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A professional journey:capturing the complicated relationship between rural teacher agency, multigrade classes and local communities
No full textThis paper explores the impact of teaching multigrade classes on developing agency through the professional lifespan of teachers. The research was located in small rural schools in Scotland, where 94 % of the land mass is rural and multigrade classes are a common feature in schools. Three data sets, from early career, experienced teachers and headteachers were examined through the analytic framework of ecological agency considering the social, cultural and individual experiences of teachers’ lives, as they taught multigrade classes in rural communities. The themes of craft of teaching, resources and understanding the school as a community were explored in depth, each demonstrating the influence of teaching multigrade classes on developing teacher agency. The analysis revealed an entanglement of agency, multigrade classrooms and local communities, demonstrating the relevance of multigrade teaching experience to professional agency and the place of multigrade classes in rural communities.</p
Human Rights in the Context of Climate Change:Emerging investment-related responsibilities in law and policy
No full textThis chapter examines the implications of human rights standards for investment activity in the context of climate change. It explores three key domains: the responsibility of businesses and investors for the human rights impacts of climate change, the role of climate change laws in regulating business and investment activities, and the ‘greening’ of human rights norms. These areas intersect to shape the responsibilities of investors in climate change mitigation. The chapter maps the evolution of these norms and their interaction, highlighting how they inform investment-related responsibilities, and delves into the implications of these evolving standards for investors. By examining these dimensions, the chapter provides insights into the emerging duties of investors within the framework of human rights and climate change
Sandwich-structured GaIn(Zn)P/ZnSeS@ZnS quantum dots-ag@Fe3O4@SiO2 magnetoplasmonic nanosensor with simulation-driven design for influenza a(H1N1) virus biosensing
Get PDFDeveloping next-generation ultrasensitive bioanalytical sensing systems requires multifunctional nanoarchitectures that integrate engineered photophysics with highly selective biorecognition interfaces. We report on a multifunctional, simulation-guided design of a fluorescence nanosensor for ultrasensitive detection of Influenza A (H1N1) virus in human saliva, integrating heavy-metal-free GaIn(Zn)P/ZnSeS@ZnS quantum dots (QDs) with magnetoplasmonic molecularly imprinted silica shell (Ag@Fe3O4@SiO₂-MIBs) interface. The QDs, engineered with a compositionally graded ZnSeS inner shell and ZnS outer shell, exhibit strong red emission (λemi = 652 nm) and high photoluminescence quantum yield (QY = 78 ± 1.4 %) in aqueous media following ligand exchange with thioglycolic acid (TGA). Self-consistent field (SCF) simulations revealed that TGA capping significantly stabilised the QDs surface and induced distinct magnetic properties, confirming favourable surface energetics for biosensing applications. The TGA-GaIn(Zn)P/ZnSeS@ZnS QDs were conjugated to H1N1-specific DNA aptamers and incorporated with graphene oxide (GO), forming a Förster resonance energy transfer (FRET)-based nanoprobe that switches from an “off” to “on” state upon viral recognition. Target-induced aptamer folding disrupted the QD-GO interaction, thereby restoring the QDs fluorescence. To amplify the fluorescence signal and enable selective enrichment, virus-imprinted Ag@Fe3O4@SiO₂-MIBs were employed. Finite-difference time-domain (FDTD) simulations demonstrated strong plasmon-exciton coupling between QDs and the Ag core, yielding approximately an 18-fold local field enhancement at a 5 nm spacing. The combined effect of molecular imprinting, magnetic separation, and plasmonic amplification enabled a detection limit of 0.15 pg/mL with high specificity against non-target viruses. This study presented a computationally guided design of hybrid nanomaterials for next-generation, point-of-care viral diagnostics with enhanced optical and molecular recognition performance
Photoacoustic imaging in prostate cancer:A systematic review and meta-analysis
No full textProstate cancer (PCa) is a leading cause of morbidity and mortality among men worldwide. Limitations in current diagnostic methods often lead to overdiagnosis or missed cases. Photoacoustic imaging (PAI), which combines ultrasound and optical imaging, has emerged as a promising tool to enhance PCa detection and management. This systematic review evaluates the diagnostic accuracy, clinical applications, and technical performance of PAI in PCa. A comprehensive literature search was conducted in PubMed, Embase, Scopus, Web of Science, and IEEE through April 2024. Original studies reporting PAI’s diagnostic accuracy, technical performance, or clinical applications in PCa were included. Data on study design, population, PAI specifications, and key outcomes were extracted, and quality was assessed using QUADAS-2 for diagnostic studies and SYRCLE for animal studies. Diagnostic accuracy was assessed using a meta-analysis of sensitivity and specificity and a summary receiver operating characteristic curve. Of the 81 included studies, a meta-analysis of four ex vivo human studies demonstrated high specificity (84 %–97 %) and variable sensitivity (69 %–87 %) for PAI in distinguishing malignant from non-malignant prostate tissues. Combined with transrectal ultrasound, PAI improved diagnostic accuracy, biopsy guidance, and treatment monitoring. However, clinical translation of PAI requires standardised protocols, comprehensive in vivo validation, regulatory approvals, and adherence to the International Photoacoustic Standardisation Consortium guidelines. Current limitations, including a lack of standardised protocols and insufficient human in vivo studies reporting key diagnostic metrics, impede clinical adoption of PAI. PAI therefore holds promise as a complementary imaging tool in PCa diagnosis and management, improving biopsy accuracy and treatment monitoring; however, further human in vivo research and protocol standardisation are needed before clinical adoption
Eplerenone improves kidney function and cardiac performance in obese male mice
Get PDFAims: Renin-angiotensin-aldosterone system (RAAS) activation mediates obesity-associated cardiorenal dysfunction. Due to an incomplete understanding of the molecular mechanisms, the clinical use of RAAS antagonism in obesity-associated cardiometabolic complications remains uncertain. The present study investigated the effects and associated molecular mechanisms of eplerenone, a selective mineralocorticoid receptor antagonist, in the heart and kidney of obesity. Methods: Male C57BL/6 mice were fed a high-fat diet (HFD) for 12 weeks before receiving either vehicle or eplerenone treatments for 30 days while maintained on HFD. Cardiac function was measured by pressure–volume (PV) loop analyses. Renal function was assessed by renal morphology and serum creatinine concentrations. Chow-fed mice were used as lean controls. Results: HFD feeding impaired cardiac and renal function in mice, evidenced by elevated blood pressures, stroke work, Tau, glomerular hypertrophy and tubular injury. Eplerenone treatment caused weight loss, which was attributed to a loss in fat mass. Moreover, eplerenone treatment ameliorated both HFD-induced cardiac and renal dysfunction, including a decrease in stroke volume, cardiac output and stroke work; an increase in ejection fraction; and a decrease in glomerular hypertrophy, tubular injury, renal fibrosis and serum creatinine concentrations. Mechanistically, eplerenone decreased CD44 but increased RHAMM and TGF-β expression in the heart. In contrast, eplerenone caused a decrease in the hyaluronan-CD44/RHAMM pathway, TGF-β, IL-6 and phosphorylation of Akt and JNK in the kidney. Conclusion: Eplerenone treatment improved kidney function and cardiac performance in obese male mice. The potential link between the mineralocorticoid receptor and the hyaluronan-CD44/RHAMM pathway is novel and has not been previously reported.</p
Sandwich-structured GaIn(Zn)P/ZnSeS@ZnS quantum dots-ag@Fe3O4@SiO2 magnetoplasmonic nanosensor with simulation-driven design for influenza a(H1N1) virus biosensing
Get PDFDeveloping next-generation ultrasensitive bioanalytical sensing systems requires multifunctional nanoarchitectures that integrate engineered photophysics with highly selective biorecognition interfaces. We report on a multifunctional, simulation-guided design of a fluorescence nanosensor for ultrasensitive detection of Influenza A (H1N1) virus in human saliva, integrating heavy-metal-free GaIn(Zn)P/ZnSeS@ZnS quantum dots (QDs) with magnetoplasmonic molecularly imprinted silica shell (Ag@Fe3O4@SiO₂-MIBs) interface. The QDs, engineered with a compositionally graded ZnSeS inner shell and ZnS outer shell, exhibit strong red emission (λemi = 652 nm) and high photoluminescence quantum yield (QY = 78 ± 1.4 %) in aqueous media following ligand exchange with thioglycolic acid (TGA). Self-consistent field (SCF) simulations revealed that TGA capping significantly stabilised the QDs surface and induced distinct magnetic properties, confirming favourable surface energetics for biosensing applications. The TGA-GaIn(Zn)P/ZnSeS@ZnS QDs were conjugated to H1N1-specific DNA aptamers and incorporated with graphene oxide (GO), forming a Förster resonance energy transfer (FRET)-based nanoprobe that switches from an “off” to “on” state upon viral recognition. Target-induced aptamer folding disrupted the QD-GO interaction, thereby restoring the QDs fluorescence. To amplify the fluorescence signal and enable selective enrichment, virus-imprinted Ag@Fe3O4@SiO₂-MIBs were employed. Finite-difference time-domain (FDTD) simulations demonstrated strong plasmon-exciton coupling between QDs and the Ag core, yielding approximately an 18-fold local field enhancement at a 5 nm spacing. The combined effect of molecular imprinting, magnetic separation, and plasmonic amplification enabled a detection limit of 0.15 pg/mL with high specificity against non-target viruses. This study presented a computationally guided design of hybrid nanomaterials for next-generation, point-of-care viral diagnostics with enhanced optical and molecular recognition performance
Kamala Harris’s Presidential Marketing Strategy in 2024
No full textThis chapter explores the challenges and limitations of Kamala Harris’s political marketing strategy in the 2024 presidential election. It highlights the challenges posed by the nature of the market environment in which her presidential bid was forged, including the impact of being vice-president to an unpopular president and the short time she had to develop and communicate her political product after becoming the nominee. But it also reveals significant problems in Harris’ strategy. The first rule of political marketing is to listen and show you listen to voters; the second is to focus on offering policies that respond to them. Harris failed to acknowledge voter dissatisfaction with the Biden presidency and differentiate herself from Biden. And she was unable to offer a product with specific policies that responded clearly and strongly enough to voters’ top concerns on the economy, cost of living and immigration. Too much focus was put on highlighting Trump’s weaknesses in an election which was more about product than personality because of a rise in significant concerns that affects people’s daily lives in terms of putting a roof over their head and paying for food
Mutations within the predicted 1 fragment-binding region of FAM83G/SACK1G abolish its interaction with the Ser/Thr kinase CK1α
No full textSACK1G (aka FAM83G, PAWS1) plays a central role in activating canonical WNT signalling via interaction with the Ser/Thr kinase CK1α. This loss of CK1α binding and WNT signalling underlies the pathogenesis of Palmoplantar Keratoderma (PPK) caused by several reported mutations in the SACK1G gene. We modelled the scaffold anchor of CK1 (SACK1) domain of SACK1G and used fragment-bound structures of the SACK1B (FAM83B) dimer to guide our analysis. This allowed us to computafonally predict several key residues near the fragment binding site in SACK1G that may be important for its funcfon. We mutated these residues, introduced them into SACK1G-/- DLD-1 colorectal cancer cells and investigated their ability to bind endogenous CK1α. We uncovered two SACK1G mutations, namely Y204A and I206A, that abolish interaction with CK1α similarly to the PPK pathogenic mutant A34E. Consistent with this loss of SACK1G-CK1α interaction, the molecular glue degrader of CK1α, DEG-77, fails to co-degrade the Y204A and I206A mutants while it still co-degrades native SACK1G. Our findings demonstrate the utility of our computational methods to uncover functional residues on proteins based on fragment-binding sites
Crystallographic characterisation and development of bi-substrate inhibitors of coronavirus nsp14 methyltransferase
No full textSARS-CoV-2 non-structural protein 14 (nsp14) is essential for viral mRNA cap guanine-N7 methylation and represents a promising but underexplored antiviral target. Herein we describe a structure-guided campaign based on a hit from a focussed SAM mimetic library. Systematic SAR exploration guided by six X-ray co-crystal structures in complex with SARS-CoV-2 led to compound 26, a bi-substrate inhibitor that bridges the SAM and RNA cap binding sites. Compound 26 achieved nanomolar potency against nsp14 from SARS-CoV-2 (IC₅₀ = 53 nM), SARS-CoV-1, and two alphacoronaviruses, with excellent selectivity over human RNMT and flaviviral MTase. In general, the compounds demonstrated favourable metabolic stability, passive permeability, and no HepG2 cytotoxicity. However, cellular antiviral activity was limited, revealing disconnects between enzyme inhibition and phenotypic response. These findings provide a structural framework for optimizing bi-substrate methyltransferase inhibitors against coronaviruses with a view for pan-coronaviral activity
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