von Willebrand factor unfolding mediates platelet deposition in a model of high-shear thrombosis.

Thrombosis under high-shear conditions is mediated by the mechanosensitive blood glycoprotein von Willebrand factor (vWF). vWF unfolds in response to strong flow gradients and facilitates rapid recruitment of platelets in flowing blood. While the thrombogenic effect of vWF is well recognized, its conformational response in complex flows has largely been omitted from numerical models of thrombosis. We recently presented a continuum model for the unfolding of vWF, where we represented vWF transport and its flow-induced conformational change using convection-diffusion-reaction equations. Here, we incorporate the vWF component into our multi-constituent model of thrombosis, where the local concentration of stretched vWF amplifies the deposition rate of free-flowing platelets and reduces the shear cleaning of deposited platelets. We validate the model using three benchmarks: in vitro model of atherothrombosis, a stagnation point flow, and the PFA-100, a clinical blood test commonly used for screening for von Willebrand disease (vWD). The simulations reproduced the key aspects of vWF-mediated thrombosis observed in these experiments, such as the thrombus location, thrombus growth dynamics, and the effect of blocking platelet-vWF interactions. The PFA-100 simulations closely matched the reported occlusion times for normal blood and several hemostatic deficiencies, namely, thrombocytopenia, vWD type 1, and vWD type 3. Overall, this multi-constituent model of thrombosis enables macro-scale 3D simulations of thrombus formation in complex geometries over a wide range of shear rates and accounts for qualitative and quantitative hemostatic deficiencies in patient blood.

Simulation of thrombosis in a stenotic microchannel: The effects of vWF-enhanced shear activation of platelets.

This study was undertaken to develop a numerical/computational simulation of von Willebrand Factor (vWF) - mediated platelet shear activation and deposition in an idealized stenosis. Blood is treated as a multi-constituent mixture comprised of a linear fluid component and a porous solid component (thrombus). Chemical and biological species involved in coagulation are modeled using a system of coupled convection-reaction-diffusion (CRD) equations. This study considers the cumulative effect of shear stress (history) on platelet activation. The vWF activity is modeled as an enhancement function for the shear stress accumulation and is related to the experimentally-observed unfolding rate of vWF. A series of simulations were performed in an idealized stenosis in which the predicted platelets deposition agreed well with previous experimental observations spatially and temporally, including the reduction of platelet deposition with decreasing expansion angle. Further simulation indicated a direct relationship between vWF-mediated platelet deposition and degree of stenosis. Based on the success with these benchmark simulations, it is hoped that the model presented here may provide additional insight into vWF-mediated thrombosis and prove useful for the development of more hemo-compatible blood-wetted devices in the future.

Simulation of blood flow in a sudden expansion channel and a coronary artery.

In this paper, we numerically simulate the flow of blood in two benchmark problems: the flow in a sudden expansion channel and the flow through an idealized curved coronary artery with pulsatile inlet velocity. Blood is modeled as a suspension (a non-linear complex fluid) and the movement of the red blood cell (RBCs) is modeled by using a concentration flux equation. The viscosity of blood is obtained from experimental data. In the sudden expansion flow, the predicted velocity profiles for two different Reynolds numbers (based on the inlet velocity) agree well with the available experiments; furthermore, the numerical results also show that after the sudden expansion there exists a RBCs depletion region. For the second problem, the idealized curved coronary artery, it is found that the RBCs move towards and concentrate near the inner surface where the viscosity is higher and the shear stress lower; this phenomenon may be related to the atherosclerotic plaque formation which usually occurs on the inside surface of the arteries.

A non-linear fluid suspension model for blood flow.

Motivated by the complex rheological behaviors observed in small/micro scale blood vessels, such as the Fahraeus effect, plasma-skimming, shear-thinning, etc., we develop a non-linear suspension model for blood. The viscosity is assumed to depend on the volume fraction (hematocrit) and the shear rate. The migration of the red blood cells (RBCs) is studied using a concentration flux equation. A parametric study with two representative problems, namely simple shear flow and a pressure driven flow demonstrate the ability of this reduced-order model to reproduce several key features of the two-fluid model (mixture theory approach), with much lower computational cost.

Study of blood flow in several benchmark micro-channels using a two-fluid approach.

It is known that in a vessel whose characteristic dimension (e.g., its diameter) is in the range of 20 to 500 microns, blood behaves as a non-Newtonian fluid, exhibiting complex phenomena, such as shear-thinning, stress relaxation, and also multi-component behaviors, such as the Fahraeus effect, plasma-skimming, etc. For describing these non-Newtonian and multi-component characteristics of blood, using the framework of mixture theory, a two-fluid model is applied, where the plasma is treated as a Newtonian fluid and the red blood cells (RBCs) are treated as shear-thinning fluid. A computational fluid dynamic (CFD) simulation incorporating the constitutive model was implemented using OpenFOAM® in which benchmark problems including a sudden expansion and various driven slots and crevices were studied numerically. The numerical results exhibited good agreement with the experimental observations with respect to both the velocity field and the volume fraction distribution of RBCs.

A numerical study of blood flow using mixture theory.

In this paper, we consider the two dimensional flow of blood in a rectangular microfluidic channel. We use Mixture Theory to treat this problem as a two-component system: One component is the red blood cells (RBCs) modeled as a generalized Reiner-Rivlin type fluid, which considers the effects of volume fraction (hematocrit) and influence of shear rate upon viscosity. The other component, plasma, is assumed to behave as a linear viscous fluid. A CFD solver based on OpenFOAM® was developed and employed to simulate a specific problem, namely blood flow in a two dimensional micro-channel, is studied. Finally to better understand this two-component flow system and the effects of the different parameters, the equations are made dimensionless and a parametric study is performed.

Cardiac progenitor cell commitment is inhibited by nuclear Akt expression.

RATIONALE: Stem cell therapies to regenerate damaged cardiac tissue represent a novel approach to treat heart disease. However, the majority of adoptively transferred stem cells delivered to damaged myocardium do not survive long enough to impart protective benefits, resulting in modest functional improvements. Strategies to improve survival and proliferation of stem cells show promise for significantly enhancing cardiac function and regeneration. OBJECTIVE: To determine whether injected cardiac progenitor cells (CPCs) genetically modified to overexpress nuclear Akt (CPCeA) increase structural and functional benefits to infarcted myocardium relative to control CPCs. METHODS AND RESULTS: CPCeA exhibit significantly increased proliferation and secretion of paracrine factors compared with CPCs. However, CPCeA exhibit impaired capacity for lineage commitment in vitro. Infarcted hearts receiving intramyocardial injection of CPCeA have increased recruitment of endogenous c-kit cells compared with CPCs, but neither population provides long-term functional and structural improvements compared with saline-injected controls. Pharmacological inhibition of Akt alleviated blockade of lineage commitment in CPCeA. CONCLUSIONS: Although overexpression of nuclear Akt promotes rapid proliferation and secretion of protective paracrine factors, the inability of CPCeA to undergo lineage commitment hinders their capacity to provide functional or structural benefits to infarcted hearts. Despite enhanced recruitment of endogenous CPCs, lack of functional improvement in CPCeA-treated hearts demonstrates CPC lineage commitment is essential to the regenerative response. Effective stem cell therapies must promote cellular survival and proliferation without inhibiting lineage commitment. Because CPCeA exhibit remarkable proliferative potential, an inducible system mediating nuclear Akt expression could be useful to augment cell therapy approaches.

Influence of Inlet Boundary Conditions on the Prediction of Flow Field and Hemolysis in Blood Pumps Using Large-Eddy Simulation.

Inlet boundary conditions (BC) are one of the uncertainties which may influence the prediction of flow field and hemolysis in blood pumps. This study investigated the influence of inlet BC, including the length of inlet pipe, type of inlet BC (mass flow rate or experimental velocity profile) and turbulent intensity (no perturbation, 5%, 10%, 20%) on the prediction of flow field and hemolysis of a benchmark centrifugal blood pump (the FDA blood pump) and a commercial axial blood pump (Heartmate II), using large-eddy simulation. The results show that the influence of boundary conditions on integral pump performance metrics, including pressure head and hemolysis, is negligible. The influence on local flow structures, such as velocity distributions, mainly existed in the inlet. For the centrifugal FDA blood pump, the influence of type of inlet BC and inlet position on velocity distributions can also be observed at the diffuser. Overall, the effects of position of inlet and type of inlet BC need to be considered if local flow structures are the focus, while the influence of turbulent intensity is negligible and need not be accounted for during numerical simulations of blood pumps.

Depression and activities of daily living in elderly people applying for admission to public nursing facilities.

OBJECTIVE: The present study aims to (1) investigate the prevalence of positive screening for depression among elderly people applying for admission to public nursing facilities in Shenzhen and (2) to explore the correlation between depression and activities of daily living (ADL) among the elderly. METHODS: Visual and hearing acuity, ADL (obtained using the Barthel index), cognition and depression levels, and communication and social interaction skills were assessed in all elderly adults aged ≥60 years who applied for admission to public nursing facilities in Shenzhen between April 1, 2018, and December 31, 2019. RESULTS: A total of 1,113 elderly adults, 34.95% of whom were assessed as being depressed, were evaluated. Regarding dependence on the care of others, the ADL assessment results showed that 11.86% of the study subjects were fully dependent, 10.51% were severely dependent, 12.58% were moderately dependent, 42.86% were mildly dependent, and only 22.19% were fully capable of self-care. The univariate analysis suggested that gender, cognition level, visual and hearing acuity, and communication and social interaction skills were all correlated with the occurrence of depression. The prevalence of positive screening for depression was relatively high among subjects with an ADL score of ≤65; With an ADL score of ≤65, the prevalence of depression increased by 6% with every 1-point ADL score decrease. CONCLUSION: The prevalence of depression among elderly adults applying for admission to public nursing facilities in Shenzhen was high. For this reason, nursing facility caregivers should focus on screening elderly adults (especially subjects with impaired ADL function) for depression in order to improve their quality of life.

Computational modeling of hemodynamics and risk of thrombosis in the left atrial appendage using patient-specific blood viscosity and boundary conditions at the mitral valve.

Hemodynamics play a vital role for the risk of thrombosis in the left atrial appendage (LAA) and left atrium (LA) for patients with atrial fibrillation. Accurate prediction of hemodynamics in the LA can provide important guidance for assessing the risk of thrombosis in the LAA. Patient specificity is a crucial factor in representing the true hemodynamic fields. In this study, we investigated the effects of blood rheology (as a function of hematocrit and shear rate), as well as patient-specific mitral valve (MV) boundary conditions (MV area and velocity profiles measured by ultrasound) on the hemodynamics and thrombosis potential of the LAA. Four scenarios were setup with different degrees of patient specificity. Though using a constant blood viscosity can classify the thrombus and non-thrombus patients for all the hemodynamic indicators, the risk of thrombosis was underestimated for all patients compared with patient-specific viscosities. The results with least patient specificities showed that patients prone to thrombosis predicted by three hemodynamic indicators were inconsistent with clinical observations. Moreover, though patients had the same MV inlet flow rate, different MV models lead to different trends in the risk of thrombosis in different patients. We also found that endothelial cell activation potential and relative residence time can effectively distinguish thrombus and non-thrombus patients for all the scenarios, relatively insensitive to patient specificities. Overall, the findings of this study provide useful insights on patients-specific hemodynamic simulations of the LA.

Collaborative Uncertainty Benefits Multi-Agent Multi-Modal Trajectory Forecasting.

In multi-modal multi-agent trajectory forecasting, two major challenges have not been fully tackled: 1) how to measure the uncertainty brought by the interaction module that causes correlations among the predicted trajectories of multiple agents; 2) how to rank the multiple predictions and select the optimal predicted trajectory. In order to handle the aforementioned challenges, this work first proposes a novel concept, collaborative uncertainty (CU), which models the uncertainty resulting from interaction modules. Then we build a general CU-aware regression framework with an original permutation-equivariant uncertainty estimator to do both tasks of regression and uncertainty estimation. Furthermore, we apply the proposed framework to current SOTA multi-agent multi-modal forecasting systems as a plugin module, which enables the SOTA systems to: 1) estimate the uncertainty in the multi-agent multi-modal trajectory forecasting task; 2) rank the multiple predictions and select the optimal one based on the estimated uncertainty. We conduct extensive experiments on a synthetic dataset and two public large-scale multi-agent trajectory forecasting benchmarks. Experiments show that: 1) on the synthetic dataset, the CU-aware regression framework allows the model to appropriately approximate the ground-truth Laplace distribution; 2) on the multi-agent trajectory forecasting benchmarks, the CU-aware regression framework steadily helps SOTA systems improve their performances. Especially, the proposed framework helps VectorNet improve by 262 cm regarding the Final Displacement Error of the chosen optimal prediction on the nuScenes dataset; 3) in multi-agent multi-modal trajectory forecasting, prediction uncertainty is proportional to future stochasticity; 4) the estimated CU values are highly related to the interactive information among agents. The proposed framework can guide the development of more reliable and safer forecasting systems in the future.

Protease-resistant stromal cell-derived factor-1 for the treatment of experimental peripheral artery disease.

BACKGROUND: Peripheral artery disease is a potentially incapacitating disease for which pharmacological options are limited. Stromal cell-derived factor-1 (SDF-1) is a chemokine that attracts endothelial progenitor cells and promotes angiogenesis. Therapeutic use of SDF-1 in hindlimb ischemia may be challenged by proteolytic degradation. We hypothesized that protease-resistant variants of SDF-1 can increase blood flow in an experimental model of hindlimb ischemia. METHODS AND RESULTS: We screened a peptide library for mutations in SDF-1 that provide resistance to matrix metalloproteinase cleavage. Recombinant SDF-1 proteins carrying the mutations were designed, expressed, and purified, and activity of mutant proteins was tested with receptor activation assays and in vivo Matrigel plug assays. SSDF-1(S4V), which is resistant to both dipeptidylpeptidase IV/CD26 and matrix metalloproteinase-2 cleavage, was active in vitro and induced angiogenesis in vivo. We then designed and purified fusion proteins of SSDF-1 and SSDF-1(S4V) with the sequence of self-assembling peptide nanofibers for incorporation into nanofibers. In a blinded and randomized hindlimb ischemia mouse study, SSDF-1(S4V) delivery by nanofibers improved blood flow as measured by laser Doppler from 23.1±1.9% (untreated control) to 55.1±5.7% 6 weeks after surgery (P<0.001). Nanofibers alone or SSDF-1 delivered by nanofibers did not improve blood flow. Furthermore, SSDF-1(S4V) delivered by nanofibers increased formation of new arterioles. In vitro, SSDF-1(S4V) attracts smooth muscle cells but does not induce mitosis. CONCLUSIONS: SDF-1 engineered to be resistant to dipeptidylpeptidase IV/CD26 and matrix metalloproteinase-2 cleavage and delivered by nanofibers improves blood flow in a model of peripheral artery disease.

Study of Thixotropic Characteristics of a Kerosene Gel Propellant by Bayesian Optimization.

The rheological behavior of gel propellants is crucial for their practical applications, especially in the rocket engine and ramjet fields. The thixotropic characteristics of gel propellants are an important component of their rheological properties and have a notable impact on their flow and injection process. However, most gel propellants contain rich, dynamic cross-linked network structures, which impart complex non-Newtonian fluid properties, and it is difficult to establish a unified mathematical model. In view of this, this study addresses the thixotropy of a prepared RP-3 kerosene gel and determines the mathematical model and model parameters describing its thixotropy. Experiments show that the kerosene gel exhibits shear-thinning properties as well as thixotropy. To describe the microstructural changes in the gel, three thixotropic constitutive models are introduced to analyze the rheological data, and the constitutive equation parameters are optimized. The three models are all structural dynamic models, which can be used to describe microstructural changes within the material. In addition, the fitting of the constitutive equation is a multiparameter optimization problem, and an appropriate optimization method must be used for parameter fitting. Therefore, the Bayesian optimization method combined with Gaussian process regression and the upper confidence bound (UCB) acquisition function is used in the multiparameter fitting of the constitutive models. Both experiments and numerical results show that the thixotropic model, which introduces a pre-factor with shear strain and assumes that the breakdown of the gel structure is related to energy dissipation rather than the shear rate, has a better fitting effect and prediction ability with regard to the gel. Combined with transient experiments at different shear rates, the model parameters of the constitutive law can be determined quickly by applying the Bayesian optimization method.

Simple and active magnetic-field stabilization for cold atom experiments.

Cold atom experiments usually need a controllable and low-noise bias magnetic field to provide a quantization axis. Most labs need home-made stabilization of the field according to the actual setup, as commercially available power supply cannot directly satisfy their requirements. Here, by measuring the field fluctuations and active feedback modulating current supply of the applied magnetic field, we successfully demonstrate a field of 10.58 G with a stability to the level of 2.8 × 10-7 in a duration of 5 min. The root mean square noise is reduced to 0.05 mG, compared to the noise of 1.3 mG without stabilization. The coherence time of the magnetic-field sensitive transition between the rubidium ground states F=1,mF=-1 and 1,0, as measured by Rabi oscillation, is extended to 19.2 ms from the unstabilized value of 1.3 ms. This result is long enough for most experiments on quantum simulation and precision measurement. As our system has no passive magnetic shielding and additional compensation coils, it is highly simple and compact to provide the stable magnetic field and would be adapted to various applications with cold atoms.

Dual-target Bridging ELISA for Bispecific Antibodies.

Bispecific antibodies (BsAbs) are typically monoclonal antibody (mAb)-derived molecular entities engineered to bind to two distinct targets, including two antigens or two epitopes on the same antigen. When compared to parental monoclonal antibodies or combinational therapies, the generated BsAbs have the ability to bridge the two targets and thus may offer additional clinical benefits. Characterizing BsAbs' ability to bind to both targets simultaneously is critical for their biotherapeutic development. A range of bi-functional quantitative bridging assays to enable target-specific capture and detection of binding properties include enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR), and cell-based flow cytometry. Developing suitable and robust cell-based bioassays is more challenging than non-cell-based binding assays because cell-based assays with complex matrices can be inherently variable and often lack precision. Compared to SPR, ELISA has a rapid setup and readily available method, being widely and extensively applied in almost every laboratory. Here, we describe a dual-target bridging ELISA assay that characterizes the ability of a HER2(human epidermal growth factor receptor 2)/PD-L1(programmed cell death ligand 1) BsAb in binding to both HER2 and PD-L1 simultaneously, a prerequisite for its envisioned mode of action. Graphical abstract.

Rheological Properties of Organic Kerosene Gel Fuel.

Gel fuel potentially combines the advantages of solid fuel and liquid fuel due to its special rheological properties, which have essential impacts on the application of gel fuel in propulsion systems. In this paper, we study the rheological property of organic kerosene gel through a series of measurements on its viscosity as a function of the shear rate, temperature, and shear history. The measured datasets are then fitted with constitutive relationships between the viscosity and shear rate at three different levels: the power law shear-thinning model, the power law dependency on both the temperature and shear rate, and the thixotropic property. It is found that intense pre-shear could exhaust thixotropy and reduce viscosity of the kerosene gel. For the power law shear-thinning model, the consistency index increases with the gellant mass fraction, whereas the power law exponent remains constant. The dependence of viscosity on temperature could be well approximated by an empirical power law relationship. As for the thixotropic property of the kerosene gel, the fitted second-order kinetic model corresponds accurately to the viscosity at different shear rates and shear times. The constitutive models fitted in this work at different levels are consistent with each other and provide useful tools for further applications of organic kerosene gel fuel.

Pim-1 kinase antagonizes aspects of myocardial hypertrophy and compensation to pathological pressure overload.

Pim-1 kinase exerts potent cardioprotective effects in the myocardium downstream of AKT, but the participation of Pim-1 in cardiac hypertrophy requires investigation. Cardiac-specific expression of Pim-1 (Pim-WT) or the dominant-negative mutant of Pim-1 (Pim-DN) in transgenic mice together with adenoviral-mediated overexpression of these Pim-1 constructs was used to delineate the role of Pim-1 in hypertrophy. Transgenic overexpression of Pim-1 protects mice from pressure-overload-induced hypertrophy relative to wild-type controls as evidenced by improved hemodynamic function, decreased apoptosis, increases in antihypertrophic proteins, smaller myocyte size, and inhibition of hypertrophic signaling after challenge. Similarly, Pim-1 overexpression in neonatal rat cardiomyocyte cultures inhibits hypertrophy induced by endothelin-1. On the cellular level, hearts of Pim-WT mice show enhanced incorporation of BrdU into myocytes and a hypercellular phenotype compared to wild-type controls after hypertrophic challenge. In comparison, transgenic overexpression of Pim-DN leads to dilated cardiomyopathy characterized by increased apoptosis, fibrosis, and severely depressed cardiac function. Furthermore, overexpression of Pim-DN leads to reduced contractility as evidenced by reduced Ca(2+) transient amplitude and decreased percentage of cell shortening in isolated myocytes. These data support a pivotal role for Pim-1 in modulation of hypertrophy by impacting responses on molecular, cellular, and organ levels.

Large eddy simulation as a fast and accurate engineering approach for the simulation of rotary blood pumps.

An accurate representation of the flow field in blood pumps is important for the design and optimization of blood pumps. The primary turbulence modeling methods applied to blood pumps have been the Reynolds-averaged Navier-Stokes (RANS) or URANS (unsteady RANS) method. Large eddy simulation (LES) method has been introduced to simulate blood pumps. Nonetheless, LES has not been widely used to assist in the design and optimization of blood pumps to date due to its formidable computational cost. The purpose of this study is to explore the potential of the LES technique as a fast and accurate engineering approach for the simulation of rotary blood pumps. The performance of "Light LES" (using the same time and spatial resolutions as the URANS) and LES in two rotary blood pumps was evaluated by comparing the results with the URANS and extensive experimental results. This study showed that the results of both "Light LES" and LES are superior to URANS, in terms of both performance curves and key flow features. URANS could not predict the flow separation and recirculation in diffusers for both pumps. In contrast, LES is superior to URANS in capturing these flows, performing well for both design and off-design conditions. The differences between the "Light LES" and LES results were relatively small. This study shows that with less computational cost than URANS, "Light LES" can be considered as a cost-effective engineering approach to assist in the design and optimization of rotary blood pumps.

On the Optimization of a Centrifugal Maglev Blood Pump Through Design Variations.

Centrifugal blood pumps are usually designed with secondary flow paths to avoid flow dead zones and reduce the risk of thrombosis. Due to the secondary flow path, the intensity of secondary flows and turbulence in centrifugal blood pumps is generally very high. Conventional design theory is no longer applicable to centrifugal blood pumps with a secondary flow path. Empirical relationships between design variables and performance metrics generally do not exist for this type of blood pump. To date, little scientific study has been published concerning optimization and experimental validation of centrifugal blood pumps with secondary flow paths. Moreover, current hemolysis models are inadequate in an accurate prediction of hemolysis in turbulence. The purpose of this study is to optimize the hydraulic and hemolytic performance of an inhouse centrifugal maglev blood pump with a secondary flow path through variation of major design variables, with a focus on bringing down intensity of turbulence and secondary flows. Starting from a baseline design, through changing design variables such as blade angles, blade thickness, and position of splitter blades. Turbulent intensities have been greatly reduced, the hydraulic and hemolytic performance of the pump model was considerably improved. Computational fluid dynamics (CFD) combined with hemolysis models were mainly used for the evaluation of pump performance. A hydraulic test was conducted to validate the CFD regarding the hydraulic performance. Collectively, these results shed light on the impact of major design variables on the performance of modern centrifugal blood pumps with a secondary flow path.

Influence of shear rate and surface chemistry on thrombus formation in micro-crevice.

Thromboembolic complications remain a central issue in management of patients on mechanical circulatory support. Despite the best practices employed in design and manufacturing of modern ventricular assist devices, complexity and modular nature of these systems often introduces internal steps and crevices in the flow path which can serve as nidus for thrombus formation. Thrombotic potential is influenced by multiple factors including the characteristics of the flow and surface chemistry of the biomaterial. This study explored these elements in the setting of blood flow over a micro-crevice using a multi-constituent numerical model of thrombosis. The simulations reproduced the platelet deposition patterns observed experimentally and elucidated the role of flow, shear rate, and surface chemistry in shaping the deposition. The results offer insights for design and operation of blood-contacting devices.