Systems practice in several communities in Philadelphia

Several volunteer community groups in inner-city Philadelphia have been working to improve their blighted neighborhoods. This article describes how they applied Ackoff's interactive planning and Forrester's system dynamics and then details two programs that were implemented as a result. Examples of government efforts and “community development” funding structures are included for contrast. Local and federal government efforts tend to address the symptoms, but not the producers of problems, and are short-sighted because they tend to ignore the context that creates the problem situation. The structures for allocating resources appear to serve the purposes of decision makers who allocate funds, at the expense of the communities that desperately need services. A major point of this article is that such systems approaches as interactive management and system dynamics offer hope for solving seemingly intractable problems that threaten many communities and societies today.     

Genome-wide detection and characterization of positive selection in human populations

With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.     

A dynamic early East Antarctic Ice Sheet suggested by ice-covered fjord landscapes

The first Cenozoic ice sheets initiated in Antarctica from the Gamburtsev Subglacial Mountains and other highlands as a result of rapid global cooling ～34 million years ago. In the subsequent 20 million years, at a time of declining atmospheric carbon dioxide concentrations and an evolving Antarctic circumpolar current, sedimentary sequence interpretation and numerical modelling suggest that cyclical periods of ice-sheet expansion to the continental margin, followed by retreat to the subglacial highlands, occurred up to thirty times. These fluctuations were paced by orbital changes and were a major influence on global sea levels. Ice-sheet models show that the nature of such oscillations is critically dependent on the pattern and extent of Antarctic topographic lowlands. Here we show that the basal topography of the Aurora Subglacial Basin of East Antarctica, at present overlain by 2-4.5?km of ice, is characterized by a series of well-defined topographic channels within a mountain block landscape. The identification of this fjord landscape, based on new data from ice-penetrating radar, provides an improved understanding of the topography of the Aurora Subglacial Basin and its surroundings, and reveals a complex surface sculpted by a succession of ice-sheet configurations substantially different from today's. At different stages during its fluctuations, the edge of the East Antarctic Ice Sheet lay pinned along the margins of the Aurora Subglacial Basin, the upland boundaries of which are currently above sea level and the deepest parts of which are more than 1?km below sea level. Although the timing of the channel incision remains uncertain, our results suggest that the fjord landscape was carved by at least two iceflow regimes of different scales and directions, each of which would have over-deepened existing topographic depressions, reversing valley floor slopes.     

Comprehensive analysis of the chromatin landscape in Drosophila melanogaster

Chromatin is composed of DNA and a variety of modified histones and non-histone proteins, which have an impact on cell differentiation, gene regulation and other key cellular processes. Here we present a genome-wide chromatin landscape for Drosophila melanogaster based on eighteen histone modifications, summarized by nine prevalent combinatorial patterns. Integrative analysis with other data (non-histone chromatin proteins, DNase I hypersensitivity, GRO-Seq reads produced by engaged polymerase, short/long RNA products) reveals discrete characteristics of chromosomes, genes, regulatory elements and other functional domains. We find that active genes display distinct chromatin signatures that are correlated with disparate gene lengths, exon patterns, regulatory functions and genomic contexts. We also demonstrate a diversity of signatures among Polycomb targets that include a subset with paused polymerase. This systematic profiling and integrative analysis of chromatin signatures provides insights into how genomic elements are regulated, and will serve as a resource for future experimental investigations of genome structure and function.     

Oxysterols direct immune cell migration via EBI2

Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) is a G-protein-coupled receptor that is required for humoral immune responses; polymorphisms in the receptor have been associated with inflammatory autoimmune diseases. The natural ligand for EBI2 has been unknown. Here we describe the identification of 7α,25-dihydroxycholesterol (also called 7α,25-OHC or 5-cholesten-3β,7α,25-triol) as a potent and selective agonist of EBI2. Functional activation of human EBI2 by 7α,25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high-affinity radioligand binding. Furthermore, we find that 7α,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A critical enzyme required for the generation of 7α,25-OHC is cholesterol 25-hydroxylase (CH25H). Similar to EBI2 receptor knockout mice, mice deficient in CH25H fail to position activated B cells within the spleen to the outer follicle and mount a reduced plasma cell response after an immune challenge. This demonstrates that CH25H generates EBI2 biological activity in vivo and indicates that the EBI2-oxysterol signalling pathway has an important role in the adaptive immune response.     

An integrated semiconductor device enabling non-optical genome sequencing

The seminal importance of DNA sequencing to the life sciences, biotechnology and medicine has driven the search for more scalable and lower-cost solutions. Here we describe a DNA sequencing technology in which scalable, low-cost semiconductor manufacturing techniques are used to make an integrated circuit able to directly perform non-optical DNA sequencing of genomes. Sequence data are obtained by directly sensing the ions produced by template-directed DNA polymerase synthesis using all-natural nucleotides on this massively parallel semiconductor-sensing device or ion chip. The ion chip contains ion-sensitive, field-effect transistor-based sensors in perfect register with 1.2 million wells, which provide confinement and allow parallel, simultaneous detection of independent sequencing reactions. Use of the most widely used technology for constructing integrated circuits, the complementary metal-oxide semiconductor (CMOS) process, allows for low-cost, large-scale production and scaling of the device to higher densities and larger array sizes. We show the performance of the system by sequencing three bacterial genomes, its robustness and scalability by producing ion chips with up to 10 times as many sensors and sequencing a human genome.     

A closely packed system of low-mass, low-density planets transiting Kepler-11

When an extrasolar planet passes in front of (transits) its star, its radius can be measured from the decrease in starlight and its orbital period from the time between transits. Multiple planets transiting the same star reveal much more: period ratios determine stability and dynamics, mutual gravitational interactions reflect planet masses and orbital shapes, and the fraction of transiting planets observed as multiples has implications for the planarity of planetary systems. But few stars have more than one known transiting planet, and none has more than three. Here we report Kepler spacecraft observations of a single Sun-like star, which we call Kepler-11, that reveal six transiting planets, five with orbital periods between 10 and 47?days and a sixth planet with a longer period. The five inner planets are among the smallest for which mass and size have both been measured, and these measurements imply substantial envelopes of light gases. The degree of coplanarity and proximity of the planetary orbits imply energy dissipation near the end of planet formation.