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We built the wrong AI for the right problems: why public sector AI gets it wrong from the start
No full textFieldwork in marginalised geographies of conflict. Responding to the unexpected
No full textWe are asked to assess risk ahead of field research activities – but it is not always possible to pre-empt and identify every possible risk that may emerge. In this chapter, I reflect on a series of research activities and encounters and the various unexpected risks that emerged and the dynamic responses these demanded. In exploring these examples, it is important to note also that some dangers or risks may only be revealed in hindsight. Nonetheless, the key focus of this chapter is upon the importance of adaptability, flexibility, and the need to not only have but also be able to dynamically develop contingency plans for when things – almost inevitably – don't go quite as planned during field research
A serum-stable antimicrobial peptide-based delivery platform for selective treatment of nontargetable and chemoresistant tumors
No full textAntibody–drug conjugates (ADCs) have transformed cancer therapy but remain limited by their dependence on internalizing antigens, poor applicability to untargetable tumors, and susceptibility to drug resistance. Therefore, a modular antimicrobial-peptide (AMP)-based therapeutic system centered on a rationally designed conjugate, 270, is presented, which integrates three optimized components: a selectivity-enhanced AMP core via a membrane affinity reconstruction strategy, a conformation-driven polyethylene glycolylated blocker to minimize off-target effects, and an N-terminal cap to improve stability in human serum. By targeting nonendocytic membrane surface receptors via small-molecule ligands, conjugate 270 exhibits potent and selective cytotoxicity against target tumor cells, effectively eliminating the majority of tumor cells within a few hours. Meanwhile, it exhibits high serum stability, minimal hemolysis, and negligible cytotoxicity toward normal cells at therapeutic concentrations. Mechanistic studies confirm ligand-dependent membrane localization, rapid depolarization, and disruption, along with mitochondrial dysfunction. Moreover, it demonstrates significant therapeutic efficacy against four cell lines resistant to conventional chemotherapeutic agents. While additional in vivo validation is warranted, this work lays the foundation for a flexible AMP-based approach to address untargetable and drug-resistant cancers.<br/
Significance of extreme reflection angles in RIS-assisted wireless networks
No full textThis study examines the importance of the extreme reflection angles in terms of the spectral efficiency in a Reconfigurable Intelligent Surfaces (RIS) - assisted wireless communication system. The investigation considers practical RIS unit cells with a non-ideal reflection response, which is typical, especially when the extreme angles of incidence, as well as reflection, are considered. A significant disparity was found in spectral efficiency when RIS is employed to reflect signals at extreme angles, with a notable 150 % - 200 % increase in the required number of unit cells to maintain the same spectral efficiency compared to scenarios with normal reflection angles. This observation underscores the importance of considering reflection angles in the design and optimization of RIS hardware. The results contribute valuable insights to the understanding of RIS behaviour in practical scenarios, paving the way for enhanced spectral efficiency and improved network performance.</p
Allosteric modulation and biased signalling at free fatty acid receptor 2
No full textFree fatty acid receptor 2 (FFA2) is a G protein-coupled receptor (GPCR) that is a primary sensor for short-chain fatty acids produced by gut microbiota. Consequently, FFA2 is a promising drug target for immunometabolic disorders1-4. Here we report cryogenic electronic microscopy structures of FFA2 in complex with two G proteins and three distinct classes of positive allosteric modulators (PAMs), and describe noncanonical activation mechanisms that involve conserved structural features of class A GPCRs. Two PAMs disrupt the E/DRY activation microswitch5 and stabilize the conformation of intracellular loop 2 by binding to lipid-facing pockets near the cytoplasmic side of the receptor. By contrast, the third PAM promotes the separation of transmembrane helices 6 and 7 by interacting with transmembrane helix 6 at the receptor-lipid interface. Molecular dynamic simulations and mutagenesis experiments confirm these noncanonical activation mechanisms. Furthermore, we demonstrate the molecular basis for the Gi versus Gq bias, which is due to distinct conformations of intracellular loop 2 stabilized by different PAMs. These findings provide a framework for the design of tailored GPCR modulators, with implications that extend beyond FFA2 to the broader field of GPCR drug discovery.</p
Wake effects of tilted wind turbines in neutral and unstable atmospheres: large eddy simulation of two-turbine arrays with downtilt
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Double trouble: aquatic invasive plants can promote mosquitoes
No full textHuman activities continue to facilitate biological invasions, profoundly impacting our environment and economy. Plants and insects constitute the majority of invasions to date, with facilitative links established between them, particularly in terrestrial habitats. These relationships remain understudied in aquatic environments, including potential associations between aquatic invasive plants and disease vectors such as mosquitoes. Here, we synthesise current knowledge on the co-occurrence of aquatic invasive plants and mosquitoes, identify key research gaps and present a conceptual framework underpinned by testable hypotheses on how aquatic invasive plants may influence immature and adult mosquito populations. We provide evidence suggesting that these plant-mosquito relationships could pose previously unrecognised risks and highlight priority areas for future research to better understand the potential public health implications of aquatic plant invasions. We call for targeted in situ and ex situ investigations to test the proposed hypotheses and increase our understanding of the interactions between aquatic invasive plants and mosquito population dynamics. Testing these hypotheses will inform adaptive, evidence-based management strategies to simultaneously control aquatic invasive species and vector mosquitoes
