WeRLman: To Tackle Whale (Transactions), Go Deep (RL)

The security of proof-of-work blockchain protocols critically relies on incentives. Their operators, called miners, receive rewards for creating blocks containing user-generated transactions. Each block rewards its creator with newly minted tokens and with transaction fees paid by the users. The protocol stability is violated if any of the miners surpasses a threshold ratio of the computational power; she is then motivated to deviate with selfish mining and increase her rewards. Previous analyses of selfish mining strategies assumed constant rewards. But with statistics from operational systems, we show that there are occasional whales- blocks with exceptional rewards. Modeling this behavior implies a state-space that grows exponentially with the parameters, becoming prohibitively large for existing analysis tools. We present the WeRLman framework to analyze such models. WeRLman uses deep Reinforcement Learning (RL), inspired by the state-of-the-art AlphaGo Zero algorithm. Directly extending AlphaGo Zero to a stochastic model leads to high sampling noise, which is detrimental to the learning process. Therefore, WeRLman employs novel variance reduction techniques by exploiting the recurrent nature of the system and prior knowledge of transition probabilities. Evaluating WeRLman against models we can accurately solve demonstrates it achieves unprecedented accuracy in deep RL for blockchain. We use WeRLman to analyze the incentives of a rational miner in various settings and upper-bound the security threshold of Bitcoin-like blockchains. We show, for the first time, a negative relationship between fee variability and the security threshold. The previously known bound, with constant rewards, stands at 0.25. We show that considering whale transactions reduces this threshold considerably. In particular, with Bitcoin historical fees and its future minting policy, its threshold for deviation will drop to 0.2 in 10 years, 0.17 in 20 years, and to 0.12 in 30 years. With recent fees from the Ethereum smart-contract platform, the threshold drops to 0.17. These are below the common sizes of large miners

Genetically Engineering Glycolysis in T Cells Increases Their Antitumor Function

BACKGROUND: T cells play a central role in the antitumor response. However, they often face numerous hurdles in the tumor microenvironment, including the scarcity of available essential metabolites such as glucose and amino acids. Moreover, cancer cells can monopolize these resources to thrive and proliferate by upregulating metabolite transporters and maintaining a high metabolic rate, thereby outcompeting T cells. METHODS: Herein, we sought to improve T-cell antitumor function in the tumor vicinity by enhancing their glycolytic capacity to better compete with tumor cells. To achieve this, we engineered human T cells to express a key glycolysis enzyme, phosphofructokinase, in conjunction with Glucose transporter 3, a glucose transporter. We co-expressed these, along with tumor-specific chimeric antigen or T-cell receptors. RESULTS: Engineered cells demonstrated an increased cytokine secretion and upregulation of T-cell activation markers compared with control cells. Moreover, they displayed superior glycolytic capacity, which translated into an improved in vivo therapeutic potential in a xenograft model of human tumors. CONCLUSION: In summary, these findings support the implementation of T-cell metabolic engineering to enhance the efficacy of cellular immunotherapies for cancer

Deep Bribe: Predicting the Rise of Bribery in Blockchain Mining with Deep RL

Blockchain security relies on incentives to ensure participants, called miners, cooperate and behave as the protocol dictates. Such protocols have a security threshold – a miner whose relative computational power is larger than the threshold can deviate to improve her revenue. Moreover, blockchain participants can behave in a petty compliant manner: usually follow the protocol, but deviate to increase revenue when deviation cannot be distinguished externally from the prescribed behavior. The effect of petty compliant miners on the security threshold of blockchains is not well understood. Due to the complexity of the analysis, it remained an open question since Carlsten et al. identified it in 2016. In this work, we use deep Reinforcement Learning (RL) to analyze how a rational miner performs selfish mining by deviating from the protocol to maximize revenue when petty compliant miners are present. We find that a selfish miner can exploit petty compliant miners to increase her revenue by bribing them. Our method reveals that the security threshold is lower when petty compliant miners are present. In particular, with parameters estimated from the Bitcoin blockchain, we find the threshold drops from the known value of 25% to only 21% (or 19%) when 50% (or 75%) of the other miners are petty compliant. Hence, our deep RL analysis puts the open question to rest; the presence of petty compliant miners exacerbates a blockchain’s vulnerability to selfish mining and is a major security threat

Comment on Casiraghi et al. “Mucoadhesive Budesonide Formulation for the Treatment of Eosinophilic Esophagitis” 2020, 12, 211

In their article, Casiraghi, A. et al. describe a few relevant methods to assess the quality of a pharmaceutical preparation of oral viscous budesonide, intended to be swallowed, and treat the esophagus in eosinophilic esophagitis patients. They choose the following methods for this purpose: rheological properties, syringeability, mucoadhesiveness, and in vitro penetration of budesonide in porcine esophageal tissue. At the end of the article, they concluded that the best formulation of oral viscous budesonide was the one already being used in hospitals, based on xanthan gum. In their article, the authors did not emphasize that this specific formula was developed by the compounding pharmacist Eyal Zur from Israel and was published eight years before, as part of an article in the International Journal of Pharmaceutical Compounding. The purpose of this comment is to give the appropriate credit to the pharmacist who first developed and published this well designed formulation

Haline Convection within a Fresh-Saline Water Interface in a Stratified Coastal Aquifer Induced by Tide

Sea-tide effects on the fresh-saline water interface (FSI) in a stratified coastal aquifer are examined through laboratory experiments. The physical model, a two-dimensional rectangular flow tank, is filled with layered aquifers and aquitards. The aquifers serve as the main entrances/exits of water to/from the system through significant horizontal flows, creating unstable conditions of heavier saline water above lighter freshwater for short periods of time. Several processes create mixing; this instability results in haline convection, creating downward fingering, stable rising of horizontal saltwater front, and unstable upward fingerings of flushing freshwater. The time lag between the sea tide fluctuations and the emergence of adequate fresh- and saltwater is higher in a stratified system compared to a homogeneous system. Furthermore, longer tide cycles lead to the enlargement of the FSI’s toe horizontal movement range. The combination of tidal forcing with a layering aquifer structure leads to a wider FSI by creating a significant salt- and freshwater mixing inside each layer, vertical flows between the layers, and saltwater bodies at isolated areas. Haline convection within the FSI might be the reason for the wider fresh-saline interfaces that are found in field studies

Topical Oxybutynin 10% Gel for the Treatment of Primary Focal Hyperhidrosis: A Randomized Double-blind Placebo-controlled Split Area Study

Limited efficacy, costs, side-effects and complications are issues of concern for most current therapeutic modalities for focal hyperhidrosis. This study evaluated the efficacy of topical oxybutynin 10% gel in treating 61 patients with primary focal hyperhidrosis. The gel was applied to the right or left axilla, palms or soles vs. a placebo compound to the contralateral side for 30 days. A blinded visual grading of the change in starch-iodine tests was performed by 2 non-involved physicians. The Hyperhidrosis Disease Severity Scale (HDSS) and Dermatology Life Quality Index (DLQI) questionnaires were administered before and after treatment. The patients rated their satisfaction with treatment. Fifty-three patients completed the 4-week treatment. Sweat reduction in the drug-treated sweating areas was higher than in the control-treated areas. There was a significant mean improvement in pre- and post-treatment HDSS and DQLI (p = 0.001 for both). Thirty-nine subjects (74%) reported moderate-to-high satisfaction. Twice-daily topical application of oxybutynin 10% gel appears to be an effective, safe and well-tolerated treatment for focal primary hyperhidrosis

Topical propranolol improves epistaxis in patients with hereditary hemorrhagic telangiectasia - a preliminary report

Abstract Background Severe epistaxis is often difficult to control in patients with hereditary hemorrhagic telangiectasia (HHT). Propranolol has been shown to have antiangiogenic properties in vitro and in vivo and is commonly used to treat hemangiomas. We present our experience with topical nasal propranolol for the treatment of moderate to severe epistaxis in patients with HHT. Methods Retrospective case series. Six patients with HHT were treated with 0.5 cm3 of 1.5% propranolol gel, applied to each nostril twice daily for at least 12 weeks. Outcome measures were epistaxis severity score (ESS), hemoglobin level, and number of blood transfusions prior to and while on treatment. Local and systemic side effects were recorded. Results The mean duration of treatment was 30 ± 5.6 weeks. A significant improvement in the ESS was found in all patients, with a mean decrease from 6.4 ± 2.1 at treatment onset to 3.5 ± 1.7 at 12 weeks (p = 0.028). Hemoglobin level increased significantly from 8.4 ± 3.1 to 11.0 ± 1.8 g/dL at 12 weeks (p = 0.043). The mean number of blood transfusions decreased from 4.5 ± 4.9 before treatment to 2.5 ± 2.9 at 12 weeks and 0.3 ± 0.8 at 24 weeks, but the difference did not reach statistical significance (p = 0.109 for both). No significant side effects of treatment were recorded. Conclusions These preliminary results suggest that topical propranolol may be effective for the treatment of epistaxis in patients with HHT. A prospective controlled trial is required to confirm our findings