Similarity between class A and class B G-protein-coupled receptors exemplified through calcitonin gene-related peptide receptor modelling and mutagenesis studies

Modelling class B G-protein-coupled receptors (GPCRs) using class A GPCR structural templates is difficult due to lack of homology. The plant GPCR, GCR1, has homology to both class A and class B GPCRs. We have used this to generate a class A–class B alignment, and by incorporating maximum lagged correlation of entropy and hydrophobicity into a consensus score, we have been able to align receptor transmembrane regions. We have applied this analysis to generate active and inactive homology models of the class B calcitonin gene-related peptide (CGRP) receptor, and have supported it with site-directed mutagenesis data using 122 CGRP receptor residues and 144 published mutagenesis results on other class B GPCRs. The variation of sequence variability with structure, the analysis of polarity violations, the alignment of group-conserved residues and the mutagenesis results at 27 key positions were particularly informative in distinguishing between the proposed and plausible alternative alignments. Furthermore, we have been able to associate the key molecular features of the class B GPCR signalling machinery with their class A counterparts for the first time. These include the [K/R]KLH motif in intracellular loop 1, [I/L]xxxL and KxxK at the intracellular end of TM5 and TM6, the NPXXY/VAVLY motif on TM7 and small group-conserved residues in TM1, TM2, TM3 and TM7. The equivalent of the class A DRY motif is proposed to involve Arg^2.39, His^2.43 and Glu^3.46, which makes a polar lock with T^6.37. These alignments and models provide useful tools for understanding class B GPCR function.     

Exploring the impact of software requirements on system-wide goals: a method using satisfaction arguments and i* goal modelling

This paper describes the application of requirements engineering concepts to support the analysis of the impact of new software systems on system-wide goals. Requirements on a new or revised software component of a socio-technical system not only have implications on the goals of the subsystem itself, but they also impact upon the goals of the existing integrated system. In industries such as air traffic management and healthcare, impacts need to be identified and demonstrated in order to assess concerns such as risk, safety, and accuracy. A method called PiLGRIM was developed which integrates means-end relationships within goal modelling with knowledge associated with the application domain. The relationship between domain knowledge and requirements, as described in a satisfaction argument, adds traceability rationale to help determine the impacts of new requirements across a network of heterogeneous actors. We report procedures that human analysts follow to use the concepts of satisfaction arguments in a software tool for i* goal modelling. Results were demonstrated using models and arguments developed in two case studies, each featuring a distinct socio-technical system??a new controlled airspace infringement detection tool for NATS (the UK??s air navigation service provider), and a new version of the UK??s HIV/AIDS patient reporting system. Results provided evidence towards our claims that the conceptual integration of i* and satisfaction arguments is usable and useful to human analysts, and that the PiLGRIM impact analysis procedures and tool support are effective and scalable to model and analyse large and complex socio-technical systems.     

Organizing Sexuality: Silencing and the Push–Pull Process of Co-sexuality in the Workplace

How human beings think about, talk about, and organize around sexuality is changing. Growing social legitimization for sexual minority relationships and a more fluid social understanding of sexual identities has shifted how we bound “normal” sexuality. In the workplace, these shifting norms affect employees of all sexual identities who must make sense of new policies and complex daily practices. This paper introduces the concept of co-sexuality, the push-and-pull process of communicatively organizing around sexuality. Using this concept, we take a grounded theory approach to exploring how employees of various sexualities and in different occupations understand “normal” sexuality and subsequently organize around it. Ultimately, participants described being silenced or silencing another to maintain sexual “norms” at work.     

Too Small to Notice? Constructions of Childhood and Discourses of 'Race' in Predominantly White Contexts

This paper is organised around three possible meanings that can be given to the question 'Too small to notice?' in relation to racism and anti-racism in the early years of schooling (up to the age of eight). Firstly, are young children too small to have notice taken of their serious concerns and questions? Secondly, are young children too small to notice and/or engage with racism and difference? And thirdly, is racism too small a problem in predominantly white early years contexts? Using anti-racist education as a case study, the paper argues that dominant constructions of childhood and discourses of developmental psychology make it difficult to undertake education for social justice in the early years of schooling.     

Swimmer risk of gastrointestinal illness from exposure to tropical coastal waters impacted by terrestrial dry-weather runoff

This study used molecular methods to measure concentrations of four enteric viruses (adenovirus, enterovirus, norovirus GI, and norovirus GII) and fecal source tracking markers (human, ruminant, and pig Bacteroidales) in land-based runoff from 22 tropical streams on O'ahu, Hawai'i. Each stream was sampled twice in the morning and afternoon during dry weather. Viruses and human Bacteroidales were widespread in the streams. Watershed septic tank densities were positively associated with higher occurrence of human Bacteroidales and norovirus. There were no associations between occurrence of viruses and fecal indicator concentrations. Virus concentrations and previously reported culturable Salmonella and Campylobacter were used as inputs to a quantitative microbial risk assessment (QMRA) model to estimate the risk of acquiring gastrointestinal (GI) illness from swimming in tropical marine waters adjacent to discharging streams. Monte Carlo methods were used to incorporate uncertainties in the dilution of stream discharge with seawater, swimmer ingestion volumes, pathogen concentrations, and dose-response parameters into the model. Median GI illness risk to swimmers from exposure to coastal waters adjacent to the 22 streams ranged from 0 to 21/1000. GI illness risks from viral exposures were generally orders of magnitude greater than bacterial exposures. Swimming adjacent to streams positive for norovirus or adenovirus resulted in the highest risks. The median risk adjacent to each stream was positively, significantly correlated to the concentration of Clostridium perfringens in the stream. Although a number of important assumptions were made to complete the QMRA, results suggest land-based runoff in the tropics as a potential source of GI illness risk, with pathogens coming from both human and nonhuman nonpoint sources including septic tanks.     

New dietetic practitioners' perspectives on their education and training

Purpose: To elucidate the complex phenomenon of dietitian professional socialization, we examined factors that influence people's decisions to pursue a career in dietetics and how education and training processes influence the professional socialization of dietitians. Methods: Participants (n=12) had less than three years of work experience and included alumni from three Canadian universities representing different models of entry to practice. Three one-on-one interviews were conducted with each participant. Results: The key influencing factor in participants' decision to pursue dietetics was the perceived congruence between dietetics and other aspects of their lives, including early interests and experiences (sports, food and cooking, an eating disorder), career aspirations (science, health care), and social networks (the desire to be a professional). A pivotal experience during high school or while enrolled in or after graduation from another program prompted participants' awareness of and subsequent decision to pursue a career in dietetics. Supportive relationships were vital to participants' professional socialization. Conclusions: Recruitment materials and education opportunities should help aspiring dietitians develop a clear idea of what being a dietitian means. Dietetic educators must attend to the informational and relational aspects involved in shaping future practitioners' dietitian identities.