Validity of the Cauchy-Born rule applied to discrete cellular-scale models of biological tissues.

The development of new models of biological tissues that consider cells in a discrete manner is becoming increasingly popular as an alternative to continuum methods based on partial differential equations, although formal relationships between the discrete and continuum frameworks remain to be established. For crystal mechanics, the discrete-to-continuum bridge is often made by assuming that local atom displacements can be mapped homogeneously from the mesoscale deformation gradient, an assumption known as the Cauchy-Born rule (CBR). Although the CBR does not hold exactly for noncrystalline materials, it may still be used as a first-order approximation for analytic calculations of effective stresses or strain energies. In this work, our goal is to investigate numerically the applicability of the CBR to two-dimensional cellular-scale models by assessing the mechanical behavior of model biological tissues, including crystalline (honeycomb) and noncrystalline reference states. The numerical procedure involves applying an affine deformation to the boundary cells and computing the quasistatic position of internal cells. The position of internal cells is then compared with the prediction of the CBR and an average deviation is calculated in the strain domain. For center-based cell models, we show that the CBR holds exactly when the deformation gradient is relatively small and the reference stress-free configuration is defined by a honeycomb lattice. We show further that the CBR may be used approximately when the reference state is perturbed from the honeycomb configuration. By contrast, for vertex-based cell models, a similar analysis reveals that the CBR does not provide a good representation of the tissue mechanics, even when the reference configuration is defined by a honeycomb lattice. The paper concludes with a discussion of the implications of these results for concurrent discrete and continuous modeling, adaptation of atom-to-continuum techniques to biological tissues, and model classification

Using a probabilistic approach to derive a two-phase model of flow-induced cell migration

Interstitial fluid flow is a feature of many solid tumours. In vitro experiments have shown that such fluid flow can direct tumour cell movement upstream or downstream depending on the balance between the competing mechanisms of tensotaxis and autologous chemotaxis. In this work we develop a probabilistic-continuum, two-phase model for cell migration in response to interstitial flow. We use a Fokker-Planck type equation for the cell-velocity probability density function, and model the flow-dependent mechanochemical stimulus as a forcing term which biases cell migration upstream and downstream. Using velocity-space averaging, we reformulate the model as a system of continuum equations for the spatio-temporal evolution of the cell volume fraction and flux, in response to forcing terms which depend on the local direction and magnitude of the mechanochemical cues. We specialise our model to describe a one-dimensional cell layer subject to fluid flow. Using a combination of numerical simulations and asymptotic analysis, we delineate the parameter regime where transitions from downstream to upstream cell migration occur. As has been observed experimentally, the model predicts downstream-oriented, chemotactic migration at low cell volume fractions, and upstream-oriented, tensotactic migration at larger volume fractions. We show that the locus of the critical volume fraction, at which the system transitions from downstream to upstream migration, is dominated by the ratio of the rate of chemokine secretion and advection. Our model predicts that, because the tensotactic stimulus depends strongly on the cell volume fraction, upstream migration occurs only transiently when the cells are initially seeded, and transitions to downstream migration occur at later times due to the dispersive effect of cell diffusion.Comment: 20 pages, 6 figures. Submitted to Biophysical Journa

Enhanced perfusion following exposure to radiotherapy: a theoretical investigation

Tumour angiogenesis leads to the formation of blood vessels that are structurally and spatially heterogeneous. Poor blood perfusion, in conjunction with increased hypoxia and oxygen heterogeneity, impairs a tumour’s response to radiotherapy. The optimal strategy for enhancing tumour perfusion remains unclear, preventing its regular deployment in combination therapies. In this work, we first identify vascular architectural features that correlate with enhanced perfusion following radiotherapy, using in vivo imaging data from vascular tumours. Then, we present a novel computational model to determine the relationship between these architectural features and blood perfusion in silico. If perfusion is defined to be the proportion of vessels that support blood flow, we find that vascular networks with small mean diameters and large numbers of angiogenic sprouts show the largest increases in perfusion post-irradiation for both biological and synthetic tumours. We also identify cases where perfusion increases due to the pruning of hypoperfused vessels, rather than blood being rerouted. These results indicate the importance of considering network composition when determining the optimal irradiation strategy. In the future, we aim to use our findings to identify tumours that are good candidates for perfusion enhancement and to improve the efficacy of combination therapies

Subclinical hepatitis E virus infection in laboratory ferrets in the UK

Ferrets are widely used for experimental modelling of viral infections. However, background disease in ferrets could potentially confound intended experimental interpretation. Here we report the detection of a subclinical infection of ferret hepatitis E virus (FRHEV) within a colony sub-group of female laboratory ferrets that had been enrolled on an experimental viral infection study (non-hepatitis). Lymphoplasmacytic cuffing of periportal spaces was identified on histopathology but was negative for the RNA and antigens of the administered virus. Follow-up viral metagenomic analysis conducted on liver specimens revealed sequences attributed to FRHEV and these were confirmed by reverse-transcriptase polymerase chain reaction. Further genomic analysis revealed contiguous sequences spanning 79-95 % of the FRHEV genome and that the sequences were closely related to those reported previously in Europe. Using in situ hybridization by RNAScope, we confirmed the presence of HEV-specific RNA in hepatocytes. The HEV open reading frame 2 (ORF2) protein was also detected by immunohistochemistry in the hepatocytes and the biliary canaliculi. In conclusion, the results of our study provide evidence of background infection with FRHEV in laboratory ferrets. As this infection can be subclinical, we recommend routine monitoring of ferret populations using virological and liver function tests to avoid incorrect causal attribution of any liver disease detected in in vivo studies

Sustainability of the chemical manufacturing industry - Towards a new paradigm?

This paper describes the current situation of the chemicalmanufacturingindustry, with special reference to Europe and looks to the future sustainability demands on the sector, and the implications of these demands for chemical engineering education. These implications include definitions of sustainability criteria for the sector and the need for transparent reporting under the Triple Bottom Line approach. The response of the education system to the sustainability agenda over the years and a number of strategies to incorporate it into courses are described. The important role of chemical (or more generally, process) engineers in delivering sustainable solutions is emphasised but this also suggests that anew way of thinking about the discipline is required. Indeed, this paper argues that the demand for a sustainable chemicalmanufacturing sector could bring about the next paradigm shift in the discipline which has been predicted for some time

Focal, remote-controlled, chronic chemical modulation of brain microstructures

Direct delivery of fluid to brain parenchyma is critical in both research and clinical settings. This is usually accomplished through acutely inserted cannulas. This technique, however, results in backflow and significant dispersion away from the infusion site, offering little spatial or temporal control in delivering fluid. We present an implantable, MRI-compatible, remotely controlled drug delivery system for minimally invasive interfacing with brain microstructures in freely moving animals. We show that infusions through acutely inserted needles target a region more than twofold larger than that of identical infusions through chronically implanted probes due to reflux and backflow. We characterize the dynamics of in vivo infusions using positron emission tomography techniques. Volumes as small as 167 nL of copper-64 and fludeoxyglucose labeled agents are quantified. We further demonstrate the importance of precise drug volume dosing to neural structures to elicit behavioral effects reliably. Selective modulation of the substantia nigra, a critical node in basal ganglia circuitry, via muscimol infusion induces behavioral changes in a volume-dependent manner, even when the total dose remains constant. Chronic device viability is confirmed up to 1-y implantation in rats. This technology could potentially enable precise investigation of neurological disease pathology in preclinical models, and more efficacious treatment in human patients. Keywords: brain; drug delivery; substantia nigra; neural implant; PETNational Institutes of Health (U.S.) (Grant R01 EB016101)National Institute of Biomedical Imaging and Bioengineering (U.S.) (Grant R01 EB016101)National Cancer Institute (U.S.) (Grant P30-CA14051

Abnormal morphology biases haematocrit distribution in tumour vasculature and contributes to heterogeneity in tissue oxygenation

Oxygen heterogeneity in solid tumors is recognized as a limiting factor for therapeutic efficacy. This heterogeneity arises from the abnormal vascular structure of the tumor, but the precise mechanisms linking abnormal structure and compromised oxygen transport are only partially understood. In this paper, we investigate the role that red blood cell (RBC) transport plays in establishing oxygen heterogeneity in tumor tissue. We focus on heterogeneity driven by network effects, which are challenging to observe experimentally due to the reduced fields of view typically considered. Motivated by our findings of abnormal vascular patterns linked to deviations from current RBC transport theory, we calculated average vessel lengths L⎯⎯ and diameters d⎯⎯ from tumor allografts of three cancer cell lines and observed a substantial reduction in the ratio λ=L⎯⎯/d⎯⎯ compared to physiological conditions. Mathematical modeling reveals that small values of the ratio λ (i.e., λ<6 ) can bias hematocrit distribution in tumor vascular networks and drive heterogeneous oxygenation of tumor tissue. Finally, we show an increase in the value of λ in tumor vascular networks following treatment with the antiangiogenic cancer agent DC101. Based on our findings, we propose λ as an effective way of monitoring the efficacy of antiangiogenic agents and as a proxy measure of perfusion and oxygenation in tumor tissue undergoing antiangiogenic treatment

Enhanced perfusion following exposure to radiotherapy: a theoretical investigation

Tumour angiogenesis leads to the formation of blood vessels that are structurally and spatially heterogeneous. Poor blood perfusion, in conjunction with increased hypoxia and oxygen heterogeneity, impairs a tumour’s response to radiotherapy. The optimal strategy for enhancing tumour perfusion remains unclear, preventing its regular deployment in combination therapies. In this work, we first identify vascular architectural features that correlate with enhanced perfusion following radiotherapy, using in vivo imaging data from vascular tumours. Then, we present a novel computational model to determine the relationship between these architectural features and blood perfusion in silico. If perfusion is defined to be the proportion of vessels that support blood flow, we find that vascular networks with small mean diameters and large numbers of angiogenic sprouts show the largest increases in perfusion post-irradiation for both biological and synthetic tumours. We also identify cases where perfusion increases due to the pruning of hypoperfused vessels, rather than blood being rerouted. These results indicate the importance of considering network composition when determining the optimal irradiation strategy. In the future, we aim to use our findings to identify tumours that are good candidates for perfusion enhancement and to improve the efficacy of combination therapies

Detection of Highly Pathogenic Avian Influenza Virus H5N1 Clade 2.3.4.4b in Great Skuas:A Species of Conservation Concern in Great Britain

The UK and Europe have seen successive outbreaks of highly pathogenic avian influenza across the 2020/21 and 2021/22 autumn/winter seasons. Understanding both the epidemiology and transmission of these viruses in different species is critical to aid mitigating measures where outbreaks cause extensive mortalities in both land- and waterfowl. Infection of different species can result in mild or asymptomatic outcomes, or acute infections that result in high morbidity and mortality levels. Definition of disease outcome in different species is of great importance to understanding the role different species play in the maintenance and transmission of these pathogens. Further, the infection of species that have conservation value is also important to recognise and characterise to understand the impact on what might be limited wild populations. Highly pathogenic avian influenza virus H5N1 clade 2.3.4.4b has been detected in great skuas (Stercorarius skua) across different colonies on islands off the shore of Scotland, Great Britain during summer 2021. A large number of great skuas were observed as developing severe clinical disease and dying during the epizootic and mortalities were estimated to be high where monitored. Of eight skuas submitted for post-mortem examination, seven were confirmed as being infected with this virus using a range of diagnostic assays. Here we overview the outbreak event that occurred in this species, listed as species of conservation concern in Great Britain and outline the importance of this finding with respect to virus transmission and maintenance

Pestivirus Apparent Prevalence in Sheep and Goats in Northern Ireland: A Serological Survey

Publication history: Accepted - 30 October 2020; Published - 12 January 2021.Background: Bovine viral diarrhoea virus (BVDV) and border disease virus (BDV) can cause significant health problems in ruminants and economic impacts for farmers. The aim of this study was to evaluate pestivirus exposure in Northern Ireland sheep and goat flocks, and to compare findings with a previous study from the region. Methods: Up to 20 animals were sampled from 188 sheep and 9 goat flocks (n = 3,418 animals; 3,372 sheep and 46 goats) for pestivirus antibodies. Differentiation of the causative agent in positive samples was inferred using serum neutralisation. Abortion samples from 177 ovine cases were tested by BVDV reverse-transcription polymerase chain reaction and antigen ELISA. Results: Apparent animal and flock (one antibody positive animal within a flock) prevalence was 1.7% and 17.3%, respectively, a statistically significant drop in apparent prevalence since a survey in 1999. 52.6% of samples testing positive had higher antibody titres to BVDV than to BDV. Of the ovine abortion samples, only one positive foetal fluid sample was detected by ELISA. Conclusion: The present study found that, since 1999, there has been a decrease in apparent animal and flock prevalence of 3.7 and 12.8 percentage points respectively, suggesting pestivirus prevalence has decreased across Northern Ireland between 1999 and 2018.This research was funded by the Department of Agriculture, Environment and Rural Affairs