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Hypoxic and pharmacological activation of HIFs inhibits SARS-CoV-2 infection of lung epithelial cells
No full textCOVID-19, caused by the novel coronavirus SARS-CoV-2, is a global health issue with more than 1 million fatalities to date. Understanding how host factors modify the viral life cycle could inform susceptibility to viral infection and the design of new therapies. Viral replication is shaped by the cellular microenvironment and one important factor is local oxygen tension, where hypoxia inducible factor (HIF) regulates transcriptional responses to hypoxia. SARS-CoV-2 primarily infects cells of the respiratory tract, entering via its Spike glycoprotein binding to angiotensin-converting enzyme (ACE2). We demonstrate that hypoxia and the HIF prolyl hydroxylase inhibitor Roxadustat (FG-4592) reduce ACE2 expression and inhibit SARS-CoV-2 entry and replication in lung epithelial cells via a HIF-1α dependent signalling pathway. Further, hypoxia and Roxadustat inhibit viral replication in SARS-CoV-2 infected cells, showing that post-entry steps in the viral life cycle are oxygen-sensitive. This study highlights the importance of hypoxia and HIF signalling in regulating multiple aspects of SARS-CoV-2 infection and raises the potential use of HIF prolyl hydroxylase inhibitors in the prevention and/or treatment of COVID-19
Researching pre-school teachers’ knowledge of oral language pedagogy using video
No full textThe Observing Language Pedagogy (OLP) tool uses videos of authentic classroom interactions to elicit the procedural knowledge which pre-school teachers can access, activate and use to support classroom decision-making. Three facets are captured: perceiving (the ability to identify salient language-supporting strategies); naming (the use of specific professional vocabulary to describe interactions); and interpreting (the ability to interpret the interactions observed). Prior research has shown that the OLP predicts classroom quality; with naming and interpreting proving the strongest predictors. This study examines OLP responses from 104 teachers to consider the nature of their pedagogical knowledge (perceiving, naming, interpreting), and describe differences between expert teachers (those leading language-supporting classrooms) and non-expert teachers (those leading lower quality classrooms). It offers insight into the nature of language-related expertise and to guide design of teacher professional development, suggesting a tri-fold focus on knowledge of linguistic input, relational pedagogy and cognitive challenging interactions
Redesign of ultrasensitive and robust RecA gene circuit to sense DNA damage
No full textSOS box of the recA promoter, PVRecA from Vibrio natriegens was characterized, cloned and expressed in a probiotic strain E. coli Nissle 1917. This promoter was then rationally engineered according to predicted interactions between LexA repressor and PVRecA. The redesigned PVRecA‐AT promoter showed a sensitive and robust response to DNA damage induced by UV and genotoxic compounds. Rational design of PVRecA coupled to an amplification gene circuit increased circuit output amplitude 4.3‐fold in response to a DNA damaging compound mitomycin C. A TetR‐based negative feedback loop was added to the PVRecA‐AT amplifier to achieve a robust SOS system, resistant to environmental fluctuations in parameters including pH, temperature, oxygen and nutrient conditions. We found that E. coli Nissle 1917 with optimized PVRecA‐AT adapted to UV exposure and increased SOS response 128‐fold over 40 h cultivation in turbidostat mini‐reactor. We also showed the potential of this PVRecA‐AT system as an optogenetic actuator, which can be controlled spatially through UV radiation. We demonstrated that the optimized SOS responding gene circuits were able to detect carcinogenic biomarker molecules with clinically relevant concentrations. The ultrasensitive SOS gene circuits in probiotic E. coli Nissle 1917 would be potentially useful for bacterial diagnosis
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