Abstract:Herpes simplex virus (HSV) infection is the most common cause of corneal blindness in the Western world. Despite effective anti-viral drugs such as acyclovir (ACV), disease recurrence due to the virus establishing latency within the corneal nerves and possibly cells makes treatment very challenging. Furthermore, although effective, current systemic and topical preparations of anti-viral drugs do not appear to deliver sufficient quantities to the cornea to prevent reactivation. Current treatment for HSV vision loss is transplantation with donor corneas, but the surgery itself can reactivate viruses. We examined the feasibility of preventing viral reactivation during surgery, by sustained delivery of ACV introduced during corneal transplantation surgery, through encapsulation of the drug within silica (SiO 2 ) nanoparticles (NP) incorporated into biosynthetic alternatives to donor corneas. We show that incorporation of NPs did not affect optical clarity of the collagen-based corneal substitutes nor their biocompatibility. NP-encapsulation effectively sustained ACV release from the biosynthetic implants over 10 days, compared to free ACV incorporated directly into the hydrogel constructs. The NP-enabled sustained release resulted in effective prevention of virally-induced cell death, not observed with the free drug. This early model demonstrates the feasibility of using biomimetic corneal substitutes that incorporate a drug release system (e.g. silica nanoparticles encapsulating ACV) as future alternatives to human donor tissue grafts, for transplantation of HSV-infected corneas.

Lysine acetylation (Kac) as an important posttranslational modification of histones is essential for the regulation of gene expression in hepatocellular carcinoma (HCC). However, the atlas of whole acetylated proteins in HCC tissues and the difference in protein acetylation between normal human tissues and HCC tissues are unknown. In this report, we characterized the proteome and acetyl proteome (acetylome) profile of normal, paracancerous, and HCC liver tissues in human clinical samples by quantitative proteomics techniques. We identified 6781 acetylation sites of 2582 proteins and quantified 2492 acetylation sites of 1190 proteins in normal, paracancerous, and HCC liver tissues. Among them, 15 proteins were multiacetylated with more than 10 lysine residues. The histone acetyltransferases p300 and CBP were found to be hyperacetylated in hepatitis B virus pathway. Moreover, we found that 250 Kac sites of 214 proteins were upregulated and 662 Kac sites of 451 proteins were downregulated in HCC compared with normal liver tissues. Additionally, the acetylation levels of lysine 120 in histone H2B (H2BK120ac), lysine 18 in histone H3.3 (H3.3K18ac), and lysine 77 in histone H4 (H4K77ac) were increased in HCC. Interestingly, the higher levels of H2BK120ac, H3.3K18ac, and H4K77ac were significantly associated with worse prognosis, such as poorer survival and higher recurrence in an independent clinical cohort of HCC patients. Overall, this study lays a foundation for understanding the functions of acetylation in HCC and provides potential prognostic factors for the diagnosis and therapy of HCC.

Electronic supplementary information (ESI) available: Experimental details, EDS patterns, part of XRD patterns, XPS spectra, UV-vis diffusive reflectance spectra and photocatalytic results. See

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