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This is the Editorial for JJS 3.2, written by Rob Breton and David Owen.

Background It is controversial whether or not the carpometacarpal joint (CMCJ) should be included in total wrist arthrodesis (TWA). Complications commonly occur at this site and studies examining its inclusion and exclusion are conflicting. A randomised clinical trial comparing wrist arthrodesis with CMCJ arthrodesis and spanning plate to wrist arthrodesis with CMCJ preservation and non-CMCJ spanning plate has not been performed. Method A single centre randomised clinical trial including 120 adults with end-stage isolated wrist arthritis will be performed to compare TWA with and without the CMCJ included in the arthrodesis. The primary outcome is complications in the first post-operative year. Secondary outcomes are Disabilities of the Arm, Shoulder and Hand (DASH) score, Patient Rated Wrist Evaluation (PRWE) and grip strength measured at 1, 2 and 5 years. Late complications, return to work and satisfaction will also be recorded. Discussion It is unknown whether the CMCJ should be included in TWA. This trial will contribute to an improved understanding of optimal management of the CMCJ in total wrist arthrodesis. Trial registration This trial was prospectively registered with the Australia New Zealand Clinical Trials Registry with identifying number ACTRN12621000169842 on the 16th February 2021. WHO: U1111–12626523. ANZCTR: ACTRN12621000169842

In this chapter I consider debates concerning migration and global justice in terms of the governance of transnational migration. The relationship between migration and global justice is not simply a question about ‘justice in migration’, that is, the rights of individuals to engage in transnational migration or the rights of states to control such movement, it is also a matter of the value of migration as an instrument for realizing other ends of global justice (according to whatever one’s favoured view of global justice is). Addressing three views - liberal statism, liberal cosmopolitanism and republican internationalism - the chapter brings normative theory into dialogue with the theory of goods in order to elaborate the institutional implications of each view and to consider the theoretical and practical challenges that each faces.

The main protease (Mpro) of SARS-CoV-2 is central to viral maturation and is a promising drug target, but little is known about structural aspects of how it binds to its 11 natural cleavage sites. We used biophysical and crystallographic data and an array of biomolecular simulation techniques, including automated docking, molecular dynamics (MD) and interactive MD in virtual reality, QM/MM, and linear-scaling DFT, to investigate the molecular features underlying recognition of the natural Mpro substrates. We extensively analysed the subsite interactions of modelled 11-residue cleavage site peptides, crystallographic ligands, and docked COVID Moonshot-designed covalent inhibitors. Our modelling studies reveal remarkable consistency in the hydrogen bonding patterns of the natural Mpro substrates, particularly on the N-terminal side of the scissile bond. They highlight the critical role of interactions beyond the immediate active site in recognition and catalysis, in particular plasticity at the S2 site. Building on our initial Mpro-substrate models, we used predictive saturation variation scanning (PreSaVS) to design peptides with improved affinity. Non-denaturing mass spectrometry and other biophysical analyses confirm these new and effective ‘peptibitors’ inhibit Mpro competitively. Our combined results provide new insights and highlight opportunities for the development of Mpro inhibitors as anti-COVID-19 drugs., The main protease (Mpro) of SARS-CoV-2 is central to viral maturation and is a promising drug target. In silico methods reveal structural aspects of how it binds to its 11 natural cleavage sites, the design of novel peptide inhibitors, and insights into drug design.

Effective agents to treat coronavirus infection are urgently required, not only to treat COVID-19, but to prepare for future outbreaks. Repurposed anti-virals such as remdesivir and human anti-inflammatories such as barcitinib have received emergency approval but their overall benefits remain unclear. Vaccines are the most promising prospect for COVID-19, but will need to be redeveloped for any future coronavirus outbreak. Protecting against future outbreaks requires the identification of targets that are conserved between coronavirus strains and amenable to drug discovery. Two such targets are the main protease (Mpro) and the papain-like protease (PLpro) which are essential for the coronavirus replication cycle. We describe the discovery of two non-antiviral therapeutic agents, the caspase-1 inhibitor SDZ 224015 and Tarloxotinib that target Mpro and PLpro, respectively. These were identified through extensive experimental screens of the drug repurposing ReFRAME library of 12,000 therapeutic agents. The caspase-1 inhibitor SDZ 224015, was found to be a potent irreversible inhibitor of Mpro (IC50 30 nM) while Tarloxotinib, a clinical stage epidermal growth factor receptor inhibitor, is a sub micromolar inhibitor of PLpro (IC50 300 nM, Ki 200 nM) and is the first reported PLpro inhibitor with drug-like properties. SDZ 224015 and Tarloxotinib have both undergone safety evaluation in humans and hence are candidates for COVID-19 clinical evaluation.

Focusing on the activities of LARGE (the Live Action Role-Playing Guild of Edmonton), several performance concepts are explored using the primary sources of five interview subjects and the author’s auto-ethnographic perspective on participating in LARPs in the Edmonton area. Some of these performance concepts are how LARP can be considered “improv in disguise,” how the use of rules systems both helps and hinders ideas of agency and immersion, and how issues of consent are essential to the success of creating a shared reality among diverse personalities. The article begins with an auto-ethnographic description of the LARP event Broken Covenant, which leads to explaining how LARGE began and how it differs from more well-known boffer LARPS. The article then drills down on the varied histories of the interview subjects and explores the concept of improvisation in LARP as ‘yes, but…,’ in comparison to the well-known improv mantra of ‘yes, and. …’ Agency and immersion are explored, leading to a discussion of emotional investment and, most important, consent. The article demonstrates that there is a vibrant and sophisticated LARP community in Edmonton (mostly transplanted from Saskatoon) creating performances in the non-traditional milieu of LARP.

This article addresses current norms of the ‘dispersed’ regime of global migration governance centred on state control of borders as pivotal to the reproduction of structural injustice in the form of racialized patterns of transnational positional difference. It focuses on the implications of this structural injustice for global inequality and, more specifically, for fair access to migration opportunities. Drawing on Rawls’ discussion of background justice and Young's work on structural injustice, it argues that addressing this structural injustice requires constructing a regime of global migration governance that regulates state migration policies and proceeds to outline, within the terms of non-ideal theory, the basic norms of such a regime and to indicate some practical steps that could be taken toward such a regime

A high-throughput mass spectrometry based Mpro assay identifies penicillin esters as new SARS-CoV-2 Mpro inhibitors., The main viral protease (Mpro) of SARS-CoV-2 is a nucleophilic cysteine hydrolase and a current target for anti-viral chemotherapy. We describe a high-throughput solid phase extraction coupled to mass spectrometry Mpro assay. The results reveal some β-lactams, including penicillin esters, are active site reacting Mpro inhibitors, thus highlighting the potential of acylating agents for Mpro inhibition.

Nontypeable Haemophilus influenzae (NTHi) is a significant pathogen in respiratory disease and otitis media. Important for NTHi survival, colonization and persistence in vivo is the Sap (sensitivity to antimicrobial peptides) ABC transporter system. Current models propose a direct role for Sap in heme and antimicrobial peptide (AMP) transport. Here, the crystal structure of SapA, the periplasmic component of Sap, in a closed, ligand bound conformation, is presented. Phylogenetic and cavity volume analysis predicts that the small, hydrophobic SapA central ligand binding cavity is most likely occupied by a hydrophobic di- or tri- peptide. The cavity is of insufficient volume to accommodate heme or folded AMPs. Crystal structures of SapA have identified surface interactions with heme and dsRNA. Heme binds SapA weakly (Kd 282 μM) through a surface exposed histidine, while the dsRNA is coordinated via residues which constitute part of a conserved motif (estimated Kd 4.4 μM). The RNA affinity falls within the range observed for characterized RNA/protein complexes. Overall, we describe in molecular-detail the interactions of SapA with heme and dsRNA and propose a role for SapA in the transport of di- or tri-peptides.

The availability and repartition of fucosylated glycans within the gastrointestinal tract contributes to the adaptation of gut bacteria species to ecological niches. To access this source of nutrients, gut bacteria encode α-l-fucosidases (fucosidases) which catalyze the hydrolysis of terminal α-l-fucosidic linkages. We determined the substrate and linkage specificities of fucosidases from the human gut symbiont Ruminococcus gnavus. Sequence similarity network identified strain-specific fucosidases in R. gnavus ATCC 29149 and E1 strains that were further validated enzymatically against a range of defined oligosaccharides and glycoconjugates. Using a combination of glycan microarrays, mass spectrometry, isothermal titration calorimetry, crystallographic and saturation transfer difference NMR approaches, we identified a fucosidase with the capacity to recognize sialic acid-terminated fucosylated glycans (sialyl Lewis X/A epitopes) and hydrolyze α1–3/4 fucosyl linkages in these substrates without the need to remove sialic acid. Molecular dynamics simulation and docking showed that 3′-Sialyl Lewis X (sLeX) could be accommodated within the binding site of the enzyme. This specificity may contribute to the adaptation of R. gnavus strains to the infant and adult gut and has potential applications in diagnostic glycomic assays for diabetes and certain cancers.

Designing covalent inhibitors is increasingly important, although it remains challenging. Here, we present covalentizer, a computational pipeline for identifying irreversible inhibitors based on structures of targets with non-covalent binders. Through covalent docking of tailored focused libraries, we identify candidates that can bind covalently to a nearby cysteine while preserving the interactions of the original molecule. We found ∼11,000 cysteines proximal to a ligand across 8,386 complexes in the PDB. Of these, the protocol identified 1,553 structures with covalent predictions. In a prospective evaluation, five out of nine predicted covalent kinase inhibitors showed half-maximal inhibitory concentration (IC50) values between 155 nM and 4.5 μM. Application against an existing SARS-CoV Mpro reversible inhibitor led to an acrylamide inhibitor series with low micromolar IC50 values against SARS-CoV-2 Mpro. The docking was validated by 12 co-crystal structures. Together these examples hint at the vast number of covalent inhibitors accessible through our protocol., Graphical Abstract, Designing covalent inhibitors is a challenging task. Covalentizer is a computational pipeline for identifying irreversible inhibitors based on known non-covalent binders. Within the PDB, Zaidman and Gehrtz et al. identified >1,553 structures with covalent predictions, leading to the discovery of covalent kinase inhibitors and an inhibitor of SARS-CoV-2 Mpro.

Herein we provide a living summary of the data generated during the COVID Moonshot project focused on the development of SARS-CoV-2 main protease (Mpro) inhibitors. Our approach uniquely combines crowdsourced medicinal chemistry insights with high throughput crystallography, exascale computational chemistry infrastructure for simulations, and machine learning in triaging designs and predicting synthetic routes. This manuscript describes our methodologies leading to both covalent and non-covalent inhibitors displaying protease IC50 values under 150 nM and viral inhibition under 5 uM in multiple different viral replication assays. Furthermore, we provide over 200 crystal structures of fragment-like and lead-like molecules in complex with the main protease. Over 1000 synthesized and ordered compounds are also reported with the corresponding activity in Mpro enzymatic assays using two different experimental setups. The data referenced in this document will be continually updated to reflect the current experimental progress of the COVID Moonshot project, and serves as a citable reference for ensuing publications. All of the generated data is open to other researchers who may find it of use.

COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease., The SARS-CoV-2 main protease is an important target for the development of COVID-19 therapeutics. Here, the authors combine X-ray crystallography and mass spectrometry and performed a large scale fragment screening campaign, which yielded 96 liganded structures of this essential viral protein that are of interest for further drug development efforts.

In this selection, published in The New Yorker in 2004, journalist David Owen argues that far from being “an ecological nightmare, a wasteland of concrete and garbage,” Manhattan was “the greenest community in the United States” and the very “model of environmental responsibility,” a bold proposition that reflects a shift in thinking about the built environment from concerns about congestion, pollution, health, and morality to broader, more technical issues of environmental sustainability. Owen admits that places like New York do indeed use massive amounts of energy and generate huge amounts of greenhouse gases and solid wastes when calculated by the square foot. But when calculated on a per capita basis, putting “one and a half million people on a 23-square-mile island … forces the majority to live in some of the more inherently energy-efficient structures in the world: apartment buildings.” Density also allows urban residents to walk, bike, and take transit to run errands and go to work. As a result, Manhattanites use private automobiles at one-tenth the rate of suburbanites and consume a small fraction – again, on a per capita basis – of energy as compared to average Americans. “Barring an almost inconceivable reduction in the earth’s population,” Owen concludes, “dense urban centers offer one of the few plausible remedies for some of the world’s most discouraging environmental ills.”