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High-dimensional approaches have revealed heterogeneity amongst dendritic cells (DCs), including a population of transitional DCs (tDCs) in mice and humans. However, the origin and relationship of tDCs to other DC subsets has been unclear. Here we show that tDCs are distinct from other well-characterized DCs and conventional DC precursors (pre-cDCs). We demonstrate that tDCs originate from bone marrow progenitors shared with plasmacytoid DCs (pDCs). In the periphery, tDCs contribute to the pool of ESAM+ type 2 DCs (DC2s), and these DC2s have pDC-related developmental features. Different from pre-cDCs, tDCs have less turnover, capture antigen, respond to stimuli and activate antigen-specific naïve T cells, all characteristics of differentiated DCs. Different from pDCs, viral sensing by tDCs results in IL-1ß secretion and fatal immune pathology in a murine coronavirus model. Our findings suggest that tDCs are a distinct pDC-related subset with a DC2 differentiation potential and unique proinflammatory function during viral infections.
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Medula Óssea , Células Dendríticas , Animais , Camundongos , Antivirais , Medula Óssea/imunologia , Diferenciação Celular , Células Dendríticas/classificação , Células Dendríticas/imunologiaRESUMO
Class-switched antibodies to double-stranded DNA (dsDNA) are prevalent and pathogenic in systemic lupus erythematosus (SLE), yet mechanisms of their development remain poorly understood. Humans and mice lacking secreted DNase DNASE1L3 develop rapid anti-dsDNA antibody responses and SLE-like disease. We report that anti-DNA responses in Dnase1l3-/- mice require CD40L-mediated T cell help, but proceed independently of germinal center formation via short-lived antibody-forming cells (AFCs) localized to extrafollicular regions. Type I interferon (IFN-I) signaling and IFN-I-producing plasmacytoid dendritic cells (pDCs) facilitate the differentiation of DNA-reactive AFCs in vivo and in vitro and are required for downstream manifestations of autoimmunity. Moreover, the endosomal DNA sensor TLR9 promotes anti-dsDNA responses and SLE-like disease in Dnase1l3-/- mice redundantly with another nucleic acid-sensing receptor, TLR7. These results establish extrafollicular B cell differentiation into short-lived AFCs as a key mechanism of anti-DNA autoreactivity and reveal a major contribution of pDCs, endosomal Toll-like receptors (TLRs), and IFN-I to this pathway.
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Linfócitos B/imunologia , Linfócitos B/metabolismo , Comunicação Celular , DNA/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Interferon Tipo I/metabolismo , Animais , Anticorpos Antinucleares/imunologia , Autoantígenos/imunologia , Autoimunidade , Biomarcadores , Ligante de CD40/deficiência , Comunicação Celular/genética , Comunicação Celular/imunologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Endodesoxirribonucleases/deficiência , Imunofluorescência , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/metabolismo , Camundongos , Camundongos Knockout , Receptor 7 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismoRESUMO
BACKGROUND: The COVID-19 pandemic affected home and work routines, which may exacerbate existing academic professional disparities. Objectives were to describe the impact of the pandemic on pediatric faculty's work productivity, identify groups at risk for widening inequities, and explore mitigation strategies. METHODS: A cross-sectional study of faculty members was conducted at nine U.S. pediatric departments. Responses were analyzed by demographics, academic rank, and change in home caregiving responsibility. RESULTS: Of 5791 pediatric faculty members eligible, 1504 (26%) completed the survey. The majority were female (64%), over 40 years old (60%), and assistant professors (47%). Only 7% faculty identified as underrepresented in medicine. Overall 41% reported an increase in caregiving during the pandemic. When comparing clinical, administrative, research, and teaching activities, faculty reported worse 1-year outlook for research activities. Faculty with increased caregiving responsibilities were more likely to report concerns over delayed promotion and less likely to have a favorable outlook regarding clinical and research efforts. Participants identified preferred strategies to mitigate challenges. CONCLUSIONS: The COVID-19 pandemic negatively impacted pediatric faculty productivity with the greatest effects on those with increased caregiving responsibilities. COVID-19 was particularly disruptive to research outlook. Mitigation strategies are needed to minimize the long-term impacts on academic pediatric careers. IMPACT: The COVID-19 pandemic most negatively impacted work productivity of academic pediatric faculty with caregiving responsibilities. COVID-19 was particularly disruptive to short-term (1-year) research outlook among pediatric faculty. Faculty identified mitigation strategies to minimize the long-term impacts of the pandemic on academic pediatric career pathways.
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COVID-19 , Pandemias , Humanos , Masculino , Feminino , Criança , Adulto , Estudos Transversais , Docentes de Medicina , Instituições AcadêmicasRESUMO
BACKGROUND: Healthy Dads Healthy Kids (HDHK) is a unique lifestyle obesity intervention for fathers and children that demonstrated weight loss among the fathers and behavior change among fathers and children in Australia. The program is gender-tailored to specifically target fathers for weight loss and 5-12 year old children for obesity prevention. The aim of this formative study was to examine an Expert Panel's and Hispanic Family Panel's perceptions about the program and suggestions for the cultural adaptation of HDHK for Hispanic families in southwestern US. METHODS: Forty-four Hispanic participants (22 fathers, 13 mothers and 9 children) made up the Family Panel. They participated in 1-5 study contacts (focus groups, online survey, and/or interviews). The scripts and qualitative guides assessed participants' perceptions of the HDHK content and material using the Ecological Validity Model. Studies were conducted in English or Spanish, depending on the preference of the participant. Focus groups and interviews were audio-recorded, transcribed, translated, and thematically coded. Findings were reviewed with the Expert Panel who helped inform the cultural adaptation. RESULTS: 80% of parents were foreign-born, 57% spoke only Spanish at home, and 60% did not graduate from high school. Several themes emerged to inform the cultural adaptation of the program. Parents agreed with the HDHK goals and recommended the program place greater emphasis on parenting and limiting children's screen time. Some mothers and fathers wanted greater mother engagement. Weekly videos and a Facebook group emerged as favorite alternative options to engage mothers. Greater promotion of familism (inclusion and impact on whole family) was recommended for the program goals and activities. Gender roles for mothers and fathers, and differences in how fathers interact with male and female children, emerged and should be considered in program activities. Several barriers to father engagement surfaced, including lack of time due to work schedules, physically demanding jobs, concerns of caring for children without mother, fathers' current fitness/weight, and lack of knowledge of how to eat more healthfully. The reading level of the HDHK materials was too high for some parents. CONCLUSION: Findings from these formative qualitative studies informed the cultural adaptation of HDHK for Hispanic families, to account for literacy level, cultural values, and barriers to participation and engagement.
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Família/etnologia , Relações Pai-Filho , Pai/psicologia , Estilo de Vida/etnologia , Obesidade Infantil/prevenção & controle , Redução de Peso , Adulto , Criança , Pré-Escolar , Feminino , Grupos Focais , Hispânico ou Latino , Humanos , Alfabetização , Masculino , Mães/psicologia , Poder Familiar/etnologia , Desenvolvimento de Programas , Fatores Socioeconômicos , Inquéritos e Questionários , Texas/epidemiologiaRESUMO
This paper explores culturally-related concerns that arose during a multi-year study of obsessive-compulsive disorder (OCD) along the U.S.-Mexico border and describes adaptations made to better connect the research process to study participants. The purpose of this exploration is two-fold: (1) to offer suggestions for culturally sensitive borderland mental health research; and (2) to enhance dialog focused on culture, mental health research and the U.S.-Mexico border. Systematic coding of the written record of weekly research team meetings identified six recurring cultural concerns: emotionally charged and poorly understood terminology; differing meanings of ethnicity and acculturation; quality of life-regional variation and uncertainty; overlap of research and care; hopeful but hesitant; and fatalism. We conclude that diligence in the initial planning phase of a study is only part of the challenge in doing culturally sensitive research. Equally important is an ongoing process of evaluation to make explicit cultural concerns that arise during research, as well as a readiness to implement culturally sensitive research adaptations.
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Comparação Transcultural , Assistência à Saúde Culturalmente Competente , Emigrantes e Imigrantes/psicologia , Americanos Mexicanos/psicologia , Transtorno Obsessivo-Compulsivo/etnologia , Transtorno Obsessivo-Compulsivo/enfermagem , Enfermagem Psiquiátrica , Aculturação , Pesquisa sobre Serviços de Saúde , Humanos , México , Transtorno Obsessivo-Compulsivo/psicologia , Qualidade de Vida/psicologia , Estados UnidosRESUMO
Although lipomas are the most common mesenchymal tumors, the intramuscular type is rare. We report the case of a patient with rotator cuff arthropathy with a lipoma in the teres minor. Wide surgical excision and total shoulder arthroplasty with reverse prosthesis was performed and 18 months of follow up showed excellent results with any recurrence. The teres minor is extremely important for the proper function of a reverse prosthesis, and lipoma growth in the muscular belly can compromise the functionality of the prosthesis. To the best of our knowledge, this is the first case report of a rotator cuff arthropathy with a lipoma in the teres minor.
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OBJECTIVE: Accurate measurement of adult and child screen media use are needed to robustly assess its impact on health outcomes. Our objective was to systematically review screen media use measurement tools that have been validated against an objective "gold standard" tool. METHODS: The search strategy was initially conducted in Medline Ovid and translated to Embase, Web of Science, PsychInfo and Cochrane. A modified natural language search was conducted in Google Scholar and IEEE. The initial search was conducted in March 2021, and an updated search was conducted in June 2022. Additional studies were included from the references. Studies had to describe the validation of a tool to measure screen media use on participants of any age against a 'gold standard' or comparable objective measure. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) was used to assess the criterion validity. Four authors reviewed the titles in two rounds and extracted data. RESULTS: Twenty-nine articles were included in the review. Studies measured TV, computer, mobile device and social media site screen media use through: self or parent report, direct or video observation, computer and mobile device use tracking programs, and through other novel devices such as wearable devices and cameras. Correlations of self or parent report of screen media with the gold standard were lower than correlations of technology-based measures, and video observation with the gold standard. The COSMIN criterion validity ratings ranged from poor to excellent; most of the studies received a global score of fair or poor. CONCLUSIONS: Technology based validated tools that more directly measure screen use are emerging that have been validated against a gold standard for measuring screen use. However, practical, objective measures of diverse types of screen media use that have been tested on diverse populations are needed to better understand the impact of screen media use on the development and physical and mental health of children and adults.
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Computadores de Mão , Criança , Humanos , Padrões de ReferênciaRESUMO
BACKGROUND: Television viewing among children is associated with developmental and health outcomes, yet measurement techniques for television viewing are prone to errors, biases, or both. OBJECTIVE: This study aims to develop a system to objectively and passively measure children's television viewing time. METHODS: The Family Level Assessment of Screen Use in the Home-Television (FLASH-TV) system includes three sequential algorithms applied to video data collected in front of a television screen: face detection, face verification, and gaze estimation. A total of 21 families of diverse race and ethnicity were enrolled in 1 of 4 design studies to train the algorithms and provide proof of concept testing for the integrated FLASH-TV system. Video data were collected from each family in a laboratory mimicking a living room or in the child's home. Staff coded the video data for the target child as the gold standard. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were calculated for each algorithm, as compared with the gold standard. Prevalence and biased adjusted κ scores and an intraclass correlation using a generalized linear mixed model compared FLASH-TV's estimation of television viewing duration to the gold standard. RESULTS: FLASH-TV demonstrated high sensitivity for detecting faces (95.5%-97.9%) and performed well on face verification when the child's gaze was on the television. Each of the metrics for estimating the child's gaze on the screen was moderate to good (range: 55.1% negative predictive value to 91.2% specificity). When combining the 3 sequential steps, FLASH-TV estimation of the child's screen viewing was overall good, with an intraclass correlation for an overall time watching television of 0.725 across conditions. CONCLUSIONS: FLASH-TV offers a critical step forward in improving the assessment of children's television viewing.
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Background: The coronavirus disease 2019 (COVID-19) pandemic has affected both home and work routines and may have exacerbated existing inequities. The objectives of this study were to describe pediatric faculty work productivity and caregiving responsibilities during the pandemic, identify groups at risk, and better understand mitigation strategy preferences. Materials and Methods: We conducted a cross-sectional electronic survey of Department of Pediatric faculty. Responses were analyzed by demographic data as well as academic context. Results: Women (p = 0.003) and junior faculty (p = 0.02) reported greater increases in caregiving responsibilities than men and senior faculty during the pandemic compared with the previous year. Faculty perceived a worse one-year outlook for their research than for their teaching or clinical responsibilities (p < 0.01). More than a third (37%) of faculty reported wellness concerns affecting job performance, which was more common among those with increased caregiving responsibility (p = 0.01). Junior faculty (p = 0.01) and those whose increased caregiving (p = 0.01) were two and threefold more likely to report that their caregiving responsibilities would affect promotion, for those likely to go up for promotion within 10 years. Preferred mitigation strategies included clear communication of expectations by leadership, acknowledging the need for adjustments in expectations, flexible work hours, and allowances for an off-line day. Conclusion: Pediatric faculty with increased caregiving responsibilities and junior faculty are at highest risk for the pandemic, affecting their readiness for promotion. Wellness concerns by faculty could affect work performance. Researchers report a worse 1-year outlook than the other groups. Faculty identified preferred strategies to potentially assist in maintaining their productivity.
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COVID-19 , Desempenho Profissional , Criança , Estudos Transversais , Docentes de Medicina , Feminino , Humanos , Masculino , PandemiasRESUMO
BACKGROUND: There is a strong association between increased mobile device use and worse dietary habits, worse sleep outcomes, and poor academic performance in children. Self-report or parent-proxy report of children's screen time has been the most common method of measuring screen time, which may be imprecise or biased. OBJECTIVE: The objective of this study was to assess the feasibility of measuring the screen time of children on mobile devices using the Family Level Assessment of Screen Use (FLASH)-mobile approach, an innovative method that leverages the existing features of the Android platform. METHODS: This pilot study consisted of 2 laboratory-based observational feasibility studies and 2 home-based feasibility studies in the United States. A total of 48 parent-child dyads consisting of a parent and child aged 6 to 11 years participated in the pilot study. The children had to have their own or shared Android device. The laboratory-based studies included a standardized series of tasks while using the mobile device or watching television, which were video recorded. Video recordings were coded by staff for a gold standard comparison. The home-based studies instructed the parent-child dyads to use their mobile device as they typically use it over 3 days. Parents received a copy of the use logs at the end of the study and completed an exit interview in which they were asked to review their logs and share their perceptions and suggestions for the improvement of the FLASH-mobile approach. RESULTS: The final version of the FLASH-mobile approach resulted in user identification compliance rates of >90% for smartphones and >80% for tablets. For laboratory-based studies, a mean agreement of 73.6% (SD 16.15%) was achieved compared with the gold standard (human coding of video recordings) in capturing the target child's mobile use. Qualitative feedback from parents and children revealed that parents found the FLASH-mobile approach useful for tracking how much time their child spends using the mobile device as well as tracking the apps they used. Some parents revealed concerns over privacy and provided suggestions for improving the FLASH-mobile approach. CONCLUSIONS: The FLASH-mobile approach offers an important new research approach to measure children's use of mobile devices more accurately across several days, even when the child shares the device with other family members. With additional enhancement and validation studies, this approach can significantly advance the measurement of mobile device use among young children.
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OBJECTIVE: Qualitatively assess culturally adapted lifestyle intervention, Papás Saludables, Niños Saludables (PSNS; Healthy Dads, Healthy Kids), for Hispanic fathers and children. METHODS: Semistructured interviews of parents and children after participation in 10-week PSNS program for Hispanic fathers and children. Qualitative data double-coded inductively and deductively until consensus reached. RESULTS: Total of 26 fathers, 26 mothers, and 45 children interviewed. Parents and children had positive feedback about program content on culturally relevant nutrition and physical activity and reported improved father-child bonding. Mothers noted increased involvement among fathers in child's well-being. Participants suggested lengthening the program. CONCLUSIONS AND IMPLICATIONS: Papás Saludables, Niños Saludables is an innovative approach with promise in engaging Hispanic fathers and children in a lifestyle program that emphasizes the role of fathers in children's lifestyle behaviors. Familism, respeto (respect), and promoting father-child relationships were important to engage fathers. Results from this study will inform future trials of PSNS and help identify ways to increase engagement of Hispanic men in other programs.
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Relações Pai-Filho , Pai , Obesidade/prevenção & controle , Hispânico ou Latino , Humanos , Masculino , PaisRESUMO
Plasmacytoid dendritic cells (pDCs) can rapidly produce interferons and other soluble factors in response to extracellular viruses or virus mimics such as CpG-containing DNA. pDCs can also recognize live cells infected with certain RNA viruses, but the relevance and functional consequences of such recognition remain unclear. We studied the response of primary DCs to the prototypical persistent DNA virus, human cytomegalovirus (CMV). Human pDCs produced high amounts of type I interferon (IFN-I) when incubated with live CMV-infected fibroblasts but not with free CMV; the response involved integrin-mediated adhesion, transfer of DNA-containing virions to pDCs, and the recognition of DNA through TLR9. Compared with transient polyfunctional responses to CpG or free influenza virus, pDC response to CMV-infected cells was long-lasting, dominated by the production of IFN-I and IFN-III, and lacked diversification into functionally distinct populations. Similarly, pDC activation by influenza-infected lung epithelial cells was highly efficient, prolonged, and dominated by interferon production. Prolonged pDC activation by CMV-infected cells facilitated the activation of natural killer cells critical for CMV control. Last, patients with CMV viremia harbored phenotypically activated pDCs and increased circulating IFN-I and IFN-III. Thus, recognition of live infected cells is a mechanism of virus detection by pDCs that elicits a unique antiviral immune response.
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Células Dendríticas/imunologia , Fibroblastos/imunologia , Interferon Tipo I/metabolismo , Interferons/metabolismo , Células Cultivadas , Técnicas de Cocultura , Ilhas de CpG/imunologia , Citomegalovirus/imunologia , Células Dendríticas/metabolismo , Fibroblastos/virologia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Cultura Primária de Células , Interferon lambdaRESUMO
Antibodies to double-stranded DNA (dsDNA) are prevalent in systemic lupus erythematosus (SLE), particularly in patients with lupus nephritis, yet the nature and regulation of antigenic cell-free DNA (cfDNA) are poorly understood. Null mutations in the secreted DNase DNASE1L3 cause human monogenic SLE with anti-dsDNA autoreactivity. We report that >50% of sporadic SLE patients with nephritis manifested reduced DNASE1L3 activity in circulation, which was associated with neutralizing autoantibodies to DNASE1L3. These patients had normal total plasma cfDNA levels but showed accumulation of cfDNA in circulating microparticles. Microparticle-associated cfDNA contained a higher fraction of longer polynucleosomal cfDNA fragments, which bound autoantibodies with higher affinity than mononucleosomal fragments. Autoantibodies to DNASE1L3-sensitive antigens on microparticles were prevalent in SLE nephritis patients and correlated with the accumulation of cfDNA in microparticles and with disease severity. DNASE1L3-sensitive antigens included DNA-associated proteins such as HMGB1. Our results reveal autoantibody-mediated impairment of DNASE1L3 activity as a common nongenetic mechanism facilitating anti-dsDNA autoreactivity in patients with severe sporadic SLE.
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Anticorpos Antinucleares/imunologia , Autoanticorpos/imunologia , DNA/imunologia , Endodesoxirribonucleases/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/imunologia , Adulto , Animais , Anticorpos Antinucleares/sangue , Autoanticorpos/sangue , Micropartículas Derivadas de Células/imunologia , Micropartículas Derivadas de Células/metabolismo , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/imunologia , Criança , Endodesoxirribonucleases/sangue , Endodesoxirribonucleases/genética , Endodesoxirribonucleases/metabolismo , Feminino , Células HEK293 , Proteína HMGB1/imunologia , Proteína HMGB1/metabolismo , Humanos , Lúpus Eritematoso Sistêmico/metabolismo , Nefrite Lúpica/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Índice de Gravidade de DoençaRESUMO
Glioma pathogenesis-related protein 1 (GLIPR1) is a member of the CAP superfamily that includes proteins from a wide range of eukaryotic organisms. The biological functions of most CAP proteins, including GLIPR1, are unclear. GLIPR1 is up-regulated in aggressive glioblastomas and contributes to the invasiveness of cultured glioblastoma cells. In contrast, decreased GLIPR1 expression is associated with advanced prostate cancer. Forced GLIPR1 overexpression is pro-apoptotic in prostate cancer cells and is being tested in clinical trials as an experimental prostate-cancer therapy. Human GLIPR1 was expressed as a truncated soluble protein (sGLIPR1), purified and crystallized. Useful X-ray data have been collected to beyond 1.9â Å resolution from a crystal that belonged to the orthorhombic space group P2(1)2(1)2 with average unit-cell parameters a = 85.1, b = 79.5, c = 38.9â Å and either a monomer or dimer in the asymmetric unit.
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Proteínas de Neoplasias/química , Proteínas do Tecido Nervoso/química , Cristalização , Cristalografia por Raios X , Expressão Gênica , Humanos , Proteínas de Membrana , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/isolamento & purificação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/isolamento & purificação , SolubilidadeRESUMO
Background: Hispanic children and men carry a high burden for obesity and associated medical conditions. Healthy Dads Healthy Kids was the first obesity prevention intervention targeting fathers and demonstrated weight loss among fathers and behavior change among fathers and children in Australia. The aim of this study was to assess the feasibility of a culturally adapted version of the program for Hispanic families, Papás Saludables Niños Saludables. Methods: A randomized waitlist controlled trial with a process evaluation was conducted to assess the feasibility of Papás Saludables Niños Saludables(NCT03532048). Fathers, their partner (mother), and one to three children were enrolled. A priori feasibility criteria were: (1) recruit 40 Hispanic fathers and their families in ≤4 months; (2) retain 80% of participants for pre- and postassessments; (3) maintain ≥70% attendance to the 10 sessions; (4) obtain 80% "excellent" or "good" satisfaction from participants; and (5) collect anthropometric and behavioral data on ≥75% of participants at baseline and follow-up. Results: The study enrolled 90% (n = 36) of the goal from one local pediatric clinic between May and August 2018; retained 75% of participants for postassessment; maintained 72% attendance among those who started the program; and achieved 100% "excellent/good" satisfaction ratings among the participating fathers and mothers. One hundred percent of participants had most anthropometric and behavioral data at baseline and 72% at follow-up. Conclusions: With oversampling and improvements in the recruitment strategies, Papás Saludables Niños Saludables is feasible for a randomized controlled clinical trial to address whether a father-targeted lifestyle program is efficacious among low-income Hispanic men and their children.
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Relações Pai-Filho , Pai/estatística & dados numéricos , Obesidade Infantil/prevenção & controle , Programas de Redução de Peso/organização & administração , Adulto , Austrália , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Humanos , Masculino , Obesidade Infantil/etnologia , Comportamento de Redução do RiscoRESUMO
Tissue-resident macrophages are a diverse population of cells that perform specialized functions including sustaining tissue homeostasis and tissue surveillance. Here, we report an interstitial subset of CD169+ lung-resident macrophages that are transcriptionally and developmentally distinct from alveolar macrophages (AMs). They are primarily localized around the airways and are found in close proximity to the sympathetic nerves in the bronchovascular bundle. These nerve- and airway-associated macrophages (NAMs) are tissue resident, yolk sac derived, self-renewing, and do not require CCR2+ monocytes for development or maintenance. Unlike AMs, the development of NAMs requires CSF1 but not GM-CSF. Bulk population and single-cell transcriptome analysis indicated that NAMs are distinct from other lung-resident macrophage subsets and highly express immunoregulatory genes under steady-state and inflammatory conditions. NAMs proliferated robustly after influenza infection and activation with the TLR3 ligand poly(I:C), and in their absence, the inflammatory response was augmented, resulting in excessive production of inflammatory cytokines and innate immune cell infiltration. Overall, our study provides insights into a distinct subset of airway-associated pulmonary macrophages that function to maintain immune and tissue homeostasis.
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Macrófagos Alveolares/imunologia , Neurônios/imunologia , Animais , Homeostase/imunologia , Fator Estimulador de Colônias de Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Saco Vitelino/citologia , Saco Vitelino/imunologiaRESUMO
The phosphatidylinositol 3-kinase (PI3K) signaling cascade downstream of the B cell receptor (BCR) signalosome is essential for B cell maturation. Proper signaling strength is maintained through the PI3K negative regulator phosphatase and tensin homolog (PTEN). Although a role for microRNA (miRNA)-dependent control of the PTEN-PI3K axis has been described, the contribution of individual miRNAs to the regulation of this crucial signaling modality in mature B lymphocytes remains to be elucidated. Our analyses reveal that ablation of miR-29 specifically in B lymphocytes results in an increase in PTEN expression and dampening of the PI3K pathway in mature B cells. This dysregulation has a profound impact on the survival of B lymphocytes and results in increased class switch recombination and decreased plasma cell differentiation. Furthermore, we demonstrate that ablation of one copy of Pten is sufficient to ameliorate the phenotypes associated with miR-29 loss. Our data suggest a critical role for the miR-29-PTEN-PI3K regulatory axis in mature B lymphocytes.
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Linfócitos B/metabolismo , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Animais , Diferenciação Celular , Humanos , Camundongos , Transdução de Sinais , Análise de SobrevidaRESUMO
Plasmacytoid dendritic cells (pDCs) are sensor cells with diverse immune functions, from type I interferon (IFN-I) production to antigen presentation, T cell activation, and tolerance. Regulation of these functions remains poorly understood but could be mediated by functionally specialized pDC subpopulations. We address pDC diversity using a high-dimensional single-cell approach: mass cytometry (CyTOF). Our analysis uncovers a murine pDC-like population that specializes in antigen presentation with limited capacity for IFN-I production. Using a multifaceted cross-species comparison, we show that this pDC-like population is the definitive murine equivalent of the recently described human AXL+ DCs, which we unify under the name transitional DCs (tDCs) given their continuum of pDC and cDC2 characteristics. tDCs share developmental traits with pDCs, as well as recruitment dynamics during viral infection. Altogether, we provide a framework for deciphering the function of pDCs and tDCs during diseases, which has the potential to open new avenues for therapeutic design.
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Apresentação de Antígeno , Células Dendríticas/imunologia , Interferon gama/metabolismo , Adulto , Animais , Células Cultivadas , Células Dendríticas/citologia , Células Dendríticas/virologia , Feminino , Citometria de Fluxo/métodos , Humanos , Interferon gama/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Orthomyxoviridae/imunologia , Orthomyxoviridae/patogenicidade , Análise de Célula Única/métodos , Especificidade da Espécie , TranscriptomaRESUMO
PURPOSE OF REVIEW: There is a growing evidence of the important role that fathers play in influencing their children's eating and other weight-related behaviors. Latino children are at high risk for obesity and associated medical conditions. Engaging Latino fathers is a potentially important and unique way to help promote healthy lifestyles for Latino children, but doing so requires a culturally sensitive understanding both of fathers' current role and the family perceptions of this role. RECENT FINDINGS: Here, we review recent data and argue that there are subtle but important differences between the qualitative and quantitative research conducted regarding the role Latino fathers may play in promoting healthy eating and physical activity for their children. We suggest how to synthesize these findings and also present qualitative results for ways to best engage Latino fathers in research studies with a focus on physical activity. Results from the review support that Latino fathers are important potential targets for child obesity prevention, but our findings stress the importance of considering cultural values when trying to recruit, engage and retain Latino fathers for such research.
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Exercício Físico , Relações Pai-Filho , Pai , Comportamento Alimentar , Promoção da Saúde/métodos , Hispânico ou Latino , Obesidade Infantil/prevenção & controle , Atitude , Criança , Comportamento Infantil , Cultura , Dieta , Ingestão de Alimentos , Família , Comportamentos Relacionados com a Saúde , Humanos , Obesidade Infantil/etnologiaRESUMO
An IRF8-dependent subset of conventional dendritic cells (cDCs), termed cDC1, effectively cross-primes CD8+ T cells and facilitates tumor-specific T cell responses. Etv6 is an ETS family transcription factor that controls hematopoietic stem and progenitor cell (HSPC) function and thrombopoiesis. We report that like HSPCs, cDCs express Etv6, but not its antagonist, ETS1, whereas interferon-producing plasmacytoid dendritic cells (pDCs) express both factors. Deletion of Etv6 in the bone marrow impaired the generation of cDC1-like cells in vitro and abolished the expression of signature marker CD8α on cDC1 in vivo. Moreover, Etv6-deficient primary cDC1 showed a partial reduction of cDC-specific and cDC1-specific gene expression and chromatin signatures and an aberrant up-regulation of pDC-specific signatures. Accordingly, DC-specific Etv6 deletion impaired CD8+ T cell cross-priming and the generation of tumor antigen-specific CD8+ T cells. Thus, Etv6 optimizes the resolution of cDC1 and pDC expression programs and the functional fitness of cDC1, thereby facilitating T cell cross-priming and tumor-specific responses.