Design and evaluation of inhibitors targeting HIV capsid and cofactors

Our favoured model is that upon entry into the target cell, the HIV-1 capsid remains intact, performing crucial functions within the early viral lifecycle. This includes, binding to cofactors, protecting the viral genome, regulating reverse transcription and entry into the nucleus. Five of the six current HIV-1 antiretrovirals target early lifecycle events, from entry to integration. Due to its multitude of functions, capsid and its cofactors are an attractive target for antiviral inhibitors, yet there is no licensed anti-HIV-1 drug targeting these. Our aim is to develop potent inhibitors, which perturb capsid integrity and function, to push HIV-1 to adopt different, less successful behaviour. We are calling our first inhibitor series the allosteres, as we hypothesise that they are breaking allosteric mechanisms of the capsid. We have established that our highly potent allosteres when bound to HIV-1 capsid are causing significant activation of the innate immune system. As well as developing new potent HIV-1 antiretroviral therapies, these allosteres will be used as probes of capsid function confirming how vital it is for the capsid to remain whole within the cytoplasm leading to productive infection. Additionally, our second series of inhibitors are cyclophilin A targeting. Although cyclophilin A’s cellular functions have remained elusive, we know a number of unrelated viruses recruit and exploit this host protein as a cofactor. When the interaction between capsid and cyclophilin A is prevented, it leads to activation of innate immune sensing pathways within macrophages. Although, it remains incompletely understood how cyclophilin A is protecting the capsid, we aim to use our inhibitors to probe cyclophilin A roles within the early viral lifecycle. Overall our investigations confirm the roles of capsid and its interaction with cyclophilin A, demonstrating that by using inhibitors to directly target and manipulate these roles can significantly disrupt infection. Hopefully, the merits of this research can act as a paradigm for the development of capsid and cofactors inhibitors, not only for HIV-1, but also for many other viruses dependent on these mechanisms

Assessment of family impact in pediatric chronic pain

Pediatric chronic pain causes significant interference in daily functioning for children and their families. While parents and families have been examined in previous research, gaps exist in the current literature base, particularly related to accurate conceptualization and assessment of family functioning. The current study sought to develop a measure of family impact of pediatric pain and examine the effects that pain severity, functional disability, and parent and child psychosocial functioning have on family functioning. Results indicated parents of children with chronic pain appear to be impacted across several domains, with psychological distress in the child and parent being a significant predictor of parent functioning, above and beyond pain severity and functional disability. Though these findings provide contributions to the current literature, a thorough understanding of family impact is limited by a lack of validated assessments examining this construct within pediatric chronic pain populations. While still in the early stages of the development, the Family Impact of Pediatric Pain (FIPP), which was developed for the current study, attempts to fill several gaps that exist within the literature related to accurate conceptualization and assessment of family functioning in chronic pain populations

One + One \u3e Two: The Effects of Pair Quizzes on Student Attitudes and Perceptions

Pair Quizzes are cooperative pop quizzes, taken by a pair of students working together for the same grade. The first author, Chuck, had used pair quizzes in many of his courses through his tenure teaching and was interested in determining their perceived effect on student learning and attitude toward mathematics.To this end, we designed a questionnaire and distributed it to all students currently taking and who had taken two different mathematics courses within a span of four years. Responses from those who chose to complete the survey seem to indicate that the pair quizzes had a positive effect on students’ perceived learning and on their perceived attitude toward mathematics, as we had originally hoped

Sex and conflict: How competition shapes reproduction, behaviour and life-histories in various animals

Males compete against each other for female attention, for mating opportunities, and the sperm of multiple males can compete to fertilise a female's eggs. Thus, male-male competition is a ubiquitous component of sexual selection. In this thesis I examine how male-male competition for mates influences reproduction, life-histories, and, ultimately, produces sex differences in the behaviour of male and female animals. Chapter 1 takes a meta-analytic approach to examine the role of sexual selection in producing sex differences in shared behaviours. Using a dataset of over 2,000 effect sizes covering more than 200 different animal species, I test the generality of the 'greater male variability' hypothesis by comparing male and female animal personality behaviours. I find no consistent pattern for greater male variability and no moderating role of sexual selection (using sexual size dimorphism as a proxy). I discuss the importance of these findings for human behavioural studies. Chapters 2 and 3 investigate the role of contest outcomes, specifically 'winner-loser effects', on the plasticity of male reproductive investment into pre- and post-copulatory sexually selected traits (Chapter 2), and how male reproductive investment interacts with contest experiences to then influence lifespan (Chapter 3). I find no plasticity in male investment following winning-losing experiences, but strong winner effects on pre-copulatory mating effort. Most notably, I discuss the general importance of controlling for inherent male condition when exploring male investment into condition-dependent traits. Chapter 3 then explores how contest outcomes and reproductive effort influence rates of telomere shortening and other traits. I find equivocal evidence that long-term winners have shorter telomeres than losers, and evidence for a high mating cost for males that could freely mate during their treatments. I discuss the importance of considering the socio-sexual environment when quantifying relative male investment. Chapter 4 investigates male visual courtship synchrony in a fiddler crab species. Males wave their enlarged claw in almost perfect synchrony to attract potential females to their burrow to mate. Yet females strongly prefer the 'leader' whose waves slightly lead those of the rest of the group. So why do the 'followers' continue to wave if females prefer leaders? I discuss the potential for cooperation and competition to operate simultaneously to generate synchronised courtship displays in this species. Finally, Chapter 5 focuses on female-female competition for dominance and its potential role in male mate choice. Using groups of size-matched female mosquitofish, I replicate an earlier study that reported a strong preference for male mosquitofish to preferentially mate with dominant females when males and females can freely interact. I include standard two-choice mate choice tests to disentangle female-female interactions from male mate choice and discuss the general importance of replication. In sum, my thesis chapters highlight the surprising ways in which sexual selection can shape animal traits

Raman spectroscopy investigation of biochemical changes in tumour spheroids with ageing and after treatment with staurosporine

There has been increasing use of in vitro cell culture models that more realistically replicate the three dimensional (3D) environment found in vivo. Multicellular tumour spheroids (MTS) using cell lines or patient-derived organoids have become an important in vitro drug development tool, where cells are grown in a 3D 'sphere' that exhibits many of the characteristics found in vivo. Significantly, MTS develop gradients in nutrients and oxygen, commonly found in tumours, that contribute to therapy resistance. While MTS show promise as a more realistic in vitro culture model, there is a massive need to improve imaging technologies for assessing biochemical characteristics and drug response in such models to maximize their translation into useful applications such as high throughput screening (HTS). In this study we investigate the potential for Raman spectroscopy to unveil biochemical information in MTS and have investigated how spheroid age influences drug response, shedding light on increased therapy resistance in developing tumours. The wealth of molecular level information delivered by Raman spectroscopy in a noninvasive manner, could aid translation of these 3D models into HTS applications.PostprintPeer reviewe

Sex and Intimacy in the Postpartum Period: A Qualitative Reddit Analysis of Women’s and Men’s Experiences

Background: After a birth, physical, mental, social, and structural changes are common, and this may impact parents’ experiences of sex and intimacy. Women often report increased sexual morbidity and a decline in sexual desire, sexual satisfaction and sexual frequency. While much is known about women’s sexual dysfunction postpartum, less is known about experiences of intimacy and the meaning parents attach to the changes in sex and intimacy. Additionally, very little is known about men’s experiences of sex and intimacy postpartum. Research Questions: This study aimed to explore women’s and men’s experiences of sex and intimacy following the birth of a child by asking the following questions: (1) what (if any) changes do women and men experience in sex and/ or intimacy during the postpartum period?; (2) how do parents negotiate these changes?; and (3) how is the return to sex negotiated by men and women after birth? Methods: This was a qualitative study that used the online public forum Reddit to conduct a secondary data analysis. Constructivist grounded theory was used to analyze posts by men and women. Results: Reddit posts shared by men and women showed that they experienced significant changes in sex and intimacy postpartum that were often difficult to navigate. Parents identified a variety of barriers to sex and intimacy, and this often negatively impacted their well-being and relationships. Gender norms shaped the experiences of sex and intimacy as parents followed sexual scripts within heterosexual relationships, and women’s and men’s experiences were sometimes perceived differently based on gender roles by the members of the Reddit community. The transition into parenthood and new parenting responsibilities often conflicted with women’s and men’s roles as romantic partners. Additionally, the sex education women and men received prior to the postpartum period had a significant impact on their experiences and left some parents unprepared. Conclusion: The transitions that occur in the postpartum period provide a variety of challenges for parents that may negatively impact their experiences of sex and intimacy. Health care providers should initiate conversations with parents about sex and intimacy in the postpartum period to normalize common experiences and educate parents about additional resources should they be required

Appliquer une « optique systémique » : ESEC et fragilité à l’ère numérique

Affaires mondiales Canad

Understanding Training and Workforce Pathways to Develop and Retain Black Maternal Health Clinicians in California

Despite evidence that greater diversity in health professions increases quality of care, the maternal health field has made little progress on increasing and sustaining the number of Black maternal health care workers. In this study, Urban researchers examine opportunities for and barriers to increasing the workforce of Black obstetrician/gynecologists (OB/GYNs), labor and delivery (L&D) nurses, and midwives, especially in light of the ongoing US maternal health crisis. Through interviews with Black maternal health clinicians and training program staff, we recommend actions that federal and state policymakers, leaders at higher education and health system institutions, and philanthropies can take to address structural barriers to entering and staying within the field and to support a thriving workforce

Parent Responses to Their Child's Pain: Systematic Review and Meta-Analysis of Measures

OBJECTIVE: Parent responses can have a major impact on their child's pain. The purpose of this systematic review is to (a) identify and describe measures assessing pain-related cognitive, affective, and behavioral responses in parents of children with chronic pain and (b) meta-analyze reported correlations between parent constructs and child outcomes (i.e., pain intensity, functional disability, and school functioning). Prospero protocol registration ID: CRD42019125496. METHODS: We conducted a systematic search of studies including a measure of parent/caregiver responses to their child's chronic pain. Study characteristics and correlations between parent measures and child outcomes were extracted. Data were summarized and meta-analyzed. RESULTS: Seventy-nine met inclusion criteria using 18 different measures of cognitive/affective (n = 3), behavioral (n = 5), and multidimensional responses (n = 10). Measures were used a median of three times (range 1-48), predominantly completed by mothers (88%), and primarily in mixed pain samples. Psychometrics of measures were generally adequate. Meta-analyses were based on 42 papers across five measures. Results showed that each of the cognitive, affective, and behavioral parent constructs we examined was significantly associated with pain-related functional disability. A small number of measures assessing parent cognitions and affective functioning were associated with higher child pain intensity; however, the majority were not. CONCLUSION: Findings demonstrate that there is a wealth of measures available, with adequate reliability overall but a lack of psychometrics on temporal stability. Synthesizing data across studies revealed small effects between parent responses and child functioning, and even smaller and/or absent effects on child pain intensity.</p