Mechanophotocatalysis : a generalizable approach to solvent-minimized photocatalytic reactions for organic synthesis

The authors thank the Leverhulme Trust (RPG-2023-110), the Engineering and Physical Sciences Research Council for funding (EP/W007517, EP/W015137/1) and the European Commission (PhotoReAct ITN: 956324). F. M. thanks the EaSI-CAT CDT at the University of St Andrews for support in the form of a studentship.This proof-of-concept study cements the viability and generality of mechanophotocatalysis, merging mechanochemistry and photocatalysis to enable solvent-minimized photocatalytic reactions. We demonstrate the transmutation of four archetypal solution-state photocatalysis reactions to a solvent-minimized environment driven by the combined actions of milling, light, and photocatalysts. The chlorosulfonylation of alkenes and the pinacol coupling of aldehydes and ketones were conducted under solvent-free conditions with competitive or superior efficiencies to their solution-state analogues. Furthermore, decarboxylative alkylations are shown to function efficiently under solvent-minimized conditions, while the photoinduced energy transfer promoted [2+2] cycloaddition of chalcone experiences a significant initial rate enhancement over its solution-state variant. This work serves as a platform for future discoveries in an underexplored field: validating that solvent-minimized photocatalysis is not only generalizable and competitive with solution-state photocatalysis, but can also offer valuable advantages.Peer reviewe

Transgressing the moral economy: Wheelerism and management of the nationalised coal industry in Scotland

This article illuminates the links between managerial style and political economy in post-1945 Britain, and explores the origins of the 1984–1985 miners' strike, by examining in longer historical context the abrasive attitudes and policies of Albert Wheeler, Scottish Area Director of the National Coal Board (NCB). Wheeler built on an earlier emphasis on production and economic criteria, and his micro-management reflected pre-existing centralising tendencies in the industries. But he was innovative in one crucial aspect, transgressing the moral economy of the Scottish coalfield, which emphasised the value of economic security and changes by joint industrial agreement

NSC23925, Identified in a High-Throughput Cell-Based Screen, Reverses Multidrug Resistance

Multidrug resistance (MDR) is a major factor which contributes to the failure of cancer chemotherapy, and numerous efforts have been attempted to overcome MDR. To date, none of these attempts have yielded a tolerable and effective therapy to reverse MDR; thus, identification of new agents would be useful both clinically and scientifically.To identify small molecule compounds that can reverse chemoresistance, we developed a 96-well plate high-throughput cell-based screening assay in a paclitaxel resistant ovarian cancer cell line. Coincubating cells with a sublethal concentration of paclitaxel in combination with each of 2,000 small molecule compounds from the National Cancer Institute Diversity Set Library, we identified a previously uncharacterized molecule, NSC23925, that inhibits Pgp1 and reverses MDR1 (Pgp1) but does not inhibit MRP or BCRP-mediated MDR. The cytotoxic activity of NSC23925 was further evaluated using a panel of cancer cell lines expressing Pgp1, MRP, and BCRP. We found that at a concentration of >10 microM NSC23925 moderately inhibits the proliferation of both sensitive and resistant cell lines with almost equal activity, but its inhibitory effect was not altered by co-incubation with the Pgp1 inhibitor, verapamil, suggesting that NSC23925 itself is not a substrate of Pgp1. Additionally, NSC23925 increases the intracellular accumulation of Pgp1 substrates: calcein AM, Rhodamine-123, paclitaxel, mitoxantrone, and doxorubicin. Interestingly, we further observed that, although NSC23925 directly inhibits the function of Pgp1 in a dose-dependent manner without altering the total expression level of Pgp1, NSC23925 actually stimulates ATPase activity of Pgp, a phenomenon seen in other Pgp inhibitors.The ability of NSC23925 to restore sensitivity to the cytotoxic effects of chemotherapy or to prevent resistance could significantly benefit cancer patients

A new method of discriminating different types of post-Archean ophiolitic basalts and their tectonic significance using Th-Nb and Ce-Dy-Yb systematics

AbstractIn this paper, a new discrimination diagram using absolute measures of Th and Nb is applied to post-Archean ophiolites to best discriminate a large number of different ophiolitic basalts. This diagram was obtained using >2000 known ophiolitic basalts and was tested using ∼560 modern rocks from known tectonic settings. Ten different basaltic varieties from worldwide ophiolitic complexes have been examined. They include two basaltic types that have never been considered before, which are: (1) medium-Ti basalts (MTB) generated at nascent forearc settings; (2) a type of mid-ocean ridge basalts showing garnet signature (G-MORB) that characterizes Alpine-type (i.e., non volcanic) rifted margins and ocean-continent transition zones (OCTZ). In the Th-Nb diagram, basalts generated in oceanic subduction-unrelated settings, rifted margins, and OCTZ can be distinguished from subduction-related basalts with a misclassification rate <1%. This diagram highlights the chemical variation of oceanic, rifted margin, and OCTZ basalts from depleted compositions to progressively more enriched compositions reflecting, in turn, the variance of source composition and degree of melting within the MORB-OIB array. It also highlights the chemical contributions of enriched (OIB-type) components to mantle sources. Enrichment of Th relative to Nb is particularly effective for highlighting crustal input via subduction or crustal contamination. Basalts formed at continental margin arcs and island arc with a complex polygenetic crust can be distinguished from those generated in intra-oceanic arcs in supra-subduction zones (SSZ) with a misclassification rate <1%. Within the SSZ group, two sub-settings can be recognized with a misclassification rate <0.5%. They are: (1) SSZ influenced by chemical contribution from subduction-derived components (forearc and intra-arc sub-settings) characterized by island arc tholeiitic (IAT) and boninitic basalts; (2) SSZ with no contribution from subduction-derived components (nascent forearc sub-settings) characterized by MTBs and depleted-MORBs. Two additional discrimination diagrams are proposed: (1) a Dy-Yb diagram is used for discriminating boninite and IAT basalts; (2) a Ce/Yb-Dy/Yb diagram is used for discriminating G-MORBs and normal MORBs. The proposed method may effectively assist in recovering the tectonic affinity of ancient ophiolites, which is fundamental for establishing the geodynamic evolution of ancient oceanic and continental domains, as well as orogenic belts

Mechanical Influences on Morphogenesis of the Knee Joint Revealed through Morphological, Molecular and Computational Analysis of Immobilised Embryos

Very little is known about the regulation of morphogenesis in synovial joints. Mechanical forces generated from muscle contractions are required for normal development of several aspects of normal skeletogenesis. Here we show that biophysical stimuli generated by muscle contractions impact multiple events during chick knee joint morphogenesis influencing differential growth of the skeletal rudiment epiphyses and patterning of the emerging tissues in the joint interzone. Immobilisation of chick embryos was achieved through treatment with the neuromuscular blocking agent Decamethonium Bromide. The effects on development of the knee joint were examined using a combination of computational modelling to predict alterations in biophysical stimuli, detailed morphometric analysis of 3D digital representations, cell proliferation assays and in situ hybridisation to examine the expression of a selected panel of genes known to regulate joint development. This work revealed the precise changes to shape, particularly in the distal femur, that occur in an altered mechanical environment, corresponding to predicted changes in the spatial and dynamic patterns of mechanical stimuli and region specific changes in cell proliferation rates. In addition, we show altered patterning of the emerging tissues of the joint interzone with the loss of clearly defined and organised cell territories revealed by loss of characteristic interzone gene expression and abnormal expression of cartilage markers. This work shows that local dynamic patterns of biophysical stimuli generated from muscle contractions in the embryo act as a source of positional information guiding patterning and morphogenesis of the developing knee joint

Immune boosting by B.1.1.529 (Omicron) depends on previous SARS-CoV-2 exposure

The Omicron, or Pango lineage B.1.1.529, variant of SARS-CoV-2 carries multiple spike mutations with high transmissibility and partial neutralizing antibody (nAb) escape. Vaccinated individuals show protection from severe disease, often attributed to primed cellular immunity. We investigated T and B cell immunity against B.1.1.529 in triple mRNA vaccinated healthcare workers (HCW) with different SARS-CoV-2 infection histories. B and T cell immunity against previous variants of concern was enhanced in triple vaccinated individuals, but magnitude of T and B cell responses against B.1.1.529 spike protein was reduced. Immune imprinting by infection with the earlier B.1.1.7 (Alpha) variant resulted in less durable binding antibody against B.1.1.529. Previously infection-naïve HCW who became infected during the B.1.1.529 wave showed enhanced immunity against earlier variants, but reduced nAb potency and T cell responses against B.1.1.529 itself. Previous Wuhan Hu-1 infection abrogated T cell recognition and any enhanced cross-reactive neutralizing immunity on infection with B.1.1.529

Quantitative, multiplexed, targeted proteomics for ascertaining variant specific SARS-CoV-2 antibody response

Determining the protection an individual has to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern (VoCs) is crucial for future immune surveillance, vaccine development, and understanding of the changing immune response. We devised an informative assay to current ELISA-based serology using multiplexed, baited, targeted proteomics for direct detection of multiple proteins in the SARS-CoV-2 anti-spike antibody immunocomplex. Serum from individuals collected after infection or first- and second-dose vaccination demonstrates this approach and shows concordance with existing serology and neutralization. Our assays show altered responses of both immunoglobulins and complement to the Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.1) VoCs and a reduced response to Omicron (B1.1.1529). We were able to identify individuals who had prior infection, and observed that C1q is closely associated with IgG1 (r > 0.82) and may better reflect neutralization to VoCs. Analyzing additional immunoproteins beyond immunoglobulin (Ig) G, provides important information about our understanding of the response to infection and vaccination

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome