Limited impact of contact tracing in a University setting for COVID-19 due to asymptomatic transmission and social distancing.

Contact tracing is an important tool for controlling the spread of infectious diseases, including COVID-19. Here, we investigate the spread of COVID-19 and the effectiveness of contact tracing in a university population, using a data-driven ego-centric network model constructed with social contact data collected during 2020 and similar data collected in 2010. We find that during 2020, university staff and students consistently reported fewer social contacts than in 2010, however those contacts occurred more frequently and were of longer duration. We find that contact tracing in the presence of social distancing is less impactful than without social distancing. By combining multiple data sources, we show that University-aged populations are likely to develop asymptomatic COVID-19 infections. We find that asymptomatic index cases cannot be reliably discovered through contact tracing and consequently transmission in their social network is not significantly reduced through contact tracing. In summary, social distancing restrictions had a large impact on limiting COVID-19 outbreaks in universities; to reduce transmission further contact tracing should be used in conjunction with alternative interventions.

In-silico and in-vitro morphometric analysis of intestinal organoids.

Organoids offer a powerful model to study cellular self-organisation, the growth of specific tissue morphologies in-vitro, and to assess potential medical therapies. However, the intrinsic mechanisms of these systems are not entirely understood yet, which can result in variability of organoids due to differences in culture conditions and basement membrane extracts used. Improving the standardisation of organoid cultures is essential for their implementation in clinical protocols. Developing tools to assess and predict the behaviour of these systems may produce a more robust and standardised biological model to perform accurate clinical studies. Here, we developed an algorithm to automate crypt-like structure counting on intestinal organoids in both in-vitro and in-silico images. In addition, we modified an existing two-dimensional agent-based mathematical model of intestinal organoids to better describe the system physiology, and evaluated its ability to replicate budding structures compared to new experimental data we generated. The crypt-counting algorithm proved useful in approximating the average number of budding structures found in our in-vitro intestinal organoid culture images on days 3 and 7 after seeding. Our changes to the in-silico model maintain the potential to produce simulations that replicate the number of budding structures found on days 5 and 7 of in-vitro data. The present study aims to aid in quantifying key morphological structures and provide a method to compare both in-vitro and in-silico experiments. Our results could be extended later to 3D in-silico models.

Evaluating the impact and cost-effectiveness of chlamydia management strategies in Hong Kong: A modeling study.

Objectives: To illustrate the epidemiologic and cost-effectiveness impact of shifting the focus from population-based screening toward a targeted management approach for genital chlamydia infection. Design: Modeling study, implementing an individual-based, stochastic, dynamic network model. Setting: Hong Kong. Population: A hypothetical sample network of 10,000 people with a partnership distribution based on Hong Kong's sexually active population of reproductive age (age 18-49 years). Interventions: In this study, we present several scenarios with different implementations of universal vs. targeted screening (based on partner numbers). We also explored the impact of (1) screening only, (2) screening plus expedited partner therapy, and (3) screening plus partner testing. Primary outcome measures: Change of chlamydia prevalence before and after implementing the different strategies. The cost-effectiveness analysis reports total direct cost from a health provider perspective, the QALYs gained, and incremental cost-effectiveness ratios (ICER). Results: In comparing the effects of universal screening only and targeted screening of the high-risk population, the mean prevalence during the 10th year of intervention was 2.75 ± 0.30% and 2.35 ± 0.21%, respectively (compared with 3.24 ± 0.30% and 3.35 ± 0.21% before the interventions, respectively). The addition of contact tracing to the latter targeted screening scenario reduces the mean prevalence during the 10th year of intervention to 1.48 ± 0.13% (compared with 3.31 ± 0.33% at baseline) in the best-case of testing before treatment and maximal contact-tracing effectiveness (40%). Overall, the most effective scenarios were those for which interventions focused on the high-risk population defined by the number of partners, with contact tracing included. The ICER for targeted screening with contact tracing at 20% and 40% efficiency was $4,634 and $7,219 per QALY gained, respectively (10-year time horizon). Expedited partner therapy did not significantly impact overall chlamydia prevalence and caused overtreatment. Conclusions: Our study suggests that targeted screening with strengthened contact tracing efforts is the most cost-effective strategy to reduce the prevalence of chlamydia in Hong Kong.

Sharp thresholds limit the benefit of defector avoidance in cooperation on networks.

Consider a cooperation game on a spatial network of habitat patches, where players can relocate between patches if they judge the local conditions to be unfavorable. In time, the relocation events may lead to a homogeneous state where all patches harbor the same relative densities of cooperators and defectors, or they may lead to self-organized patterns, where some patches become safe havens that maintain an elevated cooperator density. Here we analyze the transition between these states mathematically. We show that safe havens form once a certain threshold in connectivity is crossed. This threshold can be analytically linked to the structure of the patch network and specifically to certain network motifs. Surprisingly, a forgiving defector avoidance strategy may be most favorable for cooperators. Our results demonstrate that the analysis of cooperation games in ecological metacommunity models is mathematically tractable and has the potential to link topics such as macroecological patterns, behavioral evolution, and network topology.

Cross-talk between Hippo and Wnt signalling pathways in intestinal crypts: Insights from an agent-based model.

Intestinal crypts are responsible for the total cell renewal of the lining of the intestines; this turnover is governed by the interplay between signalling pathways and the cell cycle. The role of Wnt signalling in cell proliferation and differentiation in the intestinal crypt has been extensively studied, with increased signalling found towards the lower regions of the crypt. Recent studies have shown that the Wnt signalling gradient found within the crypt may arise as a result of division-based spreading from a Wnt 'reservoir' at the crypt base. The discovery of the Hippo pathway's involvement in maintaining crypt homeostasis is more recent; a mechanistic understanding of Hippo pathway dynamics, and its possible cross-talk with the Wnt pathway, remains lacking. To explore how the interplay between these pathways may control crypt homeostasis, we extended an ordinary differential equation model of the Wnt signalling pathway to include a phenomenological description of Hippo signalling in single cells, and then coupled it to a cell-based description of cell movement, proliferation and contact inhibition in agent-based simulations. Furthermore, we compared an imposed Wnt gradient with a division-based Wnt gradient model. Our results suggest that Hippo signalling affects the Wnt pathway by reducing the presence of free cytoplasmic ß-catenin, causing cell cycle arrest. We also show that a division-based spreading of Wnt can form a Wnt gradient, resulting in proliferative dynamics comparable to imposed-gradient models. Finally, a simulated APC double mutant, with misregulated Wnt and Hippo signalling activity, is predicted to cause monoclonal conversion of the crypt.

Mathematical Models of Organoid Cultures.

Organoids are engineered three-dimensional tissue cultures derived from stem cells and capable of self-renewal and self-organization into a variety of progenitors and differentiated cell types. An organoid resembles the cellular structure of an organ and retains some of its functionality, while still being amenable to in vitro experimental study. Compared with two-dimensional cultures, the three-dimensional structure of organoids provides a more realistic environment and structural organization of in vivo organs. Similarly, organoids are better suited to reproduce signaling pathway dynamics in vitro, due to a more realistic physiological environment. As such, organoids are a valuable tool to explore the dynamics of organogenesis and offer routes to personalized preclinical trials of cancer progression, invasion, and drug response. Complementary to experiments, mathematical and computational models are valuable instruments in the description of spatiotemporal dynamics of organoids. Simulations of mathematical models allow the study of multiscale dynamics of organoids, at both the intracellular and intercellular levels. Mathematical models also enable us to understand the underlying mechanisms responsible for phenotypic variation and the response to external stimulation in a cost- and time-effective manner. Many recent studies have developed laboratory protocols to grow organoids resembling different organs such as the intestine, brain, liver, pancreas, and mammary glands. However, the development of mathematical models specific to organoids remains comparatively underdeveloped. Here, we review the mathematical and computational approaches proposed so far to describe and predict organoid dynamics, reporting the simulation frameworks used and the models' strengths and limitations.

Agent-based modelling study of antimicrobial-resistant Neisseria gonorrhoeae transmission in men who have sex with men: towards individualised diagnosis and treatment.

Background Antimicrobial-resistant (AMR) gonorrhoea is a global public health threat. Discriminatory point-of-care tests (POCT) to detect drug sensitivity are under development, enabling individualised resistance-guided therapy. METHODS: An individual-based dynamic transmission model of gonorrhoea infection in MSM living in London has been developed, incorporating ciprofloxacin-sensitive and resistant strains. The time-dependent sexual contact network is captured by periodically restructuring active connections to reflect the transience of contacts. Different strategies to improve treatment selection were explored, including discriminatory POCT and selecting partner treatment based on either the index case or partner susceptibility. Outcomes included population prevalence of gonorrhoea and drug dose counts. RESULTS: It is shown that using POCT to detect ciprofloxacin-sensitive infections could result in a large decrease in ceftriaxone doses (by 70% compared with the reference case in the simulations of this study). It also suggests that ceftriaxone use can be reduced with existing technologies, albeit to a lesser degree; either using index case sensitivity profiles to direct treatment of partners, or testing notified partners with strain discriminatory laboratory tests before treatment, reduced ceftriaxone use in our model (by 27% and 47% respectively). CONCLUSIONS: POCT to detect ciprofloxacin-sensitive gonorrhoea are likely to dramatically reduce reliance on ceftriaxone, but requires the implementation of new technology. In the meantime, the proportion of unnecessary ceftriaxone treatment by testing partners before treatment could be reduced significantly. Alternatively, index case sensitivity profiles could be used to select effective treatments for partners.

Emergent acoustic order in arrays of mosquitoes.

The yellow fever mosquito Aedes aegypti forms aerial swarms that serve as mating aggregations [1]. Despite lacking the remarkable collective order of other animal ensembles, such as fish and birds [2], the kinematic properties of these swarms bear the hallmarks of local interaction and global cohesion [3,4]. However, the mechanisms responsible for collective behaviour in mosquitoes are not well understood. Mosquitoes use their antennae as hearing organs to locate and interact with one another via the frequencies of sounds generated by their beating wings [5]. Acoustic detection and recognition are known to mediate copula formation in opposite-sex pairs [6], but have not been investigated in larger groups. By recording the flight tones of multiple, tethered, male Ae. aegypti, we test the hypothesis that acoustic signalling is a determinant of swarm morphology and present the first compelling evidence that flight tone interactions between males drive observed group coherence in the frequency domain. We find that group size critically affects collective and individual acoustic traits: cohesive acoustic behaviours emerge in groups of more than six male mosquitoes, occurring to a greater degree than predicted in the absence of interaction. Importantly, acoustic interactions between multiple males differ from those reported previously for same-sex pairs [7,8]. Our findings enable future research targeting key behavioural and reproductive aspects of the biology of mosquitoes of epidemiological importance.

An extended model for culture-dependent heterogenous gene expression and proliferation dynamics in mouse embryonic stem cells.

During development, pluripotency is a transient state describing a cell's ability to give rise to all three germ layers and germline. Recent studies have shown that, in vitro, pluripotency is highly dynamic: exogenous stimuli provided to cultures of mouse embryonic stem cells, isolated from pre-implantation blastocysts, significantly affect the spectrum of pluripotency. 2i/LIF, a recently defined serum-free medium, forces mouse embryonic stem cells into a ground-state of pluripotency, while serum/LIF cultures promote the co-existence of ground-like and primed-like mouse embryonic stem cell subpopulations. The latter heterogeneity correlates with temporal fluctuations of pluripotency markers, including the master regulator Nanog, in single cells. We propose a mathematical model of Nanog dynamics in both media, accounting for recent experimental data showing the persistence of a small Nanog Low subpopulation in ground-state pluripotency mouse embryonic stem cell cultures. The model integrates into the core pluripotency Gene Regulatory Network both inhibitors present in 2i/LIF (PD and Chiron), and feedback interactions with genes found to be differentially expressed in the two media. Our simulations and bifurcation analysis show that, in ground-state cultures, Nanog dynamics result from the combination of reduced noise in gene expression and the shift of the system towards a monostable, but still excitable, regulation. Experimental data and agent-based modelling simulations indicate that mouse embryonic stem cell proliferation dynamics vary in the two media, and cannot be reproduced by accounting only for Nanog-dependent cell-cycle regulation. We further demonstrate that both PD and Chiron play a key role in regulating heterogeneity in transcription factor expression and, ultimately, mouse embryonic stem cell fate decision.

Quantitative analysis of harmonic convergence in mosquito auditory interactions.

This article analyses the hearing and behaviour of mosquitoes in the context of inter-individual acoustic interactions. The acoustic interactions of tethered live pairs of Aedes aegypti mosquitoes, from same and opposite sex mosquitoes of the species, are recorded on independent and unique audio channels, together with the response of tethered individual mosquitoes to playbacks of pre-recorded flight tones of lone or paired individuals. A time-dependent representation of each mosquito's non-stationary wing beat frequency signature is constructed, based on Hilbert spectral analysis. A range of algorithmic tools is developed to automatically analyse these data, and used to perform a robust quantitative identification of the 'harmonic convergence' phenomenon. The results suggest that harmonic convergence is an active phenomenon, which does not occur by chance. It occurs for live pairs, as well as for lone individuals responding to playback recordings, whether from the same or opposite sex. Male-female behaviour is dominated by frequency convergence at a wider range of harmonic combinations than previously reported, and requires participation from both partners in the duet. New evidence is found to show that male-male interactions are more varied than strict frequency avoidance. Rather, they can be divided into two groups: convergent pairs, typified by tightly bound wing beat frequencies, and divergent pairs, that remain widely spaced in the frequency domain. Overall, the results reveal that mosquito acoustic interaction is a delicate and intricate time-dependent active process that involves both individuals, takes place at many different frequencies, and which merits further enquiry.

Mathematical modeling reveals differential effects of erythropoietin on proliferation and lineage commitment of human hematopoietic progenitors in early erythroid culture.

Erythropoietin is essential for the production of mature erythroid cells, promoting both proliferation and survival. Whether erythropoietin and other cytokines can influence lineage commitment of hematopoietic stem and progenitor cells is of significant interest. To study lineage restriction of the common myeloid progenitor to the megakaryocyte/erythroid progenitor of peripheral blood CD34(+) cells, we have shown that the cell surface protein CD36 identifies the earliest lineage restricted megakaryocyte/erythroid progenitor. Using this marker and carboxyfluorescein succinimidyl ester to track cell divisions in vitro, we have developed a mathematical model that accurately predicts population dynamics of erythroid culture. Parameters derived from the modeling of cultures without added erythropoietin indicate that the rate of lineage restriction is not affected by erythropoietin. By contrast, megakaryocyte/erythroid progenitor proliferation is sensitive to erythropoietin from the time that CD36 first appears at the cell surface. These results shed new light on the role of erythropoietin in erythropoiesis and provide a powerful tool for further study of hematopoietic progenitor lineage restriction and erythropoiesis.

Hiding the squid: patterns in artificial cephalopod skin.

Cephalopods employ their chromomorphic skins for rapid and versatile active camouflage and signalling effects. This is achieved using dense networks of pigmented, muscle-driven chromatophore cells which are neurally stimulated to actuate and affect local skin colouring. This allows cephalopods to adopt numerous dynamic and complex skin patterns, most commonly used to blend into the environment or to communicate with other animals. Our ultimate goal is to create an artificial skin that can mimic such pattern generation techniques, and that could produce a host of novel and compliant devices such as cloaking suits and dynamic illuminated clothing. This paper presents the design, mathematical modelling and analysis of a dynamic biomimetic pattern generation system using bioinspired artificial chromatophores. The artificial skin is made from electroactive dielectric elastomer: a soft, planar-actuating smart material that we show can be effective at mimicking the actuation of biological chromatophores. The proposed system achieves dynamic pattern generation by imposing simple local rules into the artificial chromatophore cells so that they can sense their surroundings in order to manipulate their actuation. By modelling sets of artificial chromatophores in linear arrays of cells, we explore the capability of the system to generate a variety of dynamic pattern types. We show that it is possible to mimic patterning seen in cephalopods, such as the passing cloud display, and other complex dynamic patterning.

Time-frequency composition of mosquito flight tones obtained using Hilbert spectral analysis.

Techniques for estimating temporal variation in the frequency content of acoustic tones based on short-time fast Fourier transforms are fundamentally limited by an inherent time-frequency trade-off. This paper presents an alternative methodology, based on Hilbert spectral analysis, which is not affected by this weakness, and applies it to the accurate estimation of mosquito wing beat frequencies. Mosquitoes are known to communicate with one another via the sounds generated by their flapping wings. Active frequency modulation between pairs of mosquitoes is thought to take place as a precursor to courtship. Studying the acoustically-based interactions of mosquitoes therefore relies on an accurate representation of flight frequency as a time-evolving property, yet conventional Fourier spectrograms are unable to capture the rapid modulations in frequency that mosquito flight tones exhibit. The algorithms introduced in this paper are able to automatically detect and extract fully temporally resolved frequency information from audio recordings. Application of the technique to experimental recordings of single tethered mosquitoes in flight reveals corroboration with previous reported findings. The advantages of the method for animal communication studies are discussed, with particular attention given to its potential utility for studying pairwise mosquito interactions.

Comparison of nonlinear mammalian cochlear-partition models.

Various simple mathematical models of the dynamics of the organ of Corti in the mammalian cochlea are analyzed and their dynamics compared. The specific models considered are phenomenological Hopf and cusp normal forms, a recently proposed description combining active hair-bundle motility and somatic motility, a reduction thereof, and finally a model highlighting the importance of the coupling between the nonlinear transduction current and somatic motility. It is found that for certain models precise tuning to any bifurcation is not necessary and that a compressively nonlinear response over a range similar to experimental observations and that the normal form of the Hopf bifurcation is not the only description that reproduces compression and tuning similar to experiment.

Mathematical modeling of the radial profile of basilar membrane vibrations in the inner ear.

Motivated by recent experimental results, an explanation is sought for the asymmetry in the radial profile of basilar membrane vibrations in the inner ear. A sequence of one-dimensional beam models is studied which take into account variations in the bending stiffness of the basilar membrane as well as the potential presence of structural hinges. The results suggest that the main cause of asymmetry is likely to be differences between the boundary conditions at the two extremes of the basilar membrane's width. This has fundamental implications for more detailed numerical simulations of the entire cochlea.