ABSTRACT
MicroRNAs (miRNAs) regulate the expression of many mammalian genes and play key roles in embryonic hair follicle development; however, little is known of their functions in postnatal hair growth. We compared the effects of deleting the essential miRNA biogenesis enzymes Drosha and Dicer in mouse skin epithelial cells at successive postnatal time points. Deletion of either Drosha or Dicer during an established growth phase (anagen) caused failure of hair follicles to enter a normal catagen regression phase, eventual follicular degradation and stem cell loss. Deletion of Drosha or Dicer in resting phase follicles did not affect follicular structure or epithelial stem cell maintenance, and stimulation of anagen by hair plucking caused follicular proliferation and formation of a primitive transient amplifying matrix population. However, mutant matrix cells exhibited apoptosis and DNA damage and hair follicles rapidly degraded. Hair follicle defects at early time points post-deletion occurred in the absence of inflammation, but a dermal inflammatory response and hyperproliferation of interfollicular epidermis accompanied subsequent hair follicle degradation. These data reveal multiple functions for Drosha and Dicer in suppressing DNA damage in rapidly proliferating follicular matrix cells, facilitating catagen and maintaining follicular structures and their associated stem cells. Although Drosha and Dicer each possess independent non-miRNA-related functions, the similarity in phenotypes of the inducible epidermal Drosha and Dicer mutants indicates that these defects result primarily from failure of miRNA processing. Consistent with this, Dicer deletion resulted in the upregulation of multiple direct targets of the highly expressed epithelial miRNA miR-205.
Subject(s)
DEAD-box RNA Helicases/genetics , Gene Deletion , MicroRNAs/metabolism , Ribonuclease III/genetics , Skin/growth & development , Animals , Crosses, Genetic , DEAD-box RNA Helicases/physiology , Epidermal Cells , Hair Follicle/metabolism , Mice , Microscopy, Fluorescence/methods , Phenotype , Ribonuclease III/physiology , Signal Transduction , Skin/metabolism , Stem Cells/cytology , Wound HealingABSTRACT
Interactions between niche cells and stem cells are vital for proper control over stem cell self-renewal and differentiation. However, there are few tissues where the initial establishment of a niche has been studied. The Drosophila testis houses two stem cell populations, which each lie adjacent to somatic niche cells. Although these niche cells sustain spermatogenesis throughout life, it is not understood how their fate is established. Here, we show that Notch signaling is necessary to specify niche cell fate in the developing gonad. Surprisingly, our results indicate that adjacent endoderm is the source of the Notch-activating ligand Delta. We also find that niche cell specification occurs earlier than anticipated, well before the expression of extant markers for niche cell fate. This work further suggests that endoderm plays a dual role in germline development. The endoderm assists both in delivering germ cells to the somatic gonadal mesoderm, and in specifying the niche where these cells will subsequently develop as stem cells. Because in mammals primordial germ cells also track through endoderm on their way to the genital ridge, our work raises the possibility that conserved mechanisms are employed to regulate germline niche formation.
Subject(s)
Drosophila Proteins/metabolism , Endoderm/metabolism , Germ Cells/metabolism , Membrane Proteins/metabolism , Mesoderm/metabolism , Receptors, Notch/metabolism , Stem Cell Niche/metabolism , Testis/embryology , Animals , Animals, Genetically Modified , Drosophila/cytology , Drosophila/embryology , Drosophila/metabolism , Endoderm/cytology , Germ Cells/cytology , Immunohistochemistry , In Situ Hybridization , Intracellular Signaling Peptides and Proteins , Male , Mesoderm/cytology , Signal Transduction/physiology , Spermatogenesis/physiology , Stem Cells/cytology , Stem Cells/metabolism , Testis/cytology , Testis/metabolismABSTRACT
To function properly, tissue-specific stem cells must reside in a niche. The Drosophila testis niche is one of few niches studied in vivo. Here, a single niche, comprising ten hub cells, maintains both germline stem cells (GSC) and somatic stem cells (CySC). Here, we show that lines is an essential CySC factor. Surprisingly, lines-depleted CySCs adopted several characteristics of hub cells, including the recruitment of new CySCs. This led us to examine the developmental relationship between CySCs and hub cells. In contrast to a previous report, we did not observe significant conversion of steady-state CySC progeny to hub fate. However, we found that these two cell types derive from a common precursor pool during gonadogenesis. Furthermore, lines mutant embryos exhibited gonads containing excess hub cells, indicating that lines represses hub cell fate during gonadogenesis. In many tissues, lines acts antagonistically to bowl, and we found that this is true for hub specification, establishing bowl as a positively acting factor in the development of the testis niche.
Subject(s)
Carrier Proteins/physiology , DNA-Binding Proteins/physiology , Drosophila Proteins/physiology , Drosophila/embryology , Stem Cell Niche , Testis/cytology , Testis/embryology , Transcription Factors/physiology , Animals , Animals, Genetically Modified , Body Patterning/genetics , Carrier Proteins/genetics , Cell Dedifferentiation/genetics , Cell Dedifferentiation/physiology , Cell Differentiation/genetics , Cell Differentiation/physiology , Cell Proliferation , DNA-Binding Proteins/genetics , Drosophila/genetics , Drosophila/metabolism , Drosophila Proteins/genetics , Embryo, Nonmammalian , Germ Cells/cytology , Germ Cells/metabolism , Male , Testis/metabolism , Transcription Factors/geneticsABSTRACT
INTRODUCTION: The COVID-19 pandemic has disrupted access to critical health services, resulting in diminished gains in HIV epidemic control. This review assesses the magnitude of the impact that the COVID-19 pandemic has had on HIV services for adolescents. METHODS: PEPFAR Monitoring, Evaluation, and Reporting programmatic data were analyzed from across 16 USAID-supported adolescent care and treatment programs for fiscal year 2020 (FY20; October 2019-September 2020). Descriptive statistics were used to calculate absolute number and percent change between the pre-COVID-19 (Quarters 1-2; October 2019-March 2020) and COVID-19 periods (Quarters 3-4; April 2020-September 2020) for clinical cascade indicators. All analyses were conducted in Microsoft Excel. RESULTS: The number of HIV tests conducted during COVID-19 decreased by 21.4% compared with pre-COVID-19, with a subsequent 28% decrease in adolescents identified living with HIV. The rate of proxy linkage to antiretroviral therapy increased between periods, from 86.9% to 90.4%. There was a 25.9% decrease in treatment initiations among adolescents during COVID-19. During FY20, viral load coverage rates for adolescents dropped from 81.6% in FY20Q1 to 76.5% in FY20Q4, whereas the rates of viral load suppression for adolescents increased from 76.1% in FY20Q1 to 80.5% in FY20Q4. CONCLUSION: There was a substantial decrease in case-finding, treatment initiations, and viral load coverage rates for adolescents supported in USAID/PEPFAR programs during the COVID-19 pandemic. Additional health systems adaptations and strategies are required to ensure adolescents have continued access to HIV services during pandemic disruptions.
Subject(s)
COVID-19 , HIV Infections , United States/epidemiology , Humans , Adolescent , HIV Infections/drug therapy , HIV Infections/epidemiology , COVID-19/epidemiology , Pandemics , United States Agency for International Development , Health ServicesABSTRACT
INTRODUCTION: In 2020, an estimated 150,000 infants acquired HIV infection through vertical transmission. With pregnant and breastfeeding women facing numerous social and health system barriers, continuity of care for mother-infant pairs (MIPs) requires prioritized engagement for timely infant HIV testing and linkage to treatment. METHODS: PEPFAR Monitoring, Evaluation, and Reporting indicators were analyzed from across 14 USAID-supported countries across 3 fiscal years (FYs) (October 2018-September 2021): number of HIV-exposed infants (HEIs) with a sample collected for an HIV test by age 2 months, percentage of HEI who received an HIV test by age 2 months (EID 2 mo coverage), and final outcome status of HEIs. Qualitative information on implementation of PVT interventions was gathered using a structured survey disseminated to USAID/PEPFAR country teams. RESULTS: From October 2018 to September 2021, 716,383 samples were collected for infant HIV tests. EID 2 mo coverage increased across the FYs from 77.3% in FY19% to 83.5% in FY21. Eswatini, Lesotho, and South Africa demonstrated the highest EID 2 mo coverage across all 3 FYs. Burundi (93.6%), DRC (92%), and Nigeria (90%) had the highest percentage of infants with a known final HIV outcome. Qualitative survey data showed that the most implemented interventions used by the countries were mentor mothers, appointment reminders, cohort registers, and joint provision of MIP services. CONCLUSIONS: Achieving eVT requires a client-centered and multipronged approach, typically combining several PVT interventions. Country and program implementers should use person-centered solutions to best target MIPs to be retained in the continuum of care.
Subject(s)
HIV Infections , Pregnancy Complications, Infectious , Infant , Pregnancy , Humans , Female , HIV Infections/diagnosis , HIV Infections/prevention & control , Mothers , Breast Feeding , Nigeria , Infectious Disease Transmission, Vertical/prevention & control , Early Diagnosis , Pregnancy Complications, Infectious/prevention & controlABSTRACT
BACKGROUND: Adolescents have poorer outcomes across the HIV cascade compared with adults. We aimed to assess progress in HIV case finding, antiretroviral treatment (ART), viral load coverage (VLC), and viral load suppression (VLS) among adolescents enrolled in the US President's Emergency Plan for AIDS Relief (PEPFAR)-supported programs over a 3-year period that included the beginning of the COVID-19 pandemic. METHODS: We analyzed PEPFAR program data in 28 countries/regions for adolescents aged 10-19 years between year 1 (October 2017to September 2018), year 2 (October 2018 to September 2019), and year 3 (October 2019 to September 2020). We calculated the number and percent change for HIV tests, HIV-positive tests, and total number on ART. Calculated indicators included positivity, percent of positives newly initiated on ART (ART linkage), VLC (percent of ART patients on ART for ≥6 months with a documented viral load result within the past 12 months), and VLS (percent of viral load tests with <1000 copies/mL). RESULTS: Between years 1 and 3, the number of HIV tests conducted decreased by 44.2%, with a 29.1% decrease in the number of positive tests. Positivity increased from 1.3%-1.6%. The number of adolescents receiving ART increased by 10.4%. In addition, ART linkage increased (77.8%-86.7%) as did VLC (69.4%-79.4%) and VLS (72.8%-81.5%). CONCLUSIONS: Our findings demonstrate PEPFAR's success in increasing the adolescent treatment cohort. We identified ongoing gaps in adolescent case finding, linkage, VLC, and VLS that could be addressed with a strategic mix of testing strategies, optimal ART regimens, and adolescent-focused service delivery models.
Subject(s)
COVID-19 , HIV Infections , Adult , Humans , Adolescent , HIV Infections/drug therapy , Pandemics , Anti-Retroviral Agents/therapeutic use , Longitudinal StudiesABSTRACT
Historically, the terms African American and Black have been used interchangeably to describe any person with African ancestry living in the United States. However, Black Americans are not a monolith, and legitimate differences exist between those with generational roots in the United States and either African or Caribbean immigrants. American descendants of slavery (ADOS) are underrepresented in many fields, but I have noticed during my decades long career in global health that they are acutely absent in this field. Here, I offer seven recommendations to improve recruitment, retention, and advancement of ADOS in the global health field. Immediate implementation of these recommendations will not only bring diverse perspectives and immense capacity to the field but also allow ADOS an opportunity to engage in compelling and meaningful work and to collaborate with those from their ancestral homelands.
Subject(s)
Black People/ethnology , Black or African American/ethnology , Enslavement/history , Global Health/ethnology , Health Workforce/organization & administration , Africa , Black or African American/psychology , Black People/history , Black People/psychology , Caribbean Region , Emigrants and Immigrants/psychology , Global Health/ethics , Health Workforce/ethics , History, 18th Century , History, 19th Century , Humans , United States , West IndiesABSTRACT
The Republic of Benin faces high maternal, newborn, and child mortality; low modern contraceptive use; and a critical shortage of health workers. In 2013, the Government of Benin made 3 reproductive health commitments to improve national health indicators, including expanding provision of family planning services at the community level through task sharing. Since 2016, the Advancing Partners & Communities (APC) project has been helping the Benin Ministry of Health (MOH) provide subcutaneous depot medroxyprogesterone acetate (DMPA-SC; brand name Sayana Press) through facility-based health care providers and community health workers known as relais communautaires (RCs). DMPA-SC is an easy-to-administer, discreet injectable contraceptive that provides 3 months of protection from pregnancy. Beginning in May 2017, the government introduced DMPA-SC through a phased approach in 10 health zones, which encompassed 149 health centers and 614 villages. Between June 2017 and June 2018, the MOH and APC trained 278 facility-based providers and 917 RCs to provide DMPA-SC, and nearly 11,000 doses were subsequently administered to 7,997 women at facilities and in communities. This article presents findings from an assessment of community-level and health facility service data collected during the first 13 months of DMPA-SC introduction in Benin. Because of this intervention, nearly 35,000 women received family planning counseling and 7,997 women chose DMPA-SC. At the community level, 3,111 DMPA-SC users were first-time users of modern contraception. The initial success of the DMPA-SC rollout in Benin shows promise for helping the country meet its reproductive health commitments.