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Metabolism in the tumour-bone microenvironment
No full textPurpose of Review
For solid tumours such as breast and prostate cancer, and haematological malignancies such as myeloma, bone represents a supportive home, where the cellular crosstalk is known to underlie both tumour growth and survival, and the development of the associated bone disease. The importance of metabolic reprogramming is becoming increasingly recognised, particularly within cancer biology, enabling tumours to adapt to changing environments and pressures. This review will discuss our current understanding of metabolic requirements and adaptations within the tumour-bone microenvironment.
Recent Findings
The bone provides a unique metabolic microenvironment, home to highly energy-intensive processes such as bone resorption and bone formation, both of which are dysregulated in the presence of cancer. Approaches such as metabolomics demonstrate metabolic plasticity in patients with advanced disease. Metabolic crosstalk between tumour cells and surrounding stroma supports disease pathogenesis.
Summary
There is increasing evidence for a key role for metabolic reprogramming within the tumour-bone microenvironment to drive disease progression. As such, understanding these metabolic adaptations should reveal new therapeutic targets and approaches
Controlled human malaria infection with a clone of Plasmodium vivax with high quality genome assembly
No full textControlled human malaria infection (CHMI) provides a highly informative means to investigate host-pathogen interactions and enable in vivo proof-of-concept efficacy testing of new drugs and vaccines. However, unlike Plasmodium falciparum, well-characterized P. vivax parasites that are safe and suitable for use in modern CHMI models are limited. Here, two healthy malaria-naïve UK adults with universal donor blood group were safely infected with a clone of P. vivax from Thailand by mosquito-bite CHMI. Parasitemia developed in both volunteers and, prior to treatment, each volunteer donated blood to produce a cryopreserved stabilate of infected red blood cells. Following stringent safety screening, the parasite stabilate from one of these donors ("PvW1") was thawed and used to inoculate six healthy malaria-naïve UK adults by blood-stage CHMI, at three different dilutions. Parasitemia developed in all volunteers, who were then successfully drug treated. PvW1 parasite DNA was isolated and sequenced to produce a high quality genome assembly by using a hybrid assembly method. We analysed leading vaccine candidate antigens and multigene families, including the Vivax interspersed repeat (VIR) genes of which we identified 1145 in the PvW1 genome. Our genomic analysis will guide future assessment of candidate vaccines and drugs, as well as experimental medicine studies
The risk of SARS-CoV-2 outbreaks in low prevalence settings following the removal of travel restrictions
No full textBackground
Countries around the world have introduced travel restrictions to reduce SARS-CoV-2 transmission. As vaccines are gradually rolled out, attention has turned to when travel restrictions and other non-pharmaceutical interventions (NPIs) can be relaxed.
Methods
Using SARS-CoV-2 as a case study, we develop a mathematical branching process model to assess the risk that, following the removal of NPIs, cases arriving in low prevalence settings initiate a local outbreak. Our model accounts for changes in background population immunity due to vaccination. We consider two locations with low prevalence in which the vaccine rollout has progressed quickly – specifically, the Isle of Man (a British crown dependency in the Irish Sea) and the country of Israel.
Results
We show that the outbreak risk is unlikely to be eliminated completely when travel restrictions and other NPIs are removed. This general result is the most important finding of this study, rather than exact quantitative outbreak risk estimates in different locations. It holds even once vaccine programmes are completed. Key factors underlying this result are the potential for transmission even following vaccination, incomplete vaccine uptake, and the recent emergence of SARS-CoV-2 variants with increased transmissibility.
Conclusions
Combined, the factors described above suggest that, when travel restrictions are relaxed, it may still be necessary to implement surveillance of incoming passengers to identify infected individuals quickly. This measure, as well as tracing and testing (and/or isolating) contacts of detected infected passengers, remains useful to suppress potential outbreaks while global case numbers are high
Transition between instability and seeded self-modulation of a relativistic particle bunch in plasma
No full textWe use a relativistic ionization front to provide various initial transverse wakefield amplitudes for the self-modulation of a long proton bunch in plasma. We show experimentally that, with sufficient initial amplitude [≥(4.1±0.4) MV/m], the phase of the modulation along the bunch is reproducible from event to event, with 3%-7% (of 2π) rms variations all along the bunch. The phase is not reproducible for lower initial amplitudes. We observe the transition between these two regimes. Phase reproducibility is essential for deterministic external injection of particles to be accelerated
Shock and detonation waves at an interface and the collision of action potentials
No full textAction potentials in neurons are known to annihilate each other upon collision, while there are cases where they might penetrate each other. The fate of two waves upon collision is critically dependent on the underlying mechanism of propagation and therefore an understanding of possible outcomes of collision under different conditions is important. Previously, compression waves that travel within the plasma membrane of a neuron have been proposed as a thermodynamic basis for the propagation of action potentials. In this context, it was recently shown that two-dimensional compressive shock waves in the model system of lipid monolayers behave strikingly similar to action potentials in neurons and can even annihilate each other upon head-on collision. However, even a qualitative mechanism remained unclear. To this end, we summarise the fundamentals of shock physics as applied to an interface and recap how it explained the observation of threshold and saturation of shockwaves in the lipid monolayer (all - or - none). We then compare the theory with the soliton model that has the same fundamental premise, i.e. the conservation laws and thermodynamics, and was previously proposed as a model for the nerve pulse propagation. We elaborate on how the two approaches make different predictions with regards to collisions and the detailed structure of the wave-front. As a case study and a new qualitative result, we finally show that previously unexplained annihilation of shock waves in the lipid monolayer is a direct consequence of the nature of state changes, i.e. jump conditions, within these shockwaves
Computing CQ lower-bounds over OWL 2 through approximation to RSA: extended abstract
No full textConjunctive query (CQ) answering over knowledge bases is an important reasoning task. However, with expressive ontology languages such as OWL, query answering is computationally very expensive. The PAGOdA system addresses this issue by using a tractable reasoner to compute lower and upper-bound approximations, falling back to a fully fledged OWL reasoner only when these bounds don’t coincide. The effectiveness of this approach critically depends on the quality of the approximations, and in this paper we explore a technique for computing closer approximations via RSA, an ontology language that subsumes all the OWL 2 profiles while still maintaining tractability of standard reasoning tasks. We present a novel approximation of OWL 2 ontologies into RSA, and an algorithm to compute a closer lower bound approximation using the RSA combined approach. We have implemented these algorithms in our prototype and conducted an extensive evaluation thereof
Attribution of the Australian bushfire risk to anthropogenic climate change
No full textDisastrous bushfires during the last months of 2019 and January 2020 affected Australia, raising the question to what extent the risk of these fires was exacerbated by anthropogenic climate change. To answer the question for southeastern Australia, where fires were particularly severe, affecting people and ecosystems, we use a physically based index of fire weather, the Fire Weather Index; long-term observations of heat and drought; and 11 large ensembles of state-of-the-art climate models. We find large trends in the Fire Weather Index in the fifth-generation European Centre for Medium-Range Weather Forecasts (ECMWF) Atmospheric Reanalysis (ERA5) since 1979 and a smaller but significant increase by at least 30 % in the models. Therefore, we find that climate change has induced a higher weather-induced risk of such an extreme fire season. This trend is mainly driven by the increase of temperature extremes. In agreement with previous analyses we find that heat extremes have become more likely by at least a factor of 2 due to the long-term warming trend. However, current climate models overestimate variability and tend to underestimate the long-term trend in these extremes, so the true change in the likelihood of extreme heat could be larger, suggesting that the attribution of the increased fire weather risk is a conservative estimate. We do not find an attributable trend in either extreme annual drought or the driest month of the fire season, September–February. The observations, however, show a weak drying trend in the annual mean. For the 2019/20 season more than half of the July–December drought was driven by record excursions of the Indian Ocean Dipole and Southern Annular Mode, factors which are included in the analysis here. The study reveals the complexity of the 2019/20 bushfire event, with some but not all drivers showing an imprint of anthropogenic climate change. Finally, the study concludes with a qualitative review of various vulnerability and exposure factors that each play a role, along with the hazard in increasing or decreasing the overall impact of the bushfires
Product attributes affecting the substitutability of saiga horn drinks among young adult consumers in Singapore
No full textGlobally, illegal and unsustainable wildlife trade can drive biodiversity loss. Understanding which product attributes consumers consider when deciding between products of threatened species or alternatives, is key for conservation interventions. Labeled Discrete Choice Experiments (DCEs) are underutilized in wildlife trade literature but can aid this understanding. In labeled DCEs, the alternatives presented to respondents have specific names (e.g., paracetamol) as opposed to being generic bundles (e.g., option A). We used a labeled DCE to assess young adult preferences toward “cooling water” used to treat fever and heatiness (a traditional Chinese medicine state of illness) in Singapore. One popular cooling water contains saiga horn, made from Critically Endangered Saiga tatarica antelope. Data from 639 university-enrolled respondents were analyzed using latent class models. Middle- to high-income Chinese Singaporeans were the respondents most likely to choose saiga horn. Overall, however, respondents significantly preferred lower price products sold in nearby outlets—suggesting that for young adults in Singapore, saiga horn cooling water may be substitutable if its physical and financial availability is reduced
Cells of the human intestinal tract mapped across space and time
No full textThe cellular landscape of the human intestinal tract is dynamic throughout life, developing in utero and changing in response to functional requirements and environmental exposures. Here, to comprehensively map cell lineages, we use single-cell RNA sequencing and antigen receptor analysis of almost half a million cells from up to 5 anatomical regions in the developing and up to 11 distinct anatomical regions in the healthy paediatric and adult human gut. This reveals the existence of transcriptionally distinct BEST4 epithelial cells throughout the human intestinal tract. Furthermore, we implicate IgG sensing as a function of intestinal tuft cells. We describe neural cell populations in the developing enteric nervous system, and predict cell-type-specific expression of genes associated with Hirschsprung’s disease. Finally, using a systems approach, we identify key cell players that drive the formation of secondary lymphoid tissue in early human development. We show that these programs are adopted in inflammatory bowel disease to recruit and retain immune cells at the site of inflammation. This catalogue of intestinal cells will provide new insights into cellular programs in development, homeostasis and disease
Self-organization scheme for balanced routing in large-scale multi-hop networks
No full textWe propose a self-organization scheme for cost-effective and load-balanced routing in multi-hop networks. To avoid overloading nodes that provide favourable routing conditions, we assign each node with a cost function that penalizes high loads. Thus, finding routes to sink nodes is formulated as an optimization problem in which the global objective function strikes a balance between route costs and node loads. We apply belief propagation (its min-sum version) to solve the network optimization problem and obtain a distributed algorithm whereby the nodes collectively discover globally optimal routes by performing low-complexity computations and exchanging messages with their neighbours. We prove that the proposed method converges to the global optimum after a finite number of local exchanges of messages. Finally, we demonstrate numerically our framework's efficacy in balancing the node loads and study the trade-off between load reduction and total cost minimization