Structural but Not Functional Alterations in Cones in the Absence of the Retinal Disease Protein Retinitis Pigmentosa 2 (RP2) in a Cone-Only Retina

X-linked retinitis pigmentosa 2 (XLRP2) patients and Rp2 (null) mice exhibit severe cone photoreceptor degeneration. However, due to the paucity of cones in mammalian model systems, it is not clear how cones respond to the loss of RP2. Here we have used the Nrl(-/-) mice, which develop a rodless and short wavelength (S) opsin-containing cone-only retina, to generate Rp2 (null)::Nrl(-/-) double knock out (Rp2-DKO) mice. We found that the ciliary axoneme and the outer segments (OSs) of the cones were significantly longer with disorganized membrane infoldings as compared to the Nrl(-/-) mice. Additionally, we found misregulation in the expression of the genes related to ophthalmic disease, cell trafficking, and stress-response in the Rp2-DKO mice prior to the onset of cone degeneration. Surprisingly, the loss of RP2 did not affect progressive photoreceptor dysfunction of the Nrl(-/-) mice and the trafficking of S opsin. Our data suggest that RP2 is a negative regulator of cone OS length but does not affect S-opsin trafficking and S-cone function. Our studies also provide a cone-only platform to design cone-targeted therapeutic strategies for X-linked RP2

Wasserstein Diversity-Enriched Regularizer for Hierarchical Reinforcement Learning

Hierarchical reinforcement learning composites subpolicies in different hierarchies to accomplish complex tasks.Automated subpolicies discovery, which does not depend on domain knowledge, is a promising approach to generating subpolicies.However, the degradation problem is a challenge that existing methods can hardly deal with due to the lack of consideration of diversity or the employment of weak regularizers. In this paper, we propose a novel task-agnostic regularizer called the Wasserstein Diversity-Enriched Regularizer (WDER), which enlarges the diversity of subpolicies by maximizing the Wasserstein distances among action distributions. The proposed WDER can be easily incorporated into the loss function of existing methods to boost their performance further.Experimental results demonstrate that our WDER improves performance and sample efficiency in comparison with prior work without modifying hyperparameters, which indicates the applicability and robustness of the WDER

Evolutionary dynamics of cryptocurrency transaction networks: An empirical study

Cryptocurrency is a well-developed blockchain technology application that is currently a heated topic throughout the world. The public availability of transaction histories offers an opportunity to analyze and compare different cryptocurrencies. In this paper, we present a dynamic network analysis of three representative blockchain-based cryptocurrencies: Bitcoin, Ethereum, and Namecoin. By analyzing the accumulated network growth, we find that, unlike most other networks, these cryptocurrency networks do not always densify over time, and they are changing all the time with relatively low node and edge repetition ratios. Therefore, we then construct separate networks on a monthly basis, trace the changes of typical network characteristics (including degree distribution, degree assortativity, clustering coefficient, and the largest connected component) over time, and compare the three. We find that the degree distribution of these monthly transaction networks cannot be well fitted by the famous power-law distribution, at the same time, different currency still has different network properties, e.g., both Bitcoin and Ethereum networks are heavy-tailed with disassortative mixing, however, only the former can be treated as a small world. These network properties reflect the evolutionary characteristics and competitive power of these three cryptocurrencies and provide a foundation for future research

Ablation of retinal ciliopathy protein RPGR results in altered photoreceptor ciliary composition

Cilia regulate several developmental and homeostatic pathways that are critical to survival. Sensory cilia of photoreceptors regulate phototransduction cascade for visual processing. Mutations in the ciliary protein RPGR (retinitis pigmentosa GTPase regulator) are a prominent cause of severe blindness disorders due to degeneration of mature photoreceptors. However, precise function of RPGR is still unclear. Here we studied the involvement of RPGR in ciliary trafficking by analyzing the composition of photoreceptor sensory cilia (PSC) in Rpgr(ko) retina. Using tandem mass spectrometry analysis followed by immunoblotting, we detected few alterations in levels of proteins involved in proteasomal function and vesicular trafficking in Rpgr(ko) PSC, prior to onset of degeneration. We also found alterations in the levels of high molecular weight soluble proteins in Rpgr(ko) PSC. Our data indicate RPGR regulates entry or retention of soluble proteins in photoreceptor cilia but spares the trafficking of key structural and phototransduction-associated proteins. Given a frequent occurrence of RPGR mutations in severe photoreceptor degeneration due to ciliary disorders, our results provide insights into pathways resulting in altered mature cilia function in ciliopathies

Bitcoin Exchange Addresses Identification and Its Application in Online Drug Trading Regulation

A typical example of the impact of the use of Bitcoin on smart health is the darknet market, the website for Bitcoin-based drug sales, and the anonymity exacerbates regulatory difficulties. Bitcoin exchanges are critical portals that link the physical world with cyberspace through buying and selling Bitcoins using fiat money, such as USD and Euro. Thus, identifying exchange addresses in the Bitcoin transaction network is the primary step to detect drug trading in darknet markets. In this paper, we first validate that the exchange addresses are identifiable. Then we propose identification methods based on embedding representation of transaction network. Experimental results on a dataset with records of one-week transactions validated the effectiveness of our method. This work will offer the basis for subsequent applications in smart health

Gene Therapy Using a miniCEP290 Fragment Delays Photoreceptor Degeneration in a Mouse Model of Leber Congenital Amaurosis

Mutations in the cilia-centrosomal protein CEP290 are frequently observed in autosomal recessive childhood blindness disorder Leber congenital amaurosis (LCA). No treatment or cure currently exists for this disorder. The Cep290(rd16) (retinal degeneration 16) mouse (a model of LCA) carries a mutation in the Cep290 gene. This mutation leads to shorter cilia formation and defective photoreceptor structure and function. A roadblock to developing a gene replacement strategy for CEP290 using conventional adeno-associated virus (AAV) vectors is its large size. The identification and characterization is reported of a miniCEP290 gene that is amenable to AAV2/8-mediated delivery and delaying retinal degeneration in the Cep290(rd16) mice. Using the ability of Cep290(rd16) mouse embryonic fibroblasts to from shorter cilia as a platform, a human CEP290 domain encoded by amino acids 580-1180 (miniCEP290(580-1180)) was identified that can recover the cilia length in vitro. Furthermore, subretinal injection of AAV particles carrying the cDNA expressing miniCEP290(580-1180) into neonatal Cep290(rd16) mice resulted in significantly improved photoreceptor survival, morphology, and function compared to control injected mice. These studies show the potential of using a truncated CEP290 to treat this fast progressing and devastating disease