Allele-specific siRNA Therapy for Keratitis-Ichthyosis-Deafness Syndrome

Dominant mutations in the gene GJB2 cause keratitis-ichthyosis-deafness (KID) syndrome, a severe condition affecting the skin, cornea and inner ear. GJB2 encodes the protein connexin-26 (Cx26) which forms hemichannels or gap junction channels allowing the passage of signalling molecules. Approximately 80% of KID syndrome patients carry a c.148G>A (p.D50N) mutation in GJB2, which results in aberrant channel function. We hypothesised that silencing of the mutant allele in patient keratinocytes using allele-specific siRNA could correct the channel function. First, to confirm whether patient keratinocytes with only one wildtype GJB2 allele formed functional channels following allele-specific siRNA treatment, GJB2+/- keratinocytes were generated using CRISPR/Cas9. The scrape-loading dye transfer (SLDT) assay showed no distinguishable difference in gap junction intercellular communication (GJIC) between GJB2+/- and GJB2+/+ cells, suggesting normal GJIC in GJB2+/- keratinocytes. Nineteen siRNAs were designed and tested in HeLa cells expressing wildtype or mutant GJB2-GFP transgene. A lead siRNA, was discovered, which potently inhibited the mutant mRNA and protein without affecting wildtype GJB2 expression. The efficacy of the lead siRNA was assessed using keratinocytes derived from a KID syndrome patient (KID-KC) harbouring heterozygous c.148G>A mutation. These cells displayed pathological features of KID syndrome, with reduced gap junction plaque formation, impaired GJIC and hyperactive hemichannels confirmed by immunostaining, SLDT, patch clamp and neurobiotin uptake assays. Following treatment with the siRNA, selective silencing of mutant GJB2 allele in KID-KCs was confirmed at mRNA and protein levels. Significant improvement of GJIC and reversal of hemichannel activity were detected, with the latter corrected to a level comparable to that recorded in normal keratinocytes. Furthermore, RNA-Seq analysis showed that only six genes in the KID-KC transcriptome were significantly altered by the siRNA treatment, suggesting low-level off-target effects. In conclusion, allele-specific siRNA silencing of pathogenic dominant GJB2 mutation could be a potential therapeutic intervention for KID syndrome

The Association between Virus Prevalence and Intercolonial Aggression Levels in the Yellow Crazy Ant, Anoplolepis Gracilipes (Jerdon).

The recent discovery of multiple viruses in ants, along with the widespread infection of their hosts across geographic ranges, provides an excellent opportunity to test whether viral prevalence in the field is associated with the complexity of social interactions in the ant population. In this study, we examined whether the association exists between the field prevalence of a virus and the intercolonial aggression of its ant host, using the yellow crazy ant (Anoplolepis gracilipes) and its natural viral pathogen (TR44839 virus) as a model system. We delimitated the colony boundary and composition of A. gracilipes in a total of 12 study sites in Japan (Okinawa), Taiwan, and Malaysia (Penang), through intercolonial aggression assay. The spatial distribution and prevalence level of the virus was then mapped for each site. The virus occurred at a high prevalence in the surveyed colonies of Okinawa and Taiwan (100% infection rate across all sites), whereas virus prevalence was variable (30%-100%) or none (0%) at the sites in Penang. Coincidentally, colonies in Okinawa and Taiwan displayed a weak intercolonial boundary, as aggression between colonies is generally low or moderate. Contrastingly, sites in Penang were found to harbor a high proportion of mutually aggressive colonies, a pattern potentially indicative of complex colony composition. Our statistical analyses further confirmed the observed correlation, implying that intercolonial interactions likely contribute as one of the effective facilitators of/barriers to virus prevalence in the field population of this ant species

Maximizing Friend-Making Likelihood for Social Activity Organization

The social presence theory in social psychology suggests that computer-mediated online interactions are inferior to face-to-face, in-person interactions. In this paper, we consider the scenarios of organizing in person friend-making social activities via online social networks (OSNs) and formulate a new research problem, namely, Hop-bounded Maximum Group Friending (HMGF), by modeling both existing friendships and the likelihood of new friend making. To find a set of attendees for socialization activities, HMGF is unique and challenging due to the interplay of the group size, the constraint on existing friendships and the objective function on the likelihood of friend making. We prove that HMGF is NP-Hard, and no approximation algorithm exists unless P = NP. We then propose an error-bounded approximation algorithm to efficiently obtain the solutions very close to the optimal solutions. We conduct a user study to validate our problem formulation and per- form extensive experiments on real datasets to demonstrate the efficiency and effectiveness of our proposed algorithm

Asymmetrically interacting spreading dynamics on complex layered networks

The spread of disease through a physical-contact network and the spread of information about the disease on a communication network are two intimately related dynamical processes. We investigate the asymmetrical interplay between the two types of spreading dynamics, each occurring on its own layer, by focusing on the two fundamental quantities underlying any spreading process: epidemic threshold and the final infection ratio. We find that an epidemic outbreak on the contact layer can induce an outbreak on the communication layer, and information spreading can effectively raise the epidemic threshold. When structural correlation exists between the two layers, the information threshold remains unchanged but the epidemic threshold can be enhanced, making the contact layer more resilient to epidemic outbreak. We develop a physical theory to understand the intricate interplay between the two types of spreading dynamics.Comment: 29 pages, 14 figure