Systems approaches and algorithms for discovery of combinatorial therapies

Effective therapy of complex diseases requires control of highly non-linear complex networks that remain incompletely characterized. In particular, drug intervention can be seen as control of signaling in cellular networks. Identification of control parameters presents an extreme challenge due to the combinatorial explosion of control possibilities in combination therapy and to the incomplete knowledge of the systems biology of cells. In this review paper we describe the main current and proposed approaches to the design of combinatorial therapies, including the empirical methods used now by clinicians and alternative approaches suggested recently by several authors. New approaches for designing combinations arising from systems biology are described. We discuss in special detail the design of algorithms that identify optimal control parameters in cellular networks based on a quantitative characterization of control landscapes, maximizing utilization of incomplete knowledge of the state and structure of intracellular networks. The use of new technology for high-throughput measurements is key to these new approaches to combination therapy and essential for the characterization of control landscapes and implementation of the algorithms. Combinatorial optimization in medical therapy is also compared with the combinatorial optimization of engineering and materials science and similarities and differences are delineated.Comment: 25 page

Reconstruction strategy for echo planar spectroscopy and its application to partially undersampled imaging.

The most commonly encountered form of echo planar spectroscopy involves oscillating gradients in one spatial dimension during readout. Data are consequently not sampled on a Cartesian grid. A fast gridding algorithm applicable to this particular situation is presented. The method is optimal, i.e., it performs as well as the full discrete Fourier transform for band limited signals while allowing for use of the fast Fourier transform. The method is demonstrated for reconstruction of data that are partially undersampled in the time domain. The advantages of undersampling are lower hardware requirements or fewer interleaves per acquisition. The method is of particular interest when large bandwidths are needed (e.g., for high field scanning) and for scanners with limited gradient performance. The unavoidable artifacts resulting from undersampling are demonstrated to be acceptable for spectroscopy with long echo times

Fifty years of spellchecking

A short history of spellchecking from the late 1950s to the present day, describing its development through dictionary lookup, affix stripping, correction, confusion sets, and edit distance to the use of gigantic databases

Holographic three-point functions of giant gravitons

Working within the AdS/CFT correspondence we calculate the three-point function of two giant gravitons and one pointlike graviton using methods of semiclassical string theory and considering both the case where the giant gravitons wrap an S^3 in S^5 and the case where the giant gravitons wrap an S^3 in AdS_5. We likewise calculate the correlation function in N=4 SYM using two Schur polynomials and a single trace chiral primary. We find that the gauge and string theory results have structural similarities but do not match perfectly, and interpret this in terms of the Schur polynomials' inability to interpolate between dual giant and pointlike gravitons.Comment: 21 page

Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer

Apoptosis is an evolutionarily conserved and tightly regulated cell death modality. It serves important roles in physiology by sculpting complex tissues during embryogenesis and by removing effete cells that have reached advanced age or whose genomes have been irreparably damaged. Apoptosis culminates in the rapid and decisive removal of cell corpses by efferocytosis, a term used to distinguish the engulfment of apoptotic cells from other phagocytic processes. Over the past decades, the molecular and cell biological events associated with efferocytosis have been rigorously studied, and many eat-me signals and receptors have been identified. The externalization of phosphatidylserine (PS) is arguably the most emblematic eat-me signal that is in turn bound by a large number of serum proteins and opsonins that facilitate efferocytosis. Under physiological conditions, externalized PS functions as a dominant and evolutionarily conserved immunosuppressive signal that promotes tolerance and prevents local and systemic immune activation. Pathologically, the innate immunosuppressive effect of externalized PS has been hijacked by numerous viruses, microorganisms, and parasites to facilitate infection, and in many cases, establish infection latency. PS is also profoundly dysregulated in the tumor microenvironment and antagonizes the development of tumor immunity. In this review, we discuss the biology of PS with respect to its role as a global immunosuppressive signal and how PS is exploited to drive diverse pathological processes such as infection and cancer. Finally, we outline the rationale that agents targeting PS could have significant value in cancer and infectious disease therapeutics

Synergies for Improving Oil Palm Production and Forest Conservation in Floodplain Landscapes

Lowland tropical forests are increasingly threatened with conversion to oil palm as global demand and high profit drives crop expansion throughout the world’s tropical regions. Yet, landscapes are not homogeneous and regional constraints dictate land suitability for this crop. We conducted a regional study to investigate spatial and economic components of forest conversion to oil palm within a tropical floodplain in the Lower Kinabatangan, Sabah, Malaysian Borneo. The Kinabatangan ecosystem harbours significant biodiversity with globally threatened species but has suffered forest loss and fragmentation. We mapped the oil palm and forested landscapes (using object-based-image analysis, classification and regression tree analysis and on-screen digitising of high-resolution imagery) and undertook economic modelling. Within the study region (520,269 ha), 250,617 ha is cultivated with oil palm with 77% having high Net-Present-Value (NPV) estimates ($413/ha?yr–$637/ha?yr); but 20.5% is under-producing. In fact 6.3% (15,810 ha) of oil palm is commercially redundant (with negative NPV of $-299/ha?yr-$-65/ha?yr) due to palm mortality from flood inundation. These areas would have been important riparian or flooded forest types. Moreover, 30,173 ha of unprotected forest remain and despite its value for connectivity and biodiversity 64% is allocated for future oil palm. However, we estimate that at minimum 54% of these forests are unsuitable for this crop due to inundation events. If conversion to oil palm occurs, we predict a further 16,207 ha will become commercially redundant. This means that over 32,000 ha of forest within the floodplain would have been converted for little or no financial gain yet with significant cost to the ecosystem. Our findings have globally relevant implications for similar floodplain landscapes undergoing forest transformation to agriculture such as oil palm. Understanding landscape level constraints to this crop, and transferring these into policy and practice, may provide conservation and economic opportunities within these seemingly high opportunity cost landscapes

Constructing large DNA segments by iterative clone recombination

Methods for constructing large contiguous segments of DNA will be enabling for Synthetic Biology, where the assembly of genes encoding circuits, biosynthetic pathways or even whole microbial organisms is of interest. Currently, in vitro approaches to DNA synthesis are adequate for generating DNAs that are up to 10s of kbp in length, and in vivo recombination strategies are more suitable for building DNA constructs that are 100 kbp or larger. We have developed a vector system for efficient assembly of large DNA molecules by iterative in vivo recombination of fosmid clones. Two custom fosmid vectors have been built, pFOSAMP and pFOSKAN, that support antibiotic switching. Using this technique we rebuilt two non-contiguous regions of the Haemophilus influenzae genome as episomes in recombinogenic Escherichia coli host cells. These regions together comprise190 kbp, or 10.4% of the H. influenze genome