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New Mechanistic Insights into Targeted Protein Degradation Using Raman-Active Theranostic Hydrophobic Tags
No full textHydrophobic tagging (HyT) has emerged as a useful tool within the field of targeted protein degradation for the targeting and removal of a protein of interest (POI) from the cell. Development of new hydrophobic tags with increased efficiency not only allows increased POI degradation but also provides an opportunity to further study the mechanisms of HyT, which are not fully understood. Herein, we describe the development of new theranostic hydrophobic tags that can be used to induceprotein degradation and simultaneously enable drug imaging using stimulated Raman scattering (SRS) microscopy. By coupling our dual-purpose theranostic hydrophobic tags to the PARP inhibiting, anticancer therapeutic olaparib, we explore the degradation efficiency, mode of action and potency that these theranostics confer in ovarian cancer cells. Lead compound 2c effectively degrades intracellularPARP-1 (DC50 = 0.618 μM, Dmax = 55%) and has more potent antiproliferative activity than the parent compound olaparib (IC50 = 62 nM vs 11.52 μM for olaparib), whilst maintaining on-target PARP inhibitory activity. Using mass spectrometry-based proteomic analysis, we demonstrate activation of the unfolded protein response, ER-stress and cell cycle arrest after incubation with 2c. Using SRS imaging, via the inherent Raman activity of the theranostic alkyne tag, we demonstrate involvementof the ER and autophagy after treatment with our drug conjugates. These results provide new insight into the mechanisms involved in HyT-induced protein degradation
In-Depth Review of Multiphysics and Circuit Simulation Approaches for Perovskite Solar Cells
No full textPerovskite solar cells (PSCs) have attracted much attention due to their high power conversion efficiency and low-cost fabrication using abundant materials. However, a comprehensive understanding of the key physical mechanisms remain limited, despite its importance for future enhancement. Through simulation, PSC designs can be rapidly evaluated and optimized, considering various factors such as physical mechanisms, photoelectric models, device parameters, and equivalent circuits. In recent years, there has been a surge in research focused on device simulations for PSCs, but a clear classification and summary of these simulations remains lacking. This review categorizes PSC device simulations into multiphysics field simulations and circuit simulations, providing an overview of the latest research in both areas to support future PSC design. First, we summarize the common modeling techniques (such as transfer matrices, finite difference time domain, and finite element methods) and basic equations for various models, which not only explore light loss during light generation but also investigate charge recombination mechanisms. Next, we discuss equivalent circuit models, distinguishing between those that account for ion migration and those that do not. The inclusion of ion migration models helps explain changes in the electric field, cell dynamics, and voltage–current hysteresis. Finally, we present future directions for the development of PSC simulations.</p
Scaffolds for teachers’ integration of social justice issues in mathematics education:A pilot study
No full textIn this article we report on a pilot study conducted in the Philippines in which the aim was to investigate the scaffolding that mathematics teachers needed to participate in a project in which social justice issues were incorporated in their classroom activities. We collaborated with 2 mathematics teachers at public high schools to implement activities developed by us in which social justice issues were integrated in their mathematics classes. We then interviewed the teachers to gain insight into (1) the teachers’ decisions and actions during the implementation of these activities, and (2) their learners’ experiences and views working on such mathematics activities. Based on an analysis of their interview responses, it was found that both the teachers and learners welcomed the incorporation of social justice themes in their lessons. However, it was also found that teachers required more support to develop their agency in two main areas: (1) crafting contextualised mathematics activities incorporating social justice issues, and (2) creating learning environments that develop learners’ agency to participate effectively in such activities
In Vivo Imaging of Blood-Brain Barrier Leakage Using a Contrast Agent in Patients With Cerebral Amyloid Angiopathy:An Exploratory Study
No full textBACKGROUND AND OBJECTIVES: Blood-brain barrier (BBB) leakage may be an early step in the pathophysiology of cerebral amyloid angiopathy (CAA), possibly preceding hemorrhages. This exploratory study measured BBB leakage in vivo at the level of the leptomeningeal and small parenchymal vessels in patients with probable CAA. We hypothesized that BBB leakage from leptomeningeal and cortical small vessels would be higher in patients with CAA compared with controls and that leakage would be associated with hemorrhagic manifestations of CAA, that is, cortical superficial siderosis (cSS) and lobar cerebral microbleeds (CMBs).METHODS: Patients with probable CAA without previous intracerebral hemorrhage and non-CAA patients with mild cognitive impairment from the memory clinic were recruited in this prospective observational exploratory study. Participants underwent 3T brain MRI with injection of a gadolinium-based contrast agent (Dotarem). Leakage from leptomeningeal vessels was assessed on postcontrast vs precontrast T2-fluid-attenuated inversion recovery as either focal or sulcal CSF enhancements. Dynamic contrast-enhanced scans were analyzed to quantify permeability-surface area product (PS): a measure of leakage from parenchymal small vessels.RESULTS: Fourteen patients with CAA (mean age 67.7 ± 9.0 years; 57% female) and 7 non-CAA patients with mild cognitive impairment (mean age 70.1 ± 6.5 years; 29% female) were recruited. Focal CSF enhancements were observed similarly often in patients with CAA (7 [50%]) and non-CAA controls (4 [57%], p = 0.98), whereas sulcal CSF enhancements were only seen in patients with CAA (5 [36%] vs 0 [0%]). In patients with CAA, focal and sulcal CSF enhancement counts were associated with higher cSS volume ( B = 2.61, p = 0.003; B = 1.02, p = 0.02), but not with CMBs. PS was numerically higher in the cortex in patients with CAA (5.08 ± 4.02 × 10 -4 min -1) than in non-CAA controls (1.29 ± 4.08 × 10 -4 min -1, p = 0.07), but it was not associated with CMB count or cSS volume ( p > 0.67). DISCUSSION: Leakage of gadolinium-based contrast agent through the BBB can be measured in vivo in CAA from the leptomeningeal vessels, and findings point to likely leakage from cortical small vessels as well. Leakage from leptomeningeal vessels was associated with cSS. Studies with follow-up data need to determine whether these measures could serve as a predictive biomarker in CAA.</p
Mapping physical education in Northern Ireland:Exploring the structure and discourses of the PE curriculum in a segregated school system
No full textThis paper is the first study that exclusively explores the structure and discourses evident within the physical education (PE) curriculum in Northern Ireland (NI). In doing so, it highlights the opportunities and challenges of the PE curriculum within this unique segregated school system, addressing a gap in the literature. For decades, research has recognised that many PE curricula are organised and delivered around units of games with a focus on the skill/sport performance. This study utilised a discourse analysis to identify the key discourses within curriculum documents whilst also drawing on the work of Penney and Chandler to explore the structure of the curriculum and how it, along with contextual factors, shapes the opportunities and challenges of the NI PE curriculum. Our findings illustrate the possibilities offered by the holistic, interdisciplinary ‘Big Picture’ approach in policy while acknowledging the potential challenges of this in practice, given the complex political and religious context of NI. Further work in schools, with teachers, is needed in this novel area moving forward, to build a richer body of knowledge and better inform future policy and practice
Mathematical artifacts in slope-intercept correlations invalidate biological inferences in aging research
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Accurate Prediction of Drug Resistance for Intrinsically Disordered Protein Regions
No full textRelative alchemical binding free energy calculations can be used to predict the effect of amino acid mutations on ligand binding affinities. However, these protocols are not well established for proteins containing intrinsically disordered regions (IDRs). In this work, we focus on the development of robust protein-free energy perturbation (FEP) protocols to reproduce experimental binding affinities that have been measured for a panel of mutants of the protein MDM2 against two ligands, AM-7209 and Nutlin-3a. We focus on mutations that occur in the N-terminal IDR lid of MDM2, which is known to undergo ligand-dependent folding upon binding. We systematically assess the effectiveness of both equilibrium and nonequilibrium alchemical protocols in reproducing these experimental binding affinities, in particular for mutations with slowly varying degrees of freedom. We show that the equilibrium protocol outperforms the nonequilibrium protocol in the precision of the free energy estimates obtained. In addition, we demonstrate the effect of the protein force field and the water model used to simulate the highly flexible IDR region. Overall, our findings demonstrate an accurate FEP protocol capable of reproducing these trends and further show the applicability of FEP protocols for elucidating the mutational effects on ligand binding affinity in highly dynamic intrinsically disordered protein regions
In Ovo Sexing and Genotyping using PCR techniques: A Contribution to the 3R Principles in Chicken Breeding
No full textEarly sex determination and genotyping of chicken embryos is crucial for ethical and resource efficient animal research, addressing concerns about surplus animals. We developed a reproducible workflow using whole genome amplification combined with Kompetitive Allele Specific PCR (KASP) and standard endpoint PCR to perform in ovo sexing and genotyping from embryonic day four (ED4/96h) onwards. The overall efficiency improved with embryonic age. Both standard PCR and KASP provided high success for sexing and genotyping (70–100% of samples yielding a result) and accuracy (92–100%) across multiple chicken lines, including a genetically modified line. Optimal reliability and hatchability were achieved when sampling at ED7. These PCR-based techniques enable precise early identification of sex and genotype, allowing selective removal of unwanted embryonated eggs before the assumed onset of nociception. This approach supports more humane and efficient practices in chicken breeding and research, contributing to the replacement, reduction and refinement (3R) principles in animal experimentatio
David Headley Green 1936–2024
No full textDavid Headley Green AM, FAA, FRS was an outstanding Australian geologist and world leader in experimental petrology and geochemistry. His research, initially at the Australian National University with A. E. Ringwood, and later at the University of Tasmania, shaped our understanding of the composition of the Earth’s mantle and the origin of the wide spectrum of volcanic rocks erupted in different global tectonic settings. David also had a significant impact on Antarctic science through studies of high-grade metamorphic rocks, but more broadly in fostering marine and climate science by championing the establishment at the University of Tasmania of a multidisciplinary research centre (now the Institute for Marine and Antarctic Studies). His achievements and scientific leadership were recognised with many international and national awards, including membership of the Order of Australia. A considerate and compassionate man, David is also remembered for his interest in and care for others
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