Programmable interactions with biomimetic DNA linkers at fluid membranes and interfaces

At the heart of the structured architecture and complex dynamics of biological systems are specific and timely interactions operated by biomolecules. In many instances, biomolecular agents are spatially confined to flexible lipid membranes where, among other functions, they control cell adhesion, motility and tissue formation. Besides being central to several biological processes, \emph{multivalent interactions} mediated by reactive linkers confined to deformable substrates underpin the design of synthetic-biological platforms and advanced biomimetic materials. Here we review recent advances on the experimental study and theoretical modelling of a heterogeneous class of biomimetic systems in which synthetic linkers mediate multivalent interactions between fluid and deformable colloidal units, including lipid vesicles and emulsion droplets. Linkers are often prepared from synthetic DNA nanostructures, enabling full programmability of the thermodynamic and kinetic properties of their mutual interactions. The coupling of the statistical effects of multivalent interactions with substrate fluidity and deformability gives rise to a rich emerging phenomenology that, in the context of self-assembled soft materials, has been shown to produce exotic phase behaviour, stimuli-responsiveness, and kinetic programmability of the self-assembly process. Applications to (synthetic) biology will also be reviewed.Comment: 63 pages, revie

The Inhuman Overhang: On Differential Heterogenesis and Multi-Scalar Modeling

As a philosophical paradigm, differential heterogenesis offers us a novel descriptive vantage with which to inscribe Deleuze’s virtuality within the terrain of “differential becoming,” conjugating “pure saliences” so as to parse economies, microhistories, insurgencies, and epistemological evolutionary processes that can be conceived of independently from their representational form. Unlike Gestalt theory’s oppositional constructions, the advantage of this aperture is that it posits a dynamic context to both media and its analysis, rendering them functionally tractable and set in relation to other objects, rather than as sedentary identities. Surveying the genealogy of differential heterogenesis with particular interest in the legacy of Lautman’s dialectic, I make the case for a reading of the Deleuzean virtual that departs from an event-oriented approach, galvanizing Sarti and Citti’s dynamic a priori vis-à-vis Deleuze’s philosophy of difference. Specifically, I posit differential heterogenesis as frame with which to examine our contemporaneous epistemic shift as it relates to multi-scalar computational modeling while paying particular attention to neuro-inferential modes of inductive learning and homologous cognitive architecture. Carving a bricolage between Mark Wilson’s work on the “greediness of scales” and Deleuze’s “scales of reality”, this project threads between static ecologies and active externalism vis-à-vis endocentric frames of reference and syntactical scaffolding

Isolating intrinsic noise sources in a stochastic genetic switch

The stochastic mutual repressor model is analysed using perturbation methods. This simple model of a gene circuit consists of two genes and three promotor states. Either of the two protein products can dimerize, forming a repressor molecule that binds to the promotor of the other gene. When the repressor is bound to a promotor, the corresponding gene is not transcribed and no protein is produced. Either one of the promotors can be repressed at any given time or both can be unrepressed, leaving three possible promotor states. This model is analysed in its bistable regime in which the deterministic limit exhibits two stable fixed points and an unstable saddle, and the case of small noise is considered. On small time scales, the stochastic process fluctuates near one of the stable fixed points, and on large time scales, a metastable transition can occur, where fluctuations drive the system past the unstable saddle to the other stable fixed point. To explore how different intrinsic noise sources affect these transitions, fluctuations in protein production and degradation are eliminated, leaving fluctuations in the promotor state as the only source of noise in the system. Perturbation methods are then used to compute the stability landscape and the distribution of transition times, or first exit time density. To understand how protein noise affects the system, small magnitude fluctuations are added back into the process, and the stability landscape is compared to that of the process without protein noise. It is found that significant differences in the random process emerge in the presence of protein noise

Fully Integrated Biochip Platforms for Advanced Healthcare

Recent advances in microelectronics and biosensors are enabling developments of innovative biochips for advanced healthcare by providing fully integrated platforms for continuous monitoring of a large set of human disease biomarkers. Continuous monitoring of several human metabolites can be addressed by using fully integrated and minimally invasive devices located in the sub-cutis, typically in the peritoneal region. This extends the techniques of continuous monitoring of glucose currently being pursued with diabetic patients. However, several issues have to be considered in order to succeed in developing fully integrated and minimally invasive implantable devices. These innovative devices require a high-degree of integration, minimal invasive surgery, long-term biocompatibility, security and privacy in data transmission, high reliability, high reproducibility, high specificity, low detection limit and high sensitivity. Recent advances in the field have already proposed possible solutions for several of these issues. The aim of the present paper is to present a broad spectrum of recent results and to propose future directions of development in order to obtain fully implantable systems for the continuous monitoring of the human metabolism in advanced healthcare applications

Global convergence of quorum-sensing networks

In many natural synchronization phenomena, communication between individual elements occurs not directly, but rather through the environment. One of these instances is bacterial quorum sensing, where bacteria release signaling molecules in the environment which in turn are sensed and used for population coordination. Extending this motivation to a general non- linear dynamical system context, this paper analyzes synchronization phenomena in networks where communication and coupling between nodes are mediated by shared dynamical quan- tities, typically provided by the nodes' environment. Our model includes the case when the dynamics of the shared variables themselves cannot be neglected or indeed play a central part. Applications to examples from systems biology illustrate the approach.Comment: Version 2: minor editions, added section on noise. Number of pages: 36

Chromatin regulation at the frontier of synthetic biology

As synthetic biology approaches are extended to diverse applications throughout medicine, biotechnology and basic biological research, there is an increasing need to engineer yeast, plant and mammalian cells. Eukaryotic genomes are regulated by the diverse biochemical and biophysical states of chromatin, which brings distinct challenges, as well as opportunities, over applications in bacteria. Recent synthetic approaches, including 'epigenome editing', have allowed the direct and functional dissection of many aspects of physiological chromatin regulation. These studies lay the foundation for biomedical and biotechnological engineering applications that could take advantage of the unique combinatorial and spatiotemporal layers of chromatin regulation to create synthetic systems of unprecedented sophistication.National Institute of General Medical Sciences (U.S.) (Ruth L. Kirschstein Postdoctoral Fellowship )United States. Defense Advanced Research Projects AgencyNational Institutes of Health (U.S.) (R24 Grant)Wyss Institute for Biologically Inspired EngineeringHoward Hughes Medical Institut

Supraspinal activity patterns underpinning locomotor diversity in larval zebrafish

How do supraspinal circuits produce the diversity of locomotor outputs needed for an animal’s survival? To answer this question, I study the reticulospinal (RS) system of larval zebrafish, as these cells provide the main source of descending motor control. I combine two-photon calcium imaging of RS neurons with high-speed behavioural tracking to study RS activity across a range of kinematically distinct swim types. Examination of reticulospinal recruitment across different swim types has revealed unique, but partially overlapping activity patterns, suggesting that some cells encode kinematics common to multiple swim types, while others encode kinematics which are characteristic of a specific swim type. By developing regression-based encoding models which describe a cell’s activity using low-level tail kinematics, we identify “kinematic modules”. These modules contain cells with similar kinematic encoding and thus represent the core combinations of kinematic features encoded by RS activity. I find that laser ablation of cells within a module produce specific kinematic deficits without affecting shared elements of locomotion. This data suggest a circuit architecture where kinematic modules can be differentially combined to produce locomotor diversity through the context-specific recruitment of particular groups of RS neurons. I also describe a novel preparation for the imaging of fluorescent activity indicators in larval zebrafish using an acousto-optic lens microscope. This methodology allows for rapid 3D point scanning of the entire reticulospinal complex during visual stimulus presentation and behavioural tracking. The improved temporal resolution and sampling across the whole population provides an opportunity to examine the relative timing of activity between reticulospinal neurons

Single DNA conformations and biological function

From a nanoscience perspective, cellular processes and their reduced in vitro imitations provide extraordinary examples for highly robust few or single molecule reaction pathways. A prime example are biochemical reactions involving DNA molecules, and the coupling of these reactions to the physical conformations of DNA. In this review, we summarise recent results on the following phenomena: We investigate the biophysical properties of DNA-looping and the equilibrium configurations of DNA-knots, whose relevance to biological processes are increasingly appreciated. We discuss how random DNA-looping may be related to the efficiency of the target search process of proteins for their specific binding site on the DNA molecule. And we dwell on the spontaneous formation of intermittent DNA nanobubbles and their importance for biological processes, such as transcription initiation. The physical properties of DNA may indeed turn out to be particularly suitable for the use of DNA in nanosensing applications.Comment: 53 pages, 45 figures. Slightly revised version of a review article, that is going to appear in the J. Comput. Theoret. Nanoscience; some typos correcte

Neurofly 2008 abstracts : the 12th European Drosophila neurobiology conference 6-10 September 2008 Wuerzburg, Germany

This volume consists of a collection of conference abstracts