Enig: Player Replaceable Finality Layers with Optimal Validity

We present two new provably secure finality layers for Nakamoto style blockchains. One is for partially synchronous networks and the other is for networks with periods of synchrony. Both protocols are player replaceable and therefore enjoy protection against denial of service attacks when run with a proof-of-stake lottery to elect the parties. The finality layers are proven secure to run on top of any Nakamoto style blockchain which has a property called \emph{finality friendliness}. Both finality layers improve on all existing provably secure finality layers in terms of communication complexity or security. A proof-of-stake finality layer has $v$-validity if whenever it declares a block $B$ final then honest parties holding a fraction $v$ of the stake had $B$ on the longest chain. Validity is important to prevent that the finality layer finalises blocks that were not ``good\u27\u27 according to the Nakamoto style blockchain. We prove upper bounds on the achievable validity in partially synchronous networks and networks with periods of synchrony. Both our finality layers match these upper bounds

Targeting of human interleukin-12B by small hairpin RNAs in xenografted psoriatic skin

<p>Abstract</p> <p>Background</p> <p>Psoriasis is a chronic inflammatory skin disorder that shows as erythematous and scaly lesions. The pathogenesis of psoriasis is driven by a dysregulation of the immune system which leads to an altered cytokine production. Proinflammatory cytokines that are up-regulated in psoriasis include tumor necrosis factor alpha (TNFα), interleukin-12 (IL-12), and IL-23 for which monoclonal antibodies have already been approved for clinical use. We have previously documented the therapeutic applicability of targeting TNFα mRNA for RNA interference-mediated down-regulation by anti-TNFα small hairpin RNAs (shRNAs) delivered by lentiviral vectors to xenografted psoriatic skin. The present report aims at targeting mRNA encoding the shared p40 subunit (IL-12B) of IL-12 and IL-23 by cellular transduction with lentiviral vectors encoding anti-IL12B shRNAs.</p> <p>Methods</p> <p>Effective anti-IL12B shRNAs are identified among a panel of shRNAs by potency measurements in cultured cells. The efficiency and persistency of lentiviral gene delivery to xenografted human skin are investigated by bioluminescence analysis of skin treated with lentiviral vectors encoding the luciferase gene. shRNA-expressing lentiviral vectors are intradermally injected in xenografted psoriatic skin and the effects of the treatment evaluated by clinical psoriasis scoring, by measurements of epidermal thickness, and IL-12B mRNA levels.</p> <p>Results</p> <p>Potent and persistent transgene expression following a single intradermal injection of lentiviral vectors in xenografted human skin is reported. Stable IL-12B mRNA knockdown and reduced epidermal thickness are achieved three weeks after treatment of xenografted psoriatic skin with lentivirus-encoded anti-IL12B shRNAs. These findings mimick the results obtained with anti-TNFα shRNAs but, in contrast to anti-TNFα treatment, anti-IL12B shRNAs do not ameliorate the psoriatic phenotype as evaluated by semi-quantitative clinical scoring and by immunohistological examination.</p> <p>Conclusions</p> <p>Our studies consolidate the properties of lentiviral vectors as a tool for potent gene delivery and for evaluation of mRNA targets for anti-inflammatory therapy. However, in contrast to local anti-TNFα treatment, the therapeutic potential of targeting IL-12B at the RNA level in psoriasis is questioned.</p

Weight-Based Nakamoto-Style Blockchains

We propose a framework for building Nakamoto-style proof-of-work blockchains where blocks are treated differently in the ``longest chain rule\u27\u27. The crucial parameter is a weight function assigning different weights to blocks according to their hash value. Our framework enables the analysis of different weight functions while proving all statements at the appropriate level of abstraction. This allows us to quickly derive protocol guarantees for different weight functions. We exemplify the usefulness of our framework by capturing the classical Bitcoin protocol as well as exponentially growing functions as special cases. We show the typical properties---chain growth, chain quality and common prefix---for both, and further show that the latter provide an additional guarantee, namely a weak form of optimistic responsiveness. More precisely, we prove for a certain class of exponentially growing weight functions that in periods without corruption, the confirmation time only depends on the unknown actual network delay instead of the known upper bound