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Comparing the molecular pharmacological properties of existing β-blockers to determine the theoretically most “ideal” anti-cancer β-blocker
No full textThere is increasing evidence, from cellular, animal and human epidemiological studies, linking β-blockers with reductions in cancer growth and metastasis. Propranolol is the most investigated β-blocker for cancer; although as many different off-patent β-blockers exist, there is little commercial incentive to drive comparative clinical trials. To minimize any chance of endogenous β-agonist driven cancer growth or metastasis, theoretically, the “ideal” anti-cancer β-blocker would have high affinity, no partial agonism, and long duration of action at β2-adrenoceptors (and for some cancers, additionally at β1 or β3-AR). Using CHO cells stably expressing the wildtype and polymorphic variants of the human β1 and β1-adrenoceptors, this study assessed 35 β-blockers for the affinity and duration of binding (using 3H-CGP12177 whole cell binding) and intrinsic efficacy (CRE-gene transcription). Despite high affinity, some β-blockers had a short binding duration (e.g., alprenolol, bupranolol, levobunolol, nadolol and oxprenolol). Other compounds had substantial partial agonism (e.g., cyanopindolol, bucindolol, pindolol, pronethalol and xamoterol) and other compounds had a biphasic washout (e.g., bucindolol, timolol, carpindolol, and CGP12177) for reasons unknown. Considering all 3 factors, carazolol and ICI118551 may be more “ideal” than propranolol; however, carvedilol, with higher affinity and substantially longer duration of β2 (and β1) receptor binding than propranolol whilst maintaining low partial agonism, may be the most theoretically optimal. Furthermore, it is already widely used in cardiovascular medicine as an off-patent tablet. Thus, carvedilol may have more optimal molecular pharmacological characteristics for an “anti-cancer” β-blocker than propranolol and could enter prospective comparative clinical trials without needing any further clinical workup
Signalling for success: Subsequent grant support and female-founded university spinouts
No full textThis article adopts a signalling perspective to explore how grant-backed university spinouts (USOs) can deploy signals to mitigate information asymmetries and secure subsequent access to grant support. We theorise that grant-backed USOs can signal their capability through the spinout portfolio of the parent university and timing of the initial grant. Given the gendered nature of academic entrepreneurship, we analyse whether, and how, access to, and signalling for, subsequent grants may differ in female-founded USOs. Using data on UK USOs, our results suggest that the initial grant timing of a grant-backed USO is a valuable signal for both female- and male-founded USOs. We find that being female-founded does not significantly influence grant-backed USO subsequent grant access. Our study contributes novel insights on how grant-backed USOs can signal to overcome information asymmetries and access subsequent grant support, and on the role of founder gender in follow-on financing
Binding of Staling Aldehydes to the Beer Matrix: Insights into the Equilibria Through Shelf-Life Which Drive Beer Flavor Instability
Full text linkThe binding and subsequent release of aldehydes from beers through aging is of central importance to beer flavor change through shelf-life. Here we report fundamental studies, targeted at improving understanding of the nature of aldehyde binding to, and release from, the beer matrix. Three commercial brands of lager beer, brewed using different adjunct grist bills, were selected for the study. Each was freeze-dried and reconstituted (30% w/w, freeze dried extract/ultra-pure water) to form a concentrated solution of “beer matrix.” With this solution, the affinity and type of interactions of the matrix toward selected aldehydes were investigated. In a series of “challenge” experiments, staling aldehydes were spiked into the concentrated beer matrices and headspace solid-phase microextraction gas chromatography–mass spectrometry (HS-SPME-GC-MS) was used to determine percentage bound and percentage displacement of aldehydes measured in each case. A key finding was that each matrix displayed unique patterns of binding behavior toward the staling aldehydes. Furthermore, competitive binding was clearly observed whereby 3-methylbutanal generally showed the greatest binding on addition (and this was not impacted by the concentrations of other aldehydes present) as well as the ability to displace other aldehydes from the matrix. The full nature and range of the binding sites from which the aldehydes are being displaced remains unknown and further research is needed to better understand the complex equilibria involved in the multiple forms of binding which are envisaged to take place between aldehydes and the beer matrix
Non-antimicrobial interventions in recovery from community acquired pneumonia in adults
No full textPurpose of review We review recent evidence on the effectiveness of non-antimicrobial adjunctive interventions on the recovery of adults diagnosed with community-acquired pneumonia (CAP).Recent findings Respiratory physiotherapy, early mobilization or tailored exercises may decrease length of stay (LoS), dyspnoea and readmissions, but there is little evidence of an effect on mortality. Nutritional interventions may decrease readmissions and improve 30-day mortality, but there are few studies on the effect of individual micronutrient supplementation. Strategies to improve discharge communications and patient education may decrease readmission rates, improve treatment compliance and patient satisfaction, whereas the implementation of guidelines and care bundles may decrease 30-day mortality but does not appear to affect length of stay or 30-day readmissions. For adjunctive therapeutic interventions, there is evidence that for severe CAP, corticosteroids probably decrease short-term mortality and possibly longer term mortality and LoS. Antiplatelet agents and statins may decrease short-term mortality.Summary A wide range of adjunctive interventions have been trialled aiming to improve patient outcomes with variable results and considerable heterogeneity between studies and populations. Future studies should involve engagement with patient groups to identify uncertainties and outcomes they consider important, utilize a core set of outcome measures, and assess long-term outcomes
Applying a Transformer-based machine-learning model to classify caregiver and infant behaviours during dyadic interactions
No full textMultimodal caregiver-infant interactions have both concurrent and long-term impacts on child attention, cognitive and social skills. These behaviours are typically manually coded by human researchers, making this approach susceptible to observer bias, dependent on inter-rater reliability, and substantial demands on time and resources. In this study, we aimed to develop a multimodal machine-learning model that could be capable of automatically detecting and classifying multimodal behaviours from video recordings of caregivers and their infants (N = 81; infant mean age = 251.3 ± 34.9 days) engaging with objects. We focused on caregiver scaffolding, caregiver intrusiveness, infant object engagement and infant distractibility. Low-level features from audio, video, and pose data were extracted using specific AI models, and input into a Transformer-based architecture capable of learning temporal patterns across modalities. Our findings revealed a significant contrast in model performance depending on how the data was partitioned. Following previous research, when the dataset was split such that data from all dyads contributed to the training, validation, and test sets - the models achieved notably high classification accuracy of over 98 %. However, when tested on entirely unseen dyads, the performance dropped markedly to around 55 %. These results suggest that the models did not learn behaviors of interest but instead relied on video-specific or dyad-specific details - underscoring key generalizability challenges in applying Transformer-based models to complex, multimodal behavioral data. Nonetheless, this work lays a foundation for future research aimed at refining these models and extending their applicability across diverse caregiving contexts
Model-based clustering of time-dependent observations with common structural changes
Full text linkWe propose a novel model-based clustering approach for samples of time series. We assume as a unique commonality that two observations belong to the same group if structural changes in their behaviors happen at the same time. We resort to a latent representation of structural changes in each time series, based on random orders, to induce ties among different observations. Such an approach results in a general modeling strategy and can be combined with many time-dependent models already known in the literature. Our studies have been motivated by an epidemiological problem. Specifically, we want to provide clusters of different countries of the European Union where two countries belong to the same cluster if the spreading processes of the COVID-19 virus show structural changes at the same time
Microwave-assisted oxidation of N2 to NOx over perovskites
No full textThe oxidation of N2 by O2 in a quartz flow reactor operated at atmospheric pressure using 2.45 GHz microwave (MW) heating of La0.65Sr0.35MnO3 and LaMnO3 perovskites was investigated here. The perovskites were activated by a brief exposure to 600 W irradiation to facilitate MW absorption, resulting in more crystalline materials. La0.65Sr0.35MnO3 exhibited an increased permittivity constant and loss factor at low temperatures. MW in combination with perovskites enabled triggering plasmas leading to NO and NO2 as sole reaction products. The plasma temperature was in excess of 1800 °C. The maximal concentration of NOx obtained was ca. 2.2 vol% for an energy cost of about 86 MJ/molNOx. This high value is typical of small-scale systems for which MW power coupling and heat losses were not optimised. The plasma could be maintained down to 30 W of MW incident power on La0.65Sr0.35MnO3. The direction of the gas had no significant effect on the NOx output, but influenced the stability of the plasma at low MW incident powers. The role of perovskites in the process, other than acting as an MW susceptor and favoring plasma formation, should be further investigated, but the present data suggest no catalytic role. Quartz appeared as the best reactor material, given that alumina and modified zirconias led to reactor breakage. This work shows that varied perovskite formulations are able to trigger stable plasma under MW at atmospheric pressure, in particular the simple stoichiometry LaMnO3 and a commercially-available La0.65Sr0.35MnO3
The Origins of Printed Man: Ian Watt, Marshall McLuhan and Rise of the Literacy Thesis
Full text linkThe IUPHAR/BPS Guide to PHARMACOLOGY in 2026
Full text linkThe IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb, https://www.guidetopharmacology.org) is an open-access database of expert-curated, high-quality pharmacological data. It provides succinct overviews and key references for pharmacological targets and their recommended experimental ligands, alongside detailed information about ligand-target activities. It includes 3103 protein targets and 13 260 ligand molecules, including approved drugs, small molecules, peptides, and antibodies. Here, we report recent improvements to the resource and describe expansion in content over the seven database releases made during the last two years. We describe developments in antibacterial pharmacology, work that has been supported through our collaboration with AntibioticDB and Global Antibiotic Research and Development Partnership. We discuss recent areas of curation, including natural products and nucleic acids, and describe an improved presentation of our approved drugs set that contains new therapeutic targets and ligands that are proposed as modulators with clinical potential. This is a useful new resource, both in being continuously updated and having coverage across multiple approval agencies. Maintaining strong links to external resources, such as PubChem, remains an important feature of GtoPdb, and here we highlight their value and utility in being a FAIR-compliant resource. We also present a comparison of our data coverage with ChEMBL and BindingDB
Gender-neutral assessment in Australia: Acceptance and eligibility among current donors
Full text linkBackground: Blood collection agencies are shifting to gender-neutral risk assessment for donor eligibility. Pre-implementation data on donor eligibility and acceptance rates are essential to understand the likely impact of these changes locally. Study Design and Methods: A cross-sectional online survey was emailed to current Australian blood donors (donated in the last 12 months). Consistent with the recommendations of the United Kingdom's For the Assessment of Individualised Risk (FAIR) project and the United States of America (USA) Food and Drug Administration (FDA) gender-neutral screening criteria, participants were asked about sexual behaviors in the last 3 months (multiple partners, new partners, anal sex) and whether being asked about these would deter them from donating. Demographic characteristics and behavioral responses were analyzed using descriptive statistics and chi-square tests. Results: Of 7938 respondents (11.3% response rate), only 0.6% (95% CI 0.4–0.8) would be ineligible under gender-neutral criteria (0.7%, 95% CI 0.2–1.8 of those who donated in the last 3 months). Those potentially ineligible were younger and less likely to identify as heterosexual. While tolerance for screening questions was generally high (≥70.0% indicated questions would not stop them donating), 12.7% (95% CI 12.0–13.4) indicated that one or more of the questions asked of all would stop or be quite likely to stop them attempting to donate. Some variation in tolerance was observed by demographic categories. Discussion: Implementation of gender-neutral screening criteria in Australia would result in minimal donor loss due to ineligibility. While questions would be generally tolerated, careful implementation considering demographic variations is warranted
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