A pharmaceutical model for the molecular evolution of microbial natural products

Abstract Microbes are talented chemists with the ability to generate tremendously complex and diverse natural products which harbor potent biological activities. Natural products are produced using sets of specialized biosynthetic enzymes encoded by secondary metabolism pathways. Here, we present a two-step evolutionary model to explain the diversification of biosynthetic pathways that account for the proliferation of these molecules. We argue that the appearance of natural product families has been a slow and infrequent process. The first step led to the original emergence of bioactive molecules and different classes of natural products. However, much of the chemical diversity observed today has resulted from the endless modification of the ancestral biosynthetic pathways. The second step rapidly modulates the pre-existing biological activities to increase their potency and to adapt to changing environmental conditions. We highlight the importance of enzyme promiscuity in this process, as it facilitates both the incorporation of horizontally transferred genes into secondary metabolic pathways and the functional differentiation of proteins to catalyze novel chemistry. We provide examples where single point mutations or recombination events have been sufficient for new enzymatic activities to emerge. A unique feature in the evolution of microbial secondary metabolism is that gene duplication is not essential but offers opportunities to synthesize more complex metabolites. Microbial natural products are highly important for the pharmaceutical industry due to their unique bioactivities. Therefore, understanding the natural mechanisms leading to the formation of diverse metabolic pathways is vital for future attempts to utilize synthetic biology for the generation of novel molecules.Peer reviewe

Automated Identification of Astronauts on Board the International Space Station: A Case Study in Space Archaeology

We develop and apply a deep learning-based computer vision pipeline to automatically identify crew members in archival photographic imagery taken on-board the International Space Station. Our approach is able to quickly tag thousands of images from public and private photo repositories without human supervision with high degrees of accuracy, including photographs where crew faces are partially obscured. Using the results of our pipeline, we carry out a large-scale network analysis of the crew, using the imagery data to provide novel insights into the social interactions among crew during their missions

Diffusion of e-health innovations in 'post-conflict' settings: a qualitative study on the personal experiences of health workers.

BACKGROUND: Technological innovations have the potential to strengthen human resources for health and improve access and quality of care in challenging 'post-conflict' contexts. However, analyses on the adoption of technology for health (that is, 'e-health') and whether and how e-health can strengthen a health workforce in these settings have been limited so far. This study explores the personal experiences of health workers using e-health innovations in selected post-conflict situations. METHODS: This study had a cross-sectional qualitative design. Telephone interviews were conducted with 12 health workers, from a variety of cadres and stages in their careers, from four post-conflict settings (Liberia, West Bank and Gaza, Sierra Leone and Somaliland) in 2012. Everett Roger's diffusion of innovation-decision model (that is, knowledge, persuasion, decision, implementation, contemplation) guided the thematic analysis. RESULTS: All health workers interviewed held positive perceptions of e-health, related to their beliefs that e-health can help them to access information and communicate with other health workers. However, understanding of the scope of e-health was generally limited, and often based on innovations that health workers have been introduced through by their international partners. Health workers reported a range of engagement with e-health innovations, mostly for communication (for example, email) and educational purposes (for example, online learning platforms). Poor, unreliable and unaffordable Internet was a commonly mentioned barrier to e-health use. Scaling-up existing e-health partnerships and innovations were suggested starting points to increase e-health innovation dissemination. CONCLUSIONS: Results from this study showed ICT based e-health innovations can relieve information and communication needs of health workers in post-conflict settings. However, more efforts and investments, preferably driven by healthcare workers within the post-conflict context, are needed to make e-health more widespread and sustainable. Increased awareness is necessary among health professionals, even among current e-health users, and physical and financial access barriers need to be addressed. Future e-health initiatives are likely to increase their impact if based on perceived health information needs of intended users

After LUX: The LZ Program

The LZ program consists of two stages of direct dark matter searches using liquid Xe detectors. The first stage will be a 1.5-3 tonne detector, while the last stage will be a 20 tonne detector. Both devices will benefit tremendously from research and development performed for the LUX experiment, a 350 kg liquid Xe dark matter detector currently operating at the Sanford Underground Laboratory. In particular, the technology used for cryogenics and electrical feedthroughs, circulation and purification, low-background materials and shielding techniques, electronics, calibrations, and automated control and recovery systems are all directly scalable from LUX to the LZ detectors. Extensive searches for potential background sources have been performed, with an emphasis on previously undiscovered background sources that may have a significant impact on tonne-scale detectors. The LZ detectors will probe spin-independent interaction cross sections as low as 5E-49 cm2 for 100 GeV WIMPs, which represents the ultimate limit for dark matter detection with liquid xenon technology.Comment: Conference proceedings from APS DPF 2011. 9 pages, 6 figure

Radiogenic and Muon-Induced Backgrounds in the LUX Dark Matter Detector

The Large Underground Xenon (LUX) dark matter experiment aims to detect rare low-energy interactions from Weakly Interacting Massive Particles (WIMPs). The radiogenic backgrounds in the LUX detector have been measured and compared with Monte Carlo simulation. Measurements of LUX high-energy data have provided direct constraints on all background sources contributing to the background model. The expected background rate from the background model for the 85.3 day WIMP search run is $(2.6\pm0.2_{\textrm{stat}}\pm0.4_{\textrm{sys}})\times10^{-3}$~events~keV$_{ee}^{-1}$~kg$^{-1}$~day$^{-1}$ in a 118~kg fiducial volume. The observed background rate is $(3.6\pm0.4_{\textrm{stat}})\times10^{-3}$~events~keV$_{ee}^{-1}$~kg$^{-1}$~day$^{-1}$, consistent with model projections. The expectation for the radiogenic background in a subsequent one-year run is presented.Comment: 18 pages, 12 figures / 17 images, submitted to Astropart. Phy

Search for the Supersymmetric Partner of the Top-Quark in ppˉp \bar{p} Collisions at s=1.8TeV\sqrt{s} = 1.8 {\rm TeV}

We report on a search for the supersymmetric partner of the top quark (stop) produced in $t \bar{t}$ events using $110 {\rm pb}^{-1}$ of $p \bar{p}$ collisions at $\sqrt{s} = 1.8 {\rm TeV}$ recorded with the Collider Detector at Fermilab. In the case of a light stop squark, the decay of the top quark into stop plus the lightest supersymmetric particle (LSP) could have a significant branching ratio. The observed events are consistent with Standard Model $t \bar{t}$ production and decay. Hence, we set limits on the branching ratio of the top quark decaying into stop plus LSP, excluding branching ratios above 45% for a LSP mass up to 40 {\rm GeV/c}$^{2}$.Comment: 11 pages, 4 figure

Measurement of the ttˉproductioncrosssectionint\bar{t} production cross section in p\bar{p}collisionsat collisions at \sqrt{s}$ = 1.8 TeV

We update the measurement of the top production cross section using the CDF detector at the Fermilab Tevatron. This measurement uses $t\bar{t}$ decays to the final states $e+\nu$+jets and $\mu+\nu$+jets. We search for $b$ quarks from $t$ decays via secondary-vertex identification or the identification of semileptonic decays of the $b$ and cascade $c$ quarks. The background to the $t\bar{t}$ production is determined primarily through a Monte Carlo simulation. However, we calibrate the simulation and evaluate its uncertainty using several independent data samples. For a top mass of 175 $GeV/c^2$, we measure $\sigma_{t\bar{t}}=5.1 \pm 1.5$ pb and $\sigma_{t\bar{t}}=9.2 \pm 4.3$ pb using the secondary vertex and the lepton tagging algorithms, respectively. Finally, we combine these results with those from other $t\bar{t}$ decay channels and obtain $\sigma_{t\bar{t}} = 6.5^{+1.7}_{-1.4}$ pb.Comment: The manuscript consists of 130 pages, 35 figures and 42 tables in RevTex. The manuscript is submitted to Physical Review D. Fixed typo in author lis

Widespread Gene Conversion of Alpha-2-Fucosyltransferase Genes in Mammals

The alpha-2-fucosyltransferases (α2FTs) are enzymes involved in the biosynthesis of α2fucosylated glycan structures. In mammalian genomes, there are three α2FT genes located in tandem—FUT1, FUT2, and Sec1—each contained within a single exon. It has been suggested that these genes originated from two successive duplications, with FUT1 being generated first and FUT2 and Sec1 second. Despite gene conversion being considered the main mechanism of concerted evolution in gene families, previous studies of primates α2FTs failed to detect it, although the occurrence of gene conversion between FUT2 and Sec1 was recently reported in a human allele. The primary aim of our work was to initiate a broader study on the molecular evolution of mammalian α2FTs. Sequence comparison leads us to confirm that the three genes appeared by two rounds of duplication. In addition, we were able to detect multiple gene-conversion events at the base of primates and within several nonprimate species involving FUT2 and Sec1. Gene conversion involving FUT1 and either FUT2 or Sec1 was also detected in rabbit. The extent of gene conversion between the α2FTs genes appears to be species-specific, possibly related to functional differentiation of these genes. With the exception of rabbits, gene conversion was not observed in the region coding the C-terminal part of the catalytic domain. In this region, the number of amino acids that are identical between FUT1 and FUT2, but different in Sec1, is higher than in other parts of the protein. The biologic meaning of this observation may be related to functional constraints