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Herd immunity to helminth infection and implications for parasite control.

Despite much research on immunological responses to helminth parasites, knowledge of the dynamic interplay between levels of herd immunity in humans and the rates of exposure, establishment and mortality of parasites remains limited. We describe here a simple mathematical model for the population dynamics of helminth infections which mirrors the development of a degree of acquired immunity within populations which are genetically heterogeneous with respect to immunological responsiveness. We interpret observed patterns in the age-specific intensity of infection and attempt to understand the possible effects of control measures based on chemotherapy and vaccination. Mass chemotherapy can, in some circumstances, reduce the level of herd immunity such that average worm burdens in the adult age classes rise above their precontrol levels. When certain individuals or groups are predisposed to heavy infection, selective or targeted drug treatment can have significantly greater impact than mass or random application. Conversely, model predictions suggest that effective parasite control by vaccination (if and when vaccines become available) is difficult to achieve in communities that are genetically heterogeneous in their ability to mount protective responses to infection.

Age Factors↗

PubMed2000

A functional model system of an hypoxic nerve injury and its evaluation.

OBJECTIVES/HYPOTHESIS: Develop an hypoxic peripheral nerve injury model with a controlled injury type and two types of clinically relevant physiological measurements of function during and after recovery. The model, controlling for injury and measurement variables, would have predictable outcomes in function. The functional model could test potential therapeutic interventions with greater sensitivity. STUDY DESIGN: Twenty-one rats were used in preliminary studies evaluating peroneal nerve injury types and functional model evaluation. Forty-eight rats were used in a controlled and blinded evaluation of the injury model followed by treatment with hyperbaric oxygen (HBO) as a potential therapeutic intervention and evaluated with functional models. METHODS: Preliminary studies compared nerve injuries: epineurectomy, epineurectomy with crush and transection with autograft for rate of return of function and final extent of return of function. The gait analysis model was also evaluated and modified to decrease variability. The final study evaluated peroneal epineurectomy and nerve crush injury with serial gait analysis during recovery, final elicited maximum force measurements, and histological analysis. Half of the animals were treated with HBO during recovery (ANOVA or regression statistical analysis were used to determine group differences.). RESULTS: Preliminary studies suggested that the peroneal nerve injury model of an epineurectomy with crush of specified length and a modification of the gait analysis model would yield a useful and predictable injury outcome. The final study resulted in predicted and consistent injury outcomes. In the HBO treatment group, a 12% improvement in function 5 days after HBO treatment was demonstrated (P < .03), but no long-term or histological benefit was seen. CONCLUSION: A reliable hypoxic nerve injury model has been developed and tested utilizing two functional methods as the primary outcome variables.

Animals↗

PubMed1993

Follicular development and ovulation in the marmoset monkey as determined by repeated laparoscopic examination.

This paper describes the course of follicular development in vivo in the marmoset monkey, the only anthropoid primate with a relatively high (2-4) and variable ovulation number. Results are presented in relation to predictions from a mathematical model of control of follicle selection and ovulation number. Repeated laparoscopic examinations during the follicular phase were conducted for 14 cycles. Ovulatory follicles were 1.0 mm (median) in diameter at Day 6 and could be distinguished from nonovulatory follicles by Day 8, at which point they were 2.0 mm in diameter. Ovulations were not synchronous; the most common observation 1-2 days after the estradiol peak was ovulation of one follicle but not the other. Examination of the course of follicular development within a cycle and the distribution of ovulation sites both supported predictions stemming from a mathematical model of follicle selection developed by Lacker et al. [Biol Reprod 1987; 37:570-580]. Specific findings were the following: 1) Variations in patterns of follicle growth within a cycle resembled those generated by the model; in 64% of cycles, the 2-3 ovulatory follicles grew at similar rates. However, in 36% of cycles, ovulatory follicles displayed disparate rates of growth. 2) An examination of the distribution of ovulation sites (right versus left) revealed no significant difference from a binomial distribution, suggesting the likelihood that interovarian (rather than intraovarian) factors control this distribution.

Animals↗

PubMed2006

Space-time interaction as an indicator of local spread during the 2001 FMD outbreak in the UK.

During the 2001 FMD outbreak in the UK, decisions on the level of implementation of control measures were supported by predictive models. Models were mainly used as macro-level tools to predict the behaviour of the disease in the whole country rather than at the local level. Here we explore the use of the magnitude and characteristics of the space-time interaction as an indicator of local spread and, indirectly, of the effectiveness of control measures aimed at reducing short-range transmission during the course of a major livestock disease epidemic. The spatiotemporal evolution patterns are described in the four main clusters that were observed during the outbreak by means of the hazard rate and space-time K-function (K(s,t)). For each local outbreak, the relative measure D(0)(s,t), derived from K(s,t), which represents the excess risk attributable to the space-time interaction was calculated for consecutive 20-day temporal windows to represent the dynamics of the space-time interaction. The dynamics of the spatiotemporal interaction were very different among the four local clusters, suggesting that the intensity of local spread, and therefore the effectiveness of control measures, markedly differed between local outbreaks. The large heterogeneity observed in the relative impact of being close in time and space to an infected premises suggests that the decision making in relation to control of the outbreak would have benefited from indicators of local spread which could be used to complement global predictive modelling results. Despite its limitations, our results suggest that the real-time analysis of the space-time interaction can be a valuable decision support tool during the course of a livestock disease epidemic.

Animals↗

PubMed2026

Deep generative models in biological sequence and structure analysis and design.

Deep generative models have transformed biological sequence modeling from predictive analysis toward increasingly controllable design. Early biological applications of Variational Autoencoders (VAEs) and Generative Adversarial Networks (GANs) established latent representation learning and sequence synthesis, while recent advances in transformer-based language models, discrete diffusion, flow-matching, and multimodal generative frameworks have substantially expanded the scope of biological design. This review examines generative models for DNA, RNA, and protein sequence design, emphasizing how different model classes represent biological constraints, operate over discrete and continuous spaces, and integrate sequence, structure, and function. We compare VAEs, GANs, autoregressive and masked language models, diffusion models, and flow-based approaches across genomics, transcriptomics, and proteomics, with particular attention to controllability, long-range dependency modeling, structural grounding, generalization, and experimental utility. We further examine evaluation strategies, out-of-distribution generalization, and closed-loop design-build-test-learn workflows that connect in silico generation with empirical validation. We distinguish fundamental modality-dependent constraints including sequence discreteness, context length, structural coupling, and physical or thermodynamic requirements from architecture-dependent advantages that reflect the current state of the field. Current studies suggest that long-context models are particularly useful for genome-scale representation and sequence modeling, whereas structure-aware diffusion, flow-based, and inverse-folding approaches provide better frameworks for geometry-constrained RNA and protein design. This perspective provides a critical framework for understanding the present capabilities, limitations, and convergence of generative approaches toward reliable and experimentally grounded biological design.

Biological sequence analysis↗

PubMed2006

Evolution of oxygen and glucose concentration profiles in a tissue-mimetic culture system of embryonic stem cells.

A tissue-mimetic culture system (TMCS) in which cells are sandwiched between two glass slides provides an ideal microenvironment for studying the effects of oxygen and nutrient gradients on cells in culture. A mathematical model was utilized to predict the time course of the development of oxygen and glucose concentration gradients within the TMCS. Oxygen and glucose consumption rates of mouse embryonic stem cells were measured as parameters for the model. The model predicts oxygen and glucose concentration profiles directly using a single experimentally controlled variable, the seeding density of cells within the system. The model predicts that the time required for the gradients to reach steady state is inversely related to the cell density, and the penetration depth of the gradients into the TMCS is inversely related to the square root of the cell density. Experimental oxygen concentration measurements were performed at a cell density of 9.1 x 10(6) cells cm(-3), and the gradient was found to develop to a steady-state profile within 20 min and penetrate approximately 2 mm into the TMCS, consistent with the theoretical predictions. This model and the TMCS provide useful tools for investigating the effect of the metabolic microenvironment on cells in culture.

Animals↗

PubMed1999

Genetic control of trichome branch number in Arabidopsis: the roles of the FURCA loci.

We are using trichome (hair) morphogenesis as a model to study how plant cell shape is controlled. During a screen for new mutations that affect trichome branch initiation in Arabidopsis, we identified seven new mutants that show a reduction in trichome branch number from three branches to two. These mutations were named furca, after the Latin word for two-pronged fork. These seven recessive mutations were placed into four complementation groups that define four new genes: FURCA1, FURCA2, FURCA3 and FURCA4. The trichome branch number phenotype indicates that the FURCA genes encode positive regulators of trichome branch initiation. Analysis of double mutants suggests that primary and secondary branch initiation events are not genetically distinct, but rely on the levels of partially redundant groups of regulators of trichome branch initiation. Based on the analysis of both epistatic and additive genetic interactions between the FURCA genes and other genes that control trichome branch number, we propose a model that explains how these genes interact to control trichome branch initiation. This model successfully predicts the phenotypes of all the single and double mutants examined and suggests points of control of the trichome branch pathway.

Arabidopsis↗

PubMed1988

A domain model for eukaryotic DNA organization: a molecular basis for cell differentiation and chromosome evolution.

A model for eukaryotic chromatin organization is presented in which the basic structural and functional unit is the DNA domain. This simple model predicts that both chromosome replication and cell type-specific control of gene expression depend on a combination of stable and dynamic DNA-nuclear matrix interactions. The model suggests that in eukaryotes, DNA regulatory processes are controlled mainly by the intranuclear compartmentalization of the specific DNA sequences, and that control of gene expression involves multiple steps of specific DNA-nuclear matrix interactions. Predictions of the model are tested using available biochemical, molecular and cell biological data. In addition, the domain model is discussed as a simple molecular mechanism to explain cell differentiation in multi-cellular organisms and to explain the evolution of eukaryotic genomes consisting mainly of repetitive sequences and "junk" DNA.

Animals↗

PubMed1999

Lineage selection and the evolution of multistage carcinogenesis.

A wide array of proto-oncogenes and tumour suppressor genes are involved in the prevention of cancer. Each form of cancer requires mutations in a characteristic group of genes, but no single group controls all cancers. This lack of generality shows that the control of cancer is not an ancient, fixed property of cells. By contrast, it supports a dynamic evolutionary model, whereby genetic controls over unregulated cell growth are recruited independently through evolutionary time in different tissues within different taxa. The complexity of this genetic control can be predicted from a population genetic model of lineage selection driven by the detrimental fitness effects of cancer. Cancer occurs because the genetic control of cell growth is vulnerable to somatic mutations (or 'hits'), particularly in large, continuously dividing tissues. Thus, compared to small rodents, humans must have evolved more complex genetic controls over cell growth in at least some of their tissues because of their greater size and longevity; an expectation relevant to the application of mouse data to humans. Similarly, the 'two-hit' model so successfully applied to retinoblastoma, which originates in a small embryonic tissue, is unlikely to be generally applicable to other human cancers; instead, more complex scenarios are expected to dominate, with complexity depending upon a tissue's size and its pattern of proliferation.

Animals↗

PubMed1996

Unstable radii in muscular blood vessels.

A model of a muscular blood vessel in equilibrium that predicts stable and unstable control of radius is presented. The equilibrium wall tension is modeled as the sum of a passive exponential function of radius and an active parabolic function of radius. The magnitude of the active tension is varied to simulate the variable level of smooth muscle activation. This tension-radius relationship is then converted to an equilibrium pressure-radius relationship via Laplace's law. This model predicts the traditional ability to control the radius below a critical level of activation. However, when the active tension is raised above this critical level, the pressure-radius relationship (with pressure plotted on the ordinate and radius on the abscissa) becomes N shaped with a relative maximal pressure (Pmax) and a relative minimal pressure (Pmin). For this N-shaped curve, there are three equilibrium radii for any pressure between Pmin and Pmax. Analysis shows that the middle radius is unstable and thus cannot be maintained at equilibrium. Previously unexplained experimental data reveal evidence of this instability.

Animals↗

PubMed2002

Modeling cerebellar flocculus and paraflocculus involvement in complex predictive smooth eye pursuit in monkeys.

The role of flocculus and paraflocculus neurons in the cerebellar control of predictive eye movements was examined using two modeling techniques. The first study characterized the dependence of individual Purkinje-cell firing patterns on oculomotor output, visual input, and response timing using multilinear regression techniques. Interestingly, no dependence on visual input was detected. Purkinje cell firing was explained by sensitivities to eye position and eye velocity alone. However, complex responses occurred when sensitivity vectors pointed in different directions. For example, some neurons showed a preference for circular pursuit in a particular rotation direction. Responses also tended to lead the eye during predictable pursuit and to lag during unpredictable, visually driven pursuit. This suggests that flocculus and paraflocculus neurons played a stronger role during predictive pursuit than visually driven pursuit. A second modeling study demonstrated how the flocculus/paraflocculus system might generate predictive pursuit. A biologically realistic neural network was simulated based on the known anatomy and physiology of this cerebellar system. It included mossy and climbing fibers with realistic responses, Purkinje cells acting on well-characterized brain-stem circuits, and granule, Golgi, basket, and stellate cells with appropriate connections. The network was able to learn new pursuit trajectories based on long-term alterations in synaptic connectivity at parallel-to-Purkinje synapses. Interestingly, this model was able to generate predictive pursuit without visual input based only on eye-motion input. Thus, both models provide complementary evidence for the generation of nonvisual predictive control by flocculus and paraflocculus neurons.

Animals↗

PubMed1998

Enhancing management of cancer pain: contribution of the internal working model.

The purpose of this article is to organize the current knowledge regarding patient-related factors that can have an impact on cancer pain management by using the construct of the internal working model: a theoretical framework for integrating current knowledge and interpreting and predicting factors related to the management of cancer pain. These factors include patients' beliefs and misconceptions about cancer pain and pain treatment, meanings that patients ascribe to their pain, their expectations about pain relief, and communication between patients and clinicians about pain control. The construct of the internal working model predicts and explains factors related to pain control and provides implications for practice. It has potential utility in enhancing the quality of cancer pain management.

Attitude to Health↗

PubMed2005

The enigma of Mayer waves: Facts and models.

Mayer waves are oscillations of arterial pressure occurring spontaneously in conscious subjects at a frequency lower than respiration (approximately 0.1 Hz in humans). Mayer waves are tightly coupled with synchronous oscillations of efferent sympathetic nervous activity and are almost invariably enhanced during states of sympathetic activation. For this reason, the amplitude of these oscillations has been proposed as a surrogate measure of sympathetic activity, although in the absence of a clear knowledge of their underlying physiology. Some studies have suggested that Mayer waves result from the activity of an endogenous oscillator located either in the brainstem or in the spinal cord. Other studies, mainly based on the effects of sinoaortic baroreceptor denervation, have challenged this view. Several models of dynamic arterial pressure control have been developed to predict Mayer waves. In these models, it was anticipated that the numerous dynamic components and fixed time delays present in the baroreflex loop would result in the production of a resonant, self-sustained oscillation of arterial pressure. Recent analysis of the various transfer functions of the rat baroreceptor reflex suggests that Mayer waves are transient oscillatory responses to hemodynamic perturbations rather than true feedback oscillations. Within this frame, the amplitude of Mayer waves would be determined both by the strength of the triggering perturbations and the sensitivity of the sympathetic component of the baroreceptor reflex.

Animals↗

PubMed2005

Modeling the dry-weather tidal cycling of fecal indicator bacteria in surface waters of an intertidal wetland.

Recreational water quality at beaches in California and elsewhere is often poor near the outlets of rivers, estuaries, and lagoons. This condition has prompted interest in the role of wetlands in modulating surface water concentrations of fecal indicator bacteria (FIB), the basis of water quality standards internationally. A model was developed and applied to predict the dry-weather tidal cycling of FIB in Talbert Marsh, an estuarine, intertidal wetland in Huntington Beach, California, in response to loads from urban runoff, bird feces, and resuspended sediments. The model predicts the advection, dispersion and die-off of total coliform, Escherichia coli, and enterococci using a depth-integrated formulation. We find that urban runoff and resuspension of contaminated wetland sediments are responsible for surface water concentrations of FIB in the wetland. Model predictions show that urban runoff controls surface water concentrations at inland sites and sediment resuspension controls surface water concentrations near the mouth. Direct wash-off of bird feces into the surface water is not a significant contributor, although bird feces can contribute to the sediment bacteria load. The key parameters needed to accurately predict FIB concentrations, using a validated hydrodynamic model, are: the load due to urban runoff, sediment erodibility parameters, and sediment concentrations and surface water die-off rates of enteric bacteria. In the present study, literature values for sediment erodibility and water column die-off rates are used and average concentrations of FIB are predicted within 1/2 log unit of measurements. Total coliform are predicted more accurately than E. coli or enterococci, both in terms of magnitude and tidal variability. Since wetland-dependent animals are natural sources of FIB, and FIB survive for long periods of time and may multiply in wetland sediments, these results highlight limitations of FIB as indicators of human fecal pollution in and near wetlands.

California↗

PubMed2002

Development of a GPC-based sliding mode controller.

This article presents a sliding mode controller that uses a generalized predictive controller in the reaching mode. The proposed predictive sliding mode controller is developed from a first-order-plus-deadtime model that represents a good approximation to many chemical processes. The predictive sliding mode controller has six tuning parameters and the tuning rules are given in the paper. Four simulation examples show the features of the proposed controller, which overcomes some of the disadvantages of sliding mode control and generalized predictive control strategies.

Algorithms↗

PubMed2005

Interaction between surgical procedure for repairing retinal detachment and clinical risk factors for proliferative vitreoretinopathy.

PURPOSE: To asses risk factors of proliferative vitreoretinopathy (PVR) and a model for predicting it. METHODS: Observational, case-control. 335 patients with non-complicated retinal detachment (RD) were included: 134 developed PVR (Cases); 201 patients did not (Controls). Risk factors for PVR were identified by multivariate analysis. Influence of variables was assayed according to the surgical approach. By logistic regression analysis a model to predict the risk of developing PVR and odds ratio (OR) values for each clinical factor were estimated. RESULTS: Risk was higher in patients > 70 years and with intraocular pressure lower than 14 (OR: 3.84; CI 95%: 2.04-7.30) and in retinal breaks larger than "1 clock hour" (OR: 2.54; CI: 1.28-5.05), extended retinal detachments (OR: 4.01; CI: 1.98-8.10) and reinterventions (OR: 1.55; CI: 1.14-9.22). Scleral surgery also was a risk factor (OR: 3.89; CI: 2.12-7.14) and aphakia/pseudophakia when scleral surgery is performed (OR: 3.33; CI: 1.54-7.22). A model to predict PVR was proposed with these results. CONCLUSIONS: Surgical approach modifies risk factors of PVR, and should be taken into account to improve the models for predicting it.

Adolescent↗

PubMed2002

A model of scale effects in mammalian quadrupedal running.

Although the effects of body size on mammalian locomotion are well documented, the underlying mechanisms are not fully understood. Here, we present a computational model of the mechanics, control and energetics that unifies some well-known scale effects in running quadrupeds. The model consists of dynamic, physics-based simulations of six running mammals ranging in size from a chipmunk to a horse (0.115-676 kg). The 'virtual animals' are made up of rigid segments (head, trunk and four legs) linked by joints and are similar in morphology to particular species. In the model, each stance limb acts as a spring operating within a narrow range of stiffness, forward motion is powered and controlled by active hip and shoulder torques, and metabolic cost is predicted from the time course of supporting body weight. Model parameters that are important for stability (joint stiffnesses, limb-retraction times and target positions and velocities of the limbs) are selected such that (i) running kinematics (aerial height, forward speed and body pitch) is smooth and periodic and (ii) overall leg stiffness is in agreement with published data. Both trotting and galloping gaits are modeled, and comparisons across size are made at speeds that are physiologically similar among species. Model predictions are in agreement with data on vertical stiffness, limb angles, metabolic cost of transport, stride frequency, peak force and duty factor. This work supports the idea that a single, integrative model can predict important features of running across size by employing simple strategies to control overall leg stiffness. More broadly, the model provides a quantitative framework for testing hypotheses that relate limb control, stability and metabolic cost.

Animals↗

PubMed2000

Regulation of herpesvirus replication by subcellular compartmentalization.

The transcriptional regulation of herpesvirus gene expression has been well documented. A second model is proposed that is superimposed on regulation at the transcriptional level. The regulation is post-translational in nature. Three examples of the model are found in viral DNA replication, capsid assembly, and the cleavage and packaging of DNA into capsids. For each example, at least one viral protein depends upon an interaction with a second viral protein for transport into the nucleus. A model is proposed whereby these protein-protein interactions control the efficiency of these processes by the formation of the appropriate protein complexes in the cytoplasm. The model predicts that these interactions impose a necessary control and that mechanisms to bypass this control would deleteriously affect virus replication. It is probable that level of regulation extends for each of these processes among other herpesviruses.

DNA, Viral↗