A holistic phylogeny of the coronin gene family reveals an ancient origin of the tandem-coronin, defines a new subfamily, and predicts protein function.

BACKGROUND: Coronins belong to the superfamily of the eukaryotic-specific WD40-repeat proteins and play a role in several actin-dependent processes like cytokinesis, cell motility, phagocytosis, and vesicular trafficking. Two major types of coronins are known: First, the short coronins consisting of an N-terminal coronin domain, a unique region and a short coiled-coil region, and secondly the tandem coronins comprising two coronin domains. RESULTS: 723 coronin proteins from 358 species have been identified by analyzing the whole-genome assemblies of all available sequenced eukaryotes (March 2011). The organisms analyzed represent most eukaryotic kingdoms but also cover every taxon several times to provide a better statistical sampling. The phylogenetic tree of the coronin domains based on the Bayesian method is in accordance with the most recent grouping of the major kingdoms of the eukaryotes and also with the grouping of more recently separated branches. Based on this "holistic" approach the coronins group into four classes: class-1 (Type I) and class-2 (Type II) are metazoan/choanoflagellate specific classes, class-3 contains the tandem-coronins (Type III), and the new class-4 represents the coronins fused to villin (Type IV). Short coronins from non-metazoans are equally related to class-1 and class-2 coronins and thus remain unclassified. CONCLUSIONS: The coronin class distribution suggests that the last common eukaryotic ancestor possessed a single and a tandem-coronin, and most probably a class-4 coronin of which homologs have been identified in Excavata and Opisthokonts although most of these species subsequently lost the class-4 homolog. The most ancient short coronin already contained the trimerization motif in the coiled-coil domain.

Exempt chemical mixtures containing gamma-butyrolactone. Final rule.

This rulemaking finalizes a November 12, 2008, Notice of Proposed Rulemaking in which DEA proposed that chemical mixtures that are 70 percent or less gamma-butyrolactone (GBL), by weight or volume, be automatically exempt from regulatory controls under the Controlled Substances Act (CSA). DEA is seeking through this rulemaking to exempt only those chemical mixtures that do not represent a significant risk of diversion. This regulation makes GBL chemical mixtures, in concentrations greater than 70 percent, subject to List I chemical regulatory requirements of the CSA, except if exempted through an existing categorical exemption. DEA is taking this action because there is a serious threat to the public safety associated with the ease by which GBL is chemically converted to the schedule I controlled substance gamma-hydroxybutyric acid (GHB). DEA recognizes that concentration criteria alone cannot identify all mixtures that warrant exemption. As a result, DEA regulations provide for an application process by which manufacturers may obtain exemptions from CSA regulatory controls for those GBL chemical mixtures that are not automatically exempt under the concentration criteria.

The coronin family of proteins.

The coronins, first described in Dictyostelium discoideum in 1991, have meanwhile been detected in all eukaryotes except plants. They belong to the superfamily of WD40-repeat proteins and represent a large family of proteins, which are often involved in cytoskeletal functions. Phylogenetic studies clearly distinguish 12 subfamilies of which six exclusively occur in vertebrates. In the present book we have made a sincere attempt to provide a comprehensive overview on all aspects of coronin proteins including history, structure, subcellular localization and function in different organisms. In addition, we also included a general overview on the WD40 family of proteins and the structurally related Kelch family. The book should be of interest for scientists outside the field, but is more importantly intended as a fast and competent guide for newcomers as well as doctoral and postdoctoral scientists to coronin research in all its facets.

Invertebrate coronins.

Coronins are highly conserved among species, but their function is far from being understood in detail. Here we will introduce members of the family of coronin like proteins from Drosophila melanogaster, Caenorhabditis elegans and the social amoeba Dictyostelium discoideum. Genetic data from D. discoideum and D. melanogaster revealed that coronins in general are important regulators of many actin-dependent processes.

Evolutionary and functional diversity of coronin proteins.

This chapter discusses various aspects of coronin phylogeny, structure and function that are of specific interest. Two subfamilies of ancient coronins of unicellular pathogens such as Entamoeba, Trypanosoma, Leishmania and Acanthamoeba as well as of Plasmodium, Babesia, and Trichomonas are presented in the first two sections. Their coronins generally bind to F-actin and apparently are involved in proliferation, locomotion and phagocytosis. However, there are so far no studies addressing a putative role of coronin in the virulence of these pathogens. The following section delineates genetic anomalies like the chimeric coronin-fusion products with pelckstrin homology and gelsolin domains that are found in amoeba. Moreover, most nonvertebrate metazoa appear to encode CRN8, CRN9 and CRN7 representatives (for these coronin symbols see Chapter 2), but in e.g., Drosophila melanogaster and Caenorhabditis elegans a CRN9 is missing. The forth section deals with the evolutionary expansion of vertebrate coronins. Experimental data on the F-actin binding CRN2 of Xenopus (Xcoronin) including a Cdc42/Rac interactive binding (CRIB) motif that is also present in other members of the coronin protein family are discussed. Xenopus laevis represents a case for the expansion of the seven vertebrate coronins due to tetraploidization events. Other examples for a change in the number of coronin paralogs are zebrafish and birds, but (coronin) gene duplication events also occurred in unicellular protozoa. The fifth section of this chapter briefly summarizes three different cellular processes in which CRN4/CORO1A is involved, namely actin-binding, superoxide generation and Ca(2+)-signaling and refers to the largely unexplored mammalian coronins CRN5/CORO2A and CRN6/CORO2B, the latter binding to vinculin. The final section discusses how, by unveiling the aspects of coronin function in organisms reported so far, one can trace a remarkable evolution and diversity in their individual roles anticipating a rather complex and intricate involvement of coronins in a variety of cellular processes.

WHO Expert Committee on Drug Dependence.

This report presents the recommendations of a WHO Expert Committee responsible for reviewing information on dependence-producing drugs to assess the need for their international control. The first part of the report contains a summary of the Committee's evaluations of seven substances (dronabinol, oripavine, buprenorphine, butorphanol, ketamine, khat and zopiclone). The report also discusses the substances that were pre-reviewed (gamma-hydroxybutyric acid and tramadol) and recommended gamma-hydroxybutyric acid for critical review at a future meeting. Two substances (gamma-butyrolactone and 1,4-butanediol) were identified for future pre-review). The second part of the report discusses the guidelines for the WHO review of dependence-producing psychoactive substances for international control. It includes sections on amending the current guidelines, interpretation of specific aspects of the guidelines and access to information necessary for the evaluation of substances. The final section considers other matters including activities of the EMCCDA, the use of pharmacovigilance data, promotion of education and information on the appropriate use of psychoactive drugs and the impact of international control on medical availability of substances.

Placement of gamma-butyrolactone in List I of the Controlled Substances Act (21 U.S.C. 802(34)). Drug Enforcement Administration, Justice. Final rule.

Public Law 106-172, signed into law on February 18, 2000, and known as the "Hillory J. Farias and Samantha Reid Date-Rape Drug Prohibition Act of 1999," amends section 102(34) of the Controlled Substances Act as amended (CSA) by designating gamma-butyrolactone (GBL), the precursor to gamma-hydroxybutyric acid (GHB), as a List I chemical. Reflecting this change in stature, the Drug Enforcement Administration (DEA) is amending its regulation to reflect the status of GBL as a List I chemical subject to the requirements of the CSA and its regulations. Establishment of a threshold for GBL will be the subject of a separate rulemaking. Therefore, unless and until a threshold is established, any distribution of GBL is a regulated transaction as described by 21 CFR 1300.02(b)(28). All handlers of GBL must comply with the CSA regulatory requirements pertaining to List I chemicals as described in the body of this document.