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In the past few years, we have identified two allosteric modulators of the urotensinergic system with probe-dependent action, termed Urocontrin (UC) and Urocontrin A (UCA). learn more Such action is atypical and important since it will allow us to understand the specific function of the functionally selective cognate ligands of this system, namely urotensin II and urotensin II-related peptide. Delineating the molecular determinants involved in this particular behavior would represent an important step toward designing small molecules suitable for pharmacologic and/or therapeutic intervention. Hence, we undertook an exploratory research by replacing the Trp4 residue of URP with several para-substituted phenylalanine amino acids in order to get a grasp on the required nature, distance, and orientation of the side chain of this residue for allosteric modulatory action. We found that the position of the second aromatic group is crucial, and we identified two new allosteric modulators [Trip4]URP and [Phe(pPy-4)4]URP with probe-dependent action.Modifications at the bridgehead position of englerin A were made to explore the effects of variation at this site on the molecule for biological activity, as judged by the NCI 60 screen, in which englerin A is highly potent and selective for renal cancer cells. Replacement of the isopropyl group by other, larger substituents yielded compounds which displayed excellent selectivity and potency comparable to the natural product. Selected compounds were also evaluated for their effect on the ion channel TRPC4 as well as for intravenous toxicity in mice, and these had lower potency in both assays compared to englerin A.The membrane permeability of nucleotide-based drugs, such as sofosbuvir (Sovaldi), requires installation of phosphate-caging groups. One strategy, termed "ProTide", masks the anionic phosphate through an N-linked amino ester and an O-linked aromatic phospho-ester, such that release of the active drug requires consecutive enzymatic liberation by an esterase and then a phosphoramidase, such as Hint1. Because Hint1 is known to be selective for nucleotides, it was not clear if the ProTide approach could be deployed for non-nucleotides. Here, we demonstrate that caging of a phosphate-containing inhibitor of the prolyl isomerase Pin1 increases its permeability. Moreover, this compound was processed by both esterase and phosphoramidase activity, releasing the active molecule to bind and inhibit Pin1 in cells. Thus, Hint1 appears to recognize a broader set of substrates than previously appreciated. It seems possible that other potent, but impermeable, phosphate-containing inhibitors might likewise benefit from this approach.Small GTPase protein Rho-kinase (ROCK) plays an important role in the pathogenesis of hypertension. Inhibition of ROCK II brings about the biochemical changes leading to vascular smooth muscles relaxation, finally resulting into potent antihypertensive activity. In the quest for potent ROCK-II inhibitors, a ligand-based pharmacophore containing four essential chemical features, namely two hydrogen bond acceptor (HBA), one hydrogen bond donor (HBD), and one hydrophobe (HY), was developed and rigorously validated. link2 The pharmacophore was used for virtual screening, and hits retrieved from the National Cancer Institute (NCI) database were sorted on the basis of fit value, estimate value, and Lipinski's violation. Potential feature interaction of hits was also observed during docking studies with the amino acids present in the active site of Rho-kinase. Based on the above screening, three hits (NSC 2488, NSC 2888, and NSC 4231) were chosen and subjected to in vitro Rho-kinase enzyme-based assay, followed by ex vivo rat aortic vasodilatory assay. All three compounds showed good biological activity as predicted by the model and confirmed by the docking studies.Protein arginine methyltransferase 5 (PRMT5) belongs to a family of enzymes that regulate the posttranslational modification of histones and other proteins via methylation of arginine. Methylation of histones is linked to an increase in transcription and regulates a manifold of functions such as signal transduction and transcriptional regulation. PRMT5 has been shown to be upregulated in the tumor environment of several cancer types, and the inhibition of PRMT5 activity was identified as a potential way to reduce tumor growth. Previously, four different modes of PRMT5 inhibition were known-competing (covalently or non-covalently) with the essential cofactor S-adenosyl methionine (SAM), blocking the substrate binding pocket, or blocking both simultaneously. Herein we describe an unprecedented conformation of PRMT5 in which the formation of an allosteric binding pocket abrogates the enzyme's canonical binding site and present the discovery of potent small molecule allosteric PRMT5 inhibitors.

Many individuals reject evolutionary theory due to a perceived conflict with their religious beliefs. To bridge this gap, educators have attempted different approaches including approaching evolution rejection as a consequence of deficit thinking and teaching students the nature of science (including the scientific process and peer review process as well as questions that science can and cannot answer).Teaching the nature of science has shown promising gains in the acceptance of evolution, although acceptance rates remain low. We propose a further approach the use of a reconciliatory model designed to help students accept evolution within the framework of their religious beliefs. We tested this approach in both biology and theology classrooms at a Nazarene-affiliated university. Both professors approached the subject in a reconciliatory fashion.

This study found that by utilizing a reconciliatory approach, the students in both classrooms saw significant gains in evolution acceptance, with gains being greatest in the biology classroom. In addition, we saw no decrease in student religiosity.

Implications of this are discussed. The results of this study confirm the effectiveness of a reconciliatory model, which opens several avenues for further research.

Implications of this are discussed. The results of this study confirm the effectiveness of a reconciliatory model, which opens several avenues for further research.For over 35 years, scholars have searched with little success for a legal safeguard that can sensitize jurors to eyewitness testimony. The present study explored whether expert testimony that uses the I-I-Eye method of analyzing eyewitness testimony can improve juror sensitivity to eyewitness evidence. Participants read a trial transcript with no expert testimony, standard expert testimony or expert testimony that used the I-I-Eye method. The two transcripts for the three expert groups had either strong or weak eyewitness testimony. Unlike the control participants, the I-I-Eye expert participants rendered significantly more guilty verdicts in the strong than in the weak case. The standard expert testimony did not affect verdicts even though it increased participants' knowledge of the eyewitness factors. link3 It appears that the I-I-Eye method improved sensitivity because it not only increased participants' knowledge of eyewitness factors, but also explained how to use that knowledge in assessing eyewitness accuracy.'Communication assistance' is a term that derives from section 80 of the Evidence Act 2006 a legislative provision that has given birth to a whole new profession in the New Zealand legal system. This legislative provision has been used to appoint a new role that of the communication assistant to support complainants, witnesses and defendants of all ages with identified communication needs. This study focuses specifically on the provision of communication assistance for young people who offend in the New Zealand criminal justice system. It provides a qualitative analysis of professionals' descriptions (n = 28 participants) of communication assistance for this population in justice processes. The findings illustrate that communication assistance shares its core with a similar role in England and Wales, that of the intermediary, but that communication assistants in New Zealand have broader scope than their counterparts working in the area of youth justice.Vicarious or secondary trauma experience has always been part of legal practice although many do not acknowledge the risk it can have on the mental health, well-being and performance of legal professionals. The listening to, observing and then detailing of traumatic events for the purposes of legal process in some cases may harm lawyers who need to work closely with clients, victims and witnesses. This article reviews the research on trauma in many areas of professional human services that could inform and improve our understanding of legal practice. It examines the discursive history of trauma and recent studies on lawyer well-being, before discussing the controversies about recognising vicarious trauma and the stigma against mental health concerns in the legal profession. The article concludes by reviewing options to assist law firms in considering trauma-informed policy, practices and supervision strategies and to help individual lawyers recognise the value of self-care.Fetal alcohol spectrum disorder (FASD) is a neurodevelopmental condition with life-long implications. Individuals with FASD can experience communication, cognitive, behavioural, social and emotional difficulties that impact their functional capacity. Due to these brain-based impairments, previous research suggests that individuals with FASD are over-represented in the justice system. The current article outlines how individuals with FASD may experience inequities within the justice system, why assessment, diagnosis and intervention is important, and the role of health and justice partnerships in promoting more equitable outcomes for justice-involved individuals with FASD. Increased resources and collaborations between health and justice professionals are required to enable the provision of neurodevelopmental assessments for all complex presentations, including FASD.Deviant sexual fantasy is identified as a risk factor for sexual offending, yet no study has examined deviant sexual fantasy across the lifespan in nonoffending adult males. To bridge this gap, this study examined the frequencies of normative and deviant sexual fantasies among 318 nonoffending adult males in the United States. Participants were recruited via Amazon Mechanical Turk™. Participants took two inventories that assessed demographics and types of sexual fantasies. Normality tests, means tests, Kruskal-Wallis 1-way analyses of variance (ANOVAs), binary logistic regressions, and odds ratio post hoc analyses were conducted. Deviant sexual fantasies progressively declined across all three age groups, while normative sexual fantasy did not. Results suggest that deviant sexual fantasy changes across the lifespan. Applicability of the findings to applied settings, such as sexually violent predator evaluations, is discussed. Limitations and future considerations are addressed.The phenomenon of haters is becoming common among adolescents. The aims of the present research were to evaluate the preliminary psychometric properties of the Hating Adolescents Test (HAT), an ad hoc questionnaire created to evaluate online and offline hate (Study 1), and possible risk factors connected with hate (Study 2). Participants (202 female and 200 male) of this study completed the HAT, the How I Think Questionnaire, the Buss-Perry Aggression Questionnaire, and the Penn State Worry Questionnaire. Descriptive statistics were calculated, and exploratory factor analysis and confirmatory factor analysis were applied. Preliminary data suggest how males reported higher level of hate than females. Cronbach's alpha coefficient suggested excellent reliability of the measure. Results of this study also revealed satisfactory construct, convergent and divergent validity. Moreover, the results show a significant gender difference on the variables of the study (pathological worry and hostility aggressiveness). The mediation model suggests how hostile aggressiveness mediated the relationship between pathological worry and hate.