On the horseshoe drag of a low-mass planet. II Migration in adiabatic disks

We evaluate the horseshoe drag exerted on a low-mass planet embedded in a gaseous disk, assuming the disk's flow in the coorbital region to be adiabatic. We restrict this analysis to the case of a planet on a circular orbit, and we assume a steady flow in the corotating frame. We also assume that the corotational flow upstream of the U-turns is unperturbed, so that we discard saturation effects. In addition to the classical expression for the horseshoe drag in barotropic disks, which features the vortensity gradient across corotation, we find an additional term which scales with the entropy gradient, and whose amplitude depends on the perturbed pressure at the stagnation point of the horseshoe separatrices. This additional torque is exerted by evanescent waves launched at the horseshoe separatrices, as a consequence of an asymmetry of the horseshoe region. It has a steep dependence on the potential's softening length, suggesting that the effect can be extremely strong in the three dimensional case. We describe the main properties of the coorbital region (the production of vortensity during the U-turns, the appearance of vorticity sheets at the downstream separatrices, and the pressure response), and we give torque expressions suitable to this regime of migration. Side results include a weak, negative feed back on migration, due to the dependence of the location of the stagnation point on the migration rate, and a mild enhancement of the vortensity related torque at large entropy gradient.Comment: Accepted for publication in Ap

A torque formula for non-isothermal Type I planetary migration - II. Effects of diffusion

We study the effects of diffusion on the non-linear corotation torque, or horseshoe drag, in the two-dimensional limit, focusing on low-mass planets for which the width of the horseshoe region is much smaller than the scale height of the disc. In the absence of diffusion, the non-linear corotation torque saturates, leaving only the Lindblad torque. Diffusion of heat and momentum can act to sustain the corotation torque. In the limit of very strong diffusion, the linear corotation torque is recovered. For the case of thermal diffusion, this limit corresponds to having a locally isothermal equation of state. We present some simple models that are able to capture the dependence of the torque on diffusive processes to within 20% of the numerical simulations.Comment: 12 pages, 8 figures, accepted for publication in MNRA

Saturated torque formula for planetary migration in viscous disks with thermal diffusion: recipe for protoplanet population synthesis

We provide torque formulae for low mass planets undergoing type I migration in gaseous disks. These torque formulae put special emphasis on the horseshoe drag, which is prone to saturation: the asymptotic value reached by the horseshoe drag depends on a balance between coorbital dynamics (which tends to cancel out or saturate the torque) and diffusive processes (which tend to restore the unperturbed disk profiles, thereby desaturating the torque). We entertain here the question of this asymptotic value, and we derive torque formulae which give the total torque as a function of the disk's viscosity and thermal diffusivity. The horseshoe drag features two components: one which scales with the vortensity gradient, and one which scales with the entropy gradient, and which constitutes the most promising candidate for halting inward type I migration. Our analysis, which is complemented by numerical simulations, recovers characteristics already noted by numericists, namely that the viscous timescale across the horseshoe region must be shorter than the libration time in order to avoid saturation, and that, provided this condition is satisfied, the entropy related part of the horseshoe drag remains large if the thermal timescale is shorter than the libration time. Side results include a study of the Lindblad torque as a function of thermal diffusivity, and a contribution to the corotation torque arising from vortensity viscously created at the contact discontinuities that appear at the horseshoe separatrices. For the convenience of the reader mostly interested in the torque formulae, section 8 is self-contained.Comment: Affiliation details changed. Fixed equation numbering issue. Biblio info adde

On the horseshoe drag of a low-mass planet. I - Migration in isothermal disks

We investigate the unsaturated horseshoe drag exerted on a low-mass planet by an isothermal gaseous disk. In the globally isothermal case, we use a formal- ism, based on the use of a Bernoulli invariant, that takes into account pressure effects, and that extends the torque estimate to a region wider than the horse- shoe region. We find a result that is strictly identical to the standard horseshoe drag. This shows that the horseshoe drag accounts for the torque of the whole corotation region, and not only of the horseshoe region, thereby deserving to be called corotation torque. We find that evanescent waves launched downstream of the horseshoe U-turns by the perturbations of vortensity exert a feed-back on the upstream region, that render the horseshoe region asymmetric. This asymmetry scales with the vortensity gradient and with the disk's aspect ratio. It does not depend on the planetary mass, and it does not have any impact on the horseshoe drag. Since the horseshoe drag has a steep dependence on the width of the horseshoe region, we provide an adequate definition of the width that needs to be used in horseshoe drag estimates. We then consider the case of locally isothermal disks, in which the tempera- ture is constant in time but depends on the distance to the star. The horseshoe drag appears to be different from the case of a globally isothermal disk. The difference, which is due to the driving of vortensity in the vicinity of the planet, is intimately linked to the topology of the flow. We provide a descriptive inter- pretation of these effects, as well as a crude estimate of the dependency of the excess on the temperature gradient.Comment: Accepted for publication in Ap

Gene therapy for inherited metabolic diseases

Over the last two decades, gene therapy has been successfully translated to many rare diseases. The number of clinical trials is rapidly expanding and some gene therapy products have now received market authorisation in the western world. Inherited metabolic diseases (IMD) are orphan diseases frequently associated with a severe debilitating phenotype with limited therapeutic perspective. Gene therapy is progressively becoming a diseasechanging therapeutic option for these patients. In this review, we aim to summarise the development of this emerging field detailing the main gene therapy strategies, routes of administration, viral and non-viral vectors and gene editing tools. We discuss the respective advantages and pitfalls of these gene therapy strategies and review their application in IMD, providing examples of clinical trials with lentiviral or adeno-associated viral gene therapy vectors in rare diseases. The rapid development of the field and implementation of gene therapy as a realistic therapeutic option for various IMD in a short term also require a good knowledge and understanding of these technologies from physicians to counsel the patients at best

Liver-directed gene therapy for inherited metabolic diseases

Gene therapy clinical trials are rapidly expanding for inherited metabolic liver diseases whilst two gene therapy products have now been approved for liver based monogenic disorders. Liver-directed gene therapy has recently become an option for treatment of haemophilias and is likely to become one of the favoured therapeutic strategies for inherited metabolic liver diseases in the near future. In this review, we present the different gene therapy vectors and strategies for liver-targeting, including gene editing. We highlight the current development of viral and nonviral gene therapy for a number of inherited metabolic liver diseases including urea cycle defects, organic acidaemias, Crigler–Najjar disease, Wilson disease, glycogen storage disease Type Ia, phenylketonuria and maple syrup urine disease. We describe the main limitations and open questions for further gene therapy development: immunogenicity, inflammatory response, genotoxicity, gene therapy administration in a fibrotic liver. The follow-up of a constantly growing number of gene therapy treated patients allows better understanding of its benefits and limitations and provides strategies to design safer and more efficacious treatments. Undoubtedly, liver-targeting gene therapy offers a promising avenue for innovative therapies with an unprecedented potential to address the unmet needs of patients suffering from inherited metabolic diseases

A Fast Potential and Self-Gravity Solver for Non-Axisymmetric Disks

Disk self-gravity could play an important role in the dynamic evolution of interaction between disks and embedded protoplanets. We have developed a fast and accurate solver to calculate the disk potential and disk self-gravity forces for disk systems on a uniform polar grid. Our method follows closely the method given by Chan et al. (2006), in which an FFT in the azimuthal direction is performed and a direct integral approach in the frequency domain in the radial direction is implemented on a uniform polar grid. This method can be very effective for disks with vertical structures that depend only on the disk radius, achieving the same computational efficiency as for zero-thickness disks. We describe how to parallelize the solver efficiently on distributed parallel computers. We propose a mode-cutoff procedure to reduce the parallel communication cost and achieve nearly linear scalability for a large number of processors. For comparison, we have also developed a particle-based fast tree-code to calculate the self-gravity of the disk system with vertical structure. The numerical results show that our direct integral method is at least two order of magnitudes faster than our optimized tree-code approach.Comment: 8 figures, accepted to ApJ

Self-gravity at the scale of the polar cell

We present the exact calculus of the gravitational potential and acceleration along the symmetry axis of a plane, homogeneous, polar cell as a function of mean radius a, radial extension e, and opening angle f. Accurate approximations are derived in the limit of high numerical resolution at the geometrical mean of the inner and outer radii (a key-position in current FFT-based Poisson solvers). Our results are the full extension of the approximate formula given in the textbook of Binney & Tremaine to all resolutions. We also clarify definitely the question about the existence (or not) of self-forces in polar cells. We find that there is always a self-force at radius except if the shape factor a.f/e reaches ~ 3.531, asymptotically. Such cells are therefore well suited to build a polar mesh for high resolution simulations of self-gravitating media in two dimensions. A by-product of this study is a newly discovered indefinite integral involving complete elliptic integral of the first kind over modulus.Comment: 4 pages, 4 figures, A&A accepte

Delivering efficient liver-directed AAV-mediated gene therapy.

Adeno-associated virus vectors (AAV) have become the leading technology for liver-directed gene therapy. After the pioneering trials using AAV2 and AAV8 to treat haemophilia B, D’Avola et al. recently reported the first-in-human clinical trial of adeno-associated virus vector serotype 5 (AAV5) in acute intermittent porphyria (AIP). Treatment was reported as safe, but the main surrogate biomarkers of AIP, porphobilinogen (PBG) and delta-aminolevulinate (ALA) were unchanged. This lack of efficacy contrasts with results from the haemophilia B trial using AAV8 capsid by Nathwani et al., which showed a significant and long-lasting improvement of the clinical phenotype. Haemophilia B is an amenable target for successful gene therapy as raising expression of plasma factor IX (FIX) level above 1% can modify the phenotype from severe to moderate. Development of a variety of capsids for clinical application is useful to overcome pre-existing neutralising antibodies. The differences in cell-specific transduction by different AAV serotypes are primarily owing to specificities in cellular uptake or post cell-entry processing. Indeed AAV5 presents several theoretical advantages as an alternative capsid to AAV8 for liver-directed gene therapy: suitable liver tropism, less off-target biodistribution, low seroprevalence in humans and minimal cross-reactivity with other serotypes

The exosome journey: from biogenesis to uptake and intracellular signalling.

The use of exosomes in clinical settings is progressively becoming a reality, as clinical trials testing exosomes for diagnostic and therapeutic applications are generating remarkable interest from the scientific community and investors. Exosomes are small extracellular vesicles secreted by all cell types playing intercellular communication roles in health and disease by transferring cellular cargoes such as functional proteins, metabolites and nucleic acids to recipient cells. An in-depth understanding of exosome biology is therefore essential to ensure clinical development of exosome based investigational therapeutic products. Here we summarise the most up-to-date knowkedge about the complex biological journey of exosomes from biogenesis and secretion, transport and uptake to their intracellular signalling. We delineate the major pathways and molecular players that influence each step of exosome physiology, highlighting the routes of interest, which will be of benefit to exosome manipulation and engineering. We highlight the main controversies in the field of exosome research: their adequate definition, characterisation and biogenesis at plasma membrane. We also delineate the most common identified pitfalls affecting exosome research and development. Unravelling exosome physiology is key to their ultimate progression towards clinical applications. Video Abstract