Glioblastoma on a microfluidic chip: Generating pseudopalisades and enhancing aggressiveness through blood vessel obstruction events

Background: Glioblastoma (GBM) is one of the most lethal tumor types. Hypercellular regions, named pseudo- palisades, are characteristic in these tumors and have been hypothesized to be waves of migrating glioblastoma cells.These “waves” of cells are thought to be induced by oxygen and nutrient depletion caused by tumor-induced blood vessel occlusion. Although the universal presence of these structures in GBM tumors suggests that they may play an instrumental role in GBM’s spread and invasion, the recreation of these structures in vitro has remained challenging. Methods: Here we present a new microfluidic model of GBM that mimics the dynamics of pseudopalisade forma- tion.To do this, we embedded U-251 MG cells within a collagen hydrogel in a custom-designed microfluidic device. By controlling the medium flow through lateral microchannels, we can mimic and control blood-vessel obstruction events associated with this disease. Results: Through the use of this new system, we show that nutrient and oxygen starvation triggers a strong migratory process leading to pseudopalisade generation in vitro.These results validate the hypothesis of pseudo- palisade formation and show an excellent agreement with a systems-biology model based on a hypoxia-driven phenomenon. Conclusions: This paper shows the potential of microfluidic devices as advanced artificial systems capable of mod- eling in vivo nutrient and oxygen gradients during tumor evolution

First direct detection of an exoplanet by optical interferometry; Astrometry and K-band spectroscopy of HR8799 e

To date, infrared interferometry at best achieved contrast ratios of a few times $10^{-4}$ on bright targets. GRAVITY, with its dual-field mode, is now capable of high contrast observations, enabling the direct observation of exoplanets. We demonstrate the technique on HR8799, a young planetary system composed of four known giant exoplanets. We used the GRAVITY fringe tracker to lock the fringes on the central star, and integrated off-axis on the HR8799e planet situated at 390 mas from the star. Data reduction included post-processing to remove the flux leaking from the central star and to extract the coherent flux of the planet. The inferred K band spectrum of the planet has a spectral resolution of 500. We also derive the astrometric position of the planet relative to the star with a precision on the order of 100$\,\mu$as. The GRAVITY astrometric measurement disfavors perfectly coplanar stable orbital solutions. A small adjustment of a few degrees to the orbital inclination of HR 8799 e can resolve the tension, implying that the orbits are close to, but not strictly coplanar. The spectrum, with a signal-to-noise ratio of $\approx 5$ per spectral channel, is compatible with a late-type L brown dwarf. Using Exo-REM synthetic spectra, we derive a temperature of $1150\pm50$\,K and a surface gravity of $10^{4.3\pm0.3}\,$cm/s$^{2}$. This corresponds to a radius of $1.17^{+0.13}_{-0.11}\,R_{\rm Jup}$ and a mass of $10^{+7}_{-4}\,M_{\rm Jup}$, which is an independent confirmation of mass estimates from evolutionary models. Our results demonstrate the power of interferometry for the direct detection and spectroscopic study of exoplanets at close angular separations from their stars.Comment: published in A&

Asymptotic analysis of an elastic rod with rounded ends

We derive a one-dimensional model for an elastic shuttle, that is, a thin rod with rounded ends and small fixed terminals, by means of an asymptotic procedure of dimension reduction. In the model, deformation of the shuttle is described by a system of ordinary differential equations with variable degenerating coefficients, and the number of the required boundary conditions at the end points of the one-dimensional image of the rod depends on the roundness exponent m is an element of(0,1). Error estimates are obtained in the case m is an element of(0,1/4) by using an anisotropic weighted Korn inequality, which was derived in an earlier paper by the authors. We also briefly discuss boundary layer effects, which can be neglected in the case m is an element of(0,1/4) but play a crucial role in the formulation of the limit problem for m >= 1/4.Peer reviewe

ACRATA: a novel electron transfer domain associated to apoptosis and cancer

BACKGROUND: Recently, several members of a vertebrate protein family containing a six trans-membrane (6TM) domain and involved in apoptosis and cancer (e.g. STEAP, STAMP1, TSAP6), have been identified in Golgi and cytoplasmic membranes. The exact function of these proteins remains unknown. METHODS: We related this 6TM domain to distant protein families using intermediate sequences and methods of iterative profile sequence similarity search. RESULTS: Here we show for the first time that this 6TM domain is homolog to the 6TM heme binding domain of both the NADPH oxidase (Nox) family and the YedZ family of bacterial oxidoreductases. CONCLUSIONS: This finding gives novel insights about the existence of a previously undetected electron transfer system involved in apoptosis and cancer, and suggests further steps in the experimental characterization of these evolutionarily related families

Accretion-ejection morphology of the microquasar SS 433 resolved at sub-au scale

This is the author accepted manuscript. the final version is available from EDP Sciences via the DOI in this recordWe present the first optical observation of the microquasar SS 433 at sub-milliarcsecond (mas) scale obtained with the GRAVITY instrument on the Very Large Telescope interferometer (VLTI). The 3.5-h exposure reveals a rich K-band spectrum dominated by hydrogen Brγand He i lines, as well as (red-shifted)emission lines coming from the jets. The K-band-continuum-emitting region is dominated by a marginally resolved point source (<1 mas) embedded inside a diffuse background accounting for 10% of the total flux. The jet line positions agree well with the ones expected from the jet kinematic model, an interpretation also supported by the consistent sign (i.e., negative/positive for the receding/approaching jet component) of the phase shifts observed in the lines. The significant visibility drop across the jet lines, together with the small and nearly identical phases for all baselines, point toward a jet that is offset by less than 0.5 mas from the continuum source and resolved in the direction of propagation, with a typical size of 2 mas. The jet position angle of ~80° is consistent with the expected one at the observation date. Jet emission so close to the central binary system would suggest that line locking, if relevant to explain the amplitude and stability of the 0.26c jet velocity, operates on elements heavier than hydrogen. The Brγprofile is broad and double peaked. It is better resolved than the continuum and the change of the phase signal sign across the line on all baselines suggests an East-West-oriented geometry similar to the jet direction and supporting a (polar) disk wind origin.Centre National d’Etudes Spatiales (CNES)Programme National Hautes Energies (PNHE)Humboldt FoundationNAS

Homogenization of nonlinearly elastic materials, microscopic bifurcation and macroscopic loss of rank-one convexity

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46162/1/205_2004_Article_BF00380256.pd

Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies

Pre-mRNA splicing factors play a fundamental role in regulating transcript diversity both temporally and spatially. Genetic defects in several spliceosome components have been linked to a set of non-overlapping spliceosomopathy phenotypes in humans, among which skeletal developmental defects and non-syndromic retinitis pigmentosa (RP) are frequent findings. Here we report that defects in spliceosome-associated protein CWC27 are associated with a spectrum of disease phenotypes ranging from isolated RP to severe syndromic forms. By whole-exome sequencing, recessive protein-truncating mutations in CWC27 were found in seven unrelated families that show a range of clinical phenotypes, including retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurological defects. Remarkably, variable expressivity of the human phenotype can be recapitulated in Cwc27 mutant mouse models, with significant embryonic lethality and severe phenotypes in the complete knockout mice while mice with a partial loss-of-function allele mimic the isolated retinal degeneration phenotype. Our study describes a retinal dystrophy-related phenotype spectrum as well as its genetic etiology and highlights the complexity of the spliceosomal gene network