Shigella sonnei genome sequencing and phylogenetic analysis indicate recent global dissemination from Europe

Shigella are human-adapted Escherichia coli that have gained the ability to invade the human gut mucosa and cause dysentery1,2, spreading efficiently via low-dose fecal-oral transmission3,4. Historically, S. sonnei has been predominantly responsible for dysentery in developed countries, but is now emerging as a problem in the developing world, apparently replacing the more diverse S. flexneri in areas undergoing economic development and improvements in water quality4-6. Classical approaches have shown S. sonnei is genetically conserved and clonal7. We report here whole-genome sequencing of 132 globally-distributed isolates. Our phylogenetic analysis shows that the current S. sonnei population descends from a common ancestor that existed less than 500 years ago and has diversified into several distinct lineages with unique characteristics. Our analysis suggests the majority of this diversification occurred in Europe, followed by more recent establishment of local pathogen populations in other continents predominantly due to the pandemic spread of a single, rapidly-evolving, multidrug resistant lineage

Discovery of extreme particle acceleration in the microquasar Cygnus X-3

The study of relativistic particle acceleration is a major topic of high-energy astrophysics. It is well known that massive black holes in active galaxies can release a substantial fraction of their accretion power into energetic particles, producing gamma-rays and relativistic jets. Galactic microquasars (hosting a compact star of 1-10 solar masses which accretes matter from a binary companion) also produce relativistic jets. However, no direct evidence of particle acceleration above GeV energies has ever been obtained in microquasar ejections, leaving open the issue of the occurrence and timing of extreme matter energization during jet formation. Here we report the detection of transient gamma-ray emission above 100 MeV from the microquasar Cygnus X-3, an exceptional X-ray binary which sporadically produces powerful radio jets. Four gamma-ray flares (each lasting 1-2 days) were detected by the AGILE satellite simultaneously with special spectral states of Cygnus X-3 during the period mid-2007/mid-2009. Our observations show that very efficient particle acceleration and gamma-ray propagation out of the inner disk of a microquasar usually occur a few days before major relativistic jet ejections. Flaring particle energies can be thousands of times larger than previously detected maximum values (with Lorentz factors of 105 and 102 for electrons and protons, respectively). We show that the transitional nature of gamma-ray flares and particle acceleration above GeV energies in Cygnus X-3 is clearly linked to special radio/X-ray states preceding strong radio flares. Thus gamma-rays provide unique insight into the nature of physical processes in microquasars.Comment: 29 pages (including Supplementary Information), 8 figures, 2 tables version submitted to Nature on August 7, 2009 (accepted version available at http://www.nature.com/nature/journal/vaop/ncurrent/pdf/nature08578.pdf

Space Telescope and Optical Reverberation Mapping Project. V. Optical Spectroscopic Campaign and Emission-line Analysis for NGC 5548

We present the results of an optical spectroscopic monitoring program targeting NGC 5548 as part of a larger multiwavelength reverberation mapping campaign. The campaign spanned 6 months and achieved an almost daily cadence with observations from five ground-based telescopes. The Hβ and He ii λ4686 broad emission-line light curves lag that of the 5100 +-optical continuum by 4.17+0.36-0.36 and 0.79+0.35-0.34 days, respectively. The Hβ lag relative to the 1158 ultraviolet continuum light curve measured by the Hubble Space Telescope is ∼50% longer than that measured against the optical continuum, and the lag difference is consistent with the observed lag between the optical and ultraviolet continua. This suggests that the characteristic radius of the broad-line region is ∼50% larger than the value inferred from optical data alone. We also measured velocity-resolved emission-line lags for Hβ and found a complex velocity-lag structure with shorter lags in the line wings, indicative of a broad-line region dominated by Keplerian motion. The responses of both the Hβ and He ii emission lines to the driving continuum changed significantly halfway through the campaign, a phenomenon also observed for C iv, Lyα, He ii(+O iii]), and Si iv(+O iv]) during the same monitoring period. Finally, given the optical luminosity of NGC 5548 during our campaign, the measured Hβ lag is a factor of five shorter than the expected value implied by the R BLR-L AGN relation based on the past behavior of NGC 5548

Small molecules, big targets: drug discovery faces the protein-protein interaction challenge.

Protein-protein interactions (PPIs) are of pivotal importance in the regulation of biological systems and are consequently implicated in the development of disease states. Recent work has begun to show that, with the right tools, certain classes of PPI can yield to the efforts of medicinal chemists to develop inhibitors, and the first PPI inhibitors have reached clinical development. In this Review, we describe the research leading to these breakthroughs and highlight the existence of groups of structurally related PPIs within the PPI target class. For each of these groups, we use examples of successful discovery efforts to illustrate the research strategies that have proved most useful.JS, DES and ARB thank the Wellcome Trust for funding.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nrd.2016.2

Urban Biodiversity and Landscape Ecology: Patterns, Processes and Planning

Effective planning for biodiversity in cities and towns is increasingly important as urban areas and their human populations grow, both to achieve conservation goals and because ecological communities support services on which humans depend. Landscape ecology provides important frameworks for understanding and conserving urban biodiversity both within cities and considering whole cities in their regional context, and has played an important role in the development of a substantial and expanding body of knowledge about urban landscapes and communities. Characteristics of the whole city including size, overall amount of green space, age and regional context are important considerations for understanding and planning for biotic assemblages at the scale of entire cities, but have received relatively little research attention. Studies of biodiversity within cities are more abundant and show that longstanding principles regarding how patch size, configuration and composition influence biodiversity apply to urban areas as they do in other habitats. However, the fine spatial scales at which urban areas are fragmented and the altered temporal dynamics compared to non-urban areas indicate a need to apply hierarchical multi-scalar landscape ecology models to urban environments. Transferring results from landscape-scale urban biodiversity research into planning remains challenging, not least because of the requirements for urban green space to provide multiple functions. An increasing array of tools is available to meet this challenge and increasingly requires ecologists to work with planners to address biodiversity challenges. Biodiversity conservation and enhancement is just one strand in urban planning, but is increasingly important in a rapidly urbanising world

STUDIES ON CHLORIDE AND SULFATE CONTENT OF WELL WATERS AND THE AMOUNTS OF CHLORIDE AND SULFATE FIXED TO SOIL IN THE MINERAL SPRING DISTRICTS (X) MATSUZAKI, TOGO AND ASOZU HOT SPRINGS AND HAMAMURA AND KACHIMI HOT SPRINGS (Continued)

At Matsuzaki, Togo and Asozu Hot Springs and at Hamamura and Kachimi Hot Springs, the amounts of chloride and sulfate fixed to soil were determined with samples which were colleted from various parts of the thermal spring zone and its outside area, more than ten days after rainfall, so as to eliminate its possible effect. The amounts of sulfate were determined by terbidimetry with BaCl(2) solution and those of chloride were determined by　mercuric thiocyanate method. In the average amounts of chloride and sulfate, no differences were found between the samples collected from the thermal spring zone and its　outside area. The same fact was described in the 5th and 8th reports, but errorneously ascribed to an effect of rainfall. From the present study it has been ascertained that the fact is independent of rainfall

Septic cardiomyopathy

Depression of left ventricular (LV) intrinsic contractility is constant in patients with septic shock. Because most parameters of cardiac function are strongly dependent on afterload, especially in this context, the cardiac performance evaluated at the bedside reflects intrinsic contractility, but also the degree of vasoplegia. Recent advances in echocardiography have allowed better characterization of septic cardiomyopathy. It is always reversible providing the patient's recovery. Unlike classic cardiomyopathy, it is not associated with high filling pressures, for two reasons: improvement in LV compliance and associated right ventricular dysfunction. Although, it is unclear to which extent it affects prognosis, a hyperkinetic state is indicative of a profound and persistent vasoplegia associated with a high mortality rate. Preliminary data suggest that the hemodynamic response to a dobutamine challenge has a prognostic value, but large studies are required to establish whether inotropic drugs should be used to treat this septic cardiac dysfunction

Wave-of-Advance Models of the Diffusion of the Y Chromosome Haplogroup R1b1b2 in Europe

Whether or not the spread of agriculture in Europe was accompanied by movements of people is a long-standing question in archeology and anthropology, which has been frequently addressed with the help of population genetic data. Estimates on dates of expansion and geographic origins obtained from genetic data are however sensitive to the calibration of mutation rates and to the mathematical models used to perform inference. For instance, recent data on the Y chromosome haplogroup R1b1b2 (M269) have either suggested a Neolithic origin for European paternal lineages or a more ancient Paleolithic origin depending on the calibration of Y-STR mutation rates. Here we examine the date of expansion and the geographic origin of hgR1b1b2 considering two current estimates of mutation rates in a total of fourteen realistic wave-of-advance models. We report that a range expansion dating to the Paleolithic is unlikely to explain the observed geographical distribution of microsatellite diversity, and that whether the data is informative with respect to the spread of agriculture in Europe depends on the mutation rate assumption in a critical way

Network theory may explain the vulnerability of medieval human settlements to the Black Death pandemic

Epidemics can spread across large regions becoming pandemics by flowing along transportation and social networks. Two network attributes, transitivity (when a node is connected to two other nodes that are also directly connected between them) and centrality (the number and intensity of connections with the other nodes in the network), are widely associated with the dynamics of transmission of pathogens. Here we investigate how network centrality and transitivity influence vulnerability to diseases of human populations by examining one of the most devastating pandemic in human history, the fourteenth century plague pandemic called Black Death. We found that, after controlling for the city spatial location and the disease arrival time, cities with higher values of both centrality and transitivity were more severely affected by the plague. A simulation study indicates that this association was due to central cities with high transitivity undergo more exogenous re-infections. Our study provides an easy method to identify hotspots in epidemic networks. Focusing our effort in those vulnerable nodes may save time and resources by improving our ability of controlling deadly epidemics

ZD6474 reverses multidrug resistance by directly inhibiting the function of P-glycoprotein

P-glycoprotein (P-gp) pumps multiple types of drugs out of the cell, using energy generated from ATP, and confers multidrug resistance (MDR) on cancer cells. ZD6474 is an orally active, selective inhibitor of the vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection tyrosine kinases. This study was designed to examine whether ZD6474 reverses P-gp-mediated MDR in cancer cells. Here, we show that clinically achievable levels of ZD6474 reverse P-gp-mediated MDR of the P-gp-overexpressing cell lines derived from breast cancer, MCF-7/adriamycin (ADR), and human oral epidermoid carcinoma, KBV200 to ADR, docetaxel, and vinorelbine. This ability to reverse the P-gp-mediated resistance is comparable to that of another frequently used reversal agent known as verapamil. ZD6474 itself moderately inhibits the proliferation of both MCF-7 and MCF-7/ADR cells with almost equal activity, but its inhibitory effect is not altered by co-incubation with verapamil, suggesting that ZD6474 may not be a substrate of P-gp. In addition, ZD6474 increases the intracellular accumulation of the P-gp substrate, rhodamine-123, and ADR, by enhancing the uptake and/or decreasing the efflux of these compounds in resistant cells. Further studies show that ZD6474 stimulates ATPase activity in a dose-dependent manner, which is required for the proper function of P-gp. In contrast, ZD6474 does not inhibit the expression level of P-gp. Our results suggest that ZD6474 is capable of reversing MDR in cancer cells by directly inhibiting the function of P-gp, a finding that may have clinical implications for ZD6474