Search

Gay, bisexual, and other men who have sex with men (GBMSM) remain most disproportionately affected by HIV in Canada. HIV- related sexual risk behaviours have been linked to high HIV risk among GBMSM, but prior research has not focused on knowledge of viral load, and the risk it presents for HIV acquisition. The purpose of this study was to explore the relationship between HIV-related sexual risk behaviour and knowledge of viral load among GBMSM. A cross-sectional survey was conducted using a convenience sample of individuals age 16 and older who self-identified as LGBTQ and lived, worked, or resided in the Waterloo region, an urban-rural area in southwestern Ontario ( N = 526). Responses were analyzed from those identifying as GBMSM ( N = 269). Logistic regression models were created to explore sociodemographic, outness, social support, and HIV-related sexual risk variables associated with knowledge of viral load. Multivariable regression models were built to explore the same associations while controlling for confounders. HIV risk was not associated with knowledge of viral load in bivariate or multivariable analyses. Point estimates for low/negligible (odds ratio [OR] 1.10; 95% CI 0.46–2.51) and high risk (OR 1.88; 95% CI 0.68–5.20) suggest trends of higher knowledge with increased HIV risk. Men who engage in sexual risk behaviour may have increased sexual health literacy and awareness of biomedical interventions (e.g., pre-exposure prophylaxis, or PrEP) that reduce HIV risk. Policies are needed that promote acceptance of sexual orientation, improve awareness and access to PrEP, and ensure optimal delivery of HIV education to at-risk groups prior to engagement in higher risk activities.

Transgender individuals face barriers to accessing gender-affirming hormone therapy, yet little is known about gynecological providers' willingness to provide such care.We surveyed gynecological providers in one healthcare system to determine their willingness to prescribe hormone therapy (HT) for transgender patients and factors associated with willingness to both initiate and refill HT.Among respondents (While gynecological providers are qualified to prescribe HT for transgender patients, willingness to do so may be influenced by both personal and educational/training factors. Encouraging and training gynecological providers to provide gender-affirming HT will help to increase access for transgender individuals.

Background Relationships between primary care providers (PCP) and trans patients remain important, necessitating discussions about gender identity, health and their intersections. Methods Using an online survey, we explored socio-demographic and psycho-social factors associated with: (1) disclosing gender identity; (2) discussing gender identity-related health issues; and (3) comfort sharing gender identity with PCPs, among trans people (n = 112) over 16 years of age, sampled in Waterloo, Ontario, Canada. Bivariate and multivariate methods using modified Poisson regression generated effect estimates. Results Age, birth presumed gender, employment status, family support, and transphobia were significantly associated with disclosing gender identity, discussing gender identity-related health issues, and comfortability sharing gender identity with PCPs. Conclusion Increasing PCPs’ knowledge of trans-related health issues is stressed to improve access and quality for trans patients.

Yeast is a valuable model organism for their ease of genetic manipulation, rapid growth rate, and relative similarity to higher eukaryotes. Historically, Saccharomyces cerevisiae has played a major role in discovering the function of complex proteins and pathways that are important for human health and disease. Heat shock protein 90 (Hsp90) is a molecular chaperone responsible for the stabilization and activation of hundreds of integral members of the cellular signaling network. Much important structural and functional work, including many seminal discoveries in Hsp90 biology are the direct result of work carried out in S. cerevisiae. Here, we have provided a brief overview of the S. cerevisiae model system and described how this eukaryotic model organism has been successfully applied to the study of Hsp90 chaperone function.

Posttranslational modifications (PTMs) regulate myriad cellular processes by modulating protein function and protein-protein interaction. Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone whose activity is responsible for the stabilization and maturation of more than 300 client proteins. Hsp90 is a substrate for numerous PTMs, which have diverse effects on Hsp90 function. Interestingly, many Hsp90 clients are enzymes that catalyze PTM, demonstrating one of the several modes of regulation of Hsp90 activity. Approximately 25 co-chaperone regulatory proteins of Hsp90 impact structural rearrangements, ATP hydrolysis, and client interaction, representing a second layer of influence on Hsp90 activity. A growing body of literature has also established that PTM of these co-chaperones fine-tune their activity toward Hsp90; however, many of the identified PTMs remain uncharacterized. Given the critical role of Hsp90 in supporting signaling in cancer, clinical evaluation of Hsp90 inhibitors is an area of great interest. Interestingly, differential PTM and co-chaperone interaction have been shown to impact Hsp90 binding to its inhibitors. Therefore, understanding these layers of Hsp90 regulation will provide a more complete understanding of the chaperone code, facilitating the development of new biomarkers and combination therapies.

Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes that plays a vital role in protecting and maintaining the functional integrity of deregulated signaling proteins in tumors. We have previously reported that the stability and activity of the mitotic checkpoint kinase Mps1 depend on Hsp90. In turn, Mps1-mediated phosphorylation Hsp90 regulates its chaperone function and is essential for the mitotic arrest. Cdc14-assisted dephosphorylation of Hsp90 is vital for the mitotic exit. Post-translational regulation of Hsp90 function is also known as the Hsp90 “Chaperone Code.” Here, we demonstrate that only the active Mps1 is ubiquitinated on K86, K827, and K848 by the tumor suppressor von Hippel-Lindau (VHL) containing E3 enzyme, in a prolyl hydroxylation-independent manner and degraded in the proteasome. Furthermore, we show that this process regulates cell exit from the mitotic checkpoint. Collectively, our data demonstrates an interplay between the Hsp90 chaperone and VHL degradation machinery in regulating mitosis.

Birt-Hogg-Dubé (BHD) and tuberous sclerosis (TS) syndromes share many clinical features. These two diseases display distinct histologic subtypes of renal tumors: chromophobe renal cell carcinoma and renal angiomyolipoma, respectively. Early work suggested a role for mTOR dysregulation in the pathogenesis of these two diseases, however their detailed molecular link remains elusive. Interestingly, a growing number of case reports describe renal angiomyolipoma in BHD patients, suggesting a common molecular origin. The BHD-associated proteins FNIP1/2 and the TS protein Tsc1 were recently identified as regulators of the molecular chaperone Hsp90. Dysregulation of Hsp90 activity has previously been reported to support tumorigenesis, providing a potential explanation for the overlapping phenotypic manifestations in these two hereditary syndromes.

Transgender (trans) people (including non-binary persons) experience high rates of violence and discrimination regarding their gender identity and expression, necessitating a deeper understanding of trans peoples’ perceptions of safety within their communities and their perspectives on well-being. The purpose of this study was to gather insight into the perceptions of safety and community inclusion among trans people, through the lens of Meyer’s Minority Stress Model. Thirty-three trans individuals residing in a mid-sized urban and rural region, 100 kms west of Toronto, Canada, were interviewed for a larger study focused on experiences of discrimination. For this paper, we conducted a thematic analysis using NVivo (version 12), that included 18 participants from the larger study, including trans men, trans women, and non-binary individuals. Both experiences of prejudice and anticipations of prejudice resulted in participants feeling unsafe. This negatively affected their well-being, consistent with Meyer’s Minority Stress Model. Additionally, we found that environments absent of prejudice or considered supportive, such as places participants received social gender affirmation and LGBT-connectedness, fostered feelings of safety and positive well-being. Our study indicates a need to address not only the external events of prejudice towards trans people, but also the stress associated with the anticipation of prejudice.

The molecular chaperone TNF-receptor-associated protein-1 (TRAP1) controls mitochondrial respiration through regulation of Krebs cycle and electron transport chain activity. Post-translational modification (PTM) of TRAP1 regulates its activity, thereby controlling global metabolic flux. O-GlcNAcylation is one PTM that is known to impact mitochondrial metabolism, however the major effectors of this regulatory PTM remain inadequately resolved. Here we demonstrate that TRAP1-O-GlcNAcylation decreases TRAP1 ATPase activity, leading to increased mitochondrial metabolism. O-GlcNAcylation of TRAP1 occurs following mitochondrial import and provides critical regulatory feedback, as the impact of O-GlcNAcylation on mitochondrial metabolism shows TRAP1-dependence. Mechanistically, loss of TRAP1-O-GlcNAcylation decreased TRAP1 binding to ATP, and interaction with its client protein succinate dehydrogenase (SDHB). Taken together, TRAP1-O-GlcNAcylation serves to regulate mitochondrial metabolism by the reversible attenuation of TRAP1 chaperone activity.

Religious social work students often report less-affirming LGB attitudes, which is often attributed to anti-LGB religious teachings. Yet research often overlooks one’s beliefs about their denominat...

Gay, bisexual, and other men who have sex with men (GBMSM) remain the group most affected by HIV in Canada. Travelling for sex and attendance at specific venues for sex have been linked to elevated HIV risk among GBMSM, but most research on these mobilities and sexual health has focused on GBMSM living in large cities. The purpose of this study was to explore HIV-related sexual risk among GBMSM from mid-sized cities and rural regions who attend gay-specific venues and/or travel for sex. A cross-sectional online survey was completed by a convenience sample of individuals (n = 526) self-identifying as LGBTQ who lived, worked, or studied in Waterloo Region, a mixed urban-rural region in the southwestern part of Ontario, Canada. Analyses for the current study were restricted to those identifying as GBMSM (n = 269). Multinomial logistic regression models were created to explore travelling outside of the Region for sex, as well as recent attendance at gay-specific venues, and their associations with a contextual measure of HIV-related sexual transmission risk. Individuals reporting high HIV risk were significantly more likely to travel outside of Waterloo Region for sex than individuals reporting no HIV risk (OR = 3.08; 95% CI: 1.20, 7.93). The association between travel and risk was strengthened after controlling for education, marital status, sexual orientation, gender modality, and social support (OR = 5.07; 95% CI: 1.73, 14.87). GBMSM who reside outside of large cities may travel farther, enter unfamiliar scenes, or be less privy to information disseminated through current health promotion initiatives for GBMSM in large cities. Due to the dynamic geographic status of GBMSM travelling for sex and attendance at venues, HIV prevention initiatives that target these individuals may benefit from additional conceptualization of health promotion delivery in terms of social and sexual networks, rather than simply by place of residence.

Pre-exposure prophylaxis (PrEP) is an effective HIV-prevention tool for gay, bisexual, and other men who have sex with men (GBMSM), a group known to be disproportionately affected by HIV/AIDS. We aimed to identify sociodemographic, psychosocial, and health factors associated with awareness of PrEP or interest in PrEP among GBMSM in a mid-sized Canadian city, where PrEP availability is arguably more scarce compared to larger metropolitan regions. The OutLook Study was a comprehensive online survey of LGBTQ health and well-being that collected data from sexual minorities aged 16+ in the Region of Waterloo, Ontario, Canada. Participants were cisgender MSM with an unknown or negative HIV status (n = 203). Bivariate logistic regression was performed to analyze factors associated with both awareness of PrEP and interest in PrEP. Multivariate logistic regression explored sexual behaviours in the past 12 months while controlling for sociodemographic and psychosocial variables. Increasing number of sexual partners (OR: 1.10; 95% CI: 1.03–1.53) was significantly associated with interest in PrEP and lifetime experiences of homophobia remained significant from the bivariate model (ORs ranged from 1.11–1.12). Since GBMSM with low educational attainment were shown to have less knowledge about PrEP, educational campaigns could be targeted in high schools rather than colleges, universities, and trade schools. Prevention initiatives should be aimed at places where single or non-monogamous GBMSM frequent due to these men being disproportionately affected by HIV/AIDS. These findings provide insights for potential interventions targeting MSM from mid-sized cities.

LGBTQ+ (lesbian, gay, bisexual, transgender, queer, plus) people, compared to their heterosexual and/or cisgender (non-transgender) counterparts, are more likely to be discriminated against based o...

Cells have a remarkable ability to synthesize large amounts of protein in a very short period of time. Under these conditions, many hydrophobic surfaces on proteins may be transiently exposed, and the likelihood of deleterious interactions is quite high. To counter this threat to cell viability, molecular chaperones have evolved to help nascent polypeptides fold correctly and multimeric protein complexes assemble productively, while minimizing the danger of protein aggregation. Heat shock protein 90 (Hsp90) is an evolutionarily conserved molecular chaperone that is involved in the stability and activation of at least 300 proteins, also known as clients, under normal cellular conditions. The Hsp90 clients participate in the full breadth of cellular processes, including cell growth and cell cycle control, signal transduction, DNA repair, transcription, and many others. Hsp90 chaperone function is coupled to its ability to bind and hydrolyze ATP, which is tightly regulated both by co-chaperone proteins and post-translational modifications (PTMs). Many reported PTMs of Hsp90 alter chaperone function and consequently affect myriad cellular processes. Here, we review the contributions of PTMs, such as phosphorylation, acetylation, SUMOylation, methylation, O-GlcNAcylation, ubiquitination, and others, toward regulation of Hsp90 function. We also discuss how the Hsp90 modification state affects cellular sensitivity to Hsp90-targeted therapeutics that specifically bind and inhibit its chaperone activity. The ultimate challenge is to decipher the comprehensive and combinatorial array of PTMs that modulate Hsp90 chaperone function, a phenomenon termed the “chaperone code.”

While considerable knowledge exists about blatant gender discrimination and violence targeting women, less is known about gender microaggressions. To understand gender microaggressions’ frequency, prevalence, and effects, researchers need robust quantitative measures. To advance gender microaggressions scholarship and support researchers’ efforts to identify high-quality measures, we conducted a psychometric scoping review. We identified 24 original, quantitative, multi-item measures designed to assess gender microaggressions or related constructs. Included measures needed at least one item assessing gender microaggressions and be used with adult women in the United States. Results indicated an increase in the number of measures including gender microaggressions’ items in recent years, with a major expansion in the number of named gender microaggressions’ measures. We found limited reporting of demographic information. Psychometric testing and characteristics varied across measures. While most ( n = 20) reported internal consistency reliability, only two-thirds ( n = 16) reported undergoing validity testing. When examining microaggressions named measures ( n = 10), we found inconsistent adherence to microaggressions’ theoretical and conceptual foundations. Substantial work remains to develop a “gold standard” measure that does not conflate subtle and blatant acts, assesses the full thematic range of gender microaggressions, and is psychometrically valid across different social contexts and diverse groups of women.

This qualitative study draws from 60 interviews with LGBTQ+ college students to highlight how a positive psychology framework illuminates aspects of LGBTQ+ student success. Utilizing the broaden-an...

Mitochondrial function is dependent on molecular chaperones, primarily due to their necessity in the formation of respiratory complexes and clearance of misfolded proteins. Heat shock proteins (Hsps) are a subset of molecular chaperones that function in all subcellular compartments, both constitutively and in response to stress. The Hsp90 chaperone TNF-receptor-associated protein-1 (TRAP1) is primarily localized to the mitochondria and controls both cellular metabolic reprogramming and mitochondrial apoptosis. TRAP1 upregulation facilitates the growth and progression of many cancers by promoting glycolytic metabolism and antagonizing the mitochondrial permeability transition that precedes multiple cell death pathways. TRAP1 attenuation induces apoptosis in cellular models of cancer, identifying TRAP1 as a potential therapeutic target in cancer. Similar to cytosolic Hsp90 proteins, TRAP1 is also subject to post-translational modifications (PTM) that regulate its function and mediate its impact on downstream effectors, or ‘clients’. However, few effectors have been identified to date. Here, we will discuss the consequence of TRAP1 deregulation in cancer and the impact of post-translational modification on the known functions of TRAP1.

The treatment of advanced and metastatic kidney cancer has entered a golden era with the addition of more therapeutic options, improved survival and new targeted therapies. Tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors and immune checkpoint blockade have all been shown to be promising strategies in the treatment of renal cell carcinoma (RCC). However, little is known about the best therapeutic approach for individual patients with RCC and how to combat therapeutic resistance. Cancers, including RCC, rely on sustained replicative potential. The cyclin-dependent kinases CDK4 and CDK6 are involved in cell-cycle regulation with additional roles in metabolism, immunogenicity and antitumour immune response. Inhibitors of CDK4 and CDK6 are now commonly used as approved and investigative treatments in breast cancer, as well as several other tumours. Furthermore, CDK4/6 inhibitors have been shown to work synergistically with other kinase inhibitors, including mTOR inhibitors, as well as with immune checkpoint inhibitors in preclinical cancer models. The effect of CDK4/6 inhibitors in kidney cancer is relatively understudied compared with other cancers, but the preclinical studies available are promising. Collectively, growing evidence suggests that targeting CDK4 and CDK6 in kidney cancer, alone and in combination with current therapeutics including mTOR and immune checkpoint inhibitors, might have therapeutic benefit and should be further explored.

The 7th Birt-Hogg-Dubé (BHD) International Symposium convened virtually in October 2021. The meeting attracted more than 200 participants internationally and highlighted recent findings in a variety of areas, including genetic insight and molecular understanding of BHD syndrome, structure and function of the tumor suppressor Folliculin (FLCN), therapeutic and clinical advances as well as patients’ experiences living with this malady.

Heat shock protein-90 (Hsp90) chaperone machinery is involved in the stability and activity of its client proteins. The chaperone function of Hsp90 is regulated by co-chaperones and post-translational modifications. Although structural evidence exists for Hsp90 interaction with clients, our understanding of the impact of Hsp90 chaperone function toward client activity in cells remains elusive. Here, we dissect the impact of recently identified higher eukaryotic co-chaperones, FNIP1/2 (FNIPs) and Tsc1, toward Hsp90 client activity. Our data show that Tsc1 and FNIP2 form mutually exclusive complexes with FNIP1, and that unlike Tsc1, FNIP1/2 interact with the catalytic residue of Hsp90. Functionally, these co-chaperone complexes increase the affinity of the steroid hormone receptors glucocorticoid receptor and estrogen receptor to their ligands in vivo. We provide a model for the responsiveness of the steroid hormone receptor activation upon ligand binding as a consequence of their association with specific Hsp90:co-chaperone subpopulations.

Purpose: Even in cases of medical emergency, mistreatment and negative experiences in life or in medical settings can deter trans patients from seeking necessary care. The purpose of this study was to identify factors associated with trans persons' emergency department (ED) avoidance in the mixed urban-rural Region of Waterloo, Ontario, Canada. Methods: The OutLook Study was a community-based partnership that created an online, cross-sectional questionnaire for lesbian, gay, bisexual, transgender, and other sexual and gender minority community members. Participants in this analysis were 16 years of age or older, lived, worked, or attended school in Waterloo Region, and identified as trans (n=112). Binary logistic regression was used to test associations between sociodemographic, resilience, and risk variables, and ED avoidance. Sociodemographic variables statistically significant at p

Dysregulated metabolism is one of the hallmarks of cancer. Under normal physiological conditions, ATP is primarily generated by oxidative phosphorylation. Cancers commonly undergo a dramatic shift toward glycolysis, despite the presence of oxygen. This phenomenon is known as the Warburg effect, and requires the activity of LDHA. LDHA converts pyruvate to lactate in the final step of glycolysis and is often upregulated in cancer. LDHA inhibitors present a promising therapeutic option, as LDHA blockade leads to apoptosis in cancer cells. Despite this, existing LDHA inhibitors have shown limited clinical efficacy. Here, we review recent progress in LDHA structure, function and regulation as well as strategies to target this critical enzyme.

This study examines the links between sexual identity and participation in political protests. Among a sample of college students (N = 2175), we determined that sexual minority students were three times more likely to join a protest than heterosexual students. “Political distinctiveness” theories are used to explain this sexual identity gap in protesting. Following a series of path analyses, we conclude that marital status, exposure to discrimination (as a victim or observer), connections to LGB communities, participation in political groups, and liberal identities mediate the sexuality difference in protesting. Conversely, measures of educational attainment, exposure to multicultural classes, and internalized homophobia were not mediators.

Few scholars have examined the experiences of LGBTQ+ college students with disabilities, but the available evidence indicating poor mental and physical health, underutilization of disability accomm...

The molecular chaperone Heat shock protein 90 (Hsp90) is essential for the folding, stability, and activity of several drivers of oncogenesis. Hsp90 inhibitors are currently under clinical evaluation for cancer treatment, however their efficacy is limited by lack of biomarkers to optimize patient selection. We have recently identified the tumor suppressor tuberous sclerosis complex 1 (Tsc1) as a new co-chaperone of Hsp90 that affects Hsp90 binding to its inhibitors. Highly variable mutations of TSC1 have been previously identified in bladder cancer and correlate with sensitivity to the Hsp90 inhibitors. Here we showed loss of TSC1 leads to hypoacetylation of Hsp90-K407/K419 and subsequent decreased binding to the Hsp90 inhibitor ganetespib. Pharmacologic inhibition of histone deacetylases (HDACs) restores acetylation of Hsp90 and sensitizes Tsc1-mutant bladder cancer cells to ganetespib, resulting in apoptosis. Our findings suggest that TSC1 status may predict response to Hsp90 inhibitors in patients with bladder cancer, and co-targeting HDACs can sensitize tumors with Tsc1 mutations to Hsp90 inhibitors.

Summary: The extracellular molecular chaperone heat shock protein 90 (eHSP90) stabilizes protease client the matrix metalloproteinase 2 (MMP2), leading to tumor cell invasion. Although co-chaperones are critical modulators of intracellular HSP90:client function, how the eHSP90:MMP2 complex is regulated remains speculative. Here, we report that the tissue inhibitor of metalloproteinases-2 (TIMP2) is a stress-inducible extracellular co-chaperone that binds to eHSP90, increases eHSP90 binding to ATP, and inhibits its ATPase activity. In addition to disrupting the eHSP90:MMP2 complex and terminally inactivating MMP2, TIMP2 loads the client to eHSP90, keeping the protease in a transient inhibitory state. Secreted activating co-chaperone AHA1 displaces TIMP2 from the complex, providing a “reactivating” mechanism for MMP2. Gene knockout or blocking antibodies targeting TIMP2 and AHA1 released by HT1080 cancer cells modify their gelatinolytic activity. Our data suggest that TIMP2 and AHA1 co-chaperones function as a molecular switch that determines the inhibition and reactivation of the eHSP90 client protein MMP2. : Hundreds of intracellular proteins depend on molecular chaperone heat shock protein 90 (HSP90) and its co-chaperones to properly function. Baker-Williams et al. identify two secreted co-chaperones that act as a molecular switch to inhibit and reactivate extracellular HSP90 (eHSP90) client matrix metalloproteinase 2 (MMP2). This mechanism impacts matrix degradation. Keywords: extracellular heat shock protein-90, eHSP90, co-chaperone, stress response, TIMP2, MMP2, AHA1, eATP, matrix degradation, cancer cells

Heat shock protein-90 (Hsp90) is an ATP-dependent molecular chaperone that is tightly regulated by a group of proteins termed co-chaperones. This chaperone system is essential for the stabilization and activation of many key signaling proteins. Recent identification of the co-chaperones FNIP1, FNIP2, and Tsc1 has broadened the spectrum of Hsp90 regulators. These new co-chaperones mediate the stability of critical tumor suppressors FLCN and Tsc2 as well as the various classes of Hsp90 kinase and non-kinase clients. Many early observations of the roles of FNIP1, FNIP2, and Tsc1 suggested functions independent of FLCN and Tsc2 but have not been fully delineated. Given the broad cellular impact of Hsp90-dependent signaling, it is possible to explain the cellular activities of these new co-chaperones by their influence on Hsp90 function. Here, we review the literature on FNIP1, FNIP2, and Tsc1 as co-chaperones and discuss the potential downstream impact of this regulation on normal cellular function and in human diseases.

Aerobic glycolysis in cancer cells, also known as the ‘Warburg effect’, is driven by hyperactivity of lactate dehydrogenase A (LDHA). LDHA is thought to be a substrate-regulated enzyme, but it is unclear whether a dedicated intracellular protein also regulates its activity. Here, we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. A flexible loop within the amino terminus of FLCN controls movement of the LDHA active-site loop, tightly regulating its enzyme activity and, consequently, metabolic homeostasis in normal cells. Cancer cells that experience the Warburg effect show FLCN dissociation from LDHA. Treatment of these cells with a decapeptide derived from the FLCN loop region causes cell death. Our data suggest that the glycolytic shift of cancer cells is the result of FLCN inactivation or dissociation from LDHA. Together, FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation of glycolysis.