Associations Between Adolescent and Parent Media Connection and Perceptions of Emotional Climate in the Home

An overwhelming increase in technology and media use this past decade has been found to affect family relationships in various ways. Devices such as cell phones, tablets, and computers, have been found to both be the means of bringing family members closer together by communicating from a distance, while also disrupting and straining family connection, in particular the adolescent to parent relationship. Data from the Flourishing Families Project was used to analyze the varying perceptions of adolescent and parents regarding technology communication with one another and their personal perception of the emotional climate in the home. Results from this study showed no significant relationship between primary caregiver and adolescent child reports of the frequency of communication with each other through technology and their perception of their ability to express emotions in the home. Results also imply that high amounts or frequencies of adolescent and parent technology communication with one another does not predict a negative emotional climate in one’s home. Other contextual elements such as tone of voice, warmness of the parent-adolescent relationship, and other factors should be studied to understand the impact of different motives and types of communication in the home

Student Attitudes Toward Research in an Undergraduate Social Science Research Methods Course

This study used a mixed-methods longitudinal design to investigate change in students’ understanding, attitudes, anxiety, perceptions of relevance, and disinterest in a required social science undergraduate research methods course across a semester. Participants were 78 undergraduates (94% women, 6% men; 92% white non-Hispanic/Latinx, M age = 25.62, SD = 7.17) at a university in the United States. Results suggest that participant attitudes toward and perceptions of research methods shifted over the course of the semester. Overall, anxiety decreased, while positive attitudes increased. However, initial perceptions and changes in perceptions varied among the three course sections. Over time, students largely recognized the course’s relevance and conveyed positive attitudes toward research and their success in overcoming the challenge of completing the course. Implications for pedagogy include the need for continued assessment of learners, development of students’ self-concept as researchers, teaching of research as a process, and connection to application

Development of a 2,4-diaminothiazole series for the treatment of human African trypanosomiasis highlights the importance of static-cidal screening of analogues

While treatment options for human African trypanosomiasis (HAT) have improved significantly, there is still a need for new drugs with eradication now a realistic possibility. Here, we report the development of 2,4-diaminothiazoles that demonstrate significant potency against Trypanosoma brucei, the causative agent of HAT. Using phenotypic screening to guide structure-activity relationships, potent drug-like inhibitors were developed. Proof of concept was established in an animal model of the hemolymphatic stage of HAT. To treat the meningoencephalitic stage of infection, compounds were optimized for pharmacokinetic properties, including blood-brain barrier penetration. However, in vivo efficacy was not achieved, in part due to compounds evolving from a cytocidal to a cytostatic mechanism of action. Subsequent studies identified a nonessential kinase involved in the inositol biosynthesis pathway as the molecular target of these cytostatic compounds. These studies highlight the need for cytocidal drugs for the treatment of HAT and the importance of static-cidal screening of analogues

Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (<b>1</b>) for VL

Identification of Inhibitors of the Leishmania cdc2-Related Protein Kinase CRK3

New drugs are urgently needed for the treatment of tropical parasitic diseases such as leishmaniasis and human African trypanosomiasis (HAT). This work involved a high-throughput screen of a focussed kinase set of ∼3400 compounds to identify potent and parasite-selective inhibitors of an enzymatic Leishmania CRK3–cyclin 6 complex. The aim of this study is to provide chemical validation that Leishmania CRK3–CYC6 is a drug target. Eight hit series were identified, of which four were followed up. The optimisation of these series using classical SAR studies afforded low-nanomolar CRK3 inhibitors with significant selectivity over the closely related human cyclin dependent kinase CDK2

Optimisation of the Anti-Trypanosoma brucei Activity of the Opioid Agonist U50488

Screening of the Sigma–Aldrich Library of Pharmacologically Active Compounds (LOPAC) against cultured Trypanosoma brucei, the causative agent of African sleeping sickness, resulted in the identification of a number of compounds with selective antiproliferative activity over mammalian cells. These included (+)-(1R,2R)-U50488, a weak opioid agonist with an EC50 value of 59 nm as determined in our T. brucei in vitro assay reported previously. This paper describes the modification of key structural elements of U50488 to investigate structure–activity relationships (SAR) and to optimise the antiproliferative activity and pharmacokinetic properties of this compound

Development of a 2,4-Diaminothiazole Series for the Treatment of Human African Trypanosomiasis Highlights the Importance of Static–Cidal Screening of Analogues

While treatment options for human African trypanosomiasis (HAT) have improved significantly, there is still a need for new drugs with eradication now a realistic possibility. Here, we report the development of 2,4-diaminothiazoles that demonstrate significant potency against Trypanosoma brucei, the causative agent of HAT. Using phenotypic screening to guide structure–activity relationships, potent drug-like inhibitors were developed. Proof of concept was established in an animal model of the hemolymphatic stage of HAT. To treat the meningoencephalitic stage of infection, compounds were optimized for pharmacokinetic properties, including blood–brain barrier penetration. However, in vivo efficacy was not achieved, in part due to compounds evolving from a cytocidal to a cytostatic mechanism of action. Subsequent studies identified a nonessential kinase involved in the inositol biosynthesis pathway as the molecular target of these cytostatic compounds. These studies highlight the need for cytocidal drugs for the treatment of HAT and the importance of static–cidal screening of analogues