BTN3A1 Discriminates γδ T Cell Phosphoantigens from Nonantigenic Small Molecules via a Conformational Sensor in Its B30.2 Domain.

Human Vγ9/Vδ2 T-cells detect tumor cells and microbial infections by recognizing small phosphorylated prenyl metabolites termed phosphoantigens (P-Ag). The type-1 transmembrane protein Butyrophilin 3A1 (BTN3A1) is critical to the P-Ag-mediated activation of Vγ9/Vδ2 T-cells; however, the molecular mechanisms involved in BTN3A1-mediated metabolite sensing are unclear, including how P-Ag's are discriminated from nonantigenic small molecules. Here, we utilized NMR and X-ray crystallography to probe P-Ag sensing by BTN3A1.

Rab7b modulates autophagic flux by interacting with Atg4B.

Autophagy (macroautophagy) is a highly conserved eukaryotic degradation pathway in which cytosolic components and organelles are sequestered by specialized autophagic membranes and degraded through the lysosomal system. The autophagic pathway maintains basal cellular homeostasis and helps cells adapt during stress; thus, defects in autophagy can cause detrimental effects. It is therefore crucial that autophagy is properly regulated.

Virtual Screening of Acyclovir Derivatives as Potential Antiviral Agents: Design, Synthesis, and Biological Evaluation of New Acyclic Nucleoside ProTides.

Following our findings on the anti-human immunodeficiency virus (HIV) activity of acyclovir (ACV) phosphate prodrugs, we herein report the ProTide approach applied to a series of acyclic nucleosides aimed at the identification of novel and selective antiviral, in particular anti-HIV agents. Acyclic nucleoside analogues used in this study were identified through a virtual screening using HIV-reverse transcriptase (RT), adenylate/guanylate kinase, and human DNA polymerase γ. A total of 39 new phosphate prodrugs were synthesized and evaluated against HIV-1 (in vitro and ex vivo human tonsillar tissue system) and human herpes viruses.

Route of Administration Affects Corticosteroid Sensitivity of a Combined Ovalbumin and Lipopolysaccharide Model of Asthma Exacerbation in Guinea Pigs.

Lipopolysaccharide (LPS) contributes to asthma exacerbations and development of inhaled corticosteroid insensitivity. Complete resistance to systemic corticosteroids is rare, and most patients lie on a continuum of steroid responsiveness. This study aimed to examine the sensitivity of combined ovalbumin- (Ova) and LPS-induced functional and inflammatory responses to inhaled and systemic corticosteroid in conscious guinea pigs to test the hypothesis that the route of administration affects sensitivity.

The public's perception of the role of community pharmacists in Wales.

Objective: To investigate the general public's perceptions of the community pharmacist's (CP) role in Wales by exploring understanding, awareness of services provided and potential interventions for promoting the role of CPs.

Methods: Qualitative methodology using focus group (FG) discussions exploring opinions, facilitated by a moderator (pharmacist) and an assistant. Topics discussed included the following: what a CP does; reasons for visiting; from whom they seek advice on medicines or lifestyle issues; use of traditional and newer services and promotion of services.

3-Aroyl-1,4-diarylpyrroles Inhibit Chronic Myeloid Leukemia Cell Growth through an Interaction with Tubulin.

We designed 3-aroyl-1,4-diarylpyrrole (ARDAP) derivatives as potential anticancer agents having different substituents at the 1- or 4-phenyl ring. ARDAP compounds exhibited potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARDAP derivative inhibited the proliferation of BCR/ABL-expressing KU812 and LAMA84 cells from chronic myeloid leukemia (CML) patients in blast crisis and of hematopoietic cells ectopically expressing the imatinib mesylate (IM)-sensitive KBM5-WT or its IM-resistant KBM5-T315I mutation.

Antibiotics for acute respiratory tract infections: a mixed-methods study of patient experiences of non-medical prescriber management.

Objective: To (1) explore patients' expectations and experiences of nurse and pharmacist non-medical prescriber-led management of respiratory tract infections (RTIs), (2) examine whether patient expectations for antibiotics affect the likelihood of receiving them and (3) understand factors influencing patient satisfaction with RTI consultations.

Design: Mixed methods.

Setting: Primary care.

Effects of nebulised magnesium sulphate on inflammation and function of the guinea-pig airway.

Magnesium sulphate is a potential treatment for acute severe asthma. However, the mechanisms and dose-response relationships are poorly understood. The first objective of this study was to examine whether inhaled magnesium sulphate exerts bronchodilator activity measured as bronchoprotection against histamine-induced bronchoconstriction in conscious guinea-pigs alone and combined with salbutamol.

Characterization of 6-methoxyflavanone as a novel anxiolytic agent: A behavioral and pharmacokinetic approach.

Benzodiazepines are regularly prescribed for treatment of anxiety though there are side effects. Flavonoids have selective affinity for GABA receptors implicated in anxiolytic-like activity in rodents, but are devoid of the unwanted side effects of benzodiazepines. In this study, 6-methoxyflavanone (6-MeOF), a positive allosteric modulator of γ-amino butyric acid (GABA) responses at human recombinant GABA receptors, was evaluated for its behavioral profile in the elevated plus-maze as well as the staircase- plus and open-field tests in mice.

Hydrodynamic gene delivery in human skin using a hollow microneedle device.

Microneedle devices have been proposed as a minimally invasive delivery system for the intradermal administration of nucleic acids, both plasmid DNA (pDNA) and siRNA, to treat localised disease or provide vaccination. Different microneedle types and application methods have been investigated in the laboratory, but limited and irreproducible levels of gene expression have proven to be significant challenges to pre-clinical to clinical progression. This study is the first to explore the potential of a hollow microneedle device for the delivery and subsequent expression of pDNA in human skin.

Antibodies to Glutamate Reversed the Amnesic Effects of Proinflammatory S100A9 Protein Fibrils in Aged C57Bl/6 Mice.

Chronic intranasal administration of fibrillar structures of proinflammatory S100A9 protein impaired passive avoidance learning in old C57Bl/6 mice. Combined treatment with S100A9 fibrils and antibodies to glutamate was followed by an increase in horizontal locomotor activity of animals in the open-field test and did not disturb spatial memory.

Shape-based virtual screening, synthesis and evaluation of novel pyrrolone derivatives as antiviral agents against HCV.

A ligand-based approach was applied to screen in silico a library of commercially available compounds, with the aim to find novel inhibitors of the HCV replication starting from the study of the viral NS3 helicase. Six structures were selected for evaluation in the HCV subgenomic replicon assay and one hit was found to inhibit the HCV replicon replication in the low micromolar range. A small series of new pyrrolone compounds was designed and synthesised, and novel structures were identified with improved antiviral activity.

Synthetic and natural antioxidants attenuate cisplatin-induced vomiting.

Background: Synthetic and natural antioxidants including Bacopa monnieri (L.) Pennell (Scrophulariaceae) which also possess anti-dopaminergic properties, have been proposed to be useful for emetogenic chemotherapy. In this study, synthetic [N-(2-mercaptopropionyl) glycine (MPG), vitamin C (Vit-C)] and natural [grape seed proanthocyanidin (GP), B.

The Role of BCA2 in the Endocytic Trafficking of EGFR and Significance as a Prognostic Biomarker in Cancer.

Breast Cancer Associated gene 2 (BCA2) is an E3 ubiquitin ligase that is over-expressed in >50% of primary breast cancers, and has been shown to increase cell proliferation and invasion. The protein has been linked to alterations in EGFR degradation; however there is some dispute as to its role and influence on the biology of this receptor. Our work aimed to ascertain the role of BCA2 in EGFR endocytosis and down-regulation and to examine its links with breast cancer outcome.

Awareness of Sickle Cell Trait Status: A Cross-Sectional Survey of Antenatal Women in Ghana.

This study was conducted to evaluate pregnant women's awareness of sickle cell disease and sickle cell trait and the factors that contribute to it. Two hundred and six pregnant women with at least 20 weeks gestation answered a questionnaire regarding awareness of their trait status and questions to test their knowledge of sickle cell disease. Although the majority of patients were aware of their trait status (87.

Topical gabapentin gel alleviates allodynia and hyperalgesia in the chronic sciatic nerve constriction injury neuropathic pain model.

Background: Systemic gabapentin is a mainstay treatment for neuropathic pain though there are side-effects. Localized therapy may curtail such side-effects so a topical gabapentin dermal application was examined in the chronic constriction injury (CCI) model of neuropathic pain.

Methods: Partial denervation CCI was achieved by rat sciatic nerve ligation.

Novel symmetrical phenylenediamines as potential anti-hepatitis C virus agents.

Background: Despite the great progress made in the last 10 years, alternative strategies might help improving definitive treatment options against hepatitis C virus infection.

Methods: With the aim of identifying novel inhibitors of the hepatitis C virus-1b replication targeting the viral NS3 helicase, the structures of previously reported symmetrical inhibitors of this enzyme were rationally modified, and according to docking-based studies, four novel scaffolds were selected for synthesis and evaluation in the hepatitis C virus-1b subgenomic replicon assay.

Results: Among the newly designed compounds, one new structural family was found to inhibit the hepatitis C virus-1b replication in the micromolar range.

Cellular efflux transporters and the potential role of natural products in combating efflux mediated drug resistance.

Efflux mediated multidrug resistance (MDR) is a major problem in the treatment of bacterial, fungal and protozoal infections in addition to cancer chemotherapy. Among other well known mechanisms, efflux pumps are significant contributors to chemo-resistance. Efflux mediated resistance generally occurs through up-regulation of genes responsible for the expression of transporter proteins extruding drugs from the cell to create intracellular sub-therapeutic concentrations leading to resistance.

In silico identification, design and synthesis of novel piperazine-based antiviral agents targeting the hepatitis C virus helicase.

A structure-based virtual screening of commercial compounds was carried out on the HCV NS3 helicase structure, with the aim to identify novel inhibitors of HCV replication. Among a selection of 13 commercial structures, one compound was found to inhibit the subgenomic HCV replicon in the low micromolar range. Different series of new piperazine-based analogues were designed and synthesised, and among them, several novel structures exhibited antiviral activity in the HCV replicon assay.

Virulence plasmid stability in environmentally occurring Bacillus anthracis from North East Turkey.

The Bacillus anthracis virulence plasmid pXO2, which encodes for a polypeptide capsule, can be lost during long term laboratory storage. To determine if pXO2 is lost in nature we screened B. anthracis isolates obtained from B.

Phytochemical profiling as a solution to palliate disinfectant limitations.

The indiscriminate use of biocides for general disinfection has contributed to the increased incidence of antimicrobial tolerant microorganisms. This study aims to assess the potential of seven phytochemicals (tyrosol, caffeic acid, ferulic acid, cinnamaldehyde, coumaric acid, cinnamic acid and eugenol) in the control of planktonic and sessile cells of Staphylococcus aureus and Escherichia coli. Cinnamaldehyde and eugenol showed antimicrobial properties, minimum inhibitory concentrations of 3-5 and 5-12 mM and minimum bactericidal concentrations of 10-12 and 10-14 mM against S.

A Partially Purified Acinetobacter baumannii Phage Preparation Exhibits no Cytotoxicity in 3T3 Mouse Fibroblast Cells.

A surge in the level and scale of antibiotic resistance has prompted renewed interest in the application of bacteriophages to treat bacterial infections. However, concerns still exist over their efficacy and safety. Acinetobacter baumannii phage BS46, a member of the family Myoviridae, has previously been shown to be effective in murine models.

Computer-aided identification, synthesis and evaluation of substituted thienopyrimidines as novel inhibitors of HCV replication.

A structure-based virtual screening technique was applied to the study of the HCV NS3 helicase, with the aim to find novel inhibitors of the HCV replication. A library of ∼450000 commercially available compounds was analysed in silico and 21 structures were selected for biological evaluation in the HCV replicon assay. One hit characterized by a substituted thieno-pyrimidine scaffold was found to inhibit the viral replication with an EC50 value in the sub-micromolar range and a good selectivity index.

The redistribution of medicines: could it become a reality?

Aims And Objectives: Prescription medicines that are returned unused to pharmacies in the United Kingdom (UK) cannot be supplied (or redistributed) to other patients. The aim of the study was to investigate whether or not consensus could be achieved between pharmacists on the barriers and potential solutions they perceive towards the redistribution of returned medicines.

Methods: A two-round electronic modified Delphi study was employed.