Advances in exosome therapies in ophthalmology–From bench to clinical trial

During the last decade, the fields of advanced and personalized therapeutics have been constantly evolving, utilizing novel techniques such as gene editing and RNA therapeutic approaches. However, the method of delivery and tissue specificity remain the main hurdles of these approaches. Exosomes are natural carriers of functional small RNAs and proteins, representing an area of increasing interest in the field of drug delivery. It has been demonstrated that the exosome cargo, especially miRNAs, is at least partially responsible for the therapeutic effects of exosomes. Exosomes deliver their luminal content to the recipient cells and can be used as vesicles for the therapeutic delivery of RNAs and proteins. Synthetic therapeutic drugs can also be encapsulated into exosomes as they have a hydrophilic core, which makes them suitable to carry water-soluble drugs. In addition, engineered exosomes can display a variety of surface molecules, such as peptides, to target specific cells in tissues. The exosome properties present an added advantage to the targeted delivery of therapeutics, leading to increased efficacy and minimizing the adverse side effects. Furthermore, exosomes are natural nanoparticles found in all cell types and as a result, they do not elicit an immune response when administered. Exosomes have also demonstrated decreased long-term accumulation in tissues and organs and thus carry a low risk of systemic toxicity. This review aims to discuss all the advances in exosome therapies in ophthalmology and to give insight into the challenges that would need to be overcome before exosome therapies can be translated into clinical practice

Numerical Solution of Volterra Integral Equations of First Kind by Using a Recursive Scheme

First kind integral equations can be solved numerically with several methods. In this paper we describe a recursive method for solving Volterra integral equation that don’t need to solve system of algebraic equation. This method offers several advantages in reducing computational burden. Finally by comparison of numerical results, simplicity and efficiency of this method will be show

Identifying priority core habitats and corridors for effective conservation of brown bears in Iran

Iran lies at the southernmost range limit of brown bears globally. Therefore, understanding the habitat associations and patterns of population connectivity for brown bears in Iran is relevant for the species’ conservation. We applied species distribution modeling to predict habitat suitability and connectivity modeling to identify population core areas and corridors. Our results showed that forest density, topographical roughness, NDVI and human footprint were the most influential variables in predicting brown bear distribution. The most crucial core areas and corridor networks for brown bear are concentrated in the Alborz and Zagros Mountains. These two core areas were predicted to be fragmented into a total of fifteen isolated patches if dispersal of brown bear across the landscape is limited to 50,000 cost units, and aggregates into two isolated habitat patches if the species is capable of dispersing 400,000 cost units. We found low overlap between corridors, and core habitats with protected areas, suggesting that the existing protected area network may not be adequate for the conservation of brown bear in Iran. Our results suggest that effective conservation of brown bears in Iran requires protection of both core habitats and the corridors between them, especially outside Iran’s network of protected areas.We would like to thank provincial offices of Iranian Department of Environment for supporting the study. J.V.L.B. was supported by a Ramon & Cajal research contract (RYC-2015-18932) from the Spanish Ministry of Economy, Industry and Competitiveness. V.P. was supported by (1) the Excellence Project CGL2017-82782-P financed by the Spanish Ministry of Science, Innovation and Universities, the Agencia Estatal de Investigación (AEI) and the Fondo Europeo de Desarrollo Regional (FEDER, EU), and by (2) a GRUPIN research grant from the Regional Government of Asturias (Ref.: IDI/2018/000151).Peer reviewe

Misguidance and modulation of axonal regeneration by Stat3 and Rho/ROCK signaling in the transparent optic nerve

The use of the visual system played a major role in the elucidation of molecular mechanisms controlling axonal regeneration in the injured CNS after trauma. In this model, CNTF was shown to be the most potent known neurotrophic factor for axonal regeneration in the injured optic nerve. To clarify the role of the downstream growth regulator Stat3, we analyzed axonal regeneration and neuronal survival after an optic nerve crush in adult mice. The infection of retinal ganglion cells with adeno-associated virus serotype 2 (AAV2) containing wild-type (Stat3-wt) or constitutively active (Stat3-ca) Stat3 cDNA promoted axonal regeneration in the injured optic nerve. Axonal growth was analyzed in whole-mounted optic nerves in three dimensions (3D) after tissue clearing. Surprisingly, with AAV2.Stat3-ca stimulation, axons elongating beyond the lesion site displayed very irregular courses, including frequent U-turns, suggesting massive directionality and guidance problems. The pharmacological blockade of ROCK, a key signaling component for myelin-associated growth inhibitors, reduced axonal U-turns and potentiated AAV2.Stat3-ca-induced regeneration. Similar results were obtained after the sustained delivery of CNTF in the axotomized retina. These results show the important role of Stat3 in the activation of the neuronal growth program for regeneration, and they reveal that axonal misguidance is a key limiting factor that can affect long-distance regeneration and target interaction after trauma in the CNS. The correction of axonal misguidance was associated with improved long-distance axon regeneration in the injured adult CNS