Getting the Political Architecture Right

As Australia approaches the twenty-first century, it finds itself, like a number of other Anglo-centred countries in the western world, including Canada, in the grip of continuing economic trauma. There has been a marked relative (and absolute) slip in general economic performance. This paper focuses on the linkages between this phenomenon and Australia\u27s basic political architecture. It argues that, although renovation of Australian federalism is no panacea for these problems, there are linkages between Australia\u27s aged, formal, political structure and its recent economic performance. Lack of attention to the task of serious, systematic renovation is allowing the present outdated political structure to aggravate economic and social problems. The article concludes that a much more adventurous, long-term approach to the renovation of Australia\u27s political architecture is needed

Comparison of contact patterns relevant for transmission of respiratory pathogens in Thailand and the Netherlands using respondent-driven sampling

Understanding infection dynamics of respiratory diseases requires the identification and quantification of behavioural, social and environmental factors that permit the transmission of these infections between humans. Little empirical information is available about contact patterns within real-world social networks, let alone on differences in these contact networks between populations that differ considerably on a socio-cultural level. Here we compared contact network data that were collected in the Netherlands and Thailand using a similar online respondent-driven method. By asking participants to recruit contact persons we studied network links relevant for the transmission of respiratory infections. We studied correlations between recruiter and recruited contacts to investigate mixing patterns in the observed social network components. In both countries, mixing patterns were assortative by demographic variables and random by total numbers of contacts. However, in Thailand participants reported overall more contacts which resulted in higher effective contact rates. Our findings provide new insights on numbers of contacts and mixing patterns in two different populations. These data could be used to improve parameterisation of mathematical models used to design control strategies. Although the spread of infections through populations depends on more factors, found similarities suggest that spread may be similar in the Netherlands and Thailand

Transverse-Momentum Dependence of the J/psi Nuclear Modification in d+Au Collisions at sqrt(s_NN)=200 GeV

We present measured J/psi production rates in d+Au collisions at sqrt(s_NN) = 200 GeV over a broad range of transverse momentum (p_T=0-14 GeV/c) and rapidity (-2.2<y<2.2). We construct the nuclear-modification factor R_dAu for these kinematics and as a function of collision centrality (related to impact parameter for the R_dAu collision). We find that the modification is largest for collisions with small impact parameters, and observe a suppression (R_dAu<1) for p_T<4 GeV/c at positive rapidities. At negative rapidity we observe a suppression for p_T1) for p_T>2 GeV/c. The observed enhancement at negative rapidity has implications for the observed modification in heavy-ion collisions at high p_T.Comment: 384 authors, 24 pages, 19 figures, 13 tables. Submitted to Phys. Rev. C. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are publicly available at http://www.phenix.bnl.gov/phenix/WWW/info/data/ppg123_data.htm

Partnerorientierung zwischen Realität und Imagination: Anmerkungen zu einem zentralen Konzept der Dialogtheorie

This paper attempts a critique of the notion of 'dialogue' in dialogue theory as espoused by Linell, Markova, and others building on Bakhtin’s writings. According to them, human communication, culture, language, and even cognition are dialogical in nature. This implies that these domains work by principles of other-orientation and interaction. In our paper, we reject accepting other-orientation as an a priori condition of every semiotic action. Instead, we claim that in order to be an empirically useful concept for the social sciences, it must be shown if and how observable action is other-oriented. This leads us to the following questions: how can we methodically account for other-orientation of semiotic action? Does other-orientation always imply interaction? Is every human expression oriented towards others? How does the other, as s/he is represented in semiotic action, relate to the properties which the other can be seen to exhibit as indexed by their observable behavior? We study these questions by asking how the orientation towards others becomes evident in different forms of communication. For this concern, we introduce ‘recipient design’, ‘positioning’ and ‘intersubjectivity’ as concepts which allow us to inquire how semiotic action both takes the other into account and, reflexively, shapes him/her as an addressee having certain properties. We then specifically focus on actions and situations in which other-orientation is particularly problematic, such as interactions with children, animals, machines, or communication with unknown recipients via mass media. These borderline cases are scrutinized in order to delineate both limits and constitutive properties of other-orientation. We show that there are varieties of meaningful actions which do not exhibit an orientation towards the other, which do not rest on (the possibility of) interaction with the other or which even disregard what their producer can be taken to know about the other. Available knowledge about the other may be ignored in order to reach interactional goals, e. g. in strategical interactions or for concerns of socialization. If semiotic action is otherorientated, its design depends on how the other is available to and matters for their producer. Other-orientation may build on shared biographical experiences with the other, knowledge about the other as an individual and close attention to their situated conduct. However, other-orientation may also rest on (stereo-)typification with respect to institutional roles or group membership. In any case, others as they are represented in semiotic action can never be just others-as-such, but only othersas-perceived-by-the-actor. We conclude that the strong emphasis which dialogue theories put on otherorientation obscures that other-orientation is neither universal in semiotic action, that it must be distinguished from an interactive relationship, and that the ways in which the other figures in semiotic actions is not homogeneous in any of its most general properties. Instead, there is a huge variation in the ways in which the other can be taken into account. Therefore close scrutiny of how the other precisely figures in a certain kind of semiotic action is needed in order to lend the concept of ‘other-orientation’ empirical substance and a definite sense

Cofactor-mediated conformational control in the bifunctional kinase/RNase Ire1

<p>Abstract</p> <p>Background</p> <p>Ire1 is a signal transduction protein in the endoplasmic reticulum (ER) membrane that serves to adjust the protein-folding capacity of the ER according to the needs of the cell. Ire1 signals, in a transcriptional program, the unfolded protein response (UPR) via the coordinated action of its protein kinase and RNase domains. In this study, we investigated how the binding of cofactors to the kinase domain of Ire1 modulates its RNase activity.</p> <p>Results</p> <p>Our results suggest that the kinase domain of Ire1 initially binds cofactors without activation of the RNase domain. RNase is activated upon a subsequent conformational rearrangement of Ire1 governed by the chemical properties of bound cofactors. The conformational step can be selectively inhibited by chemical perturbations of cofactors. Substitution of a single oxygen atom in the terminal β-phosphate group of a potent cofactor ADP by sulfur results in ADPβS, a cofactor that binds to Ire1 as well as to ADP but does not activate RNase. RNase activity can be rescued by thiophilic metal ions such as Mn²⁺and Cd²⁺, revealing a functional metal ion-phosphate interaction which controls the conformation and RNase activity of the Ire1 ADP complex. Mutagenesis of the kinase domain suggests that this rearrangement involves movement of the αC-helix, which is generally conserved among protein kinases. Using X-ray crystallography, we show that oligomerization of Ire1 is sufficient for placing the αC-helix in the active, cofactor-bound-like conformation, even in the absence of cofactors.</p> <p>Conclusions</p> <p>Our structural and biochemical evidence converges on a model that the cofactor-induced conformational change in Ire1 is coupled to oligomerization of the receptor, which, in turn, activates RNase. The data reveal that cofactor-Ire1 interactions occur in two independent steps: binding of a cofactor to Ire1 and subsequent rearrangement of Ire1 resulting in its self-association. The pronounced allosteric effect of cofactors on protein-protein interactions involving Ire1's kinase domain suggests that protein kinases and pseudokinases encoded in metazoan genomes may use ATP pocket-binding ligands similarly to exert signaling roles other than phosphoryl transfer.</p

Interaction of Rio1 Kinase with Toyocamycin Reveals a Conformational Switch That Controls Oligomeric State and Catalytic Activity

Rio1 kinase is an essential ribosome-processing factor required for proper maturation of 40 S ribosomal subunit. Although its structure is known, several questions regarding its functional remain to be addressed. We report that both Archaeoglobus fulgidus and human Rio1 bind more tightly to an adenosine analog, toyocamycin, than to ATP. Toyocamycin has antibiotic, antiviral and cytotoxic properties, and is known to inhibit ribosome biogenesis, specifically the maturation of 40 S. We determined the X-ray crystal structure of toyocamycin bound to Rio1 at 2.0 Å and demonstrated that toyocamycin binds in the ATP binding pocket of the protein. Despite this, measured steady state kinetics were inconsistent with strict competitive inhibition by toyocamycin. In analyzing this interaction, we discovered that Rio1 is capable of accessing multiple distinct oligomeric states and that toyocamycin may inhibit Rio1 by stabilizing a less catalytically active oligomer. We also present evidence of substrate inhibition by high concentrations of ATP for both archaeal and human Rio1. Oligomeric state studies show both proteins access a higher order oligomeric state in the presence of ATP. The study revealed that autophosphorylation by Rio1 reduces oligomer formation and promotes monomerization, resulting in the most active species. Taken together, these results suggest the activity of Rio1 may be modulated by regulating its oligomerization properties in a conserved mechanism, identifies the first ribosome processing target of toyocamycin and presents the first small molecule inhibitor of Rio1 kinase activity

The use of opioids at the end of life: knowledge level of pharmacists and cooperation with physicians

Contains fulltext : 96464.pdf (publisher's version ) (Open Access)PURPOSE: What is the level of knowledge of pharmacists concerning pain management and the use of opioids at the end of life, and how do they cooperate with physicians? METHODS: A written questionnaire was sent to a sample of community and hospital pharmacists in the Netherlands. The questionnaire was completed by 182 pharmacists (response rate 45%). RESULTS: Pharmacists were aware of the most basic knowledge about opioids. Among the respondents, 29% erroneously thought that life-threatening respiratory depression was a danger with pain control, and 38% erroneously believed that opioids were the preferred drug for palliative sedation. One in three responding pharmacists did not think his/her theoretical knowledge was sufficient to provide advice on pain control. Most pharmacists had working agreements with physicians on euthanasia (81%), but fewer had working agreements on palliative sedation (46%) or opioid therapy (25%). Based on the experience of most of responding pharmacists (93%), physicians were open to unsolicited advice on opioid prescriptions. The majority of community pharmacists (94%) checked opioid prescriptions most often only after dispensing, while it was not a common practice among the majority of hospital pharmacists (68%) to check prescriptions at all. CONCLUSIONS: Although the basic knowledge of most pharmacists was adequate, based on the responses to the questionnaire, there seems to be a lack of knowledge in several areas, which may hamper pharmacists in improving the quality of care when giving advice to physicians and preventing or correcting mistakes if necessary. If education is improved, a more active role of the pharmacist may improve the quality of end-of-life pharmacotherapy