The Landscape of Non-Viral Gene Augmentation Strategies for Inherited Retinal Diseases

Inherited retinal diseases (IRDs) are a heterogeneous group of disorders causing progressive loss of vision, affecting approximately one in 1000 people worldwide. Gene augmentation therapy, which typically involves using adeno-associated viral vectors for delivery of healthy gene copies to affected tissues, has shown great promise as a strategy for the treatment of IRDs. However, the use of viruses is associated with several limitations, including harmful immune responses, genome integration, and limited gene carrying capacity. Here, we review the advances in non-viral gene augmentation strategies, such as the use of plasmids with minimal bacterial backbones and scaffold/matrix attachment region (S/MAR) sequences, that have the capability to overcome these weaknesses by accommodating genes of any size and maintaining episomal transgene expression with a lower risk of eliciting an immune response. Low retinal transfection rates remain a limitation, but various strategies, including coupling the DNA with different types of chemical vehicles (nanoparticles) and the use of electrical methods such as iontophoresis and electrotransfection to aid cell entry, have shown promise in preclinical studies. Non-viral gene therapy may offer a safer and effective option for future treatment of IRDs

USH2A-retinopathy: From genetics to therapeutics

Bilallelic variants in the USH2A gene can cause Usher syndrome type 2 and non-syndromic retinitis pigmentosa. In both disorders, the retinal phenotype involves progressive rod photoreceptor loss resulting in nyctalopia and a constricted visual field, followed by subsequent cone degeneration, leading to the loss of central vision and severe visual impairment. The USH2A gene raises many challenges for researchers and clinicians due to a broad spectrum of mutations, a large gene size hampering gene therapy development and limited knowledge on its pathogenicity. Patients with Usher type 2 may benefit from hearing aids or cochlear implants to correct their hearing defects, but there are currently no approved treatments available for the USH2A-retinopathy. Several treatment strategies, including antisense oligonucleotides and translational readthrough inducing drugs, have shown therapeutic promise in preclinical studies. Further understanding of the pathogenesis and natural history of USH2A-related disorders is required to develop innovative treatments and design clinical trials based on reliable outcome measures. The present review will discuss the current knowledge about USH2A, the emerging therapeutics and existing challenges

There is no new physics in the multiplicative anomaly

We discuss the role of the multiplicative anomaly for a complex scalar field at finite temperature and density. It is argued that physical considerations must be applied to determine which of the many possible expressions for the effective action obtained by the functional integral method is correct. This is done by first studying the non-relativistic field where the thermodynamic potential is well-known. The relativistic case is also considered. We emphasize that the role of the multiplicative anomaly is not to lead to new physics, but rather to preserve the equality among the various expressions for the effective action.Comment: 24 pages, RevTex, no figure

Noncommutative Complex Scalar Field and Casimir Effect

A noncommutative complex scalar field, satisfying the deformed canonical commutation relations proposed by Carmona et al. [27]-[31], is constructed. Using these noncommutative deformed canonical commutation relations, a model describing the dynamics of the noncommutative complex scalar field is proposed. The noncommutative field equations are solved, and the vacuum energy is calculated to the second order in the parameter of noncommutativity. As an application to this model, the Casimir effect, due to the zero point fluctuations of the noncommutative complex scalar field, is considered. It turns out that in spite of its smallness, the noncommutativity gives rise to a repulsive force at the microscopic level, leading to a modifed Casimr potential with a minimum at the point amin= racine(5/84){\pi}{\theta}.Comment: Revtex style, 28 page

Quantized bulk fermions in the Randall-Sundrum brane model

The lowest order quantum corrections to the effective action arising from quantized massive fermion fields in the Randall-Sundrum background spacetime are computed. The boundary conditions and their relation with gauge invariance are examined in detail. The possibility of Wilson loop symmetry breaking in brane models is also analysed. The self-consistency requirements, previously considered in the case of a quantized bulk scalar field, are extended to include the contribution from massive fermions. It is shown that in this case it is possible to stabilize the radius of the extra dimensions but it is not possible to simultaneously solve the hierarchy problem, unless the brane tensions are dramatically fine tuned, supporting previous claims.Comment: 25 pages, 1 figure, RevTe

Bose-Einstein condensation as symmetry breaking in compact curved spacetimes

We examine Bose-Einstein condensation as a form of symmetry breaking in the specific model of the Einstein static universe. We show that symmetry breaking never occursin the sense that the chemical potential $\mu$ never reaches its critical value.This leads us to some statements about spaces of finite volume in general. In an appendix we clarify the relationship between the standard statistical mechanical approaches and the field theory method using zeta functions.Comment: Revtex, 25 pages, 3 figures, uses EPSF.sty. To be published in Phys. Rev.

Nonlinear Diffusion Through Large Complex Networks Containing Regular Subgraphs

Transport through generalized trees is considered. Trees contain the simple nodes and supernodes, either well-structured regular subgraphs or those with many triangles. We observe a superdiffusion for the highly connected nodes while it is Brownian for the rest of the nodes. Transport within a supernode is affected by the finite size effects vanishing as $N\to\infty.$ For the even dimensions of space, $d=2,4,6,...$, the finite size effects break down the perturbation theory at small scales and can be regularized by using the heat-kernel expansion.Comment: 21 pages, 2 figures include

Cold ideal equation of state for strongly magnetized neutron-star matter: effects on muon production and pion condensationn

Neutron stars with very strong surface magnetic fields have been suggested as the site for the origin of observed soft gamma repeaters (SGRs). In this paper we investigate the influence of such strong magnetic fields on the properties and internal structure of these magnetized neutron stars (magnetars). We study properties of a degenerate equilibrium ideal neutron-proton-electron (npe) gas with and without the effects of the anomalous nucleon magnetic moments in a magnetic field. The presence of a sufficiently strong magnetic field changes the ratio of protons to neutrons as well as the neutron drip density. We also study the appearance of muons as well as pion condensation in strong magnetic fields. We discuss the possibility that boson condensation in the interior of magnetars might be a source of SGRs.Comment: 10 pages included 9 figures, ApJ in pres

Stretching of polymers around the Kolmogorov scale in a turbulent shear flow

We present numerical studies of stretching of Hookean dumbbells in a turbulent Navier-Stokes flow with a linear mean profile, =Sy. In addition to the turbulence features beyond the viscous Kolmogorov scale \eta, the dynamics at the equilibrium extension of the dumbbells significantly below eta is well resolved. The variation of the constant shear rate S causes a change of the turbulent velocity fluctuations on all scales and thus of the intensity of local stretching rate of the advecting flow. The latter is measured by the maximum Lyapunov exponent lambda_1 which is found to increase as \lambda_1 ~ S^{3/2}, in agreement with a dimensional argument. The ensemble of up to 2 times 10^6 passively advected dumbbells is advanced by Brownian dynamics simulations in combination with a pseudospectral integration for the turbulent shear flow. Anisotropy of stretching is quantified by the statistics of the azimuthal angle $\phi$ which measures the alignment with the mean flow axis in the x-y shear plane, and the polar angle theta which determines the orientation with respect to the shear plane. The asymmetry of the probability density function (PDF) of phi increases with growing shear rate S. Furthermore, the PDF becomes increasingly peaked around mean flow direction (phi= 0). In contrast, the PDF of the polar angle theta is symmetric and less sensitive to changes of S.Comment: 16 pages, 14 Postscript figures (2 with reduced quality