BACKGROUND New treatments are needed to reduce the risk of progression of coronavirus disease 2019 (Covid-19). Molnupiravir is an oral, small-molecule antiviral prodrug that is active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19 and at least one risk factor for severe Covid-19 illness. RESULTS A total of 1433 participants underwent randomization; 716 were assigned to receive molnupiravir and 717 to receive placebo. In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, −3.0 percentage points; 95% confidence interval, −5.9 to −0.1). CONCLUSIONS Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19.

Limb regeneration is a frontier in biomedical science. Identifying triggers of innate morphogenetic responses in vivo to induce the growth of healthy patterned tissue would address the needs of millions of patients, from diabetics to victims of trauma. Organisms such as Xenopus laevis—whose limited regenerative capacities in adulthood mirror those of humans—are important models with which to test interventions that can restore form and function. Here, we demonstrate long-term (18 months) regrowth, marked tissue repatterning, and functional restoration of an amputated X. laevis hindlimb following a 24-hour exposure to a multidrug, pro-regenerative treatment delivered by a wearable bioreactor. Regenerated tissues composed of skin, bone, vasculature, and nerves significantly exceeded the complexity and sensorimotor capacities of untreated and control animals’ hypomorphic spikes. RNA sequencing of early tissue buds revealed activation of developmental pathways such as Wnt/β-catenin, TGF-β, hedgehog, and Notch. These data demonstrate the successful “kickstarting” of endogenous regenerative pathways in a vertebrate model.

The spread of SARS-CoV-2 and ongoing COVID-19 pandemic underscores the need for new treatments. Here we report that cannabidiol (CBD) inhibits infection of SARS-CoV-2 in cells and mice. CBD and its metabolite 7-OH-CBD, but not THC or other congeneric cannabinoids tested, potently block SARS-CoV-2 replication in lung epithelial cells. CBD acts after viral entry, inhibiting viral gene expression and reversing many effects of SARS-CoV-2 on host gene transcription. CBD inhibits SARS-CoV-2 replication in part by up-regulating the host IRE1α RNase endoplasmic reticulum (ER) stress response and interferon signaling pathways. In matched groups of human patients from the National COVID Cohort Collaborative, CBD (100 mg/ml oral solution per medical records) had a significant negative association with positive SARS-CoV-2 tests. This study highlights CBD as a potential preventative agent for early-stage SARS-CoV-2 infection and merits future clinical trials. We caution against use of non-medical formulations including edibles, inhalants or topicals as a preventative or treatment therapy at the present time.

Web-based management dashboards provide intuitive interfaces to support various infrastructure management tasks. However, the lack of programmability in these dashboards makes it difficult to automate management tasks. To address this limitation, we propose a system call MAIL (Management Automation through Imitation Learning) that learns from an operator’s demonstrations using imitation learning to automate management tasks on web-based dashboards. A novel Contextual Imitation Learning algorithm is proposed in MAIL to overcome the learning challenges brought by the requirements of infrastructure management automation. The effectiveness of the MAIL system has been demonstrated using both synthetic environments and production environments. It outperforms existing methods and is able to achieve an 86%-100% success rate for most tasks.

New market practices and business models are emerging around so-called stablecoins, a type of crypto asset with certain features that seek to stabilize the price of the coin. Stablecoins have the potential to offer a borderless and more accessible way to pay, addressing many shortcomings in existing payment systems around the world. Yet, these developments also raise fundamental legal issues. What questions should lawyers and financial advisors be asking to ensure risks are adequately addressed? What answers can stablecoin innovators give to financial authorities and industry stakeholders to provide comfort that there is a sound legal basis for the business models and market practices around their coin? U.S. commercial law, which is chiefly designed to support financial market activities, contains powerful principles that can usefully serve as building blocks for a foundational legal framework to uniquely advance a stablecoin’s economic purpose as a medium of exchange — allowing technologists to move fast, but safely. This Article spells out how to build such a legal basis by leveraging the core commercial law principles of (i) focusing on the principles of settlement finality, (ii) rules for adverse claims, (iii) discharge of the underlying obligation, and (iv) the concept of a security entitlement. It maps out how these principles are embodied under the U.S. commercial laws of investment securities (UCC Article 8) and of payments (UCC Articles 3, 4, and 4A). The goal in doing so is to show how innovators can incorporate novel, technology-driven market practices and business models into the existing financial law framework in a proven and effective way — how to leverage what is working today and does not need to be invented again. Awareness of the availability of these commercial law tools, and their limitations, can provide important help to stablecoin developers and market participants in managing their exposure, designing efficient

For a nation’s economy to function effectively, its citizens must have confidence in its money and payment services. The Federal Reserve, as the nation’s central bank, works to maintain the public’s confidence by fostering monetary stability, financial stability, and a safe and efficient payment system. This paper is the first step in a public discussion between the Federal Reserve and stakeholders about central bank digital currencies (CBDCs). For the purpose of this paper, a CBDC is defined as a digital liability of a central bank that is widely available to the general public. In this respect, it is analogous to a digital form of paper money. The paper has been designed to foster a broad and transparent public dialogue about CBDCs in general, and about the potential benefits and risks of a U.S. CBDC. The paper is not intended to advance any specific policy outcome, nor is it intended to signal that the Federal Reserve will make any imminent decisions about the appropriateness of issuing a U.S. CBDC.

Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.

In current political systems, the actions of both rulers and the governed are shaped by wrong incentives. Rulers have no liability and face no economic disadvantage if they make poor decisions. The governed are made to believe that “free” benefits can come into existence through the power of their votes. This politicizes the state monopoly on force and leads to constant changes to the “social contract“ and an endless struggle to influence the direction of this change. In this paper, I propose a peaceful and voluntary alternative to the political status quo: Free Private Cities. The defining feature of a Free Private City is that it is run by a for-profit company, referred to as the Operator, which acts as a “government service provider”. In this capacity, the Operator offers citizens of the Free Private City protection of life, liberty and property. The services Operators provide encompass internal and external security, a predefined legal and regulatory framework and an independent dispute resolution system. Interested individuals and companies enter into a Citizens’ Contract, paying a fixed yearly fee for these services instead of taxes. Within that framework, a “spontaneous order” can develop which emerges from the voluntary activities of the citizens. The Operator cannot later unilaterally change a Citizens’ Contract without the permission of the citizen concerned. Disputes between citizens and the Operator are heard before external arbitration tribunals, as is already customary in international commercial law. If the Operator ignores arbitral awards or abuses its power, customers will eventually leave and the Operator will face the risk of bankruptcy. Since all land is currently controlled by governments, the establishment of a Free Private City requires that an Operator enters into a contractual agreement with an existing state, referred to as the Host Nation. In this agreement, the Host Nation grants the Operator the right to establish the Free Private City on a defined territory in accordance with certain predefined conditions, normally encompassing extended regulatory autonomy in various fields. One would expect states to be willing to surrender some of their power if they expect large enough benefits in return. Such benefits could include job creation, attraction of foreign investment and a percentage of profits generated by the Operator. The existence of a large number of Special Economic Zones worldwide demonstrates the willingness of states to do this.