8-Azatetracyclines: Synthesis and Evaluation of a Novel Class of Tetracycline Antibacterial Agents

bS Supporting Information ABSTRACT: A novel series of fully synthetic 8-azatetracyclines was prepared and evaluated for antibacterial activity. Compounds were identified that overcome both efflux (tet(K)) and ribosomal protection (tet(M)) tetracycline resistance mechanisms and are active against Gram-positive and Gram-negative organisms. Two compounds were identified that exhibit comparable efficacy to marketed tetracyclines in in vivo models of bacterial infection. The tetracycline class of antibacterial agents has seen wide-spread clinical use for over 50 years due to its broad spectrum anti-bacterial activity.1 Tetracyclines inhibit bacterial growth by prevent-ing protein biosynthesis through binding to the 30S ribosome

Communications Biophysics

Contains research objectives and summary of research on five research projects, with ten sub-topics.National Institutes of Health (Grant 1 RO1 NS10916-01)National Institutes of Health (Grant 5 RO1 NS11000-03)National Institutes of Health (Grant 1 RO1 NS11153-01)Harvard-M.I.T. Rehabilitation Engineering CenterU. S. Department of Health, Education, and Welfare (Grant 23-P-55854)National Institutes of Health (Grant 1 RO1 NS11680-01)National Institutes of Health (Grant 5 ROI NS11080-02)M.I.T. Health Sciences FundNational Aeronautics and Space Administration (Grant NSG-2032)National Institutes of Health (Grant 5 TO1 GM01555-09)Massachusetts General Hospital Purchase Order F63853Boston City Hospital Purchase Order 4338-7543

The Vehicle, Spring 1993

1993 Commemorative Edition: Celebrating 35 Years Table of Contents The Vehicle Editors\u27 Lineagepage 5 Milestonespage 6 THE SIXTIES Coverspage 7 Editors\u27 Notespage 8 Sureness is Never - excerptDon Shepardsonpage 9 SophisticationBenjamin Polkpage 10 A SonnetMignon Stricklandpage 11 The Twenty-Third ChannelBen Polkpage 11 Opposite AttractionsC.E.M. (Christine McColl)page 12 John F. KennedyJoel E. Hendrickspage 13 The Girl on the White PonyLarry Gatespage 14 The TimesW.D.M. (William Moser)page 16 Home ThoughtsJane Careypage 17 1966Roger Zulaufpage 18 Nagging ThoughtJanet Andrewspage 18 THE SEVENTIES Coverspage 19 Editors\u27 Notespage 20 RevolutionsSteve Siegelpage 21 UntitledKristine Kirkhampage 23 The Arithmetic ProblemJanice Forbuspage 23 Willie Seeverson Threw a Worm at MeMary Pipekpage 24 a love poem (by approximation)Ted Baldwinpage 25 Night and Summer in Two WorldsBarry Smithpage 26 Story of a Teenage PickleTerry Louis Schultzpage 27 Danny Lonely, Danny WildDevin Brownpage 28 Always TomorrowMary McDanielpage 29 THE EIGHTIES Coverspage 31 Having ChildrenDevon Flesorpage 33 What is Unnatural Is Sometimes MagicAngelique Jenningspage 34 If My Father Were A Writer, He Would Still BuildAngelique Jenningspage 35 Photo AlbumPatrick Peterspage 36 Poet Born in Pearl HarborAngelique Jenningspage 37 The History of High School BasketballPatrick Peterspage 38 Banana BreadGail Bowerpage 39 Cover LetterBob Zordanipage 40 Home MoviesBob Zordanipage 41 MigrationPatrick Peterspage 42 THE NINETIES Ba, Ba, Black SheepVictoria Bennettpage 45 Daily LessonsJennifer Moropage 49 Folding My OwnLaurie Ann Malispage 51 About the Authorspage 53 Editors\u27 Notespage 56https://thekeep.eiu.edu/vehicle/1062/thumbnail.jp

The Vehicle, Spring 1993

1993 Commemorative Edition: Celebrating 35 Years Table of Contents The Vehicle Editors\u27 Lineagepage 5 Milestonespage 6 THE SIXTIES Coverspage 7 Editors\u27 Notespage 8 Sureness is Never - excerptDon Shepardsonpage 9 SophisticationBenjamin Polkpage 10 A SonnetMignon Stricklandpage 11 The Twenty-Third ChannelBen Polkpage 11 Opposite AttractionsC.E.M. (Christine McColl)page 12 John F. KennedyJoel E. Hendrickspage 13 The Girl on the White PonyLarry Gatespage 14 The TimesW.D.M. (William Moser)page 16 Home ThoughtsJane Careypage 17 1966Roger Zulaufpage 18 Nagging ThoughtJanet Andrewspage 18 THE SEVENTIES Coverspage 19 Editors\u27 Notespage 20 RevolutionsSteve Siegelpage 21 UntitledKristine Kirkhampage 23 The Arithmetic ProblemJanice Forbuspage 23 Willie Seeverson Threw a Worm at MeMary Pipekpage 24 a love poem (by approximation)Ted Baldwinpage 25 Night and Summer in Two WorldsBarry Smithpage 26 Story of a Teenage PickleTerry Louis Schultzpage 27 Danny Lonely, Danny WildDevin Brownpage 28 Always TomorrowMary McDanielpage 29 THE EIGHTIES Coverspage 31 Having ChildrenDevon Flesorpage 33 What is Unnatural Is Sometimes MagicAngelique Jenningspage 34 If My Father Were A Writer, He Would Still BuildAngelique Jenningspage 35 Photo AlbumPatrick Peterspage 36 Poet Born in Pearl HarborAngelique Jenningspage 37 The History of High School BasketballPatrick Peterspage 38 Banana BreadGail Bowerpage 39 Cover LetterBob Zordanipage 40 Home MoviesBob Zordanipage 41 MigrationPatrick Peterspage 42 THE NINETIES Ba, Ba, Black SheepVictoria Bennettpage 45 Daily LessonsJennifer Moropage 49 Folding My OwnLaurie Ann Malispage 51 About the Authorspage 53 Editors\u27 Notespage 56https://thekeep.eiu.edu/vehicle/1062/thumbnail.jp

Communications Biophysics

Contains research objectives and summary of research on nine research projects split into four sections.National Institutes of Health (Grant 5 ROI NS11000-03)National Institutes of Health (Grant 1 P01 NS13126-01)National Institutes of Health (Grant 1 RO1 NS11153-01)National Institutes of Health (Grant 2 R01 NS10916-02)Harvard-M.I.T. Rehabilitation Engineering CenterU. S. Department of Health, Education, and Welfare (Grant 23-P-55854)National Institutes of Health (Grant 1 ROl NS11680-01)National Institutes of Health (Grant 5 ROI NS11080-03)M.I.T. Health Sciences Fund (Grant 76-07)National Institutes of Health (Grant 5 T32 GM07301-02)National Institutes of Health (Grant 5 TO1 GM01555-10

The Deep Historical Roots of Macroeconomic Volatility

We present cross-country evidence that a country's macroeconomic volatility, measured either by the standard deviation of output growth or the occurrence of trend-growth breaks, is significantly affected by the country's historical variables. In particular, countries with longer histories of state-level political institutions experience less macroeconomic volatility in postwar periods. Robustness checks reveal that the effect of this historical variable on volatility remains significant and substantial after controlling for a host of structural variables investigated in previous studies. We also find that the state history variable is more important in countries with a higher level of macroeconomic volatility

Private Enforcement, Corruption, and Antitrust Design

Recent adoption of competition laws across the globe has highlighted the importance of institutional considerations for antitrust effectiveness and the need for comparative institutional analyses of antitrust that extend beyond matters of substantive law. Contributing to the resulting nascent research agenda, we examine how the rationale for enabling versus precluding private antitrust enforcement as one salient choice in antitrust design depends on whether antitrust enforcement is corruption-free or plagued by corruption. Contingent on the nature of adjudicatory bias, bribery either discourages private antitrust lawsuits or incentivizes firms to engage in frivolous litigation. Corruption expectedly reduces the effectiveness of antitrust enforcement at deterring antitrust violations. Yet private antitrust enforcement as a complement to public enforcement can be social welfare-enhancing even in the presence of corruption. Under some circumstances, corruption actually increases the relative social desirability of private antitrust enforcement. Our analysis highlights that the appropriate design of antitrust institutions is context-specific

Multicentric assessment of the efficacy and tolerability of dihydroartemisinin-piperaquine compared to artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in sub-Saharan Africa

<p>Abstract</p> <p>Background</p> <p>The choice of appropriate artemisinin-based combination therapy depends on several factors (cost, efficacy, safety, reinfection rate and simplicity of administration). To assess whether the combination dihydroartemisinin-piperaquine (DP) could be an alternative to artemether-lumefantrine (AL), the efficacy and the tolerability of the two products for the treatment of uncomplicated falciparum malaria in sub-Saharan Africa have been compared.</p> <p>Methods</p> <p>A multicentric open randomized controlled clinical trial of three-day treatment of DP against AL for the treatment of two parallel groups of patients aged two years and above and suffering from uncomplicated falciparum malaria was carried out in Cameroon, Côte d'Ivoire and Senegal. Within each group, patients were randomly assigned supervised treatment. DP was given once a day for three days and AL twice a day for three days. Follow-up visits were performed on day 1 to 4 and on day 7, 14, 21, 28 to evaluate clinical and parasitological results. The primary endpoint was the recovery rate by day 28.</p> <p>Results</p> <p>Of 384 patients enrolled, 197 were assigned DP and 187 AL. The recovery rates adjusted by genotyping, 99.5% in the DP group and 98.9% in the AL group, were not statistically different (p = 0.538). No Early Therapeutic Failure (ETF) was observed. At day 28, two patients in the DP group and five in AL group had recurrent parasitaemia with <it>Plasmodium falciparum</it>. In the DP group, after PCR genotyping, one of the two recurrences was classified as a new infection and the other as recrudescence. In AL group, two recurrences were classified after correction by PCR as recrudescence. All cases of recrudescence were classified as Late Parasitological Failure (LPF). In each group, a rapid recovery from fever and parasitaemia was noticed. More than 90% of patients did no longer present fever or parasitaemia 48 hours after treatment. Both drugs were well tolerated. Indeed, no serious adverse events were reported during the follow-up period. Most of the adverse events which developed were moderate and did not result in the treatment being stopped in either treatment group.</p> <p>Conclusions</p> <p>Dihydroartemisinin-piperaquine was as effective and well-tolerated as artemether-lumefantrine in the treatment of uncomplicated falciparum malaria. In addition, dihydroartemisinin-piperaquine, a single daily dose, could be an advantage over artemether-lumefantrine in Africa because of better treatment observance.</p

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts