Promoter-, cell-, and ligand-specific transactivation responses of the VDRB1 isoform

The vitamin D receptor (VDR) mediates the effects of 1,25(OH)(2)D-3, the active form of vitamin D. The human VDRB1 isoform differs from the originally described VDR by an N-terminal extension of 50 amino acids. Here we investigate cell-, promoter-, and ligand-specific transactivation by the VDRB1 isoform. Transactivation by these isoforms of the cytochrome P450 CYP24 promoter was compared in kidney (HEK293 and COS1), tumor-derived colon (Caco-2, LS174T, and HCT15), and mammary (HS578T and MCF7) cell lines. VDRB1 transactivation in response to 1,25(OH)(2)D-3 was greater in Cost and HCT15 cells (145%), lower in HEK293 and Caco-2 cells (70-85%) and similar in other cell lines tested. By contrast, on the cytochrome P450 CYP3A4 promoter, 1,25(OH)(2)D-3-induced VDRB1 transactivation was significantly lower than VDRA in Caco-2 (68%), but comparable to VDRA in HEK293 and COS1 cells. Ligand-dependence of VDRB1 differential transactivation was investigated using the secondary bile acid lithocholic acid (LCA). On the CYP24 promoter LCA-induced transactivation was similar for both isoforms in COS1, whereas in Caco-2 and HEK293 cells VDRB1 was less active. On the CYP3A4 promoter, LCA activation of VDRB1 was comparable to VDRA in all the cell lines tested. Mutational analysis indicated that both the 1,25(OH)(2)D-3 and LCA-regulated activities of both VDR isoforms required a functional ligand-dependent activation function (AF-2) domain. In gel shift assays VDR:DNA complex formation was stronger in the presence of 1,25(OH)(2)D-3 than with LCA. These results indicate that regulation of VDRB1 transactivation activity is dependent on cellular context, promoter, and the nature of the ligand. (c) 2005 Elsevier Inc. All rights reserved.

Local therapy for restenosis

The durability of all forms of open or percutaneous revascularisation is affected by the development of localised stenoses within the bypass graft or at the site of endarterectomy, stent or angioplasty. The reported incidence of significant restenosis has varied dependent on initial procedure, site, case mix and definition, but is greatest during the first 12 months (Table 1).1 Over the last 40 years tens of thousands of studies have been carried out in an effort to understand or reduce the incidence of restenosis, with two major mechanisms identified as being responsible for the luminal narrowing, namely intimal hyperplasia and constrictive remodelling. Intimal hyperplasia is provoked by changes in the balance of local cytokines controlling vascular smooth muscle cell (VSMC) proliferation, apoptosis and migration, brought about by endothelial or medial injury and alterations in haemodynamic forces. The overall vessel diameter reduction that occurs in constrictive remodelling is less well defined, but likely involves matrix turnover under the control of proteinases, particularly metalloproteinases.

Glass transition and enthalpy relaxation of amorphous food saccharides: A review

Many food materials exist in a disordered amorphous solid state due to processing. Therefore, understanding the concept of amorphous state, its important phase transition (i.e., glass transition), and the related phenomena (e.g., enthalpy relaxation) is important to food scientists. Food saccharides, including mono-, di-, oligo-, and polysaccharides, are among the most important major components in food. Focusing on the food saccharides, this review covers important topics related to amorphous solids, including the concept and molecular arrangement of amorphous solid, the formation of amorphous food saccharides, the concept of glass transition and enthalpy relaxation, physical property changes and molecular mobility around the glass transition, measurement of the glass transition and enthalpy relaxation, their mathematical descriptions and models, and influences on food stability.

COACHING E MENTORING COMO PRÁTICAS DE COMPARTILHAMENTO DO CONHECIMENTO: ESTUDOS DE CASOS EM EMPRESAS PÚBLICAS PAULISTAS

A pesquisa teve como objetivo geral analisar as principais razões pelas quais as empresas públicas paulistas utilizam coaching e mentoring como práticas de compartilhamento de conhecimento. No ano de 2009, foi instituído pelo governador do Estado de São Paulo, o decreto nº 53.963 que instituiu a Política de Gestão do Conhecimento e Inovação para as empresas públicas. Kuniyoshi e Santos (2007) realizaram uma pesquisa, na qual identificaram práticas e iniciativas de gestão do conhecimento adotadas por algumas empresas, dentre elas, coaching e mentoring. As práticas são processos que necessitam de investimento não somente financeiro, mas de tempo e pessoas adequadas, por serem processos mais complexos, instigam a investigação de ações no contexto organizacional de empresas públicas. Este estudo busca contribuir para o desenvolvimento de estudos na área pública. O método utilizado neste estudo de abordagem qualitativa é do tipo exploratória. O objeto desta pesquisa foram as empresas públicas paulistas, que, atualmente, somam 21. Foi realizado estudo de caso, com entrevista e análise documental em duas destas empresas, A Sabesp, empresa do segmento de saneamento de água e esgoto, teve como objetivo analisar a prática de coaching e, o Instituto de Pesquisa Tecnológicas (IPT), referência nacional em metrologia, teve como objetivo analisar a prática de mentoring. Uma vez que não existem práticas exclusivas à Gestão do Conhecimento, e o sucesso de uma prática está relacionado ao contexto na qual está inserida. No caso da Sabesp, a prática de coaching é utilizada como uma das atividades dentro de dois programas, visando desenvolver o capital humano como força competitiva. O IPT teve como objetivo da aplicação do programa de mentoring, especificamente, o compartilhar conhecimento tácito. Foi constatado que as práticas de coaching e mentoring podem ser utilizadas como recurso capaz de tornar a empresa singular perante as demais, mesmo empresas públicas não tendo foco em competitividade, mas utilizam o conhecimento de forma estratégica para melhorar a qualidade de atendimento à sociedade.

The debate on human automatism in mid-Victorian England

During the 1830s, Marshall Hall carried out innumerable experiments on a great variety of animals to establish the concept of a ‘reflex arc’. In France F.L.Goltz showed that decerebrate frogs were still capable of complex behaviours. Thomas Laycock in England and Ivan Sechenov in Russia sought to apply the reflex idea to the brain. This paper follows the debate in the periodical literature of mid-Victorian England and discusses the contributions of WB Carpenter, Herbert Spencer, TH Huxley, W Clifford and others. The previous outing of this issue in the post-Cartesian seventeenth century had been largely suppressed by ecclesiastical authority. In the nineteenth century ecclesiastical power had waned, at least in England, and the debate could take a more open form. As neurophysiology and behavioural science developed, with the widespread acceptance of Darwinian evolution, it became more and more difficult to deny that brain and mind were part of the natural world and subject to the usual laws of cause and effect. This, of course, had powerful implications for the human self-image and for jurisprudence. These implications are still with us and the work of neurophysiologists such as Benjamin Libet have only reinforced them. Should humans be regarded as ‘automata’ and, if so, what becomes of ‘free will’, ‘responsibility’, and the rule of law? The Victorian debate is still useful and relevant.

Systems biology approach to study permeability of paracetamol and its solid dispersion

Physiological changes that take place at cellular level are usually reflective of their level of gene expression. Different formulation excipients have an impact on physiological behavior of the exposed cells and in turn affect transporter genes, enterocyte-mediated metabolism and toxicity biomarkers. The aim of this study was to prepare solid dispersion of paracetamol and evaluate genetic changes that occur in Caco-2 cell lines during the permeability of paracetamol alone and paracetamol solid dispersion formulations. Paracetamol-PEG 8000 solid dispersion was prepared by melt fusion method and the formulation was characterised using differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). Formulation of solid dispersion resulted in the conversion of crystalline drug into an amorphous form. Permeability studies showed that paracetamol absorption was higher from the solid dispersion formulation. DNA microarrays analysis was carried out in order to investigate the involvement of any efflux/uptake transporters in paracetamol or its solid dispersion permeability. Neither transporter carriers nor efflux proteins were found to be involved in the absorption of paracetamol or its PEG solid dispersion. Gene expression analysis established that paracetamol toxicity was potentially reduced upon formulation into solid dispersion when ATP binding cassette (ABC) and solute carrier transporter (SLC) genes were analyzed.

The exchange rate exposure of UK non-financial companies

Purpose – The purpose of this paper is to investigate the exchange rate exposure of UK nonfinancial companies from January 1981 to December 2001. Design/methodology/approach – The study employs different exchange rate measures and adopts an equally weighted exchange rate. The analyses are conducted at the firm level. All analyses are conducted by regressing the firm’s exchange rate exposure coefficients on its size, foreign activity variables and financial hedging proxies over the whole sample period. Findings – The findings show that a higher percentage of UK non-financial companies are exposed to exchange rate changes than those reported in previous studies. Generally, the results provide a stronger support for the suggested equally weighted rate as an economic variable, which affects firms’ stock returns. The results also show a high proportion of positive exposure coefficients among firms with significant exchange rate exposure, indicating a higher proportion of firms benefiting from an appreciation of the pound. Finally, the results also indicate evidence that firms’ foreign operations and hedging variables affect their sensitivity to exchange rate exposure. Practical implications – This study provides important implications for public policymakers who wish to understand links between policies that affect exchange rates and relative wealth effects. Originality/value – The empirical results of this study should help investors to examine how common stock returns react to exchange rate fluctuations when making financial decisions, and prove useful for financial managers when measuring exposure to foreign exchange rate changes.

The Role of the big five personality traits, proactive behaviour, and socialisation influences in newcomer adjustment

During the early stages of employment, newly hired employees find out what their new organisations are like. Their first impressions are extremely important in determining the course of subsequent attitudes and behaviour. Recently, a considerable progress has been made towards the understanding of adjustment process, however, the literature remain divided along a number of fronts. Moreover, newcomer research has been conducted independent and irrespective of newcomer personality individual differences. This seems to be a critical oversight because there is overlap in predictions involving these constructs. The current research extended the previous one by examining these multiple antecedents, including Big Five personality traits of newcomer to the tandem process of adjustment as well as outcomes that immediate, or ?proximal? to the process of newcomer adjustment. Following a cross sectional pilot study of recent college graduate, a three- wave longitudinal study of newcomers in seven organisations examined Big Five personality traits, proactive behaviour, and socialisation influence (formal training, leaders, co-workers) as antecedents of proximal adjustment outcomes (group integration, political knowledge of organisation, and task performance). The main study results suggested that personality traits were related to proximal adjustment outcomes, specifically, Conscientiousness was positively related to all proximal adjustment outcomes. Openness to experience was related to task performance and political knowledge. Group integration is independently related to Agreeableness, Extraversion and Neuroticism. The socialisation influence moderate these relations, for example, leader socialisation moderate Conscientiousness as it relates to political knowledge and group integration, while co-worker moderate Extraversion as it relates to task performance. Finally, it was found that, the relationship between proximal adjustment outcomes and the personality dimensions Openness was mediated by proactive behaviour. Overall, the results suggested that individual differences have a role in newcomer adjustment as it facilitate the socialisation influence, and Big Five was one of the key determinants of newcomer adjustment.

Recent patents and trends in orally disintegrating tablets

Orally disintegrating tablets (ODTs) offer many advantages over the conventional oral dosage forms in terms of convenience and ease of use. Over the last decade, substantial advances in the formulation of ODTs have been achieved in academia and industry that resulted in the emerging of a large number of patents. The aim of this review is to summarise the most recent patents in ODT formulations and highlight their motivations, inventive steps and significances in the development of ODT formulations. Five major techniques have been applied in manufacturing of ODTs, namely conventional tablet press, moulding, freeze drying, tablet loading and pulverization, with majority of the patents dedicated to the use of conventional tablet pressing. The patents have addressed various issues concerning the manufacturing of robust and practical ODT formulations by disclosing new manufacturing techniques, advantageous materials, and innovative formulation steps. However, future developments are required to reduce the cost and widening the application of the new manufacturing techniques, while simplifying and shortening the formulation steps will be crucial in the well established ones.

Use of amino acids as counterions improves the solubility of the BCS II model drug, indomethacin

The number of new chemical entities (NCE) is increasing every day after the introduction of combinatorial chemistry and high throughput screening to the drug discovery cycle. One third of these new compounds have aqueous solubility less than 20µg/mL [1]. Therefore, a great deal of interest has been forwarded to the salt formation technique to overcome solubility limitations. This study aims to improve the drug solubility of a Biopharmaceutical Classification System class II (BCS II) model drug (Indomethacin; IND) using basic amino acids (L-arginine, L-lysine and L-histidine) as counterions. Three new salts were prepared using freeze drying method and characterised by FT-IR spectroscopy, proton nuclear magnetic resonance ((1)HNMR), Differential Scanning Calorimetry (DSC) and Thermogravimetric analysis (TGA). The effect of pH on IND solubility was also investigated using pH-solubility profile. Both arginine and lysine formed novel salts with IND, while histidine failed to dissociate the free acid and in turn no salt was formed. Arginine and lysine increased IND solubility by 10,000 and 2296 fold, respectively. An increase in dissolution rate was also observed for the novel salts. Since these new salts have improved IND solubility to that similar to BCS class I drugs, IND salts could be considered for possible waivers of bioequivalence.

A systematic and mechanistic evaluation of aspartic acid as filler for directly compressed tablets containing trimethoprim and trimethoprim aspartate

The generally accepted paradigm of 'inert' and 'mono functional' excipient in dosage form has been recently challenged with the development of individual excipients capable of exhibiting multiple functions (e.g. binder-disintegrants, surfactant which affect P-gp function). The proposed study has been designed within the realm of multifunctionality and is the first and novel investigation towards evaluation of aspartic acid as a filler and disintegration enhancing agent for the delivery of biopharmaceutical class IV model drug trimethoprim. The study investigated powder characteristics using angle of repose, laser diffractometry and scanning electron microscopy (SEM). The prepared tablets were characterised using Heckel analysis, disintegration time and tensile strength measurements. Although Heckel analysis revealed that both TMP and TMP aspartate salt have high elasticity, the salt form produced a stronger compact which was attributed to the formation of agglomerates. Aspartic acid was found to have high plasticity, but its incorporation into the formulations was found to have a negative impact on the compaction properties of TMP and its salt. Surface morphology investigations showed that mechanical interlocking plays a vital role in binding TMP crystals together during compaction, while the small particle size of TMP aspartate agglomerates was found to have significant impact on the tensile strength of the tablets. The study concluded that aspartic acid can be employed as filler and disintegrant and that compactability within tablets was independent of the surface charge of the excipients.

Preparation and characterisation of amino acids based trimethoprim salts

Trimethoprim (TMP) is a dihydrofolate reductase (DHFR) inhibitor which prevents the conversion of dihydrofolic acid into tetrahydrofolic acid, resulting in the depletion of the latter and leading to bacterial death. Oral bioavailability of TMP is hindered by both its low solubility and low permeability. This study aims to prepare novel salts of TMP using anionic amino acids; aspartic and glutamic acid as counter ions in order to improve solubility and dissolution. TMP salts were prepared by lyophilisation and characterized using FT-IR spectroscopy, proton nuclear magnetic resonance (1HNMR), Differential Scanning Calorimetry (DSC) and Thermogravimetric analysis (TGA). Both the amino acids formed salts with TMP in a 1:1 molar ratio and showed a 280 fold improvement in solubility. Investigation of the microbiological activity of the prepared salts against TMP sensitive Escherichia coli showed that the new salts not only retained antibacterial activity but also exhibited higher zone of inhibition which was attributed to improved physicochemical characters such as higher solubility and dissolution. The results are an important finding that could potentially impact on faster onset of antibacterial activity and reduced therapeutic dose when administered to patients. Studies are underway investigating the effect of ion-pairing TMP with amino acids on the permeability profile of the drug.

Do institutions have a greater effect on female entrepreneurs?

This paper compares the impact of institutions on individual decisions to become entrepreneurs in the form of new business start ups by males and females across 44 developed and developing economies between 1998 and 2004. We test four hypotheses; that women are less likely to undertake entrepreneurial activity in countries where the rule of law is weaker; where the state sector is larger; where the informal financial sector is weaker and where the formal financial sector is weaker. We use data from the Global Enterprise Monitor survey (GEM) which covers at least 2,000 individuals annually in each of up to 44 countries, merged with country-level data, from the WB WDI and Heritage Foundation. We start with a spectrum of institutional variables and by utilizing factor analysis prior to regression estimation models, we are able to obtain results that are more robust and address multicollinearity between the institutional measures. We find that women are less likely to undertake entrepreneurial activity in countries where the state sector is larger, and demonstrate that this result applies to both high aspiration and low aspiration entrepreneurship. We also find that women benefit more from the larger informal financial sector.

Amino acids in oral drug delivery:salts, ion-pairs and transcriptomics

Oral drug delivery is considered the most popular route of delivery because of the ease of administration, availability of a wide range of dosage forms and the large surface area for drug absorption via the intestinal membrane. However, besides the unfavourable biopharmaceutical properties of the therapeutic agents, efflux transporters such as Pglycoprotein (P-gp) and multiple resistance proteins (MRP) decrease the overall drug uptake by extruding the drug from the cells. Although, prodrugs have been investigated to improve drug partitioning by masking the polar groups covalently with pre-moieties promoting increased uptake, they present significant challenges including reduced solubility and increased toxicity. The current work investigates the use of amino acids as ion-pairs for three model drugs: indomethacin (weak acid), trimethoprim (weak base) and ciprofloxacin (zwitter ion) in an attempt to improve both solubility and uptake. Solubility was studied by salt formation while creating new routes for uptake across the membranes via amino acids transporter proteins or dipeptidyl transporters was the rationale to enhance absorption. New salts were prepared for the model drugs and the oppositely charged amino acids by freeze drying and they were characterised using FTIR, 1HNMR, DSC, SEM, pH solubility profile, solubility and dissolution. Permeability profiles were assessed using an in vitro cell based method; Caco-2 cells and the genetic changes occurring across the transporter genes and various pathways involved in the cellular activities were studied using DNA microarrays. Solubility data showed a significant increase in drug solubility upon preparing the new salts with the oppositely charged counter ions (ciprofloxacin glutamate salt exhibiting 2.9x103 fold enhancement when compared to the free drug). Moreover, permeability studies showed a 3 fold increase in trimethoprim and indomethacin permeabilities upon ion-pairing with amino acids and more than 10 fold when the zwitter ionic drug was paired with glutamic acid. Microarray data revealed that trimethoprim was absorbed actively via OCTN1 transporters while MRP7 is the main transporter gene that mediates its efflux. The absorption of trimethoprim from trimethoprim glutamic acid ion-paired formulations was affected by the ratio of glutamic acid in the formulation which was inversely proportional to the degree of expression of OCTN1. Interestingly, ciprofloxacin glutamic acid ion-pairs were found to decrease the up-regulation of ciprofloxacin efflux proteins (P-gp and MRP4) and over-express two solute carrier transporters; (PEPT2 and SLCO1A2) suggesting that a high aqueous binding constant (K11aq) enables the ion-paired formulations to be absorbed as one entity. In conclusion, formation of ion-pairs with amino acids can influence in a positive way solubility, transfer and gene expression effects of drugs.