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Modelling G protein-biased agonism using GLP-1 receptor C-terminal mutations
No full textBackground and aim: The glucagon-like peptide-1 receptor (GLP-1R) is a major therapeutic target for type 2 diabetes and obesity. Agonists showing bias in favour of G protein signalling over β-arrestin recruitment and GLP-1R internalisation, e.g. tirzepatide and orforglipron, have favourable clinical efficacy profiles. However, understanding of the effects of biased agonism has been hampered by differences in ligand properties such as affinity, efficacy, stability and pharmacokinetics. Here we used GLP-1R C-tail mutations that inhibit phosphorylation to mimic G protein-biased GLP-1R agonism without the need for ligand modifications.
Methods: Serine doublet phosphorylation sites in the human and mouse GLP-1R C-tails were mutated to alanine. Wild-type and mutant GLP-1Rs were examined for β-arrestin recruitment, internalisation, Gαs activation, and signalling readouts in HEK293 cells and pancreatic β-cell models. Native GLP-1 plus oppositely biased ligands exendin-phe1 (ExF1; G protein-biased) and exendin-asp3 (ExD3; β-arrestin-biased) were used to compare ligand- and receptor-mediated biased agonism.
Results: Loss of three C-terminal phosphorylation sites reduced GLP-1- and ExD3-mediated GLP-1R internalisation and β-arrestin recruitment to that seen with ExF1. The phosphodeficient GLP-1R showed preferential plasma membrane Gαs activation over longer stimulations, with associated increases in whole cell cAMP generation and kinomic signalling. The distal GLP-1R phosphorylation site played a larger role in β-arrestin recruitment, and the proximal sites were more important for GLP-1R internalisation and regulating cAMP production.
Conclusion: Genetic changes that reduce in β-arrestin recruitment and slow GLP-1R internalisation can enhance GLP-1R signalling, providing conceptual support for the use of G protein bias to improve GLP-1R agonist efficacy
Quantifying and regionalizing land use impacts on catchment response times with high-frequency observations
No full textLand use and land cover change (LUCC) can affect the hydrological response time of rivers. However, it is difficult to generate robust and quantitative evidence of this impact at the catchment scale. This lack of evidence also affects the development of rainfall-runoff models to make ex-ante predictions. Here, we analyze high-frequency observational data from a network of pairwise catchments in the tropical Andes and find a statistically significant impact of intensive land use on the hydrological response time, which can be used for regionalization. First, we isolated individual rainfall response events from 5-minute
precipitation and discharge time series of 16 catchments (8 pairs). We then fitted unit hydrographs on these events to estimate the catchment response times. These response
times were subsequently regionalized by, first, applying a forward stepwise regression to select statistically significant catchment characteristics including land use and land cover, then, fitting a linear mixed-effects model with the selected characteristics to account for within-site variability between pairs. We find that catchments with intensive land use have a significantly quicker response than their natural counterparts. Differences were often sub-hourly, highlighting the value of high-frequency monitoring. Forward stepwise regression identified only catchment area and intensive land use percentage as statistically significant predictors. Model coefficients show that, even when considering other catchment characteristics, increasing intensive land use percentage decreases response times. This study provides solid evidence and a robust methodology to quantify the impacts of LUCC on
catchment hydrology
Autonomous in silico optimization framework for high-performance micromixers
No full textEffective mixing at the microscale is essential for lab-on-a-chip systems, yet designing micromixers that achieve both high mixing efficiency and low pressure drop remains challenging and resource-intensive. Here, we introduce an autonomous in silico framework for designing obstacle-based micromixers through integrating 3D geometry generation, computational fluid dynamics (CFD) simulations and a multi-objective artificial intelligence optimization algorithm within a fully automated close-loop workflow. A constraint-aware NSGA-II variant is used, incorporating a repair operator to ensure design feasibility. Experimentally validated against hyperspectral imaging-based mixing characterization and pressure-drop measurements, the framework eliminates manual trial-and-error workload and alleviates researchers from the tedious tasks of navigating across 3D modeling, CFD simulations, and optimization algorithms, reducing optimization time by 48% compared to the conventional simulation-assisted approach. By autonomously screening hundreds of designs, it identifies Pareto-optimal micromixers and generates an extensive database that supports inverse design and reveals the mixing structure-performance relationship, facilitating the establishment of general design guidelines. The framework is generally applicable to a wide range of passive micromixers
Climate change eclipses La Niña cooling in Australia to drive extreme heatwave and heightened fire risk
No full textFrom recording to intervention: causal lineage tracing with primed conversion
No full textAbstract—Predicting cell fate requires reconstructing a cell’s integrated history: its lineage, the signals it received, how its internal state evolved and its spatial context. Existing recording methods write this information into DNA and read it only at the experiment’s end, allowing reconstruction of what happened but not testing whether it was required. Closing this gap demands real-time observation with the capacity to intervene: perturbing
specific cells based on what is observed, while sparing others as matched controls. Primed conversion, a dual-wavelength photoconversion method, confines activation to a single cell in three dimensions by requiring both blue and red light beams to intersect. The same photochemistry can release optogenetic actuators, so a single illumination both marks and edits a cell. Combined with oblique plane microscopy for continuous volumetric imaging, this architecture enables conditional intervention throughout development or tumour evolution, generating genetic
mosaics with internal controls that turn lineage tracing from
passive recording into an experimental test of which events were required for a given fate. In this perspective, an integrated optical platform is outlined that couples primed conversion, optogenetic actuators and oblique plane microscopy to achieve causal, real time intervention on defined cells
Embodied cross-domain intelligence in biomedical microrobots: a review
No full textMicrorobots are emerging as transformative tools for biomedical applications, including mini mally invasive diagnostics, targeted therapy, and microsurgical intervention. However, achieving reliable performance and adaptation to diverse tasks and environments requires capabilities that exceed any single form of intelligence. Here we introduce embodied cross-domain intelligence, a framework for synergistic coupling across physical (PI), biological (BI), computational (CI), and human (HI) intelligence, enabling multifunctional, collaborative, and adaptive microrobotic behaviour in dynamic, safety-critical biological settings. Unlike prior reviews that address these intelligence domains in isolation, this review aims to provide a unified framework, outlining each domain’s principles, recent advances, and limitations; analysing the interfaces that foster synergy; and mapping representative domain combinations to major biomedical applications. We further identify core challenges in integration, control, safety, and validation, and outline future research directions to accelerate clinical translation. By framing biomedical microrobot development as a cross-domain synergy challenge, this review aims to guide interdisciplinary efforts toward systems capable of executing complex, multi-stage tasks across their operational lifecycle. The associated project is available on online project page
Coast-O-Matic: an automated shoreline detection method using PlanetScope satellite imagery
No full textMultispectral satellite imagery enables routine surveying of the surf zone by discretising the land–sea interface at known water levels, supporting estimates of coastal recession and accretion. The daily revisit of PlanetScope provides near-continuous shoreline observations, increasing temporal resolution relative to traditional tasking. Many existing approaches delineate shorelines by applying a single spectral index threshold, typically NDWI, and contouring the resulting binary mask. We present an alternative, fully probabilistic method. An ensemble of multilayer perceptrons (MLPs) is trained to predict, for each pixel, the probability of "water" versus "land." The shoreline is then extracted as an isoprobability contour, eliminating the need for a global threshold and allowing spatial variability in sensor response, illumination (e.g., shadows), and local geomorphology to be accommodated. Applied to PlanetScope imagery at Seaford, UK, and evaluated against a height contour referenced to the instantaneous water level, the method achieves a root-mean-square error of ≈7 m for scenes with <50% cloud cover. These results indicate that probabilistic pixel-wise classification, coupled with high-cadence PlanetScope acquisitions, offers robust shoreline detection suitable for high-frequency coastal monitoring
A selective and augmentable butyrate-FFAR2 signal circuitry programs the cellular identity of enteroendocrine L-cells
No full textActivation of free fatty acid receptor 2 (FFAR2) on enteroendocrine L-cells mediates secretion of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY), key regulators of central appetite control with therapeutic relevance to obesity. Here, we show that butyrate, a metabolite derived from fermentation of dietary fibre and an FFAR2 agonist, stimulates a PYY-biased profile in a human L-cell model at the transcriptional, morphological and secretory level via an FFAR2-Gai axis that does not require dynamin-dependent receptor internalization. We observe that butyrate modulates active Notch cascades within a Hes1-GFP mouse organoid model, which are antagonistic to secretory differentiation, and identify butyrate-dependent regulation of late-stage human enteroendocrine maturation markers, NeuroD1 and Pax6. Butyrate-mediated upregulation of Pyy and Pax6 is enhanced by the FFAR2-selective Gai biased allosteric agonist AZ-1729. Our study reveals functions of spatiotemporally regulated butyrate-activated FFAR2 signalling mechanisms that could be pharmacologically amplified to fine-tune L-cell populations in the human colon
Stochastic fields/LES of partially-premixed lean hydrogen flames with swirl-axial air injection
No full textTurbulent hydrogen flames with varying operating conditions in the swirl-axial air injection AHEAD combustor were studied computationally with a multi-regime flame closure method, combustion LES / Stochastic fields. The method was validated by comparisons with measurements in isothermal and reacting flows. The velocity fields, flames, mixing fields and thermo-chemical states were analysed in detail. Further comparisons were carried out for different operating conditions to study the effect of global equivalence ratio and axial air injection ratio. On the one hand, it introduces higher axial momentum, which restricts flashback. On the other hand, increasing the global equivalence ratio or axial air injection ratio negatively affects the spatial mixing quality where the axial momentum flux plays an important role. The results also suggest that thermochemical states are dominantly controlled by the global equivalence ratio rather than the inlet reactant temperature or flow conditions. The effect of differential diffusion was also studied. Differential diffusion slightly increases the possibility of the upstream occurrence of the flame inner branch, which results in the
inner flame branch brush becoming broader. This was found to be related to the changes of the upstream mixing field due to differential diffusion. Nevertheless,
the global system is negligibly influenced by differential diffusion due to the high Reynolds number
Global epidemiology and disease burden of human parainfluenza virus in adults: a systematic review
No full textParainfluenza virus (PIV) is a common cause of respiratory illness in children and immunocompromised adults, but little is known about its epidemiology or disease burden in the general adult population. This review evaluates published global epidemiological and disease burden for PIV in adults, including high-risk patients (immunocompromised or with chronic illnesses), and identifies existing data gaps. A PRISMA systematic review of publications from 2014 to 2023 in PubMed reporting PIV prevalence and disease burden (including hospitalisations, mortality) in adults (≥ 18 years) and high-risk patients was performed. Sixty-five studies were included; which skewed towards Asia, Europe, and North America, highlighting a data gap in global PIV prevalence. Overall prevalence of PIV (all strains) ranged from 0 to 15.2% [median 2%] in the general adult population (not considered high-risk but tested for infection). PIV3 was the most prevalent strain (0.6−15.2% [2.9]), followed by PIV4 (0.4−6.5% [1.9]), PIV1 (0.5−2.8% [1.1]), and PIV2 (0−2.9% [1.1]). PIV prevalence was generally higher in high-risk adults (up to 41% in certain risk groups) and those aged ≥ 65. Mortality rates ranged from 2 to 40% in those high-risk, while need for respiratory assistance ranged from 0.9% to 64.2% and hospitalisation from 3.7% to 45.3%. None of the studies reported cost-related healthcare resource utilisation. Variability of study designs, data stratification, and patient populations in the selected studies challenged evaluating the true prevalence of PIV and its burden. PIV infection carries an underappreciated burden, with substantial morbidity and mortality risks, especially in high-risk patients. Significant knowledge gaps exist regarding global prevalence and economic burden in the general adult population