Transcriptomic analysis of the mouse retina after acute and chronic normobaric and hypobaric hypoxia.

Oxygen delivery to the retinal pigment epithelium and the outer retina is essential for metabolism, function, and survival of photoreceptors. Chronically reduced oxygen supply leads to retinal pathologies in patients and causes age-dependent retinal degeneration in mice. Hypoxia can result from decreased levels of inspired oxygen (normobaric hypoxia) or reduced barometric pressure (hypobaric hypoxia). Since the response of retinal cells to chronic normobaric or hypobaric hypoxia is mostly unknown, we examined the effect of six hypoxic conditions on the retinal transcriptome and photoreceptor morphology. Mice were exposed to short- and long-term normobaric hypoxia at 400 m or hypobaric hypoxia at 3450 m above sea level. Longitudinal studies over 11 weeks in normobaric hypoxia revealed four classes of genes that adapted differentially to the hypoxic condition. Seventeen genes were specifically regulated in hypobaric hypoxia and may affect the structural integrity of the retina, resulting in the shortening of photoreceptor segment length detected in various hypoxic groups. This study shows that retinal cells have the capacity to adapt to long-term hypoxia and that consequences of hypobaric hypoxia differ from those of normobaric hypoxia. Our datasets can be used as references to validate and compare retinal disease models associated with hypoxia.

The WNT receptor ROR2 drives the interaction of multiple myeloma cells with the microenvironment through AKT activation.

Multiple myeloma is the second most frequent hematological cancer after lymphoma and remains an incurable disease. The pervasive support provided by the bone marrow microenvironment to myeloma cells is crucial for their survival. Here, an unbiased assessment of receptor tyrosine kinases overexpressed in myeloma identified ROR2, a receptor for the WNT noncanonical pathway, as highly expressed in myeloma cells. Its ligand, WNT5A is the most abundant growth factor in the bone marrow of myeloma patients. ROR2 mediates myeloma cells interactions with the surrounding bone marrow and its depletion resulted in detachment of myeloma cells from their niche in an in vivo model, triggering apoptosis and thus markedly delaying disease progression. Using in vitro and ex vivo 3D-culture systems, ROR2 was shown to exert a pivotal role in the adhesion of cancer cells to the microenvironment. Genomic studies revealed that the pathways mostly deregulated by ROR2 overexpression were PI3K/AKT and mTOR. Treatment of cells with specific PI3K inhibitors already used in the clinic reduced myeloma cell adhesion to the bone marrow. Together, our findings support the view that ROR2 and its downstream targets represent a novel therapeutic strategy for the large subgroup of MM patients whose cancer cells show ROR2 overexpression.

A continuum model for platelet plug formation, growth and deformation.

A numerical framework for modelling platelet plug dynamics is presented in this work. It consists of an extension of a biochemical and plug growth model with a solid mechanics model for the plug coupled with a fluid-structure interaction model for the blood flow-plug system. The platelet plug is treated as a neo-Hookean elastic solid, of which the implementation is based on an updated Lagrangian approach. The framework is applied to different haemodynamic configurations coupled with different shear moduli of the plug. Results about plug growth, shape and size, as well as the stress distribution, are shown. Based on the simulations performed, we conclude that the deformability of the platelet plug is essential for its growth.

A continuum model for platelet plug formation and growth.

When the wall of a blood vessel is damaged, the immediate response of the body to prevent blood loss is the creation of a platelet plug. The process is both chemical (platelets are chemically activated to adhere to the injured wall) and mechanical (platelets are convected by blood flow, which interacts with the forming plug). A continuum model for platelet plug formation and growth is presented in this work, which allows to study the interaction between platelet plug morphology and local haemodynamics. The numerical framework consists of two parts: a biochemical model combined with a new plug growth model. The biochemical model is a system of convection-diffusion-reaction equations, each of which represents the dynamics of platelets and chemicals involved in the plug formation process. The plug growth model defines the plug interface displacement based on the outcome of the biochemical model, that is, on the number of deposited bounded platelets on the injured part of the vessel wall. Results for different cases are shown, together with a comparison between the sole biochemical model and the complete model that includes plug growth. The framework opens the way to the development of continuum models for full blood clot formation and growth in physiologically relevant configurations.

Exploiting distinct molecular architectures of ultrathin films made with iron phthalocyanine for sensing.

The possibility of generating distinct film properties from the same material is crucial for a number of applications, which can only be achieved by controlling the molecular architecture. In this paper we demonstrate as a proof-of-principle that ultrathin films produced from iron phthalocyanine (FePc) may be used to detect trace amounts of copper ions in water, where advantage was taken of the cross sensitivity of the sensing units that displayed distinct electrical properties. The ultrathin films were fabricated with three methods, namely physical vapor deposition (PVD), Langmuir-Blodgett (LB), and electrostatic layer-by-layer (LbL) techniques, where for the latter tetrasulfonated phthalocyanine was used (FeTsPc). PVD and LB films were more homogeneous than the LbL films at both microscopic and nanoscopic scales, according to results from micro-Raman spectroscopy and atomic force microscopy (AFM), respectively. From FTIR spectroscopy data, these more homogeneous films were found to have FePc molecules oriented preferentially, tilted in relation to the substrate surface, while FeTsPc molecules were isotropically distributed in the LbL films. Impedance spectroscopy measurements with films adsorbed onto interdigitated gold electrodes indicated that the electrical response depends on the type of film-forming method and varies with incorporation of copper ions in aqueous solutions. Using principal component analysis (PCA), we were able to exploit the cross sensitivity of the sensing units and detect copper ions (Cu(2+)) down to 0.2 mg/L, not only in ultrapure water but also in distilled and tap water. This level of sensitivity is sufficient for quality control of water for human consumption, with a fast, low-cost method.