An agonistic anti-Tie2 antibody suppresses the normal-to-tumor vascular transition in the glioblastoma invasion zone

Tumor progression is intimately associated with the vasculature, as tumor proliferation induces angiogenesis and tumor cells metastasize to distant organs via blood vessels. However, whether tumor invasion is associated with blood vessels remains unknown. As glioblastoma (GBM) is featured by aggressive invasion and vascular abnormalities, we characterized the onset of vascular remodeling in the diffuse tumor infiltrating zone by establishing new spontaneous GBM models with robust invasion capacity. Normal brain vessels underwent a gradual transition to severely impaired tumor vessels at the GBM periphery over several days. Increasing vasodilation from the tumor periphery to the tumor core was also found in human GBM. The levels of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) showed a spatial correlation with the extent of vascular abnormalities spanning the tumor-invading zone. Blockade of VEGFR2 suppressed vascular remodeling at the tumor periphery, confirming the role of VEGF-VEGFR2 signaling in the invasion-associated vascular transition. As angiopoietin-2 (ANGPT2) was expressed in only a portion of the central tumor vessels, we developed a ligand-independent tunica interna endothelial cell kinase 2 (Tie2)-activating antibody that can result in Tie2 phosphorylation in vivo. This agonistic anti-Tie2 antibody effectively normalized the vasculature in both the tumor periphery and tumor center, similar to the effects of VEGFR2 blockade. Mechanistically, this antibody-based Tie2 activation induced VE-PTP-mediated VEGFR2 dephosphorylation in vivo. Thus, our study reveals that the normal-to-tumor vascular transition is spatiotemporally associated with GBM invasion and may be controlled by Tie2 activation via a novel mechanism of action.Subject terms: Tumour angiogenesis, CNS cancer, Targeted therapies     

Evidence of a Uranium-Paddlewheel Node in a Catecholate-Based Metal–Organic Framework

The interactions between uranium and non-innocent organic species are an essential component of fundamental uranium redox chemistry. However, they have seldom been explored in the context of multidimensional, porous materials. Uranium-based metal–organic frameworks (MOFs) offer a new angle to study these interactions, as these self-assembled species stabilize uranium species through immobilization by organic linkers within a crystalline framework, while potentially providing a method for adjusting metal oxidation state through coordination of non-innocent linkers. We report the synthesis of the MOF NU-1700 , assembled from U⁴⁺-paddlewheel nodes and catecholate-based linkers. We propose this highly unusual structure, which contains two U⁴⁺ ions in a paddlewheel built from four linkers—a first among uranium materials—as a result of extensive characterization via powder X-ray diffraction (PXRD), sorption, transmission electron microscopy (TEM), and thermogravimetric analysis (TGA), in addition to density functional theory (DFT) calculations.     

Toward a Holistic Understanding and Models of Nonphotochemical Quenching Effects on In Vivo Fluorometry of Chlorophyll a in Coastal Waters

Nonphotochemical quenching (NPQ) is known to depress in vivo fluorescence (IVF) of chlorophyll a (Chla) in aquatic environments, which makes it difficult to interpret the hour-to-hour variations in Chla measured by in situ fluorometers. We hypothesized that ratios between quenched and unquenched IVF are a function of both NPQ and photochemical quenching. In this study, two diatom model species Thalassiosira pseudonana (CCMP1335) and Thalassiosira weissflogii (CCMP1047) incubated under a sinusoidal light:dark cycle were studied; IVF was recorded continuously, and Chla and photo-physiological variables were measured seven times a day. The maximal decline in Chla-specific IVF (IVF^B) attributable to quenching was 50% under the experimental settings. An NPQ and photochemical quenching-based modeling equation exhibited a better match to the measured IVF^B than equations representing the sole NPQ effect. Photochemical quenching induced by measuring light beam varied substantially during the day, and the part of the model for this process is excitation intensity-dependent (which is differed between models of in situ fluorometers, implying no straightforward method to correct Chla for all instrument models, instrument-specific parameterization is required). The forms of the IVF^B-light relationship are discussed as well. The findings foster a holistic understanding of NPQ effects on in vivo Chla fluorometry.     

Functionalized latexes as substrates for atom transfer radical polymerization

The application of atom transfer radical polymerization (ATRP) to the homopolymerization of 2‐hydroxyethyl acrylate and 2‐(methacryloyloxy) ethyl trimethylammonium chloride at the surface of a crosslinked polystyrene latex functionalized with alkyl bromide groups is reported. Polymerization was carried out using the surface groups of the dialyzed latex as initiators. The resulting hydrophobic core, hydrophilic shell latexes, were analyzed by FTIR, ¹³C‐NMR spectroscopy, and dynamic light scattering.     

Polymer electrostatics: detection and speciation of trapped electric charges by electric probe and analytical electron microscopy

This work reviews new probe and electron microscopy approaches for the detection of charged domains in insulating polymers, as well as for the identification of the charge-bearing species: scanning electric potential microscopy (SEPM), electric force microscopy (EFM) and energy-loss spectroscopy imaging in the transmission electron microscope (ESI-TEM). The SEPM and EFM micrographs show patterned domains bearing excess electric charges and extending for tens of nanometers, in polymer latex particles and films. The charged species are identified by ESI-TEM as emulsion polymerization initiator and surfactant residues, as well as the associated counter-ions. Charged domains are also observed in common thermoplastic polymers, producing unexpectedly large electric potential gradients.