Pharmacological Modulation of the Wnt/ß-Catenin Pathway Inhibits Proliferation and Promotes Differentiation of Long-Lived Memory CD4+ T Cells in Antiretroviral Therapy-Suppressed Simian Immunodeficiency Virus-Infected Macaques.

The major obstacle to human immunodeficiency type 1 virus (HIV-1) eradication is a reservoir of latently infected cells that persists despite long-term antiretroviral therapy (ART) and is maintained through cellular proliferation. Long-lived memory CD4+ T cells with high self-renewal capacity, such as central memory (CM) T cells and stem cell memory (SCM) T cells, are major contributors to the viral reservoir in HIV-infected individuals on ART. The Wnt/ß-catenin signaling pathway regulates the balance between self-renewal and differentiation of SCM and CM T cells, and pharmacological manipulation of this pathway offers an opportunity to interfere with the proliferation of latently infected cells. Here, we evaluated in vivo a novel approach to inhibit self-renewal of SCM and CM CD4+ T cells in the rhesus macaque (RM) model of simian immunodeficiency (SIV) infection. We used an inhibitor of the Wnt/ß-catenin pathway, PRI-724, that blocks the interaction between the coactivator CREB-binding protein (CBP) and ß-catenin, resulting in the cell fate decision to differentiate rather than proliferate. Our study shows that PRI-724 treatment of ART-suppressed SIVmac251-infected RMs resulted in decreased proliferation of SCM and CM T cells and modified the SCM and CM CD4+ T cell transcriptome toward a profile of more differentiated memory T cells. However, short-term treatment with PRI-724 alone did not significantly reduce the size of the viral reservoir. This work demonstrates for the first time that stemness pathways of long-lived memory CD4+ T cells can be pharmacologically modulated in vivo, thus establishing a novel strategy to target HIV persistence.IMPORTANCE Long-lasting CD4+ T cell subsets, such as central memory and stem cell memory CD4+ T cells, represent critical reservoirs for human immunodeficiency virus (HIV) persistence despite suppressive antiretroviral therapy. These cells possess stem cell-like properties of enhanced self-renewal/proliferation, and proliferation of latently infected memory CD4+ T cells plays a key role in maintaining the reservoir over time. Here, we evaluated an innovative strategy targeting the proliferation of long-lived memory CD4+ T cells to reduce viral reservoir stability. Using the rhesus macaque model, we tested a pharmacological inhibitor of the Wnt/ß-catenin signaling pathway that regulates T cell proliferation. Our study shows that administration of the inhibitor PRI-724 decreased the proliferation of SCM and CM CD4+ T cells and promoted a transcriptome enriched in differentiation genes. Although the viral reservoir size was not significantly reduced by PRI-724 treatment alone, we demonstrate the potential to pharmacologically modulate the proliferation of memory CD4+ T cells as a strategy to limit HIV persistence.

Genome-wide association study of positive emotion identifies a genetic variant and a role for microRNAs.

Positive affect denotes a state of pleasurable engagement with the environment eliciting positive emotion such as contentment, enthusiasm or happiness. Positive affect is associated with favorable psychological, physical and economic outcomes in many longitudinal studies. With a heritability of ⩽64%, positive affect is substantially influenced by genetic factors; however, our understanding of genetic pathways underlying individual differences in positive affect is still limited. Here, through a genome-wide association study of positive affect in African-American participants, we identify a single-nucleotide polymorphism, rs322931, significantly associated with positive affect at P<5 × 10-8, and replicate this association in another cohort. Furthermore, we show that the minor allele of rs322931 predicts expression of microRNAs miR-181a and miR-181b in human brain and blood, greater nucleus accumbens reactivity to positive emotional stimuli and enhanced fear inhibition. Prior studies have suggested that miR-181a is part of the reward neurocircuitry. Taken together, we identify a novel genetic variant for further elucidation of genetic underpinning of positive affect that mediates positive emotionality potentially via the nucleus accumbens and miR-181.

CD57(+) CD4 T Cells Underlie Belatacept-Resistant Allograft Rejection.

Belatacept is a B7-specific fusion protein used to prevent allograft rejection by blocking T cell costimulation. Generally efficacious, it fails to prevent acute rejection in a sizable minority of patients. In experimental models, memory T cells mediate costimulation blockade-resistant rejection (CoBRR), but this remains undefined in humans. To explore relationships between individual patients' immune cell phenotypes and CoBRR, we studied patients receiving belatacept or conventional calcineurin inhibitor-based immunosuppression. We identified a population of CD57(+) PD1(-) CD4 T cells present prior to transplantation that correlated with CoBRR. Contrary to data recognizing CD57 as a marker of senescence on CD8 T cells, we discovered a nonsenescent, cytolytic phenotype associated with CD57 on CD4 T cells. Moreover, CD57(+) CD4 T cells expressed high levels of adhesion molecules implicated in experimental CoBRR, were CD28(-) , expressed a transcriptional phenotype broadly defining allograft rejection and were shown to be present in rejecting human kidney allografts. These data implicate CD57(+) CD4 T cells in clinical CoBRR. If prospectively validated, this characteristic could identify patients at higher risk for acute rejection on belatacept-based therapy.

Cataloguing of Potential HIV Susceptibility Factors during the Menstrual Cycle of Pig-Tailed Macaques by Using a Systems Biology Approach.

UNLABELLED: Our earlier studies with pig-tailed macaques demonstrated various simian-human immunodeficiency virus (SHIV) susceptibilities during the menstrual cycle, likely caused by cyclic variations in immune responses in the female genital tract. There is concern that high-dose, long-lasting, injectable progestin-based contraception could mimic the high-progesterone luteal phase and predispose women to human immunodeficiency type 1 (HIV-1) acquisition and transmission. In this study, we adopted a systems biology approach employing proteomics (tandem mass spectrometry), transcriptomics (RNA microarray hybridization), and other specific protein assays (enzyme-linked immunosorbent assays and multiplex chemokine and cytokine measurements) to characterize the effects of hormonal changes on the expression of innate factors and secreted proteins in the macaque vagina. Several antiviral factors and pathways (including acute-phase response signaling and complement system) were overexpressed in the follicular phase. Conversely, during the luteal phase there were factors overexpressed (including moesins, syndecans, and integrins, among others) that could play direct or indirect roles in enhancing HIV-1 infection. Thus, our study showed that specific pathways and proteins or genes might work in tandem to regulate innate immunity, thus fostering further investigation and future design of approaches to help counter HIV-1 acquisition in the female genital tract. IMPORTANCE: HIV infection in women is poorly understood. High levels of the hormone progesterone may make women more vulnerable to infection. This could be the case during the menstrual cycle, when using hormone-based birth control, or during pregnancy. The biological basis for increased HIV vulnerability is not known. We used an animal model with high risk for infection during periods of high progesterone. Genital secretions and tissues during the menstrual cycle were studied. Our goal was to identify biological factors upregulated at high progesterone levels, and we indeed show an upregulation of genes and proteins which enhance the ability of HIV to infect when progesterone is high. In contrast, during low-progesterone periods, we found more HIV inhibitory factors. This study contributes to our understanding of mechanisms that may regulate HIV infection in females under hormonal influences. Such knowledge is needed for the development of novel prevention strategies.

Seroprevalence of SARS-CoV-2 in 10 Regional Capitals of Cameroon, October-December 2020.

BACKGROUND: Cameroon was among the most affected African countries during the first wave of the COVID-19 pandemic; however, the true prevalence of SARS-CoV-2 remains unknown. METHODS: From October to December 2020, we conducted a cross-sectional, age-stratified SARS-CoV-2 seroepidemiological survey at 30 purposively selected community-based sites across Cameroon's 10 regional capitals, sampling 10,000 individuals aged 5 years or older. We employed a parallel SARS-CoV-2 antibody testing algorithm (WANTAI ELISA and Abbott Architect) to improve both the positive predictive value and negative predictive value of seroprevalence. RESULTS: The overall weighted and adjusted seroprevalence of SARS-CoV-2 antibodies across the 10 urban capitals of Cameroon was 10.5% (95% CI: 9.1%-12.0%) among participants aged ≥5 years. Of the 9332 participants, 730 males (13.1%, 95% CI: 11.5%-14.9%) had SARS-CoV-2 antibodies compared to 293 females (8.0%, 95% CI: 6.8%-9.3%). Among those who reported a comorbidity at the time of testing, 15.8% (95% CI: 12.8%-19.4%) were seropositive. We estimated that over 2 million SARS-CoV-2 infections occurred in the 10 regional capitals of Cameroon between October and December 2020, compared to 21,160 cases officially reported at that time translating to one laboratory-confirmed case being reported for every 110 SARS-CoV-2 infections across the 10 urban capitals. CONCLUSION: This study's findings point to extensive and under-reported circulation of SARS-CoV-2 in Cameroon-an almost 100-fold more cases compared to the number of cases reported to the World Health Organization. This finding highlights the importance of conducting serosurveys, especially in settings where access to testing may be limited and to repeat such surveys as part of pandemic tracking.

Reviewing challenges in access to oral health services among the LGBTQ+ community in Indiana and Michigan: A cross-sectional, exploratory study.

OBJECTIVE: In healthcare settings, lesbian, gay, bisexual, transgender, and queer (LGBTQ+) populations often experience discrimination, leading to decreased healthcare services utilization. In this study we have tried to identify oral healthcare providers (OHP)'s perceptions toward LGBTQ+ patients, perceived barriers for LGBTQ+ patients in accessing oral health services, and whether they were open to inclusive oral healthcare practices. In addition, the experiences of LGBTQ+ patients in oral healthcare settings including their oral healthcare seeking behaviors and beliefs were also explored. METHODS: Descriptive, quantitative surveys were administered to OHPs and LGBTQ+ patients within Indiana and Michigan. Surveys contained questions about participant demographics, including gender and sexual minority status, and the presence of inclusive healthcare practices within the oral healthcare settings. Descriptive analyses and regression modeling were used to explore the distribution of participant responses and to identify predictors associated with patient comfort and OHP's attitudes toward LGBTQ+ patients. RESULTS: Overall, 71% of LGBTQ+ patients reported regularly attending dental appointments; however, 43% reported feeling uncomfortable going to appointments and 34% reported being treated unfairly during appointments because of sexual orientation. Among OHPs, 84% reported that the healthcare settings where they practiced were welcoming for LGBTQ+ populations and 84% reported willingness to improve LGBTQ+ care. The presence of inclusive healthcare practices predicted comfort for LGBTQ+ patients (P < 0.10). Additionally, OHPs who either identified as an ally or as having a family member or close friend in the LGBTQ+ community had higher odds of feeling responsible to treat LGBTQ+ patients. CONCLUSION: Many LGBTQ+ patients often experience discomfort in oral healthcare settings. While OHPs were largely unaware of this, evidence suggests the need for cultural competency training for OHPs.

Breast Cancer Early Detection in Eswatini: Evaluation of a Training Curriculum and Patient Receipt of Recommended Follow-Up Care.

[Figure: see text].

The rectal mucosa and condomless receptive anal intercourse in HIV-negative MSM: implications for HIV transmission and prevention.

Most HIV transmissions among men who have sex with men (MSM), the group that accounted for 67% of new US infections in 2014, occur via exposure to the rectal mucosa. However, it is unclear how the act of condomless receptive anal intercourse (CRAI) may alter the mucosal immune environment in HIV-negative MSM. Here, we performed a comprehensive characterization of the rectal mucosal immune environment for the phenotype and production of pro-inflammatory cytokines by CD4 and CD8 T cells, global transcriptomic analyses, and the composition of microbiota in HIV-negative MSM. Our results show that compared with men who had never engaged in anal intercourse, the rectal mucosa of MSM engaging in CRAI has a distinct phenotype characterized by higher levels of Th17 cells, greater CD8+ T cell proliferation and production of pro-inflammatory cytokines, molecular signatures associated with mucosal injury and repair likely mediated by innate immune cells, and a microbiota enriched for the Prevotellaceae family. These data provide a high-resolution model of the immunological, molecular, and microbiological perturbations induced by CRAI, will have direct utility in understanding rectal HIV transmission among MSM, and will enhance the design of future biomedical prevention interventions, including candidate HIV vaccines.

Genes located in a chromosomal inversion are correlated with territorial song in white-throated sparrows.

The genome of the white-throated sparrow (Zonotrichia albicollis) contains an inversion polymorphism on chromosome 2 that is linked to predictable variation in a suite of phenotypic traits including plumage color, aggression and parental behavior. Differences in gene expression between the two color morphs, which represent the two common inversion genotypes (ZAL2/ZAL2 and ZAL2/ZAL2(m) ), may therefore advance our understanding of the molecular underpinnings of these phenotypes. To identify genes that are differentially expressed between the two morphs and correlated with behavior, we quantified gene expression and terrirorial aggression, including song, in a population of free-living white-throated sparrows. We analyzed gene expression in two brain regions, the medial amygdala (MeA) and hypothalamus. Both regions are part of a 'social behavior network', which is rich in steroid hormone receptors and previously linked with territorial behavior. Using weighted gene co-expression network analyses, we identified modules of genes that were correlated with both morph and singing behavior. The majority of these genes were located within the inversion, showing the profound effect of the inversion on the expression of genes captured by the rearrangement. These modules were enriched with genes related to retinoic acid signaling and basic cellular functioning. In the MeA, the most prominent pathways were those related to steroid hormone receptor activity. Within these pathways, the only gene encoding such a receptor was ESR1 (estrogen receptor 1), a gene previously shown to predict song rate in this species. The set of candidate genes we identified may mediate the effects of a chromosomal inversion on territorial behavior.

Mitogenic response of T-lymphocytes to exercise training and stress.

The impact of exercise training and stress on the immune response was examined by measuring the mitogenic response of spleen lymphocytes to the T-cell mitogen concanavalin A (Con-A). Male Sprague-Dawley rats were divided into four groups: sedentary controls (n = 11), handled controls (n = 12), treadmill runners (n = 10), and voluntary runners (n = 11) housed in running wheels. The treadmill group ran at 22 m/min (0.8 mph) for 45 min, 5 days/wk for 8 wk. After the training period, spleen lymphocytes isolated from each rat were incubated with Con-A for 54 h, pulsed with radiolabeled thymidine for 18 h, and counted for tritium activity. Counts per minute per group (means +/- SE) were as follows: sedentary, 6,839 +/- 1,461; handled, 8,959 +/- 1,576; voluntary runners, 13,126 +/- 2,069; and treadmill runners, 18,950 +/- 5,975. One-way analysis of variance and Tukey's highly significant difference test found the counts per minute of the treadmill runners to be significantly different from the counts per minute of the sedentary animals. These results indicate that the responsiveness of spleen lymphocytes to Con-A increases as the level of stress and exercise increases.

Strength and anaerobic responses of elite young female sprint and distance runners.

The purpose of this study was to assess the strength and anaerobic responses of elite young female runners, in order to determine the relationship of these characteristics to age and high proficiency in sprint events. Thirty-one national junior-level sprint and middle distance runners were evaluated for isokinetic peak torque for leg extension at velocities ranging for 30 degrees to 300 degrees X s-1, anaerobic power and capacity based on the Wingate test, and body composition based on underwater weighing. Age-related and event-related differences were noted for both the peak torque and anaerobic response measures. Peak torques were greater for the older (greater than 11.67 yr) runners and greater for the sprinters when measured at the higher testing velocities. Anaerobic power and capacity were also greater for the older runners, but event-related differences only appeared when anaerobic power was adjusted for fat-free weight (adjusted anaerobic power was greater in the older sprinters). These results indicate that both age and fat-free weight influence strength and anaerobic responses in young female runners and that exceptional levels of such characteristics only appear for sprinters within the upper age groups of youth competition.

Validity of anthropometric equations for the estimation of body density in adolescent athletes.

One hundred forty-one adolescent male (age: X +/- SD = 17.43 +/- 0.96 yr) and 133 adolescent female (16.51 +/- 1.39 yr) athletes were studied to determine the validity of available anthropometric equations for estimating body density (BD). Anthropometric measures were taken of eight skinfolds, nine circumferences, and four diameters. Body density, determined by underwater weighing (corrected for residual lung volume), was 1.080 +/- 0.010 g X ml-1 for the males and 1.066 +/- 0.010 g X ml-1 for the females. Cross-validation of 17 selected equations on the males revealed validity coefficients ranging from R2 = 0.29-0.67 and total-error scores ranging from 0.0062-0.0277 g X ml-1. Among the females, cross-validation of 15 selected equations revealed validity coefficients ranging from R2 = 0.31-0.67 and total-error scores ranging from 0.0064-0.0214 g X ml-1. While equations of either linear or quadratic form demonstrated acceptable accuracy in the estimation of male BD values, only quadratic equations displayed similar levels of accuracy among the females. Based on these results, as well as consideration of characteristics related to inter-tester error and the variance of predicted scores, the quadratic equations of Jackson and Pollock, Lohman, and Pollock et al., as well as the linear equation of Forsyth and Sinning, were found to be particularly appropriate for the estimation of BD in adolescent athletes.

Body composition and somatotype characteristics of junior Olympic athletes.

Body composition and somatotype were determined in Junior Olympic competitors to evaluate the structural characteristics concomitant to high proficiency in various athletic activities. Underwater weighings and anthropometric determinations of somatotype were performed on 145 male and 133 female adolescent participants in national meet competition in the sports of track and field, gymnastics, diving, and wrestling. The most frequent differences within either the male or female Junior Olympic samples involved the performers in throwing events (shot put, discus, and javelin), who were taller, heavier, fatter, and of unique somatotype when compared to all or most other competitors. Additional structural differences, generally of a lesser magnitude, also existed between other groups of Junior Olympians. Differences in body composition characteristics were also noted when Junior Olympians were compared with other adolescent athletes or non-athletes.

Basketball exercise and secretory immunoglobulin A.

This study examined saliva levels of immunoglobulin A (IgA) before and after three games and three practice sessions during the basketball season. Saliva was collected from 27 prepubescent boys (10-12 years) in a small Fry league and 23 postpubescent boys (16-18 years) on a high school varsity team. Saliva samples were frozen for later assay using a standard enzyme-linked immunosorbent assay technique. IgA levels were significantly increased after games 1 and 3 in both age groups and after practice 3 in the high school athletes. Over the 2 months of saliva collections the pre-exercise IgA increased significantly with games 2 and 3 higher than game 1, and practice 3 higher than practices 1 and 2, in both age groups. These results indicate that basketball exercise can increase saliva IgA levels and that chronic exercise over the basketball season may increase the resting levels of IgA. These changes may give athletes more protection against respiratory infections both after exercise and in the resting state later in the season.

Relationship between personality type and achievement in an undergraduate physiology course.

The Myers-Briggs type indicator (MBTI) was given to 163 students in an undergraduate Human Physiology course at a large state university. Selected MBTI personality types were compared for achievement in the course using a t test to compare total points earned. High grades were earned by students stronger in the traits of introversion (I) and judgment (J), whereas the extraverted (E) and perceptive (P) types had the lowest grades and dropped out of the course in the largest numbers. When combinations of MBTI types were compared, the highest grades were earned as follows: SJ greater than ST greater than IN greater than IJ greater than IS (S, sensing; T, thinking; N, intuitive). This ranking indicates that a sensing personality also has a strong relationship to achievement in this Human Physiology course when it is combined with judgment, thinking, or introversion. Instructors and students need to be aware of the relationship between personality and learning so they can modify their teaching style and learning behavior to enhance academic achievement.

The role of glucocorticoids in exercise.

From the literature we can make the following statements concerning the role of glucocorticoids in exercise and training. These conclusions are summarized graphically in Figure 3. 1. The principle physiological functions of glucocorticoids are stimulation of gluconeogenesis and mobilization of amino acids and fatty acids from body stores. 2. Injected glucocorticoids produce significant increases in the work produced by isolated muscle and by intact animals. 3. Light to moderate exercise work loads may produce an increase, decrease or no change in plasma glucocorticoid (GC) levels; depending on the degree of psychological and/or physiological stress involved in the exercise. 4. In moderate to exhaustive exercise the plasma GC levels progressively increase. In some subjects (especially animals) exhaustion produces a decrease in plasma GC which may represent a defense mechanism to prevent depletion of body resources. 5. Chronic exercise training produces adrenal cortex hypertrophy and usually a smaller rise in plasma GC during an acute exercise bout than that obtained with nontrained subjects. The resting GC levels frequently increase initially during training but return to normal as the trained state is reached. 6. The changes in GC response during training appear to be produced by decreased responsiveness of the adrenal cortex itself to ACTH stimulation and possibly by adaptation of the hypothalamus-hypophysis axis which reduces the ACTH released in response to stress. 7. The many combinations of psychological and physiological stress present in different exercise regimens probably account for the variety of GC responses to exercise reported in the literature.