Restriction of Viral Replication, Rather than T Cell Immunopathology, Drives Lethality in Murine Norovirus CR6-Infected STAT1-Deficient Mice.

Recent evidence indicates that viral components of the microbiota can contribute to intestinal homeostasis and protection from local inflammatory or infectious insults. However, host-derived mechanisms that regulate the virome remain largely unknown. In this study, we used colonization with the model commensal murine norovirus (MNV; strain CR6) to interrogate host-directed mechanisms of viral regulation, and we show that STAT1 is a central coordinator of both viral replication and antiviral T cell responses. In addition to restricting CR6 replication to the intestinal tract, we show that STAT1 regulates antiviral CD4+ and CD8+ T cell responses and prevents systemic viral-induced tissue damage and disease. Despite altered T cell responses that resemble those that mediate lethal immunopathology in systemic viral infections in STAT1-deficient mice, depletion of adaptive immune cells and their associated effector functions had no effect on CR6-induced disease. However, therapeutic administration of an antiviral compound limited viral replication, preventing virus-induced tissue damage and death without impacting the generation of inflammatory antiviral T cell responses. Collectively, our data show that STAT1 restricts MNV CR6 replication within the intestinal mucosa and that uncontrolled viral replication mediates disease rather than the concomitant development of dysregulated antiviral T cell responses in STAT1-deficient mice. IMPORTANCE The intestinal microbiota is a collection of bacteria, archaea, fungi, and viruses that colonize the mammalian gut. Coevolution of the host and microbiota has required development of immunological tolerance to prevent ongoing inflammatory responses against intestinal microbes. Breakdown of tolerance to bacterial components of the microbiota can contribute to immune activation and inflammatory disease. However, the mechanisms that are necessary to maintain tolerance to viral components of the microbiome, and the consequences of loss of tolerance, are less well understood. Here, we show that STAT1 is integral for preventing escape of a commensal-like virus, murine norovirus CR6 (MNV CR6), from the gut and that in the absence of STAT1, mice succumb to infection-induced disease. In contrast to the case with other systemic viral infections, mortality of STAT1-deficient mice is not driven by immune-mediated pathology. Our data demonstrate the importance of host-mediated geographical restriction of commensal-like viruses.

Pancreatic duct pressure: A review of technical aspects and clinical significance.

Pancreatic duct pressure (PDP) dynamics comprise an intricately modulated system that helps maintain homeostasis of pancreatic function. It is affected by various factors, including the rate of pancreatic fluid secretion, patency of the ductal system, sphincter of Oddi function, and pancreatic fluid characteristics. Disease states such as acute and chronic pancreatitis can alter the normal PDP dynamics. Ductal hypertension or increased PDP is suspected to be involved in the pathogenesis of pancreatic pain, endocrine and exocrine pancreatic insufficiency, and recurrent pancreatitis. This review provides a comprehensive appraisal of the available literature on PDP, including the methods used in the measurement and clinical implications of elevated PDP.

Reconstructing the pressure field around swimming fish using a physics-informed neural network.

Fish detect predators, flow conditions, environments and each other through pressure signals. Lateral line ablation is often performed to understand the role of pressure sensing. In the present study, we propose a non-invasive method for reconstructing the instantaneous pressure field sensed by a fish's lateral line system from two-dimensional particle image velocimetry (PIV) measurements. The method uses a physics-informed neural network (PINN) to predict an optimized solution for the pressure field near and on the fish's body that satisfies both the Navier-Stokes equations and the constraints put forward by the PIV measurements. The method was validated using a direct numerical simulation of a swimming mackerel, Scomber scombrus, and was applied to experimental data of a turning zebrafish, Danio rerio. The results demonstrate that this method is relatively insensitive to the spatio-temporal resolution of the PIV measurements and accurately reconstructs the pressure on the fish's body.

Quantifying the Effect of Body Habitus on Cardiac Auscultation Via Computational Hemoacoustics.

The effect of body habitus on auscultation of heart murmurs is investigated via computational hemoacoustic modeling. The source of the heart murmur is first obtained from a hemodynamic simulation of blood flow through a stenosed aortic valve. This sound source is then placed at the aortic valve location in four distinct human thorax models, and the propagation of the murmur in each thorax model is simulated by solving the elastic wave equations in the time-domain. Placing the same sound source in different thorax models allows for the disambiguation of the effect of body habitus on cardiac auscultation. The surface acceleration resulting from the murmur on each subject's chest surface shows that subjects with higher body-mass index and thoracic cross-sectional area yield smaller acceleration values for the S1 sound. Moreover, the spectral analysis of the signal shows that slope from linear regression in the normal heart sound frequency range (10-150 Hz) is larger for children at the aortic, pulmonic, and mitral auscultation points compared to that for adults. The slope in the murmur frequency range (150-400 Hz) was larger for female subjects at the mitral point compared to that for male subjects. The trends from the results show the potential of the proposed computational method to provide quantitative insights regarding the effect of various anatomical factors on cardiac auscultation.

Computational Modeling of Aortic Stenosis With a Reduced Degree-of-Freedom Fluid-Structure Interaction Valve Model.

In this study, a novel reduced degree-of-freedom (rDOF) aortic valve model is employed to investigate the fluid-structure interaction (FSI) and hemodynamics associated with aortic stenosis. The dynamics of the valve leaflets are determined by an ordinary differential equation with two parameters and this rDOF model is shown to reproduce key features of more complex valve models. The hemodynamics associated with aortic stenosis is studied for three cases: a healthy case and two stenosed cases. The focus of the study is to correlate the hemodynamic features with the source generation mechanism of systolic murmurs associated with aortic stenosis. In the healthy case, extremely weak flow fluctuations are observed. However, in the stenosed cases, simulations show significant turbulent fluctuations in the ascending aorta, which are responsible for the generation of strong wall pressure fluctuations after the aortic root mostly during the deceleration phase of the systole. The intensity of the murmur generation increases with the severity of the stenosis, and the source locations for the two diseased cases studied here lie around 1.0 inlet duct diameters (Do) downstream of the ascending aorta.

A Noninvasive Assessment of Flow Based on Contrast Dispersion in Computed Tomography Angiography: A Computational and Experimental Phantom Study.

Transluminal attenuation gradient (TAG), defined as the gradient of the contrast agent attenuation drop along the vessel, is an imaging biomarker that indicates stenosis in the coronary arteries. The transluminal attenuation flow encoding (TAFE) equation is a theoretical platform that quantifies blood flow in each coronary artery based on computed tomography angiography (CTA) imaging. This formulation couples TAG (i.e., contrast dispersion along the vessel) with fluid dynamics. However, this theoretical concept has never been validated experimentally. The aim of this proof-of-principle phantom study is to validate TAFE based on CTA imaging. Dynamic CTA images were acquired every 0.5 s. The average TAFE estimated flow rates were compared against four predefined pump values in a straight (20, 25, 30, 35, and 40 ml/min) and a tapered phantom (25, 35, 45, and 55 ml/min). Using the TAFE formulation with no correction, the flow rates were underestimated by 33% and 81% in the straight and tapered phantoms, respectively. The TAFE formulation was corrected for imaging artifacts focusing on partial volume averaging and radial variation of contrast enhancement. After corrections, the flow rates estimated in the straight and tapered phantoms had an excellent Pearson correlation of r = 0.99 and 0.87 (p < 0.001), respectively, with only a 0.6%±0.2 mL/min difference in estimation of the flow rate. In this proof-of-concept phantom study, we corrected the TAFE formulation and showed a good agreement with the actual pump values. Future clinical validations are needed for feasibility of TAFE in clinical use.

Computational Modeling and Analysis of Murmurs Generated by Modeled Aortic Stenoses.

In this study, coupled hemodynamic-acoustic simulations are employed to study the generation and propagation of murmurs associated with aortic stenoses where the aorta with a stenosed aortic valve is modeled as a curved pipe with a constriction near the inlet. The hemodynamics of the poststenotic flow is investigated in detail in our previous numerical study (Zhu et al., 2018, "Computational Modelling and Analysis of Haemodynamics in a Simple Model of Aortic Stenosis," J. Fluid Mech., 851, pp. 23-49). The temporal history of the pressure on the aortic lumen is recorded during the hemodynamic study and used as the murmur source in the acoustic simulations. The thorax is modeled as an elliptic cylinder and the thoracic tissue is assumed to be homogeneous, linear and viscoelastic. A previously developed high-order numerical method that is capable of dealing with immersed bodies is applied in the acoustic simulations. To mimic the clinical practice of auscultation, the sound signals from the epidermal surface are collected. The simulations show that the source of the aortic stenosis murmur is located at the proximal end of the aortic arch and that the sound intensity pattern on the epidermal surface can predict the source location of the murmurs reasonably well. Spectral analysis of the murmur reveals the disconnect between the break frequency obtained from the flow and from the murmur signal. Finally, it is also demonstrated that the source locations can also be predicted by solving an inverse problem using the free-space Green's function. The implications of these results for cardiac auscultation are discussed.

Flow Dynamics in the Aortic Arch and Its Effect on the Arterial Input Function in Cardiac Computed Tomography.

The arterial input function (AIF)-time-density curve (TDC) of contrast at the coronary ostia-plays a central role in contrast enhanced computed tomography angiography (CTA). This study employs computational modeling in a patient-specific aorta to investigate mixing and dispersion of contrast in the aortic arch (AA) and to compare the TDCs in the coronary ostium and the descending aorta. Here, we examine the validity of the use of TDC in the descending aorta as a surrogate for the AIF. Computational fluid dynamics (CFD) was used to study hemodynamics and contrast dispersion in a CTA-based patient model of the aorta. Variations in TDC between the aortic root, through the AA and at the descending aorta and the effect of flow patterns on contrast dispersion was studied via postprocessing of the results. Simulations showed complex unsteady patterns of contrast mixing and dispersion in the AA that are driven by the pulsatile flow. However, despite the relatively long intra-aortic distance between the coronary ostia and the descending aorta, the TDCs at these two locations were similar in terms of rise-time and up-slope, and the time lag between the two TDCs was 0.19 s. TDC in the descending aorta is an accurate analog of the AIF. Methods that use quantitative metrics such as rise-time and slope of the AIF to estimate coronary flowrate and myocardial ischemia can continue with the current practice of using the TDC at the descending aorta as a surrogate for the AIF.

A Computational Method for Analyzing the Biomechanics of Arterial Bruits.

A computational framework consisting of a one-way coupled hemodynamic-acoustic method and a wave-decomposition based postprocessing approach is developed to investigate the biomechanics of arterial bruits. This framework is then applied for studying the effect of the shear wave on the generation and propagation of bruits from a modeled stenosed artery. The blood flow in the artery is solved by an immersed boundary method (IBM) based incompressible flow solver. The sound generation and propagation in the blood volume are modeled by the linearized perturbed compressible equations, while the sound propagation through the surrounding tissue is modeled by the linear elastic wave equation. A decomposition method is employed to separate the acoustic signal into a compression/longitudinal component (curl free) and a shear/transverse component (divergence free), and the sound signals from cases with and without the shear modulus are monitored on the epidermal surface and are analyzed to reveal the influence of the shear wave. The results show that the compression wave dominates the detected sound signal in the immediate vicinity of the stenosis, whereas the shear wave has more influence on surface signals further downstream of the stenosis. The implications of these results on cardiac auscultation are discussed.

A coupled chemo-fluidic computational model for thrombogenesis in infarcted left ventricles.

A coupled chemo-fluidic computational model for investigating flow-mediated thrombogenesis in infarcted left ventricles (LVs) is proposed. LV thrombus (LVT) formation after the acute myocardial infarction (AMI) may lead to thromboembolic events that are associated with high mortality and morbidity, and reliable stratification of LVT risk is the key to managing the treatment of AMI patients. There have been several studies emphasizing the importance of LV blood flow patterns on thrombus formation; however, given the complex interplay between ventricular flow dynamics and biochemistry of thrombogenesis, current understanding is mostly empirical. In the present model, blood flow in the LV is obtained by solving the incompressible Navier-Stokes equations, and this is coupled to the biochemical modeling of the coagulation cascade, platelet activation, and fibrinogen polymerization. The coupled model is used to examine the effect of ventricular flow patterns on thrombogenesis in modeled ventricles. It is expected that the method developed here will enable in-depth studies of thrombogenesis in patient-derived infarcted LV models.

Computational Study of Computed Tomography Contrast Gradients in Models of Stenosed Coronary Arteries.

Recent computed tomography coronary angiography (CCTA) studies have noted higher transluminal contrast agent gradients in arteries with stenotic lesions, but the physical mechanism responsible for these gradients is not clear. We use computational fluid dynamics (CFD) modeling coupled with contrast agent dispersion to investigate the mechanism for these gradients. Simulations of blood flow and contrast agent dispersion in models of coronary artery are carried out for both steady and pulsatile flows, and axisymmetric stenoses of severities varying from 0% (unobstructed) to 80% are considered. Simulations show the presence of measurable gradients with magnitudes that increase monotonically with stenotic severity when other parameters are held fixed. The computational results enable us to examine and validate the hypothesis that transluminal contrast gradients (TCG) are generated due to the advection of the contrast bolus with time-varying contrast concentration that appears at the coronary ostium. Since the advection of the bolus is determined by the flow velocity in the artery, the magnitude of the gradient, therefore, encodes the coronary flow velocity. The correlation between the flow rate estimated from TCG and the actual flow rate in the computational model of a physiologically realistic coronary artery is 96% with a R2 value of 0.98. The mathematical formulae connecting TCG to flow velocity derived here represent a novel and potentially powerful approach for noninvasive estimation of coronary flow velocity from CT angiography.

Effect of schooling on flow generated sounds from carangiform swimmers.

Computational models are used to examine the effect of schooling on flow generated noise from fish swimming using their caudal fins. We simulate the flow as well as the far-field hydrodynamic sound generated by the time-varying pressure loading on these carangiform swimmers. The effect of the number of swimmers in the school, the relative phase of fin flapping of the swimmers, and their spatial arrangement is examined. The simulations indicate that the phase of the fin flapping is a dominant factor in the total sound radiated into the far-field by a group of swimmers. For small schools, a suitable choice of relative phase between the swimmers can significantly reduce the overall intensity of the sound radiated to the far-field. The relative positioning of the swimmers is also shown to have an impact on the total radiated noise. For a larger school, even highly uncorrelated phases of fin movement between the swimmers in the school are very effective in significantly reducing the overall intensity of sound radiated into the far-field. The implications of these findings for fish ethology as well as the design and operation of bioinspired vehicles are discussed.

Changes in aorta hemodynamics in Left-Right Type 1 bicuspid aortic valve patients after replacement with bioprosthetic valves: An in-silico study.

Bicuspid aortic valve (BAV) is the most common cardiac congenital abnormality with a high rate of concomitant aortic valve and ascending aorta (AAo) pathologic changes throughout the patient's lifetime. The etiology of BAV-related aortopathy was historically believed to be genetic. However, recent studies theorize that adverse hemodynamics secondary to BAVs also contribute to aortopathy, but their precise role, specifically, that of wall shear stress (WSS) magnitude and directionality remains controversial. Moreover, the primary therapeutic option for BAV patients is aortic valve replacement (AVR), but the role of improved post-AVR hemodynamics on aortopathy progression is also not well-understood. To address these issues, this study employs a computational fluid dynamics model to simulate personalized AAo hemodynamics before and after TAVR for a small cohort of 6 Left-Right fused BAV patients. Regional distributions of five hemodynamic metrics, namely, time-averaged wall shear stress (TAWSS) and oscillating shear index (OSI), divergence of wall shear (DWSS), helicity flux integral & endothelial cell activation potential (ECAP), which are hypothesized to be associated with potential aortic injury are computed in the root, proximal and distal ascending aorta. BAVs are characterized by strong, eccentric jets, with peak velocities exceeding 4 m/s and axially circulating flow away from the jets. Such conditions result in focused WSS loading along jet attachment regions on the lumen boundary and weaker, oscillating WSS on other regions. The jet attachment regions also show alternating streaks of positive and negative DWSS, which may increase risk for local tissue stretching. Large WSS magnitudes, strong helical flows and circumferential WSS have been previously implicated in the progression of BAV aortopathy. Post-intervention hemodynamics exhibit weaker, less eccentric jets. Significant reductions are observed in flow helicity, TAWSS and DWSS in localized regions of the proximal AAo. On the other hand, OSI increases post-intervention and ECAP is observed to be low in both pre- and post-intervention scenarios, although significant increases are also observed in this ECAP. These results indicate a significant alleviation of pathological hemodynamics post AVR.

In silico modelling of the effect of pyloric intervention procedures on gastric flow and emptying in a stomach with gastroparesis.

Pyloric interventions are surgical procedures employed to increase the gastric emptying rate in gastroparesis patients. In this study, we use an in silico model to investigate the consequences of pyloric intervention on gastric flow and emptying for two phenotypes of gastroparesis: antral hypomotility and decreased gastric tone. The transpyloric pressure gradient predicted by the in silico model, based on viscous fluid flow equations, is compared against in vivo measurements. Both phenotypes exhibit a similar pre-procedural emptying rate reduction, but after pyloric surgery, antral hypomotility case with preserved gastric tone shows significant improvements in emptying rates, up to 131%, accompanied by bile reflux from the duodenum into the stomach. Conversely, severely reduced gastric tone cases exhibited a post-procedural reduction in the net emptying rate due to the relatively larger bile reflux. In cases with a combination of antral hypomotility and reduced gastric tone, post-procedural improvements were observed only when both conditions were mild. Our findings highlight the pivotal role of the relative increase in pyloric orifice diameter in determining post-operative emptying rates. The study suggests a possible explanation for the selective response of patients toward these procedures and underscores the potential of in silico modelling to generate valuable insights to inform gastric surgery.

T4 Bacteriophage and E. coli Interaction in the Murine Intestine: A Prototypical Model for Studying Host-Bacteriophage Dynamics In Vivo.

Bacteriophages (phages) are viruses that infect bacteria with species- and strain-level specificity and are the most abundant biological entities across all known ecosystems. Within bacterial communities, such as those found in the gut microbiota, phages are implicated in regulating microbiota population dynamics and driving bacterial evolution. There has been renewed interest in phage research in the last decade, in part due to the host-specific killing capabilities of lytic phages, which offer a promising tool to counter the increasing threat of antimicrobial resistant bacteria. Furthermore, recent studies demonstrating that phages adhere to intestinal mucus suggest they may have a protective role in preventing bacterial invasion into the underlying epithelium. Importantly, like bacterial microbiomes, disrupted phageomes have been associated with worsened outcomes in diseases such as inflammatory bowel disease. Previous studies have demonstrated that phages can modulate the microbiome of animals and humans through fecal filtrate transplants, benefiting the host's health. With this recent wave of research comes the necessity to establish and standardize protocols for studying phages in the context of the gut microbiome. This protocol provides a set of procedures to study isolated T4 phages and their bacterial host, Escherichia coli, in the context of the murine gastrointestinal tract. The methods described here outline how to start from a phage lysate, administer it to mice and assess effects on bacterial host and phage levels. This protocol can be modified and applied to other phage-bacterial pairs and provides a starting point for studying host-phage dynamics in vivo.

Elevated IL-7 availability does not account for T cell proliferation in moderate lymphopenia.

Lymphopenia-induced proliferation (LIP) is a proliferative program initiated in response to T cell insufficiency caused by acute or chronic immunodepletion. Studies of lymphopenic mice have demonstrated that the cytokine IL-7 and TCR signaling are critical for LIP. We examined how these two factors impact T cell proliferation following transfer into moderately lymphopenic mice. In this study, we show that moderate lymphopenia (∼25% of wild-type lymphocytes) of IL-7Rα knock-in mutant (IL-7Rα(449F)) mice supports T cell proliferation, although with decreased frequency and kinetics compared with cells transferred to severely lymphopenic (5% of wild-type lymphocytes) IL-7Rα(-/-) hosts. Although previous studies have demonstrated that elevated IL-7 levels play an important role in LIP, IL-7 availability was not elevated in IL-7Rα(449F) mice. However, moderate lymphopenia increased access of transferred T cells to self-peptide presented on APCs that can trigger TCR signaling and proliferation. Importantly, we did not detect significant changes in TCR Vß usage of proliferated T cells recovered from either moderately or severely lymphopenic hosts. Our work demonstrates that polyclonal T cells retain a diverse TCR repertoire following proliferation mediated by either self-peptide-MHC interaction alone or in combination with IL-7, and that T cell reconstitution is most efficient in the presence of increased IL-7 availability.

Origin and evolution of immersed boundary methods in computational fluid dynamics.

This article presents the evolutionary history of Immersed Boundary Methods (IBMs), tracing their origins to the very beginning of computational fluid dynamics in the late 1950s all the way to the present day. The article highlights the advancements in this simulation methodology over the last fifty years and explores the interplay between IBMs and body-conformal grid (BCG) methods during this time. Drawing upon the author's combined experience of over forty years in this arena, the perspective offered is personal and subjective. By employing a critical and comparative approach through the chronological lens, we hope that this article empowers the reader to understand both the capabilities and limitations of these methods, and to pursue advancements that fill the key gaps and break new ground.

Towards Longitudinal Monitoring of Leaflet Mobility in Prosthetic Aortic Valves via In-Situ Pressure Sensors: In-Silico Modeling and Analysis.

BACKGROUND: Transcatheter aortic valves (TAVs) are susceptible to leaflet thrombosis which may lead to thromboembolic events, and early detection and intervention are believed to be the key to avoiding such adverse outcomes. An embedded sensor system installed on the valve stent, coupled with an appropriate machine learning-based continuous monitoring algorithm can facilitate early detection to predict severity of reduced leaflet motion (RLM) and avoid adverse outcomes. METHODS: We present a data-driven, in silico, proof-of-concept analysis of a pressure microsensor based system for quantifying RLM in TAVs. We generate a dataset of 21 high-fidelity transvalvular flow simulations with healthy and mildly stenotic TAVs to train a logistic regression model to correlate individual leaflet mobility in each simulation with principal components of corresponding hemodynamic pressure recorded at strategic locations of the TAV stent. A separate test dataset of 7 simulations is also generated for prospective assessment of model performance. RESULTS: An array of 6 sensors embedded on the TAV stent, with two sensors tracking individual leaflet, successfully correlates leaflet mobility with recorded pressure. The sensors are placed along leaflet centerlines, one in the sinus, and the other at the sino-tubular junction. The regression model is tuned using cross-validation to achieve high accuracy on both training (R2 = 0.93) and test (R2 = 0.77) sets. CONCLUSION: Discrete blood pressure recordings on TAV stents can be successfully correlated with individual leaflet mobility. Further development of this technology can enable longitudinal monitoring of TAVs and early detection of valve failure.

Improved swimming performance in schooling fish via leading-edge vortex enhancement.

The hydrodynamics of schooling fish has been the subject of continued investigation over the last 50 years; fish schools exhibit a variety of arrangements and several distinct mechanisms have been proposed to explain the hydrodynamic benefits of schooling. In the current study, we use direct numerical simulations to show that a caudal fin swimmer trailing another similar swimmer can significantly improve its swimming performance by positioning itself such that the wake-induced flow of the leading fish, enhances the leading-edge vortex (LEV) on the fin of the trailing fish. Improvements of up to 12% in both the thrust and efficiency of the trailing fish are possible with this mechanism. The mechanisms underlying these interactional effects are quantitatively analyzed by applying the force partitioning method, a powerful data-driven method that partitions the pressure forces on the fish into mechanistically distinct components. The analysis reveals that the LEV on the fin dominates the overall thrust production for these swimmers and its enhancement therefore provides an effective and robust means for harnessing fish-fish hydrodynamic interactions in a school. In addition to confirming the potential energetic benefits of schooling, the LEV enhancement mechanism could be exploited in coordinated swimming of bioinspired multi-vehicle or multi-foil flapping foil propulsion systems.

IL-7 induces type 2 cytokine response in lung ILC2s and regulates GATA3 and CD25 expression.

Interleukin-7 is a cytokine with well-established roles in lymphocyte development and more recently, an expanded role in immune function. IL-7Rα is highly expressed by innate lymphoid cells (ILCs), but how IL-7 directs the development or function of ILCs is not well studied. Using mice with inducible deletion of IL-7Rα, we showed that loss of IL-7 signaling led to impaired production of IL-5, IL-13 and amphiregulin in lung ST2+ group 2 innate lymphoid cells (ILC2s) following influenza/A infection. Conversely, mice treated with IL-7 increased production of IL-5 and IL-13 by lung ILC2s. Moreover, we showed that IL-7 enhanced GATA3 and CD25 expression in ILC2s and loss of IL-7 signaling led to their reduced expression. Altogether, this study demonstrates that IL-7 regulates the function of ILC2s during airway viral infection and induces GATA3 and CD25 expression.