Epithelial collective cell migration (CCM) is important in biological processes such as organ development, tissue maintenance and tissue repair. CCM usually occurs on curved surfaces such as that found in blood vessel walls and intestinal villi. However, current CCM research are still conducted on flat surfaces. This is due to lack of techniques to fabricate tubular and spherical microstructures resembling that of organs as well as difficulty in observing and measuring the collective dynamic behaviour of cells on these surfaces. Nevertheless, recent studies are beginning to show that cells do behave differently on curved surfaces. However, these studies were mainly focused on single cells, as such, there is limited insight into CCM which involves complex interactions among multiple cells.
Here, we claim that curved surfaces can significantly influence CCM. As such, we propose to systematically study CCM on such surfaces to better understand their underlying mechanisms. Our project will combine distinct but complementary scientific expertises coming from biology, biophysics and engineering. We aim to: 1) Develop novel techniques in fabricating different, well-defined curved geometries such as tubular and spherical surfaces with nano-patterns; 2) Identify biomolecules and proteins involved in CCM on curved surfaces; 3) Develop computational models to perform 3D imaging and analysis so as to better monitor and measure complex tissue dynamics; and 4) Develop a universal theory to better explain and unify experimental observations.
Together, the unique combination of these different approaches will enable us to better understand the fundamental mechanisms and impact of surface curvature on cell behaviour and tissue organization. These will shed light on related biological functions such as in organ development and tissue repair, as well as contributing towards better tissue engineering or regenerative medicine applications.

Epithelial collective cell migration (CCM) is important in biological processes such as organ development, tissue maintenance and tissue repair. CCM usually occurs on curved surfaces such as that found in blood vessel walls and intestinal villi. However, current CCM research are still conducted on flat surfaces. This is due to lack of techniques to fabricate tubular and spherical microstructures resembling that of organs as well as difficulty in observing and measuring the collective dynamic behaviour of cells on these surfaces. Nevertheless, recent studies are beginning to show that cells do behave differently on curved surfaces. However, these studies were mainly focused on single cells, as such, there is limited insight into CCM which involves complex interactions among multiple cells.
Here, we claim that curved surfaces can significantly influence CCM. As such, we propose to systematically study CCM on such surfaces to better understand their underlying mechanisms. Our project will combine distinct but complementary scientific expertises coming from biology, biophysics and engineering. We aim to: 1) Develop novel techniques in fabricating different, well-defined curved geometries such as tubular and spherical surfaces with nano-patterns; 2) Identify biomolecules and proteins involved in CCM on curved surfaces; 3) Develop computational models to perform 3D imaging and analysis so as to better monitor and measure complex tissue dynamics; and 4) Develop a universal theory to better explain and unify experimental observations.
Together, the unique combination of these different approaches will enable us to better understand the fundamental mechanisms and impact of surface curvature on cell behaviour and tissue organization. These will shed light on related biological functions such as in organ development and tissue repair, as well as contributing towards better tissue engineering or regenerative medicine applications.

Epithelial collective cell migration (CCM) is important in biological processes such as organ development, tissue maintenance and tissue repair. CCM usually occurs on curved surfaces such as that found in blood vessel walls and intestinal villi. However, current CCM research are still conducted on flat surfaces. This is due to lack of techniques to fabricate tubular and spherical microstructures resembling that of organs as well as difficulty in observing and measuring the collective dynamic behaviour of cells on these surfaces. Nevertheless, recent studies are beginning to show that cells do behave differently on curved surfaces. However, these studies were mainly focused on single cells, as such, there is limited insight into CCM which involves complex interactions among multiple cells.
Here, we claim that curved surfaces can significantly influence CCM. As such, we propose to systematically study CCM on such surfaces to better understand their underlying mechanisms. Our project will combine distinct but complementary scientific expertises coming from biology, biophysics and engineering. We aim to: 1) Develop novel techniques in fabricating different, well-defined curved geometries such as tubular and spherical surfaces with nano-patterns; 2) Identify biomolecules and proteins involved in CCM on curved surfaces; 3) Develop computational models to perform 3D imaging and analysis so as to better monitor and measure complex tissue dynamics; and 4) Develop a universal theory to better explain and unify experimental observations.
Together, the unique combination of these different approaches will enable us to better understand the fundamental mechanisms and impact of surface curvature on cell behaviour and tissue organization. These will shed light on related biological functions such as in organ development and tissue repair, as well as contributing towards better tissue engineering or regenerative medicine applications.

Epithelial collective cell migration (CCM) is important in biological processes such as organ development, tissue maintenance and tissue repair. CCM usually occurs on curved surfaces such as that found in blood vessel walls and intestinal villi. However, current CCM research are still conducted on flat surfaces. This is due to lack of techniques to fabricate tubular and spherical microstructures resembling that of organs as well as difficulty in observing and measuring the collective dynamic behaviour of cells on these surfaces. Nevertheless, recent studies are beginning to show that cells do behave differently on curved surfaces. However, these studies were mainly focused on single cells, as such, there is limited insight into CCM which involves complex interactions among multiple cells.
Here, we claim that curved surfaces can significantly influence CCM. As such, we propose to systematically study CCM on such surfaces to better understand their underlying mechanisms. Our project will combine distinct but complementary scientific expertises coming from biology, biophysics and engineering. We aim to: 1) Develop novel techniques in fabricating different, well-defined curved geometries such as tubular and spherical surfaces with nano-patterns; 2) Identify biomolecules and proteins involved in CCM on curved surfaces; 3) Develop computational models to perform 3D imaging and analysis so as to better monitor and measure complex tissue dynamics; and 4) Develop a universal theory to better explain and unify experimental observations.
Together, the unique combination of these different approaches will enable us to better understand the fundamental mechanisms and impact of surface curvature on cell behaviour and tissue organization. These will shed light on related biological functions such as in organ development and tissue repair, as well as contributing towards better tissue engineering or regenerative medicine applications.

Cells achieve reproducible outputs while relying on intrinsically stochastic molecular processes. In plants, cell division orientation is accurately predicted before mitosis by a microtubular ring, the preprophase band (PPB), through an unknown mechanism. Using high-throughput microscopy, quantitative image analysis, biomechanics and stochastic modeling, we will investigate how the stochasticity of microtubule (MT) self-organization is used, or filtered out, during PPB formation to sense temporal, geometric and mechanical cues in order to generate a robust placement of cell division planes. In short, we will test whether the PPB acts as a macromolecular mechanosensor. Using statistical mechanics such as Monte Carlo, event-based modeling and mean-field theory, we will assess how stochasticity leads to distinct dynamical states for MT arrays. We will develop biophysical models of dynamic MTs in 3D cells to explore how stochastic MTs self-organize into PPBs and how spatiotemporal cues modulate that process. Using the Arabidopsis shoot apical meristem, we will identify correlations between MT array dynamics, PPB behavior, cell shape, growth and mechanics, cell cycle progression, and cell division plane from statistically representative sample involving hundreds of dividing cells. To challenge the robustness of PPB and cell division in vivo and in silico, we will globally and locally increase variability in these cell parameters with mutants (MT dynamics, wall mechanics, cell cycle, mechanotransduction), inducible lines, mosaics, and micromechanical perturbations. Last, we will unravel the molecular mechanism processing molecular stochasticity to channel cell divisions: we will investigate how the TTP (TON1-TRM-PP2A) complex, a key regulator of PPB formation in connection with the cell cycle, contributes to generate reproducible divisions by monitoring MT self-organization, integrating geometric, mechanical and temporal cues. Implications of this project go beyond cell division robustness: while many cellular pathways are adapted to respond to rapid and discontinuous changes, we expect here to unravel mechanisms managing slow and continuous signals, like shape, growth or tissue-stress. We will also gain insight into the mathematical properties of stochastic extended objects like microtubules, and we will propose a mechanism for cells to perceive directional cues.

Muscles are producing the active forces that enable all our voluntary body movements. The cellular components of muscle are called muscle fibers and are very large cells that can be several centimeters in length in humans. Inside all muscle cells are millions of tiny molecular machines, called sarcomeres that produce the active forces of muscles. These sarcomeres are arrayed in highly regular long chains called myofibrils that span from one muscle end to the other. This arrangement ensures that the force produced by the myofibrils is transmitted to the connected tendons and bones at the muscles ends. The highly regular periodic organization of the myofibrils results in the cross-striated appearance of skeletal muscles under the microscope.
We assembled an international team of researchers from France, USA and Germany to study how myofibrils are built during muscle development. For this we combine two different experimental model systems, the fruit fly Drosophila muscles and human muscle cells generated in vitro from stem cells, together with mathematical modeling of myofibril assembly. Our starting hypothesis is that mechanical forces, which are generated early during muscle development, are an important factor for the polymerization of myofibrils. We will test this hypothesis in fly as well as in human muscles produced in vitro by following the localization of sarcomeric protein components with high-resolution microscopy techniques. We will measure when a sarcomeric protein pattern can be first detected and how this pattern is refined. These data will be used to generate a computer model that can produce periodic sarcomere-like structures that are linked together from homogenous components. We will further measure the strength of mechanical forces present during myofibril formation in fly muscles in vivo and in human muscles in culture. Finally, we aim to modify these forces and to observe the effect of these manipulations on the developing muscles and myofibrils. These data will be used to produce a refined computer model of myofibrillogenesis. Together, our research should lead to a better understanding of how the contractile apparatus of human muscle is built, which could eventually be helpful to treat muscle injuries or aged dependent myopathies.

Understanding how out of single cells functional tissues and organs develop is a major challenge of biology. Recent progress allows us to grow organ-like cell assemblies (organoids) from stem cells in vitro. Organoids offer great potential for studying diseases and development. However, in many cases we do not yet understand how these complex tissues emerge out of progenitor stem cells. A common feature in the initial growth phase of many organoid systems is the formation of a polarized epithelial cyst with a single or multiple internal apical lumen. This initial transition into an epithelial cyst establishes a tissue template that on the one hand enables maintenance of progenitor/stem cells (niche) and on the other hand guides the patterning of differentiated cells into a functional tissue. Our aim is to understand how the interplay between proliferation (cell divisions), polarization (epithelial transition) and differentiation (patterning) leads to self-organization of this epithelial progenitor template and how this structure facilitates correct patterning into functional organoids. To this end, we will systematically control and characterize the early growth phase of two organoid systems (pancreatic and neural tube) using microfabrication and micro-patterning approaches. We will quantify evolution of cell shapes, adhesion and cortical forces, apical-basal polarization and differentiation as a function of initial cell contact patterns. This approach will provide the means to find rules how local cell interactions (cell-cell, cell-matrix, cell-lumen) are connected to tissue growth and differentiation. We will then test sufficiency of the hypothetical rules to generate the observed organoid structures using an in silico mechano-chemical model. Taken together, by dissecting the early growth phase of two organoid systems, we aim to uncover the common rules on how progenitors establish a polarized epithelial template, and how this template is then differentially used to generate organ specific differentiation patterns.

Understanding how out of single cells functional tissues and organs develop is a major challenge of biology. Recent progress allows us to grow organ-like cell assemblies (organoids) from stem cells in vitro. Organoids offer great potential for studying diseases and development. However, in many cases we do not yet understand how these complex tissues emerge out of progenitor stem cells. A common feature in the initial growth phase of many organoid systems is the formation of a polarized epithelial cyst with a single or multiple internal apical lumen. This initial transition into an epithelial cyst establishes a tissue template that on the one hand enables maintenance of progenitor/stem cells (niche) and on the other hand guides the patterning of differentiated cells into a functional tissue. Our aim is to understand how the interplay between proliferation (cell divisions), polarization (epithelial transition) and differentiation (patterning) leads to self-organization of this epithelial progenitor template and how this structure facilitates correct patterning into functional organoids. To this end, we will systematically control and characterize the early growth phase of two organoid systems (pancreatic and neural tube) using microfabrication and micro-patterning approaches. We will quantify evolution of cell shapes, adhesion and cortical forces, apical-basal polarization and differentiation as a function of initial cell contact patterns. This approach will provide the means to find rules how local cell interactions (cell-cell, cell-matrix, cell-lumen) are connected to tissue growth and differentiation. We will then test sufficiency of the hypothetical rules to generate the observed organoid structures using an in silico mechano-chemical model. Taken together, by dissecting the early growth phase of two organoid systems, we aim to uncover the common rules on how progenitors establish a polarized epithelial template, and how this template is then differentially used to generate organ specific differentiation patterns.

Our proposal is aimed at discovering the molecular mechanisms underlying the remarkable force-sensing and responsive properties of cellular attachment to the extracellular matrix. Many proteins contribute to the intracellular machinery that links the cytoplasmic domains of the transmembrane integrin adhesion receptors to the actomyosin contractile apparatus within the cell. These integrin adhesion complexes (IACs) provide a paradigm for a distinctive class of subcellular protein complex. Rather than assembling a structure of fixed stoichiometry (e.g. ribosome, centriole) via exclusive interactions, evidence is emerging that IACs engage a dynamic set of heterogeneous interactions that evolve from IAC initiation through maturation to achieve their signaling and mechanical functions.
Thus, we hypothesize that a key feature of IACs is their ability to exchange multivalent interactions between components, so changing their composition in response to diverse inputs, including force, developmental history and location within the organism. We have selected a few pivotal components of the IACs as the focus for our project: namely talin, kindlins, the IPP sub-complex (integrin-linked-kinase (ILK), PINCH, parvin), and vinculin.
To test this hypothesis we will combine Giannone's expertise in live single protein tracking and super-resolution microscopy with Brown's expertise in Drosophila developmental genetics. First we will advance existing methods to achieve the challenging task of quantitative super-resolution imaging within IACs in living tissues. Second, we will develop new tools to image interacting proteins, study their dynamic behavior and alter the interactions. Discovering the regulation of IAC rearrangement will greatly improve our understanding not only of mechanisms mediating Integrin adhesion but also of dynamic macromolecular protein complexes.
By bringing together the contrasting approaches of the two applicants we will gain an exceptional view of how the molecular machinery at integrin adhesion sites has evolved to be able to respond diverse environments and activities within the organism. We anticipate that this will lead to an understanding of general principles directing the progressive formation of macromolecular complexes.

Sophisticated alien-like systems in squids, octopuses, and other cephalopods capture the human imagination, and are of growing research interest. Some represent unique innovations, like dynamic camouflage, high pressure jet propulsion, and stretchable arms with tasting suckers that grip. Other features are convergent traits that are surprisingly similar, but molecularly different, from familiar biological systems in ourselves and our vertebrate cousins, including large brains, sophisticated eyes, and a muscular heart that drives a high pressure circulatory system. Parallel evolution of these complex systems in cephalopods and vertebrates is likely due to an ancient evolutionary competition to dominant as large, active swimming, visual predators in early oceans, causing both groups to engineer their own genetic, cellular, anatomical and physiological solutions to similar environmental challenges. This matchless competition profoundly shaped complexity in both lineages, and offers researchers today an extraordinary and uniquely powerful opportunity to distill basic principles and reveal novel solutions of how to make a brain, complex eyes, and a heart with sophisticated cardiovascular regulation. Here, through detailed comparisons between cephalopods vs vertebrates, together with state-of-the-art technologies, we will decipher mechanisms and uncover alternative solutions: how to design a circulatory system with rhythmic heartbeats?
To characterize, reverse engineer and control novel types of circulatory systems, powerful genetic tools will be developed. We will establish, for the first time, targeted genome editing and light-based genetic tools to control activity in the world’s smallest cephalopod - the pygmy squid Idiosepius – a novel revolutionary model for biomedicine. Second, using this transparent marine organism, we will produce a genomic portrait of the entire circulatory system at single-cell resolution. Finally, with real-time imaging technologies and sophisticated genetic controls, we will develop new ways to regulate, not one, but three cephalopod hearts and their pacemakers. As a result, our international team will transform the pygmy squid into a cephalopod ‘lab rat’, and discover fundamental principles that led to the origins of high-pressure circulatory systems, providing new materials and ideas for synthetic biology and bioengineering.

According to the World Health Organization, about 600 million people around the world are obese. Not only does obesity affect developed countries, it is also becoming a major problem for low and middle-income countries. Obesity results from an increased accumulation of lipids within adipose tissue. Triglycerides are stored in lipid droplets, ultimately leading to adipocytes (ADs) hypertrophy, altered hormonal release and adipose inflammation. Hence, obesity contributes in a major way to the burden of diabetes and cardiovascular diseases (metabolic syndrome).
Growing evidence indicates that static stretching promotes adipogenesis, possibly relevant to sedentary lifestyle, while dynamic stretching or vibrations, as occurring for instance during exercise, have the opposite effect. Altogether, these observations suggest that mechanical force has a major impact on the ability of ADs to accumulate lipids, with differential responses to specific types of mechanical stress. ADs are characterized by a unique ability for volume expansion upon triglyceride accumulation, increasing their size by more than 30-fold with a marked enhancement in effective cell stiffness. Consequently, within adipose depots, hypertrophic ADs generate a mechanical stress transmitted to resident cells. We postulate that a positive mechanical feedback loop acts in the process of adipogenesis and influences hormonal production. Using a combination of transdisciplinary approaches, including soft matter physics, cell biology, biophysics, physiology, pharmacology and clinical observations we will investigate the molecular basis of adipose cells mechanosensitivity. Important questions need to be addressed: What are the mechanical forces at play in adipose tissue? Can we measure tension generated within adipose depots in vivo? How is mechanical stress transduced at the molecular level in adipose cells? Does mechanical stress impact hormonal production and adipose inflammation? We will investigate the functional role for candidate mechanosensors, including the mechanosensitive ion channel Piezo1, the adhesion molecules integrins/talins, as well as the nuclear protein lamin-A in adipose plasticity and function. In conclusion, we will provide novel insights into the mechanobiology of adipose tissue, with expected practical perspectives for the treatment of obesity.

Although apparently simple, transparency is a complex coloration strategy. Long viewed as exclusively for camouflage (obeying the ‘being invisible to go undetected’ principle), it has recently been proposed to also play a role in communication. While morphological solutions for transparency are diverse, the physical challenges and properties are poorly known, and developmental and biophysical mechanisms at work to build transparent structures remain poorly understood. Previous studies of transparency are sparse and devoted to aquatic organisms, as transparency is frequent in water but extremely rare on land. Furthermore, understanding transparency requires working at the interface between physics, evolutionary biology and developmental biology. We propose an intercontinental collaborative project that aims to elucidate the adaptive functions of transparency in clearwing butterflies and the generative processes leading to modified structures in transparent wings, bridging the gap between development, function and evolution. First, by conducting physical measurements, we will characterize structural, optical, thermal and hydrophobic properties of transparent wings. Notably, we will characterize light transmission efficiency as well as optical patterns, such as iridescence, that may be involved in communication. Second, by examining and experimentally manipulating pupal wings at various developmental stages we will identify the cellular modifications that distinguish transparent areas from opaque areas of the same species and homologous regions between species, and define genetic pathways that underlie these distinctions. Third, by analyzing physical and developmental data in a comparative phylogenetic and ecological context we will reconstruct the evolution of transparency to test functional hypotheses (camouflage, communication, thermoregulation, water repellency) and to assess the contribution of history and selection to the evolution of transparency. This project will bring significant advances in our understanding of animal coloration strategies and terrestrial transparency.

Although apparently simple, transparency is a complex coloration strategy. Long viewed as exclusively for camouflage (obeying the ‘being invisible to go undetected’ principle), it has recently been proposed to also play a role in communication. While morphological solutions for transparency are diverse, the physical challenges and properties are poorly known, and developmental and biophysical mechanisms at work to build transparent structures remain poorly understood. Previous studies of transparency are sparse and devoted to aquatic organisms, as transparency is frequent in water but extremely rare on land. Furthermore, understanding transparency requires working at the interface between physics, evolutionary biology and developmental biology. We propose an intercontinental collaborative project that aims to elucidate the adaptive functions of transparency in clearwing butterflies and the generative processes leading to modified structures in transparent wings, bridging the gap between development, function and evolution. First, by conducting physical measurements, we will characterize structural, optical, thermal and hydrophobic properties of transparent wings. Notably, we will characterize light transmission efficiency as well as optical patterns, such as iridescence, that may be involved in communication. Second, by examining and experimentally manipulating pupal wings at various developmental stages we will identify the cellular modifications that distinguish transparent areas from opaque areas of the same species and homologous regions between species, and define genetic pathways that underlie these distinctions. Third, by analyzing physical and developmental data in a comparative phylogenetic and ecological context we will reconstruct the evolution of transparency to test functional hypotheses (camouflage, communication, thermoregulation, water repellency) and to assess the contribution of history and selection to the evolution of transparency. This project will bring significant advances in our understanding of animal coloration strategies and terrestrial transparency.

Although apparently simple, transparency is a complex coloration strategy. Long viewed as exclusively for camouflage (obeying the ‘being invisible to go undetected’ principle), it has recently been proposed to also play a role in communication. While morphological solutions for transparency are diverse, the physical challenges and properties are poorly known, and developmental and biophysical mechanisms at work to build transparent structures remain poorly understood. Previous studies of transparency are sparse and devoted to aquatic organisms, as transparency is frequent in water but extremely rare on land. Furthermore, understanding transparency requires working at the interface between physics, evolutionary biology and developmental biology. We propose an intercontinental collaborative project that aims to elucidate the adaptive functions of transparency in clearwing butterflies and the generative processes leading to modified structures in transparent wings, bridging the gap between development, function and evolution. First, by conducting physical measurements, we will characterize structural, optical, thermal and hydrophobic properties of transparent wings. Notably, we will characterize light transmission efficiency as well as optical patterns, such as iridescence, that may be involved in communication. Second, by examining and experimentally manipulating pupal wings at various developmental stages we will identify the cellular modifications that distinguish transparent areas from opaque areas of the same species and homologous regions between species, and define genetic pathways that underlie these distinctions. Third, by analyzing physical and developmental data in a comparative phylogenetic and ecological context we will reconstruct the evolution of transparency to test functional hypotheses (camouflage, communication, thermoregulation, water repellency) and to assess the contribution of history and selection to the evolution of transparency. This project will bring significant advances in our understanding of animal coloration strategies and terrestrial transparency.

Although apparently simple, transparency is a complex coloration strategy. Long viewed as exclusively for camouflage (obeying the ‘being invisible to go undetected’ principle), it has recently been proposed to also play a role in communication. While morphological solutions for transparency are diverse, the physical challenges and properties are poorly known, and developmental and biophysical mechanisms at work to build transparent structures remain poorly understood. Previous studies of transparency are sparse and devoted to aquatic organisms, as transparency is frequent in water but extremely rare on land. Furthermore, understanding transparency requires working at the interface between physics, evolutionary biology and developmental biology. We propose an intercontinental collaborative project that aims to elucidate the adaptive functions of transparency in clearwing butterflies and the generative processes leading to modified structures in transparent wings, bridging the gap between development, function and evolution. First, by conducting physical measurements, we will characterize structural, optical, thermal and hydrophobic properties of transparent wings. Notably, we will characterize light transmission efficiency as well as optical patterns, such as iridescence, that may be involved in communication. Second, by examining and experimentally manipulating pupal wings at various developmental stages we will identify the cellular modifications that distinguish transparent areas from opaque areas of the same species and homologous regions between species, and define genetic pathways that underlie these distinctions. Third, by analyzing physical and developmental data in a comparative phylogenetic and ecological context we will reconstruct the evolution of transparency to test functional hypotheses (camouflage, communication, thermoregulation, water repellency) and to assess the contribution of history and selection to the evolution of transparency. This project will bring significant advances in our understanding of animal coloration strategies and terrestrial transparency.

The paths we follow when we speak.

The analysis of language processes is traditionally based on discrete, categorical variables, such as noun phrase, suffix or phoneme, quite different in nature from the continuously varying neuronal variables (firing rates, or even spike emission times) that at a microscopic level necessarily underlie them. Forms of analog-to-digital conversion have then to be assumed to link linguistic phenomena, in particular in relation to memory, to cortical network operations. Other memory-related phenomena, however, such as navigation in rodents, are beginning to be understood in detail and to reveal computations that remain analog even at the cognitive level – e.g., the choice of a trajectory in space. Are there analog computations that are relevant to understanding language, in humans?

We address this question at two different scales of complexity. First, in the choice of successive phonemes while uttering a word, which we take to be produced by a well-localized network, perhaps in the left inferior frontal gyrus. It may be envisaged as a continuous trajectory on a ‘phoneme manifold’ which expresses, in the space of all possible vocalizations, the phonological memory of one’s own language(s). We ask how the structure of such a manifold would reflect the statistical learning process with which it is gradually acquired during development, and how it would itself be reflected in the patterns of errors observed when reading aloud. To this end, we shall use network models comprised of individual neuronal units and psycholinguistic tests.

Second, to contrast analog with digital computations within the same paradigm, we consider the memory devices that have culturally evolved to remember extended verbal material, and have crystallized in poetry. Some of them, such as meter, can be thought of as expressing a quasi-continuous trajectory, while others, such as rhyme, are more punctuate and essentially digital. We intend to assess the effectiveness of devices of different nature by manipulating them in network models and in psycholinguistic and EEG experiments involving poetry recall. Since meter and rhyme are embedded in complex constructs including meaning, syntax and other components, which are beyond our scope, we shall represent the whole cortex as a network of Potts units, effectively a model of interacting cortical patches.

Filopodia are thin, actin-rich plasma membrane protrusions, which function as sensory organelles of cells. Despite a wealth of information on the physiological functions, the molecular mechanisms underlying their assembly and dynamics are incompletely understood. Filopodia are characterized by high negative membrane curvature and high density of phosphoinositides. Their formation and dynamics are controlled by an array of actin-binding and signaling proteins, many of which interact also with phospholipids. However, the mechanisms and biological roles of these lipid-interactions are largely unknown. We will collaboratively examine the molecular principles of filopodia assembly, with a specific focus on the roles of membrane curvature sensing and phosphoinositide clustering in this process. We will use advanced cell biology methods (genome editing combined with live-cell imaging approaches) to identify the mechanisms by which central filopodial proteins are recruited to these membrane protrusions in cells. Phosphoinositide and curvature sensing properties as well as potential synergetic effects of these proteins will be quantitatively measured by in vitro experiments (optical tweezers, confocal microscopy, FCS) using model membrane systems (membrane nanotubes pulled from Giant Unilamellar Vesicles) with controlled curvature, and also in silico (multiscale simulations) and in vivo with relevant mutant proteins. These computationally efficient simulations are based on systematic coarse-graining methods, in which the molecular resolution is reduced but the effects of key molecular features retained, thus adding insight into the cooperative processes underlying filopodia formation. Such insight will also help to connect the results of the in vivo and in vitro experiments. Finally, once a minimal set of proteins responsible for this synergy will have been identified, we will include actin and reconstruct a synthetic filopodium. Additional positive feedback is eventually expected to take place due to actin polymerizing against the membrane. Thus, by virtue of reconstituted systems, we will aim to identify the essential physical mechanisms underlying the very first steps of filopodia formation.

Macrophages play beneficial roles in protective immunity. However, they also favor the progression of several pathologies when they massively infiltrate diseased tissues. A present challenge in cancer, for instance, is to control macrophage tissue infiltration, which involves the mesenchymal motility. This motility is characterized by the ability of the cell to form protrusive structures called podosomes. A podosome constitutes a submicron core of actin filaments surrounded by a ring of integrin-based adhesion complexes. Our working model postulates a mechanical connection that counterbalances the actin-rich protrusive core by traction at the adhesive ring, likely embodied by acto-myosin contractile cables. Therefore core and cables would form a unique two-module protrusive force generator that balances forces at the level of a single podosome to ultimately contribute to the mechanics of macrophage migration.
Our objective is to build a sound experimental corpus to substantiate this two-module mechanism of force generation and determine its implications for macrophage 3D motility. To this end, we will characterize podosome molecular architecture and formulate its relationship to force generation. Furthermore, we will identify the mechanical role of key podosome components in cell migration.
We assembled a multidisciplinary team that combines cutting-edge expertise in: i) macrophage 3D migration, ii) 3D nanoscale imaging, iii) live super-resolution imaging, iv) cryo-electron tomography technologies allowing resolution of actin filaments within cellular networks, v) measurement of podosome protrusion forces and vi) mechanics of 3D cell migration in custom microfabricated environments.
Our ambitious research plan will deliver the nanoscale localization of podosome molecular components (applicants A1, A3), determine how the architecture evolves along with force dynamics (A2), investigate the mechanics of 3D migrating cells (A4) and reveal the role of podosome components in these uncharted features (A1-4). Thanks to this groundbreaking study, we will articulate mechanical and architectural insights into an integrated portrait of podosomes from the molecular scale up to the biological context of 3D cell migration and thus identify molecular means for the modulation of pathological macrophage tissue infiltration.

Cells in developing organisms can keep track of time. They use this to make important decisions - for example on when to turn or to stop in the case of migrating axons or cells - without being instructed to do so by signals from other cells in their surroundings. But how such internal clocks work, and importantly, how they are made to be so precise, is still largely unknown. Previous work by one of the participating teams has shown that during the development of the nematode worm C. elegans, the migration of a neuroblast is regulated through the timed expression of a signaling receptor. This system provides a powerful assay to study at single cell level how an internal clock controls gene expression. The three teams will use a unique combination of genetics, evolutionary biology and mathematical modeling to gain detailed insight into the workings of this timing mechanism. They will investigate how timing is mediated at the transcriptional level, how robust this is to environmental variations and how this mechanism has evolved in other nematode species. Importantly, these results will be used in mathematical modeling to gain insight into the underlying regulatory architecture and to make predictions that will be tested in further experiments. Such interplay between experimental and theoretical analysis is a powerful and innovative approach that will enable the three teams to gain deep understanding of how cells measure time.

Curiosity, defined as the intrinsic desire to know, is among the last unexplored frontiers of higher cognition, and we know very little about its neural mechanisms. We propose to address this question by developing a program for studying curiosity using an integrated empirical/computational approach in humans and non-human primates. We examine the hypothesis that curiosity is a family of mechanisms that evolved to allow animals to maximize their knowledge of the useful properties of the world – i.e., the regularities that exist in the world - using active, targeted investigations. In two experiments, we probe two processes that contribute to curiosity-based exploration. In experiment 1 we examine how agents ascribe value (“interest”) to surprising events, by (1) developing a new behavioral task where children and monkeys make tradeoffs between exploring for sources of reward versus exploring a surprising item, and (2) investigating single-neuron responses related to curiosity-based exploration in cortical areas implicated in the control of attention. In experiment 2 we ask whether subjects show a more sophisticated form of curiosity guided by learning progress – a meta-cognitive tracking of the amount of learning that the individual can make in a task - using new behavioral paradigms where children or non-human primates see a set of symbolic learning problems and freely choose which ones to explore. To quantitatively model curiosity we use the framework of Bayesian Reinforcement Learning, which allows us to infer the agent’s beliefs about the probabilities of various events (rewards, surprises, or learning), the value they place on sampling different events, and how this value depends on the task context. The studies closely integrate the expertise of the 3 member teams in developmental psychology (Kidd), neurophysiology of non-human primates (Gottlieb) and computational modeling of active learning in robotic systems (Oudeyer). Our goal is to develop an integrated theory that (1) incorporates curiosity in established quantitative frameworks of learning and decision making, (2) links it with core cognitive functions such as selective attention, (3) compares its expression in humans and non-human primates, and (4) begins to elucidate its neural mechanisms.