32151 research outputs found
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Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease
Get PDFFunding: Funding: R.M.R, D.K., C.S.F. and M.A.B. are supported by the UK Dementia Research Institute through UK DRI Ltd, principally funded by the UK Medical Research Council. M.A.B. is further supported by an UKRI Future Leaders Fellowship (MR/X011038/1) and an NC3Rs studentship grant (NC/W001675/1). S.S.H. is supported by an Alzheimer’s Association International Research Fellowship (AARF-23-1149637). C.A. and S.W. are supported by the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre. M.S. is supported by an MRC Career Development Award (MR/X019977/1). T.A.G. is supported by an Alzheimer’s Association Research Fellowship to Promote Diversity (23AARFD-1029918).Reduction of amyloid beta (Aβ) has been shown to be effective in treating Alzheimer’s disease (AD), but the underlying assumption that neurons are the main source of pathogenic Aβ is untested. Here, we challenge this prevailing belief by demonstrating that oligodendrocytes are an important source of Aβ in the human brain and play a key role in promoting abnormal neuronal hyperactivity in an AD knock-in mouse model. We show that selectively suppressing oligodendrocyte Aβ production improves AD brain pathology and restores neuronal function in the mouse model in vivo. Our findings suggest that targeting oligodendrocyte Aβ production could be a promising therapeutic strategy for treating AD.Peer reviewe
Exoplanets in science fiction
Get PDFScience fiction (SF) is a genre influenced by science which, in turn, influences science. Astronomers discovered the first exoplanets (planets outside our solar system) in the 1990s, but exoplanets featured in SF long before then. I aim to answer the research questions: what is the relationship between exoplanet science and science fiction worldbuilding? Can SF be used for science education? This thesis employs an interdisciplinary mix of quantitative and qualitative methodologies to study the relationship between science and SF with a focus on the portrayal of exoplanets. First, I compile a database of 212 SF exoplanets and use Bayesian network analysis to find how various characteristics of these fictional exoplanets influence each other. Results indicate fictional exoplanets created after the discovery of real exoplanets are less Earth-like, evidencing that SF changes in response to scientific discoveries of inhospitable exoplanets. Second, I collect and analyse questionnaire data from participants in my project to create short SF stories in teams of one scientist and one writer. Results show scientific concerns were incorporated into the story creation decision-making process, and suggest an inspirational role for SF towards its readership’s interest in science. Third, I interview exoplanet scientists about the relevance of the N=1 Problem, the fact that we know of only one planet with life, on their work. Analysis of interview results shows a diversity of methods to manage the N=1 Problem in exoplanet science research, as well as a trend within this set of participants of N=1 being not formally taught but rather discussed in less formal academic settings. Through the use of quantitative and qualitative methodologies, I provide statistical evidence that SF incorporates rapidly-evolving exoplanet science discoveries into its storytelling. I identify a role for SF in science education of introducing concepts and inspiring general audiences to pursue further study of science
Direct synthesis of partially ethoxylated branched polyethylenimine from ethanolamine
Get PDFFunding: This research is funded by a UKRI Future Leaders Fellowship (MR/W007460/1) and the EaSI- CAT centre for Doctoral Training (A.S.G.). M.B. wishes to thank the School of Chemistry and EaStCHEM for their support. A.E.O. gratefully acknowledges a fellowship from the Akwa Ibom State University (TETFund).We report here a method to make a branched and partially ethoxylated polyethyleneimine derivative directly from ethanolamine. The polymerization reaction is catalysed by a pincer complex of Earth-abundant metal, manganese, and produces water as the only byproduct. Industrial processes to produce polyethyleneimines involve the transformation of ethanolamine to a highly toxic chemical, aziridine, by an energy-intensive/waste-generating process followed by the ring-opening polymerization of aziridine. The reported method bypasses the need to produce a highly toxic intermediate and presents advantages over the current state-of-the-art. We propose that the polymerization process follows a hydrogen borrowing pathway that involves (a) dehydrogenation of ethanolamine to form 2-aminoacetaldehyde, (b) dehydrative coupling of 2-aminoacetaldehyde with ethanolamine to form an imine derivative, and (c) subsequent hydrogenation of imine derivative to form alkylated amines.Peer reviewe
Evaluating Mycobacterium komossense JERR01 as a possible model organism for Mycobacterium tuberculosis antibiotic resistance studies
Get PDFMulti-drug-resistant tuberculosis (MDR-TB) accounted for an estimated 410,000 cases of all TB infections in 2022 and presents a major challenge for global health. Studying TB is complicated due to the fastidiousness and high pathogenicity of Mycobacterium tuberculosis (Mtb) that requires specialized facilities, expensive equipment, and long experimentation phases. To overcome these challenges, various Mycobacterium species have been developed as model organisms that share some of the characteristics of Mtb but are less pathogenic and more amenable to experimentation have been proposed in the past. All these models have limitations, therefore new models for Mtb that better replicate properties of the pathogen are needed.
This thesis investigates a mycobacterial strain, JERR01, that was originally identified as Mycobacterium komossense as a model organism for the development of antimicrobial resistance (AMR) towards key drugs used for the treatment of TB. Through initial phenotypic characterization of the strain that originated from a human urine sample, it was determined that this strain was fast-growing and shared similar antibiotic sensitivity profiles to Mtb for six antitubercular drugs, suggesting suitability for studying AMR development. Genomic characterisation of the strain and comparison to a type strain of M. komossense revealed that its original taxonomic designation was imprecise. Wider comparison genomic analyses provided evidence that JERR01 belonged to the Fortuitum-Vaccae clade of Mycobacterium but designated it as an unclassified mycobacterial species. Having identified homologs of genes associated with resistance to antitubercular drugs in M. JERR01, in vitro studies were conducted to see how resistance to rifampicin and isoniazid, two key drugs used in tuberculosis treatment, could evolve through in vitro experimentation. For rifampicin, similar mutational pathways to Mtb were identified in the rpoB gene, the primary target of resistance. The mutations associated with decreased sensitivity to isoniazid were almost exclusively associated with inactivating katG, which encodes the gene catalase-peroxidase responsible for activating the pro-drug isoniazid. This contrasts to the mutational pathways for isoniazid in Mtb which encompass a broader range of loci and mutations. Overall, this work has identified a mycobacterial strain that can safely and rapidly grow in the laboratory to investigate the development of resistance to antituberculosis drugs and has the potential to act as a model organism for studying AMR in Mtb
One-pot access to functionalised malamides via organocatalytic enantioselective formation of spirocyclic β-lactone-oxindoles and double ring-opening.
Get PDFFunding: The research leading to these results has received funding from the EPSRC (K.K., EP/T023643/1) and the EaSI-CAT centre for Doctoral Training (A.J.N.). A.D.S. and K.K. thank the EPSRC Programme Grant “Boron: Beyond the Reagent” (EP/W007517) for support.Malamides (diamide derivatives of malic acid) are prevalent in nature and of significant biological interest, yet only limited synthetic methods to access functionalised enantiopure derivatives have been established to date. Herein an effective synthetic method to generate this molecular class is developed through in situ formation of spirocyclic β-lactone-oxindoles (employing a known enantioselective isothiourea-catalysed formal [2+2] cycloaddition of C(1)-ammonium enolates and isatin derivatives) followed by a subsequent dual ring-opening protocol (of the β-lactone and ox-indole) with amine nucleophiles. The application of this protocol is demonstrated across twelve examples to give densely functionalised malamide derivatives with high enantio- and diastereoselectivity (up to >95:5 dr and >99:1 er).Peer reviewe
Disturbance‐mediated changes to boreal mammal spatial networks in industrializing landscapes
Get PDFFunding: InnoTech Alberta. Grant Number: C2021000986; Alberta Innovates; Alberta Conservation Association; Petroleum Technology Alliance Canada. Grant Numbers: 17-ERPC-02, 18-ERPC-01, 19-ERPC-04; Algar Caribou Habitat Restoration Program. Grant Number: NXC-107980; Oil Sands Monitoring program; Natural Sciences and Engineering Research Council of Canada. Grant Numbers: RGPIN-2018–03958, Canada Research Chairs.Compound effects of anthropogenic disturbances on wildlife emerge through a complex network of direct responses and species interactions. Land‐use changes driven by energy and forestry industries are known to disrupt predator–prey dynamics in boreal ecosystems, yet how these disturbance effects propagate across mammal communities remains uncertain. Using structural equation modeling, we tested disturbance‐mediated pathways governing the spatial structure of multipredator multiprey boreal mammal networks across a landscape‐scale disturbance gradient within Canada's Athabasca oil sands region. Linear disturbances had pervasive direct effects, increasing site use for all focal species, except black bears and threatened caribou, in at least one landscape. Conversely, block (polygonal) disturbance effects were negative but less common. Indirect disturbance effects were widespread and mediated by caribou avoidance of wolves, tracking of primary prey by subordinate predators, and intraguild dependencies among predators and large prey. Context‐dependent responses to linear disturbances were most common among prey and within the landscape with intermediate disturbance. Our research suggests that industrial disturbances directly affect a suite of boreal mammals by altering forage availability and movement, leading to indirect effects across a range of interacting predators and prey, including the keystone snowshoe hare. The complexity of network‐level direct and indirect disturbance effects reinforces calls for increased investment in addressing habitat degradation as the root cause of threatened species declines and broader ecosystem change.Peer reviewe
Analogue event horizons in dielectric medium
Get PDFIn this thesis I numerically study an optical pulse travelling in a dielectric medium as an analogue event horizon. A novel numerical method is developed to study the scattering properties of this optical system. Numerical solutions of scattering problems often exhibit instabilities. The staircase approximation, in addition, can cause slow convergence. We present a differential equation for the scattering matrix which solves both of these problems. The new algorithm inherits the numerical stability of the S matrix algorithm and converges faster for a smoothly varying potential than the S matrix algorithm with the staircase approximation. We apply our equation to solve a 1D stationary scattering of plane waves from a non-periodic smoothly varying pulse/scatterer travelling with a constant velocity in a lossless medium. The properties of stability and the convergence of the Riccati matrix equation are demonstrated. Furthermore, we include a relative velocity between the scatterer and the wave medium to generalise the algorithm further where the number of right and left going modes are not equal. The algorithm is applicable for stationary scattering process from arbitrarily shaped smooth scatterers, periodic or non-periodic, even when the scatterer is varying at the scale of wavelengths. This method is used to present numerical results for a sub-femtoseconds optical pulse travelling in bulk silica. We calculate the analogue hawking radiation from the analogue system. The temperature of the hawking radiation is studied systematically with many different profiles of pulses. We find out steepness, intensity and duration of the pulse are most important in producing analogue hawking radiation in these systems. A better numerical and theoretical understanding will make the experiments better suited to detect hawking radiation
Clinical course and management of COVID-19 in the era of widespread population immunity
Get PDFThe clinical implications of COVID-19 have changed since SARS-CoV-2 first emerged in humans. The current high levels of population immunity, due to prior infection and/or vaccination, have been associated with a vastly decreased overall risk of severe disease. Some people, particularly those with immunocompromising conditions, remain at risk for severe outcomes. Through the course of the pandemic, variants with somewhat different symptom profiles from the original SARS-CoV-2 virus have emerged. The management of COVID-19 has also changed since 2020, with the increasing availability of evidence-based treatments in two main classes: antivirals and immunomodulators. Selecting the appropriate treatment(s) for patients with COVID-19 requires a deep understanding of the evidence and an awareness of the limitations of applying data that have been largely based on immune-naive populations to patients today who most likely have vaccine-derived and/or infection-derived immunity. In this Review, we provide a summary of the clinical manifestations and approaches to caring for adult patients with COVID-19 in the era of vaccine availability and the dominance of the Omicron subvariants, with a focus on the management of COVID-19 in different patient groups, including immunocompromised, pregnant, vaccinated and unvaccinated patients.Peer reviewe
Ligand hydrogenation during hydroformylation catalysis detected by in-situ high-pressure infra-red spectroscopic analysis of a rhodium/phospholene-phosphite catalyst
Get PDFPhospholane-phosphites are known to give highly unusual selectivity’s towards branched aldehydes in the hydroformylation of terminal alkenes. This paper describes the synthesis of hitherto unknown unsaturated phospholene-borane precursors and their conversion to the corresponding phospholene-phosphites. The relative stereochemistry of one of these ligands, and it’s Pd complex was assigned with the aid of X-ray crystal structure determinations. These ligands were able to approach the level of selectivity observed for phospholane-phosphites in the rhodium catalysed hydroformylation of propene. High-Pressure-Infra-Red (HPIR) spectroscopic monitoring of the catalyst formation revealed that whilst the catalysts show good thermal stability with respect to fragmentation, the C=C bond in the phospholene is slowly hydrogenated in the presence of rhodium and syngas. The ability of this spectroscopic tool to detect even subtle changes in structure, remote from the carbonyl ligands underlines the usefulness of HPIR spectroscopy in hydroformylation catalyst development.Peer reviewe
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