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PURPOSE: To determine correlations between chemicals in follicular fluid (FF) and follicular reproductive hormone levels. METHODS: The analysis was part of a larger cohort study to determine associations between exposure to EDCs and in vitro fertilization (IVF) outcomes. FF was aspirated from a single leading follicle per participant. Demographics and data on exposure to EDCs were self-reported by the participants using a questionnaire. The concentrations of estradiol (E2), progesterone (PG), anti-Mullerian hormone (AMH), and inhibin B, as well as that of 12 phthalate metabolites and 12 phenolic chemicals were measured in each FF sample. Multivariate linear regression model was used to identify the drivers of hormone levels based on participant's age, BMI, smoking status, and chemical exposure for the monitored chemicals detected in more than 50% of the samples. Benjamini-Hochberg false discovery rate (FDR) correction was applied on the resulting p values (q value). RESULTS: FF samples were obtained from 72 women (mean age 30.9 years). Most of the phthalates and phenolic substances monitored (21/24, 88%) were identified in FF. Ten compounds (7 phthalate metabolites, 3 phenols) were found in more than 50% of samples. In addition, there were positive associations between E2 levels and mono-n-butyl phthalate (MnBP) (beta = 0.01) and mono-isobutyl phthalate (MiBP) (beta = 0.03) levels (q value < 0.05). CONCLUSION: Higher concentrations of several phthalate metabolites, present among others in personal care products, were associated with increased E2 levels in FF. The results emphasize the need to further investigate the mechanisms of action of such EDCs on hormonal cyclicity and fertility in women.
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Hormônio Antimülleriano , Disruptores Endócrinos , Estradiol , Fertilização in vitro , Líquido Folicular , Ácidos Ftálicos , Progesterona , Humanos , Líquido Folicular/metabolismo , Líquido Folicular/química , Feminino , Adulto , Disruptores Endócrinos/análise , Ácidos Ftálicos/metabolismo , Ácidos Ftálicos/análise , Estradiol/análise , Estradiol/metabolismo , Progesterona/análise , Progesterona/metabolismo , Hormônio Antimülleriano/metabolismo , Inibinas/metabolismo , Fenóis/análiseRESUMO
Exposure to environmental pesticides during pregnancy is associated with adverse health outcomes such as low birth weight and impaired neuro-development. In this study, we assessed maternal leukocyte telomere lengths (TL) in Palestinian pregnant women and compared the data with urinary organophosphate concentrations, demographic, lifestyle and dietary factors, birth weight, body length, gestational age, and head circumference. Women with high urine levels of creatinine adjusted diethylphosphate(DE)derived pesticide metabolites DEP, DETP or DEDTP had shorter telomeres (p = 0.05). Women living in proximity to agricultural fields had shorter telomeres compared to women not living in proximity to agricultural fields (p = 0.011). Regular consumption of organic food was associated with shorter telomeres (p = 0.01), whereas the consumption of other vegetables such as artichokes was rather associated with longer telomeres. By contrast, urine levels of dimethylphosphate(DM)-derived pesticide metabolites DMTP and DMDTP were associated with lower birth weight (p = 0.05) but not with shrter telomeres. In conclusion organophosphate pesticides and living in proximity to agriculture are associated with shorter TL, likely due to higher consumption of contaminated fruits and vegetables and/or the transport of pesticides to non-treatment sites. DE and DM substituted pesticides seem to have different effects on telomeres and development.
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Poluentes Ambientais , Praguicidas , Humanos , Feminino , Gravidez , Praguicidas/metabolismo , Peso ao Nascer , Árabes , Poluentes Ambientais/metabolismo , Compostos Organofosforados/urina , Organofosfatos/metabolismo , Verduras/metabolismoRESUMO
During hematopoiesis, cells originating from the same stem cell reservoir differentiate into distinct cell types. The mechanisms enabling common progenitors to differentiate into alternative cell fates are not fully understood. Here, we identify cell-fate-determining transcription factors (TFs) governing dendritic cell (DC) development by annotating the enhancer landscapes of the DC lineage. Combining these analyses with detailed overexpression, knockdown, and ChIP-Seq studies, we show that Irf8 functions as a plasmacytoid DC epigenetic and fate-determining TF, regulating massive, cell-specific chromatin changes in thousands of pDC enhancers. Importantly, Irf8 forms a negative feedback loop with Cebpb, a monocyte-derived DC epigenetic fate-determining TF. We show that using this circuit logic, a pulse of TF expression can stably define epigenetic and transcriptional states, regardless of the microenvironment. More broadly, our study proposes a general paradigm that allows closely related cells with a similar set of signal-dependent factors to generate differential and persistent enhancer landscapes.
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Proteína beta Intensificadora de Ligação a CCAAT/fisiologia , Cromatina/fisiologia , Células Dendríticas/metabolismo , Elementos Facilitadores Genéticos , Fatores Reguladores de Interferon/fisiologia , Epigênese Genética , Retroalimentação Fisiológica , Células HEK293 , Humanos , Ligação Proteica , TranscriptomaRESUMO
STUDY QUESTION: Are phthalate metabolite concentrations in follicular fluid (FF) associated with the expression of extracellular vesicle microRNAs (EV-miRNAs)? SUMMARY ANSWER: Phthalate metabolite concentrations are associated with the expression of EV-miRNA and their associated pathways in FFs. WHAT IS KNOWN ALREADY: Phthalate metabolites were recently detected in FF. Urinary phthalate metabolite concentrations alter the expression of EV-miRNAs in FF. STUDY DESIGN, SIZE, DURATION: Prospective study including 105 women recruited between January 2014 and August 2016 in a tertiary university-affiliated hospital. PARTICIPANTS/MATERIALS, SETTING, METHODS: We assessed FF concentrations of 12 phthalate metabolites. EV-miRNAs were isolated from aliquots of the same FF, and their expression profiles were measured using a human miRNA panel. Associations between EV-miRNAs that were present in >50% of the samples and phthalate metabolites that were measured in >74% of the FF samples were tested. Genes regulated by EV-miRNAs that were found to be significantly (false discovery rate q-value < 0.1) correlated with FF-phthalates were analyzed for pathways linked with female fertility using miRWalk2.0 Targetscan database, DAVID Bioinformatics Resources and Kyoto Encyclopedia of Genes and Genomes (KEGG). MAIN RESULTS AND THE ROLE OF CHANCE: Of 12 phthalate metabolites, 11 were measured in at least one FF sample. Mono (6-COOH-2-methylheptyl) phthalate (MCOMHP), mono-2-ethyl-5-carboxypentyl phthalate (mECPP), mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), mono-isobutyl phthalate (MiBP), monoethyl phthalate (MEP) and mono (7-COOH-2-methyloctyl) phthalate (MCOMOP) were detected in more than 74% of the samples. Of 754 EV-miRNAs tested, 39 were significantly associated either with MEP, MBzP, MCOMOP, MCOMHP and/or with mECPP, after adjusting for multiple testing (P < 0.05). KEGG-based pathway enrichment analysis of the genes regulated by these miRNAs showed that these EV-miRNAs may be involved in pathways related to ovary or oocyte development, maturation and fertilization. LIMITATIONS, REASONS FOR CAUTION: The use of miRNA panel array limits the number of potential relevant miRNAs. Moreover, several of the phthalate metabolites examined may be biased due to internal (enzymatic activity) or external (contamination in medical interventions) causes. WIDER IMPLICATIONS OF THE FINDINGS: Phthalate metabolites may alter follicular EV-miRNAs profile and thus impair pathways that are involved with oocyte development, maturation and fertilization. Our results contribute to understanding of possible mechanism(s) in which endocrine disruptor chemicals interfere with female fertility. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the National Institutes of Environmental Health Sciences [Grant R21-ES024236]; and Environmental Health Fund, Israel [Grant 1301], no competing interests. TRIAL REGISTRATION NUMBER: N/A.
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Poluentes Ambientais , Vesículas Extracelulares , MicroRNAs , Ácidos Ftálicos , Exposição Ambiental/análise , Poluentes Ambientais/toxicidade , Feminino , Fertilização in vitro , Líquido Folicular , Humanos , Israel , MicroRNAs/genética , Estudos ProspectivosRESUMO
BACKGROUND: Recent studies conducted in several OECD countries have shown that chronic exposure to elevated levels of air pollutants (especially PM2.5, PM10 and NOx), might negatively impact COVID-19 morbidity and mortality rates. The aim of this study was to examine the association between chronic exposure to air pollution in Israeli cities and towns, their demographic and socioeconomic status, and COVID-19 morbidity, during the three local morbidity waves. METHODS: We examined the associations between: (a) annual average concentrations of NOx, CO, PM10, PM2.5 and SO2 in 2016-2019, and demographic and socioeconomic parameters, and (b) COVID-19 positive cases in 279 Israeli cities and towns, in the four state-wide morbidity peaks: 1st wave peak: March 31st, 2020; 2nd wave peaks: July 24th and September 27th, 2020, and the 3rd wave peak: January 17th, 2021, which occurred after the beginning of the nationwide vaccination campaign. These associations were calculated using both Spearman correlations and multivariate linear regressions. RESULTS: We found statistically significant positive correlations between the concentrations of most pollutants in 2016-19 and COVID-19 morbidity rate at the first three timepoints but not the 4th (January 17th, 2021). Population density and city/town total population were also positively associated with the COVID-19 morbidity rates at these three timepoints, but not the 4th, in which socioeconomic parameters were more dominant - we found a statistically significant negative correlation between socioeconomic cluster and COVID-19 morbidity. In addition, all multivariate models including PM2.5 concentrations were statistically significant, and PM2.5 concentrations were positively associated with the COVID-19 morbidity rates in all models. CONCLUSIONS: We found a nationwide association between population chronic exposure to five main air pollutants in Israeli cities and towns, and COVID-19 morbidity rates during two of the three morbidity waves experienced in Israel. The widespread morbidity that was related to socioeconomic factors during the 3rd wave, emphasizes the need for special attention to morbidity prevention in socioeconomically vulnerable populations and especially in large household communities. Nevertheless, this ecological study has several limitations, such as the inability to draw conclusions about causality or mechanisms of action. The growing body of evidence, regarding association between exacerbated COVID-19 morbidity and mortality rates and long-term chronic exposure to elevated concentrations of air pollutants should serve as a wake-up call to policy makers regarding the urgent need to reduce air pollution and its harmful effects.
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Poluentes Atmosféricos , Poluição do Ar , COVID-19 , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , COVID-19/epidemiologia , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Humanos , Israel/epidemiologia , Morbidade , Material Particulado/efeitos adversos , Material Particulado/análise , Fatores SocioeconômicosRESUMO
BACKGROUND: Exposure to ambient air pollution is related to 4.2 million premature deaths per year worldwide and is associated with a variety of adverse health outcomes, such as respiratory and cardiovascular morbidity. Furthermore, exposure to air pollution can increase human sensitivity to respiratory pathogens via damage to the respiratory tract or via airborne transmission on the surface of particulate matter, and might be an additional factor influencing COVID-19 morbidity and mortality rates. The aim of this study was to examine the association between populations' exposure to air pollution and the morbidity and mortality rates from COVID-19. METHODS: We examined the association between population-weighted long-term exposure to PM2.5 and NOx, and the morbidity and mortality over time following the detection of the first COVID-19 positive case in 36 OECD countries. Pearson and Spearman correlations between daily COVID-19 morbidity and mortality (Jan-Jun 2020) on the 10th, 20th, 40th, 60th and 80th days since first confirmed case in the country, and demographic, health, economic, and environmental data were calculated. Multivariate linear regression were used to examine the associations between demographic, health, economic and air pollution features and the rate of confirmed cases and deaths on the 60th and 80th days following the first confirmed case. RESULTS: PM2.5 concentrations in 2015-2017 were positively correlated with COVID-19 morbidity and mortality on the 10th, 20th, 40th and 60th days since the first confirmed case in all countries. NOx concentrations in 2015-2017 and country's density (population/Km2) were positively correlated with COVID-19 morbidity and mortality on the 60th day. All multivariate linear regressions consisting PM2.5 concentrations models were statistically significant. Our models also emphasize the importance of the relative number of hospital beds in decreasing the morbidity and mortality of COVID-19. CONCLUSIONS: The adverse health outcomes stemming from long-term exposure to various air pollutants has long been known to the scientific community. According to our results and previously published studies, it appears that long-term exposure to air pollutants concentrations exceeding WHO guidelines, such as PM2.5 and NOx, might exacerbate morbidity and mortality rates from COVID-19. These results should raise a red flag globally among decision makers about the urgent need to reduce air pollution and its harmful effects.
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Poluentes Atmosféricos , Poluição do Ar , COVID-19 , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/toxicidade , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Exposição Ambiental/análise , Humanos , Morbidade , Organização para a Cooperação e Desenvolvimento Econômico , Material Particulado/análise , Material Particulado/toxicidade , SARS-CoV-2RESUMO
INTRODUCTION: MRI guided focused ultrasound (MRgFUS) is a noninvasive technique for treating uterine fibroids. The presence of abdominal scars can limit the number of women eligible for the procedure, due to absorbance of beam energy. The goals of this study were to assess the number of women that fit the procedure and to compare outcomes among women with or without abdominal scars. MATERIAL AND METHODS: A prospective cohort study of all women that were interested in MRgFUS in a single University-Affiliated Hospital between November 2012 and December 2019. Rates of women that were referred to further screening, fulfilled selection criteria and underwent the procedure were compared between patients with or without abdominal scars. We evaluated the treatment parameters of the two groups and used linear regression model predict non-perfused volume (NPV) at the end of the process. RESULTS: Out of 701 patients, 21.8% were suitable for MRgFUS. Women with scars had significant lower NPV compared with women without scars (60% versus 82.4%, p = 0.021). No serious adverse events were reported in both groups. Linear regression models showed that fibroids' volume, stopping the treatment due to severe pain and the presence of abdominal scars had a statistically significantly negative effect on NPV (betas: -11.51, -6.96, and -6.29, p-values: <0.001, 0.003, and 0.007 respectively), while number of sonication had a statistically significantly positive effect on NPV (beta = 5.98, p = 0.011). CONCLUSION: Regardless of strict inclusion criteria, MRgFUS treatment is less efficient among women with abdominal scars, although still feasible for those who are interested in noninvasive option.
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Ablação por Ultrassom Focalizado de Alta Intensidade , Leiomioma , Neoplasias Uterinas , Cicatriz/diagnóstico por imagem , Feminino , Humanos , Leiomioma/diagnóstico por imagem , Leiomioma/cirurgia , Imageamento por Ressonância Magnética , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Hydraulic fracturing together with directional and horizontal well drilling (unconventional oil and gas (UOG) development) has increased substantially over the last decade. UOG development is a complex process presenting many potential environmental health hazards, raising serious public concern. AIM: To conduct a scoping review to assess what is known about the human health outcomes associated with exposure to UOG development. METHODS: We performed a literature search in MEDLINE and SCOPUS for epidemiological studies of exposure to UOG development and verified human health outcomes published through August 15, 2019. For each eligible study we extracted data on the study design, study population, health outcomes, exposure assessment approach, statistical methodology, and potential confounders. We reviewed the articles based on categories of health outcomes. RESULTS: We identified 806 published articles, most of which were published during the last three years. After screening, 40 peer-reviewed articles were selected for full text evaluation and of these, 29 articles met our inclusion criteria. Studies evaluated pregnancy outcomes, cancer incidence, hospitalizations, asthma exacerbations, sexually transmitted diseases, and injuries or mortality from traffic accidents. Our review found that 25 of the 29 studies reported at least one statistically significant association between the UOG exposure metric and an adverse health outcome. The most commonly studied endpoint was adverse birth outcomes, particularly preterm deliveries and low birth weight. Few studies evaluated the mediating pathways that may underpin these associations, highlighting a clear need for research on the potential exposure pathways and mechanisms underlying observed relationships. CONCLUSIONS: This review highlights the heterogeneity among studies with respect to study design, outcome of interest, and exposure assessment methodology. Though replication in other populations is important, current research points to a growing body of evidence of health problems in communities living near UOG sites.
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Estudos Epidemiológicos , Fraturamento Hidráulico , Resultado da Gravidez , Exposição Ambiental , Feminino , Humanos , Recém-Nascido , Gás Natural , Campos de Petróleo e Gás , GravidezRESUMO
BACKGROUND: Human biomonitoring (HBM) data is increasingly being compared to risk-based screening values to assess human health risk. However, as screening values have not been established for assessing biomarker concentrations of organophosphate (OP) pesticide metabolites, there are few studies using HBM data on urinary OP concentrations to assess human health risk. The purpose of the current study was to measure OP exposure in a sample of children in Israel; to explore associations between dietary patterns and OP exposure; and to assess risk of OP pesticides using urinary metabolite concentrations. METHODS: We recruited 103 children in Israel and collected demographic and dietary data and urinary samples, and measured creatinine and dialkyl phosphate (DAP) concentrations. We compared urinary DAP concentrations to international populations and analysed associations between fruit and vegetable consumption and urinary DAP concentrations. Using urinary DAP concentrations, we calculated estimated daily intakes (EDI) of OP pesticides in each child and compared those to the acceptable daily intake (ADI). RESULTS: Concentrations of several dialkyl phosphate metabolites (dimethylphosphate (DMP) and dimethylthiophosphate (DMTP)) were higher in our study population of Israeli children (geometric mean concentrations of DMP and DMTP were 6.6⯵g/L and 7.6⯵g/L, respectively) compared to children in the US, Canada, Spain, and Denmark. We found positive correlations between total fruit consumption and creatinine adjusted log transformed urinary DMP, DMTP, diethylthiophopshate (DETP), total dimethyl (DM) and total DAP concentrations (pâ¯<â¯0.05), positive correlations between cucumber consumption and diethylphosphate (DEP), DETP and diethyl (DE) concentrations (pâ¯<â¯0.05), and positive correlations between apple consumption and DETP concentrations (pâ¯=â¯0.02). Based on urinary DAP concentrations, we found that a portion of the children in our study had EDIs above the ADI, ranging from 2.9% to 79.4% of the children, depending on the active OP ingredient. CONCLUSIONS: We found that Israeli children in our study are widely exposed to OP pesticides; that levels of dimethyl metabolites were high compared to other international populations; and that fruit consumption was associated with higher urinary DAP levels. Using urinary DAP concentration data, we found that a portion of the children in our study may be exposed to OP pesticides at levels above those considered safe.
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Dieta , Exposição Ambiental , Compostos Organofosforados , Praguicidas , Canadá , Criança , Humanos , Israel , Organofosfatos , Medição de Risco , EspanhaRESUMO
CD74 is a cell-surface receptor for the cytokine macrophage migration inhibitory factor. Macrophage migration inhibitory factor binding to CD74 induces its intramembrane cleavage and the release of its cytosolic intracellular domain (CD74-ICD), which regulates cell survival. In the present study, we characterized the transcriptional activity of CD74-ICD in chronic lymphocytic B cells. We show that following CD74 activation, CD74-ICD interacts with the transcription factors RUNX (Runt related transcription factor) and NF-κB and binds to proximal and distal regulatory sites enriched for genes involved in apoptosis, immune response, and cell migration. This process leads to regulation of expression of these genes. Our results suggest that identifying targets of CD74 will help in understanding of essential pathways regulating B-cell survival in health and disease.
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PURPOSE: To assess whether machine learning methods provide advantage over classic statistical modeling for the prediction of IVF outcomes. METHODS: The study population consisted of 136 women undergoing a fresh IVF cycle from January 2014 to August 2016 at a tertiary, university-affiliated medical center. We tested the ability of two machine learning algorithms, support vector machine (SVM) and artificial neural network (NN), vs. classic statistics (logistic regression) to predict IVF outcomes (number of oocytes retrieved, mature oocytes, top-quality embryos, positive beta-hCG, clinical pregnancies, and live births) based on age and BMI, with or without clinical data. RESULTS: Machine learning algorithms (SVM and NN) based on age, BMI, and clinical features yielded better performances in predicting number of oocytes retrieved, mature oocytes, fertilized oocytes, top-quality embryos, positive beta-hCG, clinical pregnancies, and live births, compared with logistic regression models. While accuracies were 0.69 to 0.9 and 0.45 to 0.77 for NN and SVM, respectively, they were 0.34 to 0.74 using logistic regression models. CONCLUSIONS: Our findings suggest that machine learning algorithms based on age, BMI, and clinical data have an advantage over logistic regression for the prediction of IVF outcomes and therefore can assist fertility specialists' counselling and their patients in adjusting the appropriate treatment strategy.
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Fertilização in vitro/tendências , Nascido Vivo/genética , Aprendizado de Máquina , Oócitos/crescimento & desenvolvimento , Adulto , Feminino , Fertilidade/genética , Humanos , Modelos Logísticos , Recuperação de Oócitos/métodos , Indução da Ovulação/métodos , GravidezRESUMO
The bone marrow hosts NK cells whose distribution, motility and response to systemic immune challenge are poorly understood. At steady state, two-photon microscopy of the bone marrow in Ncr1gfp/+ mice captured motile NK cells interacting with dendritic cells. NK cells expressed markers and effector molecules of mature cells. Following poly (I:C) injection, RNA-Seq of NK cells revealed three phases of transcription featuring immune response genes followed by posttranscriptional processes and proliferation. Functionally, poly (I:C) promoted upregulation of granzyme B, enhanced cytotoxicity in vitro and in vivo, and, in the same individual cells, triggered proliferation. Two-photon imaging revealed that the proportion of sinusoidal NK cells decreased, while at the same time parenchymal NK cells accelerated, swelled and divided within the bone marrow. MVA viremia induced similar responses. Our findings demonstrate that the bone marrow is patrolled by mature NK cells that rapidly proliferate in response to systemic viral challenge while maintaining their effector functions.
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Medula Óssea/imunologia , Células Dendríticas/imunologia , Células Matadoras Naturais/imunologia , Viremia/imunologia , Animais , Antígenos Ly/genética , Diferenciação Celular , Movimento Celular , Proliferação de Células , Células Cultivadas , Citotoxicidade Imunológica , Granzimas/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Poli I-C/imunologia , Ativação ViralRESUMO
Exposure to air pollution is associated with a wide range of health effects, including increased respiratory symptoms, cancer, reproductive and birth defects, and premature death. Air quality measurements by standardized measuring equipment, although accurate, can only provide an estimate for part of the population, with decreasing accuracy further away from the monitoring sites. Estimating pollution levels over large geographical domains requires the use of air quality models which ideally incorporate air quality measurements. In order to estimate actual exposure of the population to air pollution (population-weighted concentrations of air pollutants), there is a need to combine data from air quality models with population density data. Here we present the results of exposure estimates for the entire population of Israel using a chemical transport model combined with measurements from the national monitoring network. We evaluated the individual exposure levels for the entire population to several air pollutants based on census tract units. Using this hybrid model, we found that the entire population of Israel is exposed to concentrations of PM10 and PM2.5 that exceed the target values but are below the environmental values according to the Israeli Clean Air Law. In addition, we found and that over 1.5 million residents are exposed to NOx at concentrations higher than the target values. This data may help decision makers develop targeted interventions to reduce the concentrations of specific pollutants, based on population-weighted exposure.
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Poluentes Atmosféricos/análise , Exposição Ambiental/estatística & dados numéricos , Modelos Estatísticos , Poluição do Ar/análise , Poluição do Ar/estatística & dados numéricos , Exposição Ambiental/análise , Monitoramento Ambiental , Humanos , Israel , Mortalidade Prematura , Material Particulado/análise , Fatores de TempoRESUMO
Tissue microenvironment influences the function of resident and infiltrating myeloid-derived cells. In the central nervous system (CNS), resident microglia and freshly recruited infiltrating monocyte-derived macrophages (mo-MΦ) display distinct activities under pathological conditions, yet little is known about the microenvironment-derived molecular mechanism that regulates these differences. Here, we demonstrate that long exposure to transforming growth factor-ß1 (TGFß1) impaired the ability of myeloid cells to acquire a resolving anti-inflammatory phenotype. Using genome-wide expression analysis and chromatin immunoprecipitation followed by next-generation sequencing, we show that the capacity to undergo pro- to anti-inflammatory (M1-to-M2) phenotype switch is controlled by the transcription factor interferon regulatory factor 7 (IRF7) that is down-regulated by the TGFß1 pathway. RNAi-mediated perturbation of Irf7 inhibited the M1-to-M2 switch, while IFNß1 (an IRF7 pathway activator) restored it. In vivo induction of Irf7 expression in microglia, following spinal cord injury, reduced their pro-inflammatory activity. These results highlight the key role of tissue-specific environmental factors in determining the fate of resident myeloid-derived cells under both physiological and pathological conditions.
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Regulação da Expressão Gênica/efeitos dos fármacos , Fator Regulador 7 de Interferon/metabolismo , Células Mieloides/efeitos dos fármacos , Células Mieloides/imunologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Imunoprecipitação da Cromatina , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Camundongos Endogâmicos C57BLRESUMO
T-cell development is a spatially and temporally regulated process, orchestrated by well-defined contributions of transcription factors and cytokines. Here, we identify the noncoding RNA miR-142 as an additional regulatory layer within murine thymocyte development and proliferation. MiR-142 deficiency impairs the expression of cell cycle-promoting genes in mature mouse thymocytes and early progenitors, accompanied with increased levels of cyclin-dependent kinase inhibitor 1B (Cdkn1b, also known as p27Kip1 ). By using CRISPR/Cas9 technology to delete the miR-142-3p recognition element in the 3'UTR of cdkn1b, we confirm that this gene is a novel target of miR-142-3p in vivo. Increased Cdkn1b protein expression alone however was insufficient to cause proliferation defects in thymocytes, indicating the existence of additional critical miR-142 targets. Collectively, we establish a key role for miR-142 in the control of early and mature thymocyte proliferation, demonstrating the multifaceted role of a single miRNA on several target genes.
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Inibidor de Quinase Dependente de Ciclina p27/genética , MicroRNAs/metabolismo , Timócitos/fisiologia , Regiões 3' não Traduzidas , Animais , Sistemas CRISPR-Cas , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p27/deficiência , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Regulação Neoplásica da Expressão Gênica , Camundongos , MicroRNAs/genética , Processamento Pós-Transcricional do RNARESUMO
Hundreds of immune cell types work in coordination to maintain tissue homeostasis. Upon infection, dramatic changes occur with the localization, migration, and proliferation of the immune cells to first alert the body of the danger, confine it to limit spreading, and finally extinguish the threat and bring the tissue back to homeostasis. Since current technologies can follow the dynamics of only a limited number of cell types, we have yet to grasp the full complexity of global in vivo cell dynamics in normal developmental processes and disease. Here, we devise a computational method, digital cell quantification (DCQ), which combines genome-wide gene expression data with an immune cell compendium to infer in vivo changes in the quantities of 213 immune cell subpopulations. DCQ was applied to study global immune cell dynamics in mice lungs at ten time points during 7 days of flu infection. We find dramatic changes in quantities of 70 immune cell types, including various innate, adaptive, and progenitor immune cells. We focus on the previously unreported dynamics of four immune dendritic cell subtypes and suggest a specific role for CD103(+) CD11b(-) DCs in early stages of disease and CD8(+) pDC in late stages of flu infection.
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Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Influenza Humana/imunologia , Animais , Antígenos CD/imunologia , Antígenos CD/metabolismo , Antígeno CD11b/imunologia , Citometria de Fluxo , Humanos , Influenza Humana/metabolismo , Influenza Humana/patologia , Cadeias alfa de Integrinas/imunologia , Cadeias alfa de Integrinas/metabolismo , Pulmão/imunologia , Camundongos , Transcriptoma/imunologiaRESUMO
Distance stereoacuity measurement enables the evaluation and management of binocular vision disorders. Here, we compare the results obtained using standard tests for distance stereoacuity measurement with the novel STab test. We tested 87 children (4-17 years of age) using different tests for the quantification of stereopsis at distance: Distance Randot Stereotest (DRS), M&S random dots (M&S), and STab. A strong correlation was demonstrated between M&S-DRS (0.8), M&S-STab (0.81), DRS-STab (0.85) (all P < 0.0001). The limit of agreement between M&S and DRS was 0.45; between M&S and STab, 0.47; and between DRS and STab, 0.38. Our results suggest that all three methods can be used interchangeably.
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Percepção de Profundidade , Testes Visuais , Visão Binocular , Acuidade Visual , Humanos , Criança , Pré-Escolar , Percepção de Profundidade/fisiologia , Adolescente , Acuidade Visual/fisiologia , Feminino , Masculino , Testes Visuais/métodos , Visão Binocular/fisiologia , Percepção de Distância/fisiologiaRESUMO
BACKGROUND: Climate change is leading to an increase in the frequency and intensity of heatwaves in many regions of the world. Climate change is also related to air pollution. Both heatwaves and air pollution have adverse health effects, and can also affect social behaviors, including tourism and touristic activities. The aim of this study was to examine the association between heatwaves, air pollution and visits to national parks and reserves in Israel. METHODS: Data on 68,518 visits in 51 national parks and reserves in Israel in the years 2016-2019 was crossed with temperature and air pollution data (represented by particulate matter PM10) and analyzed using statistical tests. RESULTS: Number of visits, as a function of temperature followed a unimodal distribution, in which more visits were reported on mild temperature days (in comparison to hot or cold days). In addition, the number of visits in sites with beaches was linearly correlated with temperature. Negative associations were found between number of visits and heatwaves, and between number of visits and exceedances in PM10 levels. CONCLUSIONS: Heatwaves were shown to have a negative effect on the number of visits in national parks and reserves in Israel. The negative association between exceedances in air pollution and number of visits may be mediated by the positive correlation between air pollution exceedance events and heatwaves.
Assuntos
Poluentes Atmosféricos , Poluição do Ar , Parques Recreativos , Poluição do Ar/análise , Material Particulado/análise , Temperatura , Temperatura Baixa , Poluentes Atmosféricos/análiseRESUMO
BACKGROUND: Development of antimicrobial resistance poses a major threat to human and animal health worldwide. Antimicrobials are frequently used in animal husbandry, making food-producing animals a widespread and important source of antimicrobial resistance. Indeed, recent evidence demonstrates that antimicrobial resistance in food-producing animals poses a threat to the health of humans, animals and the environment. To address this threat, national action plans have been implemented based on a 'One Health' approach, which integrates actions across human and animal health sectors to combat antimicrobial resistance. Although under development, Israel has yet to publish a national action plan against antimicrobial resistance, despite alarming findings of resistant bacteria in food-producing animals in the country. Here we review several national action plans against antimicrobial resistance around the world in order to suggest approaches to develop a national action plan in Israel. MAIN BODY: We investigated worldwide national action plans against antimicrobial resistance based on a 'One Health' approach. We also conducted interviews with representatives of relevant Israeli ministries to understand antimicrobial resistance policy and regulatory frameworks in Israel. Finally, we present recommendations for Israel towards implementing a 'One Health' national action plan against antimicrobial resistance. Many countries have developed such plans, however, only a few are currently funded. Furthermore, many countries, especially in Europe, have taken action to reduce the use of antimicrobials and the spread of antimicrobial resistance in food-producing animals by banning the use of antimicrobials to promote growth, reporting data on the use and sales of antimicrobials in food-producing animals, operating centralized antimicrobial resistance surveillance systems and preventing the use of antimicrobials important to human medicine to treat food-producing animals. CONCLUSIONS: Without a comprehensive and funded national action plan, the risks of antimicrobial resistance to the public health in Israel will escalate. Thus, several actions should be considered: (1) Reporting data on the use of antimicrobials in humans and animals. (2) Operating a centralized surveillance system for antimicrobial resistance in humans, animals and the environment. (3) Improving awareness regarding antimicrobial resistance in the general public and in health practitioners from both human and animal sectors. (4) Composing a list of critically important antimicrobials to human medicine that's use should be avoided in food-producing animals. (5) Enforcing best practices of antimicrobial use at the farm-level. (6) Reducing incidence of infection through farm biosecurity. (7) Supporting research and development of new antimicrobial treatments, vaccines and diagnostic tools.