Experimental and computational analyses reveal that environmental restrictions shape HIV-1 spread in 3D cultures

Here, using an integrative experimental and computational approach, Imle et al. show how cell motility and density affect HIV cell-associated transmission in a three-dimensional tissue-like culture system of CD4+ T cells and collagen, and how different collagen matrices restrict infection by cell-free virions

Polarity development by asymmetric protein-cluster distributions in response to cortical flows in C. elegans zygotes

Asymmetric cell-division in the one-cell embryo is a key step in embryonic development. The initially homogeneous zygote establishes an anterior-posterior axis within the cell, allowing for the unequal distribution of cell fate determinants and subsequent cell differentiation. Therefore, polarity development is a fundamental procedure that defines the information template from which all future cell processes derive their cues. Many molecular players in polarity formation in C. elegans have been identified, but the design principles that underpin their interactions and how this contributes to successful polarisation remain unclear. This thesis focuses on the role of the clustering species PAR-3 and how its integration in the governing biochemical network promotes robust polarisation. To correctly proceed to the two-cell stage, the foundational step of polarity formation must be responsive to the polarising cue and maintain established domains ready for downstream cell-cycle processes. We characterise global flows along the polarity axis and investigate coupling between the cortical flows and PAR-3 cluster sizes. We find there is no dynamic advantage for larger clusters and instead conclude all clusters flow with the same efficiency. Alternatively, we investigate whether enhancement of clusters is a response to mechanical forces within the cortex during the period of flow but find little direct evidence of this relationship. Rodriguez et al proposed kinase cycling between inactive (advective) and inactive (diffuse) state. We model two distinct reaction pathways through reaction-advection-diffusion simulation and assess their viability by implementation of Approximate Bayesian Computation. We find that direct binding through a flow-sensing, inactive state, followed by switching to a diffuse active state yields a network that is unviable and sensitive to perturbation. Sensitivity is alleviated when the advective species serves only to enhance independent binding of the active species. Therefore, we propose kinase cycling through this network motif as a mechanism towards enhanced robust polarisation.Open Acces

Recommender Systems

The ongoing rapid expansion of the Internet greatly increases the necessity of effective recommender systems for filtering the abundant information. Extensive research for recommender systems is conducted by a broad range of communities including social and computer scientists, physicists, and interdisciplinary researchers. Despite substantial theoretical and practical achievements, unification and comparison of different approaches are lacking, which impedes further advances. In this article, we review recent developments in recommender systems and discuss the major challenges. We compare and evaluate available algorithms and examine their roles in the future developments. In addition to algorithms, physical aspects are described to illustrate macroscopic behavior of recommender systems. Potential impacts and future directions are discussed. We emphasize that recommendation has a great scientific depth and combines diverse research fields which makes it of interests for physicists as well as interdisciplinary researchers.Comment: 97 pages, 20 figures (To appear in Physics Reports

Distributed Cognitive RAT Selection in 5G Heterogeneous Networks: A Machine Learning Approach

The leading role of the HetNet (Heterogeneous Networks) strategy as the key Radio Access Network (RAN) architecture for future 5G networks poses serious challenges to the current cell selection mechanisms used in cellular networks. The max-SINR algorithm, although effective historically for performing the most essential networking function of wireless networks, is inefficient at best and obsolete at worst in 5G HetNets. The foreseen embarrassment of riches and diversified propagation characteristics of network attachment points spanning multiple Radio Access Technologies (RAT) requires novel and creative context-aware system designs. The association and routing decisions, in the context of single-RAT or multi-RAT connections, need to be optimized to efficiently exploit the benefits of the architecture. However, the high computational complexity required for multi-parametric optimization of utility functions, the difficulty of modeling and solving Markov Decision Processes, the lack of guarantees of stability of Game Theory algorithms, and the rigidness of simpler methods like Cell Range Expansion and operator policies managed by the Access Network Discovery and Selection Function (ANDSF), makes neither of these state-of-the-art approaches a favorite. This Thesis proposes a framework that relies on Machine Learning techniques at the terminal device-level for Cognitive RAT Selection. The use of cognition allows the terminal device to learn both a multi-parametric state model and effective decision policies, based on the experience of the device itself. This implies that a terminal, after observing its environment during a learning period, may formulate a system characterization and optimize its own association decisions without any external intervention. In our proposal, this is achieved through clustering of appropriately defined feature vectors for building a system state model, supervised classification to obtain the current system state, and reinforcement learning for learning good policies. This Thesis describes the above framework in detail and recommends adaptations based on the experimentation with the X-means, k-Nearest Neighbors, and Q-learning algorithms, the building blocks of the solution. The network performance of the proposed framework is evaluated in a multi-agent environment implemented in MATLAB where it is compared with alternative RAT selection mechanisms

Computational Methods for Knowledge Integration in the Analysis of Large-scale Biological Networks

abstract: As we migrate into an era of personalized medicine, understanding how bio-molecules interact with one another to form cellular systems is one of the key focus areas of systems biology. Several challenges such as the dynamic nature of cellular systems, uncertainty due to environmental influences, and the heterogeneity between individual patients render this a difficult task. In the last decade, several algorithms have been proposed to elucidate cellular systems from data, resulting in numerous data-driven hypotheses. However, due to the large number of variables involved in the process, many of which are unknown or not measurable, such computational approaches often lead to a high proportion of false positives. This renders interpretation of the data-driven hypotheses extremely difficult. Consequently, a dismal proportion of these hypotheses are subject to further experimental validation, eventually limiting their potential to augment existing biological knowledge. This dissertation develops a framework of computational methods for the analysis of such data-driven hypotheses leveraging existing biological knowledge. Specifically, I show how biological knowledge can be mapped onto these hypotheses and subsequently augmented through novel hypotheses. Biological hypotheses are learnt in three levels of abstraction -- individual interactions, functional modules and relationships between pathways, corresponding to three complementary aspects of biological systems. The computational methods developed in this dissertation are applied to high throughput cancer data, resulting in novel hypotheses with potentially significant biological impact.Dissertation/ThesisPh.D. Computer Science 201

Connectable Components for Protein Design

Protein design requires reusable, trustworthy, and connectable parts in order to scale to complex challenges. The recent explosion of protein structures stored within the Protein Data Bank provides a wealth of small motifs we can harvest, but we still lack tools to combine them into larger proteins. Here I explore two approaches for connecting reusable protein components on two different length scales. On the atomic scale, I build an interactive search engine for connecting chemical fragments together. Protein fragments built using this search engine recapitulate native-like protein assemblies that can be integrated into existing protein scaffolds using backbone search engines such as MaDCaT. On the protein domain scale, I quantitatively dissect structural variations in two-component systems in order to extract general principles for engineering interfacial flexibility between modular four-helix bundles. These bundles exhibit large scissoring motions where helices move towards or away from the bundle axis and these motions propagate across domain boundaries. Together, these two approaches form the beginnings of a multiscale methodology for connecting reusable protein fragments where there is a constant interplay and feedback between design of atomic structure, secondary structure, and tertiary structure. Rapid iteration, visualization, and search glue these diverse length scales together into a cohesive whole

LSST Science Book, Version 2.0

A survey that can cover the sky in optical bands over wide fields to faint magnitudes with a fast cadence will enable many of the exciting science opportunities of the next decade. The Large Synoptic Survey Telescope (LSST) will have an effective aperture of 6.7 meters and an imaging camera with field of view of 9.6 deg^2, and will be devoted to a ten-year imaging survey over 20,000 deg^2 south of +15 deg. Each pointing will be imaged 2000 times with fifteen second exposures in six broad bands from 0.35 to 1.1 microns, to a total point-source depth of r~27.5. The LSST Science Book describes the basic parameters of the LSST hardware, software, and observing plans. The book discusses educational and outreach opportunities, then goes on to describe a broad range of science that LSST will revolutionize: mapping the inner and outer Solar System, stellar populations in the Milky Way and nearby galaxies, the structure of the Milky Way disk and halo and other objects in the Local Volume, transient and variable objects both at low and high redshift, and the properties of normal and active galaxies at low and high redshift. It then turns to far-field cosmological topics, exploring properties of supernovae to z~1, strong and weak lensing, the large-scale distribution of galaxies and baryon oscillations, and how these different probes may be combined to constrain cosmological models and the physics of dark energy.Comment: 596 pages. Also available at full resolution at http://www.lsst.org/lsst/sciboo