Long-Term Study of Hepatitis Delta Virus Infection at Secondary Care Centers: The Impact of Viremia on Liver-Related Outcomes.

Background And Aims: Hepatitis delta virus (HDV) infection is associated with fast progression to liver cirrhosis and liver complications. Previous studies have, however, been mainly from tertiary care centers, with risk for referral bias toward patients with worse outcomes. Furthermore, the impact of HDV viremia per se on liver-related outcomes is not really known outside the human immunodeficiency virus co-infection setting.

Prediction of designer drugs: Synthesis and spectroscopic analysis of synthetic cathinone analogs that may appear on the Swedish drug market.

The use of hyphenated analytical techniques in forensic drug screening enables simultaneous identification of a wide range of different compounds. However, the appearance of drug seizures containing new substances, mainly new psychoactive substances (NPS), is steadily increasing. These new and other already known substances often possess structural similarities and consequently they exhibit spectral data with slight differences.

Engineering Dirac Materials: Metamorphic InAsSb/InAsSb Superlattices with Ultralow Bandgap.

Quasiparticles with Dirac-type dispersion can be observed in nearly gapless bulk semiconductors alloys in which the bandgap is controlled through the material composition. We demonstrate that the Dirac dispersion can be realized in short-period InAsSb/InAsSb metamorphic superlattices with the bandgap tuned to zero by adjusting the superlattice period and layer strain. The new material has anisotropic carrier dispersion: the carrier energy associated with the in-plane motion is proportional to the wave vector and characterized by the Fermi velocity v, and the dispersion corresponding to the motion in the growth direction is quadratic.

Intermixing studies in GaNSb highly mismatched alloys.

GaNSb with x∼5%-7% is a highly mismatched alloy predicted to have favorable properties for application as an electrode in a photoelectrochemical cell for solar water splitting. In this study, we grew GaNSb under conditions intended to induce phase segregation. Prior experiments with the similar alloy GaNAs, the tendency of Sb to surfact, and the low growth temperatures needed to incorporate Sb all suggested that GaNSb alloys would likely exhibit phase segregation.

Materials design parameters for infrared device applications based on III-V semiconductors.

The collaborative development of infrared detector materials by the Army Research Laboratory and Stony Brook University has led to new fundamental understandings of materials, as well as new levels of control and flexibility in III-V semiconductor crystal growth by molecular beam epitaxy. Early work on mid-wave strained layer superlattice (SLS) cameras led to a subsequent focus on minority carrier lifetime studies, which resulted in the proposal of the Ga-free SLS on GaSb substrates. The later demonstration of virtual substrate technology allowed the lattice constant to become a design parameter and enabled growth of undistorted bulk InAsSb.

Resin-acid derivatives as potent electrostatic openers of voltage-gated K channels and suppressors of neuronal excitability.

Voltage-gated ion channels generate cellular excitability, cause diseases when mutated, and act as drug targets in hyperexcitability diseases, such as epilepsy, cardiac arrhythmia and pain. Unfortunately, many patients do not satisfactorily respond to the present-day drugs. We found that the naturally occurring resin acid dehydroabietic acid (DHAA) is a potent opener of a voltage-gated K channel and thereby a potential suppressor of cellular excitability.

N-Benzyl-indolo carboxylic acids: Design and synthesis of potent and selective adipocyte fatty-acid binding protein (A-FABP) inhibitors.

Small molecule inhibitors of adipocyte fatty-acid binding protein (A-FABP) have gained renewed interest following the recent publication of pharmacologically beneficial effects of such inhibitors. Despite the potential utility of selective A-FABP inhibitors within the fields of metabolic disease, inflammation and atherosclerosis, there are few examples of useful A-FABP inhibitors in the public domain. Herein, we describe the optimization of N-benzyl-tetrahydrocarbazole derivatives through the use of co-crystal structure guided medicinal chemistry efforts.

The selectivity of tyrosine 280 of human 11beta-hydroxysteroid dehydrogenase type 1 in inhibitor binding.

11beta-Hydroxysteroid dehydrogenase type 1 is a homodimer where the carboxyl terminus of one subunit covers the active site of the dimer partner. Based on the crystal structure with CHAPS, the carboxyl terminal tyrosine 280 (Y280) has been postulated to interact with the substrate/inhibitor at the binding pocket of the dimer partner. However, the co-crystal structure with carbenoxolone argues against this role.

The role of tyrosine 177 in human 11beta-hydroxysteroid dehydrogenase type 1 in substrate and inhibitor binding: an unlikely hydrogen bond donor for the substrate.

The catalytic motif (YSASK) at the active site of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is conserved across different species. The crystal structures of the human, guinea pig and mouse enzymes have been resolved to help identify the non-conserved residues at the active site. A tyrosine residue (Y177) upstream of the catalytic motif in human 11beta-HSD1 represents the largest difference at the active sites between the human and the rodent enzyme where the corresponding residue is glutamine.

Ice nucleation and phase behavior on oligo(ethylene glycol) and hydroxyl self-assembled monolayers: simulations and experiments.

The nucleation and phase behavior of ultrathin D2O-ice overlayers have been studied on oligo(ethylene glycol) (OEG)-terminated and hydroxyl self-assembled monolayers (SAMs) at low temperatures in ultrahigh vacuum. Infrared reflection-absorption spectroscopy (IRAS) is used to characterize the ice overlayers, the SAMs, and the interactions occurring between the ice and the SAM surfaces. Spectral simulations, based on optical models in conjunction with Maxwell Garnett effective medium theory, point out the importance of including voids in the modeling of the ice structures, with void fractions reaching 60% in some overlayers.

Active site variability of type 1 11beta-hydroxysteroid dehydrogenase revealed by selective inhibitors and cross-species comparisons.

The NADPH-dependent enzyme type 1 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) activates in a tissue-specific manner circulating pro-glucocorticoid hormones (cortisone in humans) to the 11beta-OH ligand (cortisol in humans), which is able to bind to its cognate receptor and regulate gene transcription. Modulation of this pre-receptor activation mechanism by selective enzyme inhibitors is a desirable goal in the treatment of insulin resistance and related metabolic disorders. Like most other hydroxysteroid dehydrogenases 11beta-HSD1 belongs to the evolutionarily conserved enzyme superfamily of short-chain dehydrogenases/reductases (SDR).

Molecular gradients: an efficient approach for optimizing the surface properties of biomaterials and biochips.

A variety of molecular gradients of alkanethiols with the structure HS-(CH(2))(m)-X (m = 15; X = COOH, CH(2)NH(2), or CH(3)) and oligo(ethylene glycol)-terminated alkanethiols with the structures HS-(CH(2))(15)-CO-NH-Eg(n) (n = 2, 4, or 6), HS-(CH(2))(15)-CO-NH-Eg(2)-(CH(2))(2)-NH-CO-(CH(2))(4)-biotin, and HS-(CH(2))(15)-CO-NH-Eg(6)-CH(2)-COOH were prepared on polycrystalline gold films. These gradients were designed to serve as model surfaces for fundamental studies of protein adsorption and immobilization phenomena. Ellipsometry, infrared spectroscopy, and X-ray photoelectron spectroscopy, operating in scanning mode, were used to monitor the layer composition, gradient profiles, tail group conformation, and overall structural quality of the gradient assemblies.

The crystal structure of guinea pig 11beta-hydroxysteroid dehydrogenase type 1 provides a model for enzyme-lipid bilayer interactions.

The metabolic reduction of 11-keto groups in glucocorticoid steroids such as cortisone leads to the nuclear receptor ligand cortisol. This conversion is an example of pre-receptor regulation and constitutes a novel pharmacological target for the treatment of metabolic disorders such as insulin resistance and possibly other derangements observed in the metabolic syndrome, such as hyperlipidemia, hypertension, and lowered insulin secretion. This reaction is carried out by the NADPH-dependent type 1 11beta-hydroxysteroid dehydrogenase (11beta-HSD1), an enzyme attached through an integral N-terminal transmembrane helix to the lipid bilayer and located with its active site within the lumen of the endoplasmic reticulum.

Discovery of inhibitors of human adipocyte fatty acid-binding protein, a potential type 2 diabetes target.

Low micromolar human A-FABP inhibitors were found by utilizing a fluorescence polarization assay, X-ray crystallography and modeling. The carbazole- and indole-based inhibitors displayed approximately 10-fold preferences over human H-FABP and E-FABP, and are highly selective against I-FABP. This communication describes the SAR for drug-like synthetic inhibitors of human A-FABP.

Crystal structure and biological implications of a bacterial albumin binding module in complex with human serum albumin.

Many bactericide species express surface proteins that interact with human serum albumin (HSA). Protein PAB from the anaerobic bacterium Finegoldia magna (formerly Peptostreptococcus magnus) represents one of these proteins. Protein PAB contains a domain of 53 amino acid residues known as the GA module.

High-level production and optimization of monodispersity of 11beta-hydroxysteroid dehydrogenase type 1.

11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is an intraluminally oriented, endoplasmic reticulum (ER)-bound enzyme catalyzing the interconversion between inactive cortisone and hormonally active cortisol. Heterologous production of 11beta-HSD1, devoid of its N-terminal transmembrane segment, is possible but yields only small amounts of soluble protein. Here we show that the soluble portion of recombinant 11beta-HSD1 produced in E.

A new class of peroxisome proliferator-activated receptor agonists with a novel binding epitope shows antidiabetic effects.

The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the NR1 subfamily of nuclear receptors. The PPARs play key roles in the control of glucose and lipid homeostasis, and the synthetic isoform-specific PPAR agonists are used clinically to improve insulin sensitivity and to lower serum triglyceride levels. All of the previously reported PPAR agonists form the same characteristic interactions with the receptor, which have been postulated to be important for the induction of agonistic activity.

Enzymatic mechanism of low-activity mouse alcohol dehydrogenase 2.

ADH2 is a member of one of the six classes of mammalian alcohol dehydrogenases, which catalyze the reversible oxidation of alcohols using NAD(+) as a cofactor. Within the ADH2 class, the rodent enzymes form a subgroup that exhibits low catalytic activity with all substrates that were examined, as compared to other groups, such as human ADH2. The low activity can be ascribed to the rigid nature of the proline residue at position 47 as the activity can be increased by approximately 100-fold by substituting Pro47 with either His (as found in human ADH2), Ala, or Gln.

Crystal structure of the heterodimeric complex of LXRalpha and RXRbeta ligand-binding domains in a fully agonistic conformation.

The nuclear receptor heterodimers of liver X receptor (LXR) and retinoid X receptor (RXR) are key transcriptional regulators of genes involved in lipid homeostasis and inflammation. We report the crystal structure of the ligand-binding domains (LBDs) of LXRalpha and RXRbeta complexed to the synthetic LXR agonist T-0901317 and the RXR agonist methoprene acid (Protein Data Base entry 1UHL). Both LBDs are in agonist conformation with GRIP-1 peptides bound at the coactivator binding sites.

Synthesis and pharmacological evaluation of a new class of peroxisome proliferator-activated receptor modulators.

A series of 5-substituted 2-benzoylaminobenzoic acids has been synthesized and assayed for PPARalpha/gamma activity. Both dual activators and selective PPARgamma agonists have been identified. This class of compounds was shown to activate the PPARgamma receptor through interaction with a novel binding site.

Comparative enzymology of 11 beta -hydroxysteroid dehydrogenase type 1 from glucocorticoid resistant (Guinea pig) versus sensitive (human) species.

Type 1 11 beta-hydroxysteroid dehydrogenase constitutes a prereceptor control mechanism through its ability to reduce dehydroglucocorticoids to the receptor ligands cortisol and corticosterone in vivo. We compared kinetic characteristics of the human and guinea pig 11 beta-hydroxysteroid dehydrogenase isozymes derived from species differing in glucocorticoid sensitivity. Both orthologs were successfully expressed as full-length enzymes in yeast and COS7 cells and as soluble transmembrane-deleted constructs in Escherichia coli.

Structure-based screening as applied to human FABP4: a highly efficient alternative to HTS for hit generation.

The time-limiting step in HTS often is the development of an appropriate assay. In addition, hits from HTS fairly often turn out to be false positives and generally display unfavorable properties for further development. Here we describe an alternative process for hit generation, applied to the human adipocyte fatty acid binding protein FABP4.

Alteration in endogenous opioid systems due to chronic inflammatory pain conditions.

The influence of chronic arthritic pain on two endogenous opioid peptides, dynorphin B and [Met5]enkephalin-Arg6-Phe7, and multiple opioid receptors in discrete brain, lumbar spinal cord and pituitary pools was investigated. Using radioimmunoassay and receptor binding assay, we examined the changes in regional opioid peptide levels and opioid receptor activity due to chronic inflammation in adjuvant arthritic rats. At 4 weeks post-inoculation, increased levels of immunoreactive dynorphin B and [Met5]enkephalin-Arg6-Phe7 were measured in tissues of arthritic rats compared with controls.