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Macrophage to neuron communication via extracellular vesicles in neuropathic pain conditions
Get PDFNeuropathic pain following peripheral nerve injury results from maladaptive changes in neurons and immune cells contribution to mechanisms underlying chronic pain. Specifically, in dorsal root ganglia (DRG), sensory neuron cell bodies release extracellular vesicles (EVs) which promote pro-inflammatory macrophage accumulation that facilitates nociceptive signalling. Here, we show that macrophages shuttle EVs to neurons. Indeed, bone marrow-derived macrophages (BMDMs) release EVs containing microRNA-155 (miR-155) which are taken up by cultured sensory neurons. EV-mediated transfer of miR-155 suppresses phosphatase Ship1 expression and increases cytokine interleukin-6 (IL-6) contents. Intrathecal-injected BMDM-derived EVs accumulate in lumbar DRG and EVs containing miR-155 antagomir result in Ship1 upregulation, Il6 downregulation in neurons in concomitance to attenuation of neuropathic mechanical hypersensitivity. These data suggest that, under neuropathic conditions, pro-inflammatory macrophages shuttle EV-containing miR-155 to neurons and contribute to the expression of pronociceptive IL-6 in DRG
A reduced order model for sea water intrusion simulation using proper orthogonal decomposition
Get PDFSea water intrusion (SWI) simulators are essential tools to assist the sustainable management of coastal aquifers. These simulators require the solution of coupled variable-density partial differential equations (PDEs), which reproduce the processes of groundwater flow and dissolved salt transport. The solution of these PDEs is typically addressed numerically with the use of density-dependent flow simulators, which are computationally intensive in most practical applications. To this end, model surrogates are generally developed as substitutes for full-scale aquifer models to trade off accuracy in exchange for computational efficiency. Surrogates represent an attractive option to support groundwater management situations in which fast simulators are required to evaluate large sets of alternative pumping strategies. Reduced-order models, a sub-category of surrogate models, are based on the original model equations and may provide quite accurate results at a small fraction of computational cost. In this study, a variable-density flow reduced-order model based on proper orthogonal decomposition (POD) and utilizing a fully coupled flow and solute-transport model is implemented with a finite-difference (FD) approach for simulating SWI in coastal aquifers. The accuracy and computational efficiency of the FD-POD approach for both homogeneous andβmore realisticβheterogeneous systems are investigated using test cases based on the classic Henry's problem (Henry 1964). The findings demonstrate that the combined FD-POD approach is effective in terms of both accuracy and computational gain and can accommodate the output of the most popular variable-density flow models, such as those from USGS's MODFLOW family
Tumour purity assessment with deep learning in colorectal cancer and impact on molecular analysis
Get PDFTumour content plays a pivotal role in directing the bioinformatic analysis of molecular profiles such as copy number variation (CNV). In clinical application, tumour purity estimation (TPE) is achieved either through visual pathological review [conventional pathology (CP)] or the deconvolution of molecular data. While CP provides a direct measurement, it demonstrates modest reproducibility and lacks standardisation. Conversely, deconvolution methods offer an indirect assessment with uncertain accuracy, underscoring the necessity for innovative approaches. SoftCTM is an open-source, multiorgan deep-learning (DL) model for the detection of tumour and non-tumour cells in H&E-stained slides, developed within the Overlapped Cell on Tissue Dataset for Histopathology (OCELOT) Challenge 2023. Here, using three large multicentre colorectal cancer (CRC) cohorts (N = 1,097 patients) with digital pathology and multi-omic data, we compare the utility and accuracy of TPE with SoftCTM versus CP and bioinformatic deconvolution methods (RNA expression, DNA methylation) for downstream molecular analysis, including CNV profiling. SoftCTM showed technical repeatability when applied twice on the same slide (r = 1.0) and excellent correlations in paired H&E slides (r > 0.9). TPEs profiled by SoftCTM correlated highly with RNA expression (r = 0.59) and DNA methylation (r = 0.40), while TPEs by CP showed a lower correlation with RNA expression (r = 0.41) and DNA methylation (r = 0.29). We show that CP and deconvolution methods respectively underestimate and overestimate tumour content compared to SoftCTM, resulting in 6β13% differing CNV calls. In summary, TPE with SoftCTM enables reproducibility, automation, and standardisation at single-cell resolution. SoftCTM estimates (M = 58.9%, SD Β±16.3%) reconcile the overestimation by molecular data extrapolation (RNA expression: M = 79.2%, SD Β±10.5, DNA methylation: M = 62.7%, SD Β±11.8%) and underestimation by CP (M = 35.9%, SD Β±13.1%), providing a more reliable middle ground. A fully integrated computational pathology solution could therefore be used to improve downstream molecular analyses for research and clinics. Β© 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland
Secondary flow-induced particle dynamics in fully developed turbulent square ducts with a free-slip boundary
Get PDFSecondary flow effects on particle dynamics are investigated in a fully developed turbulent open square duct flow at a shear Reynolds number of ReΟ = 300. The modelling of the fluid phase is based on direct numerical simulation, and the trajectories of particles are described using a one-way coupled Lagrangian particle tracking technique, with shear Stokes numbers ranging from St+ = 0.31β260. The results obtained show that particles with St+ β₯ 25 accumulate strongly in the lower corners of the duct, while the upper corners with mixed boundaries are relatively devoid of particles. The transverse cross-stream velocities for all considered particle sets exceed those of the fluid phase near the intersection of the inner and outer secondary vortices. Furthermore, the cross-sectional secondary flow is observed to encourage particle acceleration near the free surface. A further in-depth analysis regarding the impact of various hydrodynamic forces exerted on the particles in the duct cross-section is also provided
Balancing Act or Two Roads to Travel: Evaluating the Trade-offs Between Digitalization and Net Zero Innovation in SMEs
Get PDFAs firms face the dual challenges of digitalization and net zero innovation to combat climate change, understanding how these twin transitions relate is crucial. This study examines potential synergies or trade-offs between digital technologies and net zero innovations in UK SMEs. By integrating the Resource-Based View (RBV) and the Attention-Based View (ABV), we explore how categories of digital adopters relate to categories of net zero innovation adopters. Utilizing novel survey data for 964 UK SMEs, we employ ordered Probit estimation to examine the relationship between digital and net zero adoption. Our results reveal that digitally advanced SMEs are more likely to be advanced adopters of net zero innovations, suggesting that digital complementarities and enhanced capabilities can reinforce environmental innovations that reduce carbon emissions. We offer valuable contributions for both theory and practice, highlighting the importance of supporting SMEs in their twin transitions
London taxi drivers exploit neighbourhood boundaries for hierarchical route planning
Get PDFHumans show an impressive ability to plan over complex situations and environments. A classic approach to explaining such planning has been tree-search algorithms which search through alternative state sequences for the most efficient path through states. However, this approach fails when the number of states is large due to the time to compute all possible sequences. Hierarchical route planning has been proposed as an alternative, offering a computationally efficient mechanism in which the representation of the environment is segregated into clusters. Current evidence for hierarchical planning comes from experimentally created environments which have clearly defined boundaries and far fewer states than the real-world. To test for real-world hierarchical planning we exploited the capacity of London licensed taxi drivers to use their memory to construct a street by street plan across London, UK (>26,000 streets). The time to recall each successive street name was treated as the response time, with a rapid average of 1.8 s between each street. In support of hierarchical planning we find that the clustered structure of London's regions impacts the response times, with minimal impact of the distance across the street network (as would be predicted by tree-search). We also find that changing direction during the plan (e.g. turning left or right) is associated with delayed response times. Thus, our results provide real-world evidence for how humans structure planning over a very large number of states, and give a measure of human expertise in planning
Urban governance in the pandemic and beyond: framing the debate from cities of the South
No full textβHow long do I have?β β examining survival outcomes in laryngeal cancer patients managed with non-curative intent in Northern UK: insights from the northern head & neck cancer alliance retrospective study
Get PDFIntroduction
Historically, 15% of laryngeal cancer patients undergo non-curative management, but pragmatic data on this group are limited. This information is crucial to help patients make informed decisions about their care. Supported by the Northern Head & Neck Alliance, this retrospective study is the first to present survival outcomes for non-curative laryngeal cancer patients in Northern UK.
Methods
Retrospective data were compiled for patients with laryngeal squamous cell cancer from five large tertiary head and neck centres in Northern UK (Newcastle, Glasgow, Sheffield, Leeds, and Middlesbrough). The collected data encompassed demographic details, treatment and clinical outcomes.
Results
Among 373 patients, the mean age was 72, and 73% were male. The median follow-up was 6βmonths. 17% had early-stage (T1-2), and 83% had late-stage (T3-4) disease. By data collection, 99% had died.
The mean survival time (MST) was 9.1βmonths. Patients with metastases had an MST of 6.9βmonths, while those without had 9.4βmonths. Early-stage patients had an MST of 13.3βmonths, compared to 8.2βmonths for advanced disease. By subsite, MSTs were 8.2βmonths for supraglottic, 12.5 for glottic, 5.5 for subglottic, and 7.9 for transglottic cancers.
Conclusion
This study stands as the first to explore survival outcomes in laryngeal cancer patients undergoing non-curative management. The findings can provide valuable insights for informing patients about survival in the absence of radical treatment, facilitating important decision-making conversations
High strain rate behaviour of cohesive soils
Get PDFSoil-filled wire and geotextile gabions are essential components of defensive infrastructure in military bases, leveraging the attenuating properties of soils to safeguard personnel and critical assets against blast and fragmentation effects. However, understanding the behaviour of cohesive soils under extreme loading conditions remains largely unexplored, presenting a crucial knowledge gap for design engineers tasked with developing robust soil constitutive models to address evolving threats. This study investigates the response of cohesive soils, focusing primarily on kaolin clay due to its homogeneity, widespread availability and consistent properties. Through high strain rate experimental testing of kaolin clay specimens, using the split-Hopkinson pressure bar (SHPB) apparatus, both unconfined and confined conditions are explored across varying moisture contents, spanning the spectrum from unsaturated to fully saturated states. The analysis of the experimental results uncovers the strain rate dependence of cohesive soils and identifies distinct phase behaviour for transmitted and radial stresses influenced by factors such as strain rate, moisture content and confinement. Utilising LS-DYNA, and the finite element method (FEM), the SHPB tests are modelled for comparison against experimental findings. While LS-DYNA, supplemented by Smooth Particle Hydrodynamics (SPH) node modelling, provides valuable insights, significant disparities between modelled and practical results underscore the challenges inherent with the accuracy in simulating the behaviour of cohesive soils. Nonetheless, this comprehensive exploration of cohesive soil's high strain rate behaviour yields critical insights for engineers, enabling them to adapt defensive strategies to diverse threats and loading scenarios effectively
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