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Development of method for large scale manufacturing of ON constructs
No full textOligonucleotide therapeutics rapidly advanced in recent years, with several studies being conducted in the biological and medical fields. Therefore, it has become imperative to develop methodologies for the large-scale synthesis of oligonucleotides, with chemical modification to match the barriers that need to be overcome, namely instability, tissue delivery and affinity, immunogenicity and off-target effects. The primary objective of this research project is to synthesise linkers that can be used in oligonucleotide solid-phase synthesis, enabling conjugation between these oligonucleotides and biological macromolecules via click chemistry. The initial phase of the work involved the chemical synthesis of linkers, continuing ongoing studies in the host laboratory on amino and alkyne linkers. While the alkyne linkers enable conjugation with macromolecules through copper-catalysed azide-alkyne cycloaddition, the amino linker provides orthogonality through amide bond formation with biological entities, such as peptides. In addition, linkers based on dibenzoazacyclooctyne (DBCO) were investigated as DBCO can react with azide-handle biomolecules via copper-free click chemistry in biological conditions. The DBCO-based linker was designed using 5,6-dihydrodibenzo[b,f]azocine as key intermediate. This core structure can be acylated to yield the desired DBCO, followed by the reaction with amino acids or analogues. Given the requirement that the linkers undergo oligonucleotide solid-phase synthesis, a phosphoramidite moiety was incorporated into the linkers. This was achieved by introducing an aminodiol building block. This common scaffold contains an amine group for bonding with the click chemistry moiety via amide bond formation and two hydroxyl groups, one for phosphoramidite group introduction; other, DMTr-protected ensures compatibility with solid-phase oligonucleotide synthesis, enabling elongation of the oligonucleotide chain, as well as the incorporation of linkers at any position. The aminodiol building blocks studies in this project were a linear aminodiol, a cyclic aminodiol and the serinol. The second phase of the research project involved the comparison of the efficiency of the synthesized linkers in the oligonucleotide solid-phase conditions, as well as evaluating their behaviour during the handling processes after the synthesis, including cleavage, deprotection from the solid support, and purification. In addition, the conjugation of DBCO-containing oligonucleotides with biological molecules, such as peptides and monoclonal antibodies, was also investigated in this project
Long-term impacts of mixotrophy on ocean carbon storage: insights from a 10 000 year global model simulation
No full textMixotrophs – organisms that combine the use of light and inorganic resources with the ingestion of prey – have been shown in simulations to increase mean organism size and carbon export in the ocean. These simulations have, however, been limited to decade-long timescales that are insufficient to investigate the impacts of mixotrophy on the ocean's long-term capacity for carbon storage. Here we explore these long-term impacts using a low-resolution ocean model that resolves important feedbacks between surface ecology and the ocean interior over multi-millennial periods. The model was compared in two configurations: one with a strict distinction between phytoplankton and zooplankton populations and one in which all populations were assumed to be capable of mixotrophy. Consistent with earlier studies, we found that increased carbon and nutrient export associated with mixotrophy was rapidly established within the first few years of the simulation and was robust over long time scales. However, we also found that these increases were partially offset over longer time scales by a decline in “preformed” inorganic carbon and nutrients entering the deep ocean via the sinking of surface waters. Over the 10 000 year duration of the simulations, we found that ecologically-driven changes in C export increased the oceanic C inventory by up to 537 Pg, and that this was partially offset by decline of 150 Pg in the preformed C inventory, leaving a net increase of up to 387 Pg C (∼1 %)
Constructing the self: historical roots, current challenges, and future directions
No full textIn this entry, we survey key ideas about the construct of “the self,” tracing its development from evolutionary origins to contemporary theories in psychology and neuroscience. We highlight three organizing features of selfhood: reflexive consciousness, interpersonal relatedness, and agency. Drawing on work from philosophy and the cognitive sciences, we outline how the self has been conceptualized as both a product of mental processes and a participant in social life. We connect early philosophical theories, such as those proposed by Hume and James, to later psychological models that address the self-concept, motivation, regulation, and narrative identity. We also consider current challenges, including how digital environments and artificial intelligence are reshaping the way individuals construct identity, relate to others, and reflect on experience. These trends raise questions about how the self functions in technologically mediated contexts and how emerging tools might change scholarly understanding of personhood. We conclude by considering interdisciplinary approaches and future directions in research on the self
Origami bistability as a platform for programmable mechanics and multifunctional metasurfaces
No full textResponsible AI UK response to the DSIT’s call for evidence on the AI Growth Lab
No full textA response to the Department for Science, Innovation and Technology (DSIT) open call for evidence regarding the AI Growth Lab1 on behalf of Responsible AI UK (RAi UK), an open and multidisciplinary network that brings together experts from across the four nations of the UK to understand how we should shape the development of AI to benefit people, communities and societ
Price optimization for round trip car sharing
No full textCar sharing, car clubs and short-term rentals could support the transition toward net zero but their success depends on them being financially sustainable for service providers and attractive to end users. Dynamic pricing could support this by incentivizing users while balancing supply and demand. We describe the usage of a round trip car sharing fleet by a continuous time Markov chain model, which reduces to a multi-server queuing model where hire duration is assumed independent of the hourly rental price. We present analytical and simulation optimization models that allow the development of dynamic pricing strategies for round trip car sharing systems; in particular identifying the optimal hourly rental price. The analytical tractability of the queuing model enables fast optimization to maximize expected hourly revenue for either a single fare system or a system where the fare depends on the number of cars on hire, while accounting for stochasticity in customer arrival times and durations of hire. Simulation optimizationis used to optimize prices where the fare depends on the time of day or hire duration depends on price. We present optimal prices for a given customer population and show how the expected revenue and car availability depend on the customer arrival rate, willingness-to-pay distribution, dependence of the hire duration on price, and size of the customer population. The results provide optimal strategies for pricing of car sharing and inform strategic managerial decisions such as whether to use time- or state-dependent pricing and optimizing the fleet size
Rate splitting multiple access for RIS-aided URLLC MIMO broadcast channels
No full textThe performance of modern wireless communication systems is typically limited by interference. The impact of interference can be even more severe in ultra-reliable and low-latency communication (URLLC) use cases. A powerful tool for managing interference is rate splitting multiple access (RSMA), which encompasses many multiple-access technologies like non-orthogonal multiple access (NOMA), spatial division multiple access (SDMA), and broadcasting. Another effective technology to enhance the performance of URLLC systems and mitigate interference is constituted by reconfigurable intelligent surfaces (RISs). This paper develops RSMA schemes for multi-user multiple-input multiple-output (MIMO) RIS-aided broad-cast channels (BCs) based on finite block length (FBL) coding. We show that RSMA and RISs can substantially improve the spectral efficiency (SE) and energy efficiency (EE) of MIMO RIS-aided URLLC systems. Additionally, the gain of employing RSMA and RISs noticeably increases when the reliability and latency constraints are more stringent. Furthermore, RISs impact RSMA differently, depending on the user load. If the system is underloaded, RISs are able to manage the interference sufficiently well, making the gains of RSMA small. However, when the user load is high, RISs and RSMA become synergetic
Self-healing constitutive behavior of poroelastic architected matter: a new regime in smart aerospace structural design
No full textPoliticising safety and racialised and gendered criminalisation: political agenda-setting and the case of Albanian asylum-seekers in the UK
No full textHow the UK government has politicised asylum by categorising Albanian asylum-seekers as “criminals” and Albania as a “safe” country to advance an immigration deterrence agenda remains unresearched. We use agenda-setting and policy framing analytical insights to explain how and why UK government’s successful agenda-setting was underpinned by the racialised and gendered criminalisation of Albanian males and the politicisation of the safety conditions in Albania. Our findings draw on qualitative empirical data, alongside triangulation with official and stakeholder data and documents. We argue that the racialised and gendered criminalisation of Albanian males – as evidenced by political rhetoric and the media – was integral to the targeted legal and political measures making Albania a “safe” country. Nonetheless, we show that these framings misrepresent the reality in Albania and the challenges that vulnerable Albanians face when seeking protection in the UK
Discovery and target identification of SICLOPPS-derived antibacterial cyclic peptides
No full textThe rise and rapid spread of antibiotic resistance is one of the great challenges facing modern medicine, creating an urgent need for novel and innovative antibiotics. Synthetic small molecule screens have historically yielded few antibiotics used clinically, but synthetic cyclic peptide libraries may revolutionise antibiotic discovery, as they can engage a greater breadth of challenging targets than small molecule compounds. Split-intein circular ligation of peptides and proteins (SICLOPPS) is a method of generating genetically encoded cyclic peptide libraries which can be expressed and screened intracellularly. In this work, a 3.2-million-membered CXXXXX library (where X = any of the 20 canonical amino acids) was created using SICLOPPS and screened for inhibitors of the bacterial Rod system. The Rod system contains both a validated antibiotic target and potential new targets and is an attractive focus for antibiotic discovery. The Rod system is essential in E. coli and other rod-shaped bacteria, but not in E. coli exhibiting upregulation of the cell division protein FtsZ (termed FtsZUP cells). Mecillinam is an antibiotic which causes toxic malfunction of the Rod system. Therefore, Rod system inhibition confers mecillinam resistance in FtsZUP E. coli but is lethal to wild-type E. coli. The CXXXXX library was screened in FtsZUP E. coli DH5α for cyclic peptides which suppress mecillinam toxicity. NGS analysis and motif discovery identified 13 cyclic peptides of interest from the screen. One of these cyclic peptides, cyclo-CVKYKP, was found to cause modest growth inhibition of E. coli DH5α. Cyclo-CVKYKP rescued growth of FtsZUP E. coli DH5α treated with mecillinam and failed to block the growth of FtsZUP E. coli DH5α in which the Rod system is non-essential. Scanning electron microscopy found that cyclo-CVKYKP-treated FtsZUP E. coli DH5α cells exhibit morphological defects and frequently grow as spheres instead of rods. These observations indicate that cyclo-CVKYKP is a Rod system inhibitor.Cyclo-SMDIKG is a previously reported SICLOPPS-derived antibacterial cyclic peptide with an unknown mode of action. To shed light on its mode of action, eight E. coli proteins were tested for their ability to suppress cyclo-SMDIKG toxicity when overexpressed. This led to the identification of ErpA, an iron-sulfur cluster protein essential for aerobic and anaerobic respiration in E. coli, as a candidate cyclo-SMDIKG target. Microscale thermophoresis (MST) analysis of cyclo-SMDIKG binding to apo-ErpA found a likely very weak binding interaction. However, MST analysis of cyclo-SMDIKG binding to holo-ErpA suggested preferential binding to holo-ErpA with much higher affinity. Further work is needed to confirm this observation.This study showcases SICLOPPS as a promising and flexible approach to synthetic library screening for antibiotic discovery, yielding antibacterial cyclic peptides with putative novel targets to guide future innovative antibiotic development.<br/
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