scholarly journals Spatially distributed infection increases viral load in a computational model of SARS-CoV-2 lung infection

2021 ◽  
Author(s):  
Melanie E. Moses ◽  
Steve Hofmeyr ◽  
Judy L Cannon ◽  
Akil Andrews ◽  
Rebekah Gridley ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Computational Model ◽  
Computational Models ◽  
Temporal Dynamics ◽  
Growth Dynamics ◽  
T Cell Response ◽  
Viral Loads ◽  
Viral Spread ◽  
Spatially Distributed

A key question in SARS-CoV-2 infection is why viral loads and patient outcomes vary dramatically across individuals. Because spatial-temporal dynamics of viral spread and immune response are challenging to study in vivo, we developed Spatial Immune Model of Coronavirus (SIMCoV), a scalable computational model that simulates billions of lung cells, including respiratory epithelial cells and T cells. SIMCoV replicates viral growth dynamics observed in patients and shows that spatially dispersed infections lead to increased viral loads. The model shows how the timing and strength of the T cell response can affect viral persistence, oscillations, and control. When the branching airway structure is explicitly represented, we find that virus spreads faster than in a 2D layer of epithelial cells, but much more slowly than in an undifferentiated 3D grid or in a well-mixed ODE model. These results illustrate how realistic spatially explicit computational models can improve understanding of within-host dynamics of SARS-CoV-2 infection.

scholarly journals Spatially distributed infection increases viral load in a computational model of SARS-CoV-2 lung infection

2021 ◽  
Vol 17 (12) ◽  
pp. e1009735
Author(s):  
Melanie E. Moses ◽  
Steven Hofmeyr ◽  
Judy L. Cannon ◽  
Akil Andrews ◽  
Rebekah Gridley ◽  
...  
Keyword(s):  
Immune Response ◽  
Viral Load ◽  
T Cell ◽  
Epithelial Cells ◽  
Computational Model ◽  
Temporal Dynamics ◽  
T Cell Response ◽  
Cell Immune Response ◽  
Viral Loads ◽  
Viral Spread

A key question in SARS-CoV-2 infection is why viral loads and patient outcomes vary dramatically across individuals. Because spatial-temporal dynamics of viral spread and immune response are challenging to study in vivo, we developed Spatial Immune Model of Coronavirus (SIMCoV), a scalable computational model that simulates hundreds of millions of lung cells, including respiratory epithelial cells and T cells. SIMCoV replicates viral growth dynamics observed in patients and shows how spatially dispersed infections can lead to increased viral loads. The model also shows how the timing and strength of the T cell response can affect viral persistence, oscillations, and control. By incorporating spatial interactions, SIMCoV provides a parsimonious explanation for the dramatically different viral load trajectories among patients by varying only the number of initial sites of infection and the magnitude and timing of the T cell immune response. When the branching airway structure of the lung is explicitly represented, we find that virus spreads faster than in a 2D layer of epithelial cells, but much more slowly than in an undifferentiated 3D grid or in a well-mixed differential equation model. These results illustrate how realistic, spatially explicit computational models can improve understanding of within-host dynamics of SARS-CoV-2 infection.

scholarly journals Eyes Open on Sleep and Wake: In Vivo to In Silico Neural Networks

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Amaury Vanvinckenroye ◽  
Gilles Vandewalle ◽  
Christophe Phillips ◽  
Sarah L. Chellappa
Keyword(s):  
In Silico ◽  
Brain Function ◽  
Computational Models ◽  
Temporal Dynamics ◽  
Brain Plasticity ◽  
Effective Connectivity ◽  
Normal Brain ◽  
Cortical Function ◽  
Eyes Open

Functional and effective connectivity of cortical areas are essential for normal brain function under different behavioral states. Appropriate cortical activity during sleep and wakefulness is ensured by the balanced activity of excitatory and inhibitory circuits. Ultimately, fast, millisecond cortical rhythmic oscillations shape cortical function in time and space. On a much longer time scale, brain function also depends on prior sleep-wake history and circadian processes. However, much remains to be established on how the brain operates at the neuronal level in humans during sleep and wakefulness. A key limitation of human neuroscience is the difficulty in isolating neuronal excitation/inhibition drive in vivo. Therefore, computational models are noninvasive approaches of choice to indirectly access hidden neuronal states. In this review, we present a physiologically driven in silico approach, Dynamic Causal Modelling (DCM), as a means to comprehend brain function under different experimental paradigms. Importantly, DCM has allowed for the understanding of how brain dynamics underscore brain plasticity, cognition, and different states of consciousness. In a broader perspective, noninvasive computational approaches, such as DCM, may help to puzzle out the spatial and temporal dynamics of human brain function at different behavioural states.

Noninvasive In Vivo Characterization of Pediatric Human Spine: 3-D Finite Element Study

2011 ◽  
Author(s):  
Elizabeth S. Doughty ◽  
Nesrin Sarigul-Klijn
Keyword(s):  
Finite Element ◽  
Computational Model ◽  
Muscle Activation ◽  
Computational Models ◽  
Three Dimensional ◽  
Pediatric Spine ◽  
Element Analysis ◽  
Spine Stabilization ◽  
Surgical Tool

There are no full three-dimensional computational models of the pediatric spine to study the many diseases and disorders that afflict the immature spine using finite element analysis. To fully characterize the pediatric spine, we created a pediatric specific computational model of C1-L5 using noninvasive in vivo techniques to incorporate the differences between the adult and pediatric spines: un-fused vertebrae, lax ligaments, and higher water content in the intervertebral discs. Muscle follower loads were included in the model to simulate muscle activation for five muscles involved in spine stabilization. This paper is the first pediatric three-dimensional model developed to date. Due to a lack of experimental pediatric spinal studies, this 3-D computational model has the potential to become a surgical tool to ensure that the most appropriate technique is chosen for treating pediatric spinal dysfunctions such as congenital abnormalities, idiopathic scoliosis, and vertebral fractures.

scholarly journals FutureTox IV Workshop Summary: Predictive Toxicology for Healthy Children

2021 ◽  
Author(s):  
Thomas B Knudsen ◽  
Suzanne Compton Fitzpatrick ◽  
K Nadira De Abrew ◽  
Linda S Birnbaum ◽  
Anne Chappelle ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Computational Models ◽  
Temporal Dynamics ◽  
Healthy Children ◽  
Chemical Toxicity ◽  
Predictive Toxicology ◽  
Biological Organization ◽  
Adverse Pregnancy

Abstract FutureTox IV, a Society of Toxicology (SOT) Contemporary Concepts in Toxicology (CCT) workshop, was held in November 2018. Building upon FutureTox I, II, and III, this conference focused on the latest science and technology for in vitro profiling and in silico modeling as it relates to predictive developmental and reproductive toxicity (DART). Publicly available high throughput screening data sets are now available for broad in vitro profiling of bioactivities across large inventories of chemicals. Coupling this vast amount of mechanistic data with a deeper understanding of molecular embryology and post-natal development lays the groundwork for using new approach methodologies (NAMs) to evaluate chemical toxicity, drug efficacy, and safety assessment for embryo-fetal development. NAM is a term recently adopted in reference to any technology, methodology, approach, or combination thereof that can be used to provide information on chemical hazard and risk assessment to avoid the use of intact animals (USEPA, 2018). There are challenges to implementing NAMs to evaluate chemicals for developmental toxicity compared with adult toxicity. This forum article reviews the 2018 workshop activities, highlighting challenges and opportunities for applying NAMs for adverse pregnancy outcomes (e.g., preterm labor, malformations, low birth weight) as well as disorders manifesting postnatally (e.g., neurodevelopmental impairment, breast cancer, cardiovascular disease, fertility). DART is an important concern for different regulatory statutes and test guidelines. Leveraging advancements in such approaches and the accompanying efficiencies to detecting potential hazards to human development are the unifying concepts toward implementing NAMs in DART testing. Although use of NAMs for higher level regulatory decision making is still on the horizon, the conference highlighted novel testing platforms and computational models that cover multiple levels of biological organization, with the unique temporal dynamics of embryonic development, and novel approaches for estimating toxicokinetic parameters essential in supporting in vitro to in vivo extrapolation.

scholarly journals Applicability Analysis of Validation Evidence for Biomedical Computational Models

2017 ◽  
Vol 2 (2) ◽  
Author(s):  
Pras Pathmanathan ◽  
Richard A. Gray ◽  
Vicente J. Romero ◽  
Tina M. Morrison
Keyword(s):  
Computational Model ◽  
Computational Models ◽  
Supporting Evidence ◽  
Biomedical Model ◽  
Model Assessment ◽  
Clinical Implementation ◽  
Step Method ◽  
Model Predictions ◽  
Subject Matter Expertise

Computational modeling has the potential to revolutionize medicine the way it transformed engineering. However, despite decades of work, there has only been limited progress to successfully translate modeling research to patient care. One major difficulty which often occurs with biomedical computational models is an inability to perform validation in a setting that closely resembles how the model will be used. For example, for a biomedical model that makes in vivo clinically relevant predictions, direct validation of predictions may be impossible for ethical, technological, or financial reasons. Unavoidable limitations inherent to the validation process lead to challenges in evaluating the credibility of biomedical model predictions. Therefore, when evaluating biomedical models, it is critical to rigorously assess applicability, that is, the relevance of the computational model, and its validation evidence to the proposed context of use (COU). However, there are no well-established methods for assessing applicability. Here, we present a novel framework for performing applicability analysis and demonstrate its use with a medical device computational model. The framework provides a systematic, step-by-step method for breaking down the broad question of applicability into a series of focused questions, which may be addressed using supporting evidence and subject matter expertise. The framework can be used for model justification, model assessment, and validation planning. While motivated by biomedical models, it is relevant to a broad range of disciplines and underlying physics. The proposed applicability framework could help overcome some of the barriers inherent to validation of, and aid clinical implementation of, biomedical models.

scholarly journals One dose of COVID-19 nanoparticle vaccine REVC-128 provides protection against SARS-CoV-2 challenge at two weeks post immunization

2021 ◽  
Author(s):  
Maggie Gu ◽  
Jonathan L. Torres ◽  
Jack Greenhouse ◽  
Shannon Wallace ◽  
Chi-I Chiang ◽  
...  
Keyword(s):  
Single Dose ◽  
Tissue Damage ◽  
Vaccine Candidate ◽  
In Vivo Model ◽  
Single Shot ◽  
Virus Challenge ◽  
Post Immunization ◽  
Viral Loads ◽  
Viral Spread

AbstractA COVID-19 vaccine with capability to induce early protection is needed to efficiently eliminate viral spread. Here, we demonstrate the development of a nanoparticle vaccine candidate, REVC-128, in which multiple trimeric spike ectodomain subunits with glycine (G) at position 614 were multimerized onto a nanoparticle. In-vitro characterization of this vaccine confirms its structural and antigenic integrity. In-vivo immunogenicity evaluation in mice indicates that a single dose of this vaccine induces potent serum neutralizing antibody titer at two weeks post immunization, which is significantly higher than titer induced by trimeric spike protein without nanoparticle presentation. The comparison of serum binding to spike subunits between animals immunized by spike with and without nanoparticle presentation indicates that nanoparticle prefers the display of spike RBD (Receptor-Binding Domain) over S2 subunit, likely resulting in a more neutralizing but less cross-reactive antibody response. Moreover, a Syrian golden hamster in-vivo model for SARS-CoV-2 virus challenge was implemented at two weeks post a single dose of REVC-128 immunization. The results show that vaccination protects hamsters against SARS-CoV-2 virus challenge with evidence of steady body weight, suppressed viral loads and alleviation of tissue damage (lung and nares) for protected animals, compared with ~10% weight loss, higher viral loads and tissue damage in unprotected animals. Furthermore, the data show that vaccine REVC-128 is thermostable at up to 37°C for at least 4 weeks. These findings, along with a long history of safety for protein vaccines, suggest that the REVC-128 is a safe, stable and efficacious single-shot vaccine candidate to induce the earliest protection against SARS-CoV-2 infection.

Computational Models and Digital Image Analysis of Carbon Nanotube Mediated Laser Cancer Therapy

2011 ◽  
Author(s):  
Jon Whitney ◽  
Saugata Sarkar ◽  
Xuanfeng Ding ◽  
Ravi Singh ◽  
Andrew Burke ◽  
...  
Keyword(s):  
Image Analysis ◽  
Computational Model ◽  
Laser Therapy ◽  
Computational Models ◽  
Temperature Response ◽  
Thermal Exposure ◽  
Invasive Treatment ◽  
Kidney Tumors ◽  
Tissue Phantoms

Laser-based photothermal therapy can provide a minimally invasive treatment alternative to surgical resection of tumors. The selectivity and effectiveness of laser therapy can be greatly enhanced when photo-absorbing nanoparticles such as multi-walled carbon nanotubes (MWNTs) are introduced into the tissue [1,2]. The effectiveness of nanoparticle enhanced laser treatment can be determined through a combined approach using experimental measurement and computational models. This approach allows ideal laser parameters (e.g. irradiance, pulse duration) and nanoparticle properties (e.g. concentration and delivery method) to be selected to maximize treatment efficacy. We developed a computational model to predict the temperature response of tissue representative phantoms and in vivo murine renal cancer (RENCA) kidney tumors to MWNTs used in combination with external laser irradiation. The accuracy of the computational model prediction of temperature was verified by comparing with experimental measurements of temperature using magnetic resonance thermometry (MRTI). In addition, an image analysis technique is introduced for measuring the spatial viability of cancer cells suspended in tissue phantoms following nanoparticle enhanced laser therapy and correlating cell viability with thermal exposure. Spatial viability and thermal measurements are combined to predict cell death as a function of temperature in tissue phantoms.

scholarly journals Temporal dynamics of cardiac hypertrophic growth in response to pressure overload

2017 ◽  
Vol 313 (6) ◽  
pp. H1119-H1129 ◽  
Author(s):  
Yuan Wang ◽  
Yuannyu Zhang ◽  
Guanqiao Ding ◽  
Herman I. May ◽  
Jian Xu ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Cardiac Myocytes ◽  
Temporal Dynamics ◽  
Pressure Overload ◽  
Growth Dynamics ◽  
Neonatal Rat ◽  
Synthesis Rate ◽  
Protein Synthesis Rate ◽  
Hypertrophic Growth

Hypertension is one of the most important risk factors of heart failure. In response to high blood pressure, the left ventricle manifests hypertrophic growth to ameliorate wall stress, which may progress into decompensation and trigger pathological cardiac remodeling. Despite the clinical importance, the temporal dynamics of pathological cardiac growth remain elusive. Here, we took advantage of the puromycin labeling approach to measure the relative rates of protein synthesis as a way to delineate the temporal regulation of cardiac hypertrophic growth. We first identified the optimal treatment conditions for puromycin in neonatal rat ventricular myocyte culture. We went on to demonstrate that myocyte growth reached its peak rate after 8–10 h of growth stimulation. At the in vivo level, with the use of an acute surgical model of pressure-overload stress, we observed the maximal growth rate to occur at day 7 after surgery. Moreover, RNA sequencing analysis supports that the most profound transcriptomic changes occur during the early phase of hypertrophic growth. Our results therefore suggest that cardiac myocytes mount an immediate growth response in reply to pressure overload followed by a gradual return to basal levels of protein synthesis, highlighting the temporal dynamics of pathological cardiac hypertrophic growth. NEW & NOTEWORTHY We determined the optimal conditions of puromycin incorporation in cardiac myocyte culture. We took advantage of this approach to identify the growth dynamics of cardiac myocytes in vitro. We went further to discover the protein synthesis rate in vivo, which provides novel insights about cardiac temporal growth dynamics in response to pressure overload.

Temporal dynamics of ram sperm binding and survival during 48-h coculture with oviducal epithelial cells

2008 ◽  
Vol 20 (7) ◽  
pp. 835 ◽  
Author(s):  
R. E. Lloyd ◽  
E. Badia ◽  
A. Fazeli ◽  
P. F. Watson ◽  
W. V. Holt
Keyword(s):  
Epithelial Cells ◽  
Reproductive Cycle ◽  
Temporal Dynamics ◽  
Cycle Phase ◽  
Temporal Dynamic ◽  
Time Points ◽  
Sperm Binding ◽  
Ram Sperm

Following insemination, ram spermatozoa bind to oviducal epithelial cells (OEC) in vivo and remain viable for several hours before fertilisation. In the present study, we investigated whether OEC monolayers reproduce this effect in vitro, performing an analysis of ram sperm binding and survival over an extended (48 h) period at 39°C. We wanted to determine whether the reproductive cycle phase and/or oviducal region would influence ram sperm binding and survival in coculture with OEC and whether reproductive and non-reproductive epithelial cells bound and maintained the viability of ram spermatozoa equivalently. Oviducts were separated into groups based on their ovarian state (follicular or luteal) and then divided into two parts (isthmus and ampulla) for OEC isolation. Sheep kidney epithelial cells (Madin-Darby ovine kidney; MDOK) were purchased commercially. Reproductive cycle phase, but not oviducal region, affected sperm binding to OEC. Although more spermatozoa bound to luteal OEC than to follicular OEC at 1 h, at 24 h follicular OEC had bound more spermatozoa than luteal OEC. Generally, spermatozoa that were bound to OEC and MDOK had enhanced viability at each of the time points investigated (1, 6, 24 and 48 h), but the viability of the OEC-bound spermatozoa was greater than that of the MDOK-bound spermatozoa at 48 h. In conclusion, ram sperm–epithelial cell interactions are temporal, dynamic and depend on the origin of the epithelial cells.

scholarly journals Chk1 and the Host Cell DNA Damage Response as a Potential Antiviral Target in BK Polyomavirus Infection

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1353
Author(s):  
Lydia E. Hainley ◽  
Martina S. Hughson ◽  
Amithi Narendran ◽  
Ralph Smith ◽  
Justin Arthur ◽  
...  
Keyword(s):  
Dna Damage ◽  
Epithelial Cells ◽  
Dna Damage Response ◽  
Interstitial Fibrosis ◽  
Graft Loss ◽  
Viral Spread ◽  
Bk Polyomavirus ◽  
Damage Response

The human BK polyomavirus (BKPyV) is latent in the kidneys of most adults, but can be reactivated in immunosuppressed states, such as following renal transplantation. If left unchecked, BK polyomavirus nephropathy (PyVAN) and possible graft loss may result from viral destruction of tubular epithelial cells and interstitial fibrosis. When coupled with regular post-transplant screening, immunosuppression reduction has been effective in limiting BKPyV viremia and the development of PyVAN. Antiviral drugs that are safe and effective in combating BKPyV have not been identified but would be a benefit in complementing or replacing immunosuppression reduction. The present study explores inhibition of the host DNA damage response (DDR) as an antiviral strategy. Immunohistochemical and immunofluorescent analyses of PyVAN biopsies provide evidence for stimulation of a DDR in vivo. DDR pathways were also stimulated in vitro following BKPyV infection of low-passage human renal proximal tubule epithelial cells. The role of Chk1, a protein kinase known to be involved in the replication stress-induced DDR, was examined by inhibition with the small molecule LY2603618 and by siRNA-mediated knockdown. Inhibition of Chk1 resulted in decreased replication of BKPyV DNA and viral spread. Activation of mitotic pathways was associated with the reduction in BKPyV replication. Chk1 inhibitors that are found to be safe and effective in clinical trials for cancer should also be evaluated for antiviral activity against BKPyV.

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