Cambridge University Research Outputs
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Item Embargo Accepted version Peer-reviewed Application of the cellular thermal shift assay (CETSA) to validate drug target engagement in platelets(Taylor and Francis) Dear, Joanna-Marie; Harper, Matthew; Harper, Matthew [0000-0002-4740-637X]Small molecule drugs play a major role in the study of human platelets. Effective action of a drug requires it to bind to one or more targets within the platelet (target engagement). However, although in vitro assays with isolated proteins can be used to determine drug affinity to these targets, additional factors affect target engagement and its consequences in an intact platelet, including plasma membrane permeability, intracellular metabolism or compartmentalisation, and level of target expression. Mechanistic interpretation of the effect of drugs on platelet activity requires comprehensive investigation of drug binding in the proper cellular context i.e., in intact platelets. The Cellular Thermal Shift Assay (CETSA) is a valuable method to investigate target engagement within complex cellular environments. The assay is based on the principle that drug binding to a target protein increases that protein’s thermal stability. In this technical report we describe the application of CETSA to platelets. We highlight CETSA as a quick and informative technique for confirming the direct binding of drugs to platelet protein targets, providing a platform for understanding the mechanism of action of drugs in platelets, and which will be a valuable tool for investigating platelet signalling and function.Item Open Access Accepted version Peer-reviewed Scalar and tensor charmonium resonances in coupled-channel scattering from QCD(American Physical Society, 2023-09-25) Wilson, David J; Thomas, Christopher E; Dudek, Jozef J; Edwards, Robert G; Wilson, David [0000-0003-2364-1161]; Thomas, Christopher [0000-0001-8817-4977]We determine $J^{PC}=0^{++}$ and $2^{++}$ hadron-hadron scattering amplitudes in the charmonium energy region up to 4100 MeV using lattice QCD, a first-principles approach to QCD. Working at $m_\pi\approx 391$ MeV, more than 200 finite-volume energy levels are computed and these are used in extensions of the L\"uscher formalism to determine infinite-volume coupled-channel scattering amplitudes. We find that this energy region contains a single $\chi_{c0}$ and a single $\chi_{c2}$ resonance. Both are found as pole singularities on the closest unphysical Riemann sheet, just below 4000 MeV with widths around 70 MeV. The largest couplings are to kinematically-closed $D^* \bar{D}^*$ channels in $S$-wave, and couplings to several decay channels consisting of pairs of open-charm mesons are found to be large and significant in both cases. Above the ground state $\chi_{c0}$, no other scalar bound-states or near-$D\bar{D}$ threshold resonances are found, in contrast to several theoretical and experimental studies.Item Embargo Accepted version Peer-reviewed Capturing Carbon Dioxide from Air with Charged-Sorbents(Nature Research) Li, Huaiguang; Zick, Mary; Trisukhon, Teedhat; Signorile, Matteo; Liu, Xinyu; Eastmond, Helen; Sharma, Shivani; Spreng, Tristan; Taylor, Jack; Gittins, James; Farrow, Cavan; Lim, S Alexandra; Crocella, Valentina; Milner, Phillip; Forse, Alexander; Forse, Alexander [0000-0001-9592-9821]Emissions reduction and greenhouse gas removal from the atmosphere are both necessary to achieve net-zero emissions and limit climate change. There is thus a need for improved sorbents for the capture of carbon dioxide from the atmosphere, a process known as direct air capture. In particular, low-cost materials that can be regenerated at low temperatures would overcome the limitations of current technologies. In this work, we introduce a new class of designer sorbent materials known as “charged-sorbents”. These materials are prepared through a battery-like charging process which accumulates ions in the pores of low-cost activated carbons, with the inserted ions then serving as adsorption sites for carbon dioxide adsorption. We use our charging process to accumulate reactive hydroxide ions in the pores of a carbon electrode, and find that the resulting sorbent material can rapidly capture carbon dioxide from ambient air via (bi)carbonate formation. Unlike traditional bulk carbonates, charged-sorbent regeneration can be achieved at low temperatures (90-100 ºC), and the sorbent's conductive nature permits direct Joule heating regeneration using renewable electricity. Given their highly tailorable pore environments and low cost, we anticipate that charged-sorbents will find numerous potential applications in chemical separations, catalysis, and beyond.Item Open Access Published version Peer-reviewed Breaking down in fits and starts: navigating a good naturalisation of J. H. Prynne’s ‘Blue Slides at Rest’ (2004)(Informa UK Limited) Heuvels, Max EliottItem Embargo Accepted version Peer-reviewed Magnetic zinc oxide/silica microbeads for the photocatalytic degradation of azo dyes(Elsevier BV, 2024-05) Al-Sharabi, Mohammed; Baiocco, Daniele; Lobel, Benjamin T; Cayre, Olivier J; Zhang, Zhibing; Routh, Alexander F; Al-Sharabi, Mohammed [0000-0001-5442-3373]; Baiocco, Daniele [0000-0002-0572-5065]; Lobel, Benjamin T [0000-0003-0472-6362]; Cayre, Olivier J [0000-0003-1339-3686]; Zhang, Zhibing [0000-0003-2797-9098]; Routh, Alexander F [0000-0002-3443-3053]Item Embargo Accepted version Peer-reviewed The acceptability and clinical impact of using polygenic scores for risk-estimation of common cancers in primary care: a systematic review(Springer) Dannhauser, Faye; Taylor, Lily; Tung, Joanna; Usher-Smith, Juliet; Usher-Smith, Juliet [0000-0002-8501-2531]Background: Polygenic scores (PGS) have been developed for cancer risk-estimation and show potential as tools to prompt earlier referral for high-risk individuals and aid risk-stratification within cancer screening programmes. This review explores the potential for using PGS to identify individuals at risk of the most common cancers seen in primary care. Methods: Two electronic databases were searched up until November 2023 to identify quantitative, qualitative, and mixed methods studies that reported on the acceptability and clinical impact of using PGS to identify individuals at highest risk of breast, prostate, colorectal and lung cancer in primary care. The Mixed Methods Appraisal Tool (MMAT) was used to assess the quality of included studies and a narrative synthesis was used to analyse data. Results: A total of 190 papers were identified, 18 of which were eligible for inclusion. A cancer risk-assessment tool incorporating PGS was acceptable to the general practice population and their healthcare providers but major challenges to implementation were identified, including lack of evidence for PGS in non-European ancestry and a need for healthcare provider education in genomic medicine. A PGS cancer risk-assessment had relatively limited impact on psychosocial outcomes and health behaviours. However, for prostate cancer, potential applications of it’s use in primary care were shown. Conclusions: Cancer risk assessment incorporating PGS in primary care is acceptable to patients and healthcare providers but there is a paucity of research exploring clinical impact. Few studies were identified, and more research is required before clinical implementation of PGS can be recommended.Item Embargo Accepted version Peer-reviewed A synoptic review of plant disease epidemics and outbreaks published in 2022(American Phytopathological Society) Cunniffe, Nicholas; Cunniffe, Nik [0000-0002-3533-8672]This scientometric study reviews the scientific literature and CABI distribution records published in 2022 to find evidence of major disease outbreaks and first reports of pathogens in new locations or on new hosts. This is the second time we have done this, and this study builds on our work documenting and analysing reports from 2021. Pathogens with three or more articles identified in 2022 literature were: Xylella fastidiosa, Bursaphelenchus xylophilus, Meloidogyne species complexes, Candidatus Liberibacter asiaticus, Raffaelea lauricola, Fusarium oxysporum formae specialis and Puccinia graminis f. sp. tritici. Our review of CABI distribution records found 29 pathogens with confirmed first reports in 2022. Pathogens with four or more first reports were: Meloidogyne species complexes, Pantoea ananatis, grapevine red globe virus and Thekopsora minima. Analysis of the proportion of new distribution records from 2022 indicated that grapevine red globe virus, sweet potato chlorotic stunt virus and Ca. Phytoplasma vitis may have been actively spreading. As we saw last year, there was little overlap between the pathogens identified by reviewing scientific literature versus distribution records. We hypothesise that this lack of concordance is because of the unavoidable lag between first reports of the type reported in the CABI database of a pathogen in a new location and any subsequent major disease outbreaks being reported in the scientific literature, particularly since the latter depends on journal policy on types of papers to be considered, whether the affected crop is major or minor, and whether the pathogen is of current scientific interest. Strikingly, too, there was also no overlap between species assessed to be actively spreading in this year’s study and those identified last year. We hypothesise this is because of inconsistencies in sampling coverage and effort over time, and delays between the first arrival of a pathogen in a new location and its first report, particularly for certain classes of pathogens causing only minor or non-economically damaging symptoms, which may have been endemic for some time before being reported. In general, introduction of new pathogens and outbreaks of extant pathogens threaten food security and ecosystem services. Continued monitoring of these threats is essential to support phytosanitary measures intended to prevent pathogen introductions and management of threats within a country.Item Embargo Accepted version Peer-reviewed Maternal obesity increases hypothalamic miR-505-5p expression in mouse offspring leading to altered fatty acid sensing and increased intake of high-fat food(Public Library of Science (PLoS)) Dearden, Laura; Ozanne, Susan E; Dearden, Laura [0000-0002-0804-074X]In utero exposure to maternal obesity programs increased obesity risk. Animal models show that programmed offspring obesity is preceded by hyperphagia, but the mechanisms that mediate these changes are unknown. Using a mouse model of maternal obesity, we observed increased intake of a high-fat diet in offspring of obese mothers that precedes the development of obesity. Through small RNA sequencing, we identified programmed overexpression of hypothalamic miR-505-5p that is established in the fetus, lasts to adulthood and is maintained in hypothalamic neural progenitor cells cultured in vitro. Metabolic hormones and long-chain fatty acids associated with obesity increase miR-505-5p expression in hypothalamic neurons in vitro. We demonstrate that targets of miR-505-5p are enriched in fatty acid metabolism pathways and over-expression of miR-505-5p decreased neuronal fatty acid metabolism in vitro. miR-505-5p targets are associated with increased BMI in human genetic studies. Intra-cerebroventricular injection of miR-505-5p in wild-type mice increased high-fat diet intake, mimicking the phenotype observed in offspring exposed to maternal obesity. Conversely, maternal exercise intervention in an obese mouse pregnancy rescued the programmed increase of hypothalamic miR-505-5p in offspring of obese dams and reduced high-fat diet intake to control offspring levels. This study identifies a novel mechanism by which maternal obesity programs obesity in offspring via increased intake of high-fat foods.Item Open Access Published version Peer-reviewed The potential for local environmental governance: A case study of natural Cambridgeshire(Elsevier BV, 2024-05) Hodge, Ian; Hodge, Ian [0000-0003-2679-3478]There are demands on land to provide a variety of ecosystem services alongside agricultural products. In the absence of markets, delivery is generally overseen through separate agencies. However, synergies and trade-offs amongst ecosystem services and variation across space lead to different priorities and opportunities in different areas. This creates a complex challenge for governance and implies a need to devolve decision-making. The objective of this paper is to explore the devolution of decision-making through the introduction of Local Environmental Governance Organisations (LEGO). A LEGO would assemble evidence on natural capital and coordinate stakeholders to identify local priorities. It would search for synergies and collaborative partnerships and raise funds to support priority actions. The paper first sets out a theoretical framework to identify the elements required for local governance. It then proposes two alternatives: a ‘national park’ approach for areas of higher environmental quality and a ‘local nature partnership’ approach elsewhere. The paper then provides a case study of Natural Cambridgeshire, a local nature partnership in England, as a potential LEGO, assessing the extent to which it meets the requirements identified. It has already done much to develop a stakeholder community and has begun to establish priorities for nature enhancement. However, it lacks programmes and long term funding that can incentivise the necessary actions or a forum that can bring together partners for Nature-based Solutions at scale. Central government would need to establish a framework for the operation of a system of LEGOs. It would also continue to support national standards.Item Open Access Published version Peer-reviewed Efficiency, accuracy, and transferability of machine learning potentials: Application to dislocations and cracks in iron(Elsevier BV, 2024-05) Zhang, L; Csányi, G; van der Giessen, E; Maresca, F; Zhang, L [0000-0003-4414-7111]; Maresca, F [0000-0002-3858-2267]Machine learning interatomic potentials (ML-IAPs) enable quantum-accurate, classical molecular dynamics simulations of large systems, beyond reach of density functional theory (DFT). Yet, their efficiency and ability to predict systems larger than DFT supercells are not fully explored, posing a question regarding transferability to large-scale simulations with defects (e.g. dislocations, cracks). Here, we apply a three-step validation approach to body-centered-cubic iron. First, accuracy and efficiency are assessed by optimizing ML-IAPs based on four state-of-the-art ML packages. The Pareto front of computational speed versus testing root-mean-square-error (RMSE) is computed. Second, benchmark properties relevant to plasticity and fracture are evaluated. Their relative root-mean-square-error (Q) with respect to DFT is found to correlate with RMSE. Third, transferability of ML-IAPs to dislocations and cracks is investigated by using per-atom model uncertainty quantification. The core structures and Peierls barriers of screw, M111 and three edge dislocations are compared with DFT. Traction–separation curve and critical stress intensity factor (KIc) are also predicted. Cleavage on the pre-existing crack plane is found to be the zero-temperature atomistic fracture mechanism of pure body-centered-cubic iron under mode-I loading, independent of ML package and training database. Quantitative predictions of dislocation glide paths and KIc can be sensitive to database, ML package, cutoff radius, and are limited by DFT accuracy. Our results highlight the importance of validating ML-IAPs by using indicators beyond RMSE. Moreover, significant computational speed-ups can be achieved by using the most efficient ML-IAP package, yet the assessment of the accuracy and transferability should be performed with care.Item Embargo Accepted version Peer-reviewed A novel family of defensin-like peptides from Hermetia illucens with antibacterial properties(BMC) Grant, Andrew; Fahmy, Leila; Generalovic, Tomas; Ali, Youssif; Seilly, David; Sivanesan, Kesavan; Kalmar, Lajos; Pipan, Miha; Christie, Graham; Grant, Andrew [0000-0001-9746-2989]Background The world faces a major infectious disease challenge. Interest in the discovery, design, or development of antimicrobial peptides (AMPs) as an alternative approach for the treatment of bacterial infections has increased. Insects are a good source of AMPs which are the main effector molecules of their innate immune system. Black Soldier Fly Larvae (BSFL) are being developed for large-scale rearing for food sustainability, waste reduction and as sustainable animal and fish feed. Bioinformatic studies have suggested that BSFL have the largest number of AMPs identified in insects. However, most AMPs identified in BSF have not yet undergone antimicrobial evaluation but are promising leads to treat critical infections. Results Jg7197.t1, Jg7902.t1 and Jg7904.t1 were expressed into the haemolymph of larvae following infection with Salmonella enterica serovar Typhimurium and were predicted to be AMPs using the computational tool ampir. The genes encoding these proteins were within 2 distinct clusters in chromosome 1 of the BSF genome. Following removal of signal peptides, predicted structures of the mature proteins were superimposed, highlighting a high degree of structural conservation. The 3 AMPs share primary sequences with proteins that contain a Kunitz-binding domain; characterised for inhibitory action against proteases, and antimicrobial activities. An in vitro antimicrobial screen indicated that heterologously expressed SUMO-Jg7197.t1 and SUMO-Jg7902.t1 did not show activity against 12 bacterial strains. While recombinant SUMO-Jg7904.t1 had antimicrobial activity against a range of Gram-negative and Gram-positive bacteria, including the serious pathogen Pseudomonas aeruginosa. Conclusions We have cloned and purified putative AMPs from BSFL and performed initial in vitro experiments to evaluate their antimicrobial activity. In doing so, we have identified a putative novel defensin-like AMP, Jg7904.t1, encoded in a paralogous gene cluster, with antimicrobial activity against P. aeruginosa.Item Embargo Accepted version Peer-reviewed PSMC5 insufficiency and P320R mutation impair proteasome function(Oxford University Press (OUP)) Rubinsztein, David; Yu, Zhong-Qiu; Carmichael, Jenny; Firth, Helen; Harijan, Pooja; Rubinsztein, David [0000-0001-5002-5263]The ubiquitin-proteasome system mediates the degradation of a wide variety of proteins. Proteasome dysfunction is associated with neurodegenerative diseases and neurodevelopmental disorders in humans. Here we identified mutations in PSMC5, an AAA ATPase subunit of the proteasome 19S regulatory particle, in individuals with neurodevelopmental disorders, which were initially considered as variants of unknown significance. We have now found heterozygotes with the following mutations: P320R (6 individuals), R325W, Q160A, and one nonsense mutation at Q69. We focused on understanding the functional consequence of PSMC5 insufficiency and the P320R mutation in cells and found that both impair proteasome function and activate apoptosis. Interestingly, the P320R mutation impairs proteasome function by weakening the association between the 19S regulatory particle and the 20S core particle. Our study supports that proteasome dysfunction is the pathogenic cause of neurodevelopmental disorders in individuals carrying PSMC5 variants.Item Embargo Accepted version Peer-reviewed Where is everybody? The unburied dead in Late Roman and early medieval England(Cambridge University Press) Brownlee, Emma; Klevnäs, Alison; Brownlee, Emma [0000-0001-7430-526X]A lack of burial evidence in England dating to the fifth century AD has long been noted. Some have suggested that this is due to inadequate artefact chronologies, or that there may have been a phase of unfurnished inhumation. Here we argue that the ‘missing fifth century’ is explained in part by continuation of archaeologically invisible mortuary treatment from the Iron Age and Roman periods. We present a series of radiocarbon-dated human remains from cave and riverine contexts, demonstrating that a range of modes of disposal of the dead outside formal cemeteries was practised in the first millennium AD.Item Embargo Accepted version Peer-reviewed Magma mingling during the 1959 eruption of Kīlauea Iki, Hawaiʻi(Springer) Marsh, Jennifer; Edmonds, Marie; Houghton, Bruce; Buisman, Iris; Herd, Richard; Edmonds, Marie [0000-0003-1243-137X]Magma mingling and mixing are common processes at basaltic volcanoes and play a fundamental role in magma petrogenesis and eruption dynamics. Mingling occurs most commonly when hot primitive magma is introduced into cooler magma. Here, we investigate a scenario whereby cool, partially degassed lava is drained back into a conduit, where it mingles with hotter, less degassed magma. The 1959 eruption of Kīlauea Iki, Hawaiʻi involved 16 high fountaining episodes. During each episode, fountains fed a lava lake in a pit crater, which then partially drained back into the conduit during and after each episode. We infer highly crystalline tachylite inclusions and streaks in the erupted crystal-poor scoria to be the result of recycling of this drain-back lava. The crystal phases present are dendrites of plagioclase, augite and magnetite/ilmenite, at sizes of up to 10 microns. Host sideromelane glass contains 7-8 wt% MgO and the tachylite glass (up to 0.5% by area) contains 2.5-6 wt% MgO. The vesicle population in the tachylite is depleted in the smallest size classes (<0.5 mm), has overall lower vesicle number densities and a higher degree of vesicle coalescence than the sideromelane component. The tachylite exhibits increasingly complex ‘stretching and folding’ mingling textures through the episodes, with discrete blocky tachylite inclusions in episode 1 and 3 giving way to complex, folded, thin filaments of tachylite in pyroclasts erupted in episodes 15 and 16. We calculate that a lava lake crust 8-35 cm thick may have formed in the repose times between episodes, and then foundered and been entrained into the conduit during drain-back. The recycled fragments of crust would have been reheated in the conduit, inducing glass devitrification and crystallization of pyroxene, magnetite and plagioclase dendrites and eventually undergoing ductile flow as the temperature of the fragments approached the host magma temperature. We use simple models of magma mingling to establish that stretching and folding of recycled, ductile lava could involve thinning of the clasts by up to a factor of 10 during the timescale of the eruption, consistent with observations of streaks and filaments of tachylite erupted during episodes 15 and 16, which may have undergone multiple cycles of eruption, drain-back and reheating.Item Open Access Accepted version Peer-reviewed Homological Lagrangian monodromy for some monotone tori(EMS Press, 2022-01-25) Augustynowicz, Marcin; Smith, Jack; Wornbard, Jakub; Smith, Jack [0000-0003-1384-0255]Given a Lagrangian submanifold $L$ in a symplectic manifold $X$, the homological Lagrangian monodromy group $\mathcal{H}_L$ describes how Hamiltonian diffeomorphisms of $X$ preserving $L$ setwise act on $H_*(L)$. We begin a systematic study of this group when $L$ is a monotone Lagrangian $n$-torus. Among other things, we describe $\mathcal{H}_L$ completely when $L$ is a monotone toric fibre, make significant progress towards classifying the groups than can occur for $n=2$, and make a conjecture for general $n$. Our classification results rely crucially on arithmetic properties of Floer cohomology rings.Item Embargo Accepted version Peer-reviewed A two-step post-optimality approach for a multi-objective railway maintenance planning problem(Elsevier) Petchrompo, Sanyapong; Kirwan, Andy; Modhara, Sunny; Wattanapongsakorn, N; Parlikad, Ajith; Parlikad, Ajith [0000-0001-6214-1739]Maintenance planning for railway networks is an exacting task, impacting numerous stakeholders with diverse objectives. While a multi-objective opti- mization model addresses the problem, it often results in numerous solutions on a Pareto front. Past researchers have introduced various Pareto pruning methods to autonomously create a shortlist of promising solutions. Nonethe- less, solely relying on data-driven approaches to finalize solutions can lead to undesirable outcomes for the decision maker (DM). To strike a balance between a human-involved and a data-centric decision, this article proposes a two-step approach. In the first step, Latent Profile Analysis (LPA) is utilized to group similar solutions on the Pareto front together, and a representative solution from each group is presented to the DM. After the DM identifies a focus region, Data Envelopment Analysis (DEA), including CCR and BCC models, is employed in the second step to rank the solutions in a selected group by their relative efficiency. Applying the proposed approach to a real- world case study demonstrates its capability in the railway asset management context. Key advantages of LPA lie in its ability to provide the appropriate number of solutions in the pruned set and its flexibility in grouping solutions. DEA enhances decision-making by ranking solutions within the focus region. Ultimately, by integrating automated algorithms with human insight, the two-step approach successfully identifies an efficient solution and mitigates the risk of obtaining undesirable outcomes on the Pareto front.Item Embargo Accepted version Peer-reviewed Recurrent flow patterns as a basis for turbulence: predicting statistics from structures(National Academy of Sciences) Page, Jacob; Norgaard, Peter; Brenner, Michael P; Kerswell, Rich R; Kerswell, Richard [0000-0001-5460-5337]A dynamical systems approach to turbulence envisions the flow as a trajectory through a high-dimensional state space transiently visiting the neighbourhoods of unstable simple invariant solutions (E. Hopf, Commun. Appl. Maths 1, 303, 1948). The hope has always been to turn this appealing picture into a predictive framework where the statistics of the flow follows from a weighted sum of the statistics of each simple invariant solution. Two outstanding obstacles have prevented this goal from being achieved: (1) paucity of known solutions and (2) the lack of a rational theory for predicting the required weights. Here we describe a method to substantially solve these problems, and thereby provide the first compelling evidence that the PDFs of a fully developed turbulent flow can be reconstructed with a set of unstable periodic orbits. Our new method for finding solutions uses automatic differentiation, with high-quality guesses constructed by minimising a trajectory-dependent loss function. We use this approach to find hundreds of new solutions in turbulent, two-dimensional Kolmogorov flow. Robust statistical predictions are then computed by learning weights after converting a turbulent trajectory into a Markov chain for which the states are individual solutions, and the nearest solution to a given snapshot is determined using a deep convolutional autoencoder. To our knowledge, this is the first time the PDFs of a spatio-temporally-chaotic system have been successfully reproduced with a set of simple invariant states, and provides a fascinating connection between self-sustaining dynamical processes and the more well-known statistical properties of turbulence.Item Open Access Published version Peer-reviewed Brownian snails with removal: epidemics in diffusing populations*(Institute of Mathematical Statistics, 2022-01-01) Grimmett, GR; Li, Z; Grimmett, Geoffrey [0000-0001-7646-3368]Two stochastic models of susceptible/infected/removed (SIR) type are introduced for the spread of infection through a spatially-distributed population. Individuals are initially distributed at random in space, and they move continuously according to independent diffusion processes. The disease may pass from an infected individual to an uninfected individual when they are sufficiently close. Infected individuals are permanently removed at some given rate $\alpha$. Such processes are reminiscent of so-called frog models, but differ through the action of removal, as well as the fact that frogs jump whereas snails slither. Two models are studied here, termed the `delayed diffusion' and the `diffusion' models. In the first, individuals are stationary until they are infected, at which time they begin to move; in the second, all individuals start to move at the initial time $0$. Using a perturbative argument, conditions are established under which the disease infects a.s. only finitely many individuals. It is proved for the delayed diffusion model that there exists a critical value $\alpha_c\in(0,\infty)$ for the survival of the epidemic.Item Open Access Published version Peer-reviewed Integrating AIPSS-MF and molecular predictors: A comparative analysis of prognostic models for myelofibrosis.(Wiley, 2024-03) Mosquera-Orgueira, Adrián; Arellano-Rodrigo, Eduardo; Garrote, Marta; Martín, Iván; Pérez-Encinas, Manuel; Gómez-Casares, María-Teresa; Hernández-Sánchez, Alberto; Ferrer-Marín, Francisca; Mora, Elvira; Velez, Patricia; Ayala, Rosa; Angona, Anna; Heras, Natalia de Las; Magro, Elena; Pérez-Míguez, Carlos; Crucitti, Davide; Mata-Vázquez, María-Isabel; Fox, María-Laura; González de Villambrosía, Sonia; Ramírez, María-José; García, Ana; García-Gutiérrez, Valentín; Cáceres, Amparo; Durán, María-Antonia; Senín, María-Alicia; Raya, José-María; González, José A; Cuevas, Beatriz; Xicoy, Blanca; Nangalia, Jyoti; Hernández-Rivas, Jesús M; Bellosillo, Beatriz; Álvarez-Larrán, Alberto; Hernández-Boluda, Juan C; Spanish MPN Group (GEMFIN); Mosquera-Orgueira, Adrián [0000-0003-4838-6750]; Hernández-Boluda, Juan C [0000-0002-4289-3113]Item Open Access Published version Peer-reviewed Mathematical modelling of cerebral haemodynamics and their effects on ICP.(Elsevier BV, 2024) Chu, Ka Hing; Olakorede, Ihsane; Beqiri, Erta; Czosnyka, Marek; Smielewski, Peter; Beqiri, Erta [0000-0002-8108-0000]; Smielewski, Peter [0000-0001-5096-3938]INTRODUCTION: Electrical-equivalence mathematical models that integrate vascular and cerebrospinal fluid (CSF) compartments perform well in simulations of dynamic cerebrovascular variations and their transient effects on intracranial pressure (ICP). However, ICP changes due to sustained vascular diameter changes have not been comprehensively examined. We hypothesise that changes in cerebrovascular resistance (CVR) alter the resistance of the bulk flow of interstitial fluid (ISF). RESEARCH QUESTION: We hypothesise that changes in CVR alter the resistance of the bulk flow of ISF, thus allowing simulations of ICP in response to sustained vascular diameter changes. MATERIAL AND METHODS: A lumped parameter model with vascular and CSF compartments was constructed and converted into an electrical analogue. The flow and pressure responses to transient hyperaemic response test (THRT) and CSF infusion test (IT) were observed. Arterial blood pressure (ABP) was manipulated to simulate ICP plateau waves. The experiments were repeated with a modified model that included the ISF compartment. RESULTS: Simulations of the THRT produced identical cerebral blood flow (CBF) responses. ICP generated by the new model reacted in a similar manner as the original model during ITs. Plateau pressure reached during ITs was however higher in the ISF model. Only the latter was successful in simulating the onset of ICP plateau waves in response to selective blood pressure manipulations. DISCUSSION AND CONCLUSION: Our simulations highlighted the importance of including the ISF compartment, which provides mechanism explaining sustained haemodynamic influences on ICP. Consideration of such interactions enables accurate simulations of the cerebrovascular effects on ICP.