Candida albicans Dicer (CaDcr1) is required for efficient ribosomal and spliceosomal RNA maturation.

The generation of mature functional RNAs from nascent transcripts requires the precise and coordinated action of numerous RNAs and proteins. One such protein family, the ribonuclease III (RNase III) endonucleases, includes Rnt1, which functions in fungal ribosome and spliceosome biogenesis, and Dicer, which generates the siRNAs of the RNAi pathway. The recent discovery of small RNAs in Candida albicans led us to investigate the function of C.

Clinical manufacturing of recombinant human interleukin 15. I. Production cell line development and protein expression in E. coli with stop codon optimization.

Interleukin 15 (IL-15) has shown remarkable biological properties of promoting NK- and T-cell activation and proliferation, as well as enhancing antitumor immunity of CD8(+) T cells in preclinical models. Here, we report the development of an E. coli cell line to express recombinant human Interleukin-15 (rhIL-15) for clinical manufacturing.

IL-15:IL-15 receptor alpha superagonist complex: high-level co-expression in recombinant mammalian cells, purification and characterization.

IL-15, a promising cytokine for treating cancer and viral diseases, is presented in trans by the IL-15 receptor (IL-15R) alpha-chain to the IL-15Rβγc complex displayed on the surface of T cells and natural killer (NK) cells. We previously reported that an asparagine to aspartic acid substitution at amino acid 72 (N72D) of IL-15 provides a 4-5-fold increase in biological activity compared to the native molecule. In this report, we describe Chinese hamster ovary (CHO) cell expression of a soluble complex (IL-15 N72D:IL-15RαSu/Fc) consisting of the IL-15 N72D superagonist and a dimeric IL-15Rα sushi domain-IgG1 Fc fusion protein.

Characterization of recombinant human IL-15 deamidation and its practical elimination through substitution of asparagine 77.

Purpose: The use of recombinant human interleukin (rhIL)-15 as a potential therapeutic immune modulator and anticancer agent requires pure, stable preparations. However, purified rhIL-15 preparations readily accumulated heterogeneities. We sought to improve rhIL-15 stability through process, formulation, and targeted amino acid changes.

Quantitative characterization of the influence of the nanoscale morphology of nanostructured surfaces on bacterial adhesion and biofilm formation.

Bacterial infection of implants and prosthetic devices is one of the most common causes of implant failure. The nanostructured surface of biocompatible materials strongly influences the adhesion and proliferation of mammalian cells on solid substrates. The observation of this phenomenon has led to an increased effort to develop new strategies to prevent bacterial adhesion and biofilm formation, primarily through nanoengineering the topology of the materials used in implantable devices.

Differences between training GPs to manage depression in primary care and issuing them with guidelines, and a system of collaborative care in the treatment of depression between primary and secondary care.

Here we describe the differences and similarities between training General Practitioners (GPs) to manage depression in primary care and issuing them with guidelines, and a system of Collaborative care in the treatment of depression between primary and secondary care. From these we deduce the reasons why collaborative care may offer better treatment outcomes than the issuing of guidelines to GPs.

Depression management - from neurobiology to a shared care approach.

The management of depression has recently been the focus of several articles, in particular regarding the efficacy of pharmacological and other treatments. In order for these to be effective as possible, correct diagnosis, consideration of the underlying neurobiology and an appropriate provision of healthcare services must be ensured.

Charge delocalization in self-assembled mixed-valence aromatic cation radicals.

The spontaneous assembly of aromatic cation radicals (D(+•)) with their neutral counterpart (D) affords dimer cation radicals (D(2)(+•)). The intermolecular dimeric cation radicals are readily characterized by the appearance of an intervalence charge-resonance transition in the NIR region of their electronic spectra and by ESR spectroscopy. The X-ray crystal structure analysis and DFT calculations of a representative dimer cation radical (i.

Recent developments in the medicinal chemistry and therapeutic potential of dihydroorotate dehydrogenase (DHODH) inhibitors.

Dihydroorotate dehydrogenase (DHODH) is a flavin-dependent mitochondrial enzyme that catalyzes fourth reaction of pyrimidine de-novo synthesis. Pyrimidine bases are essential for cellular metabolism and cell growth, and are considered as important precursors used in DNA (thymine and cytosine), RNA (uracil and cytosine), glycoproteins and phospholipids biosynthesis. The significance of pyrimidines biosynthesis in DNA and RNA makes them ideal targets for pharmacological intervention.

Probing nanoscale interactions on biocompatible cluster-assembled titanium oxide surfaces by atomic force microscopy.

We report on the investigation of the adhesive properties of cluster-assembled nanostructured TiO(x) (ns-TiO(x)) films against a Si3N4 AFM tip, in air and in water. The interacting AFM tip apex represents a model nanometer-sized probe, carrying both silanol (Si-OH) and silamine (Si2-NH) groups: it is therefore well suited to investigate biologically relevant molecular interactions with the biocompatible ns-TiO(x) surface. Coupling nanosphere lithography with supersonic cluster beam deposition we produced sub-micrometer patterns of ns-TiO(x) on a reference amorphous silica surface.

Unique presentation of maxillary artery, lingual nerve, and inferior alveolar nerve complex.

Knowledge of variations in arteries and nerves of infratemporal fossa may be helpful in radical neck dissection and in dental procedures to avoid the complications. We present an unusual case in which maxillary artery was found deep (medial) to lateral pterygoid muscle. Lingual nerve originated from two roots: anterior and posterior.

Comparison of kriging and cokriging for the geostatistical estimation of specific capacity in the Newark Basin (NJ) aquifer system.

Groundwater is a major water source in New Jersey; hence, accurate hydrogeologic data are extremely important. However, most measured data have inadequate spatial density and their locations are often clustered. Our study focuses on implementing geostatistical methods to generate the spatial distribution of specific capacity over the Newark Basin in New Jersey.

Substituted benzimidazole derivatives as angiotensin II-AT1 receptor antagonist: a review.

The renin angiotensin system (RAS) plays an important role in regulation of blood pressure and fluid-electrolyte homeostasis. The renin-angiotensin system consists of a cascade of enzymatic reactions producing angiotensin II (Ang II). Ang II is a vasoconstrictive peptide hormone that exerts a wide variety of physiological actions on cardiovascular, renal, endocrine and central nervous systems.

Proton magnetic resonance ((1)HNMR) spectroscopy and physicochemical studies of zaleplon-hydroxypropyl-β-cyclodextrin inclusion compounds.

Proton magnetic resonance spectroscopy ((1)HNMR) studies on inclusion compounds of zaleplon with hydroxypropyl-β- cyclodextrin (HPβCD) were carried out in order to elucidate the strength and binding mode of association. Chemical shift measurements revealed that inclusion complexes of zaleplon and HPβCD were formed by penetration of aromatic rings into the HPβCD cavity from the wider rim side with deep penetration of the amide-substituted ring while inclusion of the cyano-substituted pyrazole ring was shallow. A higher magnitude of ΔδH-3' and ΔδH-5' protons of HPβCD indicated higher stability of the lyophilized product than the kneaded one.

Preparation of a tetraphenylethylene-based emitter: synthesis, structure and optoelectronic properties of tetrakis(pentaphenylphenyl)ethylene.

Soluble tetrakis(pentaphenylphenyl)ethylene (1), prepared in three steps, allows non-emissive tetraphenylethylene (TPE) to turn into an emitter (Phi(F) = 0.13) owing to the steric bulk of the four large hexaphenylbenzene propellers which hamper =C-Ph and C=C bond rotations in the TPE core.

Physicochemical characterization of solid dispersion systems of tadalafil with poloxamer 407.

Dissolution behaviour of a poorly water-soluble drug, tadalafil, from its solid dispersion systems with poloxamer 407 has been investigated. Solid dispersion systems of tadalafil were prepared with poloxamer 407 in 1:0.5, 1:1.

MTS dye based colorimetric CTLL-2 cell proliferation assay for product release and stability monitoring of interleukin-15: assay qualification, standardization and statistical analysis.

A colorimetric cell proliferation assay using soluble tetrazolium salt [(CellTiter 96(R) Aqueous One Solution) cell proliferation reagent, containing the (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) and an electron coupling reagent phenazine ethosulfate], was optimized and qualified for quantitative determination of IL-15 dependent CTLL-2 cell proliferation activity. An in-house recombinant Human (rHu)IL-15 reference lot was standardized (IU/mg) against an international reference standard. Specificity of the assay for IL-15 was documented by illustrating the ability of neutralizing anti-IL-15 antibodies to block the product specific CTLL-2 cell proliferation and the lack of blocking effect with anti-IL-2 antibodies.

Physicochemical investigation of the solid dispersion systems of etoricoxib with poloxamer 188.

Solid dispersion systems of a poorly water-soluble drug, etoricoxib were prepared with poloxamer 188 in 1:0.5, 1:1.5 and 1:2.

Preparation and physicochemical characterization of surfactant based solid dispersions of ezetimibe.

Solid dispersions of the poorly water-soluble drug ezetimibe were prepared with a surfactant, Pluronic 188 in different ratios and characterized by FTIR, XRD, DSC and dissolution studies. The melting method was employed to prepare the solid dispersions whereas a physical mixture (1:3) was prepared by co-grinding the individual components in a mortar. Physical studies demonstrated a significant reduction in crystallinity with a possibility of presence of amorphous character of drug in the solid dispersions of ezetimibe.

N-aryl-oxazolidin-2-imine muscle selective androgen receptor modulators enhance potency through pharmacophore reorientation.

A novel selective androgen receptor modulator (SARM) scaffold was discovered as a byproduct obtained during synthesis of our earlier series of imidazolidin-2-ones. The resulting oxazolidin-2-imines are among the most potent SARMs known, with many analogues exhibiting sub-nM in vitro potency in binding and functional assays. Despite the potential for hydrolytic instability at gut pH, compounds of the present class showed good oral bioavailability and were highly active in a standard rodent pharmacological model.

Pharmacokinetics of the dipeptidyl peptidase 4 inhibitor saxagliptin in rats, dogs, and monkeys and clinical projections.

Saxagliptin is a potent, selective, reversible dipeptidyl peptidase 4 (DPP4) inhibitor specifically designed for extended inhibition of the DPP4 enzyme and is currently under development for the treatment of type-2 diabetes. The pharmacokinetics of saxagliptin were evaluated in rats, dogs, and monkeys and used to predict its human pharmacokinetics. Saxagliptin was rapidly absorbed and had good bioavailability (50-75%) in the species tested.

Prediction of human oral pharmacokinetics using nonclinical data: examples involving four proprietary compounds.

The oral pharmacokinetics (concentration-time profile) of four proprietary compounds in humans were predicted using the C(vss)-MRT method. The first step was to demonstrate superposition of intravenous (i.v.