Network-based vaccination improves prospects for disease control in wild chimpanzees

Many endangered wildlife populations are vulnerable to infectious diseases for which vaccines exist; yet, pragmatic considerations often preclude large-scale vaccination efforts. These barriers could be reduced by focusing on individuals with the highest contact rates. However, the question then becomes whether targeted vaccination is sufficient to prevent large outbreaks. To evaluate the efficacy of targeted wildlife vaccinations, we simulate pathogen transmission and control on monthly association networks informed by behavioural data from a wild chimpanzee community (Kanyawara N = 37, Kibale National Park, Uganda). Despite considerable variation across monthly networks, our simulations indicate that targeting the most connected individuals can prevent large outbreaks with up to 35% fewer vaccines than random vaccination. Transmission heterogeneities might be attributed to biological differences among individuals (e.g. sex, age, dominance and family size). Thus, we also evaluate the effectiveness of a trait-based vaccination strategy, as trait data are often easier to collect than interaction data. Our simulations indicate that a trait-based strategy can prevent large outbreaks with up to 18% fewer vaccines than random vaccination, demonstrating that individual traits can serve as effective estimates of connectivity. Overall, these results suggest that fine-scale behavioural data can help optimize pathogen control efforts for endangered wildlife.     

Invasion,persistence and control in epidemic models for plant pathogens: the effect of host demography

Many epidemiological models for plant disease include host demography to describe changes in the availability of susceptible tissue for infection. We compare the effects of using two commonly used formulations for host growth, one linear and the other nonlinear, upon the outcomes for invasion, persistence and control of pathogens in a widely used, generic model for botanical epidemics. The criterion for invasion, reflected in the basic reproductive number, R₀, is unaffected by host demography: R₀ is simply a function of epidemiological parameters alone. When, however, host growth is intrinsically nonlinear, unexpected results arise for persistence and the control of disease. The endemic level of infection (I_∞) also depends upon R₀. We show, however, that the sensitivity of I_∞ to changes in R₀ > 1 depends upon which underlying epidemiological parameter is changed. Increasing R₀ by shortening the infectious period results in a monotonic increase in I_∞. If, however, an increase in R₀ is driven by increases in transmission rates or by decreases in the decay of free-living inoculum, I_∞ first increases (R₀ < 2), but then decreases (R₀ > 2). This counterintuitive result means that increasing the intensity of control can result in more endemic infection.     

Regulatory principles and experimental approaches to the circadian control of starch turnover

In many plants, starch is synthesized during the day and degraded during the night to avoid carbohydrate starvation in darkness. The circadian clock participates in a dynamic adjustment of starch turnover to changing environmental condition through unknown mechanisms. We used mathematical modelling to explore the possible scenarios for the control of starch turnover by the molecular components of the plant circadian clock. Several classes of plausible models were capable of describing the starch dynamics observed in a range of clock mutant plants and light conditions, including discriminating circadian protocols. Three example models of these classes are studied in detail, differing in several important ways. First, the clock components directly responsible for regulating starch degradation are different in each model. Second, the intermediate species in the pathway may play either an activating or inhibiting role on starch degradation. Third, the system may include a light-dependent interaction between the clock and downstream processes. Finally, the clock may be involved in the regulation of starch synthesis. We discuss the differences among the models’ predictions for diel starch profiles and the properties of the circadian regulators. These suggest additional experiments to elucidate the pathway structure, avoid confounding results and identify the molecular components involved.     

Novel temperature-responsive polymer brushes with carbohydrate residues facilitate selective adhesion and collection of hepatocytes

Temperature-responsive glycopolymer brushes were designed to investigate the effects of grafting architectures of the copolymers on the selective adhesion and collection of hypatocytes. Homo, random and block sequences of N-isopropylacrylamide and 2-lactobionamidoethyl methacrylate were grafted on glass substrates via surface-initiated atom transfer radical polymerization. The galactose/lactose-specific lectin RCA₁₂₀ and HepG2 cells were used to test for specific recognition of the polymer brushes containing galactose residues over the lower critical solution temperatures (LCSTs). RCA₁₂₀ showed a specific binding to the brush surfaces at 37 °C. These brush surfaces also facilitated the adhesion of HepG2 cells at 37 °C under nonserum conditions, whereas no adhesion was observed for NIH-3T3 fibroblasts. When the temperature was decreased to 25 °C, almost all the HepG2 cells detached from the block copolymer brush, whereas the random copolymer brush did not release the cells. The difference in releasing kinetics of cells from the surfaces with different grafting architectures can be explained by the correlated effects of significant changes in LCST, mobility, hydrophilicity and mechanical properties of the grafted polymer chains. These findings are important for designing ‘on–off’ cell capture/release substrates for various biomedical applications such as selective cell separation.     

Insights into mucosal innate responses to Escherichia coli O157 : H7 colonization of cattle by mathematical modelling of excretion dynamics

Mathematical model-based statistical inference applied to within-host dynamics of infectious diseases can help dissect complex interactions between hosts and microbes. This work has applied advances in model-based inference to understand colonization of cattle by enterohaemorrhagic Escherichia coli O157 : H7 at the terminal rectum. A mathematical model was developed based on niche replication and transition rates at this site. A nested-model comparison, applied to excretion curves from 25 calves, was used to reduce complexity while maintaining integrity. We conclude that, 5–9 days post inoculation, the innate immune response negates bacterial replication on the epithelium and either reduces attachment to or increases detachment from the epithelium of the terminal rectum. Thus, we provide a broadly applicable model that gives novel insights into bacterial replication rates in vivo and the timing and impact of host responses.     

Transmission dynamics of methicillin-resistant Staphylococcus aureus in a medical intensive care unit

Intensive care units (ICUs) play an important role in the epidemiology of methicillin-resistant Staphyloccocus aureus (MRSA). Although successful interventions are multi-modal, the relative efficacy of single measures remains unknown. We developed a discrete time, individual-based, stochastic mathematical model calibrated on cross-transmission observed through prospective surveillance to explore the transmission dynamics of MRSA in a medical ICU. Most input parameters were derived from locally acquired data. After fitting the model to the 46 observed cross-transmission events and performing sensitivity analysis, several screening and isolation policies were evaluated by simulating the number of cross-transmissions and isolation-days. The number of all cross-transmission events increased from 54 to 72 if only patients with a past history of MRSA colonization are screened and isolated at admission, to 75 if isolation is put in place only after the results of the admission screening become available, to 82 in the absence of admission screening and with a similar reactive isolation policy, and to 95 when no isolation policy is in place. The method used (culture or polymerase chain reaction) for admission screening had no impact on the number of cross-transmissions. Systematic regular screening during ICU stay provides no added-value, but aggressive admission screening and isolation effectively reduce the number of cross-transmissions. Critically, colonized healthcare workers may play an important role in MRSA transmission and their screening should be reinforced.     

Embodied linearity of speed control in Drosophila melanogaster

Fruitflies regulate flight speed by adjusting their body angle. To understand how low-level posture control serves an overall linear visual speed control strategy, we visually induced free-flight acceleration responses in a wind tunnel and measured the body kinematics using high-speed videography. Subsequently, we reverse engineered the transfer function mapping body pitch angle onto flight speed. A linear model is able to reproduce the behavioural data with good accuracy. Our results show that linearity in speed control is realized already at the level of body posture-mediated speed control and is therefore embodied at the level of the complex aerodynamic mechanisms of body and wings. Together with previous results, this study reveals the existence of a linear hierarchical control strategy, which can provide relevant control principles for biomimetic implementations, such as autonomous flying micro air vehicles.     

A linear-encoding model explains the variability of the target morphology in regeneration

A fundamental assumption of today''s molecular genetics paradigm is that complex morphology emerges from the combined activity of low-level processes involving proteins and nucleic acids. An inherent characteristic of such nonlinear encodings is the difficulty of creating the genetic and epigenetic information that will produce a given self-assembling complex morphology. This ‘inverse problem’ is vital not only for understanding the evolution, development and regeneration of bodyplans, but also for synthetic biology efforts that seek to engineer biological shapes. Importantly, the regenerative mechanisms in deer antlers, planarian worms and fiddler crabs can solve an inverse problem: their target morphology can be altered specifically and stably by injuries in particular locations. Here, we discuss the class of models that use pre-specified morphological goal states and propose the existence of a linear encoding of the target morphology, making the inverse problem easy for these organisms to solve. Indeed, many model organisms such as Drosophila, hydra and Xenopus also develop according to nonlinear encodings producing linear encodings of their final morphologies. We propose the development of testable models of regeneration regulation that combine emergence with a top-down specification of shape by linear encodings of target morphology, driving transformative applications in biomedicine and synthetic bioengineering.     

The wake of hovering flight in bats

Hovering means stationary flight at zero net forward speed, which can be achieved by animals through muscle powered flapping flight. Small bats capable of hovering typically do so with a downstroke in an inclined stroke plane, and with an aerodynamically active outer wing during the upstroke. The magnitude and time history of aerodynamic forces should be reflected by vorticity shed into the wake. We thus expect hovering bats to generate a characteristic wake, but this has until now never been studied. Here we trained nectar-feeding bats, Leptonycteris yerbabuenae, to hover at a feeder and using time-resolved stereoscopic particle image velocimetry in conjunction with high-speed kinematic analysis we show that hovering nectar-feeding bats produce a series of bilateral stacked vortex loops. Vortex visualizations suggest that the downstroke produces the majority of the weight support, but that the upstroke contributes positively to the lift production. However, the relative contributions from downstroke and upstroke could not be determined on the basis of the wake, because wake elements from down- and upstroke mix and interact. We also use a modified actuator disc model to estimate lift force, power and flap efficiency. Based on our quantitative wake-induced velocities, the model accounts for weight support well (108%). Estimates of aerodynamic efficiency suggest hovering flight is less efficient than forward flapping flight, while the overall energy conversion efficiency (mechanical power output/metabolic power) was estimated at 13%.     

The Use of Structural Templates in Protein Backbone Modeling

The procedures used to model a protein structure are well established when the novel protein has high sequence similarity to a protein of known structure. Many proteins of interest have low (i.e. <50%) sequence similarity to any known structure. In these cases new approaches to prediction of structure are required.The use of sequence profiles which relate sequence to known structure has been proposed as one method to assign local regions of structure. As a first stage, templates or “icons” of the many relevant substructural motifs found in proteins must be defined. The sequences which gave rise to these structures are then aligned and a weighted profile obtained.Average structures of the 8 and 12 residue helix-turn and turn-helix motifs have been prepared. These coordinate templates were then used to scan through the Brookhaven protein structural database for similar, superimposable fragments. A composite template of 100 similar fragments for each element was found to be internally consistent to a rmsd=0.92 Å for HT8, 1.54 Å for HT12, 0.41 Å for TH8 and 1.40 Å for TH12. All of the sequences, from these structures, were then used to create an overall sequence profile.The four sequence profiles were scanned against the amino acid sequences of the proteins in the Brookhaven database: tertiary structure was correctly identified only about 10% of the time. This value is too low for predictive purposes. However, it could be increased by checking for multiple occurrences of the template in one protein.     

Aggregation by depletion attraction in cultures of bacteria producing exopolysaccharide

In bacteria, the production of exopolysaccharides—polysaccharides secreted by the cells into their growth medium—is integral to the formation of aggregates and biofilms. These exopolysaccharides often form part of a matrix that holds the cells together. Investigating the bacterium Sinorhizobium meliloti, we found that a mutant that overproduces the exopolysaccharide succinoglycan showed enhanced aggregation, resulting in phase separation of the cultures. However, the aggregates did not appear to be covered in polysaccharides. Succinoglycan purified from cultures was applied to different concentrations of cells, and observation of the phase behaviour showed that the limiting polymer concentration for aggregation and phase separation to occur decreased with increasing cell concentration, suggesting a ‘crowding mechanism’ was occurring. We suggest that, as found in colloidal dispersions, the presence of a non-adsorbing polymer in the form of the exopolysaccharide succinoglycan drives aggregation of S. meliloti by depletion attraction. This force leads to self-organization of the bacteria into small clusters of laterally aligned cells, and, furthermore, leads to aggregates clustering into biofilm-like structures on a surface.     

The management of fluid and wave resistances by whirligig beetles

Whirligig beetles (Coleoptera: Gyrinidae) are semi-aquatic insects with a morphology and propulsion system highly adapted to their life at the air–water interface. When swimming on the water surface, beetles are subject to both fluid resistance and wave resistance.The purpose of this study was to analyse swimming speed, leg kinematics and the capillarity waves produced by whirligig beetles on the water surface in a simple environment. Whirligig beetles of the species Gyrinus substriatus were filmed in a large container, with a high-speed camera. Resistance forces were also estimated.These beetles used three types of leg kinematics, differing in the sequence of leg strokes: two for swimming at low speed and one for swimming at high speed. Four main speed patterns were produced by different combinations of these types of leg kinematics, and the minimum speed for the production of surface waves (23 cm s⁻¹) corresponded to an upper limit when beetles used low-speed leg kinematics. Each type of leg kinematics produced characteristic capillarity waves, even if the beetles moved at a speed below 23 cm s⁻¹. Our results indicate that whirligig beetles use low- and high-speed leg kinematics to avoid maximum drag and swim at speed corresponding to low resistances.     

The interplay between a self-organized process and an environmental template: corpse clustering under the influence of air currents in ants

Many spatial patterns observed in nature emerge from local processes and their interactions with the local environment. The clustering of objects by social insects represents such a pattern formation process that can be observed at both the individual and the collective level. In this paper, we study the interaction between air currents and clustering behaviour in order to address the coordinating mechanisms at the individual level that underlie the spatial pattern formation process in a heterogeneous environment. We choose the corpse clustering behaviour of the ant Messor sanctus as an experimental paradigm. In a specifically designed experimental set-up with a well-controlled laminar air flow (approx. 1 cm s-1), we first quantify the modulation of the individual corpse aggregation behaviour as a function of corpse density, air flow intensity and the ant's position with respect to corpse piles and air flow direction. We then explore by numerical simulation how the forming corpse piles modify the laminar air flow around them and link this result with the individual behaviour modulation. Finally, we demonstrate on the collective level that this laminar air flow leads to an elongation and a slow displacement of the formed corpse piles in the direction of the air current. Both the individual behaviour modulated by air flow and the air flow modulated by the forming corpse piles can explain the pile patterns observed on the collective level as a stigmergic process. We discuss the generality of this coordinating mechanism to explain the clustering phenomena in heterogeneous environments reported in the literature.     

The effect of individual variation on the structure and function of interaction networks in harvester ants

Social insects exhibit coordinated behaviour without central control. Local interactions among individuals determine their behaviour and regulate the activity of the colony. Harvester ants are recruited for outside work, using networks of brief antennal contacts, in the nest chamber closest to the nest exit: the entrance chamber. Here, we combine empirical observations, image analysis and computer simulations to investigate the structure and function of the interaction network in the entrance chamber. Ant interactions were distributed heterogeneously in the chamber, with an interaction hot-spot at the entrance leading further into the nest. The distribution of the total interactions per ant followed a right-skewed distribution, indicating the presence of highly connected individuals. Numbers of ant encounters observed positively correlated with the duration of observation. Individuals varied in interaction frequency, even after accounting for the duration of observation. An ant''s interaction frequency was explained by its path shape and location within the entrance chamber. Computer simulations demonstrate that variation among individuals in connectivity accelerates information flow to an extent equivalent to an increase in the total number of interactions. Individual variation in connectivity, arising from variation among ants in location and spatial behaviour, creates interaction centres, which may expedite information flow.     

The dynamic balance of import and export of zinc in Escherichia coli suggests a heterogeneous population response to stress

Zinc is essential for life, but toxic in excess. Thus all cells must control their internal zinc concentration. We used a systems approach, alternating rounds of experiments and models, to further elucidate the zinc control systems in Escherichia coli. We measured the response to zinc of the main specific zinc import and export systems in the wild-type, and a series of deletion mutant strains. We interpreted these data with a detailed mathematical model and Bayesian model fitting routines. There are three key findings: first, that alternate, non-inducible importers and exporters are important. Second, that an internal zinc reservoir is essential for maintaining the internal zinc concentration. Third, our data fitting led us to propose that the cells mount a heterogeneous response to zinc: some respond effectively, while others die or stop growing. In a further round of experiments, we demonstrated lower viable cell counts in the mutant strain tested exposed to excess zinc, consistent with this hypothesis. A stochastic model simulation demonstrated considerable fluctuations in the cellular levels of the ZntA exporter protein, reinforcing this proposal. We hypothesize that maintaining population heterogeneity could be a bet-hedging response allowing a population of cells to survive in varied and fluctuating environments.     

The canine distemper epidemic in Serengeti: are lions victims of a new highly virulent canine distemper virus strain,or is pathogen circulation stochasticity to blame?

In the year 1994, the Serengeti lion population was decimated by a canine distemper disease outbreak. Retrospective investigations showed that this host population had already been in contact with the pathogen in 1981 without any detected sign of disease. As an alternative to the virus mutation hypothesis to explain this difference in virulences observed in 1981 and 1994, we propose a novel mechanism of disease emergence based on variation in population immunity. We use a stochastic model to show that stochastic fluctuations in pathogen circulation, owing to a low probability of virus transmission from its reservoir to the target host and thereby resulting in variations in the global immunity level of the target host population, can explain the observations made in Serengeti. This mechanism may also be involved in other infectious disease emergences or re-emergences.     

The Pole Term in Linear Response Theory: An Example From the Transverse Response of the Electron Gas

In linear response theory, the dielectric response at zero frequency sometimes appears to violate the f-sum rule, which has apparent implications for causality. Here, we study the origin of this apparent discrepancy, focusing on Lindhard’s formula for the transverse response of the electron gas. At non-zero frequency, first-order poles contribute to the imaginary part of the dielectric function in the usual way. At zero frequency, second-order poles contribute in a way which forces a careful consideration of the notation of summation and integration to avoid an error. A compact formula for the contribution of the second-order poles is presented. The sense in which the f-sum rule is satisfied is discussed.     

The biological seal of the implant–soft tissue interface evaluated in a tissue-engineered oral mucosal model

For dental implants, it is vital that an initial soft tissue seal is achieved as this helps to stabilize and preserve the peri-implant tissues during the restorative stages following placement. The study of the implant–soft tissue interface is usually undertaken in animal models. We have developed an in vitro three-dimensional tissue-engineered oral mucosal model (3D OMM), which lends itself to the study of the implant–soft tissue interface as it has been shown that cells from the three-dimensional OMM attach onto titanium (Ti) surfaces forming a biological seal (BS). This study compares the quality of the BS achieved using the three-dimensional OMM for four types of Ti surfaces: polished, machined, sandblasted and anodized (TiUnite). The BS was evaluated quantitatively by permeability and cell attachment tests. Tritiated water (HTO) was used as the tracing agent for the permeability test. At the end of the permeability test, the Ti discs were removed from the three-dimensional OMM and an Alamar Blue assay was used for the measurement of residual cells attached to the Ti discs. The penetration of the HTO through the BS for the four types of Ti surfaces was not significantly different, and there was no significant difference in the viability of residual cells that attached to the Ti surfaces. The BS of the tissue-engineered oral mucosa around the four types of Ti surface topographies was not significantly different.