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.

Little is known about the drivers of critically important antibacterial resistance in species with zoonotic potential present on farms (e.g. CTX-M β-lactamase-positive Escherichia coli). We collected samples – monthly, between January 2017 and December 2018 - on 53 dairy farms in South West England along with data for 610 variables concerning antibacterial usage, management practices and meteorological factors. We detected E. coli resistant to amoxicillin, ciprofloxacin, streptomycin and tetracycline, respectively, in 2754/4145 (66%), 263/4145 (6%), 1475/4145 (36%) and 2874/4145 (69%) of all samples from faecally contaminated on-farm and near-farm sites. E. coli positive for blaCTX-M were detected in 224/4145 (5.4%) of samples. Multilevel, multivariable logistic regression showed antibacterial dry cow therapeutic choice (including use of cefquinome or framycetin) to be associated with higher odds of blaCTX-M positivity. Low average monthly ambient temperature was associated with lower odds of blaCTX-M E. coli positivity in samples and with lower odds of finding E. coli resistant to each of the four test antibacterials. This was additional to the effect of temperature on total E. coli density. Furthermore, samples collected close to calves had higher odds of having E. coli resistant to each antibacterial as well as positive for blaCTX-M. Samples collected on pastureland had lower odds of having E. coli resistant to amoxicillin or tetracycline as well as lower odds of being positive for blaCTX-M. Importance Antibacterial resistance poses a significant threat to human and animal health and global food security. Surveillance for resistance on farms is important for many reasons, including to track the impacts of interventions aimed at reducing the prevalence of resistance. In this longitudinal survey of dairy farm antibacterial resistance, we showed that local temperature - as it changes over the course of a year - was associated with the prevalence of antibacterial-resistant E. coli. We also showed that prevalence of resistant E. coli was lower on pastureland and higher in environments inhabited by young animals. These findings have profound implications for routine surveillance and for surveys carried out for research. They provide important evidence that sampling at a single time-point and/or single location on a farm is unlikely to be adequate to accurately determine the status of the farm regarding the presence of samples containing resistant E. coli.

16Little is known about the drivers of critically important antibacterial resistance in 17 species with zoonotic potential present on farms (e.g. CTX-M ꞵ-lactamase-positive 18 Escherichia coli). There is also debate about the influence of farms on the circulation 19 of resistance in local human populations. This was a two-year surveillance study on 20 53 dairy farms. E. coli positive for blaCTX-M were detected in 224/4145 (5.4%) of all 21 samples from faecally-contaminated sites. E. coli positive for blaCTX-M were more 22 prevalent (98/631; 15.5%) in calf samples and less prevalent (12/630; 1.9%) in 23 samples collected from pastureland, including publicly accessible sites. Multilevel, 24 multivariable logistic regression showed antibiotic dry cow therapeutic choice to be 25 associated with risk of blaCTX-M positivity, including use of cefquinome or framycetin; 26 74% of blaCTX-M-positive E. coli were framycetin-resistant. Low temperature was 27 associated with low risk of blaCTX-M positivity. This was additional to the effect of 28 temperature on total E. coli density, a finding with profound implications for 29 surveillance. There was no evidence that study farms had a significant impact on 30 circulating blaCTX-M plasmids in the local human population: across 296 fully 31 sequenced E. coli isolates, two cattle isolates shared blaCTX-M plasmids with eight 32 urinary isolates collected in parallel.33 34 Antimicrobial resistance (AMR) -and particularly antibacterial resistance (ABR) -is a 35 significant global challenge. Many countries are implementing plans to reduce the 36 use of antibacterial drugs (ABs) in food-producing animals. For example, the most 37 recent UK five-year National Action Plan includes a target to reduce AB use (ABU) in 38the treatment of food-producing animals by 25% (1). In Europe, AB sales for food-39 producing animals fell by 20% from 2011 to 2016 (2). In the UK dairy industry, 40 overall ABU dropped from 24 mg/kg in 2015 to 17 mg/kg in 2017 (3, 4). In 2018, 41 additional industry-led policies were enforced in the UK that aim to almost eliminate 42 the use of highest priority critically important antimicrobials (HP-CIAs) such as third-43 and fourth-generation cephalosporins (3GCs and 4GCs) and fluoroquinolones on 44 dairy farms. One reason for reducing ABU in farming is the belief that such 45 measures will reduce the prevalence of ABR bacteria carried by farm animals. 46 However, there is a need for better data on drivers of ABR in farming. More 47 granularity of understanding is required concerning the risks of using individual ABs 48 and other management practices. This is especially important in terms of drivers of 49 HP-CIA resistance. One key focus is on 3GC resistance in Escherichia coli, a 50 species commonly found in animal faeces and considered one of the most significant 51 potential zoonotic threats to humans (5). 523GC-resistance is increasingly common in E. coli causing infections in humans (6) 53 and is also found in farmed and domestic animals around the world (7). The...

Playables are mini-games used in digital advertising and may offer a novel and engaging avenue to improve young people’s well-being at scale. This randomised controlled trial evaluated the immediate impact and protective properties of a psychoeducational playable on adolescents’ body satisfaction and negative affect, and engagement in prosocial behaviours, relative to two active control conditions. Girls and boys aged 13–14 years ( N = 6575) were randomised into one of three conditions: body image playable, body image social networking posts (i.e. static images of the body image playable messages; control 1) or an ocean conservation playable (control 2). Both body image micro-interventions significantly improved state body satisfaction and negative affect, relative to the oceanic playable. No condition buffered against the negative effects associated with viewing idealised media images. Developing playables to counteract the potentially harmful effects associated with surrounding digital environments is a promising avenue for mental health.

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