Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability

Nitric oxide (NO) plays a critical role in vascular endothelial growth factor (VEGF)-induced angiogenesis and vascular hyperpermeability. However, the relative contribution of different NO synthase (NOS) isoforms to these processes is not known. Here, we evaluated the relative contributions of endothelial and inducible NOS (eNOS and iNOS, respectively) to angiogenesis and permeability of VEGF-induced angiogenic vessels. The contribution of eNOS was assessed by using an eNOS-deficient mouse, and iNOS contribution was assessed by using a selective inhibitor [l-N6-(1-iminoethyl) lysine, l-NIL] and an iNOS-deficient mouse. Angiogenesis was induced by VEGF in type I collagen gels placed in the mouse cranial window. Angiogenesis, vessel diameter, blood flow rate, and vascular permeability were proportional to NO levels measured with microelectrodes: Wild-type (WT) ≥ WT with l-NIL or iNOS−/− > eNOS−/− ≥ eNOS−/− with l-NIL. The role of NOS in VEGF-induced acute vascular permeability increase in quiescent vessels also was determined by using eNOS- and iNOS-deficient mice. VEGF superfusion significantly increased permeability in both WT and iNOS−/− mice but not in eNOS−/− mice. These findings suggest that eNOS plays a predominant role in VEGF-induced angiogenesis and vascular permeability. Thus, selective modulation of eNOS activity is a promising strategy for altering angiogenesis and vascular permeability in vivo.

Role of tumor–host interactions in interstitial diffusion of macromolecules: Cranial vs. subcutaneous tumors

The large size of many novel therapeutics impairs their transport through the tumor extracellular matrix and thus limits their therapeutic effectiveness. We propose that extracellular matrix composition, structure, and distribution determine the transport properties in tumors. Furthermore, because the characteristics of the extracellular matrix largely depend on the tumor–host interactions, we postulate that diffusion of macromolecules will vary with tumor type as well as anatomical location. Diffusion coefficients of macromolecules and liposomes in tumors growing in cranial windows (CWs) and dorsal chambers (DCs) were measured by fluorescence recovery after photobleaching. For the same tumor types, diffusion of large molecules was significantly faster in CW than in DC tumors. The greater diffusional hindrance in DC tumors was correlated with higher levels of collagen type I and its organization into fibrils. For molecules with diameters comparable to the interfibrillar space the diffusion was 5- to 10-fold slower in DC than in CW tumors. The slower diffusion in DC tumors was associated with a higher density of host stromal cells that synthesize and organize collagen type I. Our results point to the necessity of developing site-specific drug carriers to improve the delivery of molecular medicine to solid tumors.

Epstein–Barr virus latent-infection membrane proteins are palmitoylated and raft-associated: Protein 1 binds to the cytoskeleton through TNF receptor cytoplasmic factors

Epstein–Barr virus encodes integral membrane proteins LMP1 and LMP2A in transformed lymphoblastoid cell lines. We now find that LMP1 associates with the cell cytoskeleton through a tumor necrosis factor receptor-associated factor-interacting domain, most likely mediated by tumor necrosis factor receptor-associated factor 3. LMP1 is palmitoylated, and the transmembrane domains associate with lipid rafts. Mutation of LMP1 cysteine-78 abrogates palmitoylation but does not affect raft association or NF-κB or c-Jun N-terminal kinase activation. LMP2A also associates with rafts and is palmitoylated but does not associate with the cell cytoskeleton. The associations of LMP1 and LMP2A with rafts and of LMP1 with the cell cytoskeleton are likely to effect interactions with cell proteins involved in shape, motility, signal transduction, growth, and survival.

Tumor necrosis factor receptor associated factor 2 is a mediator of NF-kappa B activation by latent infection membrane protein 1, the Epstein-Barr virus transforming protein.

Latent infection membrane protein 1 (LMP1), the Epstein-Barr virus transforming protein, associates with tumor necrosis factor receptor (TNFR) associated factor 1 (TRAF1) and TRAF3. Since TRAF2 has been implicated in TNFR-mediated NF-kappa B activation, we have evaluated the role of TRAF2 in LMP1-mediated NF-kappa B activation. TRAF2 binds in vitro to the LMP1 carboxyl-terminal cytoplasmic domain (CT), coprecipitates with LMP1 in B lymphoblasts, and relocalizes to LMP1 plasma membrane patches. A dominant negative TRAF2 deletion mutant that lacks amino acids 6-86 (TRAF/ delta 6-86) inhibits NF-kappa B activation from the LMP1 CT and competes with TRAF2 for LMP1 binding. TRAF2 delta 6-86 inhibits NF-kappa B activation mediated by the first 45 amino acids of the LMP1 CT by more than 75% but inhibits NF-kappa B activation through the last 55 amino acids of the CT by less than 40%. A TRAF interacting protein, TANK, inhibits NF-kappa B activation by more than 70% from both LMP1 CT domains. These data implicate TRAF2 aggregation in NF-kappa B activation by the first 45 amino acids of the LMP1 CT and suggest that a different TRAF-related pathway may be involved in NF-kappa B activation by the last 55 amino acids of the LMP1 CT.

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Basic measurements of radiation from the Baseline Surface Radiation Network (BSRN) in the years 1992 to 2012, reference list of 6378 datasets

In the framework of the global energy balance, the radiative energy exchanges between Sun, Earth and space are now accurately quantified from new satellite missions. Much less is known about the magnitude of the energy flows within the climate system and at the Earth surface, which cannot be directly measured by satellites. In addition to satellite observations, here we make extensive use of the growing number of surface observations to constrain the global energy balance not only from space, but also from the surface. We combine these observations with the latest modeling efforts performed for the 5th IPCC assessment report to infer best estimates for the global mean surface radiative components. Our analyses favor global mean downward surface solar and thermal radiation values near 185 and 342 Wm**-2, respectively, which are most compatible with surface observations. Combined with an estimated surface absorbed solar radiation and thermal emission of 161 Wm**-2 and 397 Wm**-2, respectively, this leaves 106 Wm**-2 of surface net radiation available for distribution amongst the non-radiative surface energy balance components. The climate models overestimate the downward solar and underestimate the downward thermal radiation, thereby simulating nevertheless an adequate global mean surface net radiation by error compensation. This also suggests that, globally, the simulated surface sensible and latent heat fluxes, around 20 and 85 Wm**-2 on average, state realistic values. The findings of this study are compiled into a new global energy balance diagram, which may be able to reconcile currently disputed inconsistencies between energy and water cycle estimates.

Reference list of 265 sources used for the discovery of relationships between data clusters and metadata properties

Visual cluster analysis provides valuable tools that help analysts to understand large data sets in terms of representative clusters and relationships thereof. Often, the found clusters are to be understood in context of belonging categorical, numerical or textual metadata which are given for the data elements. While often not part of the clustering process, such metadata play an important role and need to be considered during the interactive cluster exploration process. Traditionally, linked-views allow to relate (or loosely speaking: correlate) clusters with metadata or other properties of the underlying cluster data. Manually inspecting the distribution of metadata for each cluster in a linked-view approach is tedious, specially for large data sets, where a large search problem arises. Fully interactive search for potentially useful or interesting cluster to metadata relationships may constitute a cumbersome and long process. To remedy this problem, we propose a novel approach for guiding users in discovering interesting relationships between clusters and associated metadata. Its goal is to guide the analyst through the potentially huge search space. We focus in our work on metadata of categorical type, which can be summarized for a cluster in form of a histogram. We start from a given visual cluster representation, and compute certain measures of interestingness defined on the distribution of metadata categories for the clusters. These measures are used to automatically score and rank the clusters for potential interestingness regarding the distribution of categorical metadata. Identified interesting relationships are highlighted in the visual cluster representation for easy inspection by the user. We present a system implementing an encompassing, yet extensible, set of interestingness scores for categorical metadata, which can also be extended to numerical metadata. Appropriate visual representations are provided for showing the visual correlations, as well as the calculated ranking scores. Focusing on clusters of time series data, we test our approach on a large real-world data set of time-oriented scientific research data, demonstrating how specific interesting views are automatically identified, supporting the analyst discovering interesting and visually understandable relationships.

Sedimentology of a Middle Jurassic Base-of-Slope environment, Cutri Formation, Mallorca

The Cutri Formation’s, type location, exposed in the NW of Mallorca, Spain has previously been described by Álvaro et al., (1989) and further interpreted by Abbots (1989) unpublished PhD thesis as a base-of-slope carbonate apron. Incorporating new field and laboratory analysis this paper enhances this interpretation. From this analysis, it can be shown without reasonable doubt that the Cutri Formation was deposited in a carbonate base-of-slope environment on the palaeowindward side of a Mid-Jurassic Tethyan platform. Key evidence such as laterally extensive exposures, abundant deposits of calciturbidtes and debris flows amongst hemipelagic deposits strongly support this interpretation.