Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders

For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from...

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Hormones and endocrine-disrupting chemicals: Low-dose effects and nonmonotonic dose responses

III. Foldamer Research 3910 A. Overview 3910 B. Motivation 3910 C. Methods 3910 D. General Scope 3912 IV. Peptidomimetic Foldamers 3912 A. The R-Peptide Family 3913 1. Peptoids 3913 2. N,N-Linked Oligoureas 3914 3. Oligopyrrolinones 3915 4. Oxazolidin-2-ones 3916 5. Azatides and Azapeptides 3916 B. The â-Peptide Family 3917 1. â-Peptide Foldamers 3917 2. R-Aminoxy Acids 3937 3. Sulfur-Containing â-Peptide Analogues 3937 4. Hydrazino Peptides 3938 C. The γ-Peptide Family 3938 1. γ-Peptide Foldamers 3938 2. Other Members of the γ-Peptide Family 3941 D. The δ-Peptide Family 3941 1. Alkene-Based δ-Amino Acids 3941 2. Carbopeptoids 3941 V. Single-Stranded Abiotic Foldamers 3944 A. Overview 3944 B. Backbones Utilizing Bipyridine Segments 3944 1. Pyridine−Pyrimidines 3944 2. Pyridine−Pyrimidines with Hydrazal Linkers 3945

A field guide to foldamers.

Large-scale applications of transition metal-catalyzed couplings for the synthesis of pharmaceuticals.

Therapeutic oligonucleotide analogues which have improved nuclease resistance and improved cellular uptake are provided. Replacement of the normal phosphorodiester inter-sugar linkages found in natural oligomers with four atom linking groups forms unique di- and poly-nucleosides and nucleotides useful in regulating RNA expression and in therapeutics. Methods of synthesis and use are also disclosed.

Backbone modified oligonucleotide analogues

Facile Preparation of Nucleoside-5‘-carboxylic Acids

To compare the relative potencies of a variety of enzyme-inhibiting compounds, a quantitative measure must be employed. IC50 values and Ki values are often reported in the literature, but direct comparison of these values is not possible. The relationship of Ki and IC50 for a given compound varies depending on the assay conditions and the compound’s mechanism of inhibition. The Cheng–Prusoff equations describe this relationship mathematically, and an intuitive description of this relationship is presented. Although there are currently a number of means to graphically determine IC50 values, there is not a biochemically intuitive linear method. A novel use of the Dixon plot will aid students in the determination of IC50 values. While the Dixon plot has been traditionally used to determine Ki in limited cases, a more widely applicable use is in IC50 determination. A new convention for presenting IC50 values is suggested.

An Intuitive Look at the Relationship of Ki and IC50: A More General Use for the Dixon Plot

The invention provides methods and compositions for polymerizing a particular nucleotide with a polymerase. In general, the method involves (a) forming a mixture of a polymerase and a nucleoside triphosphate (NTP) comprising α, β and η phosphates and a η-phosphate phosphoester-linked functional group; and incubating the mixture under conditions wherein the polymerase catalyzes cleavage of the NTP between the α and β phosphate, liberating a pyrophosphate comprising the functional group and polymerizing the resultant nucleoside monophosphate, i.e. incorporate the nucleoside monophosphate in a nascent polynucleotide. A variety of functional groups compatible with the polymerization reaction are provided.

Gamma-phosphoester nucleoside triphosphates

CP47,497-C8 and JWH073, commonly found in ‘Spice’ herbal blends, are potent and efficacious CB1 cannabinoid receptor agonists

A comprehensive approach to the synthesis of sulfate esters was developed. This approach permits the direct and high-yielding synthesis of protected sulfate monoesters. Subsequent deblocking to reveal sulfate monoesters is accomplished in near-quantitative yield. The exceptionally stable neopentyl protecting group and the labile isobutyl protecting group were utilized in the synthesis of aromatic and aliphatic sulfate monoesters. Strategies for tuning protecting group reactivity were also explored and developed.

Theodore S. Widlanski

Papers

Facile Preparation of Nucleoside-5‘-carboxylic Acids

An Intuitive Look at the Relationship of Ki and IC50: A More General Use for the Dixon Plot

Gamma-phosphoester nucleoside triphosphates

CP47,497-C8 and JWH073, commonly found in ‘Spice’ herbal blends, are potent and efficacious CB1 cannabinoid receptor agonists

A comprehensive approach to the synthesis of sulfate esters.