Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 97
Filtrar
1.
FEMS Microbiol Ecol ; 100(7)2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38886123

RESUMO

Fungi are increasingly recognized to play diverse roles within honey bee hives, acting as pathogens, mutualists, and commensals. Pollen products, essential for hive nutrition, host significant fungal communities with potential protective and nutritional benefits. In this study, we profile the fungal communities and antifungal properties of three pollen products from healthy and stressed hives: fresh pollen collected by forager bees from local plants; stored pollen packed into the comb inside the hive; and bee bread, which is stored pollen following anaerobic fermentation used for bee and larval nutrition. Using amplicon sequencing, we found significant differences in fungal community composition, with hive health and sample type accounting for 8.8% and 19.3% of variation in beta diversity, respectively. Pollen and bee bread extracts had species-specific antimicrobial activity and inhibited the fungal hive pathogens Ascosphaera apis, Aspergillus flavus, and Aspergillus fumigatus, and the bacterial hive pathogen Paenibacillus larvae. Activity was positively correlated with phenolic and antioxidant content and was diminished in stressed hives. The plant source of pollen determined by amplicon sequencing differed in stressed hives, suggesting altered foraging behaviour. These findings illustrate the complex interplay between honey bees, fungal communities, and hive products, which should be considered in hive management and conservation.


Assuntos
Fungos , Pólen , Abelhas/microbiologia , Animais , Fungos/genética , Fungos/classificação , Estresse Fisiológico , Paenibacillus larvae/genética , Micobioma , Ascomicetos , Anti-Infecciosos/farmacologia
2.
BMC Public Health ; 24(1): 1544, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849769

RESUMO

INTRODUCTION: Globally, the COVID-19 pandemic upended healthcare services and created economic vulnerability for many. Criminalization of sex work meant sex workers were largely ineligible for Canada's government-based financial pandemic relief, the Canadian Emergency Response Benefit. Sex workers' loss of income and inability to access financial support services during the pandemic resulted in many unable to pay rent or mortgage, and in need of assistance with basic needs items including food. Little is known about the unique experiences of sex workers who faced challenges in accessing food during the pandemic and its impact on healthcare access. Thus, we aimed to identify the association between pandemic-related challenges accessing food and primary healthcare among sex workers. METHODS: Prospective data were drawn from a cohort of women sex workers in Vancouver, Canada (An Evaluation of Sex Workers' Health Access, AESHA; 2010-present). Data were collected via questionnaires administered bi-annually from October 2020-August 2021. We used univariate and multivariable logistic regression with generalized estimating equations to assess the association between pandemic-related challenges accessing food and challenges accessing primary healthcare over the study period. RESULTS: Of 170 participants, 41% experienced pandemic-related challenges in accessing food and 26% reported challenges accessing healthcare. Median age was 45 years (IQR:36-53), 56% were of Indigenous ancestry, 86% experienced intimate partner violence in the last six months, and 62% reported non-injection substance use in the last six months. Experiencing pandemic-related challenges accessing food was positively associated with challenges accessing primary healthcare (Adjusted Odds Ratio: 1.99, 95% Confidence Interval: 1.02-3.88) after adjustment for confounders. CONCLUSIONS: Findings provide insight about the potential role community-based healthcare delivery settings (e.g., community clinics) can play in ameliorating access to basic needs such as food among those who are highly marginalized. Future pandemic response efforts should also take the most marginalized populations' needs into consideration by establishing strategies to ensure continuity of essential services providing food and other basic needs. Lastly, policies are needed establishing basic income support and improve access to food resources for marginalized women in times of crisis.


Assuntos
COVID-19 , Acessibilidade aos Serviços de Saúde , Atenção Primária à Saúde , Profissionais do Sexo , Humanos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Feminino , Profissionais do Sexo/estatística & dados numéricos , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Adulto , Atenção Primária à Saúde/estatística & dados numéricos , Estudos Prospectivos , Colúmbia Britânica/epidemiologia , Canadá/epidemiologia , Pandemias , Pessoa de Meia-Idade , SARS-CoV-2 , Insegurança Alimentar , Estudos de Coortes , Abastecimento de Alimentos/estatística & dados numéricos
3.
PLoS One ; 18(6): e0286993, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37339139

RESUMO

Refugee communities are vulnerable to housing insecurity, which drives numerous health disparity outcomes in a historically marginalized population. The COVID-19 pandemic has only worsened the ongoing affordable housing crisis in the United States while continuing to highlight disparities in health outcomes across populations. We conducted interviewer-administered surveys with refugee and asylum seekers in San Diego County at the height of the COVID-19 pandemic to understand the social effects and drivers of COVID-19 in one of the largest refugee communities in the United States. Staff from a community-based refugee advocacy and research organization administered the surveys from September-November 2020. 544 respondents participated in the survey, which captured the diversity of the San Diego refugee community including East African (38%), Middle Eastern (35%), Afghan (17%), and Southeast Asian (11%) participants. Nearly two-thirds of respondents (65%) reported living in overcrowded conditions (> 1 individual per room) and 30% in severely crowded conditions (> 1.5 individuals per room). For each additional person per room, self-reported poor emotional health increased. Conversely, family size was associated with a lower likelihood of reporting poor emotional health. Crowded housing was significantly associated with a lower probability of accessing a COVID-19 diagnostic test, with every additional reported person per room there was approximately an 11% increase in the probability of having never accessed a COVID-19 testing. Access to affordable housing had the largest effect size and was associated with fewer people per room. Overcrowding housing is a structural burden that reduces COVID-19 risk mitigation behaviors. Improved access to affordable housing units or receiving vouchers could reduce overcrowded housing in vulnerable refugee communities.


Assuntos
COVID-19 , Refugiados , Humanos , Estados Unidos , Habitação , Refugiados/psicologia , Teste para COVID-19 , Pandemias/prevenção & controle , COVID-19/epidemiologia , COVID-19/prevenção & controle
4.
Microbiol Spectr ; 11(4): e0074223, 2023 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-37289060

RESUMO

Honey bees (Apis mellifera) face increasing threats to their health, particularly from the degradation of floral resources and chronic pesticide exposure. The properties of honey and the bee gut microbiome are known to both affect and be affected by bee health. Using samples from healthy hives and hives showing signs of stress from a single apiary with access to the same floral resources, we profiled the antimicrobial activity and chemical properties of honey and determined the bacterial and fungal microbiome of the bee gut and the hive environment. We found honey from healthy hives was significantly more active than honey from stressed hives, with increased phenolics and antioxidant content linked to higher antimicrobial activity. The bacterial microbiome was more diverse in stressed hives, suggesting they may have less capacity to exclude potential pathogens. Finally, bees from healthy and stressed hives had significant differences in core and opportunistically pathogenic taxa in gut samples. Our results emphasize the need for understanding and proactively managing bee health. IMPORTANCE Honey bees serve as pollinators for many plants and crops worldwide and produce valuable hive products such as honey and wax. Various sources of stress can disrupt honey bee colonies, affecting their health and productivity. Growing evidence suggests that honey is vitally important to hive functioning and overall health. In this study, we determined the antimicrobial activity and chemical properties of honey from healthy hives and hives showing signs of stress, finding that honey from healthy hives was significantly more antimicrobial, with increased phenolics and antioxidant content. We next profiled the bacterial and fungal microbiome of the bee gut and the hive environment, finding significant differences between healthy and stressed hives. Our results underscore the need for greater understanding in this area, as we found even apparently minor stress can have implications for overall hive fitness as well as the economic potential of hive products.


Assuntos
Anti-Infecciosos , Microbioma Gastrointestinal , Microbiota , Urticária , Abelhas , Animais , Antioxidantes , Bactérias
5.
Am J Public Health ; 113(4): 442-452, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36888950

RESUMO

Objectives. To model the relationship of unstable housing and evictions with physical and sexual violence perpetrated against women sex workers in intimate and workplace settings. Methods. We used bivariate and multivariable logistic regression with generalized estimating equations to model the association of unstable housing exposure and evictions with intimate partner violence (IPV) and workplace violence among a community-based longitudinal cohort of cisgender and transgender women sex workers in Vancouver, Canada, from 2010 through 2019. Results. Of 946 women, 85.9% experienced unstable housing, 11.1% eviction, 26.2% IPV, and 31.8% workplace violence. In multivariable generalized estimating equation models, recent exposure to unstable housing (adjusted odds ratio [AOR] = 2.04; 95% confidence interval [CI] = 1.45, 2.87) and evictions (AOR = 2.45; 95% CI = 0.99, 6.07) were associated with IPV, and exposure to unstable housing was associated with workplace violence (AOR = 1.46; 95% CI = 1.06, 2.00). Conclusions. Women sex workers face a high burden of unstable housing and evictions, which are linked to increased odds of intimate partner and workplace violence. Increased access to safe, women-centered, and nondiscriminatory housing is urgently needed. (Am J Public Health. 2023;113(4):442-452. https://doi.org/10.2105/AJPH.2022.307207).


Assuntos
Violência por Parceiro Íntimo , Profissionais do Sexo , Violência no Trabalho , Humanos , Feminino , Estudos Prospectivos , Instabilidade Habitacional , Canadá/epidemiologia , Fatores de Risco
6.
J Cancer Surviv ; 17(5): 1461-1470, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-35080699

RESUMO

PURPOSE: To describe perceptions of financial navigation staff concerning patients' cancer-related financial burden. METHODS: This qualitative descriptive study used a semi-structured interview guide to examine perceptions of financial navigation staff concerning patients' cancer-related financial burden. Staff who provided financial navigation support services to cancer patients were interviewed from different types of cancer programs across seven states representing rural, micropolitan, and urban settings. Interviews lasted approximately one hour, were audio recorded, and transcribed. Transcripts were double coded for thematic analysis. RESULTS: Thirty-five staff from 29 cancer centers were interviewed. The first theme involved communication issues related to patient and financial navigation staff expectations, timing and the sensitive nature of financial discussions. The second theme involved the multi-faceted impact of financial burden on patients, including stress, difficulty adhering to treatments, and challenges meeting basic, non-medical needs. CONCLUSIONS AND IMPLICATIONS FOR CANCER SURVIVORS: Cancer-related financial burden has a profound impact on cancer survivors' health and non-health outcomes. Discussions regarding cancer-related costs between cancer survivors and healthcare team members could help to normalize conversations and mitigate the multi-faceted determinants and effects of cancer-related financial burden. As treatment may span months and years and unexpected costs arise, having this discussion regularly and systematically is needed.


Assuntos
Sobreviventes de Câncer , Neoplasias , Humanos , Estresse Financeiro , Atenção à Saúde , Custos e Análise de Custo , Pesquisa Qualitativa , Neoplasias/terapia
7.
Int J Hyg Environ Health ; 247: 114044, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36395654

RESUMO

BACKGROUND: Safe drinking water is a fundamental human right, yet more than 785 million people do not have access to it. The burden of water management disproportionately falls on women and young girls, and they suffer the health, psychosocial, political, educational, and economic effects. While water conditions and disease outcomes have been widely studied, few studies have summarized the research on drinking water and implications for gender equity and empowerment (GEE). METHODS: A systematic review of primary literature published between 1980 and 2019 was conducted on drinking water exposures and management and the implications for GEE. Ten databases were utilized (EMBASE, PubMed, Web of Science, Cochrane, ProQuest, Campbell, the British Library for Development Studies, SSRN, 3ie International Initiative for Impact Evaluation, and clinicaltrials.gov). Drinking water studies with an all-female cohort or disaggregated findings according to gender were included. RESULTS: A total of 1280 studies were included. GEE outcomes were summarized in five areas: health, psychosocial stress, political power and decision-making, social-educational conditions, and economic and time-use conditions. Water quality exposures and implications for women's health dominated the literature reviewed. Women experienced higher rates of bladder cancer when exposed to arsenic, trihalomethanes, and chlorine in drinking water and higher rates of breast cancer due to arsenic, trichloroethylene, and disinfection byproducts in drinking water, compared to men. Women that were exposed to arsenic experienced higher incidence rates of anemia and adverse pregnancy outcomes compared to those that were not exposed. Water-related skin diseases were associated with increased levels of psychosocial stress and social ostracization among women. Women had fewer decision-making responsibilities, economic independence, and employment opportunities around water compared to men. CONCLUSION: This systematic review confirms the interconnected nature of gender and WaSH outcomes. With growing attention directed towards gender equity and empowerment within WaSH, this analysis provides key insights to inform future research and policy.


Assuntos
Arsênio , Água Potável , Doenças Transmitidas pela Água , Masculino , Gravidez , Feminino , Humanos , Equidade de Gênero , Trialometanos
8.
Cell ; 185(22): 4135-4152.e22, 2022 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-36257314

RESUMO

Recent studies have begun to reveal critical roles for the brain's professional phagocytes, microglia, and their receptors in the control of neurotoxic amyloid beta (Aß) and myelin debris accumulation in neurodegenerative disease. However, the critical intracellular molecules that orchestrate neuroprotective functions of microglia remain poorly understood. In our studies, we find that targeted deletion of SYK in microglia leads to exacerbated Aß deposition, aggravated neuropathology, and cognitive defects in the 5xFAD mouse model of Alzheimer's disease (AD). Disruption of SYK signaling in this AD model was further shown to impede the development of disease-associated microglia (DAM), alter AKT/GSK3ß-signaling, and restrict Aß phagocytosis by microglia. Conversely, receptor-mediated activation of SYK limits Aß load. We also found that SYK critically regulates microglial phagocytosis and DAM acquisition in demyelinating disease. Collectively, these results broaden our understanding of the key innate immune signaling molecules that instruct beneficial microglial functions in response to neurotoxic material.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Animais , Camundongos , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Modelos Animais de Doenças , Camundongos Transgênicos , Microglia/patologia , Fagocitose
9.
Front Nutr ; 9: 954170, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35958247

RESUMO

Honey is the source of energy for the European honey bee, Apis mellifera. Beyond simple nutrition and a hedge against the seasonal, geographic, and chemical unpredictability of nectar, honey has properties that protect the hive against various stresses. Enzyme-mediated detoxification during honey ripening neutralizes potentially toxic phytochemicals, and bees that consume honey have enhanced tolerance to other ingested toxins. Catalase and antioxidant phenolics protect honey bees from oxidative damage caused by reactive oxygen species, promoting their longevity. Phytochemical components of honey and microRNAs have the potential to influence developmental pathways, with diet playing a large role in honey bee caste determination. Components of honey mediate stress response and promote cold tolerance during overwintering. Honey has a suite of antimicrobial mechanisms including osmotic pressure, low water activity, low pH, hydrogen peroxide, and plant-, honey bee-, and microbiota-derived compounds such as phytochemicals and antimicrobial peptides. Certain types of honey, particularly polyfloral honeys, have been shown to inhibit important honey bee pathogens including the bacteria responsible for American and European Foulbrood, the microsporidian Nosema ceranae, and the fungi responsible for Stonebrood. Understanding the diverse functional properties of honey has far-ranging implications for honey bee and hive health and management by beekeepers.

10.
AIDS Behav ; 26(10): 3210-3219, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35380288

RESUMO

Economic vulnerability is often reported to underlie involvement in sex work among female sex workers (FSW), but may also create urgency in women's work, limiting women's negotiating power with clients and in turn, increasing their vulnerability for violence and HIV. This study assessed economic vulnerability in relation to violence and sexual risk behaviors for HIV among a sample of FSW in Tijuana, Mexico. FSW at least 18 years of age were recruited through venue-based sampling for a survey (n = 228) and in-depth interviews (n = 50) to investigate HIV risk factors in this region. Using crude and adjusted logistic regression models, we assessed lack of financial support from others as well as reports of financial hardship separately in relation to experiencing sexual violence (e.g. by clients, police, relationship partners, in the past 6 months), physical violence (past 6 months), STI diagnosis, and inconsistent condom use (past 30 days). Qualitative interviews (n = 50), conducted with a subsample of the survey participants, were also examined for related themes. FSW who reported no financial support were more likely to report sexual violence (OR = 2.1; 95% CI:1.1-4.2). FSW who reported financial hardship were more likely to experience sexual violence (OR = 1.9; 95% CI:1.1-3.6) and physical violence (OR = 1.9; 95% CI:1.1-3.6), as well as to report past 30-day inconsistent condom use (OR = 2.4; 95%CI: 1.3-4.6) and to test positive for an STI (OR = 1.9; 95% CI:1.1-3.4). Qualitative data substantiated these findings. Findings suggest that interventions to improve economic well-being may be useful to prevent the intersecting concerns of violence and HIV among FSW.


Assuntos
Infecções por HIV , Profissionais do Sexo , Estudos Transversais , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Humanos , México/epidemiologia , Fatores de Risco , Sexo sem Proteção , Violência
12.
Support Care Cancer ; 30(3): 2047-2058, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34655327

RESUMO

PURPOSE: Financial toxicity is associated with negative patient outcomes, and rural populations are disproportionately affected by the high costs of cancer care compared to urban populations. Our objective was to (1) understand cancer programs' perceptions of rural-urban differences in cancer patients' experiences of financial hardship, (2) evaluate the resources available to cancer patients across the rural-urban continuum, and (3) determine how rural and urban health care teams assess and address financial distress in cancer patients. METHODS: Seven research teams within the Cancer Prevention and Research Control Network conducted semi-structured interviews with cancer program staff who have a role in connecting cancer patients with financial assistance services in both rural and urban counties. Interviews were audio-recorded and transcribed. We identified themes using descriptive content and thematic analysis. RESULTS: We interviewed 35 staffs across 29 cancer care programs in seven states, with roughly half of respondents from programs in rural counties. Participants identified differences in rural and urban patients' experiences of financial hardship related to distance required to travel for treatment, underinsurance, and low socioeconomic status. Insufficient staffing was an identified barrier to addressing rural and urban patients' financial concerns. CONCLUSIONS: Improved financial navigation services could mitigate the effects of financial toxicity experienced by cancer patients, particularly rural patients, throughout treatment and survivorship. Future research is needed to improve how cancer programs assess financial hardship in patients and to expand financial navigation services to better serve rural cancer patients.


Assuntos
Estresse Financeiro , Neoplasias , Custos e Análise de Custo , Humanos , Neoplasias/terapia , População Rural , População Urbana
13.
Drug Alcohol Depend ; 221: 108615, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33652378

RESUMO

BACKGROUND: Federally funded health centers (HCs) provide care to the most vulnerable populations in the U.S., including populations with disproportionately higher smoking prevalence such as those with lower incomes. METHODS: This study compared characteristics of adult HC patients, by cigarette smoking status, and assessed smoking cessation-related behaviors using 2014 Health Center Patient Survey data; analysis was restricted to adults with data on cigarette smoking status (n = 5583). Chi-square and logistic regression analyses were conducted. RESULTS: Overall, 28.1 % were current smokers and 19.2 % were former smokers. Current smokers were more likely to report fair/poor health (48.2 %) and a high burden of behavioral health conditions (e.g., severe psychological distress 23.9 %) versus former and never smokers. Most current smokers reported wanting to quit in the past 12 months (79.0 %) and receiving advice to quit from a healthcare professional (78.7 %). In a multivariable model, age <45, non-white race, COPD diagnosis, and past 3-month marijuana use were significantly associated with desire to quit. Few former smokers (15.2 %) reported using cessation treatment, though use was higher among those who quit within the previous year (30.6 %). CONCLUSIONS: Although most current smokers reported a desire to quit, low uptake of evidence-based treatment may reduce the number who attempt to quit and succeed. Given the burden of tobacco use, future efforts could focus on identifying and overcoming unique personal, healthcare professional, or health system barriers to connecting them with cessation treatments. Increasing access to cessation treatments within HCs could reduce smoking-related disparities and improve population health.


Assuntos
Fumar Cigarros/psicologia , Hospitais Federais/estatística & dados numéricos , Fumantes/psicologia , Abandono do Hábito de Fumar/psicologia , Populações Vulneráveis/psicologia , Adolescente , Adulto , Distribuição de Qui-Quadrado , Fumar Cigarros/epidemiologia , Feminino , Comportamentos Relacionados com a Saúde , Disparidades nos Níveis de Saúde , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prevalência , Fumantes/estatística & dados numéricos , Abandono do Hábito de Fumar/estatística & dados numéricos , Inquéritos e Questionários , Estados Unidos/epidemiologia , Populações Vulneráveis/estatística & dados numéricos , Adulto Jovem
14.
Nat Commun ; 11(1): 4524, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913280

RESUMO

Traumatic brain injury (TBI) is a leading global cause of death and disability. Here we demonstrate in an experimental mouse model of TBI that mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that begin within hours and last out to at least one month post-injury. To investigate a mechanism underlying impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics. We demonstrate that increased ICP can contribute to meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction before TBI leads to increased neuroinflammation and negative cognitive outcomes. Finally, we report that rejuvenation of meningeal lymphatic drainage function in aged mice can ameliorate TBI-induced gliosis. These findings provide insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI.


Assuntos
Lesões Encefálicas/fisiopatologia , Gliose/fisiopatologia , Sistema Glinfático/fisiologia , Meninges/fisiopatologia , Animais , Lesões Encefálicas/complicações , Lesões Encefálicas/patologia , Lesões Encefálicas/terapia , Dependovirus/genética , Modelos Animais de Doenças , Feminino , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Gliose/etiologia , Gliose/patologia , Gliose/prevenção & controle , Sistema Glinfático/patologia , Humanos , Masculino , Meninges/patologia , Camundongos , Fator C de Crescimento do Endotélio Vascular/genética , Fator C de Crescimento do Endotélio Vascular/uso terapêutico
15.
Elife ; 92020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32940605

RESUMO

JCPyV polyomavirus, a member of the human virome, causes progressive multifocal leukoencephalopathy (PML), an oft-fatal demyelinating brain disease in individuals receiving immunomodulatory therapies. Mutations in the major viral capsid protein, VP1, are common in JCPyV from PML patients (JCPyV-PML) but whether they confer neurovirulence or escape from virus-neutralizing antibody (nAb) in vivo is unknown. A mouse polyomavirus (MuPyV) with a sequence-equivalent JCPyV-PML VP1 mutation replicated poorly in the kidney, a major reservoir for JCPyV persistence, but retained the CNS infectivity, cell tropism, and neuropathology of the parental virus. This mutation rendered MuPyV resistant to a monoclonal Ab (mAb), whose specificity overlapped the endogenous anti-VP1 response. Using cryo-EM and a custom sub-particle refinement approach, we resolved an MuPyV:Fab complex map to 3.2 Å resolution. The structure revealed the mechanism of mAb evasion. Our findings demonstrate convergence between nAb evasion and CNS neurovirulence in vivo by a frequent JCPyV-PML VP1 mutation.


Assuntos
Anticorpos Monoclonais/imunologia , Capsídeo/imunologia , Mutação , Polyomavirus/patogenicidade , Animais , Feminino , Leucoencefalopatia Multifocal Progressiva/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Polyomavirus/imunologia , Virulência
16.
Nature ; 580(7805): 647-652, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32350463

RESUMO

Neurodevelopment is characterized by rapid rates of neural cell proliferation and differentiation followed by massive cell death in which more than half of all recently generated brain cells are pruned back. Large amounts of DNA damage, cellular debris, and by-products of cellular stress are generated during these neurodevelopmental events, all of which can potentially activate immune signalling. How the immune response to this collateral damage influences brain maturation and function remains unknown. Here we show that the AIM2 inflammasome contributes to normal brain development and that disruption of this immune sensor of genotoxic stress leads to behavioural abnormalities. During infection, activation of the AIM2 inflammasome in response to double-stranded DNA damage triggers the production of cytokines as well as a gasdermin-D-mediated form of cell death known as pyroptosis1-4. We observe pronounced AIM2 inflammasome activation in neurodevelopment and find that defects in this sensor of DNA damage result in anxiety-related behaviours in mice. Furthermore, we show that the AIM2 inflammasome contributes to central nervous system (CNS) homeostasis specifically through its regulation of gasdermin-D, and not via its involvement in the production of the cytokines IL-1 and/or IL-18. Consistent with a role for this sensor of genomic stress in the purging of genetically compromised CNS cells, we find that defective AIM2 inflammasome signalling results in decreased neural cell death both in response to DNA damage-inducing agents and during neurodevelopment. Moreover, mutations in AIM2 lead to excessive accumulation of DNA damage in neurons as well as an increase in the number of neurons that incorporate into the adult brain. Our findings identify the inflammasome as a crucial player in establishing a properly formed CNS through its role in the removal of genetically compromised cells.


Assuntos
Encéfalo/crescimento & desenvolvimento , Dano ao DNA , Proteínas de Ligação a DNA/metabolismo , Inflamassomos/metabolismo , Animais , Animais Recém-Nascidos , Ansiedade/patologia , Ansiedade/fisiopatologia , Ansiedade/psicologia , Comportamento Animal/fisiologia , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/patologia , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Caspase 1/deficiência , Caspase 1/metabolismo , Morte Celular , Proteínas de Ligação a DNA/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Mutação , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Neurônios/patologia , Proteínas de Ligação a Fosfato/metabolismo
17.
RNA Biol ; 17(8): 1183-1195, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31983265

RESUMO

tRNA-derived small fragments (tRFs) and tRNA halves have emerging functions in different biological pathways, such as regulating gene expression, protein translation, retrotransposon activity, transgenerational epigenetic changes and response to environmental stress. However, small RNAs like tRFs and microRNAs in the maternal-fetal interface during gestation have not been studied extensively. Here we investigated the small RNA composition of mouse placenta/decidua, which represents the interface where the mother communicates with the foetus, to determine whether there are specific differences in tRFs and microRNAs during fetal development and in response to maternal immune activation (MIA). Global tRF expression pattern, just like microRNAs, can distinguish tissue types among placenta/decidua, fetal brain and fetal liver. In particular, 5' tRNA halves from tRNAGly, tRNAGlu, tRNAVal and tRNALys are abundantly expressed in the normal mouse placenta/decidua. Moreover, tRF and microRNA levels in the maternal-fetal interface change dynamically over the course of embryonic development. To see if stress alters non-coding RNA expression at the maternal-fetal interface, we treated pregnant mice with a viral infection mimetic, which has been shown to promote autism-related phenotypes in the offspring. Acute changes in the levels of specific tRFs and microRNAs were observed 3-6 h after MIA and are suppressed thereafter. A group of 5' tRNA halves is down-regulated by MIA, whereas a group of 18-nucleotide tRF-3a is up-regulated. In conclusion, tRFs show tissue-specificity, developmental changes and acute response to environmental stress, opening the possibility of them having a role in the fetal response to MIA.


Assuntos
Transtorno Autístico/etiologia , MicroRNAs/genética , Placenta/metabolismo , Pequeno RNA não Traduzido/genética , RNA de Transferência/genética , Animais , Transtorno Autístico/metabolismo , Transtorno Autístico/psicologia , Decídua/metabolismo , Feminino , Regulação da Expressão Gênica , Camundongos , MicroRNAs/metabolismo , Gravidez , Pequeno RNA não Traduzido/metabolismo , RNA de Transferência/metabolismo
18.
Front Immunol ; 10: 783, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31105690

RESUMO

Programmed cell death-1 (PD-1) receptor signaling dampens the functionality of T cells faced with repetitive antigenic stimulation from chronic infections or tumors. Using intracerebral (i.c.) inoculation with mouse polyomavirus (MuPyV), we have shown that CD8 T cells establish a PD-1hi, tissue-resident memory population in the brains (bTRM) of mice with a low-level persistent infection. In MuPyV encephalitis, PD-L1 was expressed on infiltrating myeloid cells, microglia and astrocytes, but not on oligodendrocytes. Engagement of PD-1 on anti-MuPyV CD8 T cells limited their effector activity. NanoString gene expression analysis showed that neuroinflammation was higher in PD-L1-/- than wild type mice at day 8 post-infection, the peak of the MuPyV-specific CD8 response. During the persistent phase of infection, however, the absence of PD-1 signaling was found to be associated with a lower inflammatory response than in wild type mice. Genetic disruption and intracerebroventricular blockade of PD-1 signaling resulted in an increase in number of MuPyV-specific CD8 bTRM and the fraction of these cells expressing CD103, the αE integrin commonly used to define tissue-resident T cells. However, PD-L1-/- mice persistently infected with MuPyV showed impaired virus control upon i.c. re-infection with MuPyV. Collectively, these data reveal a temporal duality in PD-1-mediated regulation of MuPyV-associated neuroinflammation. PD-1 signaling limited the severity of neuroinflammation during acute infection but sustained a level of inflammation during persistent infection for maintaining control of virus re-infection.


Assuntos
Encéfalo/imunologia , Linfócitos T CD8-Positivos/imunologia , Encefalite Viral/imunologia , Infecções por Polyomavirus/imunologia , Polyomavirus/imunologia , Receptor de Morte Celular Programada 1/imunologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Encéfalo/patologia , Linfócitos T CD8-Positivos/patologia , Encefalite Viral/genética , Encefalite Viral/patologia , Feminino , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Camundongos , Camundongos Knockout , Infecções por Polyomavirus/genética , Infecções por Polyomavirus/patologia , Receptor de Morte Celular Programada 1/genética
19.
Nat Neurosci ; 21(10): 1380-1391, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30224810

RESUMO

Neuroinflammatory diseases, such as multiple sclerosis, are characterized by invasion of the brain by autoreactive T cells. The mechanism for how T cells acquire their encephalitogenic phenotype and trigger disease remains, however, unclear. The existence of lymphatic vessels in the meninges indicates a relevant link between the CNS and peripheral immune system, perhaps affecting autoimmunity. Here we demonstrate that meningeal lymphatics fulfill two critical criteria: they assist in the drainage of cerebrospinal fluid components and enable immune cells to enter draining lymph nodes in a CCR7-dependent manner. Unlike other tissues, meningeal lymphatic endothelial cells do not undergo expansion during inflammation, and they express a unique transcriptional signature. Notably, the ablation of meningeal lymphatics diminishes pathology and reduces the inflammatory response of brain-reactive T cells during an animal model of multiple sclerosis. Our findings demonstrate that meningeal lymphatics govern inflammatory processes and immune surveillance of the CNS and pose a valuable target for therapeutic intervention.


Assuntos
Encefalite/patologia , Encefalite/fisiopatologia , Vasos Linfáticos/fisiologia , Meninges/patologia , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Células Dendríticas/patologia , Modelos Animais de Doenças , Encefalite/induzido quimicamente , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Linfonodos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , MicroRNAs/genética , MicroRNAs/metabolismo , Glicoproteína Mielina-Oligodendrócito/toxicidade , Fragmentos de Peptídeos/toxicidade , Fármacos Fotossensibilizantes/farmacologia , Receptores CCR7/deficiência , Receptores CCR7/genética , Baço/patologia , Linfócitos T/fisiologia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
20.
J Immunol ; 201(3): 845-850, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29967099

RESUMO

Recent studies suggest that autism is often associated with dysregulated immune responses and altered microbiota composition. This has led to growing speculation about potential roles for hyperactive immune responses and the microbiome in autism. Yet how microbiome-immune cross-talk contributes to neurodevelopmental disorders currently remains poorly understood. In this study, we report critical roles for prenatal microbiota composition in the development of behavioral abnormalities in a murine maternal immune activation (MIA) model of autism that is driven by the viral mimetic polyinosinic-polycytidylic acid. We show that preconception microbiota transplantation can transfer susceptibility to MIA-associated neurodevelopmental disease and that this is associated with modulation of the maternal immune response. Furthermore, we find that ablation of IL-17a signaling provides protection against the development of neurodevelopmental abnormalities in MIA offspring. Our findings suggest that microbiota landscape can influence MIA-induced neurodevelopmental disease pathogenesis and that this occurs as a result of microflora-associated calibration of gestational IL-17a responses.


Assuntos
Transtorno Autístico/imunologia , Transtorno Autístico/microbiologia , Sistema Imunitário/imunologia , Microbiota/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Animais , Modelos Animais de Doenças , Feminino , Interleucina-17/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Poli I-C/imunologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/microbiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA