoGDI binding sites, supporting a model of receptor activation triggered by separation of DDs. These structures reveal how competitive protein-protein interactions orchestrate the hierarchical activation of downstream pathways in non-catalytic receptors. DOI: http://dx.doi.org/10.7554/eLife.11692.001 PMID:26646181

Distance Determination by Gated Viewing Systems Taking into Account the Illuminating Pulse Shape

NASA Astrophysics Data System (ADS)

Gorobets, V. A.; Kuntsevich, B. F.; Shabrov, D. V.

2017-11-01

For gated viewing systems with triangular and trapezoidal illuminating pulses, we have obtained the range-intensity profiles (RIPs) of the signal as the time delay was varied between the leading edges of the gate pulse and the illuminating pulse. We have established that if the duration of the illuminating pulse Δtlas is less than or equal to the duration of the gate pulse ΔtIC, then the expressions for the characteristic distances are the same as for rectangular pulses and they can be used to determine the distance to objects. When Δtlas > ΔtIC, in the case of triangular illuminating pulses the RIP is bell-shaped. For trapezoidal pulses, the RIP is bell-shaped with or without a plateau section. We propose an empirical method for determining the characteristic distances to the RIP maximum and the boundary points for the plateau section, which we then use to calculate the distance to the object. Using calibration constants, we propose a method for determining the distance to an object and we have experimentally confirmed the feasibility of this method.

Type I interferon enhances necroptosis of Salmonella Typhimurium–infected macrophages by impairing antioxidative stress responses

PubMed Central

Hos, Nina Judith; Hos, Deniz; Klimek, Jennifer; Abdullah, Zeinab; Krönke, Martin

2017-01-01

Salmonella enterica serovar Typhimurium exploits the host’s type I interferon (IFN-I) response to induce receptor-interacting protein (RIP) kinase–mediated necroptosis in macrophages. However, the events that drive necroptosis execution downstream of IFN-I and RIP signaling remain elusive. In this study, we demonstrate that S. Typhimurium infection causes IFN-I–mediated up-regulation of the mitochondrial phosphatase Pgam5 through RIP3. Pgam5 subsequently interacts with Nrf2, which sequesters Nrf2 in the cytosol, thereby repressing the transcription of Nrf2-dependent antioxidative genes. The impaired ability to respond to S. Typhimurium–induced oxidative stress results in reactive oxygen species–mediated mitochondrial damage, energy depletion, transient induction of autophagy, and autophagic degradation of p62. Reduced p62 levels impair interaction of p62 with Keap1, which further decreases Nrf2 function and antioxidative responses to S. Typhimurium infection, eventually leading to cell death. Collectively, we identify impaired Nrf2-dependent redox homeostasis as an important mechanism that promotes cell death downstream of IFN-I and RIP3 signaling in S. Typhimurium–infected macrophages. PMID:29055012

Resident intruder paradigm-induced aggression relieves depressive-like behaviors in male rats subjected to chronic mild stress

PubMed Central

Wei, Sheng; Ji, Xiao-wei; Wu, Chun-ling; Li, Zi-fa; Sun, Peng; Wang, Jie-qiong; Zhao, Qi-tao; Gao, Jie; Guo, Ying-hui; Sun, Shi-guang; Qiao, Ming-qi

2014-01-01

Background Accumulating epidemiological evidence shows that life event stressors are major vulnerability factors for psychiatric diseases such as major depression. It is also well known that the resident intruder paradigm (RIP) results in aggressive behavior in male rats. However, it is not known how resident intruder paradigm-induced aggression affects depressive-like behavior in isolated male rats subjected to chronic mild stress (CMS), which is an animal model of depression. Material/Methods Male Wistar rats were divided into 3 groups: non-stressed controls, isolated rats subjected to the CMS protocol, and resident intruder paradigm-exposed rats subjected to the CMS protocol. Results In the sucrose intake test, ingestion of a 1% sucrose solution by rats in the CMS group was significantly lower than in control and CMS+RIP rats after 3 weeks of stress. In the open-field test, CMS rats had significantly lower open-field scores compared to control rats. Furthermore, the total scores given the CMS group were significantly lower than in the CMS+RIP rats. In the forced swimming test (FST), the immobility times of CMS rats were significantly longer than those of the control or CMS+RIP rats. However, no differences were observed between controls and CMS+RIP rats. Conclusions Our data show that aggressive behavior evoked by the resident intruder paradigm could relieve broad-spectrum depressive-like behaviors in isolated adult male rats subjected to CMS. PMID:24911067

Breaking the DNA-binding code of Ralstonia solanacearum TAL effectors provides new possibilities to generate plant resistance genes against bacterial wilt disease.

PubMed

de Lange, Orlando; Schreiber, Tom; Schandry, Niklas; Radeck, Jara; Braun, Karl Heinz; Koszinowski, Julia; Heuer, Holger; Strauß, Annett; Lahaye, Thomas

2013-08-01

Ralstonia solanacearum is a devastating bacterial phytopathogen with a broad host range. Ralstonia solanacearum injected effector proteins (Rips) are key to the successful invasion of host plants. We have characterized Brg11(hrpB-regulated 11), the first identified member of a class of Rips with high sequence similarity to the transcription activator-like (TAL) effectors of Xanthomonas spp., collectively termed RipTALs. Fluorescence microscopy of in planta expressed RipTALs showed nuclear localization. Domain swaps between Brg11 and Xanthomonas TAL effector (TALE) AvrBs3 (avirulence protein triggering Bs3 resistance) showed the functional interchangeability of DNA-binding and transcriptional activation domains. PCR was used to determine the sequence of brg11 homologs from strains infecting phylogenetically diverse host plants. Brg11 localizes to the nucleus and activates promoters containing a matching effector-binding element (EBE). Brg11 and homologs preferentially activate promoters containing EBEs with a 5' terminal guanine, contrasting with the TALE preference for a 5' thymine. Brg11 and other RipTALs probably promote disease through the transcriptional activation of host genes. Brg11 and the majority of homologs identified in this study were shown to activate similar or identical target sequences, in contrast to TALEs, which generally show highly diverse target preferences. This information provides new options for the engineering of plants resistant to R. solanacearum. © 2013 The Authors. New Phytologist © 2013 New Phytologist Trust.

Circulating Current Suppressing Control’s Impact on Arm Inductance Selection for Modular Multilevel Converter

DOE PAGES

Li, Yalong; Jones, Edward A.; Wang, Fred

2016-10-13

Arm inductor in a modular multilevel converter (MMC) is used to limit the circulating current and dc short circuit fault current. The circulating current in MMC is dominated by second-order harmonic, which can be largely reduced with circulating current suppressing control. By analyzing the mechanism of the circulating current suppressing control, it is found that the circulating current at switching frequency becomes the main harmonic when suppression control is implemented. Unlike the second-order harmonic that circulates only within the three phases, switching frequency harmonic also flows through the dc side and may further cause high-frequency dc voltage harmonic. This articlemore » develops the theoretical relationship between the arm inductance and switching frequency circulating current, which can be used to guide the arm inductance selection. The experimental results with a downscaled MMC prototype verify the existence of the switching frequency circulating current and its relationship with arm inductance.« less

Resistance to hypoxia-induced necroptosis is conferred by glycolytic pyruvate scavenging of mitochondrial superoxide in colorectal cancer cells.

PubMed

Huang, C-Y; Kuo, W-T; Huang, Y-C; Lee, T-C; Yu, L C H

2013-05-02

Cancer cells may survive under oxygen and nutrient deprivation by metabolic reprogramming for high levels of anaerobic glycolysis, which contributes to tumor growth and drug resistance. Abnormally expressed glucose transporters (GLUTs) are colocalized with hypoxia (Hx) inducible factor (HIF)1α in peri-necrotic regions in human colorectal carcinoma. However, the underlying mechanisms of anti-necrotic resistance conferred by glucose metabolism in hypoxic cancer cells remain poorly understood. Our aim was to investigate signaling pathways of Hx-induced necroptosis and explore the role of glucose pyruvate metabolite in mechanisms of death resistance. Human colorectal carcinoma cells were Hx exposed with or without glucose, and cell necroptosis was examined by receptor-interacting protein (RIP)1/3 kinase immunoprecipitation and (32)P kinase assays. Our results showed increased RIP1/3 complex formation and phosphorylation in hypoxic, but not normoxic cells in glucose-free media. Blocking RIP1 signaling, by necrostatin-1 or gene silencing, decreased lactodehydrogenase (LDH) leakage and plasma membrane disintegration. Generation of mitochondrial superoxide was noted after hypoxic challenge; its reduction by antioxidants inhibited RIP signaling and cell necrosis. Supplementation of glucose diminished the RIP-dependent LDH leakage and morphological damage in hypoxic cells, whereas non-metabolizable sugar analogs did not. Hypoxic cells given glucose showed nuclear translocation of HIF1α associated with upregulation of GLUT-1 and GLUT-4 expression, as well as increase of intracellular ATP, pyruvate and lactate levels. The glucose-mediated death resistance was ablated by iodoacetate (an inhibitor to glyceraldehyde-3-phosphate dehydrogenase), but not by UK5099 (an inhibitor to mitochondrial pyruvate carrier), suggesting that glycolytic pathway was involved in anti-necrotic mechanism. Lastly, replacing glucose with cell-permeable pyruvate derivative also led to decrease of Hx-induced necroptosis by suppression of mitochondrial superoxide in an energy-independent manner. In conclusion, glycolytic metabolism confers resistance to RIP-dependent necroptosis in hypoxic cancer cells partly through pyruvate scavenging of mitochondrial free radicals.

Use of Chest Wall Electromyography to Detect Respiratory Effort during Polysomnography

PubMed Central

Berry, Richard B.; Ryals, Scott; Girdhar, Ankur; Wagner, Mary H.

2016-01-01

Study Objectives: To evaluate the ability of chest wall EMG (CW-EMG) using surface electrodes to classify apneas as obstructive, mixed, or central compared to classification using dual channel uncalibrated respiratory inductance plethysmography (RIP). Methods: CW-EMG was recorded from electrodes in the eighth intercostal space at the right mid-axillary line. Consecutive adult clinical sleep studies were retrospectively reviewed, and the first 60 studies with at least 10 obstructive and 10 mixed or central apneas and technically adequate tracings were selected. Four obstructive and six central or mixed apneas (as classified by previous clinical scoring) were randomly selected. A blinded experienced scorer classified the apneas on the basis of tracings showing either RIP channels or the CW-EMG channel. The agreement using the two classification methods was determined by kappa analysis and intraclass correlation. Results: The percentage agreement was 89.5%, the kappa statistic was 0.83 (95% confidence interval 0.79 to 0.87), and the intraclass correlation was 0.83, showing good agreement. Of the 249 apneas classified as central by RIP, 26 were classified as obstructive (10.4%) and 7 as mixed (2.8%) by CW-EMG. Of the 229 events classified as central by CW-EMG, 7 (3.1%) were classified as obstructive and 6 (2.6%) as mixed by RIP. Conclusions: Monitoring CW-EMG may provide a clinically useful method of detection of respiratory effort when used with RIP and can prevent false classification of apneas as central. RIP can rarely detect respiratory effort not easily discernible by CW-EMG and the combination of the two methods is more likely to avoid apnea misclassification. Citation: Berry RB, Ryals S, Girdhar A, Wagner MH. Use of chest wall electromyography to detect respiratory effort during polysomnography. J Clin Sleep Med 2016;12(9):1239–1244. PMID:27306391

Endothelial cell-derived exosomes protect SH-SY5Y nerve cells against ischemia/reperfusion injury.

PubMed

Xiao, Bing; Chai, Yi; Lv, Shigang; Ye, Minhua; Wu, Miaojing; Xie, Liyuan; Fan, Yanghua; Zhu, Xingen; Gao, Ziyun

2017-10-01

Cerebral ischemia is a leading cause of death and disability. A previous study indicated that remote ischemic postconditioning (RIP) in the treatment of cerebral ischemia reduces ischemia/reperfusion (I/R) injury. However, the underlying mechanism is not well understood. In the present study, the authors hypothesized that the protective effect of RIP on neurological damage is mediated by exosomes that are released by endothelial cells in femoral arteries. To test this, right middle cerebral artery occlusion/reperfusion with RIP was performed in rats. In addition, an I/R injury cell model was tested that included human umbilical vein endothelial cells (HUVECs) and SH-SY5Y cells. Both the in vivo and in vitro models were examined for injury. Markers of exosomes (CD63, HSP70 and TSG101) were assessed by immunohistochemistry, western blot analysis and flow cytometry. Exosomes were extracted from both animal serum and HUVEC culture medium and identified by electron microscopy. They investigated the role of endothelial cell-derived exosomes in the proliferation, apoptosis, cell cycle, migration and invasion of I/R-injured SH-SY5Y cells. In addition, apoptosis-related molecules caspase-3, Bax and Bcl-2 were detected. RIP was determined to increase the number of exosomes and the expression levels of CD63, HSP70 and TSG101 in plasma, but not in brain hippocampal tissue. The size of exosomes released after I/R in HUVECs was similar to the size of exosomes released in rats subjected to RIP. Endothelial cell-derived exosomes partly suppressed the I/R-induced cell cycle arrest and apoptosis, and inhibited cell proliferation, migration and invasion in SH-SY5Y nerve cells. Endothelial cell-derived exosomes directly protect nerve cells against I/R injury, and are responsible for the protective role of RIP in I/R.

Protective Effect of Unacylated Ghrelin on Compression-Induced Skeletal Muscle Injury Mediated by SIRT1-Signaling

PubMed Central

Ugwu, Felix N.; Yu, Angus P.; Sin, Thomas K.; Tam, Bjorn T.; Lai, Christopher W.; Wong, S. C.; Siu, Parco M.

2017-01-01

Unacylated ghrelin, the predominant form of circulating ghrelin, protects myotubes from cell death, which is a known attribute of pressure ulcers. In this study, we investigated whether unacylated ghrelin protects skeletal muscle from pressure-induced deep tissue injury by abolishing necroptosis and apoptosis signaling and whether these effects were mediated by SIRT1 pathway. Fifteen adult Sprague Dawley rats were assigned to receive saline or unacylated ghrelin with or without EX527 (a SIRT1 inhibitor). Animals underwent two 6-h compression cycles with 100 mmHg static pressure applied over the mid-tibialis region of the right limb whereas the left uncompressed limb served as the intra-animal control. Muscle tissues underneath the compression region, and at the similar region of the opposite uncompressed limb, were collected for analysis. Unacylated ghrelin attenuated the compression-induced muscle pathohistological alterations including rounding contour of myofibers, extensive nucleus accumulation in the interstitial space, and increased interstitial space. Unacylated ghrelin abolished the increase in necroptosis proteins including RIP1 and RIP3 and attenuated the elevation of apoptotic proteins including p53, Bax, and AIF in the compressed muscle. Furthermore, unacylated ghrelin opposed the compression-induced phosphorylation and acetylation of p65 subunit of NF-kB. The anti-apoptotic effect of unacylated ghrelin was shown by a decrease in apoptotic DNA fragmentation and terminal dUTP nick-end labeling index in the compressed muscle. The protective effects of unacylated ghrelin vanished when co-treated with EX527. Our findings demonstrated that unacylated ghrelin protected skeletal muscle from compression-induced injury. The myoprotective effects of unacylated ghrelin on pressure-induced tissue injury were associated with SIRT1 signaling. PMID:29225581

Sub-lethal radiation enhances anti-tumor immunotherapy in a transgenic mouse model of pancreatic cancer

PubMed Central

Cao, Zhu Alexander; Daniel, Dylan; Hanahan, Douglas

2002-01-01

Background It is not uncommon to observe circulating tumor antigen-specific T lymphocytes in cancer patients despite a lack of significant infiltration and destruction of their tumors. Thus, an important goal for tumor immunotherapy is to identify ways to modulate in vivo anti-tumor immunity to achieve clinical efficacy. We investigate this proposition in a spontaneous mouse tumor model, Rip1-Tag2. Methods Experimental therapies were carried out in two distinctive trial designs, intended to either intervene in the explosive growth of small tumors, or regress bulky end-stage tumors. Rip1-Tag2 mice received a single transfer of splenocytes from Tag-specific, CD4+ T cell receptor transgenic mice, a single sub-lethal radiation, or a combination therapy in which the lymphocyte transfer was preceded by the sub-lethal radiation. Tumor burden, the extent of lymphocyte infiltration into solid tumors and host survival were used to assess the efficacy of these therapeutic approaches. Results In either intervention or regression, the transfer of Tag-specific T cells alone did not result in significant lymphocyte infiltration into solid tumors, not did it affect tumor growth or host survival. In contrast, the combination therapy resulted in significant reduction in tumor burden, increase in lymphocyte infiltration into solid tumors, and extension of survival. Conclusions The results indicate that certain types of solid tumors may be intrinsically resistant to infiltration and destruction by tumor-specific T lymphocytes. Our data suggest that such resistance can be disrupted by sub-lethal radiation. The combinatorial approach presented here merits consideration in the design of clinical trials aimed to achieve T cell-mediated anti-tumor immunity. PMID:12019035

Does gang ripping hold the potential for higher clear cutting yields

Treesearch

Hiram Hallock; Pamela Giese

1980-01-01

Cutting yields from gang ripping hardwood lumber graded by the National Hardwood Lumber Association standard grades are determined using the technique of mathematical modeling. The lumber used is the same as that in an earlier mathematically modeled determination of cutting yields from traditional rough mill procedures. Mechanical cutting factors such as kerf, cutting...

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Yalong; Jones, Edward A.; Wang, Fred

Arm inductor in a modular multilevel converter (MMC) is used to limit the circulating current and dc short circuit fault current. The circulating current in MMC is dominated by second-order harmonic, which can be largely reduced with circulating current suppressing control. By analyzing the mechanism of the circulating current suppressing control, it is found that the circulating current at switching frequency becomes the main harmonic when suppression control is implemented. Unlike the second-order harmonic that circulates only within the three phases, switching frequency harmonic also flows through the dc side and may further cause high-frequency dc voltage harmonic. This articlemore » develops the theoretical relationship between the arm inductance and switching frequency circulating current, which can be used to guide the arm inductance selection. The experimental results with a downscaled MMC prototype verify the existence of the switching frequency circulating current and its relationship with arm inductance.« less

Necroptosis in cancer: An angel or a demon?

PubMed

Wang, Tianzhen; Jin, Yinji; Yang, Weiwei; Zhang, Lei; Jin, Xiaoming; Liu, Xi; He, Yan; Li, Xiaobo

2017-06-01

In the past few decades, apoptosis has been regarded as the only form of programmed cell death. However, the traditional view has been challenged by the identification of several forms of regulated necrosis, including necroptosis. Necroptosis is typified by a necrotic cell death morphology and is controlled by RIP1, RIP3, and mixed lineage kinase domain-like protein. The physiological role of necroptosis is to serve as a "fail-safe" form of cell death for cells that fail to undergo apoptosis during embryonic development and disease defense. Currently, established studies have indicated that necroptosis is involved in cancer initiation and progression. Although elevated necroptosis contributes to cancer cell death, extensive cell death also increases the risk of proliferation and metastasis of the surviving cells by inducing the generation reactive oxygen species, activation of inflammation, and suppression of the immune response. Thus, questions regarding the overall impact of necroptosis on cancer remain open. In this review, we introduce the basic knowledge regarding necroptosis, summarize its dual effects on cancer progression, and analyze its advantages and disadvantages in clinical applications.

Real price and affordability as challenges for effective tobacco control policies: an analysis for Argentina.

PubMed

Rodríguez-Iglesias, Germán; González-Rozada, Martín; Champagne, Beatriz Marcet; Schoj, Verónica

2015-02-01

To describe the evolution of cigarettes' real price and affordability during the last decade in Argentina. To analyze the real price of cigarettes, the weighted average monthly price of a pack of 20 cigarettes was divided by the consumer price index (CPI) from 2004 to 2014. The relative income price (RIP) was evaluated for the same period, defining RIP as the percentage of the income required to buy 100 packs of 20-per-pack cigarettes. The RIP was calculated for first-quartile, median, and third-quartile income groups. The lower the RIP, the higher the affordability. The nominal price of a pack of 20 cigarettes sold in Argentina increased from AR$ 2.24 in March 2004 to AR$ 14.36 in June 2014 (nominal price increase of about 19.7% per year). The real price fell from AR$ 2.24 in March 2004 to AR$ 2.11 in June 2014 (real price drop of about 0.6% per year). Between June 2004 and June 2014, the RIP decreased about 39% for the 3rd quartile income group (from 31.3% to 19.2%), about 42% for the median (from 55.7% to 32.0%), and about 50% for the 1st quartile (from 104.4% to 51.8%). In Argentina, inflation and rising income were greater than growth in cigarette prices. Cigarette affordability increased for each income group, with the highest shifts occurring among the poorest and most vulnerable income earners. The increased affordability of cigarettes might reduce the impact of implemented tobacco control policies.

Towards a theoretical determination of the geographical probability distribution of meteoroid impacts on Earth

NASA Astrophysics Data System (ADS)

Zuluaga, Jorge I.; Sucerquia, Mario

2018-06-01

Tunguska and Chelyabinsk impact events occurred inside a geographical area of only 3.4 per cent of the Earth's surface. Although two events hardly constitute a statistically significant demonstration of a geographical pattern of impacts, their spatial coincidence is at least tantalizing. To understand if this concurrence reflects an underlying geographical and/or temporal pattern, we must aim at predicting the spatio-temporal distribution of meteoroid impacts on Earth. For this purpose we designed, implemented, and tested a novel numerical technique, the `Gravitational Ray Tracing' (GRT) designed to compute the relative impact probability (RIP) on the surface of any planet. GRT is inspired by the so-called ray-casting techniques used to render realistic images of complex 3D scenes. In this paper we describe the method and the results of testing it at the time of large impact events. Our findings suggest a non-trivial pattern of impact probabilities at any given time on the Earth. Locations at 60-90° from the apex are more prone to impacts, especially at midnight. Counterintuitively, sites close to apex direction have the lowest RIP, while in the antapex RIP are slightly larger than average. We present here preliminary maps of RIP at the time of Tunguska and Chelyabinsk events and found no evidence of a spatial or temporal pattern, suggesting that their coincidence was fortuitous. We apply the GRT method to compute theoretical RIP at the location and time of 394 large fireballs. Although the predicted spatio-temporal impact distribution matches marginally the observed events, we successfully predict their impact speed distribution.

Anatomical Evidence that the Superior Colliculus Controls Saccades through Central Mesencephalic Reticular Formation Gating of Omnipause Neuron Activity

PubMed Central

Wang, Niping; Perkins, Eddie; Zhou, Lan; Warren, Susan

2013-01-01

Omnipause neurons (OPNs) within the nucleus raphe interpositus (RIP) help gate the transition between fixation and saccadic eye movements by monosynaptically suppressing activity in premotor burst neurons during fixation, and releasing them during saccades. Premotor neuron activity is initiated by excitatory input from the superior colliculus (SC), but how the tectum's saccade-related activity turns off OPNs is not known. Since the central mesencephalic reticular formation (cMRF) is a major SC target, we explored whether this nucleus has the appropriate connections to support tectal gating of OPN activity. In dual-tracer experiments undertaken in macaque monkeys (Macaca fascicularis), cMRF neurons labeled retrogradely from injections into RIP had numerous anterogradely labeled terminals closely associated with them following SC injections. This suggested the presence of an SC–cMRF–RIP pathway. Furthermore, anterograde tracers injected into the cMRF of other macaques labeled axonal terminals in RIP, confirming this cMRF projection. To determine whether the cMRF projections gate OPN activity, postembedding electron microscopic immunochemistry was performed on anterogradely labeled cMRF terminals with antibody to GABA or glycine. Of the terminals analyzed, 51.4% were GABA positive, 35.5% were GABA negative, and most contacted glycinergic cells. In summary, a trans-cMRF pathway connecting the SC to the RIP is present. This pathway contains inhibitory elements that could help gate omnipause activity and allow other tectal drives to induce the bursts of firing in premotor neurons that are necessary for saccades. The non-GABAergic cMRF terminals may derive from fixation units in the cMRF. PMID:24107960

Necroptosis in microglia contributes to neuroinflammation and retinal degeneration through TLR4 activation.

PubMed

Huang, Zijing; Zhou, Tian; Sun, Xiaowei; Zheng, Yingfeng; Cheng, Bing; Li, Mei; Liu, Xialin; He, Chang

2018-01-01

Inflammation has emerged to be a critical mechanism responsible for neural damage and neurodegenerative diseases. Microglia, the resident innate immune cells in retina, are implicated as principal components of the immunological insult to retinal neural cells. The involvement of microglia in retinal inflammation is complex and here we propose for the first time that necroptosis in microglia triggers neuroinflammation and exacerbates retinal neural damage and degeneration. We found microglia experienced receptor-interacting protein kinase 1 (RIP1)- and RIP3-dependent necroptosis not only in the retinal degenerative rd1 mice, but also in the acute retinal neural injury mice. The necroptotic microglia released various pro-inflammatory cytokines and chemokines, such as tumor necrosis factor-α and chemokine (C-C motif) ligand 2, which orchestrated the retinal inflammation. Importantly, necroptosis blockade using necrostatin-1 could suppress microglia-mediated inflammation, rescue retinal degeneration or prevent neural injury in vivo. Meanwhile, cultured microglia underwent RIP1/3-mediated necroptosis and the necroptotic microglia produced large amounts of pro-inflammatory cytokines in response to lipopolysaccharide or oxidative stress in vitro. Mechanically, TLR4 deficiency ameliorated microglia necroptosis with decreased expression levels of machinery molecules RIP1 and RIP3, and suppressed retinal inflammation, suggesting that TLR4 signaling was required in microglia necroptosis-mediated inflammation. Thus, we proposed that microglia experienced necroptosis through TLR4 activation, promoting an inflammatory response that serves to exacerbate considerable neural damage and degeneration. Necroptosis blockade therefore emerged as a novel therapeutic strategy for tempering microglia-mediated neuroinflammation and ameliorating neural injury and neurodegenerative diseases.

Necroptosis in microglia contributes to neuroinflammation and retinal degeneration through TLR4 activation

PubMed Central

Huang, Zijing; Zhou, Tian; Sun, Xiaowei; Zheng, Yingfeng; Cheng, Bing; Li, Mei; Liu, Xialin; He, Chang

2018-01-01

Inflammation has emerged to be a critical mechanism responsible for neural damage and neurodegenerative diseases. Microglia, the resident innate immune cells in retina, are implicated as principal components of the immunological insult to retinal neural cells. The involvement of microglia in retinal inflammation is complex and here we propose for the first time that necroptosis in microglia triggers neuroinflammation and exacerbates retinal neural damage and degeneration. We found microglia experienced receptor-interacting protein kinase 1 (RIP1)- and RIP3-dependent necroptosis not only in the retinal degenerative rd1 mice, but also in the acute retinal neural injury mice. The necroptotic microglia released various pro-inflammatory cytokines and chemokines, such as tumor necrosis factor-α and chemokine (C-C motif) ligand 2, which orchestrated the retinal inflammation. Importantly, necroptosis blockade using necrostatin-1 could suppress microglia-mediated inflammation, rescue retinal degeneration or prevent neural injury in vivo. Meanwhile, cultured microglia underwent RIP1/3-mediated necroptosis and the necroptotic microglia produced large amounts of pro-inflammatory cytokines in response to lipopolysaccharide or oxidative stress in vitro. Mechanically, TLR4 deficiency ameliorated microglia necroptosis with decreased expression levels of machinery molecules RIP1 and RIP3, and suppressed retinal inflammation, suggesting that TLR4 signaling was required in microglia necroptosis-mediated inflammation. Thus, we proposed that microglia experienced necroptosis through TLR4 activation, promoting an inflammatory response that serves to exacerbate considerable neural damage and degeneration. Necroptosis blockade therefore emerged as a novel therapeutic strategy for tempering microglia-mediated neuroinflammation and ameliorating neural injury and neurodegenerative diseases. PMID:28885615

Minesoil grading and ripping affect black walnut growth and survival

DOE Office of Scientific and Technical Information (OSTI.GOV)

Josiah, S.J.

In 1980 and 1981, the Botany Department of Southern Illinois University and Sahara Coal Company, Inc. of Harrisburg, Illinois established a series of experimental tree plantings, including black walnut, on a variety of minesoils to explore the effects of different intensities of grading on tree growth. Subsequent walnut stem and root growth were examined during 1985 on five different mine sites: unmined former agricultural land, graded minespoil, replaced (with pan scrapers) topsoil over graded spoil, ripped-graded spoil, and ungraded spoil. Soil bulk density, resistance to penetration, and spoil/soil fertility levels were also measured. The most vigorous trees were found onmore » sites having the lowest soil bulk density and soil strength and lacking horizontal barriers to root growth - the ungraded and ripped sites. Topsoiled sites had the poorest growth and survival, and the greatest stem dieback of any site measured, probably attributable to the confinement of root growth to the upper 15 cm of friable soil above the severely compacted zone. The overall results indicate that most of the minesoil construction techniques examined in this study, which are representative of techniques commonly used in the midwestern US, cause severe minesoil compaction and do not create the proper soil conditions necessary for the survival and vigorous growth of black walnut. Ripping compacted spoil in this and other studies proved to be very effective in alleviating the negative impacts of minesoil compaction. When planning surface mine reclamation activities, ripping should be considered as a possible ameliorative technique when compaction of mined lands is unavoidable and trees are the desired vegetative cover. 4 figures.« less

Anatomical evidence that the superior colliculus controls saccades through central mesencephalic reticular formation gating of omnipause neuron activity.

PubMed

Wang, Niping; Perkins, Eddie; Zhou, Lan; Warren, Susan; May, Paul J

2013-10-09

Omnipause neurons (OPNs) within the nucleus raphe interpositus (RIP) help gate the transition between fixation and saccadic eye movements by monosynaptically suppressing activity in premotor burst neurons during fixation, and releasing them during saccades. Premotor neuron activity is initiated by excitatory input from the superior colliculus (SC), but how the tectum's saccade-related activity turns off OPNs is not known. Since the central mesencephalic reticular formation (cMRF) is a major SC target, we explored whether this nucleus has the appropriate connections to support tectal gating of OPN activity. In dual-tracer experiments undertaken in macaque monkeys (Macaca fascicularis), cMRF neurons labeled retrogradely from injections into RIP had numerous anterogradely labeled terminals closely associated with them following SC injections. This suggested the presence of an SC-cMRF-RIP pathway. Furthermore, anterograde tracers injected into the cMRF of other macaques labeled axonal terminals in RIP, confirming this cMRF projection. To determine whether the cMRF projections gate OPN activity, postembedding electron microscopic immunochemistry was performed on anterogradely labeled cMRF terminals with antibody to GABA or glycine. Of the terminals analyzed, 51.4% were GABA positive, 35.5% were GABA negative, and most contacted glycinergic cells. In summary, a trans-cMRF pathway connecting the SC to the RIP is present. This pathway contains inhibitory elements that could help gate omnipause activity and allow other tectal drives to induce the bursts of firing in premotor neurons that are necessary for saccades. The non-GABAergic cMRF terminals may derive from fixation units in the cMRF.

Diurnal Sea Breeze Effects on Nearshore Temperature Variability in Southern Monterey Bay

DTIC Science & Technology

2017-12-01

from multi-year, single-location measurements of the velocity profiles (Fewings et al. 2008; Lentz et al. 2008; Hendrickson and MacMahan 2009) to...shorter O(0-2 months) experiments with multi-location moorings (Hally- Rosendahl et al. 2015; Reniers et al. 2009). Direct approaches for accounting for...zone (~5m). Two cross-shore arrays were deployed to account for the spatial heterogeneity of cross- shore flows associated with rip currents on the

Detection of a new QTL/gene for growth habit in chickpea CaLG1 using wide and narrow crosses

USDA-ARS?s Scientific Manuscript database

A recombinant inbred line population (RIP-9) derived from an interspecific cross (ILC72 × Cr5-10) was evaluated for growth habit during two years (2003 and 2004). This RIP was used to develop a pair of near isogenic lines (NILs) for erect vs prostrate growth habit in chickpea. Molecular characteriza...

Prioritizing parts from cutting bills when gang-ripping first

Treesearch

R. Edward Thomas

1996-01-01

Computer optimization of gang-rip-first processing is a difficult problem when working with specific cutting bills. Interactions among board grade and size, arbor setup, and part sizes and quantities greatly complicate the decision making process. Cutting the wrong parts at any moment will mean that more board footage will be required to meet the bill. Using the ROugh...

Grass control improves early growth of black walnut more than either deep ripping or irrigation

Treesearch

J.W. Van Sambeek; F.D. McBride

1991-01-01

Chemical control of a tall fescue sod (Festuca arundinacea Schreb.) using glyphosate and simazine improved early tree growth of black walnut (Juglans nigra L.) more than either deep ripping or irrigation on an upland old field site in southern Illinois. Growth of trees with irrigation and grass control was less than with grass...

Crystal Structure of Ribosome-Inactivating Protein Ricin A Chain in Complex with the C-Terminal Peptide of the Ribosomal Stalk Protein P2.

PubMed

Shi, Wei-Wei; Tang, Yun-Sang; Sze, See-Yuen; Zhu, Zhen-Ning; Wong, Kam-Bo; Shaw, Pang-Chui

2016-10-13

Ricin is a type 2 ribosome-inactivating protein (RIP), containing a catalytic A chain and a lectin-like B chain. It inhibits protein synthesis by depurinating the N-glycosidic bond at α-sarcin/ricin loop (SRL) of the 28S rRNA, which thereby prevents the binding of elongation factors to the GTPase activation center of the ribosome. Here, we present the 1.6 Å crystal structure of Ricin A chain (RTA) complexed to the C-terminal peptide of the ribosomal stalk protein P2, which plays a crucial role in specific recognition of elongation factors and recruitment of eukaryote-specific RIPs to the ribosomes. Our structure reveals that the C-terminal GFGLFD motif of P2 peptide is inserted into a hydrophobic pocket of RTA, while the interaction assays demonstrate the structurally untraced SDDDM motif of P2 peptide contributes to the interaction with RTA. This interaction mode of RTA and P protein is in contrast to that with trichosanthin (TCS), Shiga-toxin (Stx) and the active form of maize RIP (MOD), implying the flexibility of the P2 peptide-RIP interaction, for the latter to gain access to ribosome.

The mushroom ribosome-inactivating protein lyophyllin exerts deleterious effects on mouse embryonic development in vitro.

PubMed

Chan, W Y; Ng, T B; Lam, Joyce S Y; Wong, Jack H; Chu, K T; Ngai, P H K; Lam, S K; Wang, H X

2010-01-01

Earlier investigations disclose that some plant ribosome-inactivating proteins (RIPs) adversely affect mouse embryonic development. In the present study, a mushroom RIP, namely lyophyllin from Lyophyllum shimeji, was isolated, partially sequenced, and its translation inhibitory activity determined. Its teratogenicity was studied by using a technique entailing microinjection and postimplantation whole-embryo culture. It was found that embryonic abnormalities during the period of organogenesis from E8.5 to E9.5 were induced by lyophyllin at a concentration as low as 50 microg/ml, and when the lyophyllin concentration was raised, the number of abnormal embryos increased, the final somite number decreased, and the abnormalities increased in severity. The affected embryonic structures included the cranial neural tube, forelimb buds, branchial arches, and body axis, while optic and otic placodes were more resistant. Lyophyllin at a concentration higher than 500 microg/ml also induced forebrain blisters within the cranial mesenchyme. When the abnormal embryos were examined histologically, an increase of cell death was found to be associated with abnormal structures, indicating that cell death may be one of the underlying causes of teratogenicity of the mushroom RIP. This constitutes the first report on the teratogenicity of a mushroom RIP.

Remote Sensing Characterization of Two-dimensional Wave Forcing in the Surf Zone

NASA Astrophysics Data System (ADS)

Carini, R. J.; Chickadel, C. C.; Jessup, A. T.

2016-02-01

In the surf zone, breaking waves drive longshore currents, transport sediment, shape bathymetry, and enhance air-sea gas and particle exchange. Furthermore, wave group forcing influences the generation and duration of rip currents. Wave breaking exhibits large gradients in space and time, making it challenging to measure in situ. Remote sensing technologies, specifically thermal infrared (IR) imagery, can provide detailed spatial and temporal measurements of wave breaking at the water surface. We construct two-dimensional maps of active wave breaking from IR imagery collected during the Surf Zone Optics Experiment in September 2010 at the US Army Corps of Engineers' Field Research Facility in Duck, NC. For each breaker identified in the camera's field of view, the crest-perpendicular length of the aerated breaking region (roller length) and wave direction are estimated and used to compute the wave energy dissipation rate. The resultant dissipation rate maps are analyzed over different time scales: peak wave period, infragravity wave period, and tidal wave period. For each time scale, spatial maps of wave breaking are used to characterize wave forcing in the surf zone for a variety of wave conditions. The following phenomena are examined: (1) wave dissipation rates over the bar (location of most intense breaking) have increased variance in infragravity wave frequencies, which are different from the peak frequency of the incoming wave field and different from the wave forcing variability at the shoreline, and (2) wave forcing has a wider spatial distribution during low tide than during high tide due to depth-limited breaking over the barred bathymetry. Future work will investigate the response of the variability in wave setup, longshore currents and rip currents, to the variability in wave forcing in the surf zone.

Vaccinia Virus Induces Rapid Necrosis in Keratinocytes by a STAT3-Dependent Mechanism

PubMed Central

He, Yong; Fisher, Robert; Chowdhury, Soma; Sultana, Ishrat; Pereira, Claudia P.; Bray, Mike; Reed, Jennifer L.

2014-01-01

Rationale Humans with a dominant negative mutation in STAT3 are susceptible to severe skin infections, suggesting an essential role for STAT3 signaling in defense against cutaneous pathogens. Methods To focus on innate antiviral defenses in keratinocytes, we used a standard model of cutaneous infection of severe combined immunodeficient mice with the current smallpox vaccine, ACAM-2000. In parallel, early events post-infection with the smallpox vaccine ACAM-2000 were investigated in cultured keratinocytes of human and mouse origin. Results Mice treated topically with a STAT3 inhibitor (Stattic) developed larger vaccinia lesions with higher virus titers and died more rapidly than untreated controls. Cultured human and murine keratinocytes infected with ACAM-2000 underwent rapid necrosis, but when treated with Stattic or with inhibitors of RIP1 kinase or caspase-1, they survived longer, produced higher titers of virus, and showed reduced activation of type I interferon responses and inflammatory cytokines release. Treatment with inhibitors of RIP1 kinase and STAT3, but not caspase-1, also reduced the inflammatory response of keratinocytes to TLR ligands. Vaccinia growth properties in Vero cells, which are known to be defective in some antiviral responses, were unaffected by inhibition of RIP1K, caspase-1, or STAT3. Conclusions Our findings indicate that keratinocytes suppress the replication and spread of vaccinia virus by undergoing rapid programmed cell death, in a process requiring STAT3. These data offer a new framework for understanding susceptibility to skin infection in patients with STAT3 mutations. Interventions which promote prompt necroptosis/pyroptosis of infected keratinocytes may reduce risks associated with vaccination with live vaccinia virus. PMID:25419841

Segmenting data sets for RIP.

PubMed

de Sanctis, Daniele; Nanao, Max H

2012-09-01

Specific radiation damage can be used for the phasing of macromolecular crystal structures. In practice, however, the optimization of the X-ray dose used to `burn' the crystal to induce specific damage can be difficult. Here, a method is presented in which a single large data set that has not been optimized in any way for radiation-damage-induced phasing (RIP) is segmented into multiple sub-data sets, which can then be used for RIP. The efficacy of this method is demonstrated using two model systems and two test systems. A method to improve the success of this type of phasing experiment by varying the composition of the two sub-data sets with respect to their separation by image number, and hence by absorbed dose, as well as their individual completeness is illustrated.

Bellman Ford algorithm - in Routing Information Protocol (RIP)

NASA Astrophysics Data System (ADS)

Krianto Sulaiman, Oris; Mahmud Siregar, Amir; Nasution, Khairuddin; Haramaini, Tasliyah

2018-04-01

In a large scale network need a routing that can handle a lot number of users, one of the solutions to cope with large scale network is by using a routing protocol, There are 2 types of routing protocol that is static and dynamic, Static routing is manually route input based on network admin, while dynamic routing is automatically route input formed based on existing network. Dynamic routing is efficient used to network extensively because of the input of route automatic formed, Routing Information Protocol (RIP) is one of dynamic routing that uses the bellman-ford algorithm where this algorithm will search for the best path that traversed the network by leveraging the value of each link, so with the bellman-ford algorithm owned by RIP can optimize existing networks.

Development of a laboratory test for knicker tearing re-creation studies.

PubMed

Carr, D J; Mitchell, J L; Niven, B E; Girvan, E; Carney, S

2016-05-01

False sexual assault and rape claims result in wasted forensic and police resources and stigma for the alleged offender. In this work a laboratory method was developed to (i) recreate the ripping of knickers and (ii) measure the force required to rip the garments. The effect of laundering was considered as a means to mimic age of garment, and the effect of speed of ripping was used as a measure of forcible removal of garments. Whilst laundering resulted in visual damage to the thongs, it did not affect the mechanical properties. Faster test speeds resulted in higher measured forces and increased levels of damage. This may allow comment to be made regarding the level of force used during an attack. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Big-Ass Holes in the Surfzone: Waves, Currents, and Sediment Transport in a Seafloor Perturbation Experiment

NASA Astrophysics Data System (ADS)

Moulton, M. R.; Elgar, S.; Raubenheimer, B.

2010-12-01

The evolution of 2-m deep, 10-m diameter holes excavated in the inner surfzone on an energetic beach was monitored with a downward-looking current profiler at the center of each hole, a surfboard-mounted GPS-sonar survey system, and tall divers with graduated poles, tape measures, marked lines, and long arms. Waves and currents were measured with up to 14 current meters and profilers over a 1600-sq-m area. The mean water depth surrounding the holes was 1.5 m and the tidal range was 1 m. Significant wave heights ranged from 0.2 to 1.2 m, and mean current speeds ranged from 0.1 to 1.2 m/s. The surfzone holes filled with sand in 2 to 6 days, in contrast to a previous study in which holes of the same size in the swashzone filled in a few hours. Preliminary results suggest that the rate of change of the sand level in the holes was correlated more strongly with wave heights (and thus with wave-orbital velocities) than with mean current speeds. In a hole dug in the trough between a sandbar and the shoreline, the sand level rose relatively slowly (1 m in 4.5 days) when wave heights were small (0.4 m) and mean currents were increasing (from 0.15 to 0.8 m/s), then filled rapidly (0.8 m in 6 hours) as wave heights increased (to 1.1 m) and mean currents increased (to 1.2 m/s). For a second hole dug in the same location, wave heights were moderate and variable (0.3 to 0.8 m), mean flow speeds were moderate and increasing (from 0.3 to 0.7 m/s), and the hole filled steadily (1.7 m in 2.5 days). In some instances, horizontal flow patterns were consistent with rip current circulation, with converging alongshore currents feeding an offshore jet centered at the depression. Here, volume changes in the hole will be compared with the observed waves, wave-orbital velocities, mean currents, and surrounding bathymetry. These data were collected in August 2010 at the US Army Corps of Engineers Field Research Facility in Duck, North Carolina. Funded by a National Security Science and Engineering Faculty Fellowship, a National Defense Science and Engineering Graduate Fellowship, and the Office of Naval Research.

Yield comparisons from floating blade and fixed arbor gang ripsaws when processing boards before and after crook removal

Treesearch

Charles J. Gatchell; Charles J. Gatchell

1991-01-01

Gang-ripping technology that uses a movable (floating) outer blade to eliminate unusable edgings is described, including new tenn1nology for identifying preferred and minimally acceptable strip widths. Because of the large amount of salvage required to achieve total yields, floating blade gang ripping is not recommended for boards with crook. With crook removed by...

Effect of cutting bill requirements on lumber yield in a rip-first rough mill

Treesearch

Urs Buehlmann; Janice K. Wiedenbeck; E. Earl Kline; E. Earl Kline

2003-01-01

In recent years, producers of solid wood dimension parts have emphasized improvements in lumber yield, focusing primarily on lumber grade and cutting technology rather than cutting bill design. Yet, cutting bills have a significant impact on yield. Using rip-first rough mill simulation software, a data bank of red oak lumber samples, and a cutting bill that resembles...

How to Learn the Natural Numbers: Inductive Inference and the Acquisition of Number Concepts

ERIC Educational Resources Information Center

Margolis, Eric; Laurence, Stephen

2008-01-01

Theories of number concepts often suppose that the natural numbers are acquired as children learn to count and as they draw an induction based on their interpretation of the first few count words. In a bold critique of this general approach, Rips, Asmuth, Bloomfield [Rips, L., Asmuth, J. & Bloomfield, A. (2006). Giving the boot to the bootstrap:…

The Coxsackievirus and Adenovirus Receptor (CAR) Undergoes Ectodomain Shedding and Regulated Intramembrane Proteolysis (RIP)

PubMed Central

Houri, Nadia; Huang, Kuo-Cheng; Nalbantoglu, Josephine

2013-01-01

The Coxsackievirus and Adenovirus Receptor (CAR) is a cell adhesion molecule originally characterized as a virus receptor but subsequently shown to be involved in physiological processes such as neuronal and heart development, epithelial tight junction integrity, and tumour suppression. Proteolysis of cell adhesion molecules and a wide variety of other cell surface proteins serves as a mechanism for protein turnover and, in some cases, cell signaling. Metalloproteases such as A Disintegrin and Metalloprotease (ADAM) family members cleave cell surface receptors to release their substrates’ ectodomains, while the presenilin/ɣ-secretase complex mediates regulated intramembrane proteolysis (RIP), releasing intracellular domain fragments from the plasma membrane. In the case of some substrates such as Notch and amyloid precursor protein (APP), the released intracellular domains enter the nucleus to modulate gene expression. We report that CAR ectodomain is constitutively shed from glioma cells and developing neurons, and is also shed when cells are treated with the phorbol ester phorbol 12-myristate 13-acetate (PMA) and the calcium ionophore ionomycin. We identified ADAM10 as a sheddase of CAR using assays involving shRNA knockdown and rescue, overexpression of wild-type ADAM10 and inhibition of ADAM10 activity by addition of its prodomain. In vitro peptide cleavage, mass spectrometry and mutagenesis revealed the amino acids M224 to L227 of CAR as the site of ADAM10-mediated ectodomain cleavage. CAR also undergoes RIP by the presenilin/γ-secretase complex, and the intracellular domain of CAR enters the nucleus. Ectodomain shedding is a prerequisite for RIP of CAR. Thus, CAR belongs to the increasing list of cell surface molecules that undergo ectodomain shedding and that are substrates for ɣ-secretase-mediated RIP. PMID:24015300

Evolution of Linked Avirulence Effectors in Leptosphaeria maculans Is Affected by Genomic Environment and Exposure to Resistance Genes in Host Plants

PubMed Central

Van de Wouw, Angela P.; Cozijnsen, Anton J.; Hane, James K.; Brunner, Patrick C.; McDonald, Bruce A.; Oliver, Richard P.; Howlett, Barbara J.

2010-01-01

Brassica napus (canola) cultivars and isolates of the blackleg fungus, Leptosphaeria maculans interact in a ‘gene for gene’ manner whereby plant resistance (R) genes are complementary to pathogen avirulence (Avr) genes. Avirulence genes encode proteins that belong to a class of pathogen molecules known as effectors, which includes small secreted proteins that play a role in disease. In Australia in 2003 canola cultivars with the Rlm1 resistance gene suffered a breakdown of disease resistance, resulting in severe yield losses. This was associated with a large increase in the frequency of virulence alleles of the complementary avirulence gene, AvrLm1, in fungal populations. Surprisingly, the frequency of virulence alleles of AvrLm6 (complementary to Rlm6) also increased dramatically, even though the cultivars did not contain Rlm6. In the L. maculans genome, AvrLm1 and AvrLm6 are linked along with five other genes in a region interspersed with transposable elements that have been degenerated by Repeat-Induced Point (RIP) mutations. Analyses of 295 Australian isolates showed deletions, RIP mutations and/or non-RIP derived amino acid substitutions in the predicted proteins encoded by these seven genes. The degree of RIP mutations within single copy sequences in this region was proportional to their proximity to the degenerated transposable elements. The RIP alleles were monophyletic and were present only in isolates collected after resistance conferred by Rlm1 broke down, whereas deletion alleles belonged to several polyphyletic lineages and were present before and after the resistance breakdown. Thus, genomic environment and exposure to resistance genes in B. napus has affected the evolution of these linked avirulence genes in L. maculans. PMID:21079787

Pokeweed Antiviral Protein, a Ribosome Inactivating Protein: Activity, Inhibition and Prospects

PubMed Central

Domashevskiy, Artem V.; Goss, Dixie J.

2015-01-01

Viruses employ an array of elaborate strategies to overcome plant defense mechanisms and must adapt to the requirements of the host translational systems. Pokeweed antiviral protein (PAP) from Phytolacca americana is a ribosome inactivating protein (RIP) and is an RNA N-glycosidase that removes specific purine residues from the sarcin/ricin (S/R) loop of large rRNA, arresting protein synthesis at the translocation step. PAP is thought to play an important role in the plant’s defense mechanism against foreign pathogens. This review focuses on the structure, function, and the relationship of PAP to other RIPs, discusses molecular aspects of PAP antiviral activity, the novel inhibition of this plant toxin by a virus counteraction—a peptide linked to the viral genome (VPg), and possible applications of RIP-conjugated immunotoxins in cancer therapeutics. PMID:25635465

Runway Safety Monitor Algorithm for Single and Crossing Runway Incursion Detection and Alerting

NASA Technical Reports Server (NTRS)

Green, David F., Jr.

2006-01-01

The Runway Safety Monitor (RSM) is an aircraft based algorithm for runway incursion detection and alerting that was developed in support of NASA's Runway Incursion Prevention System (RIPS) research conducted under the NASA Aviation Safety and Security Program's Synthetic Vision System project. The RSM algorithm provides warnings of runway incursions in sufficient time for pilots to take evasive action and avoid accidents during landings, takeoffs or when taxiing on the runway. The report documents the RSM software and describes in detail how RSM performs runway incursion detection and alerting functions for NASA RIPS. The report also describes the RIPS flight tests conducted at the Reno/Tahoe International Airport (RNO) and the Wallops Flight Facility (WAL) during July and August of 2004, and the RSM performance results and lessons learned from those flight tests.

Use of Ribosome-Inactivating Proteins from Sambucus for the Construction of Immunotoxins and Conjugates for Cancer Therapy

PubMed Central

Ferreras, José M.; Citores, Lucía; Iglesias, Rosario; Jiménez, Pilar; Girbés, Tomás

2011-01-01

The type 2 ribosome-inactivating proteins (RIPs) isolated from some species belonging to the Sambucus genus, have the characteristic that although being even more active than ricin inhibiting protein synthesis in cell-free extracts, they lack the high toxicity of ricin and related type 2 RIPs to intact cells and animals. This is due to the fact that after internalization, they follow a different intracellular pathway that does not allow them to reach the cytosolic ribosomes. The lack of toxicity of type 2 RIPs from Sambucus make them good candidates as toxic moieties in the construction of immunotoxins and conjugates directed against specific targets. Up to now they have been conjugated with either transferrin or anti-CD105 to target either transferrin receptor- or endoglin-overexpressing cells, respectively. PMID:22069717

To Make Long Character-Marked Cuttings From Low-Grade Yellow-Poplar Lumber - Rip First

Treesearch

Philip A. Araman

1979-01-01

Long, character-marked furniture cuttings are easily obtained when low-grade (2A and 2B Common) yellow-poplar lumber is first ripped into strips and then crosscut to remove objectionable defects. Overall yields of character-marked material using this procedure were 78% from 1 Common and 2A Common and 70% from 2B Common yellow-poplar lumber. Furthermore, 82% of the 1...

Rock gabion, rip-rap, and culvert treatments: Successes and failures in post-fire erosion mitigation, Schultz Fire 2010

Treesearch

Daniel G. Neary; Karen A. Koestner

2011-01-01

Following the Schultz Fire in June of 2010, several erosion mitigation efforts were undertaken to reduce the impacts of post-fire flooding expected during the 2010 monsoon. One treatment consisted of the placement of large rock rip-rap on targeted fill slopes of a high elevation forest road that contains a buried pipeline supplying water to the city of Flagstaff....

Determining the impact of sorting capacity on rip-first rough mill yield

Treesearch

Edward Thomas; John Brown

2003-01-01

The problem of increasing gang-rip-first rough mill yield often amounts to little more than optimizing the fit of needed parts into strips. However, it is rare when a part or combination of parts fits precisely in the area between two defects. Intuition tells us that the more lengths we have to choose from, the greater the chance of completely filling such an area....

[Programmed necrosis mediated by receptor-interacting protein 3: a new target for liver disease research].

PubMed

Zhang, J; Jing, Y; Li, Y N; Zhou, L; Wang, B M

2016-09-20

Hepatocyte death mainly includes apoptosis and necrosis and is a critical process in the pathophysiological mechanism of liver injury caused by various reasons. Recent studies have shown that key regulatory molecules in the inhibition of apoptosis such as caspase cannot be used as targets for inhibiting disease progression in clinical practice. In recent years, programmed necrosis mediated by receptor-interacting protein 3(RIP3)becomes a new hot research topic. It not only plays an important role in inducing inflammatory response, but also is closely regulated by intracellular signal factors, and it is a type of active cell death which can be interfered with. Compared with apoptosis, programmed necrosis is accompanied by the release of various inflammatory factors, which significantly affects local immune microenvironment. RIP3-mediated programmed necrosis has been taken seriously in many diseases. Although its mechanism of action in liver disease remains unclear, the results of recent studies confirmed its important role in the development of liver disease. This article reviews the research advances in the role of RIP3-mediated programmed necrosis signaling pathway in liver disease of various causes and investigates the possibility of RIP3-mediated programmed necrosis as a new target in the treatment of liver disease.

CLIP-seq analysis of multi-mapped reads discovers novel functional RNA regulatory sites in the human transcriptome.

PubMed

Zhang, Zijun; Xing, Yi

2017-09-19

Crosslinking or RNA immunoprecipitation followed by sequencing (CLIP-seq or RIP-seq) allows transcriptome-wide discovery of RNA regulatory sites. As CLIP-seq/RIP-seq reads are short, existing computational tools focus on uniquely mapped reads, while reads mapped to multiple loci are discarded. We present CLAM (CLIP-seq Analysis of Multi-mapped reads). CLAM uses an expectation-maximization algorithm to assign multi-mapped reads and calls peaks combining uniquely and multi-mapped reads. To demonstrate the utility of CLAM, we applied it to a wide range of public CLIP-seq/RIP-seq datasets involving numerous splicing factors, microRNAs and m6A RNA methylation. CLAM recovered a large number of novel RNA regulatory sites inaccessible by uniquely mapped reads. The functional significance of these sites was demonstrated by consensus motif patterns and association with alternative splicing (splicing factors), transcript abundance (AGO2) and mRNA half-life (m6A). CLAM provides a useful tool to discover novel protein-RNA interactions and RNA modification sites from CLIP-seq and RIP-seq data, and reveals the significant contribution of repetitive elements to the RNA regulatory landscape of the human transcriptome. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

The Tandem CARDs of NOD2: Intramolecular Interactions and Recognition of RIP2

PubMed Central

Fridh, Veronica; Rittinger, Katrin

2012-01-01

Caspase recruitment domains (CARDs) are homotypic protein interaction modules that link the stimulus-dependent assembly of large signaling platforms such as inflammasomes to the activation of downstream effectors that often include caspases and kinases and thereby play an important role in the regulation of inflammatory and apoptotic signaling pathways. NOD2 belongs to the NOD-like (NLR) family of intracellular pattern recognition receptors (PRR) and induces activation of the NF-κB pathway in response to the recognition of bacterial components. This process requires the specific recognition of the CARD of the protein kinase RIP2 by the tandem CARDs of NOD2. Here we demonstrate that the tandem CARDs of NOD2 are engaged in an intramolecular interaction that is important for the structural stability of this region. Using a combination of ITC and pull-down experiments we identify distinct surface areas that are involved in the intramolecular tandem CARD interaction and the interaction with the downstream effector RIP2. Our findings indicate that while CARDa of NOD2 might be the primary binding partner of RIP2 the two CARDs of NOD2 do not act independently of one another but may cooperate to from a binding surface that is distinct from that of single CARDs. PMID:22470564

Ubiquitin Regulates Caspase Recruitment Domain-mediated Signaling by Nucleotide-binding Oligomerization Domain-containing Proteins NOD1 and NOD2*

PubMed Central

Ver Heul, Aaron M.; Fowler, C. Andrew; Ramaswamy, S.; Piper, Robert C.

2013-01-01

NOD1 and NOD2 (nucleotide-binding oligomerization domain-containing proteins) are intracellular pattern recognition receptors that activate inflammation and autophagy. These pathways rely on the caspase recruitment domains (CARDs) within the receptors, which serve as protein interaction platforms that coordinately regulate immune signaling. We show that NOD1 CARD binds ubiquitin (Ub), in addition to directly binding its downstream targets receptor-interacting protein kinase 2 (RIP2) and autophagy-related protein 16-1 (ATG16L1). NMR spectroscopy and structure-guided mutagenesis identified a small hydrophobic surface of NOD1 CARD that binds Ub. In vitro, Ub competes with RIP2 for association with NOD1 CARD. In vivo, we found that the ligand-stimulated activity of NOD1 with a mutant CARD lacking Ub binding but retaining ATG16L1 and RIP2 binding is increased relative to wild-type NOD1. Likewise, point mutations in the tandem NOD2 CARDs at positions analogous to the surface residues defining the Ub interface on NOD1 resulted in loss of Ub binding and increased ligand-stimulated NOD2 signaling. These data suggest that Ub binding provides a negative feedback loop upon NOD-dependent activation of RIP2. PMID:23300079

Plant Ribosome-Inactivating Proteins: Progesses, Challenges and Biotechnological Applications (and a Few Digressions)

PubMed Central

Fabbrini, Maria Serena; Katayama, Miku; Nakase, Ikuhiko; Vago, Riccardo

2017-01-01

Plant ribosome-inactivating protein (RIP) toxins are EC3.2.2.22 N-glycosidases, found among most plant species encoded as small gene families, distributed in several tissues being endowed with defensive functions against fungal or viral infections. The two main plant RIP classes include type I (monomeric) and type II (dimeric) as the prototype ricin holotoxin from Ricinus communis that is composed of a catalytic active A chain linked via a disulphide bridge to a B-lectin domain that mediates efficient endocytosis in eukaryotic cells. Plant RIPs can recognize a universally conserved stem-loop, known as the α-sarcin/ ricin loop or SRL structure in 23S/25S/28S rRNA. By depurinating a single adenine (A4324 in 28S rat rRNA), they can irreversibly arrest protein translation and trigger cell death in the intoxicated mammalian cell. Besides their useful application as potential weapons against infected/tumor cells, ricin was also used in bio-terroristic attacks and, as such, constitutes a major concern. In this review, we aim to summarize past studies and more recent progresses made studying plant RIPs and discuss successful approaches that might help overcoming some of the bottlenecks encountered during the development of their biomedical applications. PMID:29023422

Smokers’ self-reported responses to the introduction of reduced ignition propensity (RIP) cigarettes

PubMed Central

Seidenberg, Andrew B; Rees, Vaughan W; Alpert, Hillel R; O'Connor, Richard J; Giovino, Gary A; Hyland, Andrew; Connolly, Gregory N

2015-01-01

Background Changes in cigarette design to meet mandated fire safety standards may have unintended effects on smoker responses by diminishing the consumer's perceptions of product acceptability, smoking and increasing fire-risk behaviours. To address these concerns, population-level data are needed from a jurisdiction where reduced ignition propensity (RIP) cigarettes have been introduced. Methods A cohort of adult smokers was recruited in Massachusetts, USA using a random-digit-dialled telephone survey. The cohort was contacted prior to, and 8 months following, the state-mandated introduction of RIP cigarettes on 1 January 2008. Changes in self-reported subjective cigarette characteristics, smoking topography, fire-risk behaviours, fire events and quitting intentions were assessed. Results A total of 620 Massachusetts smokers completed the baseline survey conducted prior to implementation of the law, and 353 (57%) completed the follow-up survey conducted after implementation. No significant changes were found in self-reported fire-risk behaviour or quitting intentions. In addition, smokers were less likely to report smoking greater than 20 cigarettes per day and inhaling deeply into the chest after the law. Conclusions The introduction of RIP cigarettes in Massachusetts yielded little change, and no adverse effect, on self-reported smoker response, among a sample of mostly Caucasian smokers. PMID:21752794

Analyzing Radio-Frequency Coverage for the ISS

NASA Technical Reports Server (NTRS)

Bolen, Steven M.; Sham, Catherine C.

2007-01-01

The Interactive Coverage Analysis Tool (iCAT) is an interactive desktop computer program serving to (1) support planning of coverage, and management of usage of frequencies, of current and proposed radio communication systems on and near the International Space Station (ISS) and (2) enable definition of requirements for development of future such systems. The iCAT can also be used in design trade studies for other (both outer-space and terrestrial) communication systems. A user can enter the parameters of a communication-system link budget in a table in a worksheet. The nominal (onaxis) link values for the bit-to-noise-energy ratio, received isotropic power (RIP), carrier-to-noise ratio (C/N), power flux density (PFD), and link margin of the system are calculated and displayed in the table. Plots of field gradients for the RIP, C/N, PFD, and link margin are constructed in an ISS coordinate system, at a specified link range, for both the forward and return link parameters, and are displayed in worksheets. The forward and reverse link antenna gain patterns are also constructed and displayed. Line-of-sight (LOS) obstructions can be both incorporated into the gradient plots and displayed on separate plots.

No. 1 and No. 2 Common red oak yields: similar part sizes when gang-ripping is used to process boards with crook

Treesearch

Charles J. Gatchell; Charles J. Gatchell

1990-01-01

Computer simulation was used to gang rip No. 1 and No. 2 Common red oak boards before and after removal of crook. While No. 1 Common produced slightly more total yield, the part yields were very similar. No. 1 Common was superior only in yielding 75-inch-long pieces. Either grade is an excellent choice for the furniture and cabinet industries.

Modeling and comparative study of linear and nonlinear controllers for rotary inverted pendulum

NASA Astrophysics Data System (ADS)

Lima, Byron; Cajo, Ricardo; Huilcapi, Víctor; Agila, Wilton

2017-01-01

The rotary inverted pendulum (RIP) is a problem difficult to control, several studies have been conducted where different control techniques have been applied. Literature reports that, although problem is nonlinear, classical PID controllers presents appropriate performances when applied to the system. In this paper, a comparative study of the performances of linear and nonlinear PID structures is carried out. The control algorithms are evaluated in the RIP system, using indices of performance and power consumption, which allow the categorization of control strategies according to their performance. This article also presents the modeling system, which has been estimated some of the parameters involved in the RIP system, using computer-aided design tools (CAD) and experimental methods or techniques proposed by several authors attended. The results indicate a better performance of the nonlinear controller with an increase in the robustness and faster response than the linear controller.

Dynamics of sediments along with their core properties in the Monastir-Bekalta coastline (Tunisia, Central Mediterranean)

NASA Astrophysics Data System (ADS)

Khiari, Nouha; Atoui, Abdelfattah; Khalil, Nadia; Charef, Abdelkrim; Aleya, Lotfi

2017-10-01

The authors report on two campaigns of high-resolution samplings along the shores of Monastir Bay in Tunisia: the first being a study of sediment dynamics, grain size and mineral composition in surface sediment, and the second, eight months later, using four sediment cores to study grain-size distribution in bottom sediments. Particle size analysis of superficial sediment shows that the sand in shallow depths is characterized by S-shaped curves, indicating a certain degree of agitation, possible transport by rip currents near the bottom and hyperbolic curves illustrating heterogeneity of sand stock. The sediments settle in a relatively calm environment. Along the bay shore (from 0 to 2 m depth), the bottom is covered by medium sand. Sediment transport is noted along the coast; from north to south and from south to north, caused by longshore drift and a rip current in the middle of the bay. These two currents are generated by wind and swell, especially by north to northeast waves which transport the finest sediment. Particle size analysis of bottom sediment indicates a mean grain size ranging from coarse to very fine sands while vertical distribution of grain size tends to decrease from surface to depth. The increase in particle size of sediment cores may be due to the coexistence of terrigenous inputs along with the sedimentary transit parallel to the coast due to the effect of longshore drift. Mineralogical analysis shows that Monastir's coastal sands and bottom sediment are composed of quartz, calcite, magnesium calcite, aragonite and hematite. The existence of a low energy zone with potential to accumulate pollutants indicates that managerial action is necessary to help preserve Monastir Bay.

Proceedings of the Annual Symposium on Frequency Control (42nd) Held in Baltimore, Maryland on 1-3 June 1988

DTIC Science & Technology

1988-06-03

STrRIP IN FiG.2. 402 rV - C U’ 0-Z --. *L ot ’Z - 0o l or Pe T -lo 000r- O*SL- 0,X01- O’SZI- DlOSI- Osl - 00&z- OH/ Pul) IN 1 3v (1 4 d S)S0’I0I I-1...current, ac short-circuit current, and small-signal ac shunt resistance. Sulfur dosimeters were used to determine the All of these quantities were...measured in the photovoltaic incremental neutron fluences. The tolerance 2 of such mode under conditions of constant illumination using the dosimeters

Recognizing interactions among lumber grading rules, gang-ripping technology, and industry needs could increase the use of No.2 Common lumber

Treesearch

Charles J. Gatchell; Charles J. Gatchell

1989-01-01

Recognizing the interactions among lumber grading rules, gang-ripping technology, and the parts needs of the furniture and cabinet industries could increase the use of No. 2 Common lumber as a raw material. The minimum piece size used in establishing the No.2 Common grade is 3 inches by 2 feet. Industry often needs shorter and narrower pieces than this. No.2 Common...

Fault Tolerant Paradigms

DTIC Science & Technology

2016-02-26

say that A is a JL(m,d,)-embedding of S into Cm. Linear JL(m,d,)-embeddings are closely related to the Restricted Isometry Property [9, 4, 18...holds ∀x ∈ Cd containing at most s nonzero coordinates. In this case we will say that A is RIP(s,). In particular, the following theorem due to Krahmer...implement reliable edge detector functions, especially in the presence of noise. Needless to say , the same issues exist in two dimensions, as

Inhibition of iron overload-induced apoptosis and necrosis of bone marrow mesenchymal stem cells by melatonin.

PubMed

Yang, Fan; Li, Yuan; Yan, Gege; Liu, Tianyi; Feng, Chao; Gong, Rui; Yuan, Ye; Ding, Fengzhi; Zhang, Lai; Idiiatullina, Elina; Pavlov, Valentin; Han, Zhenbo; Ma, Wenya; Huang, Qi; Yu, Ying; Bao, Zhengyi; Wang, Xiuxiu; Hua, Bingjie; Du, Zhimin; Cai, Benzhi; Yang, Lei

2017-05-09

Iron overload induces severe damage to several vital organs such as the liver, heart and bone, and thus contributes to the dysfunction of these organs. The aim of this study is to investigate whether iron overload causes the apoptosis and necrosis of bone marrow mesenchymal stem cells (BMSCs) and melatonin may prevent its toxicity. Perls' Prussion blue staining showed that exposure to increased concentrations of ferric ammonium citrate (FAC) induced a gradual increase of intracellular iron level in BMSCs. Trypan blue staining demonstrated that FAC decreased the viability of BMSCs in a concentration-dependent manner. Notably, melatonin protected BMSCs against apoptosis and necrosis induced by FAC and it was vertified by Live/Dead, TUNEL and PI/Hoechst stainings. Furthermore, melatonin pretreatment suppressed FAC-induced reactive oxygen species accumulation. Western blot showed that exposure to FAC resulted in the decrease of anti-apoptotic protein Bcl-2 and the increase of pro-apoptotic protein Bax and Cleaved Caspase-3, and necrosis-related proteins RIP1 and RIP3, which were significantly inhibited by melatonin treatment. At last, melatonin receptor blocker luzindole failed to block the protection of BMSCs apoptosis and necrosis by melatonin. Taken together, melatonin protected BMSCs from iron overload induced apoptosis and necrosis by regulating Bcl-2, Bax, Cleaved Caspase-3, RIP1 and RIP3 pathways.

Global Screening of Antiviral Genes that Suppress Baculovirus Transgene Expression in Mammalian Cells.

PubMed

Wang, Chia-Hung; Naik, Nenavath Gopal; Liao, Lin-Li; Wei, Sung-Chan; Chao, Yu-Chan

2017-09-15

Although baculovirus has been used as a safe and convenient gene delivery vector in mammalian cells, baculovirus-mediated transgene expression is less effective in various mammalian cell lines. Identification of the negative regulators in host cells is necessary to improve baculovirus-based expression systems. Here, we performed high-throughput shRNA library screening, targeting 176 antiviral innate immune genes, and identified 43 host restriction factor genes in a human A549 lung carcinoma cell line. Among them, suppression of receptor interaction protein kinase 1 (RIP1, also known as RIPK1) significantly increased baculoviral transgene expression without resulting in significant cell death. Silencing of RIP1 did not affect viral entry or cell viability, but it did inhibit nuclear translocation of the IRF3 and NF-κB transcription factors. Also, activation of downstream signaling mediators (such as TBK1 and IRF7) was affected, and subsequent interferon and cytokine gene expression levels were abolished. Further, Necrostatin-1 (Nec-1)-an inhibitor of RIP1 kinase activity-dramatically increased baculoviral transgene expression in RIP1-silenced cells. Using baculovirus as a model system, this study presents an initial investigation of large numbers of human cell antiviral innate immune response factors against a "nonadaptive virus." In addition, our study has made baculovirus a more efficient gene transfer vector for some of the most frequently used mammalian cell systems.

Heme induces programmed necrosis on macrophages through autocrine TNF and ROS production

PubMed Central

Fortes, Guilherme B.; Alves, Leticia S.; de Oliveira, Rosane; Dutra, Fabianno F.; Rodrigues, Danielle; Fernandez, Patricia L.; Souto-Padron, Thais; De Rosa, María José; Kelliher, Michelle; Golenbock, Douglas; Chan, Francis K. M.

2012-01-01

Diseases that cause hemolysis or myonecrosis lead to the leakage of large amounts of heme proteins. Free heme has proinflammatory and cytotoxic effects. Heme induces TLR4-dependent production of tumor necrosis factor (TNF), whereas heme cytotoxicity has been attributed to its ability to intercalate into cell membranes and cause oxidative stress. We show that heme caused early macrophage death characterized by the loss of plasma membrane integrity and morphologic features resembling necrosis. Heme-induced cell death required TNFR1 and TLR4/MyD88-dependent TNF production. Addition of TNF to Tlr4−/− or to Myd88−/− macrophages restored heme-induced cell death. The use of necrostatin-1, a selective inhibitor of receptor-interacting protein 1 (RIP1, also known as RIPK1), or cells deficient in Rip1 or Rip3 revealed a critical role for RIP proteins in heme-induced cell death. Serum, antioxidants, iron chelation, or inhibition of c-Jun N-terminal kinase (JNK) ameliorated heme-induced oxidative burst and blocked macrophage cell death. Macrophages from heme oxygenase-1 deficient mice (Hmox1−/−) had increased oxidative stress and were more sensitive to heme. Taken together, these results revealed that heme induces macrophage necrosis through 2 synergistic mechanisms: TLR4/Myd88-dependent expression of TNF and TLR4-independent generation of ROS. PMID:22262768

Identification of a Novel, Putative Rho-specific GDP/GTP Exchange Factor and a RhoA-binding Protein: Control of Neuronal Morphology

PubMed Central

Gebbink, Martijn F.B.G.; Kranenburg, Onno; Poland, Mieke; van Horck, Francis P.G.; Houssa, Brahim; Moolenaar, Wouter H.

1997-01-01

The small GTP-binding protein Rho has been implicated in the control of neuronal morphology. In N1E-115 neuronal cells, the Rho-inactivating C3 toxin stimulates neurite outgrowth and prevents actomyosin-based neurite retraction and cell rounding induced by lysophosphatidic acid (LPA), sphingosine-1-phosphate, or thrombin acting on their cognate G protein–coupled receptors. We have identified a novel putative GDP/GTP exchange factor, RhoGEF (190 kD), that interacts with both wild-type and activated RhoA, but not with Rac or Cdc42. RhoGEF, like activated RhoA, mimics receptor stimulation in inducing cell rounding and in preventing neurite outgrowth. Furthermore, we have identified a 116-kD protein, p116Rip, that interacts with both the GDP- and GTP-bound forms of RhoA in N1E-115 cells. Overexpression of p116Rip stimulates cell flattening and neurite outgrowth in a similar way to dominant-negative RhoA and C3 toxin. Cells overexpressing p116Rip fail to change their shape in response to LPA, as is observed after Rho inactivation. Our results indicate that (a) RhoGEF may link G protein–coupled receptors to RhoA activation and ensuing neurite retraction and cell rounding; and (b) p116Rip inhibits RhoA-stimulated contractility and promotes neurite outgrowth. PMID:9199174

Mono-PEGylation of Alpha-MMC and MAP30 from Momordica charantia L.: Production, Identification and Anti-Tumor Activity.

PubMed

Sun, Yun; Sun, Fenghui; Li, Jianlong; Wu, Minlu; Fan, Xiang; Meng, Yanfa; Meng, Yao

2016-10-31

PEGylation is a well-established and effective strategy to decrease immunogenicity, which can increase the stability and in vivo half-life time. However, the generation of multi-site modified products is inevitable due to the lysine chemistry, which will bring difficulties in subsequent research, such as purification and quantification. Site-specific modification by mPEG-succinimidyl carbonate (mPEG-SC) is a widely used method for N -terminal conjugation. In this study, we used it for site-directed modification on two ribosome-inactivating proteins (RIPs), alpha-momorcharin (α-MMC) and momordica anti-HIV protein (MAP30), from Momordica charantia L. According to the optimization of previous modification conditions, we compared Macro-Cap SP with SP-Sepharose FF chromatography for separating the final mPEGylated RIPs. Two kinds of methods both can obtain homogenous mPEGylated RIPs which were identified by sodium dodecylsulphate polyacrylamide gel electrophoresis (SDS-PAGE), isoelectric focusing electrophoresis (IEF), and matrix-assisted laser desorption ionization-time of flight/time of flight (MALDI-TOF/TOF) analysis. We also used iodine staining method to detect the amount of unmodified PEG. Furthermore, the inhibition activity of both mPEGylated and non-PEGylated RIPs against human lung adenocarcinoma epithelial A549 cells was detected. All of the results suggested that the mPEGylated α-MMC/MAP30 might be potentially developed as new anti-tumor drugs.

Inhibition of iron overload-induced apoptosis and necrosis of bone marrow mesenchymal stem cells by melatonin

PubMed Central

Yan, Gege; Liu, Tianyi; Feng, Chao; Gong, Rui; Yuan, Ye; Ding, Fengzhi; Zhang, Lai; Idiiatullina, Elina; Pavlov, Valentin; Han, Zhenbo; Ma, Wenya; Huang, Qi; Yu, Ying; Bao, Zhengyi; Wang, Xiuxiu; Hua, Bingjie; Du, Zhimin; Cai, Benzhi; Yang, Lei

2017-01-01

Iron overload induces severe damage to several vital organs such as the liver, heart and bone, and thus contributes to the dysfunction of these organs. The aim of this study is to investigate whether iron overload causes the apoptosis and necrosis of bone marrow mesenchymal stem cells (BMSCs) and melatonin may prevent its toxicity. Perls’ Prussion blue staining showed that exposure to increased concentrations of ferric ammonium citrate (FAC) induced a gradual increase of intracellular iron level in BMSCs. Trypan blue staining demonstrated that FAC decreased the viability of BMSCs in a concentration-dependent manner. Notably, melatonin protected BMSCs against apoptosis and necrosis induced by FAC and it was vertified by Live/Dead, TUNEL and PI/Hoechst stainings. Furthermore, melatonin pretreatment suppressed FAC-induced reactive oxygen species accumulation. Western blot showed that exposure to FAC resulted in the decrease of anti-apoptotic protein Bcl-2 and the increase of pro-apoptotic protein Bax and Cleaved Caspase-3, and necrosis-related proteins RIP1 and RIP3, which were significantly inhibited by melatonin treatment. At last, melatonin receptor blocker luzindole failed to block the protection of BMSCs apoptosis and necrosis by melatonin. Taken together, melatonin protected BMSCs from iron overload induced apoptosis and necrosis by regulating Bcl-2, Bax, Cleaved Caspase-3, RIP1 and RIP3 pathways. PMID:28415572

Improving root-zone soil properties for Trembling Aspen in a reconstructed mine-site soil

NASA Astrophysics Data System (ADS)

Dyck, M. F.; Sabbagh, P.; Bockstette, S.; Landhäusser, S.; Pinno, B.

2014-12-01

Surface mining activities have significantly depleted natural tree cover, especially trembling aspen (Populus tremuloides), in the Boreal Forest and Aspen Parkland Natural Regions of Alberta. The natural soil profile is usually destroyed during these mining activities and soil and landscape reconstruction is typically the first step in the reclamation process. However, the mine tailings and overburden materials used for these new soils often become compacted during the reconstruction process because they are subjected to high amounts of traffic with heavy equipment. Compacted soils generally have low porosity and low penetrability through increased soil strength, making it difficult for roots to elongate and explore the soil. Compaction also reduces infiltration capacity and drainage, which can cause excessive runoff and soil erosion. To improve the pore size distribution and water transmission, subsoil ripping was carried out in a test plot at Genesee Prairie Mine, Alberta. Within the site, six replicates with two treatments each, unripped (compacted) and ripped (decompacted), were established with 20-m buffers between them. The main objective of this research was to characterize the effects of subsoil ripping on soil physical properties and the longevity of those effects.as well as soil water dynamics during spring snowmelt. Results showed improved bulk density, pore size distribution and water infiltration in the soil as a result of the deep ripping, but these improvements appear to be temporary.

RIPGIS-NET: a GIS tool for riparian groundwater evapotranspiration in MODFLOW.

PubMed

Ajami, Hoori; Maddock, Thomas; Meixner, Thomas; Hogan, James F; Guertin, D Phillip

2012-01-01

RIPGIS-NET, an Environmental System Research Institute (ESRI's) ArcGIS 9.2/9.3 custom application, was developed to derive parameters and visualize results of spatially explicit riparian groundwater evapotranspiration (ETg), evapotranspiration from saturated zone, in groundwater flow models for ecohydrology, riparian ecosystem management, and stream restoration. Specifically RIPGIS-NET works with riparian evapotranspiration (RIP-ET), a modeling package that works with the MODFLOW groundwater flow model. RIP-ET improves ETg simulations by using a set of eco-physiologically based ETg curves for plant functional subgroups (PFSGs), and separates ground evaporation and plant transpiration processes from the water table. The RIPGIS-NET program was developed in Visual Basic 2005, .NET framework 2.0, and runs in ArcMap 9.2 and 9.3 applications. RIPGIS-NET, a pre- and post-processor for RIP-ET, incorporates spatial variability of riparian vegetation and land surface elevation into ETg estimation in MODFLOW groundwater models. RIPGIS-NET derives RIP-ET input parameters including PFSG evapotranspiration curve parameters, fractional coverage areas of each PFSG in a MODFLOW cell, and average surface elevation per riparian vegetation polygon using a digital elevation model. RIPGIS-NET also provides visualization tools for modelers to create head maps, depth to water table (DTWT) maps, and plot DTWT for a PFSG in a polygon in the Geographic Information System based on MODFLOW simulation results. © 2011, The Author(s). Ground Water © 2011, National Ground Water Association.

Anchorage strength models for end-debonding predictions in RC beams strengthened with FRP composites

NASA Astrophysics Data System (ADS)

Nardini, V.; Guadagnini, M.; Valluzzi, M. R.

2008-05-01

The increase in the flexural capacity of RC beams obtained by externally bonding FRP composites to their tension side is often limited by the premature and brittle debonding of the external reinforcement. An in-depth understanding of this complex failure mechanism, however, has not yet been achieved. With specific regard to end-debonding failure modes, extensive experimental observations reported in the literature highlight the important distinction, often neglected in strength models proposed by researchers, between the peel-off and rip-off end-debonding types of failure. The peel-off failure is generally characterized by a failure plane located within the first few millimetres of the concrete cover, whilst the rip-off failure penetrates deeper into the concrete cover and propagates along the tensile steel reinforcement. A new rip-off strength model is described in this paper. The model proposed is based on the Chen and Teng peel-off model and relies upon additional theoretical considerations. The influence of the amount of the internal tensile steel reinforcement and the effective anchorage length of FRP are considered and discussed. The validity of the new model is analyzed further through comparisons with test results, findings of a numerical investigation, and a parametric study. The new rip-off strength model is assessed against a database comprising results from 62 beams tested by various researchers and is shown to yield less conservative results.

A wearable respiratory monitoring device--the between-days variability of calibration.

PubMed

Heyde, C; Mahler, H; Roecker, K; Gollhofer, A

2015-01-01

The between-days variability in ascertained gain factors for calibration of a wearable respiratory inductance plethysmograph (RIP) and validity thereof for the repeated use during exercise were examined. Consecutive 5-min periods of standing still, slow running at 8 km·h(-1), fast running at 14 km·h(-1) (male) or 12 km·h(-1) (female) and recovery were repeated by 10 healthy subjects on 5 days. Breath-by-breath data were recorded simultaneously by flow meter and RIP. Gain factors were determined individually for each trial (CALIND) via least square regression. Reliability and variability in gain factors were quantified respectively by intraclass correlation coefficients (ICC) and limits of agreement. Within a predefined error range of ±20% the amount of RIP-derived tidal volumes after CALIND was compared to corresponding amounts when gain factors of the first trial were applied on the following 4 trials (CALFIRST). ICC ranged within 0.96 and 0.98. The variability in gain factors (up to ± 24.06%) was reduced compensatively by their sum. Amounts of breaths within the predefined error range did not differ between CALIND and (CALFIRST) (P>0.32). The between-days variability of gain factors for a wearable RIP-device does not show impaired reliability in further derived tidal volumes. © Georg Thieme Verlag KG Stuttgart · New York.

Toxin-induced necroptosis is a major mechanism of Staphylococcus aureus lung damage.

PubMed

Kitur, Kipyegon; Parker, Dane; Nieto, Pamela; Ahn, Danielle S; Cohen, Taylor S; Chung, Samuel; Wachtel, Sarah; Bueno, Susan; Prince, Alice

2015-04-01

Staphylococcus aureus USA300 strains cause a highly inflammatory necrotizing pneumonia. The virulence of this strain has been attributed to its expression of multiple toxins that have diverse targets including ADAM10, NLRP3 and CD11b. We demonstrate that induction of necroptosis through RIP1/RIP3/MLKL signaling is a major consequence of S. aureus toxin production. Cytotoxicity could be prevented by inhibiting either RIP1 or MLKL signaling and S. aureus mutants lacking agr, hla or Hla pore formation, lukAB or psms were deficient in inducing cell death in human and murine immune cells. Toxin-associated pore formation was essential, as cell death was blocked by exogenous K+ or dextran. MLKL inhibition also blocked caspase-1 and IL-1β production, suggesting a link to the inflammasome. Rip3(-/-) mice exhibited significantly improved staphylococcal clearance and retained an alveolar macrophage population with CD200R and CD206 markers in the setting of acute infection, suggesting increased susceptibility of these leukocytes to necroptosis. The importance of this anti-inflammatory signaling was indicated by the correlation between improved outcome and significantly decreased expression of KC, IL-6, TNF, IL-1α and IL-1β in infected mice. These findings indicate that toxin-induced necroptosis is a major cause of lung pathology in S. aureus pneumonia and suggest the possibility of targeting components of this signaling pathway as a therapeutic strategy.

Necroptosis Resumes Apoptosis in Hippocampus but Not in Frontal Cortex.

PubMed

Nikseresht, Sara; Khodagholi, Fariba; Dargahi, Leila; Ahmadiani, Abolhassan

2017-12-01

Cell death subsequent to or concurrent with neuroinflammation results in some damages like neuron loss and spatial memory impairment. In this study, we demonstrated the temporal pattern of neuroinflammation, necroptotic, and apoptotic cell deaths in hippocampus and frontal cortex following intracerebroventricular administration of lipopolysaccharide (LPS). We evaluated receptor interacting protein kinase 1 (RIP1), RIP3, and two related metabolic enzymes including glutamate-ammonia ligase (GLUL) and glutamate dehydrogenase (GLUD) as necroptosis factors. Apoptosis pathway, antioxidant status and inflammatory cytokines were also assessed. Based on the probable role of these brain regions in working memory performance, spontaneous alternation was evaluated through the Y-maze apparatus. RIP1, RIP3, and then GLUL and GLUD, as well as apoptosis markers, inflammatory regulators, and antioxidant defense demonstrated different time-dependent patterns in hippocampus and frontal cortex. Interestingly, in hippocampus but not in frontal cortex, necroptosis resumed apoptosis. Our results in behavioral section revealed that neuroinflammation along with apoptosis and necroptosis pathways could lead to reversible short-term memory impairment after LPS injection. In conclusion, it can be suggested that there is a region-specific response of cell deaths regulators activation in hippocampus and frontal cortex. In addition, elucidating the time profile of events in response to neuroinflammation would be of great help in mechanistic studies and understanding of pathways interaction. J. Cell. Biochem. 118: 4628-4638, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Detection of nitro-based and peroxide-based explosives by fast polarity-switchable ion mobility spectrometer with ion focusing in vicinity of Faraday detector.

PubMed

Zhou, Qinghua; Peng, Liying; Jiang, Dandan; Wang, Xin; Wang, Haiyan; Li, Haiyang

2015-05-29

Ion mobility spectrometer (IMS) has been widely deployed for on-site detection of explosives. The common nitro-based explosives are usually detected by negative IMS while the emerging peroxide-based explosives are better detected by positive IMS. In this study, a fast polarity-switchable IMS was constructed to detect these two explosive species in a single measurement. As the large traditional Faraday detector would cause a trailing reactant ion peak (RIP), a Faraday detector with ion focusing in vicinity was developed by reducing the detector radius to 3.3 mm and increasing the voltage difference between aperture grid and its front guard ring to 591 V, which could remove trailing peaks from RIP without loss of signal intensity. This fast polarity-switchable IMS with ion focusing in vicinity of Faraday detector was employed to detect a mixture of 10 ng 2,4,6-trinitrotoluene (TNT) and 50 ng hexamethylene triperoxide diamine (HMTD) by polarity-switching, and the result suggested that [TNT-H](-) and [HMTD+H](+) could be detected in a single measurement. Furthermore, the removal of trailing peaks from RIP by the Faraday detector with ion focusing in vicinity also promised the accurate identification of KClO4, KNO3 and S in common inorganic explosives, whose product ion peaks were fairly adjacent to RIP.

A Temporal and Spatial Analysis of Wave-Generated Foam Patterns in the Surf Zone

DTIC Science & Technology

2017-01-10

region, rectange B depicts the gap region, rectangle C is the plunging breaker, circle D represents a foam hole, rectangle E depict a top box...structures: The hidden skeleton of fluid flows . Phys. Today, 66, 41–47. 35 V. CONCLUSION Unique surf zone imagery, acquired from a UAV at Sand City...MacMahan, J. H., E . B . Thornton, T. P. Stanton, and A. J. H. M. Reniers, 2005: RIPEX: Observations of a rip current system. Mar. Geol., 218, 113–134

Estimating actigraphy from motion artifacts in ECG and respiratory effort signals.

PubMed

Fonseca, Pedro; Aarts, Ronald M; Long, Xi; Rolink, Jérôme; Leonhardt, Steffen

2016-01-01

Recent work in unobtrusive sleep/wake classification has shown that cardiac and respiratory features can help improve classification performance. Nevertheless, actigraphy remains the single most discriminative modality for this task. Unfortunately, it requires the use of dedicated devices in addition to the sensors used to measure electrocardiogram (ECG) or respiratory effort. This paper proposes a method to estimate actigraphy from the body movement artifacts present in the ECG and respiratory inductance plethysmography (RIP) based on the time-frequency analysis of those signals. Using a continuous wavelet transform to analyze RIP, and ECG and RIP combined, it provides a surrogate measure of actigraphy with moderate correlation (for ECG+RIP, ρ = 0.74, p  <  0.001) and agreement (mean bias ratio of 0.94 and 95% agreement ratios of 0.11 and 8.45) with reference actigraphy. More important, it can be used as a replacement of actigraphy in sleep/wake classification: after cross-validation with a data set comprising polysomnographic (PSG) recordings of 15 healthy subjects and 25 insomniacs annotated by an external sleep technician, it achieves a statistically non-inferior classification performance when used together with respiratory features (average κ of 0.64 for 15 healthy subjects, and 0.50 for a dataset with 40 healthy and insomniac subjects), and when used together with respiratory and cardiac features (average κ of 0.66 for 15 healthy subjects, and 0.56 for 40 healthy and insomniac subjects). Since this method eliminates the need for a dedicated actigraphy device, it reduces the number of sensors needed for sleep/wake classification to a single sensor when using respiratory features, and to two sensors when using respiratory and cardiac features without any loss in performance. It offers a major benefit in terms of comfort for long-term home monitoring and is immediately applicable for legacy ECG and RIP monitoring devices already used in clinical practice and which do not have an accelerometer built-in.

Ischemia Reperfusion Injury Triggers TNFα Induced-Necroptosis in Rat Retina.

PubMed

Kim, Cho Rong; Kim, Jie Hyun; Park, Hae-Young Lopilly; Park, Chan Kee

2017-05-01

A recent study revealed a novel form of cell death, termed necroptosis, or programmed necrosis. Previous research indicated that after ischemia-reperfusion (IR) injury to the retina, Tumor Necrosis Factor α (TNFα) is increased, which may activate necroptosis. This study observed macroglial cell activation, and in particular, astrocyte activation, after the release of TNFα and other necroptosis factors in the rat retina due to IR. IR was induced in the retinas of adult male Sprague-Dawley rats by increasing the intraocular pressure to 160 mmHg and then allowing reperfusion. In addition, to inhibit necroptosis, Nec-1 (necrostatin-1) was injected intravitreally after IR. Rats were sacrificed after reperfusion at 12 hours, 1, 3, and 5 days, and 1 and 2 weeks. Retinas from each time point were analyzed by immunohistochemistry (IHC) and Western blotting (WB) to identify the initiator of necroptosis, TNFα, the expression of necroptosis factors, such as receptor interacting protein (RIP) 1, 3, and inactive caspase 8, and Brn3a. Cell death in the IR-injured retinas was identified by cell counting. We found decreased retinal cell numbers in the inner and outer nuclear layers (INL and ONL), as well as in the ganglion cell layer (GCL). Increased glial cell activation was detected by using glial fibrillary acidic protein (GFAP) IHC. TNFα, RIP1, RIP3, and inactive caspase 8 were mainly expressed in the GCL after IR, as determined by IHC and WB. Nec-1 inhibited RIP1, a necroptosis factor, indicating protection against retinal cell loss after IR injury. We showed that IR injury triggered increases in both activation of astrocytes and the expression of TNFα. In addition, TNFα, which was activated by IR, triggered the release of necroptosis factors, particularly, in GCL. Inhibition of necroptosis using Nec-1 decreased the level of RIP1 and retinal cell loss in IR-injured retinas.

Caspase blockade induces RIP3-mediated programmed necrosis in Toll-like receptor-activated microglia.

PubMed

Kim, S J; Li, Jianrong

2013-07-11

Microglia are the resident immune cells in the central nervous system and key players against pathogens and injury. However, persistent microglial activation often exacerbates pathological damage and has been implicated in many neurological diseases. Despite their pivotal physiological and pathophysiological roles, how the survival and death of activated microglia is regulated remains poorly understood. We report here that microglia activated through Toll-like receptors (TLRs) undergo RIP1/RIP3-dependent programmed necrosis (necroptosis) when exposed to the pan caspase inhibitor zVAD-fmk. Although zVAD-fmk and the caspase-8 inhibitor IETD-fmk had no effect on unstimulated primary microglia, they markedly sensitized microglia to TLR1/2,3,4,7/8 ligands or TNF treatment, triggering programmed necrosis that was completely blocked by R1P1 kinase inhibitor necrostatin-1. Interestingly, necroptosis induced by TLR ligands and zVAD was restricted to microglial cells and was not observed in astrocytes, neurons or oligodendrocytes even though they are known to express certain TLRs. Deletion of genes encoding TNF or TNFR1 failed to prevent lipopolysaccharide- and poly(I:C)-induced microglial necroptosis, unveiling a TNF-independent programmed necrosis pathway in TLR3- and TLR4-activated microglia. Microglia from mice lacking functional TRIF were fully protected against TLR3/4 activation and zVAD-fmk-induced necrosis, and genetic deletion of rip3 also prevented microglia necroptosis. Activation of c-jun N-terminal kinase and generation of specific reactive oxygen species were downstream signaling events required for microglial cell death execution. Taken together, this study reveals a robust RIP3-dependent necroptosis signaling pathway in TLR-activated microglia upon caspase blockade and suggests that TLR signaling and programmed cell death pathways are closely linked in microglia, which could contribute to neuropathology and neuroinflammation when dysregulated.

The effects of crosscutting before gang-ripping on dimension part yields from no. 1 and 2A common red oak lumber

Treesearch

Charles, J. Gatchell; Janice K. Wiedenbeck; Elizabeth S. Walker; Elizabeth S. Walker

1996-01-01

Mills should have the option to crosscut red oak lumber prior to gang-ripping to remove crook and worthless material and to take advantage of the quality differences between board ends. At least half of No: 1 and 2A Common red oak boards will have end-to-end yield differences of at least 10 percent. Preprocessing will cause a slight decrease in overall yield but will...

Noise Hazard Evaluation Sound Level Data on Noise Sources

DTIC Science & Technology

1975-01-01

Saw, Root Woodworking 43-20-J 102 16. Construction Saw, DeWalt Industrial 2185A 96 17. Cross-Cut Sw, Automatic 1-H 94 18, Cross-Cut Saw, DeWalt 3561...Saw, GM Diehr 750 92 53. Rip Saw, Wabach Industrial 750 97 59. Rip Saw, Yates American B. 102 60. Router: Black & Decker 118 61. Ruuter, Rockwell 150B...13. Sander, Disk, National-Detroit Dual Action 100 14. Stapler , Senco Mll 94* 15. Stapling Gun, Bostich II 105* 16. Stapling Gun, Bostich III 104* 17

Research on Parallel Three Phase PWM Converters base on RTDS

NASA Astrophysics Data System (ADS)

Xia, Yan; Zou, Jianxiao; Li, Kai; Liu, Jingbo; Tian, Jun

2018-01-01

Converters parallel operation can increase capacity of the system, but it may lead to potential zero-sequence circulating current, so the control of circulating current was an important goal in the design of parallel inverters. In this paper, the Real Time Digital Simulator (RTDS) is used to model the converters parallel system in real time and study the circulating current restraining. The equivalent model of two parallel converters and zero-sequence circulating current(ZSCC) were established and analyzed, then a strategy using variable zero vector control was proposed to suppress the circulating current. For two parallel modular converters, hardware-in-the-loop(HIL) study based on RTDS and practical experiment were implemented, results prove that the proposed control strategy is feasible and effective.

Characterization of three DNA transposons in the Dutch elm disease fungi and evidence of repeat-induced point (RIP) mutations.

PubMed

Bouvet, Guillaume F; Jacobi, Volker; Bernier, Louis

2007-05-01

Transposable elements (TEs) are fundamental components of eukaryotic genomes and can contribute in various ways to genome plasticity and evolution. We describe here the first three DNA transposons in the Dutch elm disease (DED) pathogens Ophiostoma ulmi and O. novo-ulmi, named OPHIO1, OPHIO2 and OPHIO3. We demonstrate that OPHIO transposons, which show high homology to Fot1/pogo TEs within the Tc1/mariner superfamily, have different distribution patterns and specificity in the DED fungi and that interspecific hybrids could act as genetic bridges for transmission of TEs between closely related fungal species. OPHIO3 was found to have undergone repeat-induced point mutations (RIP). We have also developed a complementary method to Margolin's ratios based on the computation of cumulative transition scores (CTS) in order to visualize rapidly RIP signatures on individual DNA strands of OPHIO transposons and TEs found in other ascomycete fungi.

Future singularity avoidance in phantom dark energy models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haro, Jaume de, E-mail: jaime.haro@upc.edu

2012-07-01

Different approaches to quantum cosmology are studied in order to deal with the future singularity avoidance problem. Our results show that these future singularities will persist but could take different forms. As an example we have studied the big rip which appear when one considers the state equation P = ωρ with ω < −1, showing that it does not disappear in modified gravity. On the other hand, it is well-known that quantum geometric effects (holonomy corrections) in loop quantum cosmology introduce a quadratic modification, namely proportional to ρ{sup 2}, in Friedmann's equation that replace the big rip by amore » non-singular bounce. However this modified Friedmann equation could have been obtained in an inconsistent way, what means that the obtained results from this equation, in particular singularity avoidance, would be incorrect. In fact, we will show that instead of a non-singular bounce, the big rip singularity would be replaced, in loop quantum cosmology, by other kind of singularity.« less

Common Pharmacophore of Structurally Distinct Small-Molecule Inhibitors of Intracellular Retrograde Trafficking of Ribosome Inactivating Proteins

NASA Astrophysics Data System (ADS)

Yu, Shichao; Park, Jewn Giew; Kahn, Jennifer Nielsen; Tumer, Nilgun E.; Pang, Yuan-Ping

2013-12-01

We reported previously (+/-)-2-(5-methylthiophen-2-yl)-3-phenyl-2,3-dihydroquinazolin-4(1H)-one [(+/-)-Retro-2cycl] as the chemical structure of Retro-2 that showed mouse protection against ricin, a notorious ribosome inactivating protein (RIP). Herein we report our chemical resolution of (+/-)-Retro-2cycl, analog synthesis, and cell-based evaluation showing that the two optically pure enantiomers and their achiral analog have nearly the same degree of cell protection against ricin as (+/-)-Retro-2cycl. We also report our computational studies explaining the lack of stereo preference and revealing a common pharmacophore of structurally distinct inhibitors of intracellular retrograde trafficking of RIPs. This pharmacophore comprises a central aromatic ring o-substituted by an aromatic ring and a moiety bearing an O or S atom attached to sp2 C atom(s). These results offer new insights into lead identification and optimization for RIP antidote development to minimize the global health threat caused by ribosome-inactivating proteins.

Using drugs to target necroptosis: dual roles in disease therapy.

PubMed

Wang, Zhen; Guo, Li-Min; Zhou, Hong-Kang; Qu, Hong-Ke; Wang, Shu-Chao; Liu, Feng-Xia; Chen, Dan; Huang, Ju-Fang; Xiong, Kun

2018-02-01

Necroptosis is programmed necrosis, a process which has been studied for over a decade. The most common accepted mechanism is through the RIP1-RIP3-MLKL axis to regulate necroptotic cell death. As a result of previous studies on necroptosis, positive regulation for promoting necroptosis such as HSP90 stabilization and hyperactivation of TAK1 on RIP1 is clear. Similarly, the negative regulation of necroptosis, such as through caspase 8, c-FLIP, CHIP, MK2, PELI1, ABIN-1, is also clear. Therefore, the promise of corresponding applications in treating diseases becomes hopeful. Studies have shown that necroptosis is involved in the development of many diseases, such as ischemic injury diseases in various organs, neurodegenerative diseases, infectious diseases, and cancer. Given these results, drugs that inhibit or trigger necroptosis can be discovered to treat diseases. In this review, we briefly introduce up to date concepts concerning the mechanism of necroptosis, the diseases that involve necroptosis, and the drugs that can be applied to treat such diseases.

Type I interferon induces necroptosis in macrophages during infection with Salmonella enterica serovar Typhimurium

PubMed Central

Robinson, Nirmal; McComb, Scott; Mulligan, Rebecca; Dudani, Renu; Krishnan, Lakshmi; Sad, Subash

2014-01-01

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a virulent pathogen that induces rapid host death. Here we observed that host survival after infection with S. Typhimurium was enhanced in the absence of type I interferon signaling, with improved survival of mice deficient in the receptor for type I interferons (Ifnar1−/− mice) that was attributed to macrophages. Although there was no impairment in cytokine expression or inflammasome activation in Ifnar1−/− macrophages, they were highly resistant to S. Typhimurium–induced cell death. Specific inhibition of the kinase RIP1or knockdown of the gene encoding the kinase RIP3 prevented the death of wild-type macrophages, which indicated that necroptosis was a mechanism of cell death. Finally, RIP3-deficient macrophages, which cannot undergo necroptosis, had similarly less death and enhanced control of S. Typhimurium in vivo. Thus, we propose that S. Typhimurium induces the production of type I interferon, which drives necroptosis of macrophages and allows them to evade the immune response. PMID:22922364

The Use of Plant-Derived Ribosome Inactivating Proteins in Immunotoxin Development: Past, Present and Future Generations

PubMed Central

Rust, Aleksander; Partridge, Lynda J.; Davletov, Bazbek

2017-01-01

Ribosome inactivating proteins (RIPs) form a class of toxins that was identified over a century ago. They continue to fascinate scientists and the public due to their very high activity and long-term stability which might find useful applications in the therapeutic killing of unwanted cells but can also be used in acts of terror. We will focus our review on the canonical plant-derived RIPs which display ribosomal RNA N-glycosidase activity and irreversibly inhibit protein synthesis by cleaving the 28S ribosomal RNA of the large 60S subunit of eukaryotic ribosomes. We will place particular emphasis on therapeutic applications and the generation of immunotoxins by coupling antibodies to RIPs in an attempt to target specific cells. Several generations of immunotoxins have been developed and we will review their optimisation as well as their use and limitations in pre-clinical and clinical trials. Finally, we endeavour to provide a perspective on potential future developments for the therapeutic use of immunotoxins. PMID:29076988

A numerical study on the evolution of the wind-driven circulation in the Yellow Sea in winter

NASA Astrophysics Data System (ADS)

Tak, Y. J.; Cho, Y. K.

2016-02-01

The Yellow Sea is a semi-enclosed marginal sea and its circulation in winter is affected by the winter monsoon. In previous studies, it was found that the circulation of the Yellow Sea in winter consists of downwind and upwind currents. Downwind currents consisting of the Korean Coast Current (KCC) and the Chinese Coast Current (CCC) flow along the boundary of the Yellow Sea, whereas an upwind current consisting of the Yellow Sea Warm Current (YSWC) flows along the central trough of the Yellow Sea. Although some characteristics of such currents and the driving forces of the circulation have been studied by many scientists, the evolution of these currents has received little attention. So, the wind-driven circulation in the Yellow Sea was simulated to explain the changing pattern of these currents in winter and their evolutions were explored by the time-lagged correlation for winter season. According to the lagged correlation, downwind currents occurred in surface layer without a time lag. These downwind currents were more sensitive in the Chinese coast than that in the Korean coast. There is one day time-lag between the wind and the upwind flow developing in the Yellow Sea trough. The YSWC was shifted to the west of the trough after two days and then the KCC strengthened at the same time. It implied the westward shift of the YSWC and the clockwise circulation is developed, two days after the wind blows. The clockwise circulation was one of the reasons that the KCC was stronger than the CCC although the CCC was more sensitive to the wind than the KCC. The clockwise circulation also made the YSWC stronger in the inner YS than it at the entrance of the YS.

Modeling Rip Channel and Mega-Cusp Migration With XBeach

NASA Astrophysics Data System (ADS)

Orzech, M.; Thornton, E.; Reniers, A.; Macmahan, J.; O'Reilly, B.

2008-12-01

The relationship between alongshore rip channel migration and sediment transport is investigated using XBeach, a recently developed 2DH coastal erosion model. XBeach solves the nonlinear shallow water equations and accounts for the effects of breaking waves, wind, turbulent dispersion, and nonlinear bottom friction. It is similar to the more widely used Delft3D but focuses on morphological change to the beach and dune and includes the action of swash on a moving shoreline. Numerics have been simplified to increase model speed and ensure stability in shallow water. XBeach is first validated by recreating a three-year time series of alongshore rip migration patterns measured with video at Fort Ord, near Monterey, CA. The model is initialized with wave spectral data at 15m depth, provided by the Coastal Data Information Program (CDIP). Flow fields and transport patterns are then examined in detail over a single rip channel and mega-cusp to better understand the small scale processes associated with migration, and a range of simulations are conducted to quantify the effects on migration rates of varying wave height, incident angle, or tidal elevation. Results are presented from a four-month period of carefully monitored, accelerated shoreline erosion at the Fort Ord site, which followed the removal of a longstanding riprap barrier that had created a sand dune peninsula extending to the water's edge. Model-predicted erosion rates along the 300m stretch of shoreline are compared with dune retreat measurements for the period.

Activation of innate antiviral immune response via double-stranded RNA-dependent RLR receptor-mediated necroptosis

PubMed Central

Wang, Wei; Wang, Wei-Hua; Azadzoi, Kazem M.; Su, Ning; Dai, Peng; Sun, Jianbin; Wang, Qin; Liang, Ping; Zhang, Wentao; Lei, Xiaoying; Yan, Zhen; Yang, Jing-Hua

2016-01-01

Viruses induce double-stranded RNA (dsRNA) in the host cells. The mammalian system has developed dsRNA-dependent recognition receptors such as RLRs that recognize the long stretches of dsRNA as PAMPs to activate interferon-mediated antiviral pathways and apoptosis in severe infection. Here we report an efficient antiviral immune response through dsRNA-dependent RLR receptor-mediated necroptosis against infections from different classes of viruses. We demonstrated that virus-infected A549 cells were efficiently killed in the presence of a chimeric RLR receptor, dsCARE. It measurably suppressed the interferon antiviral pathway but promoted IL-1β production. Canonical cell death analysis by morphologic assessment, phosphatidylserine exposure, caspase cleavage and chemical inhibition excluded the involvement of apoptosis and consistently suggested RLR receptor-mediated necroptosis as the underlying mechanism of infected cell death. The necroptotic pathway was augmented by the formation of RIP1-RIP3 necrosome, recruitment of MLKL protein and the activation of cathepsin D. Contributing roles of RIP1 and RIP3 were confirmed by gene knockdown. Furthermore, the necroptosis inhibitor necrostatin-1 but not the pan-caspase inhibitor zVAD impeded dsCARE-dependent infected cell death. Our data provides compelling evidence that the chimeric RLR receptor shifts the common interferon antiviral responses of infected cells to necroptosis and leads to rapid death of the virus-infected cells. This mechanism could be targeted as an efficient antiviral strategy. PMID:26935990

RIP140/PGC-1α axis involved in vitamin A-induced neural differentiation by increasing mitochondrial function.

PubMed

Mu, Qing; Yu, Weidong; Zheng, Shuying; Shi, Hongxia; Li, Mei; Sun, Jie; Wang, Di; Hou, Xiaoli; Liu, Ling; Wang, Xinjuan; Zhao, Zhuran; Liang, Rong; Zhang, Xue; Dong, Wei; Zeng, Chaomei; Guo, Jingzhu

2018-03-07

Vitamin A deficiency and mitochondrial dysfunction are both associated with neural differentiation-related disorders, such as Alzheimer's disease (AD) and Down syndrome (DS). The mechanism of vitamin A-induced neural differentiation and the notion that vitamin A can regulate the morphology and function of mitochondria in its induction of neural differentiation through the RIP140/PGC-1α axis are unclear. The aim of this study was to investigate the roles and underlying mechanisms of RIP140/PGC-1α axis in vitamin A-induced neural differentiation. Human neuroblastoma cells (SH-SY5Y) were used as a model of neural stem cells, which were incubated with DMSO, 9-cis-retinoic acid (9-cis-RA), 13-cis-retinoic acid (13-cis-RA) and all-trans-retinoic acid (at-RA). Neural differentiation of SH-SY5Y was evaluated by Sandquist calculation, combined with immunofluorescence and real-time polymerase chain reaction (PCR) of neural markers. Mitochondrial function was estimated by ultrastructure assay using transmission electron microscopy (TEM) combined with the expression of PGC-1α and NEMGs using real-time PCR. The participation of the RA signaling pathway was demonstrated by adding RA receptor antagonists. Vitamin A derivatives are able to regulate mitochondrial morphology and function, and furthermore to induce neural differentiation through the RA signaling pathway. The RIP140/PGC-1α axis is involved in the regulation of mitochondrial function in vitamin A derivative-induced neural differentiation.

Expression of a Recombinant Anti-HIV and Anti-Tumor Protein, MAP30, in Nicotiana tobacum Hairy Roots: A pH-Stable and Thermophilic Antimicrobial Protein.

PubMed

Moghadam, Ali; Niazi, Ali; Afsharifar, Alireza; Taghavi, Seyed Mohsen

2016-01-01

In contrast to conventional antibiotics, which microorganisms can readily evade, it is nearly impossible for a microbial strain that is sensitive to antimicrobial proteins to convert to a resistant strain. Therefore, antimicrobial proteins and peptides that are promising alternative candidates for the control of bacterial infections are under investigation. The MAP30 protein of Momordica charantia is a valuable type I ribosome-inactivating protein (RIP) with anti-HIV and anti-tumor activities. Whereas the antimicrobial activity of some type I RIPs has been confirmed, less attention has been paid to the antimicrobial activity of MAP30 produced in a stable, easily handled, and extremely cost-effective protein-expression system. rMAP30-KDEL was expressed in Nicotiana tobacum hairy roots, and its effect on different microorganisms was investigated. Analysis of the extracted total proteins of transgenic hairy roots showed that rMAP30-KDEL was expressed effectively and that this protein exhibited significant antibacterial activity in a dose-dependent manner. rMAP30-KDEL also possessed thermal and pH stability. Bioinformatic analysis of MAP30 and other RIPs regarding their conserved motifs, amino-acid contents, charge, aliphatic index, GRAVY value, and secondary structures demonstrated that these factors accounted for their thermophilicity. Therefore, RIPs such as MAP30 and its derived peptides might have promising applications as food preservatives, and their analysis might provide useful insights into designing clinically applicable antibiotic agents.

Expression of a Recombinant Anti-HIV and Anti-Tumor Protein, MAP30, in Nicotiana tobacum Hairy Roots: A pH-Stable and Thermophilic Antimicrobial Protein

PubMed Central

Moghadam, Ali; Niazi, Ali; Afsharifar, Alireza; Taghavi, Seyed Mohsen

2016-01-01

In contrast to conventional antibiotics, which microorganisms can readily evade, it is nearly impossible for a microbial strain that is sensitive to antimicrobial proteins to convert to a resistant strain. Therefore, antimicrobial proteins and peptides that are promising alternative candidates for the control of bacterial infections are under investigation. The MAP30 protein of Momordica charantia is a valuable type I ribosome-inactivating protein (RIP) with anti-HIV and anti-tumor activities. Whereas the antimicrobial activity of some type I RIPs has been confirmed, less attention has been paid to the antimicrobial activity of MAP30 produced in a stable, easily handled, and extremely cost-effective protein-expression system. rMAP30-KDEL was expressed in Nicotiana tobacum hairy roots, and its effect on different microorganisms was investigated. Analysis of the extracted total proteins of transgenic hairy roots showed that rMAP30-KDEL was expressed effectively and that this protein exhibited significant antibacterial activity in a dose-dependent manner. rMAP30-KDEL also possessed thermal and pH stability. Bioinformatic analysis of MAP30 and other RIPs regarding their conserved motifs, amino-acid contents, charge, aliphatic index, GRAVY value, and secondary structures demonstrated that these factors accounted for their thermophilicity. Therefore, RIPs such as MAP30 and its derived peptides might have promising applications as food preservatives, and their analysis might provide useful insights into designing clinically applicable antibiotic agents. PMID:27459300

Water stress, CO2 and photoperiod influence hormone levels in wheat

NASA Technical Reports Server (NTRS)

Nan, Rubin; Carman, John G.; Salisbury, Frank B.; Campbell, W. F. (Principal Investigator)

2002-01-01

'Super Dwarf' wheat (Triticum aestivum L.) plants have been grown from seed to maturity in the Mir space station where they were periodically exposed, because of microgravity and other constraints, to water deficit, waterlogging, high CO2 levels, and low light intensities. The plants produced many tillers, but none of them produced viable seed. Studies have been initiated to determine why the plants responded in these ways. In the present study, effects of the listed stresses on abscisic acid (ABA), indole-3-acetic acid (IAA) and isopentenyl adenosine ([9R]iP) levels in roots and leaves of plants grown under otherwise near optimal conditions on earth were measured. Hormones were extracted, purified by HPLC, and quantified by noncompetitive indirect ELISA. In response to water deficit, ABA levels increased in roots and leaves, IAA levels decreased in roots and leaves, and [9R]iP levels increased in leaves but decreased in roots. In response to waterlogging, ABA, IAA and [9R]iP levels briefly increased in roots and leaves and then decreased. When portions of the root system were exposed to waterlogging and/or water deficit, ABA levels in leaves increased while [9R]iP and IAA levels decreased. These responses were correlated with the percentage of the root system stressed. At a low photosynthetic photon flux (100 micromoles m-2 s-1), plants grown in continuous light had higher leaf ABA levels than plants grown using an 18 or 21 h photoperiod.

Eutirucallin, a RIP-2 Type Lectin from the Latex of Euphorbia tirucalli L. Presents Proinflammatory Properties

PubMed Central

Santana, Sanzio Silva; Gennari-Cardoso, Margareth Leitão; Carvalho, Fernanda Caroline; Roque-Barreira, Maria Cristina; Santiago, André da Silva; Alvim, Fátima Cerqueira; Pirovani, Carlos Priminho

2014-01-01

Lectins are carbohydrate-binding proteins that recognize and modulate physiological activities and have been used as a toll for detection and identification of biomolecules, and therapy of diseases. In this study we have isolated a lectin present in the latex of Euphorbia tirucalli, and named it Eutirucallin. The latex protein extract was subjected to ion exchange chromatography and showed two peaks with haemagglutinating activity. Polypeptides of 32 kDa protein extract strongly interacted with immobilized galactose (α-lactose > D-N-acetylgalactosamine). The Eutirucallin was obtained with a yield of 5.6% using the α-lactose column. The lectin domain has 32 kDa subunits and at least two of which are joined by disulfide bridges. The agglutinating capacity for human erythrocytes A+, B+ and O+ is inhibited by D-galactose. The haemagglutinating activity of Eutirucallin was independent of Ca2+ and maintained until the temperature of 55°C. Eutirucallin presented biological activities such as neutrophils recruitment and cytokine prodution by macrophages. The analysis of the trypsin-digested Eutirucallin by ms/ms in ESI-Q-TOFF resulted in nine peptides similar to type 2 ribosome-inactivating protein (type-2 RIP). It's partial sequence showed a similarity of 67.4 – 83.1% for the lectin domain of type-2 RIP [Ricin and Abrin (83.1%), Viscumin, Ebulin, Pulchellin, Cinnamomin, Volkensin and type-2 RIP Iris hollandica]. Our data suggest that Eutirucallin is a new member of type 2 ribosome-inactivating protein and presents biotechnological potential. PMID:24558388

Toxin-Induced Necroptosis Is a Major Mechanism of Staphylococcus aureus Lung Damage

PubMed Central

Kitur, Kipyegon; Parker, Dane; Nieto, Pamela; Ahn, Danielle S.; Cohen, Taylor S.; Chung, Samuel; Wachtel, Sarah; Bueno, Susan; Prince, Alice

2015-01-01

Staphylococcus aureus USA300 strains cause a highly inflammatory necrotizing pneumonia. The virulence of this strain has been attributed to its expression of multiple toxins that have diverse targets including ADAM10, NLRP3 and CD11b. We demonstrate that induction of necroptosis through RIP1/RIP3/MLKL signaling is a major consequence of S. aureus toxin production. Cytotoxicity could be prevented by inhibiting either RIP1 or MLKL signaling and S. aureus mutants lacking agr, hla or Hla pore formation, lukAB or psms were deficient in inducing cell death in human and murine immune cells. Toxin-associated pore formation was essential, as cell death was blocked by exogenous K+ or dextran. MLKL inhibition also blocked caspase-1 and IL-1β production, suggesting a link to the inflammasome. Rip3 -/- mice exhibited significantly improved staphylococcal clearance and retained an alveolar macrophage population with CD200R and CD206 markers in the setting of acute infection, suggesting increased susceptibility of these leukocytes to necroptosis. The importance of this anti-inflammatory signaling was indicated by the correlation between improved outcome and significantly decreased expression of KC, IL-6, TNF, IL-1α and IL-1β in infected mice. These findings indicate that toxin-induced necroptosis is a major cause of lung pathology in S. aureus pneumonia and suggest the possibility of targeting components of this signaling pathway as a therapeutic strategy. PMID:25880560

More on the holographic Ricci dark energy model: smoothing Rips through interaction effects?

PubMed

Bouhmadi-López, Mariam; Errahmani, Ahmed; Ouali, Taoufik; Tavakoli, Yaser

2018-01-01

The background cosmological dynamics of the late Universe is analysed on the framework of a dark energy model described by an holographic Ricci dark energy component. Several kind of interactions between the dark energy and the dark matter components are considered herein. We solve the background cosmological dynamics for the different choices of interactions with the aim to analyse not only the current evolution of the universe but also its asymptotic behaviour and, in particular, possible future singularities removal. We show that in most of the cases, the Big Rip singularity, a finger print of this model in absence of an interaction between the dark sectors, is substituted by a de Sitter or a Minkowski state. Most importantly, we found two new future bouncing solutions leading to two possible asymptotic behaviours, we named Little Bang and Little Sibling of the Big Bang. At a Little Bang, as the size of the universe shrinks to zero in an infinite cosmic time, the Hubble rate and its cosmic time derivative blow up. In addition, at a Little sibling of the Big Bang, as the size of the universe shrinks to zero in an infinite cosmic time, the Hubble rate blows up but its cosmic time derivative is finite. These two abrupt events can happen as well in the past.

More on the holographic Ricci dark energy model: smoothing Rips through interaction effects?

NASA Astrophysics Data System (ADS)

Bouhmadi-López, Mariam; Errahmani, Ahmed; Ouali, Taoufik; Tavakoli, Yaser

2018-04-01

The background cosmological dynamics of the late Universe is analysed on the framework of a dark energy model described by an holographic Ricci dark energy component. Several kind of interactions between the dark energy and the dark matter components are considered herein. We solve the background cosmological dynamics for the different choices of interactions with the aim to analyse not only the current evolution of the universe but also its asymptotic behaviour and, in particular, possible future singularities removal. We show that in most of the cases, the Big Rip singularity, a finger print of this model in absence of an interaction between the dark sectors, is substituted by a de Sitter or a Minkowski state. Most importantly, we found two new future bouncing solutions leading to two possible asymptotic behaviours, we named Little Bang and Little Sibling of the Big Bang. At a Little Bang, as the size of the universe shrinks to zero in an infinite cosmic time, the Hubble rate and its cosmic time derivative blow up. In addition, at a Little sibling of the Big Bang, as the size of the universe shrinks to zero in an infinite cosmic time, the Hubble rate blows up but its cosmic time derivative is finite. These two abrupt events can happen as well in the past.

RIP-REMOTE INTERACTIVE PARTICLE-TRACER

NASA Technical Reports Server (NTRS)

Rogers, S. E.

1994-01-01

Remote Interactive Particle-tracing (RIP) is a distributed-graphics program which computes particle traces for computational fluid dynamics (CFD) solution data sets. A particle trace is a line which shows the path a massless particle in a fluid will take; it is a visual image of where the fluid is going. The program is able to compute and display particle traces at a speed of about one trace per second because it runs on two machines concurrently. The data used by the program is contained in two files. The solution file contains data on density, momentum and energy quantities of a flow field at discrete points in three-dimensional space, while the grid file contains the physical coordinates of each of the discrete points. RIP requires two computers. A local graphics workstation interfaces with the user for program control and graphics manipulation, and a remote machine interfaces with the solution data set and performs time-intensive computations. The program utilizes two machines in a distributed mode for two reasons. First, the data to be used by the program is usually generated on the supercomputer. RIP avoids having to convert and transfer the data, eliminating any memory limitations of the local machine. Second, as computing the particle traces can be computationally expensive, RIP utilizes the power of the supercomputer for this task. Although the remote site code was developed on a CRAY, it is possible to port this to any supercomputer class machine with a UNIX-like operating system. Integration of a velocity field from a starting physical location produces the particle trace. The remote machine computes the particle traces using the particle-tracing subroutines from PLOT3D/AMES, a CFD post-processing graphics program available from COSMIC (ARC-12779). These routines use a second-order predictor-corrector method to integrate the velocity field. Then the remote program sends graphics tokens to the local machine via a remote-graphics library. The local machine interprets the graphics tokens and draws the particle traces. The program is menu driven. RIP is implemented on the silicon graphics IRIS 3000 (local workstation) with an IRIX operating system and on the CRAY2 (remote station) with a UNICOS 1.0 or 2.0 operating system. The IRIS 4D can be used in place of the IRIS 3000. The program is written in C (67%) and FORTRAN 77 (43%) and has an IRIS memory requirement of 4 MB. The remote and local stations must use the same user ID. PLOT3D/AMES unformatted data sets are required for the remote machine. The program was developed in 1988.

Impact of Data Assimilation And Resolution On Modeling The Gulf Stream Pathway

DTIC Science & Technology

2011-11-18

currents could be generated by either the Deep Western Boundary Current (DWBC) associated with the Meridional Overturning Circulation (MOC) or by...abyssal gyre centered directly beneath the surface gyre. Figure 7. Meridional overturning circulation stream function for four 1/12° global HYCOM... circulation and have a weak overturning circulation . The Gulf Stream path is poorly simulated without the steering by the abyssal circulation . A

Phantom energy: dark energy with w <--1 causes a cosmic doomsday.

PubMed

Caldwell, Robert R; Kamionkowski, Marc; Weinberg, Nevin N

2003-08-15

We explore the consequences that follow if the dark energy is phantom energy, in which the sum of the pressure and energy density is negative. The positive phantom-energy density becomes infinite in finite time, overcoming all other forms of matter, such that the gravitational repulsion rapidly brings our brief epoch of cosmic structure to a close. The phantom energy rips apart the Milky Way, solar system, Earth, and ultimately the molecules, atoms, nuclei, and nucleons of which we are composed, before the death of the Universe in a "big rip."

Classical stability of sudden and big rip singularities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barrow, John D.; Lip, Sean Z. W.

2009-08-15

We introduce a general characterization of sudden cosmological singularities and investigate the classical stability of homogeneous and isotropic cosmological solutions of all curvatures containing these singularities to small scalar, vector, and tensor perturbations using gauge-invariant perturbation theory. We establish that sudden singularities at which the scale factor, expansion rate, and density are finite are stable except for a set of special parameter values. We also apply our analysis to the stability of Big Rip singularities and find the conditions for their stability against small scalar, vector, and tensor perturbations.

Influence of the Antarctic Circumpolar Current on the Atlantic Meriodional Circulation

DTIC Science & Technology

2009-03-01

Atlantic meridional overturning circulation . Rev. Geophys., 45, 2004RG000166. Marshall, J., and T. Radko (2003): Residual...ANTARCTIC CIRCUMPOLAR CURRENT ON THE ATLANTIC MERIDIONAL CIRCULATION by David J. Widener March 2009 Thesis Advisor: Timour Radko...distribution is unlimited 12b. DISTRIBUTION CODE 13. ABSTRACT (maximum 200 words) The physics of the Meridional Overturning Circulation and

Pax2 regulates a fadd-dependent molecular switch that drives tissue fusion during eye development.

PubMed

Viringipurampeer, Ishaq A; Ferreira, Todd; DeMaria, Shannon; Yoon, Jookyung J; Shan, Xianghong; Moosajee, Mariya; Gregory-Evans, Kevin; Ngai, John; Gregory-Evans, Cheryl Y

2012-05-15

Tissue fusion is an essential morphogenetic mechanism in development, playing a fundamental role in developing neural tube, palate and the optic fissure. Disruption of genes associated with the tissue fusion can lead to congenital malformations, such as spina bifida, cleft lip/palate and ocular coloboma. For instance, the Pax2 transcription factor is required for optic fissure closure, although the mechanism of Pax2 action leading to tissue fusion remains elusive. This lack of information defining how transcription factors drive tissue morphogenesis at the cellular level is hampering new treatments options. Through loss- and gain-of-function analysis, we now establish that pax2 in combination with vax2 directly regulate the fas-associated death domain (fadd) gene. In the presence of fadd, cell proliferation is restricted in the developing eye through a caspase-dependent pathway. However, the loss of fadd results in a proliferation defect and concomitant activation of the necroptosis pathway through RIP1/RIP3 activity, leading to an abnormal open fissure. Inhibition of RIP1 with the small molecule drug necrostatin-1 rescues the pax2 eye fusion defect, thereby overcoming the underlying genetic defect. Thus, fadd has an essential physiological function in protecting the developing optic fissure neuroepithelium from RIP3-dependent necroptosis. This study demonstrates the molecular hierarchies that regulate a cellular switch between proliferation and the apoptotic and necroptotic cell death pathways, which in combination drive tissue morphogenesis. Furthermore, our data suggest that future therapeutic strategies may be based on small molecule drugs that can bypass the gene defects causing common congenital tissue fusion defects.

Diabetic neuropathy: electrophysiological and morphological study of peripheral nerve degeneration and regeneration in transgenic mice that express IFNbeta in beta cells.

PubMed

Serafín, Anna; Molín, Jessica; Márquez, Merce; Blasco, Ester; Vidal, Enric; Foradada, Laia; Añor, Sonia; Rabanal, Rosa M; Fondevila, Dolors; Bosch, Fàtima; Pumarola, Martí

2010-05-01

Diabetic neuropathy is one of the most frequent complications in diabetes but there are no treatments beyond glucose control, due in part to the lack of an appropriate animal model to assess an effective therapy. This study was undertaken to characterize the degenerative and regenerative responses of peripheral nerves after induced sciatic nerve damage in transgenic rat insulin I promoter / human interferon beta (RIP/IFNbeta) mice made diabetic with a low dose of streptozotocin (STZ) as an animal model of diabetic complications. In vivo, histological and immunohistological studies of cutaneous and sciatic nerves were performed after left sciatic crush. Functional tests, cutaneous innervation, and sciatic nerve evaluation showed pronounced neurological reduction in all groups 2 weeks after crush. All animals showed a gradual recovery but this was markedly slower in diabetic animals in comparison with normoglycemic animals. The delay in regeneration in diabetic RIP/IFNbeta mice resulted in an increase in active Schwann cells and regenerating neurites 8 weeks after surgery. These findings indicate that diabetic-RIP/IFNbeta animals mimic human diabetic neuropathy. Moreover, when these animals are submitted to nerve crush they have substantial deficits in nerve regrowth, similar to that observed in diabetic patients. When wildtype animals were treated with the same dose of STZ, no differences were observed with respect to nontreated animals, indicating that low doses of STZ and the transgene are not implicated in development of the degenerative and regenerative events observed in our study. All these findings indicate that RIP/IFNbeta transgenic mice are a good model for diabetic neuropathy.

Healing the wounds in the landscape-reclaiming gravel roads in conservation areas.

PubMed

Tarvainen, Oili; Tolvanen, Anne

2016-07-01

Reclaiming abandoned and unmaintained roads, built originally for forestry and mineral extraction, is an important part of ecological restoration, because the roads running through natural habitats cause fragmentation. The roads can be reclaimed in a passive way by blocking access to the road, but successful seedling recruitment may require additional management due to the physical constraints present at the road. We established a full factorial study to compare the effects of three road reclaiming measures, namely ripping, creation of safe sites by adding mulch and pine seed addition, on soil processes, recovery of understorey vegetation and seedling recruitment in three conservation areas in eastern Finland. We surveyed soil organic matter, frequency and cover of plant functional types, litter and mineral soil, and number of tree seedlings. The soil organic matter was, on average, 1.3-fold in the 50-cm-deep ripping treatment relative to unripped and 20-cm-deep ripping treatments. The germination and survival of deciduous seedlings and grass establishment were promoted by adding mulch. The addition of pine seeds counteracted the seed limitation and enhanced the regeneration of trees. The treatment combination consisting of ripping, adding mulch and pine seed addition enhanced the vegetation succession and tree-seedling recruitment most: the cover of grasses, herbs and ericaceous dwarf shrubs was 1.3-7.6-fold and the number of coniferous tree seedlings was 3.4-7.1-fold relative to the other treatment combinations. Differences between short-term (1-3 years) and longer-term (6 years) results indicate the need for a sufficient observation period in road reclamation studies.

Accuracy and consistency of respiratory inductive plethysmography for overnight tidal volume measurement.

PubMed

Zhang, J; Ruch, E W; Bloch, K E

2001-01-01

To validate the accuracy and consistency of respiratory inductive plethysmography (RIP) in measuring tidal volume after an overnight sleep, tidal volumes of 18 patients with suspected sleep-disordered breathing and 8 normal volunteers were measured simultaneously with RIP (VTRIP) and with an ultrasonic airflow meter (VTUFM) before and after an unstrained overnight sleep on supine and lateral decubitus. The bias of the VTRIP was expressed as (VTRIP-VTUFM)/ VTUFM.100%, limits of agreement between VTRIP and VTUFM was measured by averaged bias +/- 2 s. Results showed that in normal subjects, the bias of RIP before and after overnight sleep was precise and consistent in both supine (0.7% and -1.6%) and lateral decubitus (3.7% and -0.56%). In these patients, the bias of RIP before and after sleep in supine also remained small (1.9% and 1.7%), but it became larger in lateral decubitus (24.5% and 20.4%) and 11.5% exceeded the limits of agreement observed in the evening. The patients' body mass indices (BMI) were higher than those of normal subjects (median 34.2 vs. 27.8 kg/m2). Pooled data showed that the bias of VTRIP in the morning on lateral decubitus but not on supine was correlated to BMI (Spearman R = 0.32, n = 52, P = 0.02). Thus, we were led to conclude that the accuracy of VTRIP overnight was precise and consistent in normal subjects, but the deviation of VTRIP measured on lateral decubitus in patients especially in those with excessive obesity was greater, thus, the method should not be used for quantitative determination.

Multichannel Compressive Sensing MRI Using Noiselet Encoding

PubMed Central

Pawar, Kamlesh; Egan, Gary; Zhang, Jingxin

2015-01-01

The incoherence between measurement and sparsifying transform matrices and the restricted isometry property (RIP) of measurement matrix are two of the key factors in determining the performance of compressive sensing (CS). In CS-MRI, the randomly under-sampled Fourier matrix is used as the measurement matrix and the wavelet transform is usually used as sparsifying transform matrix. However, the incoherence between the randomly under-sampled Fourier matrix and the wavelet matrix is not optimal, which can deteriorate the performance of CS-MRI. Using the mathematical result that noiselets are maximally incoherent with wavelets, this paper introduces the noiselet unitary bases as the measurement matrix to improve the incoherence and RIP in CS-MRI. Based on an empirical RIP analysis that compares the multichannel noiselet and multichannel Fourier measurement matrices in CS-MRI, we propose a multichannel compressive sensing (MCS) framework to take the advantage of multichannel data acquisition used in MRI scanners. Simulations are presented in the MCS framework to compare the performance of noiselet encoding reconstructions and Fourier encoding reconstructions at different acceleration factors. The comparisons indicate that multichannel noiselet measurement matrix has better RIP than that of its Fourier counterpart, and that noiselet encoded MCS-MRI outperforms Fourier encoded MCS-MRI in preserving image resolution and can achieve higher acceleration factors. To demonstrate the feasibility of the proposed noiselet encoding scheme, a pulse sequences with tailored spatially selective RF excitation pulses was designed and implemented on a 3T scanner to acquire the data in the noiselet domain from a phantom and a human brain. The results indicate that noislet encoding preserves image resolution better than Fouirer encoding. PMID:25965548

Polyvinylidene fluoride film based nasal sensor to monitor human respiration pattern: an initial clinical study.

PubMed

Roopa Manjunatha, G; Rajanna, K; Mahapatra, D Roy; Nayak, M M; Krishnaswamy, Uma Maheswari; Srinivasa, R

2013-12-01

Design and development of a piezoelectric polyvinylidene fluoride (PVDF) thin film based nasal sensor to monitor human respiration pattern (RP) from each nostril simultaneously is presented in this paper. Thin film based PVDF nasal sensor is designed in a cantilever beam configuration. Two cantilevers are mounted on a spectacle frame in such a way that the air flow from each nostril impinges on this sensor causing bending of the cantilever beams. Voltage signal produced due to air flow induced dynamic piezoelectric effect produce a respective RP. A group of 23 healthy awake human subjects are studied. The RP in terms of respiratory rate (RR) and Respiratory air-flow changes/alterations obtained from the developed PVDF nasal sensor are compared with RP obtained from respiratory inductance plethysmograph (RIP) device. The mean RR of the developed nasal sensor (19.65 ± 4.1) and the RIP (19.57 ± 4.1) are found to be almost same (difference not significant, p > 0.05) with the correlation coefficient 0.96, p < 0.0001. It was observed that any change/alterations in the pattern of RIP is followed by same amount of change/alterations in the pattern of PVDF nasal sensor with k = 0.815 indicating strong agreement between the PVDF nasal sensor and RIP respiratory air-flow pattern. The developed sensor is simple in design, non-invasive, patient friendly and hence shows promising routine clinical usage. The preliminary result shows that this new method can have various applications in respiratory monitoring and diagnosis.

Catalytically active Yersinia outer protein P induces cleavage of RIP and caspase-8 at the level of the DISC independently of death receptors in dendritic cells.

PubMed

Gröbner, Sabine; Adkins, Irena; Schulz, Sebastian; Richter, Kathleen; Borgmann, Stefan; Wesselborg, Sebastian; Ruckdeschel, Klaus; Micheau, Olivier; Autenrieth, Ingo B

2007-10-01

Yersinia outer protein P (YopP) is injected by Y. enterocolitica into host cells thereby inducing apoptotic and necrosis-like cell death in dendritic cells (DC). Here we show the pathways involved in DC death caused by the catalytic activity of YopP. Infection with Yersinia enterocolitica, translocating catalytically active YopP into DC, triggered procaspase-8 cleavage and c-FLIPL degradation. YopP-dependent caspase-8 activation was, however, not mediated by tumor necrosis factor (TNF) receptor family members since the expression of both CD95/Fas/APO-1 and TRAIL-R2 on DC was low, and DC were resistant to apoptosis induced by agonistic anti-CD95 antibodies or TNF-related apoptosis-inducing ligand (TRAIL). Moreover, DC from TNF-Rp55-/- mice were not protected against YopP-induced cell death demonstrating that TNF-R1 is also not involved in this process. Activation of caspase-8 was further investigated by coimmunoprecitation of FADD from Yersinia-infected DC. We found that both cleaved caspase-8 and receptor interacting protein 1 (RIP1) were associated with the Fas-associated death domain (FADD) indicating the formation of an atypical death-inducing signaling complex (DISC). Furthermore, degradation of RIP mediated by the Hsp90 inhibitor geldanamycin significantly impaired YopP-induced cell death. Altogether our findings indicate that Yersinia-induced DC death is independent of death domain containing receptors, but mediated by RIP and caspase-8 at the level of DISC.

Determining potential pregnancy status differences based on a new method of yearling heifer prebreeding examination.

PubMed

Monday, Jessica D; Larson, Robert L; Laflin, Shelie; White, Brad J; Theurer, Miles E

2018-01-01

The study objective was to evaluate the Ready-Intermediate-Problem (RIP) replacement heifer evaluation matrix's ability to classify heifers into groups with differing reproductive outcomes. Beef heifers (n = 341) from six Kansas herds were classified according to RIP matrix guidelines and then exposed to AI breeding, bull breeding, or a combination of both as per the management plans for each participating herd. Following the breeding season the heifers were evaluated to determine pregnancy status, AI pregnancy status, days bred, and the number of 21 day cycles needed during the breeding season to become pregnant. After the breeding season, 298 (87%) of the heifers were pregnant, 204 (68%) of which became pregnant in the first 21 days of the breeding season. There was a significant interaction (P = 0.01) in RIP classification and pregnancy by 21 day cycle. Ready classified heifers had a significantly greater risk of becoming pregnant after a single AI exposure (P = 0.03) and in the first 21-day cycle (P = 0.02) compared to Problem classified heifers, and significantly less risk of being non-pregnant at the end of the breeding season (P < 0.01) compared to Problem classified heifers. The RIP matrix can be useful for classifying heifers prior to the onset of the breeding season. Further research is needed to evaluate the matrix in other settings and populations of U.S. beef heifers as well as at different intervals between evaluation and the start of breeding season. Copyright © 2017 Elsevier Inc. All rights reserved.

Ischemic preconditioning of the muscle improves maximal exercise performance but not maximal oxygen uptake in humans.

PubMed

Crisafulli, Antonio; Tangianu, Flavio; Tocco, Filippo; Concu, Alberto; Mameli, Ombretta; Mulliri, Gabriele; Caria, Marcello A

2011-08-01

Brief episodes of nonlethal ischemia, commonly known as "ischemic preconditioning" (IP), are protective against cell injury induced by infarction. Moreover, muscle IP has been found capable of improving exercise performance. The aim of the study was the comparison of standard exercise performances carried out in normal conditions with those carried out following IP, achieved by brief muscle ischemia at rest (RIP) and after exercise (EIP). Seventeen physically active, healthy male subjects performed three incremental, randomly assigned maximal exercise tests on a cycle ergometer up to exhaustion. One was the reference (REF) test, whereas the others were performed after the RIP and EIP sessions. Total exercise time (TET), total work (TW), and maximal power output (W(max)), oxygen uptake (VO(2max)), and pulmonary ventilation (VE(max)) were assessed. Furthermore, impedance cardiography was used to measure maximal heart rate (HR(max)), stroke volume (SV(max)), and cardiac output (CO(max)). A subgroup of volunteers (n = 10) performed all-out tests to assess their anaerobic capacity. We found that both RIP and EIP protocols increased in a similar fashion TET, TW, W(max), VE(max), and HR(max) with respect to the REF test. In particular, W(max) increased by ∼ 4% in both preconditioning procedures. However, preconditioning sessions failed to increase traditionally measured variables such as VO(2max), SV(max,) CO(max), and anaerobic capacity(.) It was concluded that muscle IP improves performance without any difference between RIP and EIP procedures. The mechanism of this effect could be related to changes in fatigue perception.

Effects of grade control structures on the macroinvertebrate assemblage of an agriculturally impacted stream

USGS Publications Warehouse

Litvan, M.E.; Stewart, T.W.; Pierce, C.L.; Larson, C.J.

2008-01-01

Nearly 400 rock rip-rap grade control structures (hereafter GCS) were recently placed in streams of western Iowa, USA to reduce streambank erosion and protect bridge infrastructure and farmland. In this region, streams are characterized by channelized reaches, highly incised banks and silt and sand substrates that normally support low macroinvertebrate abundance and diversity. Therefore, GCS composed of rip-rap provide the majority of coarse substrate habitat for benthic macroinvertebrates in these streams. We sampled 20 sites on Walnut Creek, Montgomery County, Iowa to quantify macroinvertebrate assemblage characteristics (1) on GCS rip-rap and at sites located (2) 5-50 m upstream of GCS, (3) 5-50 m downstream of GCS and (4) at least 1 km from any GCS (five sites each). Macroinvertebrate biomass, numerical densities and diversity were greatest at sites with coarse substrates, including GCS sites and one natural riffle site and relatively low at remaining sites with soft substrates. Densities of macroinvertebrates in the orders Ephemeroptera, Trichoptera, Diptera, Coleoptera and Acariformes were abundant on GCS rip-rap. Increases in macroinvertebrate biomass, density and diversity at GCS may improve local efficiency of breakdown of organic matter and nutrient and energy flow, and provide enhanced food resources for aquatic vertebrates. However, lack of positive macroinvertebrate responses immediately upstream and downstream of GCS suggest that positive effects might be restricted to the small areas of streambed covered by GCS. Improved understanding of GCS effects at both local and ecosystem scales is essential for stream management when these structures are present. Copyright ?? 2007 John Wiley & Sons, Ltd.

Augmented trophoblast cell death in preeclampsia can proceed via ceramide-mediated necroptosis

PubMed Central

Bailey, Liane Jennifer; Alahari, Sruthi; Tagliaferro, Andrea; Post, Martin; Caniggia, Isabella

2017-01-01

Preeclampsia, a serious hypertensive disorder of pregnancy, is characterized by elevated ceramide (CER) content that is responsible for heightened trophoblast cell death rates via apoptosis and autophagy. Whether trophoblast cells undergo necroptosis, a newly characterized form of regulated necrosis, and the potential role of CER in this process remain to be established. Herein, we report that exposure of both JEG3 cells and primary isolated cytotrophoblasts to C16:0 CER in conjunction with a caspase-8 inhibitor (Q-VD-OPh) promoted necroptotic cell death, as evidenced by increased expression and association of receptor-interacting protein kinases RIP1 and RIP3, as well as phosphorylation of mixed lineage kinase domain-like (MLKL) protein. MLKL activation and oligomerization could be abrogated by pretreatment with the necroptosis inhibitor necrostatin-1 (Nec-1). CER+Q-VD-OPH-treated primary trophoblasts displayed striking necrotic morphology along with disrupted fusion processes as evidenced by maintenance of E-cadherin-stained membrane boundaries and reduced glial cell missing-1 expression, but these events were effectively reversed using Nec-1. Of clinical relevance, we established an increased susceptibility to necroptotic cell death in preeclamptic placentae relative to normotensive controls. In preeclampsia, increased necrosome (RIP1/RIP3) protein levels, as well as MLKL activation and oligomerization associated with necrotic cytotrophoblast morphology. In addition, caspase-8 activity was reduced in severe early-onset preeclampsia cases. This study is the first to report that trophoblast cells undergo CER-induced necroptotic cell death, thereby contributing to the increased placental dysfunction and cell death found in preeclampsia. PMID:28151467

Numerical modelling of the flow in the resin infusion process on the REV scale: A feasibility study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jabbari, M.; Spangenberg, J.; Hattel, J. H.

2016-06-08

The resin infusion process (RIP) has developed as a low cost method for manufacturing large fibre reinforced plastic parts. However, the process still presents some challenges to industry with regards to reliability and repeatability, resulting in expensive and inefficient trial and error development. In this paper, we show the implementation of 2D numerical models for the RIP using the open source simulator DuMu{sup X}. The idea of this study is to present a model which accounts for the interfacial forces coming from the capillary pressure on the so-called representative elementary volume (REV) scale. The model is described in detail andmore » three different test cases — a constant and a tensorial permeability as well as a preform/Balsa domain — are investigated. The results show that the developed model is very applicable for the RIP for manufacturing of composite parts. The idea behind this study is to test the developed model for later use in a real application, in which the preform medium has numerous layers with different material properties.« less

Probing the matter and dark energy sources in a viable Big Rip model of the Universe

NASA Astrophysics Data System (ADS)

Kumar, Suresh

2014-08-01

Chevallier-Polarski-Linder (CPL) parametrization for the equation of state (EoS) of dark energy in terms of cosmic redshift or scale factor have been frequently studied in the literature. In this study, we consider cosmic time-based CPL parametrization for the EoS parameter of the effective cosmic fluid that fills the fabric of spatially flat and homogeneous Robertson-Walker (RW) spacetime in General Relativity. The model exhibits two worthy features: (i) It fits the observational data from the latest H(z) and Union 2.1 SN Ia compilations matching the success of ΛCDM model. (ii) It describes the evolution of the Universe from the matter-dominated phase to the recent accelerating phase similar to the ΛCDM model but leads to Big Rip end of the Universe contrary to the everlasting de Sitter expansion in the ΛCDM model. We investigate the matter and dark energy sources in the model, in particular, behavior of the dynamical dark energy responsible for the Big Rip end of Universe.

Nrf2 Improves Leptin and Insulin Resistance Provoked by Hypothalamic Oxidative Stress.

PubMed

Yagishita, Yoko; Uruno, Akira; Fukutomi, Toshiaki; Saito, Ritsumi; Saigusa, Daisuke; Pi, Jingbo; Fukamizu, Akiyoshi; Sugiyama, Fumihiro; Takahashi, Satoru; Yamamoto, Masayuki

2017-02-21

The relationship between loss of hypothalamic function and onset of diabetes mellitus remains elusive. Therefore, we generated a targeted oxidative-stress murine model utilizing conditional knockout (KO) of selenocysteine-tRNA (Trsp) using rat-insulin-promoter-driven-Cre (RIP-Cre). These Trsp-KO (Trsp RIP KO) mice exhibit deletion of Trsp in both hypothalamic cells and pancreatic β cells, leading to increased hypothalamic oxidative stress and severe insulin resistance. Leptin signals are suppressed, and numbers of proopiomelanocortin-positive neurons in the hypothalamus are decreased. In contrast, Trsp-KO mice (Trsp Ins1 KO) expressing Cre specifically in pancreatic β cells, but not in the hypothalamus, do not display insulin and leptin resistance, demonstrating a critical role of the hypothalamus in the onset of diabetes mellitus. Nrf2 (NF-E2-related factor 2) regulates antioxidant gene expression. Increased Nrf2 signaling suppresses hypothalamic oxidative stress and improves insulin and leptin resistance in Trsp RIP KO mice. Thus, Nrf2 harbors the potential to prevent the onset of diabetic mellitus by reducing hypothalamic oxidative damage. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Features of radiation damage of vanadium and its alloys at a temperature of 330-340°C

NASA Astrophysics Data System (ADS)

Kazakov, V. A.; Ostrovsky, Z.; Goncharenko, Yu; Chakin, V.

2000-12-01

Microstructural changes of vanadium alloys after irradiation at 340°C to 12 dpa in the BOR-60 reactor in 7Li environment is analyzed. Materials are vanadium and its alloys V-3Ti, V-3Fe, V-6Cr, V-4Cr-4Ti, V-5Cr-10Ti, V-6Cr-1Zr-0.1C. Void formation was observed in the binary alloys V-3Fe, V-3Ti and V-6Cr. It is shown that three-four-fold increase in V-4Cr-4Ti yield stress is produced by the formation of dislocation loops (DLs) and fine radiation-induced precipitates (RIPs) with a density of 1.7×1017 cm-3. It is expected that embrittlement of the welds will be worse because density of DLs and RIPs is 1.4-1.6 times higher. Besides, invisible coherent or semi-coherent RIPs are formed in the fusion zone. Elemental maps of the rupture surface of irradiated V-4Cr-4Ti are presented.

Necroptosis in neurodegenerative diseases: a potential therapeutic target

PubMed Central

Zhang, Shuo; Tang, Mi-bo; Luo, Hai-yang; Shi, Chang-he; Xu, Yu-ming

2017-01-01

Neurodegenerative diseases are a group of chronic progressive disorders characterized by neuronal loss. Necroptosis, a recently discovered form of programmed cell death, is a cell death mechanism that has necrosis-like morphological characteristics. Necroptosis activation relies on the receptor-interacting protein (RIP) homology interaction motif (RHIM). A variety of RHIM-containing proteins transduce necroptotic signals from the cell trigger to the cell death mediators RIP3 and mixed lineage kinase domain-like protein (MLKL). RIP1 plays a particularly important and complex role in necroptotic cell death regulation ranging from cell death activation to inhibition, and these functions are often cell type and context dependent. Increasing evidence suggests that necroptosis plays an important role in the pathogenesis of neurodegenerative diseases. Moreover, small molecules such as necrostatin-1 are thought inhibit necroptotic signaling pathway. Understanding the precise mechanisms underlying necroptosis and its interactions with other cell death pathways in neurodegenerative diseases could provide significant therapeutic insights. The present review is aimed at summarizing the molecular mechanisms of necroptosis and highlighting the emerging evidence on necroptosis as a major driver of neuron cell death in neurodegenerative diseases. PMID:28661482

Necroptosis Execution Is Mediated by Plasma Membrane Nanopores Independent of Calcium.

PubMed

Ros, Uris; Peña-Blanco, Aida; Hänggi, Kay; Kunzendorf, Ulrich; Krautwald, Stefan; Wong, W Wei-Lynn; García-Sáez, Ana J

2017-04-04

Necroptosis is a form of regulated necrosis that results in cell death and content release after plasma membrane permeabilization. However, little is known about the molecular events responsible for the disruption of the plasma membrane. Here, we find that early increase in cytosolic calcium in TNF-induced necroptosis is mediated by treatment with a Smac mimetic via the TNF/RIP1/TAK1 survival pathway. This does not require the activation of the necrosome and is dispensable for necroptosis. Necroptosis induced by the activation of TLR3/4 pathways does not trigger early calcium flux. We also demonstrate that necroptotic plasma membrane rupture is mediated by osmotic forces and membrane pores around 4 nm in diameter. This late permeabilization step represents a hallmark in necroptosis execution that is cell and treatment independent and requires the RIP1/RIP3/MLKL core. In support of this, treatment with osmoprotectants reduces cell damage in an in vivo necroptosis model of ischemia-reperfusion injury. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Pore-forming toxin-mediated ion dysregulation leads to death receptor-independent necroptosis of lung epithelial cells during bacterial pneumonia

PubMed Central

González-Juarbe, Norberto; Bradley, Kelley Margaret; Shenoy, Anukul Taranath; Gilley, Ryan Paul; Reyes, Luis Felipe; Hinojosa, Cecilia Anahí; Restrepo, Marcos Ignacio; Dube, Peter Herman; Bergman, Molly Ann; Orihuela, Carlos Javier

2017-01-01

We report that pore-forming toxins (PFTs) induce respiratory epithelial cell necroptosis independently of death receptor signaling during bacterial pneumonia. Instead, necroptosis was activated as a result of ion dysregulation arising from membrane permeabilization. PFT-induced necroptosis required RIP1, RIP3 and MLKL, and could be induced in the absence or inhibition of TNFR1, TNFR2 and TLR4 signaling. We detected activated MLKL in the lungs from mice and nonhuman primates experiencing Serratia marcescens and Streptococcus pneumoniae pneumonia, respectively. We subsequently identified calcium influx and potassium efflux as the key initiating signals responsible for necroptosis; also that mitochondrial damage was not required for necroptosis activation but was exacerbated by MLKL activation. PFT-induced necroptosis in respiratory epithelial cells did not involve CamKII or reactive oxygen species. KO mice deficient in MLKL or RIP3 had increased survival and reduced pulmonary injury during S. marcescens pneumonia. Our results establish necroptosis as a major cell death pathway active during bacterial pneumonia and that necroptosis can occur without death receptor signaling. PMID:28387756

Pore-forming toxin-mediated ion dysregulation leads to death receptor-independent necroptosis of lung epithelial cells during bacterial pneumonia.

PubMed

González-Juarbe, Norberto; Bradley, Kelley Margaret; Shenoy, Anukul Taranath; Gilley, Ryan Paul; Reyes, Luis Felipe; Hinojosa, Cecilia Anahí; Restrepo, Marcos Ignacio; Dube, Peter Herman; Bergman, Molly Ann; Orihuela, Carlos Javier

2017-05-01

We report that pore-forming toxins (PFTs) induce respiratory epithelial cell necroptosis independently of death receptor signaling during bacterial pneumonia. Instead, necroptosis was activated as a result of ion dysregulation arising from membrane permeabilization. PFT-induced necroptosis required RIP1, RIP3 and MLKL, and could be induced in the absence or inhibition of TNFR1, TNFR2 and TLR4 signaling. We detected activated MLKL in the lungs from mice and nonhuman primates experiencing Serratia marcescens and Streptococcus pneumoniae pneumonia, respectively. We subsequently identified calcium influx and potassium efflux as the key initiating signals responsible for necroptosis; also that mitochondrial damage was not required for necroptosis activation but was exacerbated by MLKL activation. PFT-induced necroptosis in respiratory epithelial cells did not involve CamKII or reactive oxygen species. KO mice deficient in MLKL or RIP3 had increased survival and reduced pulmonary injury during S. marcescens pneumonia. Our results establish necroptosis as a major cell death pathway active during bacterial pneumonia and that necroptosis can occur without death receptor signaling.

Holographic dark energy with linearly varying deceleration parameter and escaping big rip singularity of the Bianchi type-V universe

NASA Astrophysics Data System (ADS)

Sarkar, Sanjay

2014-08-01

The present work deals with the accretion of two minimally interacting fluids: dark matter and a hypothetical isotropic fluid as the holographic dark energy components onto black hole and wormhole in a spatially homogeneous and anisotropic Bianchi type-V universe. To obtain an exact solution of the Einstein's field equations, we use the assumption of linearly varying deceleration parameter. Solution describes effectively the actual acceleration and indicates a big rip type future singularity of the universe. We have studied the evolution of the mass of black hole and the wormhole embedded in this anisotropic universe in order to reproduce a stable universe protected against future-time singularity. It is observed that the accretion of these dark components leads to a gradual decrease and increase of black hole and wormhole mass respectively. Finally, we have found that contrary to our previous case (Sarkar in Astrophys. Space. Sci. 341:651, 2014a), the big rip singularity of the universe with a divergent Hubble parameter of this dark energy model may be avoided by a big trip.

Membrane-bound transcription factors: regulated release by RIP or RUP.

PubMed

Hoppe, T; Rape, M; Jentsch, S

2001-06-01

Regulated nuclear transport of transcription factors from cytoplasmic pools is a major route by which eukaryotes control gene expression. Exquisite examples are transcription factors that are kept in a dormant state in the cytosol by membrane anchors; such proteins are released from membranes by proteolytic cleavage, which enables these transcription factors to enter the nucleus. Cleavage can be mediated either by regulated intramembrane proteolysis (RIP) catalysed by specific membrane-bound proteases or by regulated ubiquitin/proteasome-dependent processing (RUP). In both cases processing can be controlled by cues that originate at or in the vicinity of the membrane.

A new Approach for Quantifying Root-Reinforcement of Streambanks: the RipRoot Model

NASA Astrophysics Data System (ADS)

Pollen, N. L.; Simon, A.

2003-12-01

Riparian vegetation plays an important role in controlling geotechnical and fluvial processes acting along and within streambanks through the binding effects of roots. Quantification of this mechanical effect is therefore essential to accurately model streambank stability. Until now, most attempts to include the effects of root reinforcement by riparian vegetation have used root-cohesion values estimated using the Wu et al. (1979) equation, requiring the tensile strengths and diameters of the roots crossing the potential shear-plane. However, the Wu et al. equation is a static model that assumes that all roots break, and that they all break simultaneously. Field observations and laboratory experiments have shown that in reality the roots do not all break simultaneously, and that the breaking of roots during mass failure is in fact a dynamic process. Static models such as the Wu et al. equation are therefore likely to produce overestimations of cohesion due to roots. As a response to this concern, a dynamic root reinforcement model (RipRoot) was developed, based on the concepts of fiber bundle models (FBM's) used in materials science. Within the model the root-soil system is loaded incrementally resulting in progressive root breaking and redistribution of stresses from the broken roots to the remaining intact roots in the soil matrix. The redistribution and loading process continues until either all of the roots have broken, or equilibrium is reached where the root network supports the driving force imposed on the bank. The increase in bank cohesion using the static Wu et al. equation are 18% to 38% higher than RipRoot for riparian tree species, including Black Willow, Sandbar Willow, Cottonwood, River Birch and Eastern Sycamore, and 49% higher for Switch Grass. These variations in cohesion values can have a significant impact on streambank Factor of Safety (Fs) values calculated using the Simon et al. (2000) bank-stability model. For example, a 3m high silt streambank had a Fs of 0.98 without vegetation, indicating instability. With the addition of cohesion from 200 River Birch roots this value increased to 1.22 using the RipRoot value (Conditionally Stable) and 1.37 using the Wu et al. equation (Stable). In this example both of the root models produced cohesion values that were large enough to make the bank more stable, but the more conservative value from RipRoot suggests the bank may only be conditionally stable. Results to date indicate that the dynamic nature of RipRoot removes some of the overestimation from the static equation of Wu et al. (1979), therefore producing more realistic values for root reinforcement, which are particularly useful and important in the context of river management and restoration.

Evolution of wave and tide over vegetation region in nearshore waters

NASA Astrophysics Data System (ADS)

Zhang, Mingliang; Zhang, Hongxing; Zhao, Kaibin; Tang, Jun; Qin, Huifa

2017-08-01

Coastal wetlands are an important ecosystem in nearshore regions, where complex flow characteristics occur because of the interactions among tides, waves, and plants, especially in the discontinuous flow of the intertidal zone. In order to simulate the wave and wave-induced current in coastal waters, in this study, an explicit depth-averaged hydrodynamic (HD) model has been dynamically coupled with a wave spectral model (CMS-Wave) by sharing the tide and wave data. The hydrodynamic model is based on the finite volume method; the intercell flux is computed using the Harten-Lax-van Leer (HLL) approximate Riemann solver for computing the dry-to-wet interface; the drag force of vegetation is modeled as the sink terms in the momentum equations. An empirical wave energy dissipation term with plant effect has been derived from the wave action balance equation to account for the resistance induced by aquatic vegetation in the CMS-Wave model. The results of the coupling model have been verified using the measured data for the case with wave-tide-vegetation interactions. The results show that the wave height decreases significantly along the wave propagation direction in the presence of vegetation. In the rip channel system, the oblique waves drive a meandering longshore current; it moves from left to right past the cusps with oscillations. In the vegetated region, the wave height is greatly attenuated due to the presence of vegetation, and the radiation stresses are noticeably changed as compared to the region without vegetation. Further, vegetation can affect the spatial distribution of mean velocity in a rip channel system. In the co-exiting environment of tides, waves, and vegetation, the locations of wave breaking and wave-induced radiation stress also vary with the water level of flooding or ebb tide in wetland water, which can also affect the development and evolution of wave-induced current.

A compact high resolution ion mobility spectrometer for fast trace gas analysis.

PubMed

Kirk, Ansgar T; Allers, Maria; Cochems, Philipp; Langejuergen, Jens; Zimmermann, Stefan

2013-09-21

Drift tube ion mobility spectrometers (IMS) are widely used for fast trace gas detection in air, but portable compact systems are typically very limited in their resolving power. Decreasing the initial ion packet width improves the resolution, but is generally associated with a reduced signal-to-noise-ratio (SNR) due to the lower number of ions injected into the drift region. In this paper, we present a refined theory of IMS operation which employs a combined approach for the analysis of the ion drift and the subsequent amplification to predict both the resolution and the SNR of the measured ion current peak. This theoretical analysis shows that the SNR is not a function of the initial ion packet width, meaning that compact drift tube IMS with both very high resolution and extremely low limits of detection can be designed. Based on these implications, an optimized combination of a compact drift tube with a length of just 10 cm and a transimpedance amplifier has been constructed with a resolution of 183 measured for the positive reactant ion peak (RIP(+)), which is sufficient to e.g. separate the RIP(+) from the protonated acetone monomer, even though their drift times only differ by a factor of 1.007. Furthermore, the limits of detection (LODs) for acetone are 180 pptv within 1 s of averaging time and 580 pptv within only 100 ms.

Middle Eocene seagrass facies from Apennine carbonate platforms (Italy)

NASA Astrophysics Data System (ADS)

Tomassetti, Laura; Benedetti, Andrea; Brandano, Marco

2016-04-01

Two stratigraphic sections located in the Latium-Abruzzi (Monte Porchio, Central Apennines, Central Italy) and in the Apulian carbonate platform (S. Cesarea-Torre Tiggiano, Salento, Southern Italy) were measured and sampled to document the sedimentological characteristic and the faunistic assemblages of Middle Eocene seagrass deposits. The faunistic assemblages are dominated by porcellaneous foraminifera Orbitolites, Alveolina, Idalina, Spiroloculina, Quinqueloculina, Triloculina and abundant hooked-shaped gypsinids, associated with hooked red algae and green algae Halimeda. Fabiania, rotaliids and textulariids as well as nummulitids are subordinated. The samples were assigned to Lutetian (SBZ13-16) according to the occurrence of Nummulites cf. lehneri, Alveolina ex. gr. elliptica, Idalina berthelini, Orbitolites complanatus, Slovenites decastroi and Medocia blayensis. At Santa Cesarea reticulate nummulites occur in association with Alveolina spp. and Halkyardia minima marking the lower Bartonian (SBZ17). Three main facies associations have been recognised: I) larger porcellaneous foraminiferal grainstones with orbitolitids and alveolinids deposited into high-energy shallow-water settings influenced by wave processes that reworked the sediments associated with a seagrass; II) grainstone to packstone with small porcellaneous foraminifera and abundant permanently-attached gypsinids deposited in a more protected (e.g., small embayment) in situ vegetated environment; III) bioclastic packstone with parautochthonous material reworked from the seagrass by rip currents and accumulated into rip channels in a slightly deeper environment. The biotic assemblages suggest that the depositional environment is consistent with tropical to subtropical vegetated environments within oligotrophic conditions.

Breath detection by transcutaneous electromyography of the diaphragm and the Graseby capsule in preterm infants.

PubMed

de Waal, Cornelia G; Kraaijenga, Juliette V; Hutten, Gerard J; de Jongh, Frans H; van Kaam, Anton H

2017-12-01

To compare triggering, breath detection and delay time of the Graseby capsule (GC) and transcutaneous electromyography of the diaphragm (dEMG) in spontaneous breathing preterm infants. In this observational study, a 30 minutes respiration measurement was conducted by respiratory inductance plethysmography (RIP), the GC, and dEMG in stable preterm infants. Triggering was investigated with an in vitro set-up using the Infant Flow ® SiPAP TM system. The possibility to optimize breath detection was tested by developing new algorithms with the abdominal RIP band (RIP AB ) as gold standard. In a subset of breaths, the delay time was calculated between the inspiratory onset in the RIP AB signal and in the GC and dEMG signal. Fifteen preterm infants with a mean gestational age of 28 ± 2 weeks and a mean birth weight of 1086 ± 317 g were included. In total, 14 773 breaths were analyzed. Based on the GC and dEMG signal, the Infant Flow ® SiPAP™ system, respectively, triggered 67.8% and 62.6% of the breaths. Breath detection was improved to 99.9% for the GC and 113.4% for dEMG in new algorithms. In 1492 stable breaths, the median delay time of inspiratory onset detection was +154 ms (IQR +118 to +164) in the GC and -50 ms (IQR -90 to -22) in the dEMG signal. Breath detection using the GC can be improved by optimizing the algorithm. Transcutaneous dEMG provides similar breath detection but with the advantage of detecting the onset of inspiration earlier than the GC. © 2017 Wiley Periodicals, Inc.

Smac mimetics and type II interferon synergistically induce necroptosis in various cancer cell lines.

PubMed

Cekay, Michael John; Roesler, Stefanie; Frank, Tanja; Knuth, Anne-Kathrin; Eckhardt, Ines; Fulda, Simone

2017-12-01

Since cancer cells often evade apoptosis, induction of necroptosis as another mode of programmed cell death is considered a promising therapeutic alternative. Here, we identify a novel synergistic interaction of Smac mimetics that antagonize x-linked Inhibitor of Apoptosis (XIAP), cellular Inhibitor of Apoptosis (cIAP) 1 and 2 with interferon (IFN)γ to induce necroptosis in apoptosis-resistant cancer cells in which caspase activation is blocked. This synergism is confirmed by calculation of combination indices (CIs) and found in both solid and hematological cancer cell lines as well as for different Smac mimetics (i.e. BV6, Birinapant), pointing to a broader relevance. Importantly, individual genetic knockdown of key components of necroptosis signaling, i.e. receptor-interacting protein (RIP) 1, RIP3 or mixed lineage kinase domain-like pseudokinase (MLKL), significantly protects from BV6/IFNγ-induced cell death. Similarly, pharmacological inhibitors of RIP1 (necrostatin-1(Nec-1)), RIP3 (GSK'872) or MLKL (necrosulfonamide (NSA)) significantly reduce BV6/IFNγ-stimulated cell death. Of note, IFN-regulatory factor (IRF)1 is required for BV6/IFNγ-mediated necroptosis, as IRF1 silencing provides protection from cell death. By comparison, antibodies blocking tumor necrosis factor (TNF)α, TNF-related apoptosis-inducing ligand (TRAIL) or CD95 ligand fail to inhibit BV6/IFNγ-induced cell death, pointing to a mechanism independently of death receptor ligands. This is the first report showing that Smac mimetics synergize with IFNγ to trigger necroptosis in apoptosis-resistant cancer cells with important implications for Smac mimetic-based strategies for the treatment of cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

Manipulation of necroptosis by Porphyromonas gingivalis in periodontitis development.

PubMed

Ke, Xiaojing; Lei, Lang; Li, Huang; Li, Houxuan; Yan, Fuhua

2016-09-01

To eliminate invading pathogens and keep homeostasis, host employs multiple approaches such as the non-inflammation associated-apoptosis, inflammation associated-necroptosis and pyroptosis, etc. Necroptosis is known as a highly pro-inflammatory form of cell death due to the release of massive damage-associated molecular patterns (DAMPs). For the first time, we reported that Porphyromonas gingivalis induced cellular necroptosis through receptor-interacting protein 1 (RIP1)/RIP3/mixed lineage kinase domain-like (MLKL) signaling pathway in monocytes. Necroptosis in THP-1 cells was induced by MLKL phosphorylation in vitro. P. gingivalis treated-THP-1 cells exhibited lower cell death rate with pretreatment of inhibitors RIP1 and MLKL, accompanied with attenuated TNF-α and IL-6 expressions. Moreover, the necroptosis risk was also reduced via gene silencing by RIP3 or MLKL in the P. gingivalis treated-THP-1 cell lines. We further explored P. gingivalis-induced necroptosis in animal models in vivo. Firstly, C57BL/6 mice were injected with P. gingivalis in the subcutaneous chamber model. Animals pretreated with MLKL inhibitor exhibited significantly enhanced P. gingivalis clearance; in addition, levels of TNF-α and IL-6 were notably decreased by 60% via MLKL inhibition. Secondly, P. gingivalis-induced periodontitis was utilized to investigate necroptosis related-periodontopathogensis. Positive staining of phosphorylated MLKL in mice periodontitis biopsies was detected to a higher degree, while larger amount of alveolar bone loss was observed in MLKL (-) group comparing to those in the MLKL (+) group. These findings may suggest that P. gingivalis play essential roles in necroptosis process during periodontitis, and our research may shed light on the further work on the related periodontopathogenesis investigation. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Inhibition of Necroptosis Attenuates Kidney Inflammation and Interstitial Fibrosis Induced By Unilateral Ureteral Obstruction.

PubMed

Xiao, Xia; Du, Chunyang; Yan, Zhe; Shi, Yonghong; Duan, Huijun; Ren, Yunzhuo

2017-01-01

Inflammation plays a crucial role in renal interstitial fibrosis, the pathway of chronic kidney diseases. Necroptosis is a novel form of regulated cell death, which plays a potential role in inflammation and renal diseases. The small molecule necrostatin-1 (Nec-1) is a specific inhibitor of necroptosis. This study was aimed at determining the role of necroptosis, RIP1/RIP3/mixed lineage kinase domain-like (MLKL) signaling pathway, in renal inflammation and interstitial fibrosis related to primitive tubulointerstitial injury. It was also aimed at evaluating the effect of Nec-1 in renal fibrosis induced by unilateral ureteral obstruction (UUO). Renal histology, immunohistochemistry, western blot, and real-time polymerase chain reaction were performed using UUO C57BL/6J mice model. Moreover, we tested whether Nec-1 was renal-protective in the interstitial fibrosis kidney. Mice were exposed to UUO and injected intraperitoneal with Nec-1 or vehicle. The levels of RIP1/RIP3/MLKL protein and mRNA were increased in the obstructed kidneys 7 days after UUO; this was accompanied by changes in renal pathological lesions. Renal histological examination showed lesser renal damage in Nec-1-treated UUO mice. Renal inflammation, assessed by tumor necrosis factor-α, interleukin-1β, and monocyte chemotactic protein-1 was markedly attenuated by Nec-1. Furthermore, Nec-1 treatment also significantly reduced TGF-β and α-smooth muscle actin, indicating lesser renal interstitial fibrosis. These findings suggest that the participation of necroptosis in UUO is partly demonstrated. And necroptosis inhibition may have a potential role in the treatment of diseases with increased inflammatory response and interstitial fibrosis in renal. © 2017 S. Karger AG, Basel.

State dynamics of a double sandbar system

NASA Astrophysics Data System (ADS)

Price, T. D.; Ruessink, B. G.

2011-04-01

A 9.3-year dataset of low-tide time-exposure images from Surfers Paradise, Northern Gold Coast, Australia was used to characterise the state dynamics of a double sandbar system. The morphology of the nearshore sandbars was described by means of the sequential bar state classification scheme of Wright and Short [1984. Morphodynamic variability of surf zones and beaches: a synthesis. Marine Geology 56, 93-118]. Besides the two end members (the dissipative (D) and the reflective (R) states) and the four intermediate states (longshore bar and trough (LBT), rhythmic bar and beach (RBB), transverse bar and rip (TBR) and low tide terrace (LTT)), we identified two additional intermediate bar states. The erosive transverse bar and rip (eTBR) state related to the dominant oblique angle of wave incidence at the study site and the rhythmic low tide terrace (rLTT) related to the multiple bar setting. Using the alongshore barline variability and alongshore trough continuity as morphological indicators enabled the objective classification of the inner and outer bar states from the images. The outer bar was mostly in the TBR state and generally advanced sequentially through the states LBT-RBB-TBR-eTBR-LBT, with occasional transitions to the D state. Wave events led to abrupt state transitions of the outer bar, but, in contrast to expectations, did not necessarily correspond to upstate transitions. Instead, upstate (downstate) transitions coincided with angles of wave incidence θ larger (smaller) than 30°. The upstate TBR-eTBR-LBT sequence during high-angle events highlights the role of alongshore currents in bar straightening. The outer bar was found to govern the state of the inner bar to a large extent. Two types of inner bar behaviour were distinguished, based on the outer bar state. For intermediate outer bar states, the alongshore variability of the dominant inner rLTT state (52% in time) mainly related to that of the outer bar, implying some sort of morphological coupling. For dissipative outer bar states, however, the more upstate inner bar frequently separated from the shoreline and persistently developed rip channels as TBR became the most frequent state (60% in time).

40 CFR 230.23 - Current patterns and water circulation.

Code of Federal Regulations, 2012 CFR

2012-07-01

... or fill material can modify current patterns and water circulation by obstructing flow, changing the direction or velocity of water flow, changing the direction or velocity of water flow and circulation, or otherwise changing the dimensions of a water body. As a result, adverse changes can occur in: Location...

40 CFR 230.23 - Current patterns and water circulation.

Code of Federal Regulations, 2011 CFR

2011-07-01

... or fill material can modify current patterns and water circulation by obstructing flow, changing the direction or velocity of water flow, changing the direction or velocity of water flow and circulation, or otherwise changing the dimensions of a water body. As a result, adverse changes can occur in: Location...

40 CFR 230.23 - Current patterns and water circulation.

Code of Federal Regulations, 2014 CFR

2014-07-01

... or fill material can modify current patterns and water circulation by obstructing flow, changing the direction or velocity of water flow, changing the direction or velocity of water flow and circulation, or otherwise changing the dimensions of a water body. As a result, adverse changes can occur in: Location...

Runway Incursion Prevention for General Aviation Operations

NASA Technical Reports Server (NTRS)

Jones, Denise R.; Prinzel, Lawrence J., III

2006-01-01

A Runway Incursion Prevention System (RIPS) and additional incursion detection algorithm were adapted for general aviation operations and evaluated in a simulation study at the National Aeronautics and Space Administration (NASA) Langley Research Center (LaRC) in the fall of 2005. RIPS has been designed to enhance surface situation awareness and provide cockpit alerts of potential runway conflicts in order to prevent runway incidents while also improving operational capability. The purpose of the study was to evaluate the airborne incursion detection algorithms and associated alerting and airport surface display concepts for general aviation operations. This paper gives an overview of the system, simulation study, and test results.

Runway Incursion Prevention System for General Aviation Operations

NASA Technical Reports Server (NTRS)

Jones, Denise R.; Prinzel III, Lawrence J.

2006-01-01

A Runway Incursion Prevention System (RIPS) and additional incursion detection algorithm were adapted for general aviation operations and evaluated in a simulation study at the National Aeronautics and Space Administration (NASA) Langley Research Center (LaRC) in the fall of 2005. RIPS has been designed to enhance surface situation awareness and provide cockpit alerts of potential runway conflicts in order to prevent runway incidents while also improving operational capability. The purpose of the study was to evaluate the airborne incursion detection algorithms and associated alerting and airport surface display concepts for general aviation operations. This paper gives an overview of the system, simulation study, and test results.

Mobile, high-wind, balloon-launching apparatus

NASA Technical Reports Server (NTRS)

Rust, W. David; Marshall, Thomas C.

1989-01-01

In order to place instruments for measuring meteorological and electrical parameters into thunderstorms, an inexpensive apparatus has been developed which makes it possible to inflate, transport, and launch balloons in high winds. The launching apparatus is a cylinder of bubble plastic that is made by joining the sides of the cylinder together with a velcro rip strip. A balloon is launched by pulling the rip strip rapidly. This allows the balloon to pop upward into the ambient low-level wind and carry its instrumentation aloft. Different-sized launch tubes are constructed to accommodate particular sizes of balloons. Balloons have been launched in winds of about 20 m/s.

Plastid intramembrane proteolysis.

PubMed

Adam, Zach

2015-09-01

Progress in the field of regulated intramembrane proteolysis (RIP) in recent years has not surpassed plant biology. Nevertheless, reports on RIP in plants, and especially in chloroplasts, are still scarce. Of the four different families of intramembrane proteases, only two have been linked to chloroplasts so far, rhomboids and site-2 proteases (S2Ps). The lack of chloroplast-located rhomboid proteases was associated with reduced fertility and aberrations in flower morphology, probably due to perturbations in jasmonic acid biosynthesis, which occurs in chloroplasts. Mutations in homologues of S2P resulted in chlorophyll deficiency and impaired chloroplast development, through a yet unknown mechanism. To date, the only known substrate of RIP in chloroplasts is a PHD transcription factor, located in the envelope. Upon proteolytic cleavage by an unknown protease, the soluble N-terminal domain of this protein is released from the membrane and relocates to the nucleus, where it activates the transcription of the ABA response gene ABI4. Continuing studies on these proteases and substrates, as well as identification of the genes responsible for different chloroplast mutant phenotypes, are expected to shed more light on the roles of intramembrane proteases in chloroplast biology. Copyright © 2015 Elsevier B.V. All rights reserved.

DNA sequence homology induces cytosine-to-thymine mutation by a heterochromatin-related pathway in Neurospora

PubMed Central

Gladyshev, Eugene; Kleckner, Nancy

2017-01-01

Eukaryotic genomes contain substantial amounts of repetitive DNA organized in the form of constitutive heterochromatin and associated with repressive epigenetic modifications, such as H3K9me3 and C5-cytosine methylation (5mC). In the fungus Neurospora crassa, H3K9me3 and 5mC are catalyzed, respectively, by a conserved SUV39 histone methyltransferase DIM-5 and a DNMT1-like cytosine methyltransferase DIM-2. Here we show that DIM-2 can also mediate Repeat-Induced Point mutation (RIP) of repetitive DNA in N. crassa. We further show that DIM-2-dependent RIP requires DIM-5, HP1, and other known heterochromatin factors, implying the role of a repeat-induced heterochromatin-related process. Our previous findings suggest that the mechanism of repeat recognition for RIP involves direct interactions between homologous double-stranded (ds) DNA segments. We thus now propose that, in somatic cells, homologous dsDNA/dsDNA interactions between a small number of repeat copies can nucleate a transient heterochromatic state, which, on longer repeat arrays, may lead to the formation of constitutive heterochromatin. PMID:28459455

Migration and bioavailability of (137)Cs in forest soil of southern Germany.

PubMed

Konopleva, I; Klemt, E; Konoplev, A; Zibold, G

2009-04-01

To give a quantitative description of the radiocaesium soil-plant transfer for fern (Dryopteris carthusiana) and blackberry (Rubus fruticosus), physical and chemical properties of soils in spruce and mixed forest stands were investigated. Of special interest was the selective sorption of radiocaesium, which was determined by measuring the Radiocaesium Interception Potential (RIP). Forest soil and plants were taken at 10 locations of the Altdorfer Wald (5 sites in spruce forest and 5 sites in mixed forest). It was found that the bioavailability of radiocaesium in spruce forest was on average seven times higher than in mixed forest. It was shown that important factors determining the bioavailability of radiocaesium in forest soil were its exchangeability and the radiocaesium interception potential (RIP) of the soil. Low potassium concentration in soil solution of forest soils favors radiocaesium soil-plant transfer. Ammonium in forest soils plays an even more important role than potassium as a mobilizer of radiocaesium. The availability factor - a function of RIP, exchangeability and cationic composition of soil solution - characterized reliably the soil-plant transfer in both spruce and mixed forest. For highly organic soils in coniferous forest, radiocaesium sorption at regular exchange sites should be taken into account when its bioavailability is considered.

Seasonal circulation patterns of the Yellow and East China Seas derived from satellite-tracked drifter trajectories and hydrographic observations

NASA Astrophysics Data System (ADS)

Lie, Heung-Jae; Cho, Cheol-Ho

2016-08-01

We investigated seasonal circulation patterns of the Yellow and East China Seas (YECS), by reviewing previous works on the circulation and its dominant currents, and taking into account newly-compiled trajectories of satellite-tracked drifters collected between the 1980s and 2000s. The circulation patterns suggested before the 1990s can be categorized into two groups, depending on the identified origin of the Tsushima Warm Current in the Korea-Tsushima Straits: (i) branching from the Kuroshio southwest of Kyushu, or (ii) northeastward continuation of the Taiwan Strait throughflow. The branching of the Kuroshio southwest of Kyushu and northeast of Taiwan was clearly evidenced by current measurements and concurrent hydrographic surveys. However, there is still no clear evidence for the northeastward pathway of Taiwan Strait throughflow across the mid-shelf area of the East China Sea. Target-oriented surveys in the 1990s and 2000s employing advanced instruments, such as drifter tracking and acoustic Doppler current profiler measurements, now provide decisive proof of the clockwise rounding of the Cheju Warm Current around Jeju-do throughout the year, of the northeastward extension of Changjiang discharge in summer, and of the presence of the Yellow Sea Warm Current only in winter. Thus, both coastal currents in shallow water and secondary branch currents of the Kuroshio (such as the Yellow Sea Warm Current) are found to significantly change from winter to summer. To better present the basic pattern of YECS circulation and its seasonality, we have constructed seasonal circulations patterns, based on review results, on the newly-compiled drifter trajectories, and on hydrographic observations. Further investigations should be carried out in future, with support of comprehensive current measurements on shelf areas and through elaborate numerical modeling.

Interannual Variation of Surface Circulation in the Japan/East Sea due to External Forcings and Intrinsic Variability

NASA Astrophysics Data System (ADS)

Choi, Byoung-Ju; Cho, Seong Hun; Jung, Hee Seok; Lee, Sang-Ho; Byun, Do-Seong; Kwon, Kyungman

2018-03-01

The interannual variation of surface ocean currents can be as large as seasonal variation in the Japan/East Sea (JES). To identify the major factors that cause such interannual variability of surface ocean circulation in the JES, surface circulation was simulated from 1998 to 2009 using a three-dimensional model. Contributions of atmospheric forcing (ATM), open boundary data (OBC), and intrinsic variability (ITV) of the surface flow in the JES on the interannual variability of surface ocean circulation were separately examined using numerical simulations. Variability in surface circulation was quantified in terms of variance in sea surface height, 100-m depth water temperature, and surface currents. ITV was found to be the dominant factor that induced interannual variabilities of surface circulation, the main path of the East Korea Warm Current (EKWC), and surface kinetic energy on a time scale of 2-4 years. OBC and ATM were secondary factors contributing to the interannual variation of surface circulation. Interannual variation of ATM changed the separation latitude of EKWC and increased the variability of surface circulation in the Ulleung Basin. Interannual variation of OBC enhanced low-frequency changes in surface circulation and eddies in the Yamato Basin. It also modulated basin-wide uniform oscillations of sea level. This study suggests that precise estimation of initial conditions using data assimilation is essential for long-term prediction of surface circulation in the JES.

Effect of wave-current interaction on wind-driven circulation in narrow, shallow embayments

USGS Publications Warehouse

Signell, Richard P.; Beardsley, Robert C.; Graber, H. C.; Capotondi, A.

1990-01-01

The effect of wind waves on the steady wind-driven circulation in a narrow, shallow bay is investigated with a two-dimensional (y, z) circulation model and the Grant and Madsen [1979] bottom-boundary layer model, which includes wave-current interaction. A constant wind stress is applied in the along-channel x direction to a channel with a constant cross-sectional profile h(y). The wind-induced flushing of shallow bays is shown to be sensitive to both the shape of the cross section and the effects of surface waves. The flushing increases with increasing , where h′ is the standard deviation of cross-channel depth and  is the mean depth. This is consistent with the findings of Hearn et al. [1987]. The flushing decreases, however, with the inclusion of surface wave effects which act to increase the bottom drag felt by the currents. Increasing effective bottom friction reduces the strength of the circulation, while the along-bay surface slope, bottom stress and the structure of current profiles remain nearly unchanged. An implication of the circulation dependence on wave-current interaction is that low-frequency oscillatory winds may drive a mean circulation when the wave field changes with wind direction.x

The influence of surface waves on water circulation in a mid-Atlantic continental shelf region

NASA Technical Reports Server (NTRS)

Whitlock, C. H.; Talay, T. A.

1974-01-01

The importance of wave-induced currents in different weather conditions and water depths (18.3 m and 36.6 m) is assessed in a mid-Atlantic continental-shelf region. A review of general circulation conditions is conducted. Factors which perturb the general circulation are examined using analytic techniques and limited experimental data. Actual wind and wave statistics for the region are examined. Relative magnitudes of the various currents are compared on a frequency of annual occurrence basis. Results indicated that wave-induced currents are often the same order of magnitude as other currents in the region and become more important at higher wind and wave conditions. Wind-wave and ocean-swell characteristics are among those parameters which must be monitored for the analytical computation of continental-shelf circulation.

Characterization of a cable-free system based on p-type MOSFET detectors for "in vivo" entrance skin dose measurements in interventional radiology.

PubMed

Falco, Maria Daniela; D'Andrea, Marco; Strigari, Lidia; D'Alessio, Daniela; Quagliani, Francesco; Santoni, Riccardo; Bosco, Alessia Lo

2012-08-01

During radiological interventional procedures (RIP) the skin of a patient under examination may undergo a prolonged x-ray exposure, receiving a dose as high as 5 Gy in a single session. This paper describes the use of the OneDose(TM) cable-free system based on p-type MOSFET detectors to determine the entrance skin dose (ESD) at selected points during RIP. At first, some dosimetric characteristics of the detector, such as reproducibility, linearity, and fading, have been investigated using a C-arc as a source of radiation. The reference setting (RS) was: 80 kV energy, 40 cm × 40 cm field of view (FOV), current-time product of 50 mAs and source to skin distance (SSD) of 50 cm. A calibrated PMX III solid state detector was used as the reference detector and Gafchromic(®) films have been used as an independent dosimetric system to test the entire procedure. A calibration factor for the RS and correction factors as functions of tube voltage and FOV size have been determined. Reproducibility ranged from 4% at low doses (around 10 cGy as measured by the reference detector) to about 1% for high doses (around 2 Gy). The system response was found to be linear with respect to both dose measured with the PMX III and tube voltage. The fading test has shown that the maximum deviation from the optimal reading conditions (3 min after a single irradiation) was 9.1% corresponding to four irradiations in one hour read 3 min after the last exposure. The calibration factor in the RS has shown that the system response at the kV energy range is about four times larger than in the MV energy range. A fifth order and fourth order polynomial functions were found to provide correction factors for tube voltage and FOV size, respectively, in measurement settings different than the RS. ESDs measured with the system after applying the proper correction factors agreed within one standard deviation (SD) with the corresponding ESDs measured with the reference detector. The ESDs measured with Gafchromic(®) films were in agreement within one SD compared to the ESDs measured using the OneDose(TM) system, as well. The global uncertainty associated to the OneDose(TM) system established in our experiments, ranged from 7% to 10%, depending on the duration of the RIP due to fading. These values are much lower than the uncertainty commonly accepted for general diagnostic practices (20%) and of about the same size of the uncertainty recommended for practices with high risk of deterministic side effects (7%). The OneDose(TM) system has shown a high sensitivity in the kV energy range and has been found capable of measuring the entrance skin dose in RIP.

Biogenic selenium nanoparticles induce ROS-mediated necroptosis in PC-3 cancer cells through TNF activation.

PubMed

Sonkusre, Praveen; Cameotra, Swaranjit Singh

2017-06-07

Selenium is well documented to inhibit cancer at higher doses; however, the mechanism behind this inhibition varies widely depending on the cell type and selenium species. Previously, we have demonstrated that Bacillus licheniformis JS2 derived biogenic selenium nanoparticles (SeNPs) induce non-apoptotic cell death in prostate adenocarcinoma cell line, PC-3, at a minimal concentration of 2 µg Se/ml, without causing toxicity to the primary cells. However, the mechanism behind its anticancer activity was elusive. Our results have shown that these SeNPs at a concentration of 2 µg Se/ml were able to induce reactive oxygen species (ROS) mediated necroptosis in PC-3 cells by gaining cellular internalization. Real-time qPCR analysis showed increased expression of necroptosis associated tumor necrotic factor (TNF) and interferon regulatory factor 1 (IRF1). An increased expression of RIP1 protein was also observed at the translational level upon SeNP treatment. Moreover, the cell viability was significantly increased in the presence of necroptosis inhibitor, Necrostatin-1. Data suggest that our biogenic SeNPs induce cell death in PC-3 cells by the ROS-mediated activation of necroptosis, independent to RIP3 and MLKL, regulated by a RIP1 kinase.

Structure prediction and binding sites analysis of curcin protein of Jatropha curcas using computational approaches.

PubMed

Srivastava, Mugdha; Gupta, Shishir K; Abhilash, P C; Singh, Nandita

2012-07-01

Ribosome inactivating proteins (RIPs) are defense proteins in a number of higher-plant species that are directly targeted toward herbivores. Jatropha curcas is one of the biodiesel plants having RIPs. The Jatropha seed meal, after extraction of oil, is rich in curcin, a highly toxic RIP similar to ricin, which makes it unsuitable for animal feed. Although the toxicity of curcin is well documented in the literature, the detailed toxic properties and the 3D structure of curcin has not been determined by X-ray crystallography, NMR spectroscopy or any in silico techniques to date. In this pursuit, the structure of curcin was modeled by a composite approach of 3D structure prediction using threading and ab initio modeling. Assessment of model quality was assessed by methods which include Ramachandran plot analysis and Qmean score estimation. Further, we applied the protein-ligand docking approach to identify the r-RNA binding residue of curcin. The present work provides the first structural insight into the binding mode of r-RNA adenine to the curcin protein and forms the basis for designing future inhibitors of curcin. Cloning of a future peptide inhibitor within J. curcas can produce non-toxic varieties of J. curcas, which would make the seed-cake suitable as animal feed without curcin detoxification.

Utilizing Metalized Fabrics for Liquid and Rip Detection and Localization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Holland, Stephen; Mahan, Cody; Kuhn, Michael J

2013-01-01

This paper proposes a novel technique for utilizing conductive textiles as a distributed sensor for detecting and localizing liquids (e.g., blood), rips (e.g., bullet holes), and potentially biosignals. The proposed technique is verified through both simulation and experimental measurements. Circuit theory is utilized to depict conductive fabric as a bounded, near-infinite grid of resistors. Solutions to the well-known infinite resistance grid problem are used to confirm the accuracy and validity of this modeling approach. Simulations allow for discontinuities to be placed within the resistor matrix to illustrate the effects of bullet holes within the fabric. A real-time experimental system wasmore » developed that uses a multiplexed Wheatstone bridge approach to reconstruct the resistor grid across the conductive fabric and detect liquids and rips. The resistor grid model is validated through a comparison of simulated and experimental results. Results suggest accuracy proportional to the electrode spacing in determining the presence and location of discontinuities in conductive fabric samples. Future work is focused on refining the experimental system to provide more accuracy in detecting and localizing events as well as developing a complete prototype that can be deployed for field testing. Potential applications include intelligent clothing, flexible, lightweight sensing systems, and combat wound detection.« less

Experimental design and data analysis of Ago-RIP-Seq experiments for the identification of microRNA targets.

PubMed

Tichy, Diana; Pickl, Julia Maria Anna; Benner, Axel; Sültmann, Holger

2017-03-31

The identification of microRNA (miRNA) target genes is crucial for understanding miRNA function. Many methods for the genome-wide miRNA target identification have been developed in recent years; however, they have several limitations including the dependence on low-confident prediction programs and artificial miRNA manipulations. Ago-RNA immunoprecipitation combined with high-throughput sequencing (Ago-RIP-Seq) is a promising alternative. However, appropriate statistical data analysis algorithms taking into account the experimental design and the inherent noise of such experiments are largely lacking.Here, we investigate the experimental design for Ago-RIP-Seq and examine biostatistical methods to identify de novo miRNA target genes. Statistical approaches considered are either based on a negative binomial model fit to the read count data or applied to transformed data using a normal distribution-based generalized linear model. We compare them by a real data simulation study using plasmode data sets and evaluate the suitability of the approaches to detect true miRNA targets by sensitivity and false discovery rates. Our results suggest that simple approaches like linear regression models on (appropriately) transformed read count data are preferable. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

RIP-seq analysis of eukaryotic Sm proteins identifies three major categories of Sm-containing ribonucleoproteins

PubMed Central

2014-01-01

Background Sm proteins are multimeric RNA-binding factors, found in all three domains of life. Eukaryotic Sm proteins, together with their associated RNAs, form small ribonucleoprotein (RNP) complexes important in multiple aspects of gene regulation. Comprehensive knowledge of the RNA components of Sm RNPs is critical for understanding their functions. Results We developed a multi-targeting RNA-immunoprecipitation sequencing (RIP-seq) strategy to reliably identify Sm-associated RNAs from Drosophila ovaries and cultured human cells. Using this method, we discovered three major categories of Sm-associated transcripts: small nuclear (sn)RNAs, small Cajal body (sca)RNAs and mRNAs. Additional RIP-PCR analysis showed both ubiquitous and tissue-specific interactions. We provide evidence that the mRNA-Sm interactions are mediated by snRNPs, and that one of the mechanisms of interaction is via base pairing. Moreover, the Sm-associated mRNAs are mature, indicating a splicing-independent function for Sm RNPs. Conclusions This study represents the first comprehensive analysis of eukaryotic Sm-containing RNPs, and provides a basis for additional functional analyses of Sm proteins and their associated snRNPs outside of the context of pre-mRNA splicing. Our findings expand the repertoire of eukaryotic Sm-containing RNPs and suggest new functions for snRNPs in mRNA metabolism. PMID:24393626

DNA-binding proteins from marine bacteria expand the known sequence diversity of TALE-like repeats

PubMed Central

de Lange, Orlando; Wolf, Christina; Thiel, Philipp; Krüger, Jens; Kleusch, Christian; Kohlbacher, Oliver; Lahaye, Thomas

2015-01-01

Transcription Activator-Like Effectors (TALEs) of Xanthomonas bacteria are programmable DNA binding proteins with unprecedented target specificity. Comparative studies into TALE repeat structure and function are hindered by the limited sequence variation among TALE repeats. More sequence-diverse TALE-like proteins are known from Ralstonia solanacearum (RipTALs) and Burkholderia rhizoxinica (Bats), but RipTAL and Bat repeats are conserved with those of TALEs around the DNA-binding residue. We study two novel marine-organism TALE-like proteins (MOrTL1 and MOrTL2), the first to date of non-terrestrial origin. We have assessed their DNA-binding properties and modelled repeat structures. We found that repeats from these proteins mediate sequence specific DNA binding conforming to the TALE code, despite low sequence similarity to TALE repeats, and with novel residues around the BSR. However, MOrTL1 repeats show greater sequence discriminating power than MOrTL2 repeats. Sequence alignments show that there are only three residues conserved between repeats of all TALE-like proteins including the two new additions. This conserved motif could prove useful as an identifier for future TALE-likes. Additionally, comparing MOrTL repeats with those of other TALE-likes suggests a common evolutionary origin for the TALEs, RipTALs and Bats. PMID:26481363

Activation of cell-surface proteases promotes necroptosis, inflammation and cell migration.

PubMed

Cai, Zhenyu; Zhang, Anling; Choksi, Swati; Li, Weihua; Li, Tao; Zhang, Xue-Min; Liu, Zheng-Gang

2016-08-01

Necroptosis is a programmed, caspase-independent cell death that is morphologically similar to necrosis. TNF-induced necroptosis is mediated by receptor-interacting protein kinases, RIP1 and RIP3, and the mixed lineage kinase domain-like (MLKL). After being phosphorylated by RIP3, MLKL is translocated to the plasma membrane and mediates necroptosis. However, the execution of necroptosis and its role in inflammation and other cellular responses remain largely elusive. In this study, we report that MLKL-mediated activation of cell-surface proteases of the a disintegrin and metalloprotease (ADAM) family promotes necroptosis, inflammation and cell migration. ADAMs are specifically activated at the early stage of necroptosis when MLKL is phosphorylated and translocated to the cell plasma membrane. Activation of ADAMs induces ectodomain shedding of diverse cell-surface proteins including adhesion molecules, receptors, growth factors and cytokines. Importantly, the shedding of cell-surface proteins disrupts cell adhesion and accelerates necroptosis, while the soluble fragments of the cleaved proteins trigger the inflammatory responses. We also demonstrate that the shedding of E-cadherin ectodomain from necroptotic cells promotes cell migration. Thus, our study provides a novel mechanism of necroptosis-induced inflammation and new insights into the physiological and pathological functions of this unique form of cell death.

Activation of cell-surface proteases promotes necroptosis, inflammation and cell migration

PubMed Central

Cai, Zhenyu; Zhang, Anling; Choksi, Swati; Li, Weihua; Li, Tao; Zhang, Xue-Min; Liu, Zheng-Gang

2016-01-01

Necroptosis is a programmed, caspase-independent cell death that is morphologically similar to necrosis. TNF-induced necroptosis is mediated by receptor-interacting protein kinases, RIP1 and RIP3, and the mixed lineage kinase domain-like (MLKL). After being phosphorylated by RIP3, MLKL is translocated to the plasma membrane and mediates necroptosis. However, the execution of necroptosis and its role in inflammation and other cellular responses remain largely elusive. In this study, we report that MLKL-mediated activation of cell-surface proteases of the a disintegrin and metalloprotease (ADAM) family promotes necroptosis, inflammation and cell migration. ADAMs are specifically activated at the early stage of necroptosis when MLKL is phosphorylated and translocated to the cell plasma membrane. Activation of ADAMs induces ectodomain shedding of diverse cell-surface proteins including adhesion molecules, receptors, growth factors and cytokines. Importantly, the shedding of cell-surface proteins disrupts cell adhesion and accelerates necroptosis, while the soluble fragments of the cleaved proteins trigger the inflammatory responses. We also demonstrate that the shedding of E-cadherin ectodomain from necroptotic cells promotes cell migration. Thus, our study provides a novel mechanism of necroptosis-induced inflammation and new insights into the physiological and pathological functions of this unique form of cell death. PMID:27444869

CD59 signaling and membrane pores drive Syk-dependent erythrocyte necroptosis

PubMed Central

LaRocca, T J; Stivison, E A; Mal-Sarkar, T; Hooven, T A; Hod, E A; Spitalnik, S L; Ratner, A J

2015-01-01

Mature erythrocytes (red blood cells (RBCs)) undergo the programmed cell death (PCD) pathway of necroptosis in response to bacterial pore-forming toxins (PFTs) that target human CD59 (hCD59) but not hCD59-independent PFTs. Here, we investigate the biochemical mechanism of RBC necroptosis with a focus on the mechanism of induction and the minimal requirements for such RBC death. Binding or crosslinking of the hCD59 receptor led to Syk-dependent induction of vesiculated morphology (echinocytes) that was associated with phosphorylation of Band 3 and was required for Fas ligand (FasL) release. FasL-dependent phosphorylation of receptor-interacting protein kinase 1 (RIP1) in combination with plasma membrane pore formation was required for execution of RBC necroptosis. RIP1 phosphorylation led to the phosphorylation of RIP3, which was also critical for RBC necroptosis. Notably, RBC necroptosis was mediated by FasL and not by other candidate inducers, including tumor necrosis factor alpha (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL). Other types of RBC damage, such as eryptotic damage, failed to induce necroptosis when combined with hCD59 crosslinking. This work sheds light on the requirements for this recently discovered PCD in RBCs and provides a clear picture of the biochemical mechanism of induction of RBC necroptosis. PMID:26018734

CD59 signaling and membrane pores drive Syk-dependent erythrocyte necroptosis.

PubMed

LaRocca, T J; Stivison, E A; Mal-Sarkar, T; Hooven, T A; Hod, E A; Spitalnik, S L; Ratner, A J

2015-05-28

Mature erythrocytes (red blood cells (RBCs)) undergo the programmed cell death (PCD) pathway of necroptosis in response to bacterial pore-forming toxins (PFTs) that target human CD59 (hCD59) but not hCD59-independent PFTs. Here, we investigate the biochemical mechanism of RBC necroptosis with a focus on the mechanism of induction and the minimal requirements for such RBC death. Binding or crosslinking of the hCD59 receptor led to Syk-dependent induction of vesiculated morphology (echinocytes) that was associated with phosphorylation of Band 3 and was required for Fas ligand (FasL) release. FasL-dependent phosphorylation of receptor-interacting protein kinase 1 (RIP1) in combination with plasma membrane pore formation was required for execution of RBC necroptosis. RIP1 phosphorylation led to the phosphorylation of RIP3, which was also critical for RBC necroptosis. Notably, RBC necroptosis was mediated by FasL and not by other candidate inducers, including tumor necrosis factor alpha (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL). Other types of RBC damage, such as eryptotic damage, failed to induce necroptosis when combined with hCD59 crosslinking. This work sheds light on the requirements for this recently discovered PCD in RBCs and provides a clear picture of the biochemical mechanism of induction of RBC necroptosis.

Elimination of active tad elements during the sexual phase of the Neurospora crassa life cycle.

PubMed

Anderson, C; Tang, Q; Kinsey, J A

2001-06-01

Tad is an active LINE-like retrotransposon isolated from the Adiopodoumé strain of Neurospora crassa. Extensive analysis of other Neurospora strains has revealed no other strain with active Tad, but all strains tested have multiple copies of defective Tad elements. We have examined the ability of Tad to survive during the sexual cycle of Neurospora and find that active Tad is rapidly eliminated. The characteristics of this elimination suggest that the repeat-induced point mutation (RIP) mechanism was responsible. By the use of transformation to switch the mating type of the Adiopodoumé strain we concluded that this strain is not defective in the RIP process. Analysis of defective Tad elements isolated from a variety of strains indicates that the major difference between these elements and active Tad is due to the presence of a large number of G-C to A-T transition mutations. This would be expected if the changes were due primarily to the RIP process. Mapping of a selection of defective Tad elements reveals that they are present on all of the chromosomes; however, many of the elements are not widely shared among strains. This suggests that repeated introduction and elimination of Tad elements has occurred. Mechanisms that might be responsible for this repeated introduction are discussed. Copyright 2001 Academic Press.

Caspase-12 and the inflammatory response to Yersinia pestis.

PubMed

Ferwerda, Bart; McCall, Matthew B B; de Vries, Maaike C; Hopman, Joost; Maiga, Boubacar; Dolo, Amagana; Doumbo, Ogobara; Daou, Modibo; de Jong, Dirk; Joosten, Leo A B; Tissingh, Rudi A; Reubsaet, Frans A G; Sauerwein, Robert; van der Meer, Jos W M; van der Ven, André J A M; Netea, Mihai G

2009-09-01

Caspase-12 functions as an antiinflammatory enzyme inhibiting caspase-1 and the NOD2/RIP2 pathways. Due to increased susceptibility to sepsis in individuals with functional caspase-12, an early-stop mutation leading to the loss of caspase-12 has replaced the ancient genotype in Eurasia and a significant proportion of individuals from African populations. In African-Americans, it has been shown that caspase-12 inhibits the pro-inflammatory cytokine production. We assessed whether similar mechanisms are present in African individuals, and whether evolutionary pressures due to plague may have led to the present caspase-12 genotype population frequencies. No difference in cytokine induction through the caspase-1 and/or NOD2/RIP2 pathways was observed in two independent African populations, among individuals with either an intact or absent caspase-12. In addition, stimulations with Yersinia pestis and two other species of Yersinia were preformed to investigate whether caspase-12 modulates the inflammatory reaction induced by Yersinia. We found that caspase-12 did not modulate cytokine production induced by Yersinia spp. Our experiments demonstrate for the first time the involvement of the NOD2/RIP2 pathway for recognition of Yersinia. However, caspase-12 does not modulate innate host defense against Y. pestis and alternative explanations for the geographical distribution of caspase-12 should be sought.

Surfzone Currents Over Irregular Bathymetry: Drifter Observations and Numerical Model Results

NASA Astrophysics Data System (ADS)

Schmidt, W. E.; Slinn, D. N.; Guza, R. T.

2002-12-01

Surfzone currents on alongshore variable bathymetry were observed with recently developed GPS-tracked drifters and numerically modeled with the time-dependent, nonlinear shallow water equations. These currents, forced by alongshore inhomogeneous pressure and radiation stress gradients, contain flow features difficult to resolve with fixed instrument arrays, such as rips, eddies, and meanders. Drifters were repeatedly released and recovered near Scripps Beach, La Jolla, California, in July 2000, 2001, and 2002. The most recent deployment of 10 drifters yielded about 32 hours of drifter data for each 5 hour deployment day. Offshore wave heights were moderate, between 0.3-1.0 m. The bathymetry, measured over a 600-700 m alongshore span with a GPS- and sonar-equipped jetski (2001 and 2002 deployments), was alongshore inhomogeneous primarily where an irregularly shaped bar-trough feature spanned the surf zone. The model simulations suggest that the alongshore inhomogeneous bathymetry strongly influences the location and strength of the observed flow features. Research supported by the California Sea Grant College Program and the Office of Naval Research.

On the influence of reflection over a rhythmic swash zone on surf zone dynamics

NASA Astrophysics Data System (ADS)

Almar, Rafael; Nicolae Lerma, Alexandre; Castelle, Bruno; Scott, Timothy

2018-05-01

The reflection of incident gravity waves over an irregular swash zone morphology and the resulting influence on surf zone dynamics remains mostly unexplored. The wave-phase resolving SWASH model is applied to investigate this feedback using realistic low-tide terraced beach morphology with well-developed beach cusps. The rhythmic reflection generates a standing wave that mimics a subharmonic edge wave, from the superimposition of incident and two-dimensional reflected waves. This mechanism is enhanced by shore-normal, narrow-banded waves in both direction and frequency. Our study suggests that wave reflection over steep beaches could be a mechanism for the development of rhythmic morphological features such as beach cusps and rip currents.

NF-κB functions as a molecular link between tumor cells and Th1/Tc1 T cells in the tumor microenvironment to exert radiation-mediated tumor suppression

PubMed Central

Simon, Priscilla S.; Bardhan, Kankana; Chen, May R.; Paschall, Amy V.; Lu, Chunwan; Bollag, Roni J.; Kong, Feng-Chong; Jin, JianYue; Kong, Feng-Ming; Waller, Jennifer L.; Pollock, Raphael E.; Liu, Kebin

2016-01-01

Radiation modulates both tumor cells and immune cells in the tumor microenvironment to exert its anti-tumor activity; however, the molecular connection between tumor cells and immune cells that mediates radiation-exerted tumor suppression activity in the tumor microenvironment is largely unknown. We report here that radiation induces rapid activation of the p65/p50 and p50/p50 NF-κB complexes in human soft tissue sarcoma (STS) cells. Radiation-activated p65/p50 and p50/p50 bind to the TNFα promoter to activate its transcription in STS cells. Radiation-induced TNFα induces tumor cell death in an autocrine manner. A sublethal dose of Smac mimetic BV6 induces cIAP1 and cIAP2 degradation to increase tumor cell sensitivity to radiation-induced cell death in vitro and to enhance radiation-mediated suppression of STS xenografts in vivo. Inhibition of caspases, RIP1, or RIP3 blocks radiation/TNFα-induced cell death, whereas inhibition of RIP1 blocks TNFα-induced caspase activation, suggesting that caspases and RIP1 act sequentially to mediate the non-compensatory cell death pathways. Furthermore, we determined in a syngeneic sarcoma mouse model that radiation up-regulates IRF3, IFNβ, and the T cell chemokines CCL2 and CCL5 in the tumor microenvironment, which are associated with activation and increased infiltration of Th1/Tc1 T cells in the tumor microenvironment. Moreover, tumor-infiltrating T cells are in their active form since both the perforin and FasL pathways are activated in irradiated tumor tissues. Consequently, combined BV6 and radiation completely suppressed tumor growth in vivo. Therefore, radiation-induced NF-κB functions as a molecular link between tumor cells and immune cells in the tumor microenvironment for radiation-mediated tumor suppression. PMID:27014915

Therapeutic benefit of selective inhibition of p110α PI3-kinase in pancreatic neuroendocrine tumors

PubMed Central

Soler, Adriana; Figueiredo, Ana M; Castel, Pau; Martin, Laura; Monelli, Erika; Angulo-Urarte, Ana; Milà-Guasch, Maria; Viñals, Francesc; Casanovas, Oriol

2017-01-01

Purpose Mutations in the PI3-kinase (PI3K) pathway occur in 16% of patients with pancreatic neuroendocrine tumors (PanNETs), which suggests that these tumors are an exciting setting for PI3K/AKT/mTOR pharmacological intervention. Everolimus, an mTOR inhibitor, is being used to treat patients with advanced PanNETs. However, resistance to mTOR targeted therapy is emerging partially due to the loss of mTOR-dependent feedback inhibition of AKT. In contrast, the response to PI3K inhibitors in PanNETs is unknown. Experimental Design In the present study, we assessed the frequency of PI3K pathway activation in human PanNETs and in RIP1-Tag2 mice, a preclinical tumor model of PanNETs, and we investigated the therapeutic efficacy of inhibiting PI3K in RIP1-Tag2 mice using a combination of pan (GDC-0941) and p110α selective (GDC-0326) inhibitors and isoform specific PI3K kinase-dead mutant mice. Results Human and mouse PanNETs showed enhanced pAKT, pPRAS40 and pS6 positivity compared to normal tissue. While treatment of RIP1-Tag2 mice with GDC-0941 led to reduced tumor growth with no impact on tumor vessels, the selective inactivation of the p110α PI3K isoform, either genetically or pharmacologically, reduced tumor growth as well as vascular area. Furthermore, GDC-0326 reduced the incidence of liver and lymph node (LN) metastasis compared to vehicle treated mice. We also demonstrated that tumor and stromal cells are implicated in the anti-tumor activity of GDC-0326 in RIP1-Tag2 tumors. Conclusion Our data provide a rationale for p110α selective intervention in PanNETs and unravel a new function of this kinase in cancer biology through its role in promoting metastasis. PMID:27225693

Effect of the New York State cigarette fire safety standard on ignition propensity, smoke constituents, and the consumer market.

PubMed

Connolly, G N; Alpert, H R; Rees, V; Carpenter, C; Wayne, G F; Vallone, D; Koh, H

2005-10-01

This study examines empirical evidence from the New York experience testing tobacco industry arguments made in opposition to fire safety standards for cigarettes. Percentages of cigarettes exhibiting full length burns (FLBs), cigarette sales before and following the implementation of the New York standards, a sample of retail cigarette prices, brand availability, and selected smoke constituent yields were compared between cigarettes sold in New York and two other states. Cigarette paper analysis was conducted on cigarettes sold in New York. New York cigarette brands averaged 10.0% FLBs as compared to 99.8% for California and Massachusetts brands. Reduced ignition propensity (RIP) appears to have been achieved by cigarette paper banding. Cigarette sales, prices, and brand availability do not appear to have been affected by the New York standards. Yields of the majority of smoke constituents tested did not differ substantially between RIP cigarettes sold in New York as compared to the same brands sold in Massachusetts. Average yields of tar, carbon monoxide, and two compounds were slightly higher, the yields of seven compounds were higher for one brand only, and nicotine was lower, among New York brands tested. RIP cigarette brands have been designed to meet the New York fire safety standards. Their introduction has not affected cigarette sales or prices in New York. There is no evidence that the small increases in smoke constituent yields affect the already highly toxic nature of cigarette smoke. Data on smoking caused fires, deaths, and injuries dating from after the change in law are not yet available. Such data will be able to address the question of whether the demonstrated reduced ignition standards are associated with reduced fires and injuries. Based on the New York experience, prior industry objections to producing RIP cigarettes are unfounded. Other states and nations should adopt similar standards.

Growth factors FGF8 and FGF2 and their receptor FGFR1, transcriptional factors Msx-1 and MSX-2, and apoptotic factors p19 and RIP5 participate in the early human limb development.

PubMed

Becic, Tina; Kero, Darko; Vukojevic, Katarina; Mardesic, Snjezana; Saraga-Babic, Mirna

2018-04-01

The expression pattern of fibroblast growth factors FGF8 and FGF2 and their receptor FGFR1, transcription factors MSX-1 and MSX-2, as well as cell proliferation (Ki-67) and cell death associated caspase-3, p19 and RIP5 factors were analyzed in histological sections of eight 4th-9th-weeks developing human limbs by immunohistochemistry and semi-thin sectioning. Increasing expression of all analyzed factors (except FGF8) characterized both the multilayered human apical ectodermal ridge (AER), sub-ridge mesenchyme (progress zone) and chondrocytes in developing human limbs. While cytoplasmic co-expression of MSX-1 and MSX-2 was observed in both limb epithelium and mesenchyme, p19 displayed strong cytoplasmic expression in non-proliferating cells. Nuclear expression of Ki-67 proliferating cells, and partly of MSX-1 and MSX-2 was detected in the whole limb primordium. Strong expression of factors p19 and RIP5, both in the AER and mesenchyme of human developing limbs indicates their possible involvement in control of cell senescence and cell death. In contrast to animal studies, expression of FGFR1 in the surface ectoderm and p19 in the whole limb primordium might reflect interspecies differences in limb morphology. Expression of FGF2 and downstream RIP5 gene, and transcription factors Msx-1 and MSX-2 did not show human-specific changes in expression pattern. Based on their spatio-temporal expression during human limb development, our study indicates role of FGFs and Msx genes in stimulation of cell proliferation, limb outgrowth, digit elongation and separation, and additionally MSX-2 in control of vasculogenesis. The cascade of orchestrated gene expressions, including the analyzed developmental factors, jointly contribute to the complex human limb development. Copyright © 2018 Elsevier GmbH. All rights reserved.

Remote and In Situ Observations of Surfzone and Inner-Shelf Tracer Dispersion

NASA Astrophysics Data System (ADS)

Hally-Rosendahl, K.; Feddersen, F.; Clark, D.; Guza, R. T.

2014-12-01

Surfzone and inner-shelf tracer dispersion was observed at the approximately alongshore-uniform Imperial Beach, California during the IB09 experiment. Rhodamine dye tracer, released continuously near the shoreline for several hours, was advected alongshore by breaking wave- and wind-driven currents, and ejected offshore from the surfzone to the inner-shelf by transient rips. Aerial multispectral imaging of inner-shelf dye concentration complemented in situ surfzone and inner-shelf measurements of dye, temperature, waves, and currents, providing tracer transport and dispersion observations spanning approximately 400 m cross-shore and 3 km alongshore. Combined in situ and aerial measurements approximately close a surfzone and inner-shelf dye budget. Mean alongshore dye dilution follows a power-law relationship, and both spatial and temporal dye variability decrease with distance from the release. Aerial images reveal coherent inner-shelf dye plume structures extending over 300 m offshore with alongshore length scales up to 400 m. Plume tracking among successive images yields inner-shelf alongshore advection rates consistent with in situ observations. Alongshore advection is faster within the surfzone than on the inner-shelf, and the leading alongshore edge of inner-shelf dye is due to local transient rip ejections from the surfzone. A combination of in situ and aerial surfzone and inner-shelf measurements are used to quantify cross- and alongshore dye tracer transports. This work is funded by NSF (including a Graduate Research Fellowship, Grant No. DGE1144086), ONR, and California Sea Grant. Figure: Aerial multispectral image of surface dye concentration (parts per billion, see colorbar) versus cross-shore coordinate x and alongshore coordinate y, approximately 5 hours after the start of a continuous dye release (green star). The mean shoreline is at x=0 m. Dark gray indicates the beach and a pier, and light gray indicates regions outside the imaged area. Black indicates unresolved regions due to foam from wave breaking. Vertical dashed line delimits the surfzone (SZ) and inner-shelf (IS). Yellow diamonds indicate locations of in situ measurements of dye, temperature, waves, and currents. Yellow circles indicate locations of in situ dye and temperature measurements.

Library Circulation Systems: An Overview

ERIC Educational Resources Information Center

Surace, Cecily J.

1972-01-01

The model circulation system outlined is an on-line real time system in which the circulation file is created from the shelf list. The model extends beyond the operational limits of most existing circulation systems and can be considered a reflection of the current state of the art. (36 references) (Author/NH)

Experimental Demonstration of a Resonator-Induced Phase Gate in a Multiqubit Circuit-QED System.

PubMed

Paik, Hanhee; Mezzacapo, A; Sandberg, Martin; McClure, D T; Abdo, B; Córcoles, A D; Dial, O; Bogorin, D F; Plourde, B L T; Steffen, M; Cross, A W; Gambetta, J M; Chow, Jerry M

2016-12-16

The resonator-induced phase (RIP) gate is an all-microwave multiqubit entangling gate that allows a high degree of flexibility in qubit frequencies, making it attractive for quantum operations in large-scale architectures. We experimentally realize the RIP gate with four superconducting qubits in a three-dimensional circuit-QED architecture, demonstrating high-fidelity controlled-z (cz) gates between all possible pairs of qubits from two different 4-qubit devices in pair subspaces. These qubits are arranged within a wide range of frequency detunings, up to as large as 1.8 GHz. We further show a dynamical multiqubit refocusing scheme in order to isolate out 2-qubit interactions, and combine them to generate a 4-qubit Greenberger-Horne-Zeilinger state.

Magnetized strange quark model with Big Rip singularity in f(R, T) gravity

NASA Astrophysics Data System (ADS)

Sahoo, P. K.; Sahoo, Parbati; Bishi, Binaya K.; Aygün, S.

2017-07-01

Locally rotationally symmetric (LRS) Bianchi type-I magnetized strange quark matter (SQM) cosmological model has been studied based on f(R, T) gravity. The exact solutions of the field equations are derived with linearly time varying deceleration parameter, which is consistent with observational data (from SNIa, BAO and CMB) of standard cosmology. It is observed that the model begins with big bang and ends with a Big Rip. The transition of the deceleration parameter from decelerating phase to accelerating phase with respect to redshift obtained in our model fits with the recent observational data obtained by Farook et al. [Astrophys. J. 835, 26 (2017)]. The well-known Hubble parameter H(z) and distance modulus μ(z) are discussed with redshift.

Experimental Demonstration of a Resonator-Induced Phase Gate in a Multiqubit Circuit-QED System

NASA Astrophysics Data System (ADS)

Paik, Hanhee; Mezzacapo, A.; Sandberg, Martin; McClure, D. T.; Abdo, B.; Córcoles, A. D.; Dial, O.; Bogorin, D. F.; Plourde, B. L. T.; Steffen, M.; Cross, A. W.; Gambetta, J. M.; Chow, Jerry M.

2016-12-01

The resonator-induced phase (RIP) gate is an all-microwave multiqubit entangling gate that allows a high degree of flexibility in qubit frequencies, making it attractive for quantum operations in large-scale architectures. We experimentally realize the RIP gate with four superconducting qubits in a three-dimensional circuit-QED architecture, demonstrating high-fidelity controlled-z (cz) gates between all possible pairs of qubits from two different 4-qubit devices in pair subspaces. These qubits are arranged within a wide range of frequency detunings, up to as large as 1.8 GHz. We further show a dynamical multiqubit refocusing scheme in order to isolate out 2-qubit interactions, and combine them to generate a 4-qubit Greenberger-Horne-Zeilinger state.

Estimation of respiratory rhythm during night sleep using a bio-radar

NASA Astrophysics Data System (ADS)

Tataraidze, Alexander; Anishchenko, Lesya; Alekhin, Maksim; Korostovtseva, Lyudmila; Sviryaev, Yurii

2014-05-01

An assessment of bio-radiolocation monitoring of respiratory rhythm during sleep is given. Full-night respiratory inductance plethysmography (RIP) and bio-radiolocation (BRL) records were collected simultaneously in a sleep laboratory. Polysomnography data from 5 subjects without sleep breathing disorders were used. A multi-frequency bioradar with step frequency modulation was applied. It has 8 operating frequencies ranging from 3.6 to 4.0 GHz. BRL data are recorded in two quadratures. Respiratory cycles were detected in time domain. Obtained data was used for the evaluation of correlation between BRL and RIP respiration rate estimates. Strong correlation between corresponding time series was revealed. BRL method is reliably implemented for estimation of respiratory rhythm and respiratory rate variability during full night sleep.

Runway Incursion Prevention System: Demonstration and Testing at the Dallas/Fort Worth International Airport

NASA Technical Reports Server (NTRS)

Jones, Denise R.; Quach, Cuong C.; Young, Steven D.

2007-01-01

A Runway Incursion Prevention System (RIPS) was tested at the Dallas-Ft. Worth International Airport (DFW) in October 2000. The system integrated airborne and ground components to provide both pilots and controllers with enhanced situational awareness, supplemental guidance cues, a real-time display of traffic information, and warning of runway incursions in order to prevent runway incidents while also improving operational capability. A series of test runs was conducted using NASA s Boeing 757 research aircraft and a test van equipped to emulate an incurring aircraft. The system was also demonstrated to over 100 visitors from the aviation community. This paper gives an overview of the RIPS, DFW flight test activities, and quantitative and qualitative results of the testing.

Status of Beam Line Detectors for the BigRIPS Fragment Separator at RIKEN RI Beam Factory: Issues on High Rates and Resolution

NASA Astrophysics Data System (ADS)

Sato, Yuki; Fukuda, Naoki; Takeda, Hiroyuki; Kameda, Daisuke; Suzuki, Hiroshi; Shimizu, Yohei; Ahn, DeukSoon; Murai, Daichi; Inabe, Naohito; Shimaoka, Takehiro; Tsubota, Masakatsu; Kaneko, Junichi H.; Chayahara, Akiyoshi; Umezawa, Hitoshi; Shikata, Shinichi; Kumagai, Hidekazu; Murakami, Hiroyuki; Sato, Hiromi; Yoshida, Koichi; Kubo, Toshiyuki

A multiple sampling ionization chamber (MUSIC) and parallel-plate avalanche counters (PPACs) were installed within the superconducting in-flight separator, named BigRIPS, at the RIKEN Nishina Center for particle identification of RI beams. The MUSIC detector showed negligible charge collection inefficiency from recombination of electrons and ions, up to a 99-kcps incidence rate for high-energy heavy ions. For the PPAC detectors, the electrical discharge durability for incident heavy ions was improved by changing the electrode material. Finally, we designed a single crystal diamond detector, which is under development for TOF measurements of high-energy heavy ions, that has a very fast response time (pulse width <1 ns).

Necroptosis-inducing rhenium(V) oxo complexes.

PubMed

Suntharalingam, Kogularamanan; Awuah, Samuel G; Bruno, Peter M; Johnstone, Timothy C; Wang, Fang; Lin, Wei; Zheng, Yao-Rong; Page, Julia E; Hemann, Michael T; Lippard, Stephen J

2015-03-04

Rhenium(V) oxo complexes of general formula [ReO(OMe)(N^N)Cl2], where N^N = 4,7-diphenyl-1,10-phenanthroline, 1, or 3,4,7,8-tetramethyl-1,10-phenanthroline, 2, effectively kill cancer cells by triggering necroptosis, a non-apoptotic form of cell death. Both complexes evoke necrosome (RIP1-RIP3)-dependent intracellular reactive oxygen species (ROS) production and propidium iodide uptake. The complexes also induce mitochondrial membrane potential depletion, a possible downstream effect of ROS production. Apparently, 1 and 2 are the first rhenium complexes to evoke cellular events consistent with programmed necrosis in cancer cells. Furthermore, 1 and 2 display low acute toxicity in C57BL/6 mice and reasonable stability in fresh human blood.

Necroptosis-Inducing Rhenium(V) Oxo Complexes

PubMed Central

Suntharalingam, Kogularamanan; Awuah, Samuel G.; Bruno, Peter M.; Johnstone, Timothy C.; Wang, Fang; Lin, Wei; Zheng, Yao-Rong; Page, Julia E.; Hemann, Michael T.; Lippard, Stephen J.

2015-01-01

Rhenium(V) oxo complexes of general formula [ReO(OMe)(N^N)Cl2], where N^N = 4,7-diphenyl-1,10-phenanthroline, 1, or 3,4,7,8-tetramethyl-1,10-phenanthroline, 2, effectively kill cancer cells by triggering necroptsosis, a non-apoptotic form of cell death. Both complexes evoke necrosome (RIP1-RIP3)-dependent intracellular ROS production and propidium iodide uptake. The complexes also induce mitochondrial membrane potential depletion, a possible downstream effect of ROS production. Apparently, 1 and 2 are the first rhenium complexes to evoke cellular events consistent with programmed necrosis in cancer cells. Furthermore, 1 and 2 display low acute toxicity in C57BL/6 mice and reasonable stability in fresh human blood. PMID:25698398

A numerical study of circulation in the Gulf of Riga, Baltic Sea. Part I: Whole-basin gyres and mean currents

NASA Astrophysics Data System (ADS)

Lips, Urmas; Zhurbas, Victor; Skudra, Maris; Väli, Germo

2016-01-01

A regional model of the Gulf of Riga (GoR) with horizontal grid spacing of 0.5 nautical miles was applied to study the features and driving forces of the whole-basin circulation in the GoR. The initial conditions and atmospheric forcing were taken from the operational models High Resolution Operational Model for the Baltic (HIROMB) and High Resolution Limited Area Model (HIRLAM), respectively. The wind stress curl is shown to be a major contributor to the whole-basin circulation pattern. An anticyclonic circulation pattern in the summer is determined by a combined effect of the negative wind stress curl, thermal density stratification and bottom topography. Positive values of the wind stress curl and a cyclonic circulation pattern prevail during the cold period of the year when seasonal thermocline is absent. During calm periods, the anticyclonic type of circulation is established due to a combined effect of the river runoff, saltier water inflow into and mixed water outflow from the GoR. Two seasonal baroclinic jet-like currents are identified in the summer: the Northward Longshore Current in the western GoR and Southward Subsurface Longshore Current in the eastern GoR. The alteration of the circulation pattern in the GoR from cyclonic in the cold period of the year to anticyclonic in the summer, and vice versa, was shown to be observed not every year due to inter-annual variability of wind forcing.

Using a global ocean circulation model to conduct a preliminary risk assessment of oil spills in the Atlantic

NASA Astrophysics Data System (ADS)

Jacobs, Zoe; Popova, Katya; Hirschi, Joel; Coward, Andrew; Yool, Andrew; van Gennip, Simon; Anifowose, Babtunde; Harrington-Missin, Liam

2017-04-01

Although oil blowouts from deep-water drilling happen very rarely, they can cause catastrophic damage to the environment. Despite such potentially high impacts, relatively little research effort has gone into understanding subsurface oil plumes in the deep ocean. In this study, we demonstrate the significance of this problem and offer potential solutions using a novel approach based on a leading-edge, high-resolution global ocean circulation model. We present examples demonstrating: (a) the importance of ocean circulation in the propagation of oil spills; and (b) likely circulation footprints for oil spills at four key locations in the Atlantic Ocean that exist in different circulation regimes - the shelves of Brazil, the Gulf of Guinea, the Gulf of Mexico and the Faroe-Shetland Channel. In order to quantify the variability at each site on seasonal timescales, interannual timescales and at different depths, we utilize the Modified Hausdorff Distance (MHD), which is a shape-distance metric that measures the similarity between two shapes. The scale of the footprints across the four focus locations varies considerably and is determined by the main circulation features in their vicinity. For example, the hypothetical oil plume can be affected by variations in the speed and location of a particular current (e.g. Brazil Current at the Brazilian shelf site) or be influenced by different currents entirely depending on the release depth, month and year (e.g. Angola Current or Southern Equatorial Current at the Gulf of Guinea site). Overall, our results demonstrate the need to use state of the art global, or basin-scale, ocean circulation models when assessing the environmental impacts of proposed oil drilling activities.

Slow and Steady: Ocean Circulation. The Influence of Sea Surface Height on Ocean Currents

NASA Technical Reports Server (NTRS)

Haekkinen, Sirpa

2000-01-01

The study of ocean circulation is vital to understanding how our climate works. The movement of the ocean is closely linked to the progression of atmospheric motion. Winds close to sea level add momentum to ocean surface currents. At the same time, heat that is stored and transported by the ocean warms the atmosphere above and alters air pressure distribution. Therefore, any attempt to model climate variation accurately must include reliable calculations of ocean circulation. Unlike movement of the atmosphere, movement of the ocean's waters takes place mostly near the surface. The major patterns of surface circulation form gigantic circular cells known as gyres. They are categorized according to their general location-equatorial, subtropical, subpolar, and polar-and may run across an entire ocean. The smaller-scale cell of ocean circulation is known' as an eddy. Eddies are much more common than gyres and much more difficult to track in computer simulations of ocean currents.

CYTOSOL

EPA Pesticide Factsheets

Technical product bulletin: this surface washing agent for oil spill cleanups extracts and recovers weathered petroleum by flotation, remaining residual hydrocarbons are biodegraded. Suitable for sensitive/ high impact sites including fisheries, rip rap.

75 FR 22577 - Proposed Rule of Agency Procedure No. 1: Procedures for Voting by Circulation Version 2.0

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-29

... deadlines, the current policy limits EAC's ability to address the rare situations that require swift action... Procedure No. 1: Procedures for Voting by Circulation Version 2.0. EAC's current Proposed Rule of Agency...

Cosmology with nonminimal kinetic coupling and a Higgs-like potential

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matsumoto, Jiro; Sushkov, Sergey V., E-mail: jmatsumoto@kpfu.ru, E-mail: sergey_sushkov@mail.ru

2015-11-01

We consider cosmological dynamics in the theory of gravity with the scalar field possessing the nonminimal kinetic coupling to curvature given as κG{sup μν}φ{sub ,μ}φ{sub ,ν}, and the Higgs-like potential . Using the dynamical system method, we analyze stationary points, their stability, and all possible asymptotical regimes of the model under consideration. We show that the Higgs field with the kinetic coupling provides an existence of accelerated regimes of the Universe evolution. There are three possible cosmological scenarios with acceleration: (i) The late-time de Sitter epoch when the Hubble parameter tends to the constant value, as t → ∞, while the scalarmore » field tends to zero, 0φ(t)→ , so that the Higgs potential reaches its local maximum . (ii) The Big Rip when H(t)∼(t{sub *}−t){sup −1} → ∞ and φ(t)∼(t{sub *}−t){sup −2} → ∞ as t →  t{sub *}. (iii) The Little Rip when H(t)∼ t{sup 1/2} → ∞ and φ(t)∼ t{sup 1/4} → ∞ as t → ∞. Also, we derive modified slow-roll conditions for the Higgs field and demonstrate that they lead to the Little Rip scenario.« less

Alpha-momorcharin: a ribosome-inactivating protein from Momordica charantia, possessing DNA cleavage properties.

PubMed

Wang, Shuzhen; Zheng, Yinzhen; Yan, Junjie; Zhu, Zhixuan; Wu, Zhihua; Ding, Yi

2013-11-01

Ribosome-inactivating proteins (RIPs) function to inhibit protein synthesis through the removal of specific adenine residues from eukaryotic ribosomal RNA and rending the 60S subunit unable to bind elongation factor 2. They have received much attention in biological and biomedical research due to their unique activities toward tumor cells, as well as the important roles in plant defense. Alpha-momorcharin (α-MC), a member of the type I family of RIPs, is rich in the seeds of Momordica charantia L. Previous studies demonstrated that α-MC is an effective antifungal and antibacterial protein. In this study, a detailed analysis of the DNase-like activity of α-MC was conducted. Results showed that the DNase-like activity toward plasmid DNA was time-dependent, temperature-related, and pH-stable. Moreover, a requirement for divalent metal ions in the catalytic domain of α-MC was confirmed. Additionally, Tyr(93) was found to be a critical residue for the DNase-like activity, while Tyr(134), Glu(183), Arg(186), and Trp(215) were activity-related residues. This study on the chemico-physical properties and mechanism of action of α-MC will improve its utilization in scientific research, as well as its potential industrial uses. These results may also assist in the characterization and elucidation of the DNase-like enzymatic properties of other RIPs.

DNA-binding proteins from marine bacteria expand the known sequence diversity of TALE-like repeats.

PubMed

de Lange, Orlando; Wolf, Christina; Thiel, Philipp; Krüger, Jens; Kleusch, Christian; Kohlbacher, Oliver; Lahaye, Thomas

2015-11-16

Transcription Activator-Like Effectors (TALEs) of Xanthomonas bacteria are programmable DNA binding proteins with unprecedented target specificity. Comparative studies into TALE repeat structure and function are hindered by the limited sequence variation among TALE repeats. More sequence-diverse TALE-like proteins are known from Ralstonia solanacearum (RipTALs) and Burkholderia rhizoxinica (Bats), but RipTAL and Bat repeats are conserved with those of TALEs around the DNA-binding residue. We study two novel marine-organism TALE-like proteins (MOrTL1 and MOrTL2), the first to date of non-terrestrial origin. We have assessed their DNA-binding properties and modelled repeat structures. We found that repeats from these proteins mediate sequence specific DNA binding conforming to the TALE code, despite low sequence similarity to TALE repeats, and with novel residues around the BSR. However, MOrTL1 repeats show greater sequence discriminating power than MOrTL2 repeats. Sequence alignments show that there are only three residues conserved between repeats of all TALE-like proteins including the two new additions. This conserved motif could prove useful as an identifier for future TALE-likes. Additionally, comparing MOrTL repeats with those of other TALE-likes suggests a common evolutionary origin for the TALEs, RipTALs and Bats. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Evidence for a New Intermediate Phase in a Strongly Correlated 2D System near Wigner Crystallization

NASA Astrophysics Data System (ADS)

Gao, Xuan; Qiu, Richard; Goble, Nicholas; Serafin, Alex; Yin, Liang; Xia, Jian-Sheng; Sullivan, Neil; Pfeiffer, Loren; West, Ken

How the two dimensional (2D) quantum Wigner crystal (WC) transforms into the metallic liquid phase remains an outstanding problem in physics. In theories considering the 2D WC to liquid transition in the clean limit, it was suggested that a number of intermediate phases might exist. We have studied the transformation between the metallic fluid phase and the low magnetic field reentrant insulating phase (RIP) which was interpreted as due to the WC [Qiu et al., PRL 108, 106404 (2012)], in a strongly correlated 2D hole system in GaAs quantum well with large interaction parameter rs (~20-30) and high mobility. Instead of a sharp transition, we found that increasing density (or lowering rs) drives the RIP into a state where the incipient RIP coexists with Fermi liquid. This apparent mixture phase intermediate between Fermi liquid and WC also exhibits a non-trivial temperature dependent resistivity behavior which can be qualitatively understood by the reversed melting of WC in the mixture, in analogy to the Pomeranchuk effect in the solid-liquid mixture of Helium-3. X.G. thanks NSF (DMR-0906415) for supporting work at CWRU. Experiments at the NHMFL High B/T Facility were supported by NSF Grant 0654118 and the State of Florida. L.P. thanks the Gordon and Betty Moore Foundation and NSF MRSEC (DMR-0819860) for support.

Therapeutic hypothermia attenuates tissue damage and cytokine expression after traumatic brain injury by inhibiting necroptosis in the rat.

PubMed

Liu, Tao; Zhao, Dong-xu; Cui, Hua; Chen, Lei; Bao, Ying-hui; Wang, Yong; Jiang, Ji-yao

2016-04-15

Necroptosis has been shown as an alternative form of cell death in many diseases, but the detailed mechanisms of the neuron loss after traumatic brain injury (TBI) in rodents remain unclear. To investigate whether necroptosis is induced after TBI and gets involved in the neuroprotecton of therapeutic hypothermia on the TBI, we observed the pathological and biochemical change of the necroptosis in the fluid percussion brain injury (FPI) model of the rats. We found that receptor-interacting protein (RIP) 1 and 3, and mixed lineage kinase domain-like protein (MLKL), the critical downstream mediators of necroptosis recently identified in vivo, as well as HMGB1 and the pro-inflammation cytokines TNF-α, IL-6 and IL-18, were increased at an early phase (6 h) in cortex after TBI. Posttraumatic hypothermia (33 °C) led to the decreases in the necroptosis regulators, inflammatory factors and brain tissue damage in rats compared with normothermia-treated TBI animals. Immunohistochemistry studies showed that posttraumatic hypothermia also decreased the necroptosis-associated proteins staining in injured cortex and hippocampal CA1. Therefore, we conclude that the RIP1/RIP3-MLKL-mediated necroptosis occurs after experimental TBI and therapeutic hypothermia may protect the injured central nervous system from tissue damage and the inflammatory responses by targeting the necroptosis signaling after TBI.

Profound Impact of Hfq on Nutrient Acquisition, Metabolism and Motility in the Plant Pathogen Agrobacterium tumefaciens

PubMed Central

Möller, Philip; Overlöper, Aaron; Förstner, Konrad U.; Wen, Tuan-Nan; Sharma, Cynthia M.; Lai, Erh-Min; Narberhaus, Franz

2014-01-01

As matchmaker between mRNA and sRNA interactions, the RNA chaperone Hfq plays a key role in riboregulation of many bacteria. Often, the global influence of Hfq on the transcriptome is reflected by substantially altered proteomes and pleiotropic phenotypes in hfq mutants. Using quantitative proteomics and co-immunoprecipitation combined with RNA-sequencing (RIP-seq) of Hfq-bound RNAs, we demonstrate the pervasive role of Hfq in nutrient acquisition, metabolism and motility of the plant pathogen Agrobacterium tumefaciens. 136 of 2544 proteins identified by iTRAQ (isobaric tags for relative and absolute quantitation) were affected in the absence of Hfq. Most of them were associated with ABC transporters, general metabolism and motility. RIP-seq of chromosomally encoded Hfq3xFlag revealed 1697 mRNAs and 209 non-coding RNAs (ncRNAs) associated with Hfq. 56 ncRNAs were previously undescribed. Interestingly, 55% of the Hfq-bound ncRNAs were encoded antisense (as) to a protein-coding sequence suggesting that A. tumefaciens Hfq plays an important role in asRNA-target interactions. The exclusive enrichment of 296 mRNAs and 31 ncRNAs under virulence conditions further indicates a role for post-transcriptional regulation in A. tumefaciens-mediated plant infection. On the basis of the iTRAQ and RIP-seq data, we assembled a comprehensive model of the Hfq core regulon in A. tumefaciens. PMID:25330313

Profound impact of Hfq on nutrient acquisition, metabolism and motility in the plant pathogen Agrobacterium tumefaciens.

PubMed

Möller, Philip; Overlöper, Aaron; Förstner, Konrad U; Wen, Tuan-Nan; Sharma, Cynthia M; Lai, Erh-Min; Narberhaus, Franz

2014-01-01

As matchmaker between mRNA and sRNA interactions, the RNA chaperone Hfq plays a key role in riboregulation of many bacteria. Often, the global influence of Hfq on the transcriptome is reflected by substantially altered proteomes and pleiotropic phenotypes in hfq mutants. Using quantitative proteomics and co-immunoprecipitation combined with RNA-sequencing (RIP-seq) of Hfq-bound RNAs, we demonstrate the pervasive role of Hfq in nutrient acquisition, metabolism and motility of the plant pathogen Agrobacterium tumefaciens. 136 of 2544 proteins identified by iTRAQ (isobaric tags for relative and absolute quantitation) were affected in the absence of Hfq. Most of them were associated with ABC transporters, general metabolism and motility. RIP-seq of chromosomally encoded Hfq3xFlag revealed 1697 mRNAs and 209 non-coding RNAs (ncRNAs) associated with Hfq. 56 ncRNAs were previously undescribed. Interestingly, 55% of the Hfq-bound ncRNAs were encoded antisense (as) to a protein-coding sequence suggesting that A. tumefaciens Hfq plays an important role in asRNA-target interactions. The exclusive enrichment of 296 mRNAs and 31 ncRNAs under virulence conditions further indicates a role for post-transcriptional regulation in A. tumefaciens-mediated plant infection. On the basis of the iTRAQ and RIP-seq data, we assembled a comprehensive model of the Hfq core regulon in A. tumefaciens.

Interaction of the putative tyrosine recombinases RipX (UU145), XerC (UU222), and CodV (UU529) of Ureaplasma parvum serovar 3 with specific DNA

PubMed Central

Zimmerman, Carl-Ulrich R; Rosengarten, Renate; Spergser, Joachim

2013-01-01

Phase variation of two loci (‘mba locus’ and ‘UU172 phase-variable element’) in Ureaplasma parvum serovar 3 has been suggested as result of site-specific DNA inversion occurring at short inverted repeats. Three potential tyrosine recombinases (RipX, XerC, and CodV encoded by the genes UU145, UU222, and UU529) have been annotated in the genome of U. parvum serovar 3, which could be mediators in the proposed recombination event. We document that only orthologs of the gene xerC are present in all strains that show phase variation in the two loci. We demonstrate in vitro binding of recombinant maltose-binding protein fusions of XerC to the inverted repeats of the phase-variable loci, of RipX to a direct repeat that flanks a 20-kbp region, which has been proposed as putative pathogenicity island, and of CodV to a putative dif site. Co-transformation of the model organism Mycoplasma pneumoniae M129 with both the ‘mba locus’ and the recombinase gene xerC behind an active promoter region resulted in DNA inversion in the ‘mba locus’. Results suggest that XerC of U. parvum serovar 3 is a mediator in the proposed DNA inversion event of the two phase-variable loci. PMID:23305333

Anti-cyclonic circulation driven by the estuarine circulation in a gulf type ROFI

NASA Astrophysics Data System (ADS)

Fujiwara, T.; Sanford, L. P.; Nakatsuji, K.; Sugiyama, Y.

1997-08-01

Baroclinic residual circulation processes are examined in gulf type Regions Of Freshwater Influence (ROFIs), which have large rivers discharging into a rounded head wider than the Rossby internal deformation radius. Theoretical and observational investigations concentrate on Ise Bay, Japan, with supporting data from Osaka Bay and Tokyo Bay. Simplified analytical solutions are derived to describe the primary features of the circulation. Three dimensional residual current data collected using moored current meters and shipboard acoustic doppler current profilers (ADCPs), satellite imagery and density structure data observed using STDs, are presented for comparison to the theoretical predictions. There are three key points to understanding the resulting circulation in gulf type ROFIs. First, there are likely to be three distinct water masses: the river plume, a brackish upper layer, and a higher salinity lower layer. Second, baroclinic processes in gulf type ROFIs are influenced by the Earth's rotation at first order. Residual currents are quasi-geostrophic and potential vorticity is approximately conserved. Third, the combined effects of a classical longitudinal estuarine circulation and the Earth's rotation are both necessary to produce the resulting circulation. Anti-cyclonic vorticity is generated in the upper layer by the horizontal divergence associated with upward entrainment, which is part of the estuarine circulation. The interaction between anti-cyclonic vorticity and horizontal divergence results in two regions of qualitatively different circulation, with gyre-like circulation near the bay head and uniformly seaward anti-cyclonicly sheared flow further towards the mouth. The stagnation point separating the two regions is closer to (further away from) the bay head for stronger (weaker) horizontal divergence, respectively. The vorticity and spin-up time of this circulation are-(ƒ-ω 1)/2 and h/2w 0, respectively, where ƒ is the Coriolis parameter, ω 1 is the vorticity of the lower layer, h is the depth of the upper layer and w 0 is the upward entrainment velocity across the pycnocline. Under high discharge conditions the axis of the river plume proceeds in a right bounded direction, describing an inertial circle clearly seen in satellite images. Under low discharge conditions the river plume is deflected in a left bounded direction by the anti-cyclonic circulation of the upper layer.

Library construction for next-generation sequencing: Overviews and challenges

PubMed Central

Head, Steven R.; Komori, H. Kiyomi; LaMere, Sarah A.; Whisenant, Thomas; Van Nieuwerburgh, Filip; Salomon, Daniel R.; Ordoukhanian, Phillip

2014-01-01

High-throughput sequencing, also known as next-generation sequencing (NGS), has revolutionized genomic research. In recent years, NGS technology has steadily improved, with costs dropping and the number and range of sequencing applications increasing exponentially. Here, we examine the critical role of sequencing library quality and consider important challenges when preparing NGS libraries from DNA and RNA sources. Factors such as the quantity and physical characteristics of the RNA or DNA source material as well as the desired application (i.e., genome sequencing, targeted sequencing, RNA-seq, ChIP-seq, RIP-seq, and methylation) are addressed in the context of preparing high quality sequencing libraries. In addition, the current methods for preparing NGS libraries from single cells are also discussed. PMID:24502796

Analysis and Remediation of the 2013 LAC-MÉGANTIC Train Derailment

NASA Astrophysics Data System (ADS)

Brunke, Suzanne; Aubé, Guy; Legaré, Serge; Auger, Claude

2016-06-01

On July 6, 2013 a train owned by Montréal, Maine & Atlantic Railway (MMA) Company derailed in Lac-Mégantic, Quebec, Canada triggering the explosion of the tankers carrying crude oil. Several buildings in the downtown core were destroyed. The Sûreté du Québec confirmed the death of 47 people in the disaster. Through the Canadian Space Agency (CSA) Rapid Information Products and Services (RIPS) program, MDA developed value-added products that allowed stakeholders and all levels of government (municipal, provincial and federal) to get an accurate picture of the disaster. The goal of this RIPS Project was to identify the contribution that remote sensing technology can provide to disasters such as the train derailment and explosion at Lac-Mégantic through response and remediation monitoring. Through monitoring and analysis, the Lac-Mégantic train derailment response and remediation demonstrated how Earth observation data can be used for situational awareness in a disaster and in documenting the remediation process. Both high resolution optical and RADARSAT-2 SAR image products were acquired and analyzed over the disaster remediation period as each had a role in monitoring. High resolution optical imagery provided a very clear picture of the current state of remediation efforts, however it can be difficult to acquire due to cloud cover and weather conditions. The RADARSAT-2 SAR images can be acquired in all weather conditions at any time of day making it ideal for mission critical information gathering. MDA's automated change detection processing enabled rapid delivery of advanced information products.

A peptide-major histocompatibility complex II chimera favors survival of pancreatic beta-islets grafted in type 1 diabetic mice.

PubMed

Casares, Sofia; Lin, Marvin; Zhang, Nan; Teijaro, John R; Stoica, Cristina; McEvoy, Robert; Farber, Donna L; Bona, Constantin; Brumeanu, Teodor D

2008-06-27

Transplantation of pancreatic islets showed a tremendous progress over the years as a promising, new therapeutic strategy in patients with type 1 diabetes. However, additional immunosuppressive drug therapy is required to prevent rejection of engrafted islets. The current immunosuppressive therapies showed limited success in maintaining long-term islet survival as required to achieve insulin independence in type 1 diabetes, and they induce severe adverse effects. Herein, we analyzed the effects of a soluble peptide-major histocompatibility complex (MHC) class II chimera aimed at devising an antigen-specific therapy for suppression of anti-islet T cell responses and to improve the survival of pancreatic islets transplants. Pancreatic islets from transgenic mice expressing the hemagglutinin antigen in the beta islets under the rat insulin promoter (RIP-HA) were grafted under the kidney capsule of diabetic, double transgenic mice expressing hemagglutinin in the pancreas and T cells specific for hemagglutinin (RIP-HA, TCR-HA). The recipient double transgenic mice were treated or not with the soluble peptide-MHC II chimera, and the progression of diabetes, graft survival, and T cell responses to the grafted islets were analyzed. The peptide-MHC II chimera protected syngeneic pancreatic islet transplants against the islet-reactive CD4 T cells, and prolonged the survival of transplanted islets. Protection of transplanted islets occurred by polarization of antigen-specific memory CD4 T cells toward a Th2 anti-inflammatory response. The peptide-MHC II chimera approach is an efficient and specific therapeutic approach to suppress anti-islet T cell responses and provides a long survival of pancreatic grafted islets.

The presence of a phantom field in a Randall–Sundrum scenario

NASA Astrophysics Data System (ADS)

Acuña-Cárdenas, Rubén O.; Astorga-Moreno, J. A.; García-Aspeitia, Miguel A.; López-Domínguez, J. C.

2018-02-01

The presence of phantom dark energy in brane world cosmology generates important new effects, causing a premature big rip singularity when we increase the presence of extra dimensions and considerably competing with the other components of our Universe. This article first considers only a field with the characteristic equation ω<-1 and then the explicit form of the scalar field with a potential with a maximum (with the aim of avoiding a big rip singularity). In both cases we study the dynamics robustly through dynamical analysis theory, considering in detail parameters such as the deceleration q and the vector field associated to the dynamical system. Results are discussed with the purpose of treating the cosmology with a phantom field as dark energy in a Randall–Sundrum scenario.

Identity practices, ingroup projection, and the evaluation of subgroups: a study among Turkish-Dutch Sunnis.

PubMed

Lie, Jessamina Lih Yan; Verkuyten, Maykel

2012-01-01

This research focuses on religious subgroup evaluations by examining the attitude of Turkish-Dutch Sunni Muslims towards Alevi and Shiite Muslims. Following the Ingroup Projection Model, it was expected that Sunni participants who practice Islam will project their self-defining subgroup practices on the superordinate Muslim category, which will be related to more ingroup bias towards Alevis, a Muslim subgroup that performs different religious practices. Two studies yielded consistent evidence that practicing Islam increased ingroup bias towards Alevis. Furthermore, in Study 2, we found evidence that the effect of practicing Islam on ingroup bias was mediated by relative ingroup prototypicality (RIP). Moreover, practicing Islam did not affect RIP in relation to Shiites who perform the same religious practices that we examined. These findings support the Ingroup Projection Model.

Regional circulation around New Caledonia from two decades of observations

NASA Astrophysics Data System (ADS)

Cravatte, Sophie; Kestenare, Elodie; Eldin, Gérard; Ganachaud, Alexandre; Lefèvre, Jérôme; Marin, Frédéric; Menkes, Christophe; Aucan, Jérôme

2015-08-01

The regional and near-coastal circulation around New Caledonia is investigated using a compilation of more than 20 years of observations. Velocity profiles acquired by Shipboard Acoustic Doppler Current Profiler (SADCP) during 109 research cruises and ship transits since 1991 are analyzed and compared with absolute geostrophic currents inferred from hydrographic profiles and Argo floats drifts. In addition, altimetric surface currents are used to explore the variability of the circulation at various timescales. By making the best use of the strength of these various observations, this study provides an unprecedented detailed picture of the mean circulation around New Caledonia and of its variability in the upper layers. New Caledonia, together with the Vanuatu Archipelago and the Fiji Islands, acts as a 750-km long obstacle to the westward South Equatorial Current (SEC) entering the Coral Sea. On average, the SEC bifurcates against New Caledonia's east coast into a northwestward boundary current, the East Caledonian Current, beginning east of the Loyalty Islands and extending to at least 1000 m depth, and into a weak southeastward current. The latter, the Vauban Current, flows into the Loyalty channel against the mean trade winds where it extends to at least 500 m depth. It is highly variable at intraseasonal timescales; it often reverses and its variability is mainly driven by incoming mesoscale eddies east and south of New Caledonia. West of the Island, the southeastward Alis Current of New Caledonia (ACNC) flows along the reef slope in the 0-150 m layer. It overlays a weaker northwestward current, creating an unusual coastal circulation reminiscent of the current system along the Australian west coast. The ACNC is a persistent feature of the observations, even if its transport is also strongly modulated by the presence of offshore eddies. This study highlights the fact, if needed, that a snapshot view of the currents provided by a single transect can be strongly impacted by mesoscale eddies, and should be put into context, e.g. by using simultaneous altimetric data.

Pivotal Role of Receptor-Interacting Protein Kinase 1 and Mixed Lineage Kinase Domain-Like in Neuronal Cell Death Induced by the Human Neuroinvasive Coronavirus OC43

PubMed Central

Meessen-Pinard, Mathieu; Le Coupanec, Alain

2016-01-01

ABSTRACT Human coronaviruses (HCoV) are respiratory pathogens with neuroinvasive, neurotropic, and neurovirulent properties, highlighting the importance of studying the potential implication of these viruses in neurological diseases. The OC43 strain (HCoV-OC43) was reported to induce neuronal cell death, which may participate in neuropathogenesis. Here, we show that HCoV-OC43 harboring two point mutations in the spike glycoprotein (rOC/Us183–241) was more neurovirulent than the wild-type HCoV-OC43 (rOC/ATCC) in mice and induced more cell death in murine and human neuronal cells. To evaluate the role of regulated cell death (RCD) in HCoV-OC43-mediated neural pathogenesis, we determined if knockdown of Bax, a key regulator of apoptosis, or RIP1, a key regulator of necroptosis, altered the percentage of neuronal cell death following HCoV-OC43 infection. We found that Bax-dependent apoptosis did not play a significant role in RCD following infection, as inhibition of Bax expression mediated by RNA interference did not confer cellular protection against the cell death process. On the other hand, we demonstrated that RIP1 and MLKL were involved in neuronal cell death, as RIP1 knockdown and chemical inhibition of MLKL significantly increased cell survival after infection. Taken together, these results indicate that RIP1 and MLKL contribute to necroptotic cell death after HCoV-OC43 infection to limit viral replication. However, this RCD could lead to neuronal loss in the mouse CNS and accentuate the neuroinflammation process, reflecting the severity of neuropathogenesis. IMPORTANCE Because they are naturally neuroinvasive and neurotropic, human coronaviruses are suspected to participate in the development of neurological diseases. Given that the strain OC43 is neurovirulent in mice and induces neuronal cell death, we explored the neuronal response to infection by characterizing the activation of RCD. Our results revealed that classical apoptosis associated with the Bax protein does not play a significant role in HCoV-OC43-induced neuronal cell death and that RIP1 and MLKL, two cellular proteins usually associated with necroptosis (an RCD back-up system when apoptosis is not adequately induced), both play a pivotal role in the process. As necroptosis disrupts cellular membranes and allows the release of damage-associated molecular patterns (DAMP) and possibly induces the production of proinflammatory cytokines, it may represent a proinflammatory cell death mechanism that contributes to excessive neuroinflammation and neurodegeneration and eventually to neurological disorders after a coronavirus infection. PMID:27795420

The impact of the ocean observing system on estimates of the California current circulation spanning three decades

NASA Astrophysics Data System (ADS)

Moore, Andrew M.; Jacox, Michael G.; Crawford, William J.; Laughlin, Bruce; Edwards, Christopher A.; Fiechter, Jérôme

2017-08-01

Data assimilation is now used routinely in oceanography on both regional and global scales for computing ocean circulation estimates and for making ocean forecasts. Regional ocean observing systems are also expanding rapidly, and observations from a wide array of different platforms and sensor types are now available. Evaluation of the impact of the observing system on ocean circulation estimates (and forecasts) is therefore of considerable interest to the oceanographic community. In this paper, we quantify the impact of different observing platforms on estimates of the California Current System (CCS) spanning a three decade period (1980-2010). Specifically, we focus attention on several dynamically related aspects of the circulation (coastal upwelling, the transport of the California Current and the California Undercurrent, thermocline depth and eddy kinetic energy) which in many ways describe defining characteristics of the CCS. The circulation estimates were computed using a 4-dimensional variational (4D-Var) data assimilation system, and our analyses also focus on the impact of the different elements of the control vector (i.e. the initial conditions, surface forcing, and open boundary conditions) on the circulation. While the influence of each component of the control vector varies between different metrics of the circulation, the impact of each observing system across metrics is very robust. In addition, the mean amplitude of the circulation increments (i.e. the difference between the analysis and background) remains relatively stable throughout the three decade period despite the addition of new observing platforms whose impact is redistributed according to the relative uncertainty of observations from each platform. We also consider the impact of each observing platform on CCS circulation variability associated with low-frequency climate variability. The low-frequency nature of the dominant climate modes in this region allows us to track through time the impact of each observation on the circulation, and illustrates how observations from some platforms can influence the circulation up to a decade into the future.

Evaluating wave-current interaction in an urban estuary and flooding implications for coastal communities

NASA Astrophysics Data System (ADS)

Cifuentes-Lorenzen, A.; O'Donnell, J.; Howard-Strobel, M. M.; Fake, T.; McCardell, G.

2016-12-01

Accurate hydrodynamic-wave coupled coastal circulation models aid the prediction of storm impacts, particularly in areas where data is absent, and can inform mitigation options. They are essential everywhere to account for the effects of climate change. Here, the Finite Volume Community Ocean Model (FVCOM) was used to estimate the residual circulation inside a small urban estuary, Long Island Sound, during three severe weather events of different magnitude (i.e. 1/5, 1/25 and 1/50 year events). The effect of including wave coupling using a log-layer bottom boundary and the bottom wave-current coupling, following the approach of Madsen (1994) on the simulated residual circulation was assessed. Significant differences in the solutions were constrained to the near surface (s>-0.3) region. No significant difference in the depth-averaged residual circulation was detected. When the Madsen (1994) bottom boundary layer model for wave-current interaction was employed, differences in residual circulation resulted. The bottom wave-current interaction also plays an important role in the wave dynamics. Significant wave heights along the northern Connecticut shoreline were enhanced by up to 15% when the bottom wave-current interaction was included in the simulations. The wave-induced bottom drag enhancement has a substantial effect on tides in the Sound, possibly because it is nearly resonant at semidiurnal frequencies. This wave-current interaction current leads to severe tidal dampening ( 40% amplitude reduction) at the Western end of the estuary in the modeled sea surface displacement. The potential magnitude of these effects means that wave current interaction should be included and carefully evaluated in models of estuaries that are useful.

Wind, Circulation, and Topographic Effects on Alongshore Phytoplankton Variability in the California Current

NASA Astrophysics Data System (ADS)

Fiechter, Jerome; Edwards, Christopher A.; Moore, Andrew M.

2018-04-01

A physical-biogeochemical model is used to produce a retrospective analysis at 3-km resolution of alongshore phytoplankton variability in the California Current during 1988-2010. The simulation benefits from downscaling a regional circulation reanalysis, which provides improved physical ocean state estimates in the high-resolution domain. The emerging pattern is one of local upwelling intensification in response to increased alongshore wind stress in the lee of capes, modulated by alongshore meanders in the geostrophic circulation. While stronger upwelling occurs near most major topographic features, substantial increases in phytoplankton biomass only ensue where local circulation patterns are conducive to on-shelf retention of upwelled nutrients. Locations of peak nutrient delivery and chlorophyll accumulation also exhibit interannual variability and trends noticeably larger than the surrounding shelf regions, thereby suggesting that long-term planktonic ecosystem response in the California Current exhibits a significant local scale (O(100 km)) alongshore component.

Exogenous hydrogen sulfide protects human umbilical vein endothelial cells against high glucose‑induced injury by inhibiting the necroptosis pathway.

PubMed

Lin, Jiaqiong; Chen, Meiji; Liu, Donghong; Guo, Ruixian; Lin, Kai; Deng, Haiou; Zhi, Ximei; Zhang, Weijie; Feng, Jianqiang; Wu, Wen

2018-03-01

Hyperglycemia is a key factor in the development of diabetic complications, including the processes of atherosclerosis. Receptor‑interacting protein 3 (RIP3), a mediator of necroptosis, is implicated in atherosclerosis development. Additionally, hydrogen sulfide (H2S) protects the vascular endothelium against hyperglycemia‑induced injury and attenuates atherosclerosis. On the basis of these findings, the present study aimed to confirm the hypothesis that necroptosis mediates high glucose (HG)‑induced injury in human umbilical vein endothelial cells (HUVECs), and that the inhibition of necroptosis contributes to the protective effect of exogenous H2S against this injury. The results revealed that exposure of HUVECs to 40 mM HG markedly enhanced the expression level of RIP3, along with multiple injuries, including a decrease in cell viability, an increase in the number of apoptotic cells, an increase in the expression level of cleaved caspase‑3, generation of reactive oxygen species (ROS), as well as dissipation of the mitochondrial membrane potential (MMP). Treatment of the cells with sodium hydrogen sulfide (NaHS; a donor of H2S) prior to exposure to HG significantly attenuated the increased RIP3 expression and the aforementioned injuries by HG. Notably, treatment of cells with necrostatin‑1 (Nec‑1), an inhibitor of necroptosis, prior to exposure to HG ameliorated the HG‑induced injuries, leading to a decrease in ROS generation and a loss of MMP. However, pre‑treatment of the cells with Nec‑1 enhanced the HG‑induced increase in the expression levels of cleaved caspases‑3 and ‑9. By contrast, pre‑treatment with Z‑VAD‑FMK, a pan ‑caspase inhibitor, promoted the increased expression of RIP3 by HG. Taken together, the findings of the present study have demonstrated, to the best of our knowledge for the first time, that exogenous H2S protects HUVECs against HG‑induced injury through inhibiting necroptosis. The present study has also provided novel evidence that there is a negative interaction between necroptosis and apoptosis in the HG‑treated HUVECs.

Influence of depression and anxiety on circulating endothelial progenitor cells in patients with acute coronary syndromes.

PubMed

Felice, Francesca; Di Stefano, Rossella; Pini, Stefano; Mazzotta, Gianfranco; Bovenzi, Francesco M; Bertoli, Daniele; Abelli, Marianna; Borelli, Lucia; Cardini, Alessandra; Lari, Lisa; Gesi, Camilla; Michi, Paola; Morrone, Doralisa; Gnudi, Luigi; Balbarini, Alberto

2015-05-01

Circulating endothelial progenitor cells (EPCs) are related to endothelial function and progression of coronary artery disease. There is evidence of decreased numbers of circulating EPCs in patients with a current episode of major depression. We investigated the relationships between the level of circulating EPCs and depression and anxiety in patients with acute coronary syndrome (ACS). Patients with ACS admitted to three Cardiology Intensive Care Units were evaluated by the SCID-I to determine the presence of lifetime and/or current mood and anxiety disorders according to DSM-IV criteria. The EPCs were defined as CD133(+) CD34(+) KDR(+) and evaluated by flow cytometry. All patients underwent standardized cardiological and psychopathological evaluations. Parametric and nonparametric statistical tests were performed where appropriate. Out of 111 ACS patients, 57 were found to have a DSM-IV lifetime or current mood or anxiety disorder at the time of the inclusion in the study. The ACS group with mood or anxiety disorders showed a significant decrease in circulating EPC number compared with ACS patients without affective disorders. In addition, EPC levels correlated negatively with severity of depression and anxiety at index ACS episode. The current study indicates that EPCs circulate in decreased numbers in ACS patients with depression or anxiety and, therefore, contribute to explore new perspectives in the pathophysiology of the association between cardiovascular disorders and affective disorders. Copyright © 2015 John Wiley & Sons, Ltd.

Interannual variation of the South China Sea circulation during winter: intensified in the southern basin

NASA Astrophysics Data System (ADS)

Zu, Tingting; Xue, Huijie; Wang, Dongxiao; Geng, Bingxu; Zeng, Lili; Liu, Qinyan; Chen, Ju; He, Yunkai

2018-05-01

Surface geostrophic current derived from altimetry remote sensing data, and current profiles observed from in-situ Acoustic Doppler Current Profilers (ADCP) mooring in the northern South China Sea (NSCS) and southern South China Sea (SSCS) are utilized to study the kinetic and energetic interannual variability of the circulation in the South China Sea (SCS) during winter. Results reveal a more significant interannual variation of the circulation and water mass properties in the SSCS than that in the NSCS. Composite ananlysis shows a significantly reduced western boundary current (WBC) and a closed cyclonic eddy in the SSCS at the mature phase of El Niño event, but a strong WBC and an unclosed cyclonic circulation in winter at normal or La Niña years. The SST is warmer while the subsurface water is colder and fresher in the mature phase of El Niño event than that in the normal or La Niña years in the SSCS. Numerical experiments and energy analysis suggest that both local and remote wind stress change are important for the interannual variation in the SSCS, remote wind forcing and Kuroshio intrusion affect the circulation and water mass properties in the SSCS through WBC advection.

Nearshore circulation on a sea breeze dominated beach during intense wind events

NASA Astrophysics Data System (ADS)

Torres-Freyermuth, Alec; Puleo, Jack A.; DiCosmo, Nick; Allende-Arandía, Ma. Eugenia; Chardón-Maldonado, Patricia; López, José; Figueroa-Espinoza, Bernardo; de Alegria-Arzaburu, Amaia Ruiz; Figlus, Jens; Roberts Briggs, Tiffany M.; de la Roza, Jacobo; Candela, Julio

2017-12-01

A field experiment was conducted on the northern Yucatan coast from April 1 to April 12, 2014 to investigate the role of intense wind events on coastal circulation from the inner shelf to the swash zone. The study area is characterized by a micro-tidal environment, low-energy wave conditions, and a wide and shallow continental shelf. Furthermore, easterly trade winds, local breezes, and synoptic-scale events, associated with the passage of cold-fronts known as Nortes, are ubiquitous in this region. Currents were measured concurrently at different cross-shore locations during both local and synoptic-scale intense wind events to investigate the influence of different forcing mechanisms (i.e., large-scale currents, winds, tides, and waves) on the nearshore circulation. Field observations revealed that nearshore circulation across the shelf is predominantly alongshore-directed (westward) during intense winds. However, the mechanisms responsible for driving instantaneous spatial and temporal current variability depend on the weather conditions and the across-shelf location. During local strong sea breeze events (W > 10 m s-1 from the NE) occurring during spring tide, westward circulation is controlled by the tides, wind, and waves at the inner-shelf, shallow waters, and inside the surf/swash zone, respectively. The nearshore circulation is relaxed during intense land breeze events (W ≈ 9 m s-1 from the SE) associated with the low atmospheric pressure system that preceded a Norte event. During the Norte event (Wmax≈ 15 m s-1 from the NNW), westward circulation dominated outside the surf zone and was correlated to the Yucatan Current, whereas wave breaking forces eastward currents inside the surf/swash zone. The latter finding implies the existence of large alongshore velocity shear at the offshore edge of the surf zone during the Norte event, which enhances mixing between the surf zone and the inner shelf. These findings suggest that both sea breezes and Nortes play an important role in sediment and pollutant transport along/across the nearshore of the Yucatan shelf.

Southwest Pacific Ocean Circulation and Climate Experiment (SPICE) scientific advances and future west pacific coordination

NASA Astrophysics Data System (ADS)

Ganachaud, A. S.; Sprintall, J.; Lin, X.; Ando, K.

2016-02-01

The Southwest Pacific Ocean Circulation and Climate Experiment (SPICE) is an international research program under the auspices of CLIVAR (Climate Variability and Predictability). The key objectives are to understand the Southwest Pacific Ocean circulation and Convergence Zone (SPCZ) dynamics, as well as their influence on regional and basin-scale climate patterns. It was designed to measure and monitor the ocean circulation, and to validate and improve numerical models. South Pacific oceanic waters are carried from the subtropical gyre centre in the westward flowing South Equatorial Current (SEC), towards the southwest Pacific-a major circulation pathway that redistributes water from the subtropics to the equator and Southern Ocean. Water transit through the Coral and Solomon Seas is potentially of great importance to tropical climate prediction because changes in either the temperature or the amount of water arriving at the equator have the capability to modulate ENSO and produce basin-scale climate feedbacks. On average, the oceanic circulation is driven by the Trade Winds, and subject to substantial variability, related with the SPCZ position and intensity. The circulation is complex, with the SEC splitting into zonal jets upon encountering island archipelagos, before joining either the East Australian Current or the New Guinea Costal UnderCurrent towards the equator. SPICE included large, coordinated in situ measurement programs and high resolution numerical simulations of the area. After 8 years of substantial in situ oceanic observational and modeling efforts, our understanding of the region has much improved. We have a refined description of the SPCZ behavior, boundary currents, pathways, and water mass transformation, including the previously undocumented Solomon Sea. The transports are large and vary substantially in a counter-intuitive way, with asymmetries and gating effects that depend on time scales. We will review the recent advancements and discuss our current knowledge gaps and important emerging research directions. In particular we will discuss how SPICE, along with the Northwestern Pacific Ocean Circulation and Climate Experiment (NPOCE) and Indonesian ThroughFlow (ITF) programs could evolve toward an integrative observing system under CLIVAR coordination.

Metabolites associated with circulating interleukin-6 in older adults

USDA-ARS?s Scientific Manuscript database

Background: Circulating levels of the pro-inflammatory cytokine interleukin-6 (IL-6) levels are elevated in older adults, but mechanisms are unclear. In the current study, we used an untargeted metabolomic approach to develop an improved understanding about mechanisms related to circulating IL-6 in ...

Against Corporations Organizing to Rip-off the Nation Act

THOMAS, 111th Congress

Rep. McCollum, Betty [D-MN-4

2009-09-30

House - 10/23/2009 Referred to the Subcommittee on Government Management, Organization, and Procurement. (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

33 CFR 203.14 - Responsibilities of non-Federal interests.

Code of Federal Regulations, 2010 CFR

2010-07-01

... during flood situations; (3) Training personnel to operate, maintain, and patrol projects during crisis... Program (RIP), as detailed in subpart D of this part; and, (5) Responsible regulation, management, and use...

Exploiting coastal altimetry to improve the surface circulation scheme over the central Mediterranean Sea

NASA Astrophysics Data System (ADS)

Jebri, Fatma; Birol, Florence; Zakardjian, Bruno; Bouffard, Jérome; Sammari, Cherif

2016-07-01

This work is the first study exploiting along track altimetry data to observe and monitor coastal ocean features over the transition area between the western and eastern Mediterranean Basins. The relative performances of both the AVISO and the X-TRACK research regional altimetric data sets are compared using in situ observations. Both products are cross validated with tide gauge records. The altimeter-derived geostrophic velocities are also compared with observations from a moored Acoustic Doppler Current Profiler. Results indicate the good potential of satellite altimetry to retrieve dynamic features over the area. However, X-TRACK shows a more homogenous data coverage than AVISO, with longer time series in the 50 km coastal band. The seasonal evolution of the surface circulation is therefore analyzed by conjointly using X-TRACK data and remotely sensed sea surface temperature observations. This combined data set clearly depicts different current regimes and bifurcations, which allows us to propose a new seasonal circulation scheme for the central Mediterranean. The analysis shows variations of the path and temporal behavior of the main circulation features: the Atlantic Tunisian Current, the Atlantic Ionian Stream, the Atlantic Libyan Current, and the Sidra Gyre. The resulting bifurcating veins of these currents are also discussed, and a new current branch is observed for the first time.

Sea-floor geology and sedimentary processes in the vicinity of Cross Rip Channel, Nantucket Sound, offshore southeastern Massachusetts

USGS Publications Warehouse

Poppe, L.J.; McMullen, K.Y.; Ackerman, S.D.; Schaer, J.D.; Wright, D.B.

2012-01-01

Gridded multibeam bathymetry covers approximately 10.4 square kilometers of sea floor in the vicinity of Cross Rip Channel in Nantucket Sound, offshore southeastern Massachusetts. Although originally collected for charting purposes during National Oceanic and Atmospheric Administration hydrographic survey H12007, these acoustic data, and the sea-floor sediment sampling and bottom photography stations subsequently occupied to verify them, show the composition and terrain of the seabed and provide information on sediment transport and benthic habitat. This report is part of an expanding series of cooperative studies by the U.S. Geological Survey, National Oceanic and Atmospheric Administration, and Massachusetts Office of Coastal Zone Management that provide a fundamental framework for research and resource-management activities (for example, windfarms, pipelines, and dredging) along the inner continental shelf offshore of Massachusetts.

A comparative study of a new wireless continuous cardiorespiratory monitor for the diagnosis and management of patients with congestive heart failure at home.

PubMed

Andrews, D; Gouda, M S; Higgins, S; Johnson, P; Williams, A; Vandenburg, M

2002-01-01

Congestive heart failure (CHF) is a major and increasing chronic disease in Western society, with a high mortality, morbidity and cost for unplanned hospital admissions. Continuous cardiorespiratory monitoring is required to detect Cheyne-Stokes respiration (CSR). We have tested a new wireless monitoring system and compared it with polysomnography (PSG) and respiratory inductance plethysmography (RIP) in six CHF patients with CSR in a sleep laboratory. The wireless system compared well with RIP for the detection of CSR but less well with PSG, which had unexpected but significant respiratory sensing errors that led to misclassification of the respiratory disorder present. The wireless system could be used to select CHF patients for better-customized treatment at home as part of a specialist-supported community telemedicine programme.

Functional Analysis of a Type-I Ribosome Inactivating Protein Balsamin from Momordica balsamina with Anti-Microbial and DNase Activity.

PubMed

Ajji, Parminder Kaur; Walder, Ken; Puri, Munish

2016-09-01

Ribosome inactivating proteins (RIPs) have received considerable attention in biomedical research because of their unique activities towards tumor and virus-infected cells. We extracted balsamin, a type-I RIP, from Momordica balsamina. In the present study, a detailed investigation on DNase activity, antioxidant capacity and antibacterial activity was conducted using purified balsamin. DNase-like activity of balsamin towards plasmid DNA was pH, incubation time and temperature dependent. Moreover, the presence of Mg(2+) (10-50 mM) influenced the DNA cleavage activity. Balsamin also demonstrated reducing power and a capacity to scavenge free radicals in a dose dependent manner. Furthermore, the protein exhibited antibacterial activity against Staphylococcus aureus, Salmonella enterica, Staphylococcus epidermidis and Escherichia coli, which suggests potential utility of balsamin as a nutraceutical.

Structural re-alignment in an immunologic surface region of ricin A chain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zemla, A T; Zhou, C E

2007-07-24

We compared structure alignments generated by several protein structure comparison programs to determine whether existing methods would satisfactorily align residues at a highly conserved position within an immunogenic loop in ribosome inactivating proteins (RIPs). Using default settings, structure alignments generated by several programs (CE, DaliLite, FATCAT, LGA, MAMMOTH, MATRAS, SHEBA, SSM) failed to align the respective conserved residues, although LGA reported correct residue-residue (R-R) correspondences when the beta-carbon (Cb) position was used as the point of reference in the alignment calculations. Further tests using variable points of reference indicated that points distal from the beta carbon along a vector connectingmore » the alpha and beta carbons yielded rigid structural alignments in which residues known to be highly conserved in RIPs were reported as corresponding residues in structural comparisons between ricin A chain, abrin-A, and other RIPs. Results suggest that approaches to structure alignment employing alternate point representations corresponding to side chain position may yield structure alignments that are more consistent with observed conservation of functional surface residues than do standard alignment programs, which apply uniform criteria for alignment (i.e., alpha carbon (Ca) as point of reference) along the entirety of the peptide chain. We present the results of tests that suggest the utility of allowing user-specified points of reference in generating alternate structural alignments, and we present a web server for automatically generating such alignments.« less

BH3 mimetic Obatoclax (GX15-070) mediates mitochondrial stress predominantly via MCL-1 inhibition and induces autophagy-dependent necroptosis in human oral cancer cells

PubMed Central

Sulkshane, Prasad; Teni, Tanuja

2017-01-01

We have previously reported overexpression of antiapoptotic MCL-1 protein in human oral cancers and its association with therapy resistance and poor prognosis, implying it to be a potential therapeutic target. Hence, we investigated the efficacy and mechanism of action of Obatoclax, a BH3 mimetic pan BCL-2 inhibitor in human oral cancer cell lines. All cell lines exhibited high sensitivity to Obatoclax with complete clonogenic inhibition at 200–400 nM concentration which correlated with their MCL-1 expression. Mechanistic insights revealed that Obatoclax induced a caspase-independent cell death primarily by induction of a defective autophagy. Suppression of autophagy by ATG5 downregulation significantly blocked Obatoclax-induced cell death. Further, Obatoclax induced interaction of p62 with key components of the necrosome RIP1K and RIP3K. Necrostatin-1 mediated inhibition of RIP1K significantly protected the cells from Obatoclax induced cell death. Moreover, Obatoclax caused extensive mitochondrial stress leading to their dysfunction. Interestingly, MCL-1 downregulation alone caused mitochondrial stress, highlighting its importance for mitochondrial homeostasis. We also demonstrated in vivo efficacy of Obatoclax against oral cancer xenografts and its synergism with ionizing radiation in vitro. Our studies thus suggest that Obatoclax induces autophagy-dependent necroptosis in oral cancer cells and holds a great promise in the improved management of oral cancer patients. PMID:28947954

Parasitic production of slow RI-beam from a projectile fragment separator by ion guide Laser Ion Source (PALIS)

NASA Astrophysics Data System (ADS)

Sonoda, Tetsu

2009-10-01

The projectile fragment separator BigRIPS of RIBF at RIKEN provides a wide variety of short-lived radioactive isotope (RI) ions without restrictions on their lifetime or chemical properties. A universal slow RI-beam facility (SLOWRI) to decelerate the beams from BigRIPS using an RF-carpet ion guide has been proposed as a principal facility of RIBF. However, beam time at such a modern accelerator facility is always limited and operational costs are high. We therefore propose an additional scheme as a complementary option to SLOWRI to drastically enhance the usability of such an expensive facility. In BigRIPS, a single primary beam produces thousands of isotopes but only one isotope is used for an experiment while the other >99.99% of isotopes are simply dumped in the slits or elsewhere in the fragment separator. We plan to locate a compact gas cell with 1 bar Ar at the slits. The thermalized ions in the cell will be quickly neutralized and transported to the exit by gas flow and resonantly re-ionized by lasers. Such low energy RI-beams will always be provided without any restriction to the main experiment. It will allow us to run parasitic experiments for precision atomic or decay spectroscopy, mass measurements. Furthermore, the resonance ionization in the cell itself can be used for high-sensitive laser spectroscopy, which will expand our knowledge of the ground state property of unstable nuclei.

Inhibition of c-Met reduces lymphatic metastasis in RIP-Tag2 transgenic mice

PubMed Central

Sennino, Barbara; Ishiguro-Oonuma, Toshina; Schriver, Brian J.; Christensen, James G.; McDonald, Donald M.

2013-01-01

Inhibition of vascular endothelial growth factor (VEGF) signaling can promote lymph node metastasis in preclinical models, but the mechanism is not fully understood, and successful methods of prevention have not been found. Signaling of hepatocyte growth factor (HGF) and its receptor c-Met can promote the growth of lymphatics and metastasis of some tumors. We sought to explore the contributions of c-Met signaling to lymph node metastasis after inhibition of VEGF signaling. In particular, we examined whether c-Met is upregulated in lymphatics in or near pancreatic neuroendocrine tumors in RIP-Tag2 transgenic mice and whether lymph node metastasis can be reduced by concurrent inhibition of VEGF and c-Met signaling. Inhibition of VEGF signaling by anti-VEGF antibody or sunitinib in mice from age 14 to 17 weeks was accompanied by more intratumoral lymphatics, more tumor cells inside lymphatics, and more lymph node metastases. Under these conditions, lymphatic endothelial cells - like tumor cells - had strong immunoreactivity for c-Met and phospho-c-Met. c-Met blockade by the selective inhibitor PF-04217903 significantly reduced metastasis to local lymph nodes. Together, these results indicate that inhibition of VEGF signaling in RIP-Tag2 mice upregulates c-Met expression in lymphatic endothelial cells, increases the number of intratumoral lymphatics and number of tumor cells within lymphatics, and promotes metastasis to local lymph nodes. Prevention of lymph node metastasis by PF-04217903 in this setting implicates c-Met signaling in tumor cell spread to lymph nodes. PMID:23576559

New indicators based on personnel cost for management efficiency in a hospital.

PubMed

Nakagawa, Yoshiaki; Yoshihara, Hiroyuki; Nakagawa, Yoshinobu

2011-08-01

A simple and fair benchmarking system or financial indicators for use on the clinical department level have been lacking to evaluate the management efficiency and activity of each clinical department or division of a hospital. New financial indicators have therefore been developed based on personnel costs. Indicator 1: The ratio of marginal profit after personnel cost per personnel cost (RMP). Indicator 2: The ratio of investment (=indirect cost) per personnel cost (RIP). The difference between RMP and RIP demonstrates the operation profit in US Dollars for personnel cost (OPP). A turning point in profitability similar to the break-even point (BEP) and break-even ratio (BER) could be also defined by the combination of the RMP and RIP. The merits of these two indicators are not only the ability to indicate the relationship between the medical profit and the investments in the hospital, but also the capability to demonstrate such indicators as BEP, BER and OPP on a single graph. The two indicators were applied to the hospitals in the National Hospital Organization and to the clinical department in one hospital. Using these two indicators, it was possible to evaluate the management efficiency and medical activity not only in the whole hospital but also in each department and DPC/DRG group. This will be of use to a manager of a hospital in checking the management efficiency of his/her hospital despite the variations among hospitals, departments and divisions.

Type-I interferon signaling through ISGF3 complex is required for sustained Rip3 activation and necroptosis in macrophages.

PubMed

McComb, Scott; Cessford, Erin; Alturki, Norah A; Joseph, Julie; Shutinoski, Bojan; Startek, Justyna B; Gamero, Ana M; Mossman, Karen L; Sad, Subash

2014-08-05

Myeloid cells play a critical role in perpetuating inflammation during various chronic diseases. Recently the death of macrophages through programmed necrosis (necroptosis) has emerged as an important mechanism in inflammation and pathology. We evaluated the mechanisms that lead to the induction of necrotic cell death in macrophages. Our results indicate that type I IFN (IFN-I) signaling is a predominant mechanism of necroptosis, because macrophages deficient in IFN-α receptor type I (IFNAR1) are highly resistant to necroptosis after stimulation with LPS, polyinosinic-polycytidylic acid, TNF-α, or IFN-β in the presence of caspase inhibitors. IFN-I-induced necroptosis occurred through both mechanisms dependent on and independent of Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) and led to persistent phosphorylation of receptor-interacting protein 3 (Rip3) kinase, which resulted in potent necroptosis. Although various IFN-regulatory factors (IRFs) facilitated the induction of necroptosis in response to IFN-β, IRF-9-STAT1- or -STAT2-deficient macrophages were highly resistant to necroptosis. Our results indicate that IFN-β-induced necroptosis of macrophages proceeds through tonic IFN-stimulated gene factor 3 (ISGF3) signaling, which leads to persistent expression of STAT1, STAT2, and IRF9. Induction of IFNAR1/Rip3-dependent necroptosis also resulted in potent inflammatory pathology in vivo. These results reveal how IFN-I mediates acute inflammation through macrophage necroptosis.

Type-I interferon signaling through ISGF3 complex is required for sustained Rip3 activation and necroptosis in macrophages

PubMed Central

McComb, Scott; Cessford, Erin; Alturki, Norah A.; Joseph, Julie; Shutinoski, Bojan; Startek, Justyna B.; Gamero, Ana M.; Mossman, Karen L.; Sad, Subash

2014-01-01

Myeloid cells play a critical role in perpetuating inflammation during various chronic diseases. Recently the death of macrophages through programmed necrosis (necroptosis) has emerged as an important mechanism in inflammation and pathology. We evaluated the mechanisms that lead to the induction of necrotic cell death in macrophages. Our results indicate that type I IFN (IFN-I) signaling is a predominant mechanism of necroptosis, because macrophages deficient in IFN-α receptor type I (IFNAR1) are highly resistant to necroptosis after stimulation with LPS, polyinosinic-polycytidylic acid, TNF-α, or IFN-β in the presence of caspase inhibitors. IFN-I–induced necroptosis occurred through both mechanisms dependent on and independent of Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) and led to persistent phosphorylation of receptor-interacting protein 3 (Rip3) kinase, which resulted in potent necroptosis. Although various IFN-regulatory factors (IRFs) facilitated the induction of necroptosis in response to IFN−β, IRF-9–STAT1– or -STAT2–deficient macrophages were highly resistant to necroptosis. Our results indicate that IFN-β–induced necroptosis of macrophages proceeds through tonic IFN-stimulated gene factor 3 (ISGF3) signaling, which leads to persistent expression of STAT1, STAT2, and IRF9. Induction of IFNAR1/Rip3–dependent necroptosis also resulted in potent inflammatory pathology in vivo. These results reveal how IFN-I mediates acute inflammation through macrophage necroptosis. PMID:25049377

Inhibition of insulin-like growth factor receptor-1 reduces necroptosis-related markers and attenuates LPS-induced lung injury in mice.

PubMed

Lee, Su Hwan; Shin, Ju Hye; Song, Joo Han; Leem, Ah Young; Park, Moo Suk; Kim, Young Sam; Chang, Joon; Chung, Kyung Soo

2018-04-15

Insulin-like growth factor-1 (IGF-1) levels are known to increase in the bronchoalveolar lavage fluid (BALF) of patients with acute respiratory distress syndrome. Herein, we investigated the role of IGF-1 in lipopolysaccharide (LPS)-induced lung injury. In LPS-treated cells, expressions of receptor-interacting protein 3 (RIP3) and phosphorylated mixed lineage kinase domain-like protein (MLKL) were decreased in IGF-1 receptor small interfering RNA (siRNA)-treated cells compared to control cells. The levels of pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, IL-10, tumour necrosis factor-α, and macrophage inflammatory protein 2/C-X-C motif chemokine ligand 2 in the supernatant were significantly reduced in IGF-1 receptor siRNA-treated cells compared to control cells. In LPS-induced murine lung injury model, total cell counts, polymorphonuclear leukocytes counts, and pro-inflammatory cytokine levels in the BALF were significantly lower and histologically detected lung injury was less common in the group treated with IGF-1 receptor monoclonal antibody compared to the non-treated group. On western blotting, RIP3 and phosphorylated MLKL expressions were relatively decreased in the IGF-1 receptor monoclonal antibody group compared to the non-treated group. IGF-1 may be associated with RIP3-mediated necroptosis in vitro, while blocking of the IGF-1 pathway may reduce LPS-induced lung injuries in vivo. Copyright © 2018 Elsevier Inc. All rights reserved.

JMJD3 Is Crucial for the Female AVPV RIP-Cre Neuron-Controlled Kisspeptin-Estrogen Feedback Loop and Reproductive Function.

PubMed

Song, Anying; Jiang, Shujun; Wang, Qinghua; Zou, Jianghuan; Lin, Zhaoyu; Gao, Xiang

2017-06-01

The hypothalamic-pituitary-gonadal axis controls development, reproduction, and metabolism. Although most studies have focused on the hierarchy from the brain to the gonad, many questions remain unresolved concerning the feedback from the gonad to the central nervous system, especially regarding the potential epigenetic modifications in hypothalamic neurons. In the present report, we generated genetically modified mice lacking histone H3 lysine 27 (H3K27) demethylase Jumonji domain-containing 3 (JMJD3) in hypothalamic rat-insulin-promoter-expressing neurons (RIP-Cre neurons). The female mutant mice displayed late-onset obesity owing to reduced locomotor activity and decreased energy expenditure. JMJD3 deficiency in RIP-Cre neurons also results in delayed pubertal onset, an irregular estrous cycle, impaired fertility, and accelerated ovarian failure in female mice owing to the dysregulation of the hypothalamic-ovarian axis. We found that JMJD3 directly regulates Kiss1 gene expression by binding to the Kiss1 promoter and triggering H3K27me3 demethylation in the anteroventral periventricular (AVPV) nucleus. Further study confirmed that the aberrations arose from impaired kisspeptin signaling in the hypothalamic AVPV nucleus and subsequent estrogen deficiency. Estrogen replacement therapy can reverse obesity in mutant mice. Moreover, we demonstrated that Jmjd3 is an estrogen target gene in the hypothalamus. These results provide direct genetic and molecular evidence that JMJD3 is a key mediator for the kisspeptin-estrogen feedback loop. Copyright © 2017 Endocrine Society.

40 CFR 230.23 - Current patterns and water circulation.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 26 2013-07-01 2013-07-01 false Current patterns and water circulation. 230.23 Section 230.23 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) OCEAN DUMPING SECTION 404(b)(1) GUIDELINES FOR SPECIFICATION OF DISPOSAL SITES FOR DREDGED OR FILL MATERIAL Potential Impacts on Physical and Chemical...

40 CFR 230.23 - Current patterns and water circulation.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Current patterns and water circulation. 230.23 Section 230.23 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) OCEAN DUMPING SECTION 404(b)(1) GUIDELINES FOR SPECIFICATION OF DISPOSAL SITES FOR DREDGED OR FILL MATERIAL Potential Impacts on Physical and Chemical...

Pressure-gradient-driven nearshore circulation on a beach influenced by a large inlet-tidal shoal system

USGS Publications Warehouse

Shi, F.; Hanes, D.M.; Kirby, J.T.; Erikson, L.; Barnard, P.; Eshleman, J.

2011-01-01

The nearshore circulation induced by a focused pattern of surface gravity waves is studied at a beach adjacent to a major inlet with a large ebb tidal shoal. Using a coupled wave and wave-averaged nearshore circulation model, it is found that the nearshore circulation is significantly affected by the heterogeneous wave patterns caused by wave refraction over the ebb tidal shoal. The model is used to predict waves and currents during field experiments conducted near the mouth of San Francisco Bay and nearby Ocean Beach. The field measurements indicate strong spatial variations in current magnitude and direction and in wave height and direction along Ocean Beach and across the ebb tidal shoal. Numerical simulations suggest that wave refraction over the ebb tidal shoal causes wave focusing toward a narrow region at Ocean Beach. Due to the resulting spatial variation in nearshore wave height, wave-induced setup exhibits a strong alongshore nonuniformity, resulting in a dramatic change in the pressure field compared to a simulation with only tidal forcing. The analysis of momentum balances inside the surf zone shows that, under wave conditions with intensive wave focusing, the alongshore pressure gradient associated with alongshore nonuniform wave setup can be a dominant force driving circulation, inducing heterogeneous alongshore currents. Pressure-gradient- forced alongshore currents can exhibit flow reversals and flow convergence or divergence, in contrast to the uniform alongshore currents typically caused by tides or homogeneous waves.

Circulation in the Philippine Archipelago. Simulated by 1/12 deg. and 1/25 deg. Global HYCOM and EAS NCOM

DTIC Science & Technology

2011-03-01

DATE (DD-MM- YYYY) 02-16-2011 2. REPORT TYPE Journal Article 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Circulation in the... circulation . This archipelago provides two secondary routes for both the Indonesian throughflow and the western boundary current of the Pacific...Philippine Archipelago circulation , Philippine straits, Mindoro Strait transport, Indonesian throughflow 16. SECURITY CLASSIFICATION OF: a

The atmospheric ocean: eddies and jets in the Antarctic Circumpolar Current.

PubMed

Thompson, Andrew F

2008-12-28

Although the Antarctic Circumpolar Current (ACC) is the longest and the strongest oceanic current on the Earth and is the primary means of inter-basin exchange, it remains one of the most poorly represented components of global climate models. Accurately describing the circulation of the ACC is made difficult owing to the prominent role that mesoscale eddies and jets, oceanic equivalents of atmospheric storms and storm tracks, have in setting the density structure and transport properties of the current. The successes and limitations of different representations of eddy processes in models of the ACC are considered, with particular attention given to how the circulation responds to changes in wind forcing. The dynamics of energetic eddies and topographically steered jets may both temper and enhance the sensitivity of different aspects of the ACC's circulation to changes in climate.

ASTER Images Aftermath of U.S. Tornado Outbreak

NASA Image and Video Library

2011-05-06

From April 25-28, 2011, one of the largest outbreaks of tornadoes ever recorded ripped across the Southern, Midwestern and Eastern United States. NASA Terra spacecraft shows the scar the tornado left across Birmingham, Alabama.

Pathways and Hydrography in the Mesoamerican Barrier Reef System Part 1: Circulation

NASA Astrophysics Data System (ADS)

Carrillo, L.; Johns, E. M.; Smith, R. H.; Lamkin, J. T.; Largier, J. L.

2015-10-01

Acoustic Doppler Current Profiler (ADCP) measurements and surface drifters released from two oceanographic cruises conducted during March 2006 and January/February 2007 are used to investigate the circulation off the Mesoamerican Barrier Reef System (MBRS). We show that the MBRS circulation can be divided into two distinct regimes, a northern region dominated by the strong, northward-flowing Yucatan Current, and a southern region with weaker southward coastal currents and the presence of the Honduras Gyre. The latitude of impingement of the Cayman Current onto the coastline varies with time, and creates a third region, which acts as a boundary between the northern and southern circulation regimes. This circulation pattern yields two zones in terms of dispersal, with planktonic propagules in the northern region being rapidly exported to the north, whereas plankton in the southern and impingement regions may be retained locally or regionally. The latitude of the impingement region shifts interannually and intra-annually up to 3° in latitude. Sub-mesoscale features are observed in association with topography, e.g., flow bifurcation around Cozumel Island, flow wake north of Chinchorro Bank and separation of flow from the coast just north of Bahia de la Ascencion. This third feature is evident as cyclonic recirculation in coastal waters, which we call the Ascencion-Cozumel Coastal Eddy. An understanding of the implications of these different circulation regimes on water mass distributions, population connectivity, and the fate of land-based pollutants in the MBRS is critically important to better inform science-based resource management and conservation plans for the MBRS coral reefs.

South Atlantic Ocean circulation: Simulation experiments with a quasi-geostrophic model and assimilation of TOPEX/POSEIDON and ERS 1 altimeter data

NASA Astrophysics Data System (ADS)

Florenchie, P.; Verron, J.

1998-10-01

Simulation experiments of South Atlantic Ocean circulations are conducted with a 1/6°, four-layered, quasi-geostrophic model. By means of a simple nudging data assimilation procedure along satellite tracks, TOPEX/POSEIDON and ERS 1 altimeter measurements are introduced into the model to control the simulation of the basin-scale circulation for the period from October 1992 to September 1994. The model circulation appears to be strongly influenced by the introduction of altimeter data, offering a consistent picture of South Atlantic Ocean circulations. Comparisons with observations show that the assimilating model successfully simulates the kinematic behavior of a large number of surface circulation components. The assimilation procedure enables us to produce schematic diagrams of South Atlantic circulation in which patterns ranging from basin-scale currents to mesoscale eddies are portrayed in a realistic way, with respect to their complexity. The major features of the South Atlantic circulation are described and analyzed, with special emphasis on the Brazil-Malvinas Confluence region, the Subtropical Gyre with the formation of frontal structures, and the Agulhas Retroflection. The Agulhas eddy-shedding process has been studied extensively. Fourteen eddies appear to be shed during the 2-year experiment. Because of their strong surface topographic signature, Agulhas eddies have been tracked continuously during the assimilation experiment as they cross the South Atlantic basin westward. Other effects of the assimilation procedure are shown, such as the intensification of the Subtropical Gyre, the appearance of a strong seasonal cycle in the Brazil Current transport, and the increase of the mean Brazil Current transport. This last result, combined with the westward oriention of the Agulhas eddies' trajectories, leads to a southward transport of mean eddy kinetic energy across 30°S.

PAX4 preserves endoplasmic reticulum integrity preventing beta cell degeneration in a mouse model of type 1 diabetes mellitus.

PubMed

Mellado-Gil, José Manuel; Jiménez-Moreno, Carmen María; Martin-Montalvo, Alejandro; Alvarez-Mercado, Ana Isabel; Fuente-Martin, Esther; Cobo-Vuilleumier, Nadia; Lorenzo, Petra Isabel; Bru-Tari, Eva; Herrera-Gómez, Irene de Gracia; López-Noriega, Livia; Pérez-Florido, Javier; Santoyo-López, Javier; Spyrantis, Andreas; Meda, Paolo; Boehm, Bernhard O; Quesada, Ivan; Gauthier, Benoit R

2016-04-01

A strategy to enhance pancreatic islet functional beta cell mass (BCM) while restraining inflammation, through the manipulation of molecular and cellular targets, would provide a means to counteract the deteriorating glycaemic control associated with diabetes mellitus. The aims of the current study were to investigate the therapeutic potential of such a target, the islet-enriched and diabetes-linked transcription factor paired box 4 (PAX4), to restrain experimental autoimmune diabetes (EAD) in the RIP-B7.1 mouse model background and to characterise putative cellular mechanisms associated with preserved BCM. Two groups of RIP-B7.1 mice were genetically engineered to: (1) conditionally express either PAX4 (BPTL) or its diabetes-linked mutant variant R129W (mutBPTL) using doxycycline (DOX); and (2) constitutively express luciferase in beta cells through the use of RIP. Mice were treated or not with DOX, and EAD was induced by immunisation with a murine preproinsulin II cDNA expression plasmid. The development of hyperglycaemia was monitored for up to 4 weeks following immunisation and alterations in the BCM were assessed weekly by non-invasive in vivo bioluminescence intensity (BLI). In parallel, BCM, islet cell proliferation and apoptosis were evaluated by immunocytochemistry. Alterations in PAX4- and PAX4R129W-mediated islet gene expression were investigated by microarray profiling. PAX4 preservation of endoplasmic reticulum (ER) homeostasis was assessed using thapsigargin, electron microscopy and intracellular calcium measurements. PAX4 overexpression blunted EAD, whereas the diabetes-linked mutant variant PAX4R129W did not convey protection. PAX4-expressing islets exhibited reduced insulitis and decreased beta cell apoptosis, correlating with diminished DNA damage and increased islet cell proliferation. Microarray profiling revealed that PAX4 but not PAX4R129W targeted expression of genes implicated in cell cycle and ER homeostasis. Consistent with the latter, islets overexpressing PAX4 were protected against thapsigargin-mediated ER-stress-related apoptosis. Luminal swelling associated with ER stress induced by thapsigargin was rescued in PAX4-overexpressing beta cells, correlating with preserved cytosolic calcium oscillations in response to glucose. In contrast, RNA interference mediated repression of PAX4-sensitised MIN6 cells to thapsigargin cell death. The coordinated regulation of distinct cellular pathways particularly related to ER homeostasis by PAX4 not achieved by the mutant variant PAX4R129W alleviates beta cell degeneration and protects against diabetes mellitus. The raw data for the RNA microarray described herein are accessible in the Gene Expression Omnibus database under accession number GSE62846.

Meridional Circulation Dynamics from 3D Magnetohydrodynamic Global Simulations of Solar Convection

NASA Astrophysics Data System (ADS)

Passos, Dário; Charbonneau, Paul; Miesch, Mark

2015-02-01

The form of solar meridional circulation is a very important ingredient for mean field flux transport dynamo models. However, a shroud of mystery still surrounds this large-scale flow, given that its measurement using current helioseismic techniques is challenging. In this work, we use results from three-dimensional global simulations of solar convection to infer the dynamical behavior of the established meridional circulation. We make a direct comparison between the meridional circulation that arises in these simulations and the latest observations. Based on our results, we argue that there should be an equatorward flow at the base of the convection zone at mid-latitudes, below the current maximum depth helioseismic measures can probe (0.75 {{R}⊙ }). We also provide physical arguments to justify this behavior. The simulations indicate that the meridional circulation undergoes substantial changes in morphology as the magnetic cycle unfolds. We close by discussing the importance of these dynamical changes for current methods of observation which involve long averaging periods of helioseismic data. Also noteworthy is the fact that these topological changes indicate a rich interaction between magnetic fields and plasma flows, which challenges the ubiquitous kinematic approach used in the vast majority of mean field dynamo simulations.

Ocean circulation studies

NASA Technical Reports Server (NTRS)

Koblinsky, C. J.

1984-01-01

Remotely sensed signatures of ocean surface characteristics from active and passive satellite-borne radiometers in conjunction with in situ data were utilized to examine the large scale, low frequency circulation of the world's oceans. Studies of the California Current, the Gulf of California, and the Kuroshio Extension Current in the western North Pacific were reviewed briefly. The importance of satellite oceanographic tools was emphasized.

Oridonin enhances the cytotoxicity of 5-FU in renal carcinoma cells by inducting necroptotic death.

PubMed

Zheng, Wei; Zhou, Chun-Yan; Zhu, Xin-Qing; Wang, Xue-Jian; Li, Zi-Yao; Chen, Xiao-Chi; Chen, Feng; Che, Xiang-Yu; Xie, Xin

2018-06-26

5-fluorouracil (5-FU) is widely used for the treatment of renal carcinoma. However, drug resistance remains the reason for failure of chemotherapy. Oridonin, extracted from Chinese herb medicine, displays anti-tumor effect in several types of cancer. Whether oridonin could enhance the effect of 5-FU in renal carcinoma has not been studied. 786-O cells were used in the current study. Cell death was measured by MTT assay or live- and dead-cell staining assay. Glutathione (GSH) level was examined by ELISA. Necroptosis was identified by protein levels of receptors interaction protein-1 (RIP-1) and RIP-3, lactate dehydrogenase (LDH) and high mobility group box-1 protein (HMGB1) release, and poly [ADP-ribose] polymerase-1 (Parp-1) activity. Using a xenograft assay in nude mice, we tested the anti-tumor effects of the oridonin combined with 5-FU. 5-FU only induced apoptosis in 786-O cells. Oridonin activated both apoptosis and necroptosis in 786-O cells. Oridonin-induced necroptosis was reversed by addition of GSH or its precursorN-acetylcysteine (NAC). Oridonin-induced necroptosis was associated by activated JNK, p38, and ERK in 786-O cells, which were abolished by GSH or NAC treatment. However, JNK, p38, and ERK inhibitors showed no effect on oridonin induced-cell death. GSH or NAC treatment partly abolished the synergistic effects of oridonin and 5-FU on cell death. Oridonin enhanced the cytotoxicity of 5-FU both in vitro and in vivo. Oridonin enhances the cytotoxicity of 5-FU in renal cancer cells partially through inducing necroptosis, providing evidence of using necroptosis inducers in combination with chemotherapeutic agents for cancer treatment. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Linear thermal circulator based on Coriolis forces.

PubMed

Li, Huanan; Kottos, Tsampikos

2015-02-01

We show that the presence of a Coriolis force in a rotating linear lattice imposes a nonreciprocal propagation of the phononic heat carriers. Using this effect we propose the concept of Coriolis linear thermal circulator which can control the circulation of a heat current. A simple model of three coupled harmonic masses on a rotating platform permits us to demonstrate giant circulating rectification effects for moderate values of the angular velocities of the platform.

Radiation and Dissipation of Internal Waves Generated by Geostrophic Motions Impinging on Small-Scale Topography

DTIC Science & Technology

2009-02-01

the largest zonal current in the world, which links the Atlantic , Indian and Pacific Oceans. The associated Meridional Overturning Circulation (MOC...formed in polar regions (Wunsch and Ferrari, 2004). Mixing is especially important in the Southern Ocean where the Meridional Overturning Circulation ...general circulation of the ocean and an important driver of the lower cell of the Meridional Overturning Circulation . Wunsch (1998) estimated that the

ENGINEERING DEVELOPMENT UNIT SOLAR SAIL

NASA Image and Video Library

2016-01-13

TIFFANY LOCKETT OVERSEES THE HALF SCALE (36 SQUARE METERS) ENGINEERING DEVELOPMENT UNIT (EDU) SOLAR SAIL DEPLOYMENT DEMONSTRATION IN PREPARATION FOR FULL SCALE EDU (86 SQUARE METERS) DEPLOYMENT IN APRIL, 2016. DETAILS OF RIPS AND HOLES IN SOLAR SAIL FABRIC.

[Simulation and data mining model for identifying and prediction budget changes in the care of patients with hypertension].

PubMed

Joyanes-Aguilar, Luis; Castaño, Néstor J; Osorio, José H

2015-10-01

Objective To present a simulation model that establishes the economic impact to the health care system produced by the diagnostic evolution of patients suffering from arterial hypertension. Methodology The information used corresponds to that available in Individual Health Records (RIPs, in Spanish). A statistical characterization was carried out and a model for matrix storage in MATLAB was proposed. Data mining was used to create predictors. Finally, a simulation environment was built to determine the economic cost of diagnostic evolution. Results 5.7 % of the population progresses from the diagnosis, and the cost overrun associated with it is 43.2 %. Conclusions Results shows the applicability and possibility of focussing research on establishing diagnosis relationships using all the information reported in the RIPS in order to create econometric indicators that can determine which diagnostic evolutions are most relevant to budget allocation.

Atomic Force Microscopy for Investigation of Ribosome-inactivating Proteins' Type II Tetramerization

NASA Astrophysics Data System (ADS)

Savvateev, M.; Kozlovskaya, N.; Moisenovich, M.; Tonevitsky, A.; Agapov, I.; Maluchenko, N.; Bykov, V.; Kirpichnikov, M.

2003-12-01

Biology of the toxins violently depends on their carbohydrate-binding centres' organization. Toxin tetramerization can lead to both increasing of lectin-binding centres' number and changes in their structural organization. A number and three-dimensional localization of such centres per one molecule strongly influence on toxins' biological properties. Ricin was used to obtain the AFM images of natural dimeric RIPsII structures as far as ricinus agglutinin was used for achievement of AFM images of natural tetrameric RIPsII forms. It is well-known that viscumin (60 kDa) has a property to form tetrameric structures dependently on ambient conditions and its concentration. Usage of the model dimer-tetramer based on ricin-agglutinin allowed to identify viscumin tetramers in AFM scans and to differ them from dimeric viscumin structures. Quantification analysis produced with the NT-MDT software allowed to estimate the geometrical parameters of ricin, ricinus agglutinin and viscumin molecules.

Necroptotic cells release find-me signal and are engulfed without proinflammatory cytokine production.

PubMed

Wang, Qiang; Ju, Xiaoli; Zhou, Yang; Chen, Keping

2015-11-01

Necroptosis is a form of caspase-independent programmed cell death which is mediated by the RIP1-RIP3 complex. Although phagocytosis of apoptotic cells has been extensively investigated, how necroptotic cells are engulfed has remained elusive. Here, we investigated how necroptotic cells attracted and were engulfed by macrophages. We found that necroptotic cells induced the migration of THP-1 cells in a transwell migration assay. Further analysis showed that ATP released from necroptotic cells acted as a find-me signal that induced the migration of THP-1 cells. We also found that Annexin V blocked phagocytosis of necroptotic cells by macrophages. Furthermore, necroptotic cells were shown to be silently cleared by macrophages without any proinflammatory cytokine production. These data uncover an evolutionarily conserved mechanism of the find-me signal in different types of cell death and immunological consequences between apoptotic and necroptotic cells during phagocytosis.