Quantitative 3D histochemistry reveals region-specific amyloid-ß reduction by the antidiabetic drug netoglitazone.

A hallmark of Alzheimer's disease (AD) is the extracellular aggregation of toxic amyloid-beta (Aß) peptides in form of plaques. Here, we identify netoglitazone, an antidiabetic compound previously tested in humans, as an Aß aggregation antagonist. Netoglitazone improved cognition and reduced microglia activity in a mouse model of AD. Using quantitative whole-brain three-dimensional histology (Q3D), we precisely identified brain regions where netoglitazone reduced the number and size of Aß plaques. We demonstrate the utility of Q3D in preclinical drug evaluation for AD by providing a high-resolution brain-wide view of drug efficacy. Applying Q3D has the potential to improve pre-clinical drug evaluation by providing information that can help identify mechanisms leading to brain region-specific drug efficacy.

Engineering Toxoplasma gondii secretion systems for intracellular delivery of multiple large therapeutic proteins to neurons.

Delivering macromolecules across biological barriers such as the blood-brain barrier limits their application in vivo. Previous work has demonstrated that Toxoplasma gondii, a parasite that naturally travels from the human gut to the central nervous system (CNS), can deliver proteins to host cells. Here we engineered T. gondii's endogenous secretion systems, the rhoptries and dense granules, to deliver multiple large (>100 kDa) therapeutic proteins into neurons via translational fusions to toxofilin and GRA16. We demonstrate delivery in cultured cells, brain organoids and in vivo, and probe protein activity using imaging, pull-down assays, scRNA-seq and fluorescent reporters. We demonstrate robust delivery after intraperitoneal administration in mice and characterize 3D distribution throughout the brain. As proof of concept, we demonstrate GRA16-mediated brain delivery of the MeCP2 protein, a putative therapeutic target for Rett syndrome. By characterizing the potential and current limitations of the system, we aim to guide future improvements that will be required for broader application.

The volume of healthy red blood cells is optimal for advective oxygen transport in arterioles.

Red blood cells (RBCs) are vital for transporting oxygen from the lungs to the body's tissues through the intricate circulatory system. They achieve this by binding and releasing oxygen molecules to the abundant hemoglobin within their cytosol. The volume of RBCs affects the amount of oxygen they can carry, yet whether this volume is optimal for transporting oxygen through the circulatory system remains an open question. This study explores, through high-fidelity numerical simulations, the impact of RBC volume on advective oxygen transport efficiency through arterioles, which form the area of greatest flow resistance in the circulatory system. The results show that, strikingly, RBCs with volumes similar to those found in vivo are most efficient to transport oxygen through arterioles. The flow resistance is related to the cell-free layer thickness, which is influenced by the shape and the motion of the RBCs: at low volumes, RBCs deform and fold, while at high volumes, RBCs collide and follow more diffuse trajectories. In contrast, RBCs with a healthy volume maximize the cell-free layer thickness, resulting in a more efficient advective transport of oxygen.

Solving inverse problems in physics by optimizing a discrete loss: Fast and accurate learning without neural networks.

In recent years, advances in computing hardware and computational methods have prompted a wealth of activities for solving inverse problems in physics. These problems are often described by systems of partial differential equations (PDEs). The advent of machine learning has reinvigorated the interest in solving inverse problems using neural networks (NNs). In these efforts, the solution of the PDEs is expressed as NNs trained through the minimization of a loss function involving the PDE. Here, we show how to accelerate this approach by five orders of magnitude by deploying, instead of NNs, conventional PDE approximations. The framework of optimizing a discrete loss (ODIL) minimizes a cost function for discrete approximations of the PDEs using gradient-based and Newton's methods. The framework relies on grid-based discretizations of PDEs and inherits their accuracy, convergence, and conservation properties. The implementation of the method is facilitated by adopting machine-learning tools for automatic differentiation. We also propose a multigrid technique to accelerate the convergence of gradient-based optimizers. We present applications to PDE-constrained optimization, optical flow, system identification, and data assimilation. We compare ODIL with the popular method of physics-informed neural networks and show that it outperforms it by several orders of magnitude in computational speed while having better accuracy and convergence rates. We evaluate ODIL on inverse problems involving linear and nonlinear PDEs including the Navier-Stokes equations for flow reconstruction problems. ODIL bridges numerical methods and machine learning and presents a powerful tool for solving challenging, inverse problems across scientific domains.

Flow reconstruction by multiresolution optimization of a discrete loss with automatic differentiation.

We present a potent computational method for the solution of inverse problems in fluid mechanics. We consider inverse problems formulated in terms of a deterministic loss function that can accommodate data and regularization terms. We introduce a multigrid decomposition technique that accelerates the convergence of gradient-based methods for optimization problems with parameters on a grid. We incorporate this multigrid technique to the Optimizing a DIscrete Loss (ODIL) framework. The multiresolution ODIL (mODIL) accelerates by an order of magnitude the original formalism and improves the avoidance of local minima. Moreover, mODIL accommodates the use of automatic differentiation for calculating the gradients of the loss function, thus facilitating the implementation of the framework. We demonstrate the capabilities of mODIL on a variety of inverse and flow reconstruction problems: solution reconstruction for the Burgers equation, inferring conductivity from temperature measurements, and inferring the body shape from wake velocity measurements in three dimensions. We also provide a comparative study with the related, popular Physics-Informed Neural Networks (PINNs) method. We demonstrate that mODIL has three to five orders of magnitude lower computational cost than PINNs in benchmark problems including simple PDEs and lid-driven cavity problems. Our results suggest that mODIL is a very potent, fast and consistent method for solving inverse problems in fluid mechanics.

The stress-free state of human erythrocytes: Data-driven inference of a transferable RBC model.

The stress-free state (SFS) of red blood cells (RBCs) is a fundamental reference configuration for the calibration of computational models, yet it remains unknown. Current experimental methods cannot measure the SFS of cells without affecting their mechanical properties, whereas computational postulates are the subject of controversial discussions. Here, we introduce data-driven estimates of the SFS shape and the visco-elastic properties of RBCs. We employ data from single-cell experiments that include measurements of the equilibrium shape of stretched cells and relaxation times of initially stretched RBCs. A hierarchical Bayesian model accounts for these experimental and data heterogeneities. We quantify, for the first time, the SFS of RBCs and use it to introduce a transferable RBC (t-RBC) model. The effectiveness of the proposed model is shown on predictions of unseen experimental conditions during the inference, including the critical stress of transitions between tumbling and tank-treading cells in shear flow. Our findings demonstrate that the proposed t-RBC model provides predictions of blood flows with unprecedented accuracy and quantified uncertainties.

Scientific multi-agent reinforcement learning for wall-models of turbulent flows.

The predictive capabilities of turbulent flow simulations, critical for aerodynamic design and weather prediction, hinge on the choice of turbulence models. The abundance of data from experiments and simulations and the advent of machine learning have provided a boost to turbulence modeling efforts. However, simulations of turbulent flows remain hindered by the inability of heuristics and supervised learning to model the near-wall dynamics. We address this challenge by introducing scientific multi-agent reinforcement learning (SciMARL) for the discovery of wall models for large-eddy simulations (LES). In SciMARL, discretization points act also as cooperating agents that learn to supply the LES closure model. The agents self-learn using limited data and generalize to extreme Reynolds numbers and previously unseen geometries. The present simulations reduce by several orders of magnitude the computational cost over fully-resolved simulations while reproducing key flow quantities. We believe that SciMARL creates unprecedented capabilities for the simulation of turbulent flows.

Modelling glioma progression, mass effect and intracranial pressure in patient anatomy.

Increased intracranial pressure is the source of most critical symptoms in patients with glioma, and often the main cause of death. Clinical interventions could benefit from non-invasive estimates of the pressure distribution in the patient's parenchyma provided by computational models. However, existing glioma models do not simulate the pressure distribution and they rely on a large number of model parameters, which complicates their calibration from available patient data. Here we present a novel model for glioma growth, pressure distribution and corresponding brain deformation. The distinct feature of our approach is that the pressure is directly derived from tumour dynamics and patient-specific anatomy, providing non-invasive insights into the patient's state. The model predictions allow estimation of critical conditions such as intracranial hypertension, brain midline shift or neurological and cognitive impairments. A diffuse-domain formalism is employed to allow for efficient numerical implementation of the model in the patient-specific brain anatomy. The model is tested on synthetic and clinical cases. To facilitate clinical deployment, a high-performance computing implementation of the model has been publicly released.

Computing foaming flows across scales: From breaking waves to microfluidics.

Crashing ocean waves, cappuccino froths, and microfluidic bubble crystals are examples of foamy flows. Foamy flows are critical in numerous natural and industrial processes and remain notoriously difficult to compute as they involve coupled, multiscale physical processes. Computations need to resolve the interactions of the bubbles separated by stable thin liquid films. We present the multilayer volume-of-fluid method (Multi-VOF) that advances the state of the art in simulation capabilities of foamy flows. The method introduces a scheme to handle multiple bubbles that do not coalesce. Multi-VOF is verified and validated with experimental results and complemented with open-source software. We demonstrate capturing of crystalline structures of bubbles in realistic microfluidics devices and foamy flows involving tens of thousands of bubbles in a waterfall. The present technique extends the classical volume-of-fluid methodology and allows for large-scale predictive simulations of flows with multiple interfaces.

Nanopumps without Pressure Gradients: Ultrafast Transport of Water in Patterned Nanotubes.

The extreme liquid transport properties of carbon nanotubes present new opportunities for surpassing conventional technologies in water filtration and purification. We demonstrate that carbon nanotubes with wettability surface patterns act as nanopumps for the ultrafast transport of picoliter water droplets without requiring externally imposed pressure gradients. Large-scale molecular dynamics simulations evidence unprecedented speeds and accelerations on the order of 1010 g of droplet propulsion caused by interfacial energy gradients. This phenomenon is persistent for nanotubes of varying sizes, stepwise pattern configurations, and initial conditions. We present a scaling law for water transport as a function of wettability gradients through simple models for the droplet dynamic contact angle and friction coefficient. Our results show that patterned nanotubes are energy-efficient nanopumps offering a realistic path toward ultrafast water nanofiltration and precision drug delivery.

Accelerated Simulations of Molecular Systems through Learning of Effective Dynamics.

Simulations are vital for understanding and predicting the evolution of complex molecular systems. However, despite advances in algorithms and special purpose hardware, accessing the time scales necessary to capture the structural evolution of biomolecules remains a daunting task. In this work, we present a novel framework to advance simulation time scales by up to 3 orders of magnitude by learning the effective dynamics (LED) of molecular systems. LED augments the equation-free methodology by employing a probabilistic mapping between coarse and fine scales using mixture density network (MDN) autoencoders and evolves the non-Markovian latent dynamics using long short-term memory MDNs. We demonstrate the effectiveness of LED in the Müller-Brown potential, the Trp cage protein, and the alanine dipeptide. LED identifies explainable reduced-order representations, i.e., collective variables, and can generate, at any instant, all-atom molecular trajectories consistent with the collective variables. We believe that the proposed framework provides a dramatic increase to simulation capabilities and opens new horizons for the effective modeling of complex molecular systems.

Learning efficient navigation in vortical flow fields.

Efficient point-to-point navigation in the presence of a background flow field is important for robotic applications such as ocean surveying. In such applications, robots may only have knowledge of their immediate surroundings or be faced with time-varying currents, which limits the use of optimal control techniques. Here, we apply a recently introduced Reinforcement Learning algorithm to discover time-efficient navigation policies to steer a fixed-speed swimmer through unsteady two-dimensional flow fields. The algorithm entails inputting environmental cues into a deep neural network that determines the swimmer's actions, and deploying Remember and Forget Experience Replay. We find that the resulting swimmers successfully exploit the background flow to reach the target, but that this success depends on the sensed environmental cue. Surprisingly, a velocity sensing approach significantly outperformed a bio-mimetic vorticity sensing approach, and achieved a near 100% success rate in reaching the target locations while approaching the time-efficiency of optimal navigation trajectories.

Tuning the Dielectric Response of Water in Nanoconfinement through Surface Wettability.

The tunable polarity of water can be exploited in emerging technologies including catalysis, gas storage, and green chemistry. Recent experimental and theoretical studies have shown that water can be rendered into an effectively apolar solvent under nanoconfinement. We furthermore demonstrate, through molecular simulations, that the static dielectric constant of water can be modified by changing the wettability of the confining material. We find the out-of-plane dielectric response to be highly sensitive to the level of confinement and can be reduced up to 40× , in accordance with experimental data. By altering the surface wettability from superhydrophilic to superhydrophobic, we observe a 36% increase for the out-of-plane and a 31% decrease for the in-plane dielectric constants. Our findings demonstrate the feasibility of tunable water polarity, a phenomenon with great potential for scientific and technological impact.

A computational study of expiratory particle transport and vortex dynamics during breathing with and without face masks.

We present high-fidelity numerical simulations of expiratory biosol transport during normal breathing under indoor, stagnant air conditions with and without a facile mask. We investigate mask efficacy to suppress the spread of saliva particles that is underpinnings existing social distancing recommendations. The present simulations incorporate the effect of human anatomy and consider a spectrum of saliva particulate sizes that range from 0.1 to 10 µm while also accounting for their evaporation. The simulations elucidate the vorticity dynamics of human breathing and show that without a facile mask, saliva particulates could travel over 2.2 m away from the person. However, a non-medical grade face mask can drastically reduce saliva particulate propagation to 0.72 m away from the person. This study provides new quantitative evidence that facile masks can successfully suppress the spreading of saliva particulates due to normal breathing in indoor environments.

Data-driven prediction and origin identification of epidemics in population networks.

Effective intervention strategies for epidemics rely on the identification of their origin and on the robustness of the predictions made by network disease models. We introduce a Bayesian uncertainty quantification framework to infer model parameters for a disease spreading on a network of communities from limited, noisy observations; the state-of-the-art computational framework compensates for the model complexity by exploiting massively parallel computing architectures. Using noisy, synthetic data, we show the potential of the approach to perform robust model fitting and additionally demonstrate that we can effectively identify the disease origin via Bayesian model selection. As disease-related data are increasingly available, the proposed framework has broad practical relevance for the prediction and management of epidemics.

Optimal allocation of limited test resources for the quantification of COVID-19 infections.

The systematic identification of infected individuals is critical for the containment of the COVID-19 pandemic. Currently, the spread of the disease is mostly quantified by the reported numbers of infections, hospitalisations, recoveries and deaths; these quantities inform epidemiology models that provide forecasts for the spread of the epidemic and guide policy making. The veracity of these forecasts depends on the discrepancy between the numbers of reported, and unreported yet infectious, individuals. We combine Bayesian experimental design with an epidemiology model and propose a methodology for the optimal allocation of limited testing resources in space and time, which maximises the information gain for such unreported infections. The proposed approach is applicable at the onset and spread of the epidemic and can forewarn of a possible recurrence of the disease after relaxation of interventions. We examine its application in Switzerland; the open source software is, however, readily adaptable to countries around the world. We find that following the proposed methodology can lead to vastly less uncertain predictions for the spread of the disease, thus improving estimates of the effective reproduction number and the future number of unreported infections. This information can provide timely and systematic guidance for the effective identification of infectious individuals and for decision-making regarding lockdown measures and the distribution of vaccines.

Data-driven inference of the reproduction number for COVID-19 before and after interventions for 51 European countries.

The reproduction number is broadly considered as a key indicator for the spreading of the COVID-19 pandemic. Its estimated value is a measure of the necessity and, eventually, effectiveness of interventions imposed in various countries. Here we present an online tool for the data-driven inference and quantification of uncertainties for the reproduction number, as well as the time points of interventions for 51 European countries. The study relied on the Bayesian calibration of the SIR model with data from reported daily infections from these countries. The model fitted the data, for most countries, without individual tuning of parameters. We also compared the results of SIR and SEIR models, which give different estimates of the reproduction number, and provided an analytical relationship between the respective numbers. We deployed a Bayesian inference framework with efficient sampling algorithms, to present a publicly available graphical user interface (https://cse-lab.ethz.ch/coronavirus) that allows the user to assess and compare predictions for pairs of European countries. The results quantified the rate of the disease’s spread before and after interventions, and provided a metric for the effectiveness of non-pharmaceutical interventions in different countries. They also indicated how geographic proximity and the times of interventions affected the progression of the epidemic.

Optimal Flow Sensing for Schooling Swimmers.

Fish schooling implies an awareness of the swimmers for their companions. In flow mediated environments, in addition to visual cues, pressure and shear sensors on the fish body are critical for providing quantitative information that assists the quantification of proximity to other fish. Here we examine the distribution of sensors on the surface of an artificial swimmer so that it can optimally identify a leading group of swimmers. We employ Bayesian experimental design coupled with numerical simulations of the two-dimensional Navier Stokes equations for multiple self-propelled swimmers. The follower tracks the school using information from its own surface pressure and shear stress. We demonstrate that the optimal sensor distribution of the follower is qualitatively similar to the distribution of neuromasts on fish. Our results show that it is possible to identify accurately the center of mass and the number of the leading swimmers using surface only information.

Detection of arterial wall abnormalities via Bayesian model selection.

Patient-specific modelling of haemodynamics in arterial networks has so far relied on parameter estimation for inexpensive or small-scale models. We describe here a Bayesian uncertainty quantification framework which makes two major advances: an efficient parallel implementation, allowing parameter estimation for more complex forward models, and a system for practical model selection, allowing evidence-based comparison between distinct physical models. We demonstrate the proposed methodology by generating simulated noisy flow velocity data from a branching arterial tree model in which a structural defect is introduced at an unknown location; our approach is shown to accurately locate the abnormality and estimate its physical properties even in the presence of significant observational and systemic error. As the method readily admits real data, it shows great potential in patient-specific parameter fitting for haemodynamical flow models.

Ultrafast Propulsion of Water Nanodroplets on Patterned Graphene.

The directed transport of liquids at the nanoscale is of great importance for nanotechnology applications ranging from water filtration to the cooling of electronics and precision medicine. Here we demonstrate such unidirectional, pumpless transport of water nanodroplets on graphene sheets patterned with hydrophilic/phobic areas inspired by natural systems. We find that spatially varying patterning of the graphene surfaces can lead to water transport at ultrafast velocities, far exceeding macroscale estimates. We perform extensive molecular dynamics simulations to show that such high transport velocities ( O(102 m/s)) are due to differences of the advancing and receding contact angles of the moving droplet. This contact angle hysteresis and the ensuing transport depend on the surface pattern and the droplet size. We present a scaling law for the driving capillary and resisting friction forces on the water droplet and use it to predict nanodroplet trajectories on a wedge-patterned graphene sheet. The present results demonstrate that graphene with spatially variable wettability is a potent material for fast and precise transport of nanodroplets with significant potential for directed nanoscale liquid transport and precision drug delivery.