A Zeb1/MtCK1 metabolic axis controls osteoclast activation and skeletal remodeling.

Osteoclasts are bone-resorbing polykaryons responsible for skeletal remodeling during health and disease. Coincident with their differentiation from myeloid precursors, osteoclasts undergo extensive transcriptional and metabolic reprogramming in order to acquire the cellular machinery necessary to demineralize bone and digest its interwoven extracellular matrix. While attempting to identify new regulatory molecules critical to bone resorption, we discovered that murine and human osteoclast differentiation is accompanied by the expression of Zeb1, a zinc-finger transcriptional repressor whose role in normal development is most frequently linked to the control of epithelial-mesenchymal programs. However, following targeting, we find that Zeb1 serves as an unexpected regulator of osteoclast energy metabolism. In vivo, Zeb1-null osteoclasts assume a hyperactivated state, markedly decreasing bone density due to excessive resorptive activity. Mechanistically, Zeb1 acts in a rheostat-like fashion to modulate murine and human osteoclast activity by transcriptionally repressing an ATP-buffering enzyme, mitochondrial creatine kinase 1 (MtCK1), thereby controlling the phosphocreatine energy shuttle and mitochondrial respiration. Together, these studies identify a novel Zeb1/MtCK1 axis that exerts metabolic control over bone resorption in vitro and in vivo.

Stromal Cell-SLIT3/Cardiomyocyte-ROBO1 Axis Regulates Pressure Overload-Induced Cardiac Hypertrophy.

BACKGROUND: Recently shown to regulate cardiac development, the secreted axon guidance molecule SLIT3 maintains its expression in the postnatal heart. Despite its known expression in the cardiovascular system after birth, SLIT3's relevance to cardiovascular function in the postnatal state remains unknown. As such, the objectives of this study were to determine the postnatal myocardial sources of SLIT3 and to evaluate its functional role in regulating the cardiac response to pressure overload stress. METHODS: We performed in vitro studies on cardiomyocytes and myocardial tissue samples from patients and performed in vivo investigation with SLIT3 and ROBO1 (roundabout homolog 1) mutant mice undergoing transverse aortic constriction to establish the role of SLIT3-ROBO1 in adverse cardiac remodeling. RESULTS: We first found that SLIT3 transcription was increased in myocardial tissue obtained from patients with congenital heart defects that caused ventricular pressure overload. Immunostaining of hearts from WT (wild-type) and reporter mice revealed that SLIT3 is secreted by cardiac stromal cells, namely fibroblasts and vascular mural cells, within the heart. Conditioned media from cardiac fibroblasts and vascular mural cells both stimulated cardiomyocyte hypertrophy in vitro, an effect that was partially inhibited by an anti-SLIT3 antibody. Also, the N-terminal, but not the C-terminal, fragment of SLIT3 and the forced overexpression of SLIT3 stimulated cardiomyocyte hypertrophy and the transcription of hypertrophy-related genes. We next determined that ROBO1 was the most highly expressed roundabout receptor in cardiomyocytes and that ROBO1 mediated SLIT3's hypertrophic effects in vitro. In vivo, Tcf21+ fibroblast and Tbx18+ vascular mural cell-specific knockout of SLIT3 in mice resulted in decreased left ventricular hypertrophy and cardiac fibrosis after transverse aortic constriction. Furthermore, α-MHC+ cardiomyocyte-specific deletion of ROBO1 also preserved left ventricular function and abrogated hypertrophy, but not fibrosis, after transverse aortic constriction. CONCLUSIONS: Collectively, these results indicate a novel role for the SLIT3-ROBO1-signaling axis in regulating postnatal cardiomyocyte hypertrophy induced by pressure overload.

Factors influencing neonatal male circumcision uptake among expecting couples in Zambia: formative findings.

Male circumcision is a protective HIV prevention strategy. However, uncircumcised Zambian men are reluctant to undergo voluntary medical male circumcision (VMMC). Tailored interventions are necessary to stimulate the uptake of early infant male circumcision (EIMC) and VMMC in Zambia. This feasibility study presents the formative process of utilising the PRECEDE framework in the development of a family-centred EIMC/VMMC intervention, Like Father Like Son, and its application in an existing VMMC intervention, Spear & Shield. We found that fear of the pain associated with EIMC procedures, foreskin disposal, beliefs in children's autonomy and rights, and men's dominance in health decision-making were factors affecting EIMC uptake. Perceived benefits for infants included improved hygiene, protection from HIV infection, and faster recovery. Reinforcing factors included female partners and fathers' MC status. The availability and access to EIMC services and information, skill and experience of health workers, and engagement and belief in traditional circumcision practices were factors enabling EIMC uptake. These individual, interpersonal, and structural factors positively and negatively influencing EIMC uptake in the Zambian clinic context were integrated into the intervention for expecting parents. Feedback from community advisory boards suggested the process was effective in developing a culturally tailored and acceptable EIMC/VMMC promotion intervention.

New dimensions in cell migration.

Studies of cell migration in three-dimensional (3D) cell culture systems and in vivo have revealed several differences when compared with cell migration in two dimensions, including their morphology and mechanical and signalling control. Here, researchers assess the contribution of 3D models to our understanding of cell migration, both in terms of the mechanisms used to drive single cell and collective cell migration and how migrating cells respond to a changing environment in vivo.

SNAI1 is upregulated during muscle regeneration and represses FGF21 and ATF3 expression by directly binding their promoters.

During skeletal myogenesis, the zinc-finger transcription factors SNAI1 and SNAI2, are expressed in proliferating myoblasts and regulate the transition to terminally differentiated myotubes while repressing pro-differentiation genes. Here, we demonstrate that SNAI1 is upregulated in vivo during the early phase of muscle regeneration induced by bupivacaine injury. Using shRNA-mediated gene silencing in C2C12 myoblasts and whole-transcriptome microarray analysis, we identified a collection of genes belonging to the endoplasmic reticulum (ER) stress pathway whose expression, induced by myogenic differentiation, was upregulated in absence of SNAI1. Among these, key ER stress genes, such as Atf3, Ddit3/Chop, Hspa5/Bip, and Fgf21, a myokine involved in muscle differentiation, were strongly upregulated. Furthermore, by promoter mutant analysis and Chromatin immune precipitation assay, we demonstrated that SNAI1 represses Fgf21 and Atf3 in proliferating myoblasts by directly binding to multiple E boxes in their respective promoter regions. Together, these data describe a new regulatory mechanism of myogenic differentiation involving the direct repressive action of SNAI1 on ER stress and Fgf21 expression, ultimately contributing to maintaining the proliferative and undifferentiated state of myoblasts.

Zambian Parents' Perspectives on Early-Infant Versus Early-Adolescent Male Circumcision.

Despite increasing interest in Early-Infant and Early-Adolescent Medical Circumcision (EIMC and EAMC, respectively) in Zambia, parental willingness to have their sons undergo the procedure has not been explored. This study describes Zambian parents' perspectives on EIMC and EAMC. A total of N = 600 men and women (n = 300 couples) were recruited. Most parents, 89% and 83%, planned to have their newborn or adolescent sons circumcised, respectively, and 70% and 57% had plans for EIMC and EAMC, respectively. Most (91% for infants and 86% for adolescents) reported they were considering the pros and cons of circumcision. Parents' age (OR 1.05), having children living in one's home (OR 3.58), and lower education (OR 0.63) were associated with sons' circumcision. The minimal risks associated with circumcision and the lifetime benefits conferred underscore its contribution to public health in high HIV prevalence areas.

RESUMEN: A pesar del creciente interés en la Circuncisión Médica Temprana de Niños y Adolescentes (EIMC y EAMC, respectivamente, por su siglas en ingles) en Zambia, no se ha explorado la voluntad de los padres, de dar consentimiento, para que sus hijos se sometan al procedimiento. Este studio, describe las perspectivas de los padres de Zambia sobre EIMC y EAMC. Se reclutaron un total de N = 600 hombres y mujeres (n = 300 parejas) que esperaban tener un hijo. La mayoría de los padres, 89% y 83%, planeaban circuncidar a sus hijos recién nacidos o adolescentes, respectivamente, y 70% y 57% tenían planes para EIMC y EAMC, respectivamente. La mayoría (91% para bebés y 86% para adolescentes) informaron que estaban considerando las ventajas y desventajas de la circuncisión. La edad de los padres (OR 1,05), tener hijos viviendo en el hogar (OR 3,58) y menor educación (OR 0,63) se asociaron con la circuncisión de los hijos. Los riesgos mínimos asociados con la circuncisión y los beneficios conferidos de por vida subrayan su contribución a la salud pública en áreas de alta prevalencia del VIH.

Navigating ECM barriers at the invasive front: the cancer cell-stroma interface.

A seminal event in cancer progression is the ability of the neoplastic cell to mobilize the necessary machinery to breach surrounding extracellular matrix barriers while orchestrating a host stromal response that ultimately supports tissue-invasive and metastatic processes. With over 500 proteolytic enzymes identified in the human genome, interconnecting webs of protease-dependent and protease-independent processes have been postulated to drive the cancer cell invasion program via schemes of daunting complexity. Increasingly, however, a body of evidence has begun to emerge that supports a unifying model wherein a small group of membrane-tethered enzymes, termed the membrane-type matrix metalloproteinases (MT-MMPs), plays a dominant role in regulating cancer cell, as well as stromal cell, traffic through the extracellular matrix barriers assembled by host tissues in vivo. Understanding the mechanisms that underlie the regulation and function of these metalloenzymes as host cell populations traverse the dynamic extracellular matrix assembled during neoplastic states should provide new and testable theories regarding cancer invasion and metastasis.

Blood Pressure, Depression, and Suicidal Ideation Among Pregnant Women with HIV.

Although prior research has examined associations between blood pressure (BP), depression, and suicidal ideation, few studies have examined this in high-risk populations such as pregnant women with HIV (WHIV). The current study examined the association of BP with depression and suicidal ideation among pregnant WHIV (n = 217) in rural South Africa. BP data (measured ≤ 1 month before the study visit) was extracted from medical records. Depressive symptomatology and suicidal ideation were assessed using the Edinburgh Postnatal Depression Scale. Diastolic BP was positively associated with both suicidal ideation and depressive symptomatology, even after controlling for demographic variables, gestational age, and intimate partner violence. These findings suggest that WHIV with elevated BP may be at greater risk for antenatal depression and suicidal ideation. Future research should utilize longitudinal designs to examine potential mechanisms and the directionality of the relationship, as well as other contributing factors.

RESUMEN: Aunque investigaciones anteriores han examinado las asociaciones entre la presión arterial (PA), depresión e ideación suicida, pocos estudios han examinado esto en poblaciones de alto riesgo, como las mujeres embarazadas con VIH. El estudio actual examinó la asociación de la PA con la depresión y la ideación suicida entre mujeres embarazadas con VIH (n = 217) en zonas rurales de Sudáfrica. Los datos de PA (medidos ≤ 1 mes antes de la visita del estudio) se extrajeron de los registros médicos. La sintomatología depresiva y la ideación suicida se evaluaron mediante la Escala de depresión posnatal de Edimburgo. La PA diastólica se asoció positivamente tanto con la ideación suicida como con la sintomatología depresiva, incluso después de controlar variables demográficas, edad gestacional y violencia de la pareja íntima. Estos hallazgos sugieren que mujeres embarazadas con VIH con PA elevada puede tener un mayor riesgo de depresión prenatal e ideación suicida. Las investigaciones futuras deberían aprovechar diseños longitudinales para examinar los posibles mecanismos y la direccionalidad de la relación, así como otros factores contribuyentes.

Psychological and physical intimate partner violence and sexual risk behavior among South African couples: a dyadic analysis.

This study aimed to examine intimate partner violence (IPV) as it relates to both partners' perceptions of IPV and sexual behaviors, considering how their IPV might be interdependent within the relationship dynamics. The sample consisted of 713 female-male dyads in which women were pregnant and living with HIV in rural South Africa. Using an actor-partner interdependence model (APIM), we examined the interdependent influence of psychological and physical IPV on men by their female partners and psychological and physical IPV on women by their male partners on sexual risk behavior. The APIM model found there were no actor (b = -0.06, SE = 0.05, p = .221) or partner (b = -1.2, SE = 0.06, p = .056) effects contributing to protected sex by female IPV victimization. In contrast, significant actor (b = -0.28, SE = 0.06, p < .001) and partner (b = -0.29, SE = 0.06, p < .001) effects for protection were related to male IPV victimization. The model also found that the covariate of female HIV disclosure was associated with both male (b = 0.5, SE = 0.12, p < .001) and female protected sexual intercourse (b = 0.58, SE = 0.1, p < .001). Female HIV disclosure was related to an increased likelihood of protected sex by both male and female partners. As male partners reported more IPV victimization, the likelihood of protected sex between male and female partners decreased.Trial registration: ClinicalTrials.gov identifier: NCT02085356.

Examining Factors Associated with Gender Identity Among Individuals Disengaged from HIV Care in Argentina.

BACKGROUND: Transgender women (TGW) consistently show lower adherence to antiretroviral treatment (ART), than cisgender people (CP) living with HIV. This study examined sociodemographic and psychosocial factors associated with gender identity among individuals disengaged from HIV care in Argentina. METHODS: Data for this study was obtained at baseline from the Conexiones y Opciones Positivas en la Argentina 2 (COPA2) study. Forty-one TGW and 360 CP (177 male, 183 female) disengaged from HIV care completed questionnaires assessing sociodemographic information, severity of depressive symptoms, substance and alcohol use, patient-provider relationship quality, self-efficacy, ART adherence motivation, self-reported adherence, and treatment-related factors. Analyses included chi-square tests exploring the association between categorical variables and gender identity, and ANCOVAs comparing groups controlling for age. RESULTS: Being a TGW was associated with having only public health insurance; substance use, particularly cocaine; substance-related problems; and hazardous drinking. TGW showed more negative consequences related to substance use, more hazardous alcohol use, lower patient-provider relationship quality, and lower self-reported adherence, than CP. CONCLUSIONS: Harm reduction should be a key component in HIV care for TGW to address substance use. Health care teams should receive formal training in patient-provider communication skills and trans-specific competencies to enhance TGW's adherence and retention. Public policies to address structural factors that negatively affect TGW's adherence to ART are also needed.

Heart Health and Behavior Change in HIV-Infected Individuals.

Management of cardiovascular disease risk requires many lifestyle changes involving diet, smoking, and exercise. Individuals with arterial plaque are encouraged to adopt these changes to promote longevity through a variety of interventions. This study examined behavioral changes in response to the standard of care after detection of arterial plaque, specifically among HIV-infected cocaine users. 127 individuals (HIV - COC - n = 43, HIV + COC - n = 19, HIV + COC + n = 35, HIV - COC + n = 30) were followed after a standard of care intervention and assessed 1 and 2 years later on a variety of lifestyle (diet, exercise, smoking) and physiological (blood pressure, body mass index, number of arterial plaques) outcomes. Arterial plaque was found to increase over time (b = 0.003, SE = 0.002, p = .031), and a composite measure of cardiovascular disease risk did not change (b = - 0.004, SE = 0.01, p = .548). Following provision of a standard of care cardiovascular risk reduction intervention, important health behaviors related to CVD risk were resistant to change among both those HIV-infected and uninfected and among cocaine users and non-users.

RESUMEN: El manejo del riesgo para enfermedades cardiovasculares requiere muchos cambios en el estilo de vida, como dieta, dejar de fumar, y ejercicio. Se les recomienda a las personas, con placa arterial, adoptar estos cambios a través de una variedad de intervenciones. Este estudio examinó los cambios de comportamiento, en respuesta al estándar de atención, después de la detección de la placa arterial, específicamente entre los usuarios de cocaína infectados con VIH. 127 individuos (HIV − COC − n = 43, HIV + COC − n = 19, HIV + COC + n = 35, HIV − COC + n = 30) fueron seguidos después de una intervención de atención estándar y sus resultados fisiológicos (presión arterial, índice de masa corporal, número de placas arteriales) fueron evaluados 1 y 2 años después. Encontramos que la placa arterial aumento con el tiempo (b = 0.003, SE = 0.002, p = .031), y una formula que calcula el de riesgo de enfermedad cardiovascular no cambió (b = − 0.004, SE = 0.01, p = .548). Tras la provisión de una intervención estándar de atención para la reducción del riesgo cardiovascular, los comportamientos de salud importantes relacionados con el riesgo de enfermedades cardiovasculares fueron resistentes al cambio tanto entre los infectados y no infectados por el VIH como entre los usuarios y no usuarios de cocaína.

Influence of Male Partners on HIV Disclosure Among South African Women in a Cluster Randomized PMTCT Intervention.

Disclosure of HIV serostatus is beneficial for women, their partners, and their infants as it enables women to actively participate in preventative care (Hodgson et al. in PLoS ONE 9(11):e111421, 2014; Odiachi et al. in Reprod Health 15(1):36, 2018). Therefore, it is important that interventions addressing HIV prevention include elements that foster disclosure of HIV to partners. This study conducted in South Africa utilizes the "Protect Your Family" (PYF) behavioral intervention and compares Prevention of Mother to Child Transmission (PMTCT) among women participating in the program versus those in a control program. Within both groups, male partners were either present or not present for the intervention. The purpose of this study was to examine differential disclosure over time for individuals in the different conditions and partner involvement. A firth logistic regression revealed an interaction in the experimental condition with male partners participating (b = - 2.84, SE = 1.56, p = .012), in which female participants were less likely to disclose their HIV status over time. Findings from this study illustrate that additional efforts are needed to empower women to disclose their HIV status.

RESUMEN: Revelar su estado serológico del VIH a sus parejas es beneficioso para las mujeres, sus parejas y sus bebés, ya que les permite a las mujeres participar activamente en atención preventiva (Hodgson et al. in PLoS ONE 9(11):e111421, 2014; Odiachi et al. in Reprod Health 15(1):36, 2018). Por lo tanto, es importante que las intervenciones que aborden la prevención del VIH incluyan elementos que fomenten la revelación del estado serológico del VIH de las mujeres a sus parejas. Este estudio realizado en Sudáfrica utiliza la intervención conductual "Protege a tu familia" (PYF por sus siglas en Ingles) y compara la prevención de la transmisión de madre a hijo (PMTCT por sus siglas en Ingles) entre mujeres que participaron en el programa y las que participaron en un programa de control. Dentro de ambos grupos, los compañeros masculinos estuvieron presentes o no presentes para la intervención. El propósito de este estudio fue examinar la revelación diferente a lo largo del tiempo para individuos en diferentes condiciones y participación de pareja. Una regresión logística reveló de Firth una interacción en la condición experimental con la participación de parejas masculinas (b = − 2.84, SE = 1.56, p = .012), en las cuales las participantes femeninas tenían menos probabilidades de revelar su estado de VIH a lo largo del tiempo. Los resultados de este estudio ilustran que se necesitan esfuerzos adicionales para motivar a las mujeres a revelar su estado de VIH.

Motivational Interviewing Training for HIV Care Physicians in Argentina: Uptake and Sustainability of an Effective Behavior Change Intervention.

Motivational interviewing (MI) utilizes a patient-centered approach to address patient ambivalence about treatment and has been found to improve treatment ART adherence among patients living with HIV disengaged from care. This study examined MI training for clinicians, uptake, and sustainability over time. Clinics (n = 7) with N = 38 physicians were randomized to condition (MI, Enhanced Standard of Care). Physicians completed video- recorded patient consultations at baseline and 6, 12, and 18-month follow-up. MI condition physicians had greater relational and technical scores over time and were more likely to adhere to and sustain MI over time. Overall, physicians found the MI training highly acceptable and were able to sustain their skills. Results illustrate the feasibility of MI training, implementation, and sustainment over 18 months. Findings support previous research in Argentina in which trained physicians found MI useful with challenging patients. Broader implementation of MI among HIV care physicians in Argentina is merited.

RESUMEN: La entrevista motivacional (EM) es una intervención con enfoque en el paciente que sirve para abordar la ambivalencia del paciente sobre el tratamiento. Se ha descubierto que EM mejora la adherencia al tratamiento antirretroviral en pacientes con VIH y que no están recibiendo tratamiento. En este estudio se examinó la capacitación de EM entre médicos, como también la aceptación y la sostenibilidad de EM a lo largo del tiempo. Las clínicas (n = 7) con N = 38 médicos se asignaron al azar a la condición (EM o estándar de atención mejorada). Los médicos hicieron consultas de pacientes, las cuales fueron grabadas en video al inicio del estudio y a los 6, 12 y 18 meses de seguimiento. Los médicos de la condición de EM obtuvieron puntuaciones relacionales y técnicas más altas a lo largo del tiempo y fueron más propensos ha adherirse y usar la EM con el tiempo. En general, los médicos consideraron que la formación en EM era muy aceptable y pudieron mantener sus habilidades. Los resultados ilustran la viabilidad de la capacitación, implementación y mantenimiento de la EM durante 18 meses. Los descubrimientos sustentan investigaciones anteriores en Argentina en las que médicos capacitados encontraron que la EM era útil para pacientes desafiantes. Una implementación más amplia de la EM entre los médicos de atención del VIH en Argentina es necesaria para mejorar el tratamiento de personas con VIH.

The contribution of syndemic conditions to cardiovascular disease risk.

The syndemic conditions of low education, childhood maltreatment, depression, HIV, alcohol and cocaine use, and obesity have been established as independent risk factors for cardiovascular risk, but research examining the association between syndemic conditions and cardiovascular risk in high-risk populations is lacking. A total of N = 503 participants underwent an ultrasound of the carotid artery to assess for atherosclerotic plaque. Participants, HIV-infected (n = 202) and HIV-uninfected (n = 301) with and without a history of cocaine use, were a mean age of 36.13 years (SD = 9.51); 50% were male, and 62% were African-American. Each syndemic condition was associated with 8% greater odds of atherosclerotic plaque (OR = 1.08), 9% greater odds of systolic blood pressure (OR = 1.09), and 10% greater odds of diastolic blood pressure (OR = 1.10). Multilevel research, interventions, and public policy initiatives are needed to activate stakeholders at each level to maximize their impact at a community level among populations with high rates of syndemic conditions.

Cumulative Burden of Mental Health Factors and Engagement in HIV Care in Argentina.

BACKGROUND: Cumulative burden of multiple mental health conditions may worsen physical health outcomes in vulnerable populations. Accordingly, identifying cumulative burdens of mental health conditions that may affect HIV treatment and care can guide public health strategies to reduce their impact on HIV-related health outcomes. This study examined the relationship between the cumulative burden of mental health conditions and factors associated with engagement in HIV care in Argentina. METHOD: Data for this study was obtained at baseline from Conexiones y Opciones Positivas en la Argentina 2 (COPA2). Participants (N = 360) were cisgender patients living with HIV who were lost to care, recruited from seven clinics serving people living with HIV in four Argentine urban centers. Cumulative burden of mental health conditions (i.e., depressive symptoms, problematic substance use, unhealthy alcohol use, and psychotic symptoms) was assessed. RESULTS: Every one-point increase in the number of mental health conditions present was associated with a decrement in patient-provider communication (b = - 0.22, p < .001), self-efficacy (b = - 0.13, p = .012), and motivation for adherence (b = - 0.11, p = .039). CONCLUSION: This study found cumulative burden of depression, problematic substance use, unhealthy alcohol use, and psychotic symptoms to be negatively associated with factors related to engagement in HIV care. Results highlight the importance of identification and treatment of challenges to mental health, in order to ameliorate their influence on engagement in HIV care.

HIV and carotid atherosclerosis: a mediational model.

Cardiovascular disease (CVD) is the leading cause of death in the US and is a significant contributor to morbidity and mortality for people living with HIV (PLWH). This study examined the association between HIV infection, cocaine usage, and inflammatory markers, and their combined association with carotid atherosclerosis among young and middle-aged adults with HIV. Participants (N = 494) were enrolled based on HIV status and cocaine use. Blood pressure, body mass index (BMI), and cocaine use were assessed. Cytokines and growth factors, IL-1a, IL-6, TNFα and VEGF, and immune activation markers, sCD14 and sCD163 were measured. Participant age was 36.2 years (SD = 9.5); 50% were male, 49% female and 1% transgender; 39% were HIV-positive, 50% were current or past smokers, and 39% endorsed cocaine use. A path analysis showed an indirect effect of HIV serostatus on the presence of carotid atherosclerotic plaques (Indirect Effect = 0.048, SE = 0.024, p = .043), when controlling age, BMI, smoking, and cocaine use. This effect was mediated by inflammatory markers and changes in blood pressure. Findings point to putative underlying mechanisms leading to atherosclerosis among PLWH.

Development, implementation and dissemination: Couples and Parent-Child Communication Workshops in Zambia.

Over a million people are living with HIV in Zambia, representing ∼13% of the country's population. To increase HIV prevention communication, a community-based communication training program, the Parent-Child and Couples Communication Workshop, was developed from pilot data and culturally tailored for dissemination in Zambia. Workshop trainees (N = 195) were 18 years of age or more and community educators and counselors in the Copperbelt and Southern Provinces of Zambia, e.g., peer educators, lay counselors, teachers, nurses, mentors and program officers, workshops (N = 16) were conducted. Satisfaction with the workshops, readiness to conduct a workshop and implementation were assessed. Overall, readiness to conduct workshops following training and satisfaction with the workshop was similarly high across Provinces. Following the initial training, more than half of workshop trainees conducted workshops in their own communities. Zambian community members were receptive to learning techniques to disseminate communication strategies that could prevent HIV transmission. The use of culturally appropriate strategies and a training of trainers approach for communication and prevention may have enhanced workshop dissemination in Zambian communities. Future research should explore the use of culturally congruent HIV prevention initiatives in the Zambian context.

The effect of male involvement and a prevention of mother-to-child transmission (PMTCT) intervention on depressive symptoms in perinatal HIV-infected rural South African women.

This study investigated perinatal depressive symptoms among HIV-infected women enrolled in a cluster-randomized, controlled trial in South Africa. Women (n = 1370) attending 12 community health centers were consecutively enrolled in a two-phase (phase 1 = without a male partner, phase 2 = with a male partner) and two-condition (experimental or control) prevention of mother-to-child transmission (PMTCT) intervention. Women were enrolled at 8-24 weeks pregnant and followed postpartum at 6 weeks and 6 and 12 months (retention rate = 69.8%). Antenatally, 45.4% of women were above the 12-point Edinburgh Postnatal Depression Scale (EPDS) cutoff, 30.2% were above the cutoff at 6 weeks, and 34.2% and 36.9% at 6 months and 12 months postpartum, respectively. In multilevel regression analyses, depressive symptoms decreased over time among women in phase 2 participating in the intervention condition, but neither condition nor phase alone was associated with a decrease in depression. Greater HIV stigma, increased psychological intimate partner violence, less male involvement, lower education, and non-adherence during pregnancy were associated with increased depressive symptoms over the perinatal period. Results indicated that women participating had high levels of depressive symptoms (> 40% prenatally and > 30% postnatally), and the combination of the multi-session PMTCT intervention plus male partner participation contributed to a reduction in depressive symptoms. Results suggest that interventions targeting the reduction of depressive symptoms in perinatal HIV-positive women by increasing male involvement and decreasing HIV stigma and intimate partner violence are needed to reduce depression in this vulnerable population.

MT1-MMP regulates the PI3Kδ·Mi-2/NuRD-dependent control of macrophage immune function.

Macrophages play critical roles in events ranging from host defense to obesity and cancer, where they infiltrate affected tissues and orchestrate immune responses in tandem with the remodeling of the extracellular matrix (ECM). Despite the dual roles played by macrophages in inflammation, the functions of macrophage-derived proteinases are typically relegated to tissue-invasive or -degradative events. Here we report that the membrane-tethered matrix metalloenzyme MT1-MMP not only serves as an ECM-directed proteinase, but unexpectedly controls inflammatory gene responses wherein MT1-MMP(-/-) macrophages mount exaggerated chemokine and cytokine responses to immune stimuli both in vitro and in vivo. MT1-MMP modulates inflammatory responses in a protease-independent fashion in tandem with its trafficking to the nuclear compartment, where it triggers the expression and activation of a phosphoinositide 3-kinase δ (PI3Kδ)/Akt/GSK3ß signaling cascade. In turn, MT1-MMP-dependent PI3Kδ activation regulates the immunoregulatory Mi-2/NuRD nucleosome remodeling complex that is responsible for controlling macrophage immune response. These findings identify a novel role for nuclear MT1-MMP as a previously unsuspected transactivator of signaling networks central to macrophage immune responses.

Tracking the Cartoon mouse phenotype: Hemopexin domain-dependent regulation of MT1-MMP pericellular collagenolytic activity.

Following ENU mutagenesis, a phenodeviant line was generated, termed the "Cartoon mouse," that exhibits profound defects in growth and development. Cartoon mice harbor a single S466P point mutation in the MT1-MMP hemopexin domain, a 200-amino acid segment that is thought to play a critical role in regulating MT1-MMP collagenolytic activity. Herein, we demonstrate that the MT1-MMPS466P mutation replicates the phenotypic status of Mt1-mmp-null animals as well as the functional characteristics of MT1-MMP-/- cells. However, rather than a loss-of-function mutation acquired as a consequence of defects in MT1-MMP proteolytic activity, the S466P substitution generates a misfolded, temperature-sensitive mutant that is abnormally retained in the endoplasmic reticulum (ER). By contrast, the WT hemopexin domain does not play a required role in regulating MT1-MMP trafficking, as a hemopexin domain-deletion mutant is successfully mobilized to the cell surface and displays nearly normal collagenolytic activity. Alternatively, when MT1-MMPS466P-expressing cells are cultured at a permissive temperature of 25 °C that depresses misfolding, the mutant successfully traffics from the ER to the trans-Golgi network (ER → trans-Golgi network), where it undergoes processing to its mature form, mobilizes to the cell surface, and expresses type I collagenolytic activity. Together, these analyses define the Cartoon mouse as an unexpected gain-of-abnormal function mutation, wherein the temperature-sensitive mutant phenocopies MT1-MMP-/- mice as a consequence of eliciting a specific ER → trans-Golgi network trafficking defect.