Opioid Peptides: Potential for Drug Development

Opioid receptors are important targets for the treatment of pain and potentially for other disease states (e.g. mood disorders and drug abuse) as well. Significant recent advances have been made in identifying opioid peptide analogs that exhibit promising in vivo activity for treatment of these maladies. This review focuses on the development and evaluation of opioid peptide analogs demonstrating activity after systemic administration, and recent clinical evaluations of opioid peptides for possible therapeutic use

Synthesis of CJ-15,208, a novel κ-opioid receptor antagonist

The tryptophan isomers of the cyclic tetrapeptide CJ-15,208, reported to be a kappa opioid receptor (KOR) antagonist [Saito, T.; Hirai, H.; Kim, Y. J.; Kojima, Y.; Matsunaga, Y.; Nishida, H.; Sakakibara, T.; Suga, O.; Sujaku, T.; Kojima, N. J. Antibiot. (Tokyo) 2002, 55, 847–854.], were synthesized to determine the tryptophan stereochemistry in the natural product. A strategy was developed to select linear precursor peptides that favor cyclization using molecular modeling, and optimized cyclization conditions are reported. The optical rotation of the l-Trp isomer is consistent with that of the natural product. Unexpectedly both isomers exhibit similar nanomolar affinity for KOR

The Macrocyclic Peptide Natural Product CJ-15,208 Is Orally Active and Prevents Reinstatement of Extinguished Cocaine-Seeking Behavior

The macrocyclic tetrapeptide natural product CJ-15,208 (cyclo[Phe-d-Pro-Phe-Trp]) exhibited both dose-dependent antinociception and kappa opioid receptor (KOR) antagonist activity after oral administration. CJ-15,208 antagonized a centrally administered KOR selective agonist, providing strong evidence it crosses the blood–brain barrier to reach KOR in the CNS. Orally administered CJ-15,208 also prevented both cocaine- and stress-induced reinstatement of extinguished cocaine-seeking behavior in the conditioned place preference assay in a time- and dose-dependent manner. Thus, CJ-15,208 is a promising lead compound with a unique activity profile for potential development, particularly as a therapeutic to prevent relapse to drug-seeking behavior in abstinent subjects

Intelligence within BAOR and NATO's Northern Army Group

During the Cold War the UK's principal military role was its commitment to the North Atlantic Treaty Organisation (NATO) through the British Army of the Rhine (BAOR), together with wartime command of NATO's Northern Army Group. The possibility of a surprise attack by the numerically superior Warsaw Pact forces ensured that great importance was attached to intelligence, warning and rapid mobilisation. As yet we know very little about the intelligence dimension of BAOR and its interface with NATO allies. This article attempts to address these neglected issues, ending with the impact of the 1973 Yom Kippur War upon NATO thinking about warning and surprise in the mid-1970s. It concludes that the arrangements made by Whitehall for support to BAOR from national assets during crisis or transition to war were - at best - improbable. Accordingly, over the years, BAOR developed its own unique assets in the realm of both intelligence collection and special operations in order to prepare for the possible outbreak of conflict

Workplace sexual harassment and depressive symptoms:A cross-sectional multilevel analysis comparing harassment from clients or customers to harassment from other employees amongst 7603 Danish employees from 1041 organizations

Abstract Background Previous research has reported that sexual harassment can lead to reduced mental health. Few studies have focused on sexual harassment conducted by clients or customers, which might occur in person-related occupations such as eldercare work, social work or customer service work. This study examined the cross-sectional association between sexual harassment by clients or customers and depressive symptoms. We also examined if this association was different compared to sexual harassment conducted by a colleague, supervisor or subordinate. Further, we investigated if psychosocial workplace initiatives modified the association between sexual harassment by clients or customers and level of depressive symptoms. Methods We used data from the Work Environment and Health in Denmark cohort study (WEHD) and the Work Environment Activities in Danish Workplaces Study (WEADW) collected in 2012. WEHD is based on a random sample of employed individuals aged 18–64. In WEADW, organizational supervisors or employee representatives provided information on workplace characteristics. By combining WEHD and WEADW we included self-reported information on working conditions and health from 7603 employees and supervisors in 1041 organizations within 5 occupations. Data were analyzed using multilevel regression and analyses adjusted for gender, age, occupation and socioeconomic position. Results Exposure to workplace sexual harassment from clients or customers was statistically significantly associated with a higher level of depressive symptoms (2.05; 95% CI: 0.98–3.12) compared to no exposure. Employees harassed by colleagues, supervisors or subordinates had a higher mean level of depressive symptoms (2.45; 95% CI: 0.57–4.34) than employees harassed by clients or customers. We observed no statistically significant interactions between harassment from clients and customers and any of the examined psychosocial workplace initiatives (all p > 0.05). Conclusions The association between sexual harassment and depressive symptoms differed for employees harassed by clients or customers and those harassed by colleagues, supervisors or subordinates. The results underline the importance of investigating sexual harassment from clients or customers and sexual harassment by colleagues, supervisors or subordinates as distinct types of harassment. We found no modification of the association between sexual harassment by clients or customers and depressive symptoms by any of the examined psychosocial workplace initiatives

Phenylalanine Stereoisomers of CJ-15,208 and [d-Trp]CJ-15,208 Exhibit Distinctly Different Opioid Activity Profiles

This work is licensed under a Creative Commons Attribution 4.0 International License.The macrocyclic tetrapeptide cyclo[Phe-d-Pro-Phe-Trp] (CJ-15,208) and its stereoisomer cyclo[Phe-d-Pro-Phe-d-Trp] exhibit different opioid activity profiles in vivo. The present study evaluated the influence of the Phe residues’ stereochemistry on the peptides’ opioid activity. Five stereoisomers were synthesized by a combination of solid-phase peptide synthesis and cyclization in solution. The analogs were evaluated in vitro for opioid receptor affinity in radioligand competition binding assays, and for opioid activity and selectivity in vivo in the mouse 55 °C warm-water tail-withdrawal assay. Potential liabilities of locomotor impairment, respiratory depression, acute tolerance development, and place conditioning were also assessed in vivo. All of the stereoisomers exhibited antinociception following either intracerebroventricular or oral administration differentially mediated by multiple opioid receptors, with kappa opioid receptor (KOR) activity contributing for all of the peptides. However, unlike the parent peptides, KOR antagonism was exhibited by only one stereoisomer, while another isomer produced DOR antagonism. The stereoisomers of CJ-15,208 lacked significant respiratory effects, while the [d-Trp]CJ-15,208 stereoisomers did not elicit antinociceptive tolerance. Two isomers, cyclo[d-Phe-d-Pro-d-Phe-Trp] (3) and cyclo[Phe-d-Pro-d-Phe-d-Trp] (5), did not elicit either preference or aversion in a conditioned place preference assay. Collectively, these stereoisomers represent new lead compounds for further investigation in the development of safer opioid analgesics.National Institute on Drug Abuse (R01 DA18832)National Institute on Drug Abuse (R01 DA032928

Anthropometry for children's clothing: difficulties and limitations

Children's wear lacks an anthropometric study to better fit clothes on the body of the child, providing greater comfort for users. Initially, this thesis project in fashion design intended to measure Portuguese children between the ages of 2 to 10 years, enrolled in primary schools in the region of Minho in Portugal. During the data gathering, held in the months of June, July, October and November 2016, about 600 children were scanned and measured using a 3D body scanner. The purpose of this paper is to report the difficulties and limitations experienced during data collection of the anthropometric study and the adjustments that were needed, as well as discuss some of the data collected.This work is supported by FEDER funds through the Competitive Factors Operational Program (COMPETE) POCI-01-0145-FEDER-007136 and by national funds through Portuguese Foundation for Science and Technology (FCT), under the project UID/CTM/000264.info:eu-repo/semantics/publishedVersio

Influence of high-dose gamma radiation and particle size on antioxidant properties of Maize ( Zea mays L.) flour

ABSTRACT Influence of high-dose gamma radiation and particle size on antioxidant properties of maize (Zea mays L.) flour was studied using response surface methodology. A central composite design based on three levels of each of particle size, in terms of mesh number (40, 60 and 80 meshes), and gamma radiation dose (25, 50 and 75 kGy) was constructed. A statistically significant dose-dependent decrease (p<0.05) in antioxidant properties of gamma irradiated flour was observed. However, an increase in the mesh number (decrease in particle size of flour) resulted in an increase in antioxidant properties. The optimum level of radiation dose to achieve maximum value of responses was found to be 50 kGy for Trolox equivalent total antioxidant activity (TETAOA), 25 kGy for iron chelating ability (ICA), 25 kGy for reducing power (RP) and 75 kGy for linoleic acid reduction capacity (LARC). However, the optimum level of mesh number to achieve desired levels of TETAOA, ICA, RP and LARC was found to be 80 meshes

Smart homes and their users:a systematic analysis and key challenges

Published research on smart homes and their users is growing exponentially, yet a clear understanding of who these users are and how they might use smart home technologies is missing from a field being overwhelmingly pushed by technology developers. Through a systematic analysis of peer-reviewed literature on smart homes and their users, this paper takes stock of the dominant research themes and the linkages and disconnects between them. Key findings within each of nine themes are analysed, grouped into three: (1) views of the smart home-functional, instrumental, socio-technical; (2) users and the use of the smart home-prospective users, interactions and decisions, using technologies in the home; and (3) challenges for realising the smart home-hardware and software, design, domestication. These themes are integrated into an organising framework for future research that identifies the presence or absence of cross-cutting relationships between different understandings of smart homes and their users. The usefulness of the organising framework is illustrated in relation to two major concerns-privacy and control-that have been narrowly interpreted to date, precluding deeper insights and potential solutions. Future research on smart homes and their users can benefit by exploring and developing cross-cutting relationships between the research themes identified

Learning From Early Attempts to Generalize Darwinian Principles to Social Evolution

Copyright University of Hertfordshire &amp; author.Evolutionary psychology places the human psyche in the context of evolution, and addresses the Darwinian processes involved, particularly at the level of genetic evolution. A logically separate and potentially complementary argument is to consider the application of Darwinian principles not only to genes but also to social entities and processes. This idea of extending Darwinian principles was suggested by Darwin himself. Attempts to do this appeared as early as the 1870s and proliferated until the early twentieth century. But such ideas remained dormant in the social sciences from the 1920s until after the Second World War. Some lessons can be learned from this earlier period, particularly concerning the problem of specifying the social units of selection or replication