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The North Atlantic Climate System Integrated Study (ACSIS) was a large multidisciplinary research programme funded by the UK's Natural Environment Research Council (NERC). ACSIS ran from 2016 to 2022 and brought together around 80 scientists from seven leading UK-based environmental research institutes to deliver major advances in the understanding of North Atlantic climate variability and extremes. Here, we present an overview of the data generated by the ACSIS programme. The datasets described cover the North Atlantic Ocean, the atmosphere above it (including its composition), and Arctic sea ice. Atmospheric composition datasets include measurements from seven aircraft campaigns (45 flights in total, 0–10 km altitude range) in the northeastern Atlantic (∼ 15–55° N, ∼ 40° W–5° E) made at intervals of 6 months to 2 years between February 2017 and May 2022. The flights measured chemical species (including greenhouse gases; ozone precursors; and volatile organic compounds – VOCs) and aerosols (organic aerosol – OA; SO4; NH4; NO3; and non-sea salt chloride – nss-Cl) (https://doi.org/10.5285/6285564c34a246fc9ba5ce053d85e5e7, FAAM et al., 2024). Ground-based stations at the Cape Verde Atmospheric Observatory (CVAO), Penlee Point Atmospheric Observatory (PPAO), and Plymouth Marine Laboratory (PML) recorded ozone, ozone precursors, halocarbons, greenhouse gases (CO2 and methane), SO2, and photolysis rates (CVAO; http://catalogue.ceda.ac.uk/uuid/81693aad69409100b1b9a247b9ae75d5, National Centre for Atmospheric Science et al., 2010); O3 and CH4 (PPAO, https://catalogue.ceda.ac.uk/uuid/8f1ff8ea77534e08b03983685990a9b0 (Plymouth Marine Laboratory and Yang, 2017); and aerosols (PML, https://doi.org/10.5285/e74491c96ef24df29a9342a3d57b5939, Smyth, 2024), respectively. Complementary model simulations of atmospheric composition were performed with the UK Earth System Model (UKESM1) for the period from 1982 to 2020 using Coupled Model Intercomparison Project Phase 6 (CMIP6) historical forcing up to 2014 and Shared Socioeconomic Pathways (SSP) scenario SSP3-7.0 from 2015 to 2020. Model temperature and winds were relaxed towards ERA reanalysis. Monthly mean model data for ozone, NO, NO2, CO, methane, stratospheric ozone tracers, and 30 regionally emitted tracers are available for download (https://data.ceda.ac.uk/badc/acsis/UKESM1-hindcasts, Abraham, 2024). ACSIS also generated new ocean heat content diagnostics (https://doi.org/10/g6wm, https://doi.org/10/g8g2, Moat et al., 2021a–b) and gridded temperature and salinity based on objectively mapped Argo measurements (https://doi.org/10.5285/fe8e524d-7f04-41f3-e053-6c86abc04d51 King, 2023). An ensemble of atmosphere-forced global-ocean sea-ice simulations using the NEMO-CICE model was performed with horizontal resolutions of 1/4 and 1/12° covering the period from 1958 to 2020 using several different atmosphere-reanalysis-based surface forcing datasets, supplemented by additional global simulations and stand-alone sea-ice model simulations with advanced sea-ice physics using the CICE model (http://catalogue.ceda.ac.uk/uuid/770a885a8bc34d51ad71e87ef346d6a8, Megann et al., 2021e). Output is stored as monthly averages and includes 3D potential temperature, salinity, zonal velocity, meridional velocity, and vertical velocity; 2D sea-surface height, mixed-layer depth, surface heat, and freshwater fluxes; ice concentration and thickness; and a wide variety of other variables. In addition to the data presented here, we provide a very brief overview of several other datasets that were generated during ACSIS and have been described previously in the literature.

Novel substituted monohydrazides synthesized for this study displayed broad-spectrum activity against various fungal strains, including a panel of clinically relevant Candida auris strains. The activity of these compounds was either comparable or superior to amphotericin B against most of the fungal strains tested. These compounds possessed fungistatic activity in a time-kill assay and exhibited no mammalian cell toxicity. In addition, they prevented the formation of fungal biofilms. Even after repeated exposures, the Candida albicans ATCC 10231 (strain A) fungal strain did not develop resistance to these monohydrazides., Competing Interests: The authors have no conflict of interest to disclose., (This journal is © The Royal Society of Chemistry.)

Antimicrobial resistance (AMR) poses a significant threat to human health around the world. Though bacterial pathogens can develop resistance through a variety of mechanisms, one of the most prevalent is the production of antibiotic-modifying enzymes like FosB, a Mn 2+ -dependent l-cysteine or bacillithiol (BSH) transferase that inactivates the antibiotic fosfomycin. FosB enzymes are found in pathogens such as Staphylococcus aureus , one of the leading pathogens in deaths associated with AMR. fosB gene knockout experiments establish FosB as an attractive drug target, showing that the minimum inhibitory concentration (MIC) of fosfomycin is greatly reduced upon removal of the enzyme. Herein, we have identified eight potential inhibitors of the FosB enzyme from S. aureus by applying high-throughput in silico screening of the ZINC15 database with structural similarity to phosphonoformate, a known FosB inhibitor. In addition, we have obtained crystal structures of FosB complexes to each compound. Furthermore, we have kinetically characterized the compounds with respect to inhibition of FosB. Finally, we have performed synergy assays to determine if any of the new compounds lower the MIC of fosfomycin in S. aureus . Our results will inform future studies on inhibitor design for the FosB enzymes., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Tuberculosis (TB), caused by Mycobacterium tuberculosis ( Mtb ), is a deadly bacterial disease. Drug-resistant strains of Mtb make eradication of TB a daunting task. Overexpression of the enhanced intracellular survival (Eis) protein by Mtb confers resistance to the second-line antibiotic kanamycin (KAN). Eis is an acetyltransferase that acetylates KAN, inactivating its antimicrobial function. Development of Eis inhibitors as KAN adjuvant therapeutics is an attractive path to forestall and overcome KAN resistance. We discovered that an antipsychotic drug, haloperidol (HPD, 1 ), was a potent Eis inhibitor with IC 50 = 0.39 ± 0.08 μM. We determined the crystal structure of the Eis-haloperidol ( 1 ) complex, which guided synthesis of 34 analogues. The structure-activity relationship study showed that in addition to haloperidol ( 1 ), eight analogues, some of which were smaller than 1 , potently inhibited Eis (IC 50 ≤ 1 μM). Crystal structures of Eis in complexes with three potent analogues and droperidol (DPD), an antiemetic and antipsychotic, were determined. Three compounds partially restored KAN sensitivity of a KAN-resistant Mtb strain K204 overexpressing Eis. The Eis inhibitors generally did not exhibit cytotoxicity against mammalian cells. All tested compounds were modestly metabolically stable in human liver microsomes, exhibiting 30-60% metabolism over the course of the assay. While direct repurposing of haloperidol as an anti-TB agent is unlikely due to its neurotoxicity, this study reveals potential approaches to modifying this chemical scaffold to minimize toxicity and improve metabolic stability, while preserving potent Eis inhibition., Competing Interests: There is no conflict of interest to declare., (This journal is © The Royal Society of Chemistry.)

The Government of India (GOI) announced a nationwide lockdown starting 25th March 2020 to contain the spread of COVID-19, leading to an unprecedented decline in anthropogenic activities and, in turn, improvements in ambient air quality. This is the first study to focus on highly time-resolved chemical speciation and source apportionment of PM 2.5 to assess the impact of the lockdown and subsequent relaxations on the sources of ambient PM 2.5 in Delhi, India. The elemental, organic, and black carbon fractions of PM 2.5 were measured at the IIT Delhi campus from February 2020 to May 2020. We report source apportionment results using positive matrix factorization (PMF) of organic and elemental fractions of PM 2.5 during the different phases of the lockdown. The resolved sources such as vehicular emissions, domestic coal combustion, and semi-volatile oxygenated organic aerosol (SVOOA) were found to decrease by 96%, 95%, and 86%, respectively, during lockdown phase-1 as compared to pre-lockdown. An unforeseen rise in O 3 concentrations with declining NO x levels was observed, similar to other parts of the globe, leading to the low-volatility oxygenated organic aerosols (LVOOA) increasing to almost double the pre-lockdown concentrations during the last phase of the lockdown. The effect of the lockdown was found to be less pronounced on other resolved sources like secondary chloride, power plants, dust-related, hydrocarbon-like organic aerosols (HOA), and biomass burning related emissions, which were also swayed by the changing meteorological conditions during the four lockdown phases. The results presented in this study provide a basis for future emission control strategies, quantifying the extent to which constraining certain anthropogenic activities can ameliorate the ambient air. These results have direct relevance to not only Delhi but the entire Indo-Gangetic plain (IGP), citing similar geographical and meteorological conditions common to the region along with overlapping regional emission sources. SUMMARY OF MAIN FINDINGS: We identify sources like vehicular emissions, domestic coal combustion, and semi-volatile oxygenated organic aerosol (SVOOA) to be severely impacted by the lockdown, whereas ozone levels and, in turn, low-volatility oxygenated organic aerosols (LVOOA) rise by more than 95% compared to the pre-lockdown concentrations during the last phase of the lockdown. However, other sources resolved in this study, like secondary chloride, power plants, dust-related, hydrocarbon-like organic aerosols (HOA), and biomass burning related emissions, were mainly driven by the changes in the meteorological conditions rather than the lockdown., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The fact that the number of people with Alzheimer's disease is increasing, combined with the limited availability of drugs for its treatment, emphasize the need for the development of novel effective therapeutics for treating this brain disorder. Herein, we focus on generating 12 chalcone-donepezil hybrids, with the goal of simultaneously targeting amyloid-β (Aβ) peptides as well as cholinesterases (i.e., acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)). We present the design, synthesis, and biochemical evaluation of these two series of novel 1,3-chalcone-donepezil ( 15a - 15f ) or 1,4-chalcone-donepezil ( 16a - 16f ) hybrids. We evaluate the relationship between their structures and their ability to inhibit AChE/BChE activity as well as their ability to bind Aβ peptides. We show that several of these novel chalcone-donepezil hybrids can successfully inhibit AChE/BChE as well as the assembly of N -biotinylated Aβ (1-42) oligomers. We also demonstrate that the Aβ binding site of these hybrids differs from that of Pittsburgh Compound B (PIB)., Competing Interests: The authors declare no conflict of interest.

Periodontal disease is an oral chronic immune-inflammatory disease highly prevalent worldwide that is initiated by specific oral bacterial species leading to local and systemic effects. The development of new preventive/therapeutic strategies to specifically target oral periodontopathogens without perturbing oral microbiome species normally colonizing the oral cavity is needed. The fast and affordable strategy of repositioning of already FDA-approved drugs can be an answer to the development of novel treatments against periodontal pathogens such as Porphyromonas gingivalis . Herein, we report the synthesis and antibacterial activity of novel zafirlukast derivatives, their bactericidal effect, and their cytotoxicity against oral epithelial cell lines. Many of these derivatives exhibited superior antibacterial activity against P. gingivalis compared to the parent drug zafirlukast. The most promising compounds were found to be selective against P. gingivalis and they were bactericidal in their activity. Finally, we demonstrated that these potent derivatives of zafirlukast provided a better safety profile against oral epithelial cells compared to zafirlukast.

Controlled halogenation of chemically versatile substrates is difficult to achieve. Here we describe a unique flavin-dependent halogenase, PltM, which is capable of utilizing a wide range of halides for installation on a diverse array of phenolic compounds, including FDA-approved drugs and natural products, such as terbutaline, fenoterol, resveratrol, and catechin. Crystal structures of PltM in complex with phloroglucinol and FAD in different states yield insight into substrate recognition and the FAD recycling mechanism of this halogenase.

As the threat associated with fungal infections continues to rise and the availability of antifungal drugs remains a concern, it becomes obvious that the need to bolster the antifungal armamentarium is urgent. Building from our previous findings of tobramycin (TOB) derivatives with antifungal activity, we further investigate the effects of various linkers on the biological activity of these aminoglycosides. Herein, we analyze how thioether, sulfone, triazole, amide, and ether functionalities affect the antifungal activity of alkylated TOB derivatives against 22 Candida , Cryptococcus , and Aspergillus species. We also evaluate their impact on the hemolysis of murine erythrocytes and the cytotoxicity against mammalian cell lines. While the triazole linker appears to confer optimal activity overall, all of the linkers incorporated into the TOB derivatives resulted in compounds that are very effective against the Cryptococcus neoformans species, with MIC values ranging from 0.48 to 3.9 μg/mL., Competing Interests: The authors declare no conflict of interest.

Despite issues with oto/nephrotoxicity and bacterial resistance, aminoglycosides (AGs) remain an effective and widely used class of antibacterial agents. For decades now, efforts toward the development of novel AGs with potential to overcome some of these problems have been major research focuses. 1-N-Acylation, especially γ-amino-β-hydroxybutyrate (AHB) derivatization, has proven to be one of the most successful strategies for improving the overall properties of AGs, including their ability to avoid certain resistance mechanisms. More recently, 6'-N-acylation arose as another possible strategy to improve the properties of these drugs. In this study, we report on the glycinyl, carboxybenzyl, and AHB mono- and diderivatization at the 1-, 6'-, and/or 4‴-amines of the AGs amikacin, kanamycin A, netilmicin, sisomicin, and tobramycin. We also present the antibacterial activities and the reduced reactivity of AG-modifying enzymes (AMEs) toward these new AG derivatives, and identify the AMEs present in the bacterial strains tested.