997 resultados para drug potency


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The main aim of this paper is to outline a proposed program of research which will attempt to quantify the extent of the problem of alcohol and other drugs in the Australian construction industry, and furthermore, develop an appropriate industry-wide policy and cultural change management program and implementation plan to address the problem. This paper will also present preliminary results from the study. The study will use qualitative and quantitative methods (in the form of interviews and surveys, respectively) to evaluate the extent of the problem of alcohol and other drug use in this industry, to ascertain the feasibility of an industry-wide policy and cultural change management program, and to develop an appropriate implementation plan. The study will be undertaken in several construction organisations, at selected sites in South Australia, Victoria and Northern Territory. It is anticipated that approximately 500 employees from the participating organisations across Australia will take part in the study. The World Health Organisation’s Alcohol Use Disorders Identification Test (AUDIT) will be used to measure the extent of alcohol use in the industry. Illicit drug use, ‘‘readiness to change’’, impediments to reducing impairment, feasibility of proposed interventions, and employee attitudes and knowledge regarding workplace AOD impairment, will also be measured through a combination of interviews and surveys. Among the preliminary findings, for 51% (n=127) of respondents, score on the AUDIT indicated alcohol use at hazardous levels. Of the respondents who were using alcohol at hazardous levels, 76% reported (n97) that they do not have a problem with drinking and 54% (n=68) reported that it would be easy to ‘‘cut down’’ or stop drinking. Nearly half (49%) of all respondents (n=122) had used marijuana/cannabis at some time prior to being surveyed. The use of other illicit substances was much less frequently reported. Preliminary interview findings indicated a lack of adequate employee knowledge regarding the physical effects of alcohol and other drugs in the workplace. As for conclusions, the proposed study will address a major gap in the literature with regard to the extent of the problem of alcohol and other drug use in the construction industry in Australia. The study will also develop and implement a national, evidence-based workplace policy, with the aim of mitigating the deleterious effects of alcohol and other drugs in this industry.

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Through a screen to identify genes that induce multi-drug resistance when overexpressed, we have identified a fission yeast homolog of Int-6, a component of the human translation initiation factor eIF3. Disruption of the murine Int-6 gene by mouse mammary tumor virus (MMTV) has been implicated previously in tumorigenesis, although the underlying mechanism is not yet understood. Fission yeast Int6 was shown to interact with other presumptive components of eIF3 in vivo, and was present in size fractions consistent with its incorporation into a 43S translation preinitiation complex. Drug resistance induced by Int6 overexpression was dependent on the AP-1 transcription factor Pap1, and was associated with increased abundance of Pap1-responsive mRNAs, but not with Pap1 relocalization. Fission yeast cells lacking the int6 gene grew slowly. This growth retardation could be corrected by the expression of full length Int6 of fission yeast or human origin, or by a C-terminal fragment of the fission yeast protein that also conferred drug resistance, but not by truncated human Int-6 proteins corresponding to the predicted products of MMTV-disrupted murine alleles. Studies in fission yeast may therefore help to explain the ways in which Int-6 function can be perturbed during MMTV-induced mammary tumorigenesis.

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This Guide is designed to assist workers better understand the and negotiate the complex interplay of ethical, legal and organisational considerations in their practice. The goal is to provide frontline workers and managers with information, questions and principles which promote good youth AOD practice. Legal information provided relates to Queensland, Australia.

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In the context of cultural and/or differential ‘normalisation’ of certain forms of drug use, this article describes two case-studies of heavy recreational drug users. The daily lives of these users blur the line between the legal and the illegal; their drug trading is generally as a consumer and ‘friend of a friend’ small dealer in the low-level market. In the first case, problems with management of employment, time and financial budgeting are described; in the second case, such management is accomplished. Discussion refers to: differences between the two in relation to resources and vulnerability to risks, and to leisure/pleasure cultures of hedonism. The research agenda should pay more attention to users who seek to maintain a legitimate lifestyle but who develop problems managing work and their drug-related leisure. Understanding the consumer demand and dealing activity of such users is important in trying to develop a fuller understanding of drug markets.

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Background Canonical serine protease inhibitors commonly bind to their targets through a rigid loop stabilised by an internal hydrogen bond network and disulfide bond(s). The smallest of these is sunflower trypsin inhibitor (SFTI-1), a potent and broad-range protease inhibitor. Recently, we re-engineered the contact β-sheet of SFTI-1 to produce a selective inhibitor of kallikrein-related peptidase 4 (KLK4), a protease associated with prostate cancer progression. However, modifications in the binding loop to achieve specificity may compromise structural rigidity and prevent re-engineered inhibitors from reaching optimal binding affinity. Methodology/Principal Findings In this study, the effect of amino acid substitutions on the internal hydrogen bonding network of SFTI were investigated using an in silico screen of inhibitor variants in complex with KLK4 or trypsin. Substitutions favouring internal hydrogen bond formation directly correlated with increased potency of inhibition in vitro. This produced a second generation inhibitor (SFTI-FCQR Asn14) which displayed both a 125-fold increased capacity to inhibit KLK4 (Ki = 0.0386±0.0060 nM) and enhanced selectivity over off-target serine proteases. Further, SFTI-FCQR Asn14 was stable in cell culture and bioavailable in mice when administered by intraperitoneal perfusion. Conclusion/Significance These findings highlight the importance of conserving structural rigidity of the binding loop in addition to optimising protease/inhibitor contacts when re-engineering canonical serine protease inhibitors.