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The ability of cells to sense and respond to the mechanical properties of their environments is fundamental to a range of cellular behaviours, with substrate stiffness increasingly being found to be a key signalling factor. Although active contractility of the cytoskeleton is clearly necessary for stiffness sensing in cells, the physical mechanisms connecting contractility with mechanosensing and molecular conformational change are not well understood. Here we present a contractility-driven mechanism for linking changes in substrate stiffness with internal conformational changes. Cellular contractility is often assumed to imply an associated compressive strain. We show, however, that where the contractility is non-uniform, localized areas of internal stretch can be generated as stiffer substrates are encountered. This suggests a physical mechanism for the stretch-activation of mechanotransductive molecules on stiffer substrates. Importantly, the areas of internal stretch occur deep within the cell and not near the cellular perimeter, which region is more traditionally associated with stiffness sensing through e.g. focal adhesions. This supports recent experimental results on whole-cell mechanically-driven mechanotransduction. Considering cellular shape we show that aspect ratio acts as an additional control parameter, so that the onset of positive strain moves to higher stiffness values in elliptical cells.

International audience; Collective motion of chemotactic bacteria as E. Coli relies, at the individual level, on a continuous reorientation by runs and tumbles. It has been established that the length of run is decided by a stiff response to a temporal sensingof chemical cues along the pathway.We describe a novel mechanism for pattern formation stemming from the stiffness of chemotactic response relying on a kinetic chemotaxis model which includes a recently discovered formalism for the bacterial chemotaxis. We prove instability both for amicroscopic description in the space-velocity space and for the macroscopic equation, a flux-limited Keller-Segel equation, which has attracted much attention recently.A remarkable property is that the unstable frequencies remain bounded, as it is the case in Turing instability. Numerical illustrations based on a powerful Monte Carlo method show that the stationary homogeneous state of population density isdestabilized and periodic patterns are generated in realistic ranges of parameters. These theoretical developments are in accordance with several biological observations.

In August 2013, the French pharmacopoeia was enriched with 43 plants used in French overseas territories, including 15 proposed by APLAMEDAROM association of Guadeloupe. However, for most of them, no data on the chemical composition, qualitatively and quantitatively is available in the literature for these specimens; this is an issue to their commercialization in dispensary, pharmacists wishing to know their composition in order to avoid the problems of dosage and drug interactions. Among these plants, Phyllanthus amarus Schum. \& Thonn. (1827), commonly called 'Grenn anba f{��}y' [1], is well known for its potent medicinal properties especially hepatoprotective, antidiabetic, antiviral (flu), anti-inflammatory, anti-cholesterol [2]. In Guadeloupe, this plant is generally used freshly harvested in infusion but also in aqueous decoction [3]. Besides, these studies are conducted in association with APLAMEDAROM association in order to identify the polar constituents and then to understand better the origin of the observed properties. Therefore, using UHPLC-MS, we were able to identify the presence of bioactive polyphenolic compounds, including phyllanthin, rutin and gallic acid. Phyllanthin, characteristic of the specie, is a very active lignan with high antioxidant, hepatoprotective and anticancer properties [2]. Rutin is known for its antioxidant and anti-hypertensive properties [2]. Gallic acid is distinguished by antioxidant, anti-inflammatory, antidiabetic, antiviral and anticancer properties and has the advantage of being a bioavailable compound. Similarly, many compounds never listed to date in this specie were also highlighted and are currently purified., in French

Eshel Ben-Jacob, one of the co-organizers of this meeting on collective behavior and one of the pioneers in the field of collective behavior in biology, passed away suddenly just before we convened. This article presents a brief glimpse of Eshel's life-long path through science, seen from the perspective of a decades long collaboration on many disparate yet ultimately connected topics. The article attempts to convey how the concept of self-organization of complex interacting objects into higher order functional units, as evidenced so wonderfully by Eshel's experiments on bacterial colony formation, provides a unifying theme for the study of collective behavior. Our entire field will miss his unique ability to "let the complex become simple"., Comment: based on a meeting talk in June 2015; published in Landscapes of Collectivity, MIT Press https://mitpress.mit.edu/books/landscapes-collectivity-life-sciences

Recurrence and metastasis have been regarded as two of the greatest obstacles for curing cancer. Cancer stem cell (CSC) have been found. They contribute to cancer development with the distinct feature of recurrence and resistance to the popular treatments such as drugs and chemotherapy. In addition, recent discoveries suggest that the epithelial mesenchymal transition (EMT) is an essential process in normal embryogenesis and tissue repair, which is a required step in cancer metastasis. Although there are many indications showing the connections between metastasis and stem cell, researches often studied them separately or at most bi-laterally, not in an integrated way. In this study, we aim at exploring the global mechanisms and interrelationship among cancer, development and metastasis which are currently poorly understood. To start, we constructed a core gene regulatory network motif which contain specific genes and microRNAs of CSC, EMT and cancer. We uncovered seven distinct states emerged from the underlying landscape. They are identified as Normal, Premalignant, Cancer, stem cell (SC), cancer stem cell (CSC), Lesion and Hyperlasia state. Given the biological definition of each state, we also discussed the metastasis ability of each state. We show how and which types of cells can be transformed to a cancer state and the connections among cancer, CSC and EMT. The barrier height and flux of the kinetic paths are explored to quantify how and which cells switch stochastically between the states. Our landscape model provides a quantitative way which reveals the global mechanisms of cancer, development and metastasis., Comment: 6 figures,9 pages

Microbial growth and division are fundamental processes relevant to many areas of life science. Of particular interest are homeostasis mechanisms, which buffer growth and division from accumulating fluctuations over multiple cycles. These mechanisms operate within single cells, possibly extending over several division cycles. However, all experimental studies to date have relied on measurements pooled from many distinct cells. Here, we disentangle long-term measured traces of individual cells from one another, revealing subtle differences between temporal and pooled statistics. By analyzing correlations along up to hundreds of generations, we find that the parameter describing effective cell-size homeostasis strength varies significantly among cells. At the same time, we find an invariant cell size which acts as an attractor to all individual traces, albeit with different effective attractive forces. Despite the common attractor, each cell maintains a distinct average size over its finite lifetime with suppressed temporal fluctuations around it, and equilibration to the global average size is surprisingly slow (> 150 cell cycles). To demonstrate a possible source of variable homeostasis strength, we construct a mathematical model relying on intracellular interactions, which integrates measured properties of cell size with those of highly expressed proteins. Effective homeostasis strength is then influenced by interactions and by noise levels, and generally varies among cells. A predictable and measurable consequence of variable homeostasis strength appears as distinct oscillatory patterns in cell size and protein content over many generations. We discuss the implications of our results to understanding mechanisms controlling division in single cells and their characteristic timescales, In press with PNAS. 50 pages, including supplementary information

Chemotaxis is a ubiquitous biological phenomenon in which cells detect a spatial gradient of chemoattractant, and then move towards the source. Here we present a position-dependent advection-diffusion model that quantitatively describes the statistical features of the chemotactic motion of the social amoeba {\it Dictyostelium discoideum} in a linear gradient of cAMP (cyclic adenosine monophosphate). We fit the model to experimental trajectories that are recorded in a microfluidic setup with stationary cAMP gradients and extract the diffusion and drift coefficients in the gradient direction. Our analysis shows that for the majority of gradients, both coefficients decrease in time and become negative as the cells crawl up the gradient. The extracted model parameters also show that besides the expected drift in the direction of chemoattractant gradient, we observe a nonlinear dependency of the corresponding variance in time, which can be explained by the model. Furthermore, the results of the model show that the non-linear term in the mean squared displacement of the cell trajectories can dominate the linear term on large time scales.

Rapid changes in extracellular osmolarity are one of many insults microbial cells face on a daily basis. To protect against such shocks,Escherichia coliand other microbes express several types of transmembrane channels which open and close in response to changes in membrane tension. InE. coli, one of the most abundant channels is the mechanosensitive channel of large conductance (MscL). While this channel has been heavily characterized through structural methods, electrophysiology, and theoretical modeling, our understanding of its physiological role in preventing cell death by alleviating high membrane tension remains tenuous. In this work, we examine the contribution of MscL alone to cell survival after osmotic shock at single cell resolution using quantitative fluorescence microscopy. We conduct these experiments in anE. colistrain which is lacking all mechanosensitive channel genes save for MscL whose expression is tuned across three orders of magnitude through modifications of the Shine-Dalgarno sequence. While theoretical models suggest that only a few MscL channels would be needed to alleviate even large changes in osmotic pressure, we find that between 500 and 700 channels per cell are needed to convey upwards of 80% survival. This number agrees with the average MscL copy number measured in wild-typeE. colicells through proteomic studies and quantitative Western blotting. Furthermore, we observe zero survival events in cells with less than 100 channels per cell. This work opens new questions concerning the contribution of other mechanosensitive channels to survival as well as regulation of their activity.

In pancreatic $��$-cells, calcium oscillation signal is the core part of glucose-stimulated insulin secretion. Intracellular calcium concentration oscillates in response to the intake of glucose, which triggers the exocytosis of insulin secretory granules. ATP plays a crucial part in this process. ATP increases as the result of glucose intake, then ATP binds to ATP-sensitive $K^+$ channels ($K_{ATP}$), depolarizes the cell and triggers calcium oscillation, while the ion pumps on the cell membrane consumes the free energy form ATP hydrolysis. Based on Betram et. al. 2004 model, we construct a kinetic models to analyze the thermodynamic characteristics of this system, to reveal how the ATP hydrolysis free energy affects the calcium oscillation. Our results suggest that bifurcation point is sensitive to both the free energy level and cellular ATP level, and the insufficient ATP energy supply would cause dysfunction of calcium oscillation., 12 pages, 7 figures

Mechanical strain and stress play a major role in biological processes such as wound healing or morphogenesis. To assess this role quantitatively, fixed or live images of tissues are acquired at a cellular precision in large fields of views. To exploit these data, large numbers of cells have to be analyzed to extract cell shape anisotropy and cell size. Most frequently, this is performed through detailed individual cell contour determination, using so-called segmentation computer programs, complemented if necessary by manual detection and error corrections. However, a coarse grained and faster technique can be recommended in at least three situations. First, when detailed information on individual cell contours is not required, for instance in studies which require only coarse-grained average information on cell anisotropy. Second, as an exploratory step to determine whether full segmentation can be potentially useful. Third, when segmentation is too difficult, for instance due to poor image quality or too large a cell number. We developed a user-friendly, Fourier transform-based image analysis pipeline. It is fast (typically $10^4$ cells per minute with a current laptop computer) and suitable for time, space or ensemble averages. We validate it on one set of artificial images and on two sets of fully segmented images, one from a Drosophila pupa and the other from a chicken embryo; the pipeline results are robust. Perspectives include \textit{in vitro} tissues, non-biological cellular patterns such as foams, and $xyz$ stacks., Comment: 13 pages; 9 figures

Experiments and simulations have established that dynamics in a class of living and abiotic systems that are far from equilibrium exhibit super diffusive behavior at long times, which in some cases (for example evolving tumor) is preceded by slow glass-like dynamics. By using the evolution of a collection of tumor cells, driven by mechanical forces and subject to cell birth and apoptosis, as a case study we show theoretically that on short time scales the mean square displacement is sub-diffusive due to jamming, whereas at long times it is super diffusive. The results obtained using stochastic quantization method, which is needed because of the absence of fluctuation-dissipation theorem (FDT), show that the super-diffusive behavior is universal and impervious to the nature of cell-cell interactions. Surprisingly, the theory also quantitatively accounts for the non-trivial dynamics observed in simulations of a model soap foam characterized by creation and destruction of spherical bubbles, which suggests that the two non-equilibrium systems belong to the same universality class. The theoretical prediction for the super diffusion exponent is in excellent agreement with simulations for collective motion of tumor cells and dynamics associated with soap bubbles.

The motility mechanism of certain rod-shaped bacteria has long been a mystery, since no external appendages are involved in their motion which is known as gliding. However, the physical principles behind gliding motility still remain poorly understood. Using myxobacteria as a canonical example of such organisms, we identify here the physical principles behind gliding motility, and develop a theoretical model that predicts a two-regime behavior of the gliding speed as a function of the substrate stiffness. Our theory describes the elastic, viscous, and capillary interactions between the bacterial membrane carrying a traveling wave, the secreted slime acting as a lubricating film, and the substrate which we model as a soft solid. Defining the myxobacterial gliding as the horizontal motion on the substrate under zero net force, we find the two-regime behavior is due to two different mechanisms of motility thrust. On stiff substrates, the thrust arises from the bacterial shape deformations creating a flow of slime that exerts a pressure along the bacterial length. This pressure in conjunction with the bacterial shape provides the necessary thrust for propulsion. However, we show that such a mechanism cannot lead to gliding on very soft substrates. Instead, we show that capillary effects lead to the formation of a ridge at the slime-substrate-air interface, which creates a thrust in the form of a localized pressure gradient at the tip of the bacteria. To test our theory, we perform experiments with isolated cells on agar substrates of varying stiffness and find the measured gliding speeds to be in good agreement with the predictions from our elasto-capillary-hydrodynamic model. The physical mechanisms reported here serve as an important step towards an accurate theory of friction and substrate-mediated interaction between bacteria in a swarm of cells proliferating in soft media., Comment: Main article (8 pages and 8 figures) and Supplementary Information

Contact inhibition is a cell property that limits the migration and proliferation of cells in crowded environments. Here we investigate the growth dynamics of a cell colony composed of migrating and proliferating cells on a substrate using a minimal model that incorporates the mechanisms of contact inhibition of locomotion and proliferation. We find two distinct regimes. At early times, when contact inhibition is weak, the colony grows exponentially in time, fully characterised by the proliferation rate. At long times, the colony boundary moves at a constant speed, determined only by the migration speed of a single cell and independent of the proliferation rate. Further, the model demonstrates how cell-cell alignment speeds up colony growth. Our model illuminates how simple local mechanical interactions give rise to contact inhibition, and from this, how cell colony growth is self-organised and controlled on a local level.

Lymphomas are a large group of neoplasms developed from lymphoid cells (LCs) in lymph nodes (LNs) or lymphoid tissues (LTs). Some forms of lymphomas, including Burkitt lymphoma (BL), ALK+ anaplastic large cell lymphoma (ALK+-ALCL), and T-cell lymphoblastic lymphoma/leukemia (T-LBL), occur mainly in children and teenagers. Hodgkin's lymphoma (HL) has a peak incidence at age 20s. To understand pediatric lymphoma, we have recently proposed two hypotheses on the causes and the mechanism of cell transformation of a LC. Hypothesis A is: repeated bone-remodeling during bone-growth and bone-repair may be a source of cell injuries of marrow cells including hematopoietic stem cells (HSCs), myeloid cells, and LCs, and thymic involution may be a source of damage to the developing T-cells in thymus. Hypothesis B is: a LC may have three pathways on transformation: a slow, a rapid, and an accelerated. In this paper, we discuss pediatric lymphomas by this hypothesis. Having a peak incidence at young age, BL, T-LBL, ALK+-ALCL, and HL develop more likely as a result of rapid transformation of a LC. In BL, ALK+-ALCL, and HL, the cell transformations may be triggered by severe viral infections. In T-LBL, the cell transformation may be related to thymic involution. Occurring in both adults and children, diffuse large B-cell lymphoma (DLBCL) may develop via slow or accelerated pathway. In conclusion, pediatric lymphoma may develop as a result of "one-step" cell transformation of a LC, and severe viral infections may be the main trigger for the rapid transformation of a LC in a LN/LT., Comment: 28 pages, 2 figures

We develop a modeling and simulation framework capable of massively parallel simulation of multicellular systems with spatially resolved stochastic kinetics in individual cells. By the use of operator-splitting we decouple the simulation of reaction-diffusion kinetics inside the cells from the simulation of molecular cell-cell interactions occurring on the boundaries between cells. This decoupling leverages the inherent scale separation in the underlying model to enable highly horizontally scalable parallel simulation, suitable for simulation on heterogeneous, distributed computing infrastructures such as public and private clouds. Thanks to its modular structure, our frameworks makes it possible to couple just any existing single-cell simulation software together with any cell signaling simulator. We exemplify the flexibility and scalability of the framework by using the popular single-cell simulation software eGFRD to construct and simulate a multicellular model of Notch-Delta signaling over OpenStack cloud infrastructure provided by the SNIC Science Cloud., Comment: preprint, 9 pages, 9 figures, submitted to IEEE eScience 2018

Mathematical models are vital interpretive and predictive tools used to assist in the understanding of cell migration. There are typically two approaches to modelling cell migration: either micro-scale, discrete or macro-scale, continuum. The discrete approach, using agent-based models (ABMs), is typically stochastic and accounts for properties at the cell-scale. Conversely, the continuum approach, in which cell density is often modelled as a system of deterministic partial differential equations (PDEs), provides a global description of the migration at the population level. Deterministic models have the advantage that they are generally more amenable to mathematical analysis. They can lead to significant insights for situations in which the system comprises a large number of cells, at which point simulating a stochastic ABM becomes computationally expensive. However, finding an appropriate continuum model to describe the collective behaviour of a system of individual cells can be a difficult task. Deterministic models are often specified on a phenomenological basis, which reduces their predictive power. Stochastic ABMs have advantages over their deterministic continuum counterparts. In particular, ABMs can represent individual-level behaviours (such as cell proliferation and cell-cell interaction) appropriately and are amenable to direct parameterisation using experimental data. It is essential, therefore, to establish direct connections between stochastic micro-scale behaviours and deterministic macro-scale dynamics. In this Chapter we describe how, in some situations, these two distinct modelling approaches can be unified into a discrete-continuum equivalence framework. We provide an overview of some of the more recent advances in this field and we point out some of the relevant questions that remain unanswered.

Only about 8 percent of patients with pancreatic ductal adenocarcinoma, PDAC, live up to 5 years following diagnosis; by 2020 PDAC will become the second most lethal cancer in the United States. PDAC includes an anisotropic fibrous-like stroma, desmoplasia, encompassing most of the tumor mass. Desmoplasia is produced by cancer-associated fibroblasts, CAFs, and their cell-derived extracellular matrices, CDMs. Since elimination of CAFs is detrimental to patients, CDM reprogramming, as opposed to desmoplasia ablation, is therapeutically desirable. In this study we used a human mimetic three-dimensional CAF producing CDM system and proceeded to study its dynamic architectural modifications, following underlying substrate stiffness alterations, using digital imaging analyses, atomic force microscopy, mathematical modeling, cell biology, biochemistry and human tissue quantitative simultaneous multiplex immunofluorescence. Results suggested that the architecture of CDMs can be manipulated to render a tumor-suppressive microenvironment. We posit that perhaps treatments that could reprogram desmoplasia to become tumor-restrictive or that could target tumoral ERK2 might provide future new means for treating PDAC patients., Comment: Main text with 6 figures, 1 table and references, including 5 supplemental figures and legends as well as one supplemental table and a movie legend with corresponding link

The present habilitation thesis in theoretical biological physics addresses two central dynamical processes in cells and organisms: (i) active motility and motility control and (ii) self-organized pattern formation. The unifying theme is the nonlinear dynamics of biological function and its robustness in the presence of strong fluctuations, structural variations, and external perturbations. We theoretically investigate motility control at the cellular scale, using cilia and flagella as ideal model system. Cilia and flagella are highly conserved slender cell appendages that exhibit spontaneous bending waves. This flagellar beat represents a prime example of a chemo-mechanical oscillator, which is driven by the collective dynamics of molecular motors inside the flagellar axoneme. We study the nonlinear dynamics of flagellar swimming, steering, and synchronization, which encompasses shape control of the flagellar beat by chemical signals and mechanical forces. Mechanical forces can synchronize collections of flagella to beat at a common frequency, despite active motor noise that tends to randomize flagellar synchrony. In Chapter 2, we present a new physical mechanism for flagellar synchronization by mechanical self-stabilization that applies to free-swimming flagellated cells. This new mechanism is independent of direct hydrodynamic interactions between flagella. Comparison with experimental data provided by experimental collaboration partners in the laboratory of J. Howard (Yale, New Haven) confirmed our new mechanism in the model organism of the unicellular green alga Chlamydomonas. Further, we characterize the beating flagellum as a noisy oscillator. Using a minimal model of collective motor dynamics, we argue that measured non-equilibrium fluctuations of the flagellar beat result from stochastic motor dynamics at the molecular scale. Noise and mechanical coupling are antagonists ..., Comment: Habilitation thesis, 67 pages, 9 figures, without reprints of journal articles

Diabetic-induced peripheral neuropathy (DPN) is a diabetic late complication. The molecular mechanisms underlying the pathophysiology of nerve damage & sensory loss remain largely unclear. Recently, alterations in metabolic flux have gained attention a basis for organ damage in diabetes; however, peripheral sensory neurons have not been adequately analyzed. In the present study, we attempted to delineate the role of alteration of metabolic pathways in relation to nerve damage & sensory loss. We employed STZ-injected mouse model of type1 diabetes. To investigate the progression of DPN by behavioral measurements of sensitivity to thermal & mechanical stimuli and quantitative assessment of intraepidermal nerve fiber density. We employed a MS-based screen to address alterations in levels of metabolites in peripheral sciatic nerve (SN) & amino acids (AA) in serum over several months post-STZ administration. Although hyperglycemia & body weight changes occurred early, sensory loss & reduced intraepithelial branching of nociceptive nerves was only evident at 22 wks post-STZ. The longitudinal metabolites screen in SN demonstrated that mice at 12 and 22 wks post-STZ showed an early impairment the tricarboxylic acid. We found that levels of citric acid, ketoglutaric acid, succinic acid, fumaric acid & malic acid were observed to be significantly reduced in SN at 22 wks post-STZ. In addition, we also found the increase in levels of sorbitol & L-Lactate in SN from 12 wks post-STZ injection. AA screen in serum showed that the amino acids Val, Ile and Leu, increased more than 2-fold from 12 wks post-STZ. Similarly, the levels of Tyr, Asn, Ser, His, Ala, & Pro showed progressive increase. Our results indicate that the impaired TCA cycle metabolites in peripheral nerve is the primary cause of shunting metabolic substrate to compensatory pathways which leads to mitochondrial dysfunction & nerve damage., 17 pages, 3 figures

Members of the large family of Hox transcription factors are encoded by genes whose tightly regulated expression in development and in space within different embryonic tissues confer positional identity from the neck to the tips of the limbs. Many structures of the face, head, and heart10 develop from cell populations expressing few or no Hox genes. Hoxb1 is the member of its chromosomal cluster expressed in the most rostral domain during vertebrate development, but never by the multipotent neural crest cell population anterior to the cerebellum. We have developed a novel floxed transgenic mouse line, CAG-Hoxb1,-EGFP (CAG-Hoxb1), which upon recombination by Cre recombinase conditionally induces robust Hoxb1 and eGFP overexpression. When induced within the neural crest lineage, pups die at birth. A variable phenotype develops from E11.5 on, associating frontonasal hypoplasia/aplasia, micrognathia/agnathia, major ocular and forebrain anomalies, and cardiovascular malformations. Neural crest derivatives in the body appear unaffected. Transcription of effectors of developmental signaling pathways (Bmp, Shh, Vegfa) and transcription factors (Pax3, Sox9) is altered in mutants. These outcomes emphasize that repression of Hoxb1, along with other paralog group 1 and 2 Hox genes, is strictly necessary in anterior cephalic NC for craniofacial, visual, auditory, and cardiovascular development., Comment: Genesis, Wiley-Blackwell, In press

Highlights • L. mexicana behaviour near a no-slip surface is studied via boundary element methods. • Model flagellar beat for Leishmania promastigotes is identified from videomicroscopy. • Idealised simulation of boundary approach shows dichotomy of deflection or collision. • Repulsive surface forces do not induce stable boundary accumulation in this puller. • Tip-first boundary approach may be promoted by morphology-dependent drag., Graphical abstract, It is well established that the parasites of the genus Leishmania exhibit complex surface interactions with the sandfly vector midgut epithelium, but no prior study has considered the details of their hydrodynamics. Here, the boundary behaviours of motile Leishmania mexicana promastigotes are explored in a computational study using the boundary element method, with a model flagellar beating pattern that has been identified from digital videomicroscopy. In particular a simple flagellar kinematics is observed and quantified using image processing and mode identification techniques, suggesting a simple mechanical driver for the Leishmania beat. Phase plane analysis and long-time simulation of a range of Leishmania swimming scenarios demonstrate an absence of stable boundary motility for an idealised model promastigote, with behaviours ranging from boundary capture to deflection into the bulk both with and without surface forces between the swimmer and the boundary. Indeed, the inclusion of a short-range repulsive surface force results in the deflection of all surface-bound promastigotes, suggesting that the documented surface detachment of infective metacyclic promastigotes may be the result of their particular morphology and simple hydrodynamics. Further, simulation elucidates a remarkable morphology-dependent hydrodynamic mechanism of boundary approach, hypothesised to be the cause of the well-established phenomenon of tip-first epithelial attachment of Leishmania promastigotes to the sandfly vector midgut.

Recent experiments suggest that the interplay between cells and the mechanics of their substrate gives rise to a diversity of morphological and migrational behaviors. Here, we develop a Cellular Potts Model of polarizing cells on a visco-elastic substrate. We compare our model with experiments on endothelial cells plated on polyacrylamide hydrogels to constrain model parameters and test predictions. Our analysis reveals that morphology and migratory behavior are determined by an intricate interplay between cellular polarization and substrate strain gradients generated by traction forces exerted by cells (self-haptotaxis).

Micromanipulations, perfusions and measurements performed using glass microelectrodes filled with an electrolyte is a conventional technique for experimental morphological and membrane electrophysiological studies at a single cell and membrane surface level. The typical (effective) diameter of the end of the glass microelectrode is from 500 up to less than 100 nm, which prevents one from observing it using a standard optical microscope in accordance with the optical resolution criteria, since the diameter less than 500 nm is indistinguishable within the interference zone. Microprocessor programming of the puller (microforge) that provides pulling and tearing allows to obtain in certain regimes the adjusted diameter and shape of the micropipette tip, although this result is not fully controlled due to the above limitations. In this connection it is necessary to design the control devices for the micropipette tips both at the preparation and operation stages (intracellular or extracellular insertion). This method also should provide visualization of the processes occurring upon interaction of the microelectrode tip with the cell in real time, depending on the electrode type and state, which allows to level the artifacts arising with the systematic error frequency from the uncontrolled operation of the micropipette tip after different ways of the microelectrode filling with the electrolyte. We propose an installation scheme that solves the above problems by means of introducing an interferometric device for microscopic control of the microelectrode and micromanipulator or microperfusor, for the first time for a given type of optical instruments combined with the interferometric optical scheme., Comment: in Russian

International audience; Flux-limited Keller-Segel (FLKS) model has been recently derived from kinetic transport models for bacterial chemotaxis and shown to represent better the collective movement observed experimentally. Recently, associated to the kinetic model, a new instability formalism has been discovered related to stiff chemotactic response. This motivates our study of traveling wave and aggregation in population dynamics of chemotactic cells based on the FLKS model with a population growth term. Our study includes both numerical and theoretical contributions. In the numerical part, we uncover a variety of solution types in the one-dimensional FLKS model additionally to standard Fisher/KPP type traveling wave. The remarkable result is a counter-intuitive backward traveling wave, where the population density initially saturated in a stable state transits toward an unstable state in the local population dynamics. Unexpectedly, we also find that the backward traveling wave solution transits to a localized spiky solution as increasing the stiffness of chemotactic response. In the theoretical part, we obtain a novel analytic formula for the minimum traveling speed which includes the counterbalancing effect of chemotactic drift vs. reproduction/diffusion in the propagating front. The front propagation speeds of numerical results only slightly deviate from the minimum traveling speeds, except for the localized spiky solutions, even for the backward traveling waves. We also discover an analytic solution of unimodal traveling wave in the large-stiffness limit, which is certainly unstable but exists in a certain range of parameters.

In this paper, we introduce a three-dimensional mathematical model of collagen contraction with microbuckling based on the two-dimensional model previously developed by the authors. The model both qualitatively and quantitatively replicates experimental data including lattice contraction over a time course of 40 hours for lattices with various cell densities, cell density profiles within contracted lattices, radial cut angles in lattices, and cell force propagation within a lattice. The importance of the model lattice formation and the crucial nature of its connectivity are discussed including differences with models which do not include microbuckling. The model suggests that most cells within contracting lattices are engaged in directed motion.

Biological functions are typically performed by groups of cells that express predominantly the same genes, yet display a continuum of phenotypes. While it is known how one genotype can generate such non‐genetic diversity, it remains unclear how different phenotypes contribute to the performance of biological function at the population level. We developed a microfluidic device to simultaneously measure the phenotype and chemotactic performance of tens of thousands of individual, freely swimming Escherichia coli as they climbed a gradient of attractant. We discovered that spatial structure spontaneously emerged from initially well‐mixed wild‐type populations due to non‐genetic diversity. By manipulating the expression of key chemotaxis proteins, we established a causal relationship between protein expression, non‐genetic diversity, and performance that was theoretically predicted. This approach generated a complete phenotype‐to‐performance map, in which we found a nonlinear regime. We used this map to demonstrate how changing the shape of a phenotypic distribution can have as large of an effect on collective performance as changing the mean phenotype, suggesting that selection could act on both during the process of adaptation.

Microbial communities display extreme diversity. A variety of strains or species coexist even when limited by a single resource. It has been argued that metabolite secretion creates new niches and facilitates such diversity. Nonetheless, it is still a controversial topic why cells secrete even essential metabolites so often; in fact, even under isolation conditions, microbial cells secrete various metabolites, including those essential for their growth. First, we demonstrate that leaking essential metabolites can be advantageous. If the intracellular chemical reactions include multibody reactions like catalytic reactions, this advantageous leakage of essential metabolites is possible and indeed typical for most metabolic networks via "flux control" and "growth-dilution" mechanisms; the later is a result of the balance between synthesis and growth-induced dilution with autocatalytic reactions. Counterintuitively, the mechanisms can work even when the supplied resource is scarce. Next, when such cells are crowded, the presence of another cell type, which consumes the leaked chemicals is beneficial for both cell types, so that their coexistence enhances the growth of both. The latter part of the paper is devoted to the analysis of such unusual form of symbiosis: "consumer" cell types benefit from the uptake of metabolites secreted by "leaker" cell types, and such consumption reduces the concentration of metabolites accumulated in the environment; this environmental change enables further secretion from the leaker cell types. This situation leads to frequency-dependent coexistence of several cell types, as supported by extensive simulations. A new look at the diversity in a microbial ecosystem is thus presented., Comment: 9 pages, 4 figures

We present a hybrid vertex/cell-centred model for mechanically simulating planar cellular monolayers undergoing cell reorganisation. Cell centres are represented by a triangular nodal network, while the cell boundaries are formed by an associated vertex network. The two networks are coupled through a kinematic constraint which we allow to relax progressively. Special attention is paid to the change of cell-cell connectivity due to cell reorganisation or remodelling events. We handle these situations by using a variable resting length and applying an Equilibrium-Preserving Mapping (EPM) on the new connectivity, which computes a new set of resting lengths that preserve nodal and vertex equilibrium. We illustrate the properties of the model by simulating monolayers subjected to imposed extension and during a wound healing process. The evolution of forces and the EPM are analysed during the remodelling events. As a by-product, the proposed technique enables to recover fully vertex or fully cell-centred models in a seamlessly manner by modifying a numerical parameter of the model., Comment: 33 pages, 10 figures

Current models for the folding of the human genome see a hierarchy stretching down from chromosome territories, through A/B compartments and TADs (topologically-associating domains), to contact domains stabilized by cohesin and CTCF. However, molecular mechanisms underlying this folding, and the way folding affects transcriptional activity, remain obscure. Here we review physical principles driving proteins bound to long polymers into clusters surrounded by loops, and present a parsimonious yet comprehensive model for the way the organization determines function. We argue that clusters of active RNA polymerases and their transcription factors are major architectural features; then, contact domains, TADs, and compartments just reflect one or more loops and clusters. We suggest tethering a gene close to a cluster containing appropriate factors -- a transcription factory -- increases the firing frequency, and offer solutions to many current puzzles concerning the actions of enhancers, super-enhancers, boundaries, and eQTLs (expression quantitative trait loci). As a result, the activity of any gene is directly influenced by the activity of other transcription units around it in 3D space, and this is supported by Brownian-dynamics simulations of transcription factors binding to cognate sites on long polymers., Comment: 27 pages, 11 figures

We study the effect of correlations in generation times on the dynamics of population growth of microorganisms. We show that any non-zero correlation that is due to cell-size regulation, no matter how small, induces long-term oscillations in the population growth rate. The population only reaches its steady state when we include the often-neglected variability in the growth rates of individual cells. We discover that the relaxation time scale of the population to its steady state is determined by the distribution of single-cell growth rates and is surprisingly independent of details of the division process such as the noise in the timing of division and the mechanism of cell-size regulation. We validate the predictions of our model using existing experimental data and propose an experimental method to measure single-cell growth variability by observing how long it takes for the population to reach its steady state or balanced growth.

Cell shape is an important biomarker that is directly linked to cell function. However, cell morphodynamics, namely the temporal fluctuation of cell shape is much less understood. We study the morphodynamics of MDA-MB-231 cells in type I collagen extracellular matrix (ECM). We find ECM mechanics, as tuned by collagen concentration, controls the morphodynamics but not the static cell morphology. We employ machine learning to classify cell shape into five different morphological phenotypes corresponding to different migration modes. As a result, cell morphodynamics is mapped into temporal evolution of morphological phenotypes. We systematically characterize the phenotype evolutions including occurrence probability, dwell time, transition flux, and 3D migrational characteristics. We find that manipulating Rho-signaling enhances the morphodynamics and phenotype transitions. Using a tumor organoid model, we show that the distinct invasion potentials of each phenotype modulate the phenotype homeostasis. Overall invasion of a tumor organoid is facilitated by individual cells searching for and committing to phenotypes of higher invasive potential. In conclusion, we show that 3D migrating cancer cells exhibit rich morphodynamics that is regulated by ECM mechanics, Rho-signaling, and is closely related with cell motility. Our results pave the way to the systematic characterization and functional understanding of cell morphodynamics as a new biomarker for normal and malignant cells., Comment: 7 pages, 7 figures

The Voronoi-based cellular model is highly successful in describing the motion of two-dimensional confluent cell tissues. In the homogeneous version of this model, the energy of each cell is determined solely by its geometric shape and size, and the interaction between adjacent cells is a byproduct of this additive energy. We generalize this model so as to allow zero or partial contact between cells. We identify several phases, two of which (solid confluent and liquid confluent) were found in previous studies that imposed confluency but others that are novel. Transitions in this model may be relevant for understanding both normal development as well as cancer metastasis., Comment: 15 figures + 2 videos

Myxobacteria are social bacteria, that can glide in two dimensions and form counter-propagating, interacting waves. Here, we present a novel age-structured, continuous macroscopic model for the movement of myxobacteria. The derivation is based on microscopic interaction rules that can be formulated as a particle-based model and set within the Self-Organized Hydrodynamics (SOH) framework. The strength of this combined approach is that microscopic knowledge or data can be incorporated easily into the particle model, whilst the continuous model allows for easy numerical analysis of the different effects. However, we found that the derived macroscopic model lacks a diffusion term in the density equations, which is necessary to control the number of waves, indicating that a higher order approximation during the derivation is crucial. Upon ad hoc addition of the diffusion term, we found very good agreement between the age-structured model and the biology. In particular, we analyzed the influence of a refractory (insensitivity) period following a reversal of movement. Our analysis reveals that the refractory period is not necessary for wave formation, but essential to wave synchronization, indicating separate molecular mechanisms.

Most microorganisms regulate their cell size. We review here some of the mathematical formulations of the problem of cell size regulation. We focus on coarse-grained stochastic models and the statistics they generate. We review the biologically relevant insights obtained from these models. We then describe cell cycle regulation and their molecular implementations, protein number regulation, and population growth, all in relation to size regulation. Finally, we discuss several future directions for developing understanding beyond phenomenological models of cell size regulation.

We propose a discrete in continuous mathematical model describing the in vitro growth process of biophsy-derived mammalian cardiac progenitor cells growing as clusters in the form of spheres (Cardiospheres). The approach is hybrid: discrete at cellular scale and continuous at molecular level. In the present model, cells are subject to the self-organizing collective dynamics mechanism and, additionally, they can proliferate and differentiate, also depending on stochastic processes. The two latter processes are triggered and regulated by chemical signals present in the environment. Numerical simulations show the structure and the development of the clustered progenitors and are in a good agreement with the results obtained from in vitro experiments.

Dictyostelium discoideum is an ideal organism to test the pathogenicity of Pseudomonas aeruginosa, since its eukaryote nature allows for comparisons to be made to human health. Additionally, D. discoideum naturally feeds on bacteria and has a simplistic genome which improves result interpretation. P. aeruginosa is a free living bacteria that is recognized for its ability to cause nosocomial, hospital contracted, infections in immunocompromised patients. This experiment attempts to understand how various strains of D. discoideum may be more susceptible or resistant to infections caused by P. aeruginosa, as a result of environmentally induced adaptive mechanisms. Wild-type strains of D. discoideum will be isolated from Massard Prairie soil and compared to axenic-type strains that have been cultured free from association with other microbiota. The results of this experiment may support studies done on conserved virulence pathways in bacteria and give insight into virulence of P. aeruginosa in humans. There is evidence that Dictyostelium has capabilities that allow for protection against bacteria similar to P. aeruginosa.16 Therefore, it is expected that the wild-type D. discoideum will have adaptive mechanisms that which will cause resistance to P. aeruginosa, unlike axenic-type strains that will have limited resistivity., Comment: *Department of Biological Sciences and Physical Sciences, University of Arkansas Fort Smith, 5210 Grand Avenue, Fort Smith, AR 72913-3649 *Project was undertaken in a Biomedical Research course offered at the University of Arkansas Fort Smith

Cell monolayers provide an interesting example of active matter, exhibiting a phase transition from a flowing to jammed state as they age. Here we report experiments and numerical simulations illustrating how a jammed cellular layer rapidly reverts to a flowing state after a wound. Quantitative comparison between experiments and simulations shows that cells change their self-propulsion and alignement strength so that the system crosses a phase transition line, which we characterize by finite-size scaling in an active particle model. This wound-induced unjamming transition is found to occur generically in epithelial, endothelial and cancer cells., Comment: 6 figures

To observe internalization of the yeast pheromone receptor Ste2 by fluorescence microscopy in live cells in real time, we visualized only those molecules present at the cell surface at the time of agonist engagement (rather than the total cellular pool) by tagging this receptor at its N-terminus with an exocellular fluorogen-activating protein (FAP). A FAP is a single-chain antibody engineered to bind tightly a nonfluorescent, cell-impermeable dye (fluorogen), thereby generating a fluorescent complex. The utility of FAP tagging to study trafficking of integral membrane proteins in yeast, which possesses a cell wall, had not been examined previously. A diverse set of signal peptides and propeptide sequences were explored to maximize expression. Maintenance of the optimal FAP-Ste2 chimera intact required deletion of two, paralogous, glycosylphosphatidylinositol (GPI)-anchored extracellular aspartyl proteases (Yps1 and Mkc7). FAP-Ste2 exhibited a much brighter and distinct plasma membrane signal than Ste2-GFP or Ste2-mCherry yet behaved quite similarly. Using FAP-Ste2, new information was obtained about the mechanism of its internalization, including novel insights about the roles of the cargo-selective endocytic adaptors Ldb19/Art1, Rod1/Art4, and Rog3/Art7., This work was supported by Erwin Schroedinger Fellowship J3787-B21 from the Austrian Science Fund and by National Institutes of Health (NIH) R01 Research Grant GM21841. Additionally, this project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Action H2020-MSCA-IF-2016 InsiliCardio, GA No. 750835

Funding: FRM is funded by the Engineering and Physical Sciences Research Council (EPSRC) (Grant No. EP/N014642/1). Continuum models for the spatial dynamics of growing cell populations have been widely used to investigate the mechanisms underpinning tissue development and tumour invasion. These models consist of nonlinear partial differential equations that describe the evolution of cellular densities in response to pressure gradients generated by population growth. Little prior work has explored the relation between such continuum models and related single-cell-based models. We present here a simple stochastic individual-based model for the spatial dynamics of multicellular systems whereby cells undergo pressure-driven movement and pressure-dependent proliferation. We show that nonlinear partial differential equations commonly used to model the spatial dynamics of growing cell populations can be formally derived from the branching random walk that underlies our discrete model. Moreover, we carry out a systematic comparison between the individual-based model and its continuum counterparts, both in the case of one single cell population and in the case of multiple cell populations with different biophysical properties. The outcomes of our comparative study demonstrate that the results of computational simulations of the individual-based model faithfully mirror the qualitative and quantitative properties of the solutions to the corresponding nonlinear partial differential equations. Ultimately, these results illustrate how the simple rules governing the dynamics of single cells in our individual-based model can lead to the emergence of complex spatial patterns of population growth observed in continuum models. Postprint

The generation of anisotropic shapes occurs during morphogenesis of almost all organisms. With the recent renewal of the interest in mechanical aspects of morphogenesis, it has become clear that mechanics contributes to anisotropic forms in a subtle interaction with various molecular actors. Here, we consider plants, fungi, oomycetes, and bacteria, and we review the mechanisms by which elongated shapes are generated and maintained. We focus on theoretical models of the interplay between growth and mechanics, in relation with experimental data, and discuss how models may help us improve our understanding of the underlying biological mechanisms. Keywords: Morphogenesis, Cell wall, Bacteria, Fungi, Yeasts, Oomycetes, Plants, Symmetry breaking, Cell polarity

International audience; We propose a new model for the emergence of blood capillary networks. We assimilate the tissue and extra cellular matrix as a porous medium, using Darcy's law for describing both blood and intersticial fluid flows. Oxygen obeys a convection-diffusionreaction equation describing advection by the blood, diffusion and consumption by the tissue. Discrete agents named capillary elements and modelling groups of endothelial cells are created or deleted according to different rules involving the oxygen concentration gradient, the blood velocity, the sheer stress or the capillary element density. Once created, a capillary element locally enhances the hydraulic conductivity matrix, contributing to a local increase of the blood velocity and oxygen flow. No connectivity between the capillary elements is imposed. The coupling between blood, oxygen flow and capillary elements provides a positive feedback mechanism which triggers the emergence of a network of channels of high hydraulic conductivity which we identify as new blood capillaries. We provide two different, biologically relevant geometrical settings and numerically analyze the influence of each of the capillary creation mechanism in detail. All mechanisms seem to concur towards a harmonious network but the most important ones are those involving oxygen gradient and sheer stress. A detailed discussion of this model with respect to the literature and its potential future developments concludes the paper.

Recent writings on "innate immune memory" or "trained immunity," and on "hormetic responses," herald reinvigoration of an important research area with early 20th century roots. However, it is questionable that the thesis of a "major importance of the sensed dose of pathogen for the development of innate immune system-mediated responses," should be labelled a "paradigm shift." The works of Almroth Wright (1861-1947) should be taken into account., Comment: 5 pages, 1 figure

The exchange of small molecular signals within microbial populations is generally referred to as quorum sensing (QS). QS is ubiquitous in nature and enables microorganisms to respond to fluctuations in living environments by working together. In this study, a QS-based molecular communication system within a microbial population in a two-dimensional (2D) environment is analytically modeled. Microorganisms are randomly distributed on a 2D circle where each one releases molecules at random times. The number of molecules observed at each randomly-distributed bacterium is first derived by characterizing the diffusion and degradation of signaling molecules within the population. Using the derived result and some approximation, the expected density of cooperative bacteria is derived. Our model captures the basic features of QS. The analytical results for noisy signal propagation agree with simulation results where the Brownian motion of molecules is simulated by a particle-based method. Therefore, we anticipate that our model can be used to predict the density of cooperative bacteria in a variety of QS-coordinated activities, e.g., biofilm formation and antibiotic resistance., Comment: 7 pages, 7 figures; This work has been accepted by IEEE Globecom 2019

In living cells, oscillation of the concentration of cytosolic Ca2+ is an important and pervasive signal for the intercellular and intracellular information conduction. To generate the oscillation, the hydrolysis of ATP is always needed. Many recent studies show that both ATP molecules themselves and the free energy by ATP hydrolysis play significant role in the biochemical process involving ATP hydrolysis. To verify the prediction, we consider the role of ATP molecules and their hydrolysis in a classic one-pool model of Ca2+ oscillation. Our results show that the available Gibbs free energy of ATP hydrolysis {\DeltaG}, which measures the "distance" of a reaction to its equilibrium state, is another important regulatory factor of the oscillation system besides the concentration of ATP. Furthermore, our model suggest a rudimental prediction of how the oscillation system changes in an aging cell, such as the decrease of the amplitude and the increase of the least {\DeltaG} required for the oscillation., Comment: 22 pages, 8 figures

Lymphoid leukemia (LL) and lymphoma are neoplasms developed from lymphoid cells (LCs). To understand why different forms of LL/lymphoma occur at different ages, we analyzed the effects of different types of DNA changes on a LC and the cellular characteristics of LCs. Point DNA mutations (PDMs) and chromosome changes (CCs) are the two major types of DNA changes. CCs have three subtypes by their effects on a LC: great-effect CCs (GECCs), mild-effect CCs (MECCs), and intermediate-effect CCs (IECCs). PDMs and MECCs are mostly mild thus can accumulate in cells. Some of the PDMs/MECCs contribute to cell transformation. A GECC affects one or more genes and can alone drive cell transformation. An IECC affects one or more genes and participates in cell transformation. Due to cellular characteristics, a LC may have higher survivability from DNA changes and require obtaining fewer cancerous properties for transformation than a tissue cell. Hence, a LC can be more rapidly transformed by a CC. On this basis, we hypothesize that a LC may have three pathways on transformation: a slow, a rapid, and an accelerated. Slow pathway is driven by accumulation of PDMs/MECCs. Rapid pathway is driven by a GECC in "one step". Accelerated pathway is driven by accumulation of PDMs/MECCs/IECC(s). Cell transformations of a LC via different pathways occur at different ages. A transformation via slow pathway occurs mainly in adults. A transformation via rapid pathway occurs at any age and has no increasing incidence with age. A transformation via accelerated pathway occurs also at any age but has increasing incidence with age. In conclusion, a LC may have three pathways on cell transformation, and the occurring age of LL/lymphoma may be determined by the transforming pathway of a LC., Comment: 24 pages, 4 figures

Cellular mechanics plays an important role in epithelial morphogenesis, a process wherein cells reshape and rearrange to produce tissue-scale deformations. However, the study of tissue-scale mechanics is impaired by the difficulty of direct measurement of stress in-vivo. Alternative, image-based inference schemes aim to estimate stress from snapshots of cellular geometry but are challenged by sensitivity to fluctuations and measurement noise as well as the dependence on boundary conditions. Here we overcome these difficulties by introducing a new variational approach - the Geometrical Variation Method (GVM) - which exploits the fundamental duality between stress and cellular geometry that exists in the state of mechanical equilibrium of discrete mechanical networks that approximate cellular tissues. In the Geometrical Variation Method, the two dimensional apical geometry of an epithelial tissue is approximated by a 2D tiling with Circular Arc Polygons (CAP) in which the arcs represent intercellular interfaces defined by the balance of local line tension and pressure differentials between adjacent cells. We take advantage of local constraints that mechanical equilibrium imposes on CAP geometry to define a variational procedure that extracts the best fitting equilibrium configuration from images of epithelial monolayers. The GVM-based stress inference algorithm has been validated by the comparison of the predicted cellular and mesoscopic scale stress and measured myosin II patterns in the epithelial tissue during Drosophila embryogenesis. GVM prediction of mesoscopic stress tensor correlates at the 80% level with the measured myosin distribution and reveals that most of the myosin II activity is involved in a static internal force balance within the epithelial layer. Lastly, this study provides a practical method for non-destructive estimation of stress in live epithelial tissues., Comment: 12 pages, 6 figures

Changes in morphological characteristics of cells from two cultured cancer cell lines, HeLa and A549, induced by photodynamic treatment with Radachlorin photosensitizer have been monitored using digital holographic microscopy. The observed dose-dependent post-treatment dynamics of phase shift variations demonstrated several scenarios of cell death. In particular the phase shift increase at low doses can be associated with apoptosis while its decrease at high doses can be associated with necrosis. Two cell types were shown to be differently responsive to treatment at the same doses. Although the sequence of death scenarios with increasing irradiation dose was demonstrated to be the same, each specific scenario was realized at substantially different doses. Results obtained by holographic microscopy were confirmed by confocal fluorescence microscopy with the commonly used test assay., Comment: 14 pages, 3 figures

We introduce a stochastic model of coupled genetic oscillators in which chains of chemical events involved in gene regulation and expression are represented as sequences of Poisson processes. We characterize steady states by their frequency, their quality factor and their synchrony by the oscillator cross correlation. The steady state is determined by coupling and exhibits stochastic transitions between different modes. The interplay of stochasticity and nonlinearity leads to isolated regions in parameter space in which the coupled system works best as a biological pacemaker. Key features of the stochastic oscillations can be captured by an effective model for phase oscillators that are coupled by signals with distributed delays., Comment: 12 pages, 8 figures

Purpose of review: The epithelial-Mesenchymal Transition (EMT) and the generation of Cancer Stem Cells (CSC) are two fundamental aspects contributing to tumor growth, acquisition of resistance to therapy, formation of metastases, and tumor relapse. Recent experimental data identifying the circuits regulating EMT and CSCs have driven the development of computational models capturing the dynamics of these circuits and consequently various aspects of tumor progression. Recent findings: We review the contribution made by these models in a) recapitulating experimentally observed behavior, b) making experimentally testable predictions, and c) driving emerging notions in the field, including the emphasis on the aggressive potential of hybrid epithelial/mesenchymal (E/M) phenotype(s). We discuss dynamical and statistical models at intracellular and population level relating to dynamics of EMT and CSCs, and those focusing on interconnections between these two processes. Summary: These models highlight the insights gained via mathematical modeling approaches, and emphasizes that the connections between hybrid E/M phenotype(s) and stemness can be explained by analyzing underlying regulatory circuits. Such experimentally curated models have the potential of serving as platforms for better therapeutic design strategies.

Graphene-based materials are the focus of intense research efforts to devise novel theranostic strategies for targeting the central nervous system. In this work, we have investigated the consequences of long-term exposure of primary rat astrocytes to pristine graphene (GR) and graphene oxide (GO) flakes. We demonstrate that GR/GO interfere with a variety of intracellular processes as a result of their internalization through the endo-lysosomal pathway. Graphene-exposed astrocytes acquire a more differentiated morphological phenotype associated with extensive cytoskeletal rearrangements. Profound functional alterations are induced by GO internalization, including the upregulation of inward-rectifying K+ channels and of Na+-dependent glutamate uptake, which are linked to the astrocyte capacity to control the extracellular homeostasis. Interestingly, GO-pretreated astrocytes promote the functional maturation of co-cultured primary neurons by inducing an increase in intrinsic excitability and in the density of GABAergic synapses. The results indicate that graphene nanomaterials profoundly affect astrocyte physiology in vitro, with consequences for neuronal network activity. This work supports the view that GO-based materials could be of great interest to address pathologies of the central nervous system associated to astrocyte dysfunctions., Comment: This document is the unedited Author's version of a Submitted Work that was subsequently accepted for publication in Nano Letters. To access the final edited and published work see https://pubs.acs.org/articlesonrequest/AOR-wvjrggcBp7kC8NwEImXr