Uncovering the World of Dietary Supplements and Performance-Enhancing Substances in the Military.

This article highlights key topic areas related to dietary supplements (DSs) and performance-enhancing substances. It also discusses evidence-based resources the medical community can use when discussing high-quality DSs with Servicemembers interested in taking DSs. We briefly overview how DSs are regulated in the United States, discuss problematic categories and issues related to quality, expand upon what are often considered performance-enhancing substances yet sometimes sold as DSs, and then offer solutions to counter the consequences of the dark side of the DS industry.

Investigation of HCAR2 antagonists as a potential strategy to modulate bovine leukocytes.

Background: Dairy cows experiencing ketosis after calving suffer greater disease incidence and are at greater risk of leaving the herd. In vitro administration of beta-hydroxybutyric acid (BHBA; the primary blood ketone) has inhibitory effects on the function of bovine leukocytes. BHBA is a ligand of HCAR2 and the activation of these receptors promotes an anti-inflammatory response which may be related with immunosuppression observed in transition dairy cattle.

Synthesis of Chiral Tricyclic Pyrone Molecules via Palladium(0)-Catalyzed Displacement Reactions of Chiral Tricyclic Pyrone Acetate With Azide or Amine.

Tricyclic pyrone (TP) molecules have shown protection of MC65 neuroblastoma cells death induced by amyloid-β proteins through SβC gene, a decrease of amyloid-β peptide levels, and improvement of motor functions and memory in Alzheimer's disease mouse and rat models. Mechanistic studies suggest TP molecules modulate -methyl--aspartate receptor. A short synthesis of chiral TP analogs was sought using a Pd(0)-catalyzed displacement of TP allylic acetate intermediate with sodium azide or substituted benzylamines.

Indication of Pd-C or Cu-C Intermediate in Respective Bimetallic Nanoclusters Pd/Au-PVP or Cu/Au-PVP Catalyzed Oxidations of -4-Oxatricyclo[5.2.1.0]-8-decene and Tetrahydro-γ-carbolines.

Catalytic oxidations of tricyclic -norbornene-fused tetrahydrofuran with bimetallic nanoclusters Cu/Au-PVP and HO or -BuOOH as an oxidant provided C-H bond oxidation adjacent to the ether function and 4-oxa-tricyclo[5.2.1.

Chirality-driven self-assembly: application toward renewable/exchangeable resin-immobilized catalysts.

Resin-immobilized catalysts were prepared through chirality-driven self-assembly. The method allows the resin-immobilized catalyst to be regenerated under mild conditions and catalyst exchange to be carried out quantitatively. The uniqueness of the methodology was demonstrated by the preparation of a catalyst for TEMPO oxidation as well as a two-step sequential TEMPO oxidation/aldol condensation sequence enabled by facile catalyst exchange.

Synthesis and Characterization of Bimetallic Nanoclusters Stabilized by Chiral and Achiral Polyvinylpyrrolidinones. Catalytic C(sp)-H Oxidation.

Second-generation chiral-substituted poly--vinylpyrrolidinones (CSPVPs) (-)- and (+)- were synthesized by free-radical polymerization of (3a,6a)- and (3a,6a)-5-ethenyl-tetrahydro-2,2-dimethyl-4-1,3-dioxolo[4,5-]pyrrol-4-one, respectively, using thermal and photochemical reactions. They were produced from respective -isoascorbic acid and d-ribose. In addition, chiral polymer (-)- was also synthesized from the polymerization of ()-3-(methoxymethoxy)-1-vinylpyrrolidin-2-one.

Synthesis of 2,24-Diene-12,13,15,16,34,35,37,38-octaphenyl[4.4]-triphenylparacyclophane.

A new octaphenyl[4.4]triphenylparacyclophanediene was readily synthesized in six steps from -xylene via the installment of bromine atoms, replacement with a vinyl group, carbonylative coupling, intermolecular followed by intramolecular double Grubbs olefin metathesis, Knoevenagel condensation, and Diels-Alder cycloaddition. The belt-shaped structure and -stereochemistry of the alkene moieties of the octaphenyl[4.

SYNTHESIS OF PROBE MOLECULES, 6-(DIMETHYLAMINO)-2-PHENYLISOINDOLIN-1-ONES, FOR MECHANISTIC STUDIES OF FIREFLY LUCIFERASE INHIBITION.

Firefly luciferase is used in high-throughput screening based on the detection of chemiluminescence. It catalyzes an esterification reaction of luciferin with adenosine 5'-triphosphate (ATP) followed by decarbonylation with oxygen and concomitance of light. Previously, we reported that firefly luciferase also possesses acyl-CoA synthetase activity and catalyzes an aromatic carboxylic acid group of F-53, using ATP, Mg and coenzyme A (CoA), to produce F-53 covalently attached to active-site lysine-529 residue of firefly luciferase through the formation of an amide group.

Quantitative Detection of Cathepsin B Activity in Neutral pH Buffers Using Gold Microelectrode Arrays: Toward Direct Multiplex Analyses of Extracellular Proteases in Human Serum.

Proteases are critical signaling molecules and prognostic biomarkers for many diseases including cancer. There is a strong demand for multiplex bioanalytical techniques that can rapidly detect the activity of extracellular proteases with high sensitivity and specificity. This study demonstrates an activity-based electrochemical biosensor of a 3 × 3 gold microelectrode array for the detection of cathepsin B activity in human serum diluted in a neutral buffer.

Comparison of strategies for enhancing RNA interference efficiency in Ostrinia nubilalis.

Background: Targeting insect-specific genes through post-transcriptional gene silencing with RNA interference (RNAi) is a new strategy for insect pest management. However, lepidopterans are recalcitrant to RNAi, which prevents application of novel RNAi technology to many notorious pests, including Ostrinia nubilalis (ECB). Strategies for enhancing RNAi efficiency, including large doses of double-stranded RNA (dsRNA), nuclease inhibitors, transfection reagents, and nanoparticles, have proved useful in other insects exhibiting substantial dsRNA degradation, a major mechanism limiting RNAi efficacy.

SYNTHESIS OF 1,3,4-OXADIAZOLES AS SELECTIVE T-TYPE CALCIUM CHANNEL INHIBITORS.

Neuropathic pain, epilepsy, insomnia, and tremor disorder may arrive from an increase of intracellular Ca concentration through a dysfunction of T-type Ca channels. Thus, T-type calcium channels could be a target in drug discovery for the treatments of neuropathic pain and epilepsy. From rational drug design approach, a group of 2,5-disubstituted 1,3,4-oxadiazole molecules was synthesized and their selective T-type channel inhibitions were evaluated.

Simultaneous, multiplex quantification of protease activities using a gold microelectrode array.

Proteases are a large family of enzymes involved in many important biological processes. Quantitative detection of the activity profile of specific target proteases is in high demand for the diagnosis and monitoring of diseases such as cancers. This study demonstrates the fabrication and characterization of an individually addressable 3 × 3 Au microelectrode array for rapid, multiplex detection of cathepsin B activity based on a simple electrochemical method.

Broad-spectrum antifungal activities and mechanism of drimane sesquiterpenoids.

Eight drimane sesquiterpenoids including (-)-drimenol and (+)-albicanol were synthesized from (+)-sclareolide and evaluated for their antifungal activities. Three compounds, (-)-drimenol, (+)-albicanol, and (1,2,4a,8a)-2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalene-1-carbaldehyde (4) showed strong activity against . (-)-Drimenol, the strongest inhibitor of the three, (at concentrations of 8 - 64 µg/ml, causing 100% death of various fungi), acts not only against in a fungicidal manner, but also inhibits other fungi such as and fluconazole resistant strains of and These observations suggest that drimenol is a broad-spectrum antifungal agent.

Electrochemical Activity Assay for Protease Analysis Using Carbon Nanofiber Nanoelectrode Arrays.

There is a strong demand for bioanalytical techniques to rapidly detect protease activities with high sensitivity and high specificity. This study reports an activity-based electrochemical method toward this goal. Nanoelectrode arrays (NEAs) fabricated with embedded vertically aligned carbon nanofibers (VACNFs) are functionalized with specific peptide substrates containing a ferrocene (Fc) tag.

Synthesis and biological evaluation of steroidal derivatives bearing a small ring as vitamin D receptor agonists.

A novel series of 3-ketolithocholic acid derivatives as well as estrone derivatives bearing a small ring for the conformational fixation of the side chain were synthesized by using a catalytic [2+2] cycloaddition and a ring-contraction rearrangement. The steroidal derivatives were evaluated for transcriptional activation of vitamin D receptor by luciferase reporter assays. Among them, two estrone derivatives showed a higher efficacy of the transactivation of vitamin D receptor than 3-ketolithocholic acid, and the small ring moieties were found to be important for the efficacy.

The Anti-Amyloid-β and Neuroprotective Properties of a Novel Tricyclic Pyrone Molecule.

There is an urgent unmet need for new therapeutics for Alzheimer's disease (AD), the most common cause of dementia in the elderly. Therapeutic approaches targeting amyloid-β (Aβ) and its downstream toxicities have become major strategies in AD drug development. We have taken a rational design approach and synthesized a class of tricyclic pyrone (TP) compounds that show anti-Aβ and other neuroprotective actions.

Chiral-Substituted Poly-N-vinylpyrrolidinones and Bimetallic Nanoclusters in Catalytic Asymmetric Oxidation Reactions.

A new class of poly-N-vinylpyrrolidinones containing an asymmetric center at C5 of the pyrrolidinone ring were synthesized from l-amino acids. The polymers, particularly 17, were used to stabilize nanoclusters such as Pd/Au for the catalytic asymmetric oxidations of 1,3- and 1,2-cycloalkanediols and alkenes, and Cu/Au was used for C-H oxidation of cycloalkanes. It was found that the bulkier the C5 substituent in the pyrrolidinone ring, the greater the optical yields produced.

Correction: Reversal of the Progression of Fatal Coronavirus Infection in Cats by a Broad-Spectrum Coronavirus Protease Inhibitor.

[This corrects the article DOI: 10.1371/journal.ppat.

Current tools for norovirus drug discovery.

Introduction: Rapid transmission of norovirus often occurs due to its low infectious dosage, high genetic diversity and its short incubation time. The viruses cause acute gastroenteritis and may lead to death. Presently, no effective vaccine or selective drugs accepted by the United States Food and Drug Administration (FDA) are available for the treatment of norovirus.

Reversal of the Progression of Fatal Coronavirus Infection in Cats by a Broad-Spectrum Coronavirus Protease Inhibitor.

Coronaviruses infect animals and humans causing a wide range of diseases. The diversity of coronaviruses in many mammalian species is contributed by relatively high mutation and recombination rates during replication. This dynamic nature of coronaviruses may facilitate cross-species transmission and shifts in tissue or cell tropism in a host, resulting in substantial change in virulence.

Study of Class I and Class III Polyhydroxyalkanoate (PHA) Synthases with Substrates Containing a Modified Side Chain.

Polyhydroxyalkanoates (PHAs) are carbon and energy storage polymers produced by a variety of microbial organisms under nutrient-limited conditions. They have been considered as an environmentally friendly alternative to oil-based plastics due to their renewability, versatility, and biodegradability. PHA synthase (PhaC) plays a central role in PHA biosynthesis, in which its activity and substrate specificity are major factors in determining the productivity and properties of the produced polymers.

Analysis of Multidomain Protein Dynamics.

Proteins with a modular architecture of multiple domains connected by linkers often exhibit diversity in the relative positions of domains, while the domain tertiary structure remains unchanged. The biological function of these modular proteins, or the regulation of their activity, depends on the variation in domain orientation and separation. Accordingly, careful characterization of interdomain motion and correlated fluctuations of multidomain systems is relevant for understanding the functional behavior of modular proteins.

Chemical synthesis of tetracyclic terpenes and evaluation of antagonistic activity on endothelin-A receptors and voltage-gated calcium channels.

A class of tetracyclic terpenes was synthesized and evaluated for antagonistic activity of endothelin-1 (ET-1) induced vasoconstriction and inhibitory activity of voltage-activated Ca(2+) channels. Three repeated Robinson annulation reactions were utilized to construct the tetracyclic molecules. A stereoselective reductive Robinson annulation was discovered for the formation of optically pure tricyclic terpenes.

Evaluating the dynamics and electrostatic interactions of folded proteins in implicit solvents.

Three implicit solvent models, namely GBMVII, FACTS, and SCPISM, were evaluated for their abilities to emulate an explicit solvent environment by comparing the simulated conformational ensembles, dynamics, and electrostatic interactions of the Src SH2 domain and the Lyn kinase domain. This assessment in terms of structural features in folded proteins expands upon the use of hydration energy as a metric for comparison. All-against-all rms coordinate deviation, average positional fluctuations, and ion-pair distance distribution were used to compare the implicit solvent models with the TIP3P explicit solvent model.