The role of VEGF receptors in angiogenesis; complex partnerships

Abstract.: Vascular endothelial growth factors (VEGFs) regulate blood and lymphatic vessel development and homeostasis but also have profound effects on neural cells. VEGFs are predominantly produced by endothelial, hematopoietic and stromal cells in response to hypoxia and upon stimulation with growth factors such as transforming growth factors, interleukins or platelet-derived growth factor. VEGFs bind to three variants of type III receptor tyrosine kinases, VEGF receptor 1, 2 and 3. Each VEGF isoform binds to a particular subset of these receptors giving rise to the formation of receptor homo- and heterodimers that activate discrete signaling pathways. Signal specificity of VEGF receptors is further modulated upon recruitment of coreceptors, such as neuropilins, heparan sulfate, integrins or cadherins. Here we summarize the knowledge accumulated since the discovery of these proteins more than 20years ago with the emphasis on the signaling pathways activated by VEGF receptors in endothelial cells during cell migration, growth and differentiatio

Optimal Alignment Sensing of a Readout Mode Cleaner Cavity

Critically coupled resonant optical cavities are often used as mode cleaners in optical systems to improve the signal to noise ratio (SNR) of a signal that is encoded as an amplitude modulation of a laser beam. Achieving the best SNR requires maintaining the alignment of the mode cleaner relative to the laser beam on which the signal is encoded. An automatic alignment system which is primarily sensitive to the carrier field component of the beam will not, in general, provide optimal SNR. We present an approach that modifies traditional dither alignment sensing by applying a large amplitude modulation on the signal field, thereby producing error signals that are sensitive to the signal sideband field alignment. When used in conjunction with alignment actuators, this approach can improve the detected SNR; we demonstrate a factor of 3 improvement in the SNR of a kilometer-scale detector of the Laser Interferometer Gravitational-wave Observatory. This approach can be generalized to other types of alignment sensors

Postpartum osteoporosis associated with proximal tibial stress fracture

A 33-year-old woman presented with acute nonspecific knee pain, 6months postpartum. MR imaging, computed tomography and radiography were performed and a proximal tibia plateau insufficiency fracture was detected. Bone densitometry demonstrated mild postpartum osteoporosis. To our knowledge these findings have not been described in this location and in this clinical setting. The etiology of the atraumatic fracture of the tibia is presumed to be due to a low bone mineral density. The bone loss was probably due to pregnancy, lactation and postpartum hormonal changes. There were no other inciting causes and the patient was normocalcemic. We discuss the presence of a postpartum stress fracture in a hitherto undescribed site in a patient who had lactated following an uncomplicated pregnancy and had no other identifiable cause for a stress fractur

Enhanced heparan sulfate proteoglycan-mediated uptake of cell-penetrating peptide-modified liposomes

Protein transduction domains (PTDs) are used to enhance cellular uptake of drugs, proteins, polynucleotides or liposomes. In this study, functionalized Antennapedia (Antp, aa 43--58) and HIV Tat (aa 47-57) peptides were coupled to small unilamellar liposomes via thiol-maleimide linkage. Modified liposomes showed higher uptake into a panel of cell lines including tumor and dendritic cells than unmodified control liposomes. Liposome uptake was time and concentration dependent as analyzed by flow cytometry and live-cell microscopy. At least 100 PTD molecules per small unilamellar liposome (100 ± 30 nm) were necessary for efficient translocation into cells. Cellular uptake of PTD-modified liposomes was 15- to 25-fold increased compared to unmodified liposomes and was inhibited by preincubation of liposomes with heparin. Glycosaminoglycan-deficient CHO cells showed dramatically reduced cell association of PTD-modified liposomes, confirming the important role of heparan sulfate proteoglycans in PTD-mediated uptake. Antp-liposomes used as carriers of the cytotoxic drug N4-octadecyl-1-β-D-arabinofuranosylcytosine-(5′- 5′)-3′-C-ethinylcytidine showed a reduction of the IC50 by 70% on B16F1 melanoma cells compared with unmodified liposomes. PTD-functionalized liposomes, particularly Antp-liposomes, represent an interesting novel carrier system for enhanced cell-specific delivery of a large variety of liposome-entrapped molecule

Core-Exsolved SiO2 Dispersal in the Earth's Mantle

SiO2 may have been expelled from the core directly following core formation in the early stages of Earth's accretion and onward through the present day. On account of SiO2's low density with respect to both the core and the lowermost mantle, we examine the process of SiO2 accumulation at the core‐mantle boundary (CMB) and its incorporation into the mantle by buoyant rise. Today, if SiO2 is 100–10,000 times more viscous than lower mantle material, the dimensions of SiO2 diapirs formed by the viscous Rayleigh‐Taylor instability at the CMB would cause them to be swept into the mantle as inclusions of 100 m–10 km diameter. Under early Earth conditions of rapid heat loss after core formation, SiO2 diapirs of ∼1 km diameter could have risen independently of mantle flow to their level of neutral buoyancy in the mantle, trapping them there due to a combination of intrinsically high viscosity and neutral buoyancy. We examine the SiO2 yield by assuming Si + O saturation at the conditions found at the base of a magma ocean and find that for a range of conditions, dispersed bodies could reach as high as 8.5 vol % in parts of the lower mantle. At such low concentration, their effect on aggregate seismic wave speeds is within observational seismology uncertainty. However, their presence can account for small‐scale scattering in the lower mantle due to the bodies' large‐velocity contrast. We conclude that the shallow lower mantle (700–1,500 km depth) could harbor SiO2 released in early Earth times

Why did Swiss citizens vote to ban tobacco advertising?

In February 2022, Swiss citizens agreed to modify the Swiss Constitution to ban tobacco advertising reaching children and adolescents. This case study analyses the arguments used by both opponents and supporters of the constitutional amendment. Opponents argued that the proposed regulation went too far, threatened the economy, restricted personal freedom, was superfluous as the current law already protected youth and that it opened the door to marketing bans of other harmful products. Proponents focused on youth protection and invoked the burden of smoking on public health and the fact that advertising bans are an effective evidence-based measure. A comparison with previous campaigns to ban tobacco advertising that had failed suggests factors accounting for the positive vote in 2022. These include the strategic framing of youth protection, the separation of tobacco from other issues (such as alcohol advertising), the deteriorating image of the tobacco industry and the ability of the proponents to mobilise a broad coalition of health and youth organisations, with improved funding and communication. The lessons may be instructive for other campaigns seeking to regulate commercial determinants of health

Gravitational wave radiometry: Mapping a stochastic gravitational wave background

The problem of the detection and mapping of a stochastic gravitational wave background (SGWB), either of cosmological or astrophysical origin, bears a strong semblance to the analysis of CMB anisotropy and polarization. The basic statistic we use is the cross-correlation between the data from a pair of detectors. In order to `point' the pair of detectors at different locations one must suitably delay the signal by the amount it takes for the gravitational waves (GW) to travel to both detectors corresponding to a source direction. Then the raw (observed) sky map of the SGWB is the signal convolved with a beam response function that varies with location in the sky. We first present a thorough analytic understanding of the structure of the beam response function using an analytic approach employing the stationary phase approximation. The true sky map is obtained by numerically deconvolving the beam function in the integral (convolution) equation. We adopt the maximum likelihood framework to estimate the true sky map that has been successfully used in the broadly similar, well-studied CMB map making problem. We numerically implement and demonstrate the method on simulated (unpolarized) SGWB for the radiometer consisting of the LIGO pair of detectors at Hanford and Livingston. We include `realistic' additive Gaussian noise in each data stream based on the LIGO-I noise power spectral density. The extension of the method to multiple baselines and polarized GWB is outlined. In the near future the network of GW detectors, including the Advanced LIGO and Virgo detectors that will be sensitive to sources within a thousand times larger spatial volume, could provide promising data sets for GW radiometry.Comment: 24 pages, 19 figures, pdflatex. Matched version published in Phys. Rev. D - minor change

Gremlin is a novel agonist of the major pro-angiogenic receptor VEGFR2

The bone morphogenic protein antagonist gremlin is expressed during embryonic development and under different pathologic conditions, including cancer. Gremlin is a proangiogenic protein belonging to the cystine-knot superfamily that includes transforming growth factor-β proteins and the angiogenic vascular endothelial growth factors (VEGFs). Here, we demonstrate that gremlin binds VEGF receptor-2 (VEGFR2), the main transducer of VEGF-mediated angiogenic signals, in a bone morphogenic protein-independent manner. Similar to VEGF-A, gremlin activates VEGFR2 in endothelial cells, leading to VEGFR2-dependent angiogenic responses in vitro and in vivo. Gremlin thus represents a novel proangiogenic VEGFR2 agonist distinct from the VEGF family ligands with implications in vascular development, angiogenesis-dependent diseases, and tumor neovascularization