Intracellular Information Processing through Encoding and Decoding of Dynamic Signaling Features.

Cell signaling dynamics and transcriptional regulatory activities are variable within specific cell types responding to an identical stimulus. In addition to studying the network interactions, there is much interest in utilizing single cell scale data to elucidate the non-random aspects of the variability involved in cellular decision making. Previous studies have considered the information transfer between the signaling and transcriptional domains based on an instantaneous relationship between the molecular activities. These studies predict a limited binary on/off encoding mechanism which underestimates the complexity of biological information processing, and hence the utility of single cell resolution data. Here we pursue a novel strategy that reformulates the information transfer problem as involving dynamic features of signaling rather than molecular abundances. We pursue a computational approach to test if and how the transcriptional regulatory activity patterns can be informative of the temporal history of signaling. Our analysis reveals (1) the dynamic features of signaling that significantly alter transcriptional regulatory patterns (encoding), and (2) the temporal history of signaling that can be inferred from single cell scale snapshots of transcriptional activity (decoding). Immediate early gene expression patterns were informative of signaling peak retention kinetics, whereas transcription factor activity patterns were informative of activation and deactivation kinetics of signaling. Moreover, the information processing aspects varied across the network, with each component encoding a selective subset of the dynamic signaling features. We developed novel sensitivity and information transfer maps to unravel the dynamic multiplexing of signaling features at each of these network components. Unsupervised clustering of the maps revealed two groups that aligned with network motifs distinguished by transcriptional feedforward vs feedback interactions. Our new computational methodology impacts the single cell scale experiments by identifying downstream snapshot measures required for inferring specific dynamical features of upstream signals involved in the regulation of cellular responses

Optimal decision making for sperm chemotaxis in the presence of noise

For navigation, microscopic agents such as biological cells rely on noisy sensory input. In cells performing chemotaxis, such noise arises from the stochastic binding of signaling molecules at low concentrations. Using chemotaxis of sperm cells as application example, we address the classic problem of chemotaxis towards a single target. We reveal a fundamental relationship between the speed of chemotactic steering and the strength of directional fluctuations that result from the amplification of noise in the chemical input signal. This relation implies a trade-off between slow, but reliable, and fast, but less reliable, steering. By formulating the problem of optimal navigation in the presence of noise as a Markov decision process, we show that dynamic switching between reliable and fast steering substantially increases the probability to find a target, such as the egg. Intriguingly, this decision making would provide no benefit in the absence of noise. Instead, decision making is most beneficial, if chemical signals are above detection threshold, yet signal-to-noise ratios of gradient measurements are low. This situation generically arises at intermediate distances from a target, where signaling molecules emitted by the target are diluted, thus defining a `noise zone' that cells have to cross. Our work addresses the intermediate case between well-studied perfect chemotaxis at high signal-to-noise ratios close to a target, and random search strategies in the absence of navigation cues, e.g. far away from a target. Our specific results provide a rational for the surprising observation of decision making in recent experiments on sea urchin sperm chemotaxis. The general theory demonstrates how decision making enables chemotactic agents to cope with high levels of noise in gradient measurements by dynamically adjusting the persistence length of a biased persistent random walk.Comment: 9 pages, 5 figure

The fidelity of dynamic signaling by noisy biomolecular networks

This is the final version of the article. Available from Public Library of Science via the DOI in this record.Cells live in changing, dynamic environments. To understand cellular decision-making, we must therefore understand how fluctuating inputs are processed by noisy biomolecular networks. Here we present a general methodology for analyzing the fidelity with which different statistics of a fluctuating input are represented, or encoded, in the output of a signaling system over time. We identify two orthogonal sources of error that corrupt perfect representation of the signal: dynamical error, which occurs when the network responds on average to other features of the input trajectory as well as to the signal of interest, and mechanistic error, which occurs because biochemical reactions comprising the signaling mechanism are stochastic. Trade-offs between these two errors can determine the system's fidelity. By developing mathematical approaches to derive dynamics conditional on input trajectories we can show, for example, that increased biochemical noise (mechanistic error) can improve fidelity and that both negative and positive feedback degrade fidelity, for standard models of genetic autoregulation. For a group of cells, the fidelity of the collective output exceeds that of an individual cell and negative feedback then typically becomes beneficial. We can also predict the dynamic signal for which a given system has highest fidelity and, conversely, how to modify the network design to maximize fidelity for a given dynamic signal. Our approach is general, has applications to both systems and synthetic biology, and will help underpin studies of cellular behavior in natural, dynamic environments.We acknowledge support from a Medical Research Council and Engineering and Physical Sciences Council funded Fellowship in Biomedical Informatics (CGB) and a Scottish Universities Life Sciences Alliance chair in Systems Biology (PSS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Interrogating cellular perception and decision making with optogenetic tools.

Optogenetics promises to deepen our understanding of how cells perceive and respond to complex and dynamic signals and how this perception regulates normal and abnormal function. In this study, we present our vision for how these nascent tools may transform our view of fundamental cell biological processes

A survey of handover algorithms in DVB-H

Digital Video Broadcasting for Handhelds (DVB-H) is a standard for broadcasting IP Datacast (IPDC) services to mobile handheld terminals. Based on the DVB-T standard, DVB-H adds new features such as time slicing, MPE-FEC, in-depth interleavers, mandatory cell id identifier, optional 4K-modulation mode and the use of 5 MHz bandwidth in addition to the usually used 6, 7, or 8 MHz raster. IPDC over DVB-H is proposed for ETSI to complement the DVB-H standard by combining IPDC and DVB-H in an end-to-end system. Handover in such unidirectional broadcasting networks is a novel issue. In the last few years since the birth of DVB-H technology, great attention has been given to the performance analysis of DVB-H mobile terminals. Handover is one of the main research topics for DVB-H in mobile scenarios. Better reception quality and greater power efficiency are considered to be the main targets of handover research for DVB-H. New algorithms for different handover stages in DVB-H have been the subject of recent research and are currently being studied. Further novel algorithms need to be designed to improve the mobile reception quality. This article provides a comprehensive survey of the handover algorithms in DVB-H. A systematic evaluation and categorization approach is proposed based on the problems the algorithms solve and the handover stages being focused on. Criteria are proposed and analyzed to facilitate designing better handover algorithms for DVB-H that have been identified from the research conducted by the author

A stochastic and dynamical view of pluripotency in mouse embryonic stem cells

Pluripotent embryonic stem cells are of paramount importance for biomedical research thanks to their innate ability for self-renewal and differentiation into all major cell lines. The fateful decision to exit or remain in the pluripotent state is regulated by complex genetic regulatory network. Latest advances in transcriptomics have made it possible to infer basic topologies of pluripotency governing networks. The inferred network topologies, however, only encode boolean information while remaining silent about the roles of dynamics and molecular noise in gene expression. These features are widely considered essential for functional decision making. Herein we developed a framework for extending the boolean level networks into models accounting for individual genetic switches and promoter architecture which allows mechanistic interrogation of the roles of molecular noise, external signaling, and network topology. We demonstrate the pluripotent state of the network to be a broad attractor which is robust to variations of gene expression. Dynamics of exiting the pluripotent state, on the other hand, is significantly influenced by the molecular noise originating from genetic switching events which makes cells more responsive to extracellular signals. Lastly we show that steady state probability landscape can be significantly remodeled by global gene switching rates alone which can be taken as a proxy for how global epigenetic modifications exert control over stability of pluripotent states.Comment: 11 pages, 7 figure

Separation Framework: An Enabler for Cooperative and D2D Communication for Future 5G Networks

Soaring capacity and coverage demands dictate that future cellular networks need to soon migrate towards ultra-dense networks. However, network densification comes with a host of challenges that include compromised energy efficiency, complex interference management, cumbersome mobility management, burdensome signaling overheads and higher backhaul costs. Interestingly, most of the problems, that beleaguer network densification, stem from legacy networks' one common feature i.e., tight coupling between the control and data planes regardless of their degree of heterogeneity and cell density. Consequently, in wake of 5G, control and data planes separation architecture (SARC) has recently been conceived as a promising paradigm that has potential to address most of aforementioned challenges. In this article, we review various proposals that have been presented in literature so far to enable SARC. More specifically, we analyze how and to what degree various SARC proposals address the four main challenges in network densification namely: energy efficiency, system level capacity maximization, interference management and mobility management. We then focus on two salient features of future cellular networks that have not yet been adapted in legacy networks at wide scale and thus remain a hallmark of 5G, i.e., coordinated multipoint (CoMP), and device-to-device (D2D) communications. After providing necessary background on CoMP and D2D, we analyze how SARC can particularly act as a major enabler for CoMP and D2D in context of 5G. This article thus serves as both a tutorial as well as an up to date survey on SARC, CoMP and D2D. Most importantly, the article provides an extensive outlook of challenges and opportunities that lie at the crossroads of these three mutually entangled emerging technologies.Comment: 28 pages, 11 figures, IEEE Communications Surveys & Tutorials 201