Drug Discovery Using Chemical Systems Biology: Repositioning the Safe Medicine Comtan to Treat Multi-Drug and Extensively Drug Resistant Tuberculosis

The rise of multi-drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis around the world, including in industrialized nations, poses a great threat to human health and defines a need to develop new, effective and inexpensive anti-tubercular agents. Previously we developed a chemical systems biology approach to identify off-targets of major pharmaceuticals on a proteome-wide scale. In this paper we further demonstrate the value of this approach through the discovery that existing commercially available drugs, prescribed for the treatment of Parkinson's disease, have the potential to treat MDR and XDR tuberculosis. These drugs, entacapone and tolcapone, are predicted to bind to the enzyme InhA and directly inhibit substrate binding. The prediction is validated by in vitro and InhA kinetic assays using tablets of Comtan, whose active component is entacapone. The minimal inhibition concentration (MIC99) of entacapone for Mycobacterium tuberculosis (M.tuberculosis) is approximately 260.0 µM, well below the toxicity concentration determined by an in vitro cytotoxicity model using a human neuroblastoma cell line. Moreover, kinetic assays indicate that Comtan inhibits InhA activity by 47.0% at an entacapone concentration of approximately 80 µM. Thus the active component in Comtan represents a promising lead compound for developing a new class of anti-tubercular therapeutics with excellent safety profiles. More generally, the protocol described in this paper can be included in a drug discovery pipeline in an effort to discover novel drug leads with desired safety profiles, and therefore accelerate the development of new drugs

Galaxy And Mass Assembly (GAMA) : The mechanisms for quiescent galaxy formation at z<1

© 2016 The Authors. One key problem in astrophysics is understanding how and why galaxies switch off their star formation, building the quiescent population that we observe in the local Universe. From the Galaxy And Mass Assembly and VIsible MultiObject Spectrograph Public Extragalactic Redshift surveys, we use spectroscopic indices to select quiescent and candidate transition galaxies.We identify potentially rapidly transitioning post-starburst (PSB) galaxies and slower transitioning green-valley galaxies. Over the last 8Gyr, the quiescent population has grown more slowly in number density at high masses (M * > 10 11 M ⊙ ) than at intermediate masses (M * > 10 10.6 M ⊙ ). There is evolution in both the PSB and green-valley stellar mass functions, consistent with higher mass galaxies quenching at earlier cosmic times.At intermediatemasses (M * > 10 10.6 M ⊙ ), we find a green-valley transition time-scale of 2.6 Gyr. Alternatively, at z ~ 0.7, the entire growth rate could be explained by fast-quenching PSB galaxies, with a visibility time-scale of 0.5 Gyr. At lower redshift, the number density of PSBs is so low that an unphysically short visibility window would be required for them to contribute significantly to the quiescent population growth. The importance of the fast-quenching route may rapidly diminish at z 10 11 M ⊙ ), there is tension between the large number of candidate transition galaxies compared to the slow growth of the quiescent population. This could be resolved if not all high-mass PSB and green-valley galaxies are transitioning from star forming to quiescent, for example if they rejuvenate out of the quiescent population following the accretion of gas and triggering of star formation, or if they fail to completely quench their star formation

Coral larvae for restoration and research: a large-scale method for rearing Acropora millepora larvae, inducing settlement, and establishing symbiosis

Here we describe an efficient and effective technique for rearing sexually-derived coral propagules from spawning through larval settlement and symbiont uptake with minimal impact on natural coral populations. We sought to maximize larval survival while minimizing expense and daily husbandry maintenance by experimentally determining optimized conditions and protocols for gamete fertilization, larval cultivation, induction of larval settlement by crustose coralline algae, and inoculation of newly settled juveniles with their dinoflagellate symbiont Symbiodinium. Larval rearing densities at or below 0.2 larvae mL -1 were found to maximize larval survival and settlement success in culture tanks while minimizing maintenance effort. Induction of larval settlement via the addition of a ground mixture of diverse crustose coralline algae (CCA) is recommended, given the challenging nature of in situ CCA identification and our finding that non settlement-inducing CCA assemblages do not inhibit larval settlement if suitable assemblages are present. Although order of magnitude differences in infectivity were found between common Great Barrier Reef Symbiodinium clades C and D, no significant differences in Symbiodinium uptake were observed between laboratory-cultured and wild-harvested symbionts in each case. The technique presented here for Acropora millepora can be adapted for research and restoration efforts in a wide range of broadcast spawning coral species

Coral larvae for restoration and research: a large-scale method for rearing Acropora millepora larvae, inducing settlement, and establishing symbiosis

Here we describe an efficient and effective technique for rearing sexually-derived coral propagules from spawning through larval settlement and symbiont uptake with minimal impact on natural coral populations. We sought to maximize larval survival while minimizing expense and daily husbandry maintenance by experimentally determining optimized conditions and protocols for gamete fertilization, larval cultivation, induction of larval settlement by crustose coralline algae, and inoculation of newly settled juveniles with their dinoflagellate symbiont Symbiodinium. Larval rearing densities at or below 0.2 larvae mL -1 were found to maximize larval survival and settlement success in culture tanks while minimizing maintenance effort. Induction of larval settlement via the addition of a ground mixture of diverse crustose coralline algae (CCA) is recommended, given the challenging nature of in situ CCA identification and our finding that non settlement-inducing CCA assemblages do not inhibit larval settlement if suitable assemblages are present. Although order of magnitude differences in infectivity were found between common Great Barrier Reef Symbiodinium clades C and D, no significant differences in Symbiodinium uptake were observed between laboratory-cultured and wild-harvested symbionts in each case. The technique presented here for Acropora millepora can be adapted for research and restoration efforts in a wide range of broadcast spawning coral species

Coral larvae for restoration and research: A large-scale method for rearing Acropora millepora larvae, inducing settlement, and establishing symbiosis

© 2017 Pollock et al. Here we describe an efficient and effective technique for rearing sexually-derived coral propagules from spawning through larval settlement and symbiont uptake with minimal impact on natural coral populations. We sought to maximize larval survival while minimizing expense and daily husbandry maintenance by experimentally determining optimized conditions and protocols for gamete fertilization, larval cultivation, induction of larval settlement by crustose coralline algae, and inoculation of newly settled juveniles with their dinoflagellate symbiont Symbiodinium. Larval rearing densities at or below 0.2 larvae mL-1 were found to maximize larval survival and settlement success in culture tanks while minimizing maintenance effort. Induction of larval settlement via the addition of a ground mixture of diverse crustose coralline algae (CCA) is recommended, given the challenging nature of in situ CCA identification and our finding that non settlement-inducing CCA assemblages do not inhibit larval settlement if suitable assemblages are present. Although order of magnitude differences in infectivity were found between common Great Barrier Reef Symbiodinium clades C and D, no significant differences in Symbiodinium uptake were observed between laboratory-cultured and wild-harvested symbionts in each case. The technique presented here for Acropora millepora can be adapted for research and restoration efforts in a wide range of broadcast spawning coral species

Consensus Guidelines for Advancing Coral Holobiont Genome and Specimen Voucher Deposition

Coral research is being ushered into the genomic era. To fully capitalize on the potential discoveries from this genomic revolution, the rapidly increasing number of high-quality genomes requires effective pairing with rigorous taxonomic characterizations of specimens and the contextualization of their ecological relevance. However, to date there is no formal framework that genomicists, taxonomists, and coral scientists can collectively use to systematically acquire and link these data. Spurred by the recently announced “Coral symbiosis sensitivity to environmental change hub” under the “Aquatic Symbiosis Genomics Project” - a collaboration between the Wellcome Sanger Institute and the Gordon and Betty Moore Foundation to generate gold-standard genome sequences for coral animal hosts and their associated Symbiodiniaceae microalgae (among the sequencing of many other symbiotic aquatic species) - we outline consensus guidelines to reconcile different types of data. The metaorganism nature of the coral holobiont provides a particular challenge in this context and is a key factor to consider for developing a framework to consolidate genomic, taxonomic, and ecological (meta)data. Ideally, genomic data should be accompanied by taxonomic references, i.e., skeletal vouchers as formal morphological references for corals and strain specimens in the case of microalgal and bacterial symbionts (cultured isolates). However, exhaustive taxonomic characterization of all coral holobiont member species is currently not feasible simply because we do not have a comprehensive understanding of all the organisms that constitute the coral holobiont. Nevertheless, guidelines on minimal, recommended, and ideal-case descriptions for the major coral holobiont constituents (coral animal, Symbiodiniaceae microalgae, and prokaryotes) will undoubtedly help in future referencing and will facilitate comparative studies. We hope that the guidelines outlined here, which we will adhere to as part of the Aquatic Symbiosis Genomics Project sub-hub focused on coral symbioses, will be useful to a broader community and their implementation will facilitate cross- and meta-data comparisons and analyses.CV acknowledges funding from the German Research Foundation (DFG), grants 433042944 and 458901010. Open Access publication fees are covered by an institutional agreement of the University of Konstanz

The SAMI Galaxy Survey: : extraplanar gas, galactic winds, and their association with star formation history

This article has been accepted for publication in Monthly Notices of the Royal Astronomical Society. ©: 2016 The Authors. Published by Oxford University Press on behalf of the Royal Astronomical Society, the version of record is available on line at doi: 10.1093/mnras/stw017We investigate a sample of 40 local, main-sequence, edge-on disc galaxies using integral field spectroscopy with the Sydney-AAO Multi-object Integral field spectrograph (SAMI) Galaxy Survey to understand the link between properties of the extraplanar gas and their host galaxies. The kinematics properties of the extraplanar gas, including velocity asymmetries and increased dispersion, are used to differentiate galaxies hosting large-scale galactic winds from those dominated by the extended diffuse ionized gas. We find rather that a spectrum of diffuse gas-dominated to wind dominated galaxies exist. The wind-dominated galaxies span a wide range of star formation rates ($-1 \lesssim \log({\rm SFR/M_{\odot} yr^{-1}}) \lesssim 0.5$) across the whole stellar mass range of the sample ($8.5 \lesssim \log({\rm M_{*}/M_{\odot}}) \lesssim 11$). The wind galaxies also span a wide range in SFR surface densities ($10^{-3} \textrm{--} 10^{-1.5}\rm~M_{\odot} ~yr^{-1}~kpc^{-2}$) that is much lower than the canonical threshold of $\rm0.1~M_{\odot} ~yr^{-1}~kpc^{-2}$. The wind galaxies on average have higher SFR surface densities and higher $\rm H\delta_A$ values than those without strong wind signatures. The enhanced $\rm H\delta_A$ indicates that bursts of star formation in the recent past are necessary for driving large-scale galactic winds. We demonstrate with Sloan Digital Sky Survey data that galaxies with high SFR surface density have experienced bursts of star formation in the recent past. Our results imply that the galactic winds revealed in our study are indeed driven by bursts of star formation, and thus probing star formation in the time domain is crucial for finding and understanding galactic winds.Peer reviewe

H-ATLAS/GAMA: quantifying the morphological evolution of the galaxy population using cosmic calorimetry

Using results from the Herschel Astrophysical Terrahertz Large-Area Survey (H-ATLAS) and the Galaxy and Mass Assembly (GAMA) project, we show that, for galaxy masses above ≃ 108 M⊙, 51 per cent of the stellar mass-density in the local Universe is in early-type galaxies (ETGs; Sérsic n > 2.5) while 89 per cent of the rate of production of stellar mass-density is occurring in late-type galaxies (LTGs; Sérsic n < 2.5). From this zero-redshift benchmark, we have used a calorimetric technique to quantify the importance of the morphological transformation of galaxies over the history of the Universe. The extragalactic background radiation contains all the energy generated by nuclear fusion in stars since the big bang. By resolving this background radiation into individual galaxies using the deepest far-infrared survey with the Herschel Space Observatory and a deep near-infrared/optical survey with the Hubble Space Telescope (HST), and using measurements of the Sérsic index of these galaxies derived from the HST images, we estimate that ≃83 per cent of the stellar mass-density formed over the history of the Universe occurred in LTGs. The difference between this value and the fraction of the stellar mass-density that is in LTGs today implies there must have been a major transformation of LTGs into ETGs after the formation of most of the stars

IL-13 is a driver of COVID-19 severity

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here, we report that elevated IL-13 was associated with the need for mechanical ventilation in 2 independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab, a mAb that blocks IL-13 and IL-4 signaling, had less severe disease. In SARS-CoV-2–infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti–IL-13 treatment in infected mice, hyaluronan synthase 1 (Has1) was the most downregulated gene, and accumulation of the hyaluronan (HA) polysaccharide was decreased in the lung. In patients with COVID-19, HA was increased in the lungs and plasma. Blockade of the HA receptor, CD44, reduced mortality in infected mice, supporting the importance of HA as a pathogenic mediator. Finally, HA was directly induced in the lungs of mice by administration of IL-13, indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and HA has important implications for therapy of COVID-19 and, potentially, other pulmonary diseases. IL-13 levels were elevated in patients with severe COVID-19. In a mouse model of the disease, IL-13 neutralization reduced the disease and decreased lung HA deposition. Administration of IL-13–induced HA in the lung. Blockade of the HA receptor CD44 prevented mortality, highlighting a potentially novel mechanism for IL-13–mediated HA synthesis in pulmonary pathology

The Mycobacterium tuberculosis Drugome and Its Polypharmacological Implications

We report a computational approach that integrates structural bioinformatics, molecular modelling and systems biology to construct a drug-target network on a structural proteome-wide scale. The approach has been applied to the genome of Mycobacterium tuberculosis (M.tb), the causative agent of one of today's most widely spread infectious diseases. The resulting drug-target interaction network for all structurally characterized approved drugs bound to putative M.tb receptors, we refer to as the ‘TB-drugome’. The TB-drugome reveals that approximately one-third of the drugs examined have the potential to be repositioned to treat tuberculosis and that many currently unexploited M.tb receptors may be chemically druggable and could serve as novel anti-tubercular targets. Furthermore, a detailed analysis of the TB-drugome has shed new light on the controversial issues surrounding drug-target networks [1]–[3]. Indeed, our results support the idea that drug-target networks are inherently modular, and further that any observed randomness is mainly caused by biased target coverage. The TB-drugome (http://funsite.sdsc.edu/drugome/TB) has the potential to be a valuable resource in the development of safe and efficient anti-tubercular drugs. More generally the methodology may be applied to other pathogens of interest with results improving as more of their structural proteomes are determined through the continued efforts of structural biology/genomics