Structure-activity relationships of the N-terminus of calcitonin gene-related peptide:key roles of alanine-5 and threonine-6 in receptor activation

Background and purpose - The N-terminus of calcitonin gene-related peptide (CGRP) is important for receptor activation, especially the disulphide-bonded ring (residues 1-7). However, the roles of individual amino acids within this region have not been examined and so the molecular determinants of agonism are unknown. This study has examined the role of residues 1, 3-6 and 8-9, excluding Cys-2 and Cys-7. Experimental approach - CGRP derivatives were substituted with either cysteine or alanine; further residues were introduced at position 6. Their affinity was measured by radioligand binding and their efficacy by measuring cAMP production in SK-N-MC cells and ß-arrestin 2 translocation in CHO-K1 cells at the CGRP receptor. Key results - Substitution of Ala-5 by cysteine reduced affinity 270-fold and reduced efficacy for production of cAMP in SK-N-MCs. Potency at ß-arrestin translocation was reduced by 9-fold. Substitution of Thr-6 by cysteine destroyed all measurable efficacy of both cAMP and ß-arrestin responses; substitution with either alanine or serine impaired potency. Substitutions at positions 1, 4, 8 and 9 resulted in approximately 10-fold reductions in potency at both responses. Similar observations were made at a second CGRP-activated receptor, the AMY1(a) receptor. Conclusions and implications - Ala-5 and Thr-6 are key determinants of agonist activity for CGRP. Ala-5 is also very important for receptor binding. Residues outside of the 1-7 ring also contribute to agonist activity.

Interpreting adverse signals in diabetes drug development programs

Detection and interpretation of adverse signals during preclinical and clinical stages of drug development inform the benefit-risk assessment that determines suitability for use in real-world situations. This review considers some recent signals associated with diabetes therapies, illustrating the difficulties in ascribing causality and evaluating absolute risk, predictability, prevention, and containment. Individual clinical trials are necessarily restricted for patient selection, number, and duration; they can introduce allocation and ascertainment bias and they often rely on biomarkers to estimate long-term clinical outcomes. In diabetes, the risk perspective is inevitably confounded by emergent comorbid conditions and potential interactions that limit therapeutic choice, hence the need for new therapies and better use of existing therapies to address the consequences of protracted glucotoxicity. However, for some therapies, the adverse effects may take several years to emerge, and it is evident that faint initial signals under trial conditions cannot be expected to foretell all eventualities. Thus, as information and experience accumulate with time, it should be accepted that benefit-risk deliberations will be refined, and adjustments to prescribing indications may become appropriate. © 2013 by the American Diabetes Association.

Pharmacokinetics of melatonin in preterm infants

Aims - Preterm infants are deprived of the normal intra-uterine exposure to maternal melatonin and may benefit from replacement therapy. We conducted a pharmacokinetic study to guide potential therapeutic trials. Methods - Melatonin was administered to 18 preterm infants in doses ranging from 0.04–0.6 μg kg−1 over 0.5–6 h. Pharmacokinetic profiles were analyzed individually and by population methods. Results - Baseline melatonin was largely undetectable. Infants receiving melatonin at 0.1 μg kg−1 h−1 for 2 h showed a median half-life of 15.82 h and median maximum plasma concentration of 203.3 pg ml−1. On population pharmacokinetics, clearance was 0.045 l h−1, volume of distribution 1.098 l and elimination half-life 16.91 h with gender (P = 0.047) and race (P < 0.0001) as significant covariates. Conclusions - A 2 h infusion of 0.1 μg kg−1 h−1 increased blood melatonin from undetectable to approximately peak adult concentrations. Slow clearance makes replacement of a typical maternal circadian rhythm problematic. The pharmacokinetic profile of melatonin in preterm infants differs from that of adults so dosage of melatonin for preterm infants cannot be extrapolated from adult studies. Data from this study can be used to guide therapeutic clinical trials of melatonin in preterm infants.

Cyberstalking:a case study concerning sexual harassment in the UK

This paper presents the first academic case study of a UK cyberstalking incident that involved an individual known to have harassed at least four victims. The case study describes how the harasser selected victims, his use of technology to gather confidential information about them and his use of multiple personalities as part of the process of harassment. The discussion section of the paper raises a broad range of issues, including whether the case represents a genuine cyberstalking incident, how technology was used to assist the harasser's activities and how the harasser attempted to avoid detection

Angiotensin II directly induces muscle protein catabolism through the ubiquitin-proteasome proteolytic pathway and may play a role in cancer cachexia

The ability of angiotensin I (Ang I) and II (Ang II) to induce directly protein degradation in skeletal muscle has been studied in murine myotubes. Angiotensin I stimulated protein degradation with a parabolic dose-response curve and with a maximal effect between 0.05 and 0.1 μM. The effect was attenuated by coincubation with the angiotensin-converting enzyme (ACE) inhibitor imidaprilat, suggesting that angiotensin I stimulated protein degradation through conversion to Ang II. Angiotensin II also stimulated protein breakdown with a similar dose-response curve, and with a maximal effect between 1 and 2.5 μM. Total protein degradation, induced by both Ang I and Ang II, was attenuated by the proteasome inhibitors lactacystin (5 μM) and MG132 (10 μM), suggesting that the effect was mediated through upregulation of the ubiquitin-proteasome proteolytic pathway. Both Ang I and Ang II stimulated an increased proteasome 'chymotrypsin-like' enzyme activity as well as an increase in protein expression of 20S proteasome α-subunits, the 19S subunits MSSI and p42, at the same concentrations as those inducing protein degradation. The effect of Ang I was attenuated by imidaprilat, confirming that it arose from conversion to Ang II. These results suggest that Ang II stimulates protein degradation in myotubes through induction of the ubiquitin-proteasome pathway. Protein degradation induced by Ang II was inhibited by insulin-like growth factor and by the polyunsaturated fatty acid, eicosapentaenoic acid. These results suggest that Ang II has the potential to cause muscle atrophy through an increase in protein degradation. The highly lipophilic ACE inhibitor imidapril (Vitor™) (30 mg kg-1) attenuated the development of weight loss in mice bearing the MAC16 tumour, suggesting that Ang II may play a role in the development of cachexia in this model. © 2005 Cancer Research.

Maternal low-protein diet during mouse pre-implantation development induces vascular dysfunction and altered renin-angiotensin-system homeostasis in the offspring

Environmental perturbations during early mammalian development can affect aspects of offspring growth and cardiovascular health. We have demonstrated previously that maternal gestational dietary protein restriction in mice significantly elevated adult offspring systolic blood pressure. Therefore, the present study investigates the key mechanisms of blood pressure regulation in these mice. Following mating, female MF-1 mice were assigned to either a normal-protein diet (NPD; 18% casein) or an isocaloric low-protein diet throughout gestation (LPD; 9% casein), or fed the LPD exclusively during the pre-implantation period (3.5d) before returning to the NPD for the remainder of gestation (Emb-LPD). All offspring received standard chow. At 22 weeks, isolated mesenteric arteries from LPD and Emb-LPD males displayed significantly attenuated vasodilatation to isoprenaline (P=0.04 and P=0.025, respectively), when compared with NPD arteries. At 28 weeks, stereological analysis of glomerular number in female left kidneys revealed no significant difference between the groups. Real-time RT-PCR analysis of type 1a angiotensin II receptor, Na /K ATPase transporter subunits and glucocorticoid receptor expression in male and female left kidneys revealed no significant differences between the groups. LPD females displayed elevated serum angiotensin-converting enzyme (ACE) activity (P=0.044), whilst Emb-LPD males had elevated lung ACE activity (P=0.001), when compared with NPD offspring. These data demonstrate that elevated offspring systolic blood pressure following maternal gestational protein undernutrition is associated with impaired arterial vasodilatation in male offspring, elevated serum and lung ACE activity in female and male offspring, respectively, but kidney glomerular number in females and kidney gene expression in male and female offspring appear unaffected. © 2010 The Authors.

Special issue:key debates in the translation of advertising material

Much has been written about the marketing aspects of promotional material in general, and several scholars (particularly in linguistics) have addressed questions relating to the structure and function of advertisements, focusing on images, rhetorical structure, semiotic functions, discourse features and audio-visual media, amongst other aspects of the genre. Not much, on the other hand, has been written within translation studies about the complexities involved in the transfer of an advertising message. Contributors to this volume explore various interdependent aspects of the interlingual and intercultural transfer of an advertising message. They emphasize features of culture specificity, of multi-medial semiotic interaction, of values and stereotypes, and most importantly, they recommend strategies and approaches to assist translators. Topics covered include a critique of the Western-based approach to advertising in the context of the Far East; different perceptions of the concept of cleanliness in advertising texts in Italy, Russia and the UK; the Walls Cornetto strategy of internationalization of product appeal, followed by localization; the role of the translator in recreating appeal in different lingua-cultural contexts; what constitutes 'Italianness' in advertisements for British consumers; and strategies for repackaging France as a tourist destination.

Body iron is associated with cognitive executive planning function in college women

Evidence of the relationship between altered cognitive function and depleted Fe status is accumulating in women of reproductive age but the degree of Fe deficiency associated with negative neuropsychological outcomes needs to be delineated. Data are limited regarding this relationship in university women in whom optimal cognitive function is critical to academic success. The aim of the present study was to examine the relationship between body Fe, in the absence of Fe-deficiency anaemia, and neuropsychological function in young college women. Healthy, non-Anaemic undergraduate women (n 42) provided a blood sample and completed a standardised cognitive test battery consisting of one manual (Tower of London (TOL), a measure of central executive function) and five computerised (Bakan vigilance task, mental rotation, simple reaction time, immediate word recall and two-finger tapping) tasks. Women's body Fe ranged from - 4·2 to 8·1 mg/kg. General linear model ANOVA revealed a significant effect of body Fe on TOL planning time (P= 0.002). Spearman's correlation coefficients showed a significant inverse relationship between body Fe and TOL planning time for move categories 4 (r - 0.39, P= 0.01) and 5 (r - 0.47, P= 0.002). Performance on the computerised cognitive tasks was not affected by body Fe level. These findings suggest that Fe status in the absence of anaemia is positively associated with central executive function in otherwise healthy college women. Copyright © The Authors 2012.

The sound of silence. Lesbian, gay, bisexual and transgender discrimination in 'inclusive organizations'

Most studies on diversity and discrimination in the workplace have focused on 'visible' minorities such as gender or race, often neglecting the experiences of invisible minorities such as lesbian, gay, bisexual and transgender (LGBT) workers. In this paper we explore the practices of inclusion/exclusion of LGBTs in the workplace in Italian social cooperatives, which are specifically founded to create employment for people who are disadvantaged in the labour market. The study examines how organizations, which have an ethos focused on inclusion and mainly employ workers from specific social minority groups, manage the inclusion of LGBT workers. We also explore the experience of LGBT workers within these organizations. The paper reports that the culture of silence existing in the five organizations studied prevents LGBT employees from constructing a work identity which encompasses their sexual identity and prevents the organizations from achieving their aim of being fully inclusive workplaces. © 2013 British Academy of Management.

Optimization of Advertising Resources over Time: A Strategic Analysis

AMS subject classification: 90B60, 90B50, 90A80.

Degree of vertical integration and its buffering effects on political uncertainty

The focus of this study is on the governance decisions in a concurrent channels context, in the case of uncertainty. The study examines how a firm chooses to deploy its sales force in times of uncertainty, and the subsequent performance outcome of those deployment choices. The theoretical framework is based on multiple theories of governance, including transaction cost analysis (TCA), agency theory, and institutional economics. Three uncertainty variables are investigated in this study. The first two are demand and competitive uncertainty which are considered to be industry-level market uncertainty forms. The third uncertainty, political uncertainty, is chosen as it is an important dimension of institutional environments, capturing non-economic circumstances such as regulations and political systemic issues. The study employs longitudinal secondary data from a Thai hotel chain, comprising monthly observations from January 2007 – December 2012. This hotel chain has its operations in 4 countries, Thailand, the Philippines, United Arab Emirates – Dubai, and Egypt, all of which experienced substantial demand, competitive, and political uncertainty during the study period. This makes them ideal contexts for this study. Two econometric models, both deploying Newey-West estimations, are employed to test 13 hypotheses. The first model considers the relationship between uncertainty and governance. The second model is a version of Newey-West, using an Instrumental Variables (IV) estimator and a Two-Stage Least Squares model (2SLS), to test the direct effect of uncertainty on performance and the moderating effect of governance on the relationship between uncertainty and performance. The observed relationship between uncertainty and governance observed follows a core prediction of TCA; that vertical integration is the preferred choice of governance when uncertainty rises. As for the subsequent performance outcomes, the results corroborate that uncertainty has a negative effect on performance. Importantly, the findings show that becoming more vertically integrated cannot help moderate the effect of demand and competitive uncertainty, but can significantly moderate the effect of political uncertainty. These findings have significant theoretical and practical implications, and extend our knowledge of the impact on uncertainty significantly, as well as bringing an institutional perspective to TCA. Further, they offer managers novel insight into the nature of different types of uncertainty, their impact on performance, and how channel decisions can mitigate these impacts.

Protecting Your Assets: A Well-Defined Credit Policy Is The Key

In - Protecting Your Assets: A Well-Defined Credit Policy Is The Key – an essay by Steven V. Moll, Associate Professor, The School of Hospitality Management at Florida International University, Professor Moll observes at the outset: “Bad debts as a percentage of credit sales have climbed to record levels in the industry. The author offers suggestions on protecting assets and working with the law to better manage the business.” “Because of the nature of the hospitality industry and its traditional liberal credit policies, especially in hotels, bad debts as a percentage of credit sales have climbed to record levels,” our author says. “In 1977, hotels showing a net income maintained an average accounts receivable ratio to total sales of 3.4 percent. In 1983, the accounts receivable ratio to total sales increased to 4.1 percent in hotels showing a net income and 4.4 percent in hotels showing a net loss,” he further cites. As the professor implies, there are ways to mitigate the losses from bad credit or difficult to collect credit sales. In this article Professor Moll offers suggestions on how to do that. Moll would suggest that hotels and food & beverage operations initially tighten their credit extension policies, and on the following side, be more aggressive in their collection-of-debt pursuits. There is balance to consider here and bad credit in and of itself as a negative element is not the only reflection the profit/loss mirror would offer. “Credit managers must know what terms to offer in order to compete and afford the highest profit margin allowable,” Moll says. “They must know the risk involved with each guest account and be extremely alert to the rights and wrongs of good credit management,” he advocates. A sound profit policy can be the result of some marginal and additional credit risk on the part of the operation manager. “Reality has shown that high profits, not small credit losses, are the real indicator of good credit management,” the author reveals. “A low bad debt history may indicate that an establishment has an overly conservative credit management policy and is sacrificing potential sales and profits by turning away marginal accounts,” Moll would have you believe, and the science suggests there is no reason not to. Professor Moll does provide a fairly comprehensive list to illustrate when a manager would want to adopt a conservative credit policy. In the final analysis the design is to implement a policy which weighs an acceptable amount of credit risk against a potential profit ratio. In closing, Professor Moll does offer some collection strategies for loose credit accounts, with reference to computer and attorney participation, and brings cash and cash discounts into the discussion as well. Additionally, there is some very useful information about what debt collectors – can’t – do!

Organizational Behavior: Forgotten Variable in Safe Food

The war on foodborne illness in hotels and restaurants is based on microbiology and critical control points. The author argues that cooks, managers, instructors, researchers, and regulators need to start looking beyond this narrow base to include more organizational behavior processes in their arsenal.

The differential effects of *American and British trial proceedings on juror decision-making

Seven basic elements differentiate British from American trial procedures: confining attorneys to their tables; dealing with objections outside the presence of the jury; resolving disagreements between attorneys prior to objections being made; presenting the defense opening statement at the close of the prosecution case; the judge directly questions witnesses and has a wider latitude in controlling the evidence; and the judge gives a summation of all the evidence presented to the jury (Fulero & Turner, 1997). The present experiment examined the influence of these different courtroom procedures, judges' non-verbal behavior, and evidence strength on juror decision-making. Using models of persuasion to understand how the varying elements may effect juror decision-making, it was predicted that trials following American courtroom procedures would be more distracting for jurors and as such, they would be more likely to rely on the peripheral cue of the judge's expectations for trial outcome as expressed in his nonverbal behavior. In trials following British procedures jurors should be less distracted and better able to scrutinize the strength of the evidence that in turn should minimize the influence of the judge's nonverbal behavior. Two hundred forty-five participants viewed a mock civil trial in which courtroom procedure, judge's nonverbal behavior, and evidence strength were varied. Analyses suggest that courtroom procedure and evidence strength influenced the direction of participants' verdicts, but that judge's nonverbal behavior did not have a direct impact on verdict preference. Judge's nonverbal behavior appeared to influence other measures related to verdict. Participants were more confident in their verdicts when they agreed with judge's nonverbal behavior and when they viewed British courtroom procedures. Participants were more likely to return estimates of the defendant's liability that reflected judge's nonverbal behavior and a congruency with evidence strength. Participants also recalled more facts in the British conditions than in the American conditions. These findings are interpreted as indicating the importance of the impact of trial procedures and of nonverbal influence. ^

AUTOMÓVEIS CHINESES CHERY NO MERCADO BRASILEIRO (2010-2014) – UM ESTUDO DE CASO

A globalização possibilitou aos países buscarem seus consumidores em qualquer parte, sendo o Brasil o quarto mercado consumidor de automóveis do mundo, e praticamente todos os fabricantes globais buscaram estar presentes neste mercado. Com os chineses, detentores do título de maiores produtores mundiais de automóveis, não seria diferente. Contudo, ao contrário do crescimento constante de sua produção mundial, viram suas vendas estagnarem em baixos níveis no Brasil nos últimos anos. O objetivo deste estudo é compreender o mau desempenho de vendas da marca Chery no Brasil, sob a óptica dos gerentes de vendas das agências de carros usados e dos ex-proprietários. Para tentar responder a esta questão, optou-se por um estudo de caráter exploratório, por meio de uma revisão bibliográfica e uma pesquisa qualitativa, com entrevistas abertas em profundidade com base em um roteiro preestabelecido e um recorte na cidade de São Paulo – SP. Utilizou-se também uma pesquisa secundária em meios eletrônicos, que confirmou as informações obtidas na pesquisa de campo. Conforme apresentado no trabalho, todas as marcas tiveram redução em suas vendas, porém, as marcas chinesas sofreram maiores reduções que às marcas ditas nacionais. Na pesquisa, observa-se que três fatores foram decisivos para o mau desempenho das marcas chinesas e, consequentemente, da marca Chery também. O primeiro foi o aumento do Imposto sobre Produtos Industrializados (IPI), o segundo foi a crise econômica que o Brasil atravessa e o terceiro foi a rejeição aos carros da Chery. Essa rejeição deveu-se a vários fatores, somados às experiências negativas que consumidores tiveram com marcas de veículos importados que deixaram o país, a imagem de que produtos chineses são cópias e ao hipotético preconceito que produtos chineses são de baixa qualidade. Portanto, ouvindo os entrevistados e por meio dos comentários sobre a marca Chery nos meios eletrônicos, pode-se deduzir que somente a crise econômica e o aumento de impostos não justificam totalmente o mau desempenho de vendas da marca Chery. Essa análise indica que os fatores de rejeição aos veículos da marca Chery tiveram participação decisiva nesta queda significativa de suas vendas no período de 2010 a 2014.