Bon Sante (Good Health): Factors Influencing PrEP Use Among Haitians/Haitian Americans.

BACKGROUND: The HIV/AIDS epidemic has disproportionately affected Black individuals in the USA, and this health disparity has increased over time. Despite the effectiveness of pre-exposure prophylaxis (PrEP) as a prevention tool for HIV, there are disparities in its use, and uptake of this intervention remains low among racial and ethnic minorities, including Haitians/Haitian Americans. In this study, factors influencing PrEP use among Haitians/Haitian Americans in Miami, FL, are explored to provide necessary data to address disparities. METHODS: The research team collaborated with local organizations to recruit 30 individuals (Haitians/Haitian Americans) between February 4 and October 1, 2021, and conducted semi-structured interviews. All interviews were audio-recorded and transcribed, and NVivo® was used to analyze the transcripts for emergent themes. RESULTS: The study sample comprised 30 adults of Haitian descent in Miami, FL (50% female, approximately 67% with a high school education or more, mean age = 43.7 ± 13 years, and 74.2% born in Haiti). Four primary themes emerged from the analysis: (1) limited PrEP awareness, (2) underutilization of PrEP, (3) inadequate discussion of HIV prevention strategies, and (4) PrEP delivery encompassing barriers and facilitators for PrEP delivery and promotion strategies. CONCLUSION: This study indicated that there is a critical need to increase Haitians/Haitian Americans' knowledge regarding PrEP. Health communication interventions tailored specifically for Haitians/Haitian Americans that target stigma, attitudes toward HIV, and risk perception may be significant in increasing PrEP in this population.

Calcium-Sensing Receptor Contributes to Hyperoxia Effects on Human Fetal Airway Smooth Muscle.

Supplemental O2 (hyperoxia), necessary for maintenance of oxygenation in premature infants, contributes to neonatal and pediatric airway diseases including asthma. Airway smooth muscle (ASM) is a key resident cell type, responding to hyperoxia with increased contractility and remodeling [proliferation, extracellular matrix (ECM) production], making the mechanisms underlying hyperoxia effects on ASM significant. Recognizing that fetal lungs experience a higher extracellular Ca2+ ([Ca2+]o) environment, we previously reported that the calcium sensing receptor (CaSR) is expressed and functional in human fetal ASM (fASM). In this study, using fASM cells from 18 to 22 week human fetal lungs, we tested the hypothesis that CaSR contributes to hyperoxia effects on developing ASM. Moderate hyperoxia (50% O2) increased fASM CaSR expression. Fluorescence [Ca2+]i imaging showed hyperoxia increased [Ca2+]i responses to histamine that was more sensitive to altered [Ca2+]o, and promoted IP3 induced intracellular Ca2+ release and store-operated Ca2+ entry: effects blunted by the calcilytic NPS2143. Hyperoxia did not significantly increase mitochondrial calcium which was regulated by CaSR irrespective of oxygen levels. Separately, fASM cell proliferation and ECM deposition (collagens but not fibronectin) showed sensitivity to [Ca2+]o that was enhanced by hyperoxia, but blunted by NPS2143. Effects of hyperoxia involved p42/44 ERK via CaSR and HIF1α. These results demonstrate functional CaSR in developing ASM that contributes to hyperoxia-induced contractility and remodeling that may be relevant to perinatal airway disease.

Development of human ectocervical tissue models with physiologic endocrine and paracrine signaling†.

There is a shortage of research models that adequately represent the unique mucosal environment of human ectocervix, limiting development of new therapies for treating infertility, infection, or cancer. We developed three microphysiologic human ectocervix models to study hormone action during homeostasis. First, we reconstructed ectocervix using decellularized extracellular matrix scaffolds, which supported cell integration and could be clinically useful. Secondly, we generated organotypic systems consisting of ectocervical explants co-cultured with murine ovaries or cycling exogenous hormones, which mimicked human menstrual cycles. Finally, we engineered ectocervix tissue consisting of tissue-specific stromal-equivalents and fully-differentiated epithelium that mimicked in vivo physiology, including squamous maturation, hormone response, and mucin production, and remained viable for 28 days in vitro. The localization of differentiation-dependent mucins in native and engineered tissue was identified for the first time, which will allow increased efficiency in mucin targeting for drug delivery. In summary, we developed and characterized three microphysiologic human ectocervical tissue models that will be useful for a variety of research applications, including preventative and therapeutic treatments, drug and toxicology studies, and fundamental research on hormone action in a historically understudied tissue that is critical for women's health.

Class C GPCRs in the airway.

Understanding and targeting of GPCRs remain a critical aspect of airway pharmacology and therapeutics for diseases such as asthma or COPD. Most attention has been on the large Class A GPCRs towards improved bronchodilation and blunting of remodeling. Better known in the central or peripheral nervous system, there is increasing evidence that Class C GPCRs which include metabotropic glutamate and GABA receptors, the calcium sensing receptor, sweet/umami taste receptors and a number of orphan receptors, can contribute to airway structure and function. In this review, we will summarize current state of knowledge regarding the pharmacology of Class C GPCRs, their expression and potential functions in the airways, and the application of pharmacological agents targeting this group in the context of airway diseases.

YAP/TAZ are Activated by Mechanical and Hormonal Stimuli in Myometrium and Exhibit Increased Baseline Activation in Uterine Fibroids.

Uterine fibroids (UFs) are benign myometrial neoplasms. The mechanical environment activates signaling through the Hippo pathway effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding domain (TAZ) in other fibrotic disorders. Here, we assess the differences in YAP/TAZ responsiveness to signals in UF compared with myometrium (Myo). Matched samples of UF and Myo were collected. Atomic force microscopy (AFM) was used to determine in situ stiffness. Cells were plated sparsely on hydrogels or at confluence. Ten nanomolars of estradiol (E2) and 100 nM progesterone (P4) were used. Immunostaining for YAP/TAZ and extracellular matrix (ECM) proteins was performed. Cells were incubated with control or YAP1 (YAP)/WWTR1 (TAZ) small interfering RNA (siRNA). Real time qPCR was completed for connective tissue growth factor (CTGF). Cells were treated with verteporfin (a YAP inhibitor) or Y27632 (a ROCK inhibitor), and ECM gene expression was analyzed. Paired t test and Wilcoxon sign-rank test were used. AFM-measured tissue stiffness and YAP/TAZ nuclear localization in situ and in confluent cells were higher in UF compared with Myo (p < 0.05). Decreasing substrate stiffness reduced YAP/TAZ nuclear localization for both Myo and UF (p = 0.05). Stimulating cells with E2 or P4 increased YAP/TAZ nuclear localization, but only in Myo (p = 0.01). UFs had increased FN, COLI, and COLIII deposition. Following siRNA targeting, CTGF was found to be statistically decreased. Verteporfin treatment reduced cell survival and reduced FN deposition. Treatment with Y27632 demonstrated better cell tolerance and a reduction in ECM deposition. The mechanosensitive pathway may be linked to YAP/TAZ function and involved in transducing fibroid growth.

Calcium sensing receptor in developing human airway smooth muscle.

Airway smooth muscle (ASM) regulation of airway structure and contractility is critical in fetal/neonatal physiology in health and disease. Fetal lungs experience higher Ca2+ environment that may impact extracellular Ca2+ ([Ca2+ ]o ) sensing receptor (CaSR). Well-known in the parathyroid gland, CaSR is also expressed in late embryonic lung mesenchyme. Using cells from 18-22 week human fetal lungs, we tested the hypothesis that CaSR regulates intracellular Ca2+ ([Ca2+ ]i ) in fetal ASM (fASM). Compared with adult ASM, CaSR expression was higher in fASM, while fluorescence Ca2+ imaging showed that [Ca2+ ]i was more sensitive to altered [Ca2+ ]o . The fASM [Ca2+ ]i responses to histamine were also more sensitive to [Ca2+ ]o (0-2 mM) compared with an adult, enhanced by calcimimetic R568 but blunted by calcilytic NPS2143. [Ca2+ ]i was enhanced by endogenous CaSR agonist spermine (again higher sensitivity compared with adult). Inhibition of phospholipase C (U73122; siRNA) or inositol 1,4,5-triphosphate receptor (Xestospongin C) blunted [Ca2+ ]o sensitivity and R568 effects. NPS2143 potentiated U73122 effects. Store-operated Ca2+ entry was potentiated by R568. Traction force microscopy showed responsiveness of fASM cellular contractility to [Ca2+ ]o and NPS2143. Separately, fASM proliferation showed sensitivity to [Ca2+ ]o and NPS2143. These results demonstrate functional CaSR in developing ASM that modulates airway contractility and proliferation.

Hyperoxia-induced Cellular Senescence in Fetal Airway Smooth Muscle Cells.

Supplemental O2 (hyperoxia; 30-90% O2) is a necessary intervention for premature infants, but it contributes to development of neonatal and pediatric asthma, necessitating better understanding of contributory mechanisms in hyperoxia-induced changes to airway structure and function. In adults, environmental stressors promote formation of senescent cells that secrete factors (senescence-associated secretory phenotype), which can be inflammatory and have paracrine effects that enhance chronic lung diseases. Hyperoxia-induced changes in airway structure and function are mediated in part by effects on airway smooth muscle (ASM). In the present study, using human fetal ASM cells as a model of prematurity, we ascertained the effects of clinically relevant moderate hyperoxia (40% O2) on cellular senescence. Fetal ASM exposed to 40% O2 for 7 days exhibited elevated concentrations of senescence-associated markers, including ß-galactosidase; cell cycle checkpoint proteins p16, p21, and p-p53; and the DNA damage marker p-γH2A.X (phosphorylated γ-histone family member X). The combination of dasatinib and quercetin, compounds known to eliminate senescent cells (senolytics), reduced the number of hyperoxia-exposed ß-galactosidase-, p21-, p16-, and p-γH2A.X-positive ASM cells. The senescence-associated secretory phenotype profile of hyperoxia-exposed cells included both profibrotic and proinflammatory mediators. Naive ASM exposed to media from hyperoxia-exposed senescent cells exhibited increased collagen and fibronectin and higher contractility. Our data show that induction of cellular senescence by hyperoxia leads to secretion of inflammatory factors and has a functional effect on naive ASM. Cellular senescence in the airway may thus contribute to pediatric airway disease in the context of sequelae of preterm birth.