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Immune networks: multi-tasking capabilities at medium load

Associative network models featuring multi-tasking properties have been introduced recently and studied in the low load regime, where the number $P$ of simultaneously retrievable patterns scales with the number $N$ of nodes as $P\sim \log N$. In addition to their relevance in artificial intelligence, these models are increasingly important in immunology, where stored patterns represent strategies to fight pathogens and nodes represent lymphocyte clones. They allow us to understand the crucial ability of the immune system to respond simultaneously to multiple distinct antigen invasions. Here we develop further the statistical mechanical analysis of such systems, by studying the medium load regime, $P \sim N^δ$ with $δ\in (0,1]$. We derive three main results. First, we reveal the nontrivial architecture of these networks: they exhibit a high degree of modularity and clustering, which is linked to their retrieval abilities. Second, by solving the model we demonstrate for $δ<1$ the existence of large regions in the phase diagram where the network can retrieve all stored patterns simultaneously. Finally, in the high load regime $δ=1$ we find that the system behaves as a spin glass, suggesting that finite-connectivity frameworks are required to achieve effective retrieval.

cond-mat.dis-nn↗

Naturally Occurring Genetic Variation Influences the Severity of Drosophila Eye Degeneration Induced by Expression of a Mutant Human Insulin Gene

Dominant negative mutations in the insulin gene are the second most common cause of permanent neonatal diabetes. However, variation in severity and penetrance of neonatal diabetes, as in other complex genetic diseases, cannot be accounted for by known disease mutations. In a novel approach to this problem, we have utilized the genetic tools available in Drosophila to model the effects of the C96Y mutation, a cysteine to tyrosine mutation in the insulin protein that can cause permanent neonatal diabetes in humans. This mutation, which disrupts a disulfide bridge in the proinsulin molecule, has been shown to lead to partial protein unfolding and aggregation in the endoplasmic reticulum. It is thought to induce beta cell death in humans and mice through endoplasmic reticulum stress-mediated apoptosis. We employed the UAS/GAL4 system to create a stable fly laboratory stock expressing human insulin with the C96Y mutation (INSC96Y) in the Drosophila eye. We crossed these transgenic INSC96Y flies to 36 isogenic lines derived from a wild population. The F1 flies displayed a disrupted eye development phenotype, with both reduced eye size and irregularity in ommatidia, which varied between lines and with sex. By backcrossing F1 offspring to their wild parents, we were able to analyze the effects of naturally occurring genetic variation on the INSC96Y phenotype in flies both heterozygous and homozygous for wild third chromosomes. We observed significant differences between lines in terms of eye size, eye shape, the presence or absence of lesions, and degree of ommatidial structure present, indicating that an approach that takes into account quantitative variation in the genetic background can yield valuable insights into the phenotypic severity and penetrance of a complex genetic disease.

q-bio.PE↗

How Uncertainty bounds the shape index of simple cells

We propose a theoretical motivation to quantify actual physiological features, such as the shape index distributions measured by Jones and Palmer in cats and by Ringach in macaque monkeys. We will adopt the Uncertainty Principle associated to the task of detection of position and orientation as the main tool to provide quantitative bounds on the family of simple cells concretely implemented in primary visual cortex.

q-bio.CB↗

A pathway-based mean-field model for E. coli chemotaxis: Mathematical derivation and Keller-Segel limit

A pathway-based mean-field theory (PBMFT) was recently proposed for E. coli chemotaxis in [G. Si, T. Wu, Q. Quyang and Y. Tu, Phys. Rev. Lett., 109 (2012), 048101]. In this paper, we derived a new moment system of PBMFT by using the moment closure technique in kinetic theory under the assumption that the methylation level is locally concentrated. The new system is hyperbolic with linear convection terms. Under certain assumptions, the new system can recover the original model. Especially the assumption on the methylation difference made there can be understood explicitly in this new moment system. We obtain the Keller-Segel limit by taking into account the different physical time scales of tumbling, adaptation and the experimental observations. We also present numerical evidence to show the quantitative agreement of the moment system with the individual based E. coli chemotaxis simulator.

q-bio.CB↗

Stem-Like Adaptive Aneuploidy and Cancer Quasispecies

We analyze and reinterpret experimental evidence from the literature to argue for an ability of tumor cells to self-regulate their aneuploidy rate. We conjecture that this ability is mediated by a diversification factor that exploits molecular mechanisms common to embryo stem cells and, to a lesser extent, adult stem cells, that is eventually reactivated in tumor cells. Moreover, we propose a direct use of the quasispecies model to cancer cells based on their significant genomic instability (i.e. aneuploidy rate), by defining master sequences lengths as the sum of all copy numbers of physically distinct whole and fragmented chromosomes. We compute an approximate error threshold such that any aneuploidy rate larger than the threshold would lead to a loss of fitness of a tumor population, and we confirm that highly aneuploid cancer populations already function with aneuploidy rates close to the estimated threshold.

q-bio.CB↗

Epigenetic Tracking: a Model for Multicellular Biology

Epigenetic Tracking is a mathematical model of biological cells, originally conceived to study embryonic development. Computer simulations proved the capacity of the model to generate complex 3-dimensional cellular structures, and the potential to reproduce the complexity typical of living beings. The most distinctive feature of this model is the presence in the body of a homogeneous distribution of stem cells, which are dinamically and continuously created during development from non-stem cells and reside in niches. Embryonic stem cells orchestrate early developmental events, adult stem cells direct late developmental and regeneration events, ageing stem cells cause ageing and cancer stem cells are responsible for cancer growth. The conceptual backbone provided by Epigenetic Tracking brings together a wide range of biological phenomena: for this reason, we think it can be proposed as a general model for multicellular biology. Despite, or perhaps due to its theoretical origin, the model allowed us to make predictions relevant to very diverse fields of biology, such as transposable elements, and cancer-related patterns of gene mutations. This paper contains a summary of the model and its implications.

q-bio.CB↗

Tumor can originate from not only rare cancer stem cells

Tumors are believed to consist of a heterogeneous population of tumor cells originating from rare cancer stem cells (CSCs). However, emerging evidences show that tumor may also originate from non-CSCs. Here, we give evidences supporting that the number of tumorigenic tumor cells is higher than the number of CSCs and tumor can also derive from non-CSCs. First, we applied an idealized mathematical model and theoretically calculated that non-CSCs could initiate tumor if their proliferation potential was adequate. Next, we demonstrated by experimental studies that 17.7%, 38.6% and 5.2% of tumor cells in murine B16 solid melanoma, H22 hepatoma and Lewis lung carcinoma, respectively, were potentially tumorigenic. We propose that the rare CSCs, if exist, are not the only origination of a tumor.

q-bio.CB↗

Quorum sensing inhibitory compounds from extremophilic microorganisms isolated from a hypersaline cyanobacterial mat

In this study extremely halophilic and moderately thermophilic microorganisms from a hypersaline microbial mat were screened for their ability to produce antibacterial, antidiatom, antialgal and quorum sensing (QS) inhibitory compounds. Five bacterial strains belonging to the genera Marinobacter and Halomonas and one archaeal strain belonging to the genus Haloterrigena were isolated from a microbial mat. The strains were able to grow at a maximum salinity of 22-25% and a maximum temperature of 45-60°C. Hexanes, dichloromethane and butanol extracts from the strains inhibited the growth of at least one out of nine human pathogens. Only butanol extracts of supernatants of Halomonas sp. SK-1 inhibited growth of the microalga Dunaliella salina. Most extracts from isolates inhibited QS of the acyl homoserine lactone producer and reporter Chromobacterium violaceum CV017. Purification of QS inhibitory dichloromethane extracts of Marinobacter sp. SK-3 resulted in isolation of four related diketopiperazines (DKPs): cyclo(L-Pro-L-Phe), cyclo(L-Pro-L-Leu), cyclo(L-Pro-L-isoLeu) and cyclo(L-Pro-D-Phe). QS inhibitory properties of these DKPs were tested using C. violaceum CV017 and Escherichia coli-based QS reporters (pSB401 and pSB1075) deficient in AHL production. Cyclo(L-Pro-L-Phe) and cyclo(L-Pro-L-isoLeu) inhibited QS dependent production of violacein by C. violaceum CV017. Cyclo(L-Pro-L-Phe), cyclo(L-Pro-L-Leu), and cyclo(L-Pro-L-isoLeu) reduced QS dependent luminescence of the reporter E. coli pSB401 induced by 3-oxo-C6-HSL. Our study demonstrated the ability of halophilic and moderately thermophilic strains from a hypersaline microbial mat produce biotechnologically-relevant compounds that could be used as antifouling agents

q-bio.CB↗

Vitamin D sensitivity to the immune responses and autoimmunity: A chemical network model study

Although Vitamin D is believed to be involved in a large number of immune responses our understanding of these processes at cellular level remained at infancy. We develop and solve a coarse grained kinetic network model to quantify the effects of variation of vitamin D on human immunity. The system of equations accounts for known inter-relation between active and inactive vitamin D, antigen presenting cells, effector T cells, regulatory T cells and pathogen. Both time dependent and steady state solutions are obtained. The time dependent solution of the system of equations reveals that the immune response is rather strongly regulated in presence of vitamin D. We found quantitatively that lower than optimum levels of concentration of active vitamin D correspond to weak regulation where, once a pathogen/antigen enters the body, the nature of the immune response would be less regulatory and hence more aggressive, or inflammatory. The steady state solution of our model shows that vitamin D enhances the tolerance level of immune system, thereby increasing resistance to autoimmune diseases. Our model and accompanied numerical analyses reveal another important aspect of immunity: While extremely low levels of vitamin D could lead to increased risk of autoimmune responses, an overdose (toxic) level would give rise to too large a tolerant response, leading to the increased risk of tumors and cancerous cell growth.

q-bio.MN↗

Retrieving Infinite Numbers of Patterns in a Spin-Glass Model of Immune Networks

The similarity between neural and immune networks has been known for decades, but so far we did not understand the mechanism that allows the immune system, unlike associative neural networks, to recall and execute a large number of memorized defense strategies {\em in parallel}. The explanation turns out to lie in the network topology. Neurons interact typically with a large number of other neurons, whereas interactions among lymphocytes in immune networks are very specific, and described by graphs with finite connectivity. In this paper we use replica techniques to solve a statistical mechanical immune network model with `coordinator branches' (T-cells) and `effector branches' (B-cells), and show how the finite connectivity enables the system to manage an extensive number of immune clones simultaneously, even above the percolation threshold. The system exhibits only weak ergodicity breaking, so that both multiple antigen defense and homeostasis can be accomplished.

cond-mat.dis-nn↗

Modeling the Dichotomy of the Immune Response to Cancer: Cytotoxic Effects and Tumor-Promoting Inflammation

Although the immune response is often regarded as acting to suppress tumor growth, it is now clear that it can be both stimulatory and inhibitory. The interplay between these competing influences has complex implications for tumor development and cancer dormancy. To study this biological phenomenon theoretically we construct a minimally parameterized framework that incorporates all aspects of the immune response. We combine the effects of all immune cell types, general principles of self-limited logistic growth, and the physical process of inflammation into one quantitative setting. Simulations suggest that while there are pro-tumor or antitumor immunogenic responses characterized by larger or smaller final tumor volumes, respectively, each response involves an initial period where tumor growth is stimulated beyond that of growth without an immune response. The mathematical description is non-identifiable which allows us to capture inherent biological variability in tumor growth that can significantly alter tumor-immune dynamics and thus treatment success rates. The ability of this model to predict immunomodulation of tumor growth may offer a template for the design of novel treatment approaches that exploit immune response to improve tumor suppression, including the potential attainment of an immune-induced dormant state.

q-bio.CB↗

Delayed self-regulation leads to novel states in epigenetic landscapes

The epigenetic pathway of a cell as it differentiates from a stem cell state to a mature lineage-committed one has been historically understood in terms of Waddington's landscape, consisting of hills and valleys. The smooth top and valley-strewn bottom of the hill represents their undifferentiated and differentiated states respectively. Although mathematical ideas rooted in nonlinear dynamics and bifurcation theory have been used to quantify this picture, the importance of time delays arising from multistep chemical reactions or cellular shape transformations have been ignored so far. We argue that this feature is crucial in understanding cell differentiation and explore the role of time delay in a model of a single gene regulatory circuit. We show that the interplay of time-dependant drive and delay introduces a new regime where the system shows sustained oscillations between the two admissible steady states. We interpret these results in the light of recent perplexing experiments on inducing the pluripotent state in mouse somatic cells. We also comment on how such an oscillatory state can provide a framework for understanding more general feedback circuits in cell development.

q-bio.CB↗

Lateral migration of living cells in inertial microfluidic systems explored by fully three-dimensional numerical simulation

The effects of cell size and deformability on the lateral migration and deformation of living cells flowing through a rectangular microchannel has been numerically investigated and compared with the inertial-microfluidics data on detection and separation of cells. The results of this work indicate that the cells move closer to the centerline if they are bigger and/or more deformable and that their equilibrium position is largely determined by the solvent (cytosol) viscosity, which is much less than the polymer (cytoskeleton) viscosity measured in most rheological systems. Simulations also suggest that decreasing channel dimensions leads to larger differences in equilibrium position for particles of different viscoelastic properties, giving design guidance for the next generation of microfluidic cell separation chips.

physics.flu-dyn↗

Motor function in interpolar microtubules during metaphase

We analyze experimental observations of microtubules undergoing small fluctuations about a "balance point" when mixed in solution of two different kinesin motor proteins, KLP61F and Ncd. It has been proposed that the microtubule movement is due to stochastic variations in the densities of the two species of motor proteins. We test this hypothesis here by showing how it maps onto a one-dimensional random walk in a random environment. Our estimate of the amplitude of the fluctuations agrees with experimental observations. We point out that there is an initial transient in the position of the microtubule where it will typically move of order its own length. We compare the physics of this gliding assay to a recent theory of the role of antagonistic motors on restricting interpolar microtubule sliding of a cell's mitotic spindle during prometaphase. It is concluded that randomly positioned antagonistic motors can restrict relative movement of microtubules, however they do so imperfectly. A variation in motor concentrations is also analyzed and shown to lead to greater control of spindle length.

q-bio.CB↗

The Cancer Diaspora: Metastasis beyond the seed and soil hypothesis

Do cancer cells escape their confinement of their original habitat in the primary tumor or are they forced out by ecological changes in their home niche? Describing metastasis in terms of a simple one-way migration of cells from the primary to target organs is an insufficient concept to cover the nuances of cancer spread. A diaspora is the scattering of people away from an established homeland. To date, diaspora has been a uniquely human term utilized by social scientists, however, the application of the diaspora concept to metastasis may yield new biological insights as well as therapeutic paradigms. The diaspora paradigm takes into account and models several variables: the quality of the primary tumor microenvironment, the fitness of individual cancer cell migrants as well as migrant populations, the rate of bidirectional migration of cancer and host cells between cancer sites, and the quality of the target microenvironments to establish metastatic sites. Ecological scientific principles can be applied to the cancer diaspora to develop new therapeutic strategies. For example, ecological traps, habitats that lead to the extinction of a species, can be developed to attract cancer cells to a place where they can be better exposed to treatments or to cells of the immune system for improved antigen presentation. Merging the social science concept of diaspora with ecological and population sciences concepts can inform the cancer field to understand the biology of tumorigenesis and metastasis and inspire new ideas for therapy.

q-bio.TO↗

Distinct cell shapes determine accurate chemotaxis

The behaviour of an organism often reflects a strategy for coping with its environment. Such behaviour in higher organisms can often be reduced to a few stereotyped modes of movement due to physiological limitations, but finding such modes in amoeboid cells is more difficult as they lack these constraints. Here, we examine cell shape and movement in starved Dictyostelium amoebae during migration toward a chemoattractant in a microfluidic chamber. We show that the incredible variety in amoeboid shape across a population can be reduced to a few modes of variation. Interestingly, cells use distinct modes depending on the applied chemical gradient, with specific cell shapes associated with shallow, difficult-to-sense gradients. Modelling and drug treatment reveals that these behaviours are intrinsically linked with accurate sensing at the physical limit. Since similar behaviours are observed in a diverse range of cell types, we propose that cell shape and behaviour are conserved traits.

q-bio.CB↗

Self tolerance in a minimal model of the idiotypic network

We consider the problem of self tolerance in the frame of a minimalistic model of the idiotypic network. A node of this network represents a population of B lymphocytes of the same idiotype which is encoded by a bit string. The links of the network connect nodes with (nearly) complementary strings. The population of a node survives if the number of occupied neighbours is not too small and not too large. There is an influx of lymphocytes with random idiotype from the bone marrow. Previous investigations have shown that this system evolves toward highly organized architectures, where the nodes can be classified into groups according to their statistical properties. The building principles of these architectures can be analytically described and the statistical results of simulations agree very well with results of a modular mean field theory. In this paper we present simulation results for the case that one or several nodes, playing the role of self, are permanently occupied. We observe that the group structure of the architecture is very similar to the case without self antigen, but organized such that the neighbours of the self are only weakly occupied, thus providing self tolerance. We also treat this situation in mean field theory which give results in good agreement with data from simulation.

q-bio.CB↗

Viscoelastic Properties of Vascular Endothelial Cells Exposed to Stretch

In this paper, we study how cytoskeletal remodeling is correlated to changes in subcellular microrheology. We analyze the changes in the magnitude and directionality of the shear and elastic moduli of bovine aortic endothelial cells (BAECs) exposed to cyclical, uniaxial stretch. We find that, when stretched, BAECs stiffen and align their softest direction of mechanical polarization perpendicular to stretch. We hypothesize that the response of VECs to stretch acts to minimize intracellular strain in response to stress.

q-bio.QM↗