RESUMO
Regulatory landscapes drive complex developmental gene expression, but it remains unclear how their integrity is maintained when incorporating novel genes and functions during evolution. Here, we investigated how a placental mammal-specific gene, Zfp42, emerged in an ancient vertebrate topologically associated domain (TAD) without adopting or disrupting the conserved expression of its gene, Fat1. In ESCs, physical TAD partitioning separates Zfp42 and Fat1 with distinct local enhancers that drive their independent expression. This separation is driven by chromatin activity and not CTCF/cohesin. In contrast, in embryonic limbs, inactive Zfp42 shares Fat1's intact TAD without responding to active Fat1 enhancers. However, neither Fat1 enhancer-incompatibility nor nuclear envelope-attachment account for Zfp42's unresponsiveness. Rather, Zfp42's promoter is rendered inert to enhancers by context-dependent DNA methylation. Thus, diverse mechanisms enabled the integration of independent Zfp42 regulation in the Fat1 locus. Critically, such regulatory complexity appears common in evolution as, genome wide, most TADs contain multiple independently expressed genes.
Assuntos
Cromatina , Placenta , Animais , Fator de Ligação a CCCTC/metabolismo , Montagem e Desmontagem da Cromatina , Elementos Facilitadores Genéticos , Evolução Molecular , Feminino , Genoma , Mamíferos/metabolismo , Placenta/metabolismo , Gravidez , Regiões Promotoras Genéticas , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Developmental genes such as Xist, which initiates X chromosome inactivation, are controlled by complex cis-regulatory landscapes, which decode multiple signals to establish specific spatiotemporal expression patterns. Xist integrates information on X chromosome dosage and developmental stage to trigger X inactivation in the epiblast specifically in female embryos. Through a pooled CRISPR screen in differentiating mouse embryonic stem cells, we identify functional enhancer elements of Xist at the onset of random X inactivation. Chromatin profiling reveals that X-dosage controls the promoter-proximal region, while differentiation cues activate several distal enhancers. The strongest distal element lies in an enhancer cluster associated with a previously unannotated Xist-enhancing regulatory transcript, which we named Xert. Developmental cues and X-dosage are thus decoded by distinct regulatory regions, which cooperate to ensure female-specific Xist upregulation at the correct developmental time. With this study, we start to disentangle how multiple, functionally distinct regulatory elements interact to generate complex expression patterns in mammals.
Assuntos
Elementos Facilitadores Genéticos , Loci Gênicos , Células-Tronco Embrionárias Murinas/metabolismo , Regiões Promotoras Genéticas , RNA Longo não Codificante/genética , Inativação do Cromossomo X , Cromossomo X , Animais , Diferenciação Celular , Linhagem Celular , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Regulação para CimaRESUMO
Mouse models are a critical tool for studying human diseases, particularly developmental disorders1. However, conventional approaches for phenotyping may fail to detect subtle defects throughout the developing mouse2. Here we set out to establish single-cell RNA sequencing of the whole embryo as a scalable platform for the systematic phenotyping of mouse genetic models. We applied combinatorial indexing-based single-cell RNA sequencing3 to profile 101 embryos of 22 mutant and 4 wild-type genotypes at embryonic day 13.5, altogether profiling more than 1.6 million nuclei. The 22 mutants represent a range of anticipated phenotypic severities, from established multisystem disorders to deletions of individual regulatory regions4,5. We developed and applied several analytical frameworks for detecting differences in composition and/or gene expression across 52 cell types or trajectories. Some mutants exhibit changes in dozens of trajectories whereas others exhibit changes in only a few cell types. We also identify differences between widely used wild-type strains, compare phenotyping of gain- versus loss-of-function mutants and characterize deletions of topological associating domain boundaries. Notably, some changes are shared among mutants, suggesting that developmental pleiotropy might be 'decomposable' through further scaling of this approach. Overall, our findings show how single-cell profiling of whole embryos can enable the systematic molecular and cellular phenotypic characterization of mouse mutants with unprecedented breadth and resolution.
Assuntos
Deficiências do Desenvolvimento , Embrião de Mamíferos , Mutação , Fenótipo , Análise da Expressão Gênica de Célula Única , Animais , Camundongos , Núcleo Celular/genética , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Mutação com Ganho de Função , Genótipo , Mutação com Perda de Função , Modelos Genéticos , Modelos Animais de DoençasRESUMO
Long non-coding RNAs (lncRNAs) can be important components in gene-regulatory networks1, but the exact nature and extent of their involvement in human Mendelian disease is largely unknown. Here we show that genetic ablation of a lncRNA locus on human chromosome 2 causes a severe congenital limb malformation. We identified homozygous 27-63-kilobase deletions located 300 kilobases upstream of the engrailed-1 gene (EN1) in patients with a complex limb malformation featuring mesomelic shortening, syndactyly and ventral nails (dorsal dimelia). Re-engineering of the human deletions in mice resulted in a complete loss of En1 expression in the limb and a double dorsal-limb phenotype that recapitulates the human disease phenotype. Genome-wide transcriptome analysis in the developing mouse limb revealed a four-exon-long non-coding transcript within the deleted region, which we named Maenli. Functional dissection of the Maenli locus showed that its transcriptional activity is required for limb-specific En1 activation in cis, thereby fine-tuning the gene-regulatory networks controlling dorso-ventral polarity in the developing limb bud. Its loss results in the En1-related dorsal ventral limb phenotype, a subset of the full En1-associated phenotype. Our findings demonstrate that mutations involving lncRNA loci can result in human Mendelian disease.
Assuntos
Extremidades , Proteínas de Homeodomínio/genética , Deformidades Congênitas dos Membros/genética , RNA Longo não Codificante/genética , Deleção de Sequência/genética , Transcrição Gênica , Ativação Transcricional/genética , Animais , Linhagem Celular , Cromatina/genética , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos TransgênicosRESUMO
During embryogenesis, precise gene transcription in space and time requires that distal enhancers and promoters communicate by physical proximity within gene regulatory landscapes. To achieve this, regulatory landscapes fold in nuclear space, creating complex 3D structures that influence enhancer-promoter communication and gene expression and that, when disrupted, can cause disease. Here, we provide an overview of how enhancers and promoters construct regulatory landscapes and how multiple scales of 3D chromatin structure sculpt their communication. We focus on emerging views of what enhancer-promoter contacts and chromatin domains physically represent and how two antagonistic fundamental forces-loop extrusion and homotypic attraction-likely form them. We also examine how these same forces spatially separate regulatory landscapes by functional state, thereby creating higher-order compartments that reconfigure during development to enable proper enhancer-promoter communication.
Assuntos
Cromatina/ultraestrutura , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica no Desenvolvimento , Genoma , Regiões Promotoras Genéticas , Transcrição Gênica , Animais , Núcleo Celular/genética , Núcleo Celular/metabolismo , Núcleo Celular/ultraestrutura , Cromatina/metabolismo , Embrião de Mamíferos , Desenvolvimento Embrionário/genética , Células Eucarióticas/metabolismo , Células Eucarióticas/ultraestrutura , Humanos , Conformação MolecularRESUMO
Heteromorphic sex chromosomes (XY or ZW) present problems of gene dosage imbalance between sexes and with autosomes. A need for dosage compensation has long been thought to be critical in vertebrates. However, this was questioned by findings of unequal mRNA abundance measurements in monotreme mammals and birds. Here, we demonstrate unbalanced mRNA levels of X genes in platypus males and females and a correlation with differential loading of histone modifications. We also observed unbalanced transcripts of Z genes in chicken. Surprisingly, however, we found that protein abundance ratios were 1:1 between the sexes in both species, indicating a post-transcriptional layer of dosage compensation. We conclude that sex chromosome output is maintained in chicken and platypus (and perhaps many other non therian vertebrates) via a combination of transcriptional and post-transcriptional control, consistent with a critical importance of sex chromosome dosage compensation.
Assuntos
Galinhas , Mecanismo Genético de Compensação de Dose , Ornitorrinco , Cromossomos Sexuais , Animais , Galinhas/genética , Cromossomos Sexuais/genética , Masculino , Feminino , Ornitorrinco/genética , Transcrição Gênica , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
The first record of captive-bred red foxes (Vulpes vulpes) dates to 1896 when a breeding enterprise emerged in the provinces of Atlantic Canada. Because its domestication happened during recent history, the red fox offers a unique opportunity to examine the genetic diversity of an emerging domesticated species in the context of documented historical and economic influences. In particular, the historical record suggests that North American and Eurasian farm-bred populations likely experienced different demographic trajectories. Here, we focus on the likely impacts of founder effects and genetic drift given historical trends in fox farming on North American and Eurasian farms. A total of 15 mitochondrial haplotypes were identified in 369 foxes from 10 farm populations that we genotyped (nâ =â 161) or that were previously published. All haplotypes are endemic to North America. Although most haplotypes were consistent with eastern Canadian ancestry, a small number of foxes carried haplotypes typically found in Alaska and other regions of western North America. The presence of these haplotypes supports historical reports of wild foxes outside of Atlantic Canada being introduced into the breeding stock. These putative Alaskan and Western haplotypes were more frequently identified in Eurasian farms compared to North American farms, consistent with historical documentation suggesting that Eurasian economic and breeding practices were likely to maintain low-frequency haplotypes more effectively than in North America. Contextualizing inter- vs. intra-farm genetic diversity alongside the historical record is critical to understanding the origins of this emerging domesticate and the relationships between wild and farm-bred fox populations.
Assuntos
Raposas , Variação Genética , Haplótipos , Raposas/genética , Animais , DNA Mitocondrial/genética , Canadá , Genética Populacional , Animais Domésticos/genética , Domesticação , Cruzamento , Efeito Fundador , Deriva Genética , FazendasRESUMO
Whether gene repositioning to the nuclear periphery during differentiation adds another layer of regulation to gene expression remains controversial. Here, we resolve this by manipulating gene positions through targeting the nuclear envelope transmembrane proteins (NETs) that direct their normal repositioning during myogenesis. Combining transcriptomics with high-resolution DamID mapping of nuclear envelope-genome contacts, we show that three muscle-specific NETs, NET39, Tmem38A, and WFS1, direct specific myogenic genes to the nuclear periphery to facilitate their repression. Retargeting a NET39 fragment to nucleoli correspondingly repositioned a target gene, indicating a direct tethering mechanism. Being able to manipulate gene position independently of other changes in differentiation revealed that repositioning contributes â to â of a gene's normal repression in myogenesis. Together, these NETs affect 37% of all genes changing expression during myogenesis, and their combined knockdown almost completely blocks myotube formation. This unequivocally demonstrates that NET-directed gene repositioning is critical for developmental gene regulation.
Assuntos
Posicionamento Cromossômico , Regulação da Expressão Gênica no Desenvolvimento , Canais Iônicos/genética , Proteínas de Membrana/genética , Desenvolvimento Muscular/genética , Fibras Musculares Esqueléticas/metabolismo , Mioblastos Esqueléticos/metabolismo , Membrana Nuclear/metabolismo , Proteínas Nucleares/genética , Animais , Diferenciação Celular , Linhagem Celular , Regulação para Baixo , Humanos , Canais Iônicos/metabolismo , Cinética , Proteínas de Membrana/metabolismo , Camundongos , Proteínas Nucleares/metabolismo , Interferência de RNA , TransfecçãoRESUMO
BACKGROUND: Improving the understanding of non-clinical factors that lead to the increasing caesarean section (CS) rates in many low- and middle-income countries is currently necessary to meet the challenge of implementing effective interventions in hospitals to reverse the trend. The objective of this study was to study the influence of organizational factors on the CS use in Argentina, Vietnam, Thailand and Burkina Faso. METHODS: A cross-sectional hospital-based postpartum survey was conducted in 32 hospitals (8 per country). We selected women with no potential medical need for CS among a random sample of women who delivered at each of the participating facilities during the data collection period. We used multilevel multivariable logistic regression to analyse the association between CS use and organizational factors, adjusted on women's characteristics. RESULTS: A total of 2,092 low-risk women who had given birth in the participating hospitals were included. The overall CS rate was 24.1%, including 4.9% of pre-labour CS and 19.3% of intra-partum CS. Pre-labour CS was significantly associated with a 24-hour anaesthetist dedicated to the delivery ward (ORa = 3.70 [1.41; 9.72]) and with the possibility to have an individual room during labour and delivery (ORa = 0.28 [0.09; 0.87]). Intra-partum CS was significantly associated with a higher bed occupancy level (ORa = 1.45 [1.09; 1.93]): intrapartum CS rate would increase of 6.3% points if the average number of births per delivery bed per day increased by 10%. CONCLUSION: Our results suggest that organisational norms and convenience associated with inadequate use of favourable resources, as well as the lack of privacy favouring women's preference for CS, and the excessive workload of healthcare providers drive the CS overuse in these hospitals. It is also crucial to enhance human and physical resources in delivery rooms and the organisation of intrapartum care to improve the birth experience and the working environment for those providing care. TRIAL REGISTRATION: The QUALI-DEC trial is registered on the Current Controlled Trials website ( https://www.isrctn.com/ ) under the number ISRCTN67214403.
Assuntos
Cesárea , Países em Desenvolvimento , Gravidez , Feminino , Humanos , Estudos Transversais , Argentina , Burkina Faso , Tailândia , Vietnã , HospitaisRESUMO
Antibodies to neutrophil and monocyte myeloperoxidase and proteinase 3 are a feature of anti-neutrophil cytoplasmic antibody vasculitis, a disease with significant morbidity for which new treatments are needed. Mice with a myeloid-specific deletion of the anti-apoptotic protein Mcl1 have reduced numbers of circulating neutrophils. Here, we assessed if myeloid-specific Mcl1 was required in murine anti-myeloperoxidase vasculitis and whether inhibition of myeloperoxidase was protective. In a murine model of anti-neutrophil cytoplasmic antibody vasculitis, induced by anti-myeloperoxidase antibody, mice with a myeloid-specific deletion of Mcl1 were protected from disease. They had fewer crescents, neutrophils, and macrophages in the glomeruli, lower serum creatinine levels and reduced albuminuria compared with controls. At baseline and day six after disease induction they had fewer circulating neutrophils than controls. At day six there were also fewer circulating monocytes. Myeloperoxidase inhibition with AZD5904 had no effect on histological or biochemical parameters of disease, and there was also no reduction in albuminuria at day one, two, five or seven after disease induction. These findings persisted when disease was induced without granulocyte-colony stimulating factor, which increases disease severity. A second myeloperoxidase inhibitor, AZM198, also showed no evidence of an effect, although both AZD5904 and AZM198 inhibited human neutrophil extracellular trap formation in vitro. Thus, our results show that while myeloid-specific Mcl1 is required in this model of anti-myeloperoxidase vasculitis, myeloperoxidase inhibition is not protective.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Glomerulonefrite , Vasculite , Camundongos , Humanos , Animais , Anticorpos Anticitoplasma de Neutrófilos , Proteínas Reguladoras de Apoptose/metabolismo , Albuminúria/prevenção & controle , Albuminúria/metabolismo , Vasculite/prevenção & controle , Neutrófilos , Peroxidase , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismoRESUMO
Antimyeloperoxidase (anti-MPO) and antiproteinase 3 (anti-PR3) antibodies are found in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). We investigated the effect of both anti-MPO and anti-PR3 IgG on human monocytes. Peripheral blood monocytes were cultured under a range of conditions that included TLR agonists, anti-MPO IgG and anti-PR3 IgG with appropriate controls. Experiments included whole transcriptome profiling and an assessment of the role of Fc receptors. When monocytes were stimulated with LPS or R848, anti-MPO but not anti-PR3 IgG, caused a reduction in IL-10 secretion and had a profound effect on cell-surface marker expression. Anti-MPO but not anti-PR3 IgG enhanced monocyte survival in the absence of TLR stimulation. These effects depended on the Fc receptor CD32a. With TLR stimulation, the effect of anti-MPO but not anti-PR3 IgG on the transcriptional response at 6 h was variable, but we identified a core set of transcripts likely to be important. Without TLR stimulation, there was a robust effect of anti-MPO but not anti-PR3 IgG on the transcriptional response at 24 h, and there was a highly significant enrichment of genes encoding extracellular matrix and extracellular matrix-associated proteins. Analysis with nCounter confirmed many of the differentially expressed transcripts and supported a role for CD32a. These data show that anti-MPO, but not anti-PR3 IgG, from patients with AAV has wide-ranging effects on monocytes which depend on CD32a. The activation of a profibrotic transcriptional response by anti-MPO but not anti-PR3 IgG may give insights into the differences in disease phenotype.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Monócitos , Humanos , Mieloblastina , Receptores Fc/genética , Imunoglobulina G , Anticorpos Anticitoplasma de Neutrófilos , PeroxidaseRESUMO
Cesarean birth has increased substantially in many parts of the world over recent decades and concerns have been raised about the propriety of this change in obstetric practice. Sometimes, a cesarean is necessary to preserve fetal and maternal health. But in balancing the risks of surgical intervention the implicit assumption has been that cesarean birth is an equivalent alternative to vaginal birth from the standpoint of the immediate and long-term health of the fetus and neonate. Increasingly, we realize this is not necessarily so. Delivery mode per se may influence short-term and abiding problems with homeostasis in offspring, quite independent of the indications for the delivery and other potentially confounding factors. The probability of developing various disorders, including respiratory compromise, obesity, immune dysfunction, and neurobehavioral disorders has been shown in some studies to be higher among individuals born by cesarean. Moreover, many of these adverse effects are not confined to the neonatal period and may develop over many years. Although the associations between delivery mode and long-term health are persuasive, their pathogenesis and causality remain uncertain. Full exploration and a clear understanding of these relationships is of great importance to the health of offspring.
Assuntos
Cesárea , Obesidade , Gravidez , Recém-Nascido , Feminino , Humanos , Cesárea/efeitos adversos , Parto , Cuidado Pré-Natal , Parto ObstétricoRESUMO
AIMS: Rapidly progressive crescentic glomerulonephritis occurs in number systemic and primary glomerular diseases, including anti-glomerular basement membrane disease, anti-neutrophil cytoplasmic antibody vasculitis and lupus nephritis. Our understanding of pathogenic mechanisms comes from animal models of disease such as the nephrotoxic nephritis model. The lectin pathway of complement activation has been shown to play a key role in several models of inflammation including renal ischaemia reperfusion. However, the lectin pathway is not required for crescentic glomerulonephritis in the anti-myeloperoxidase model of anti-neutrophil cytoplasmic antibody vasculitis. The aim of the current study was to explore the role of the lectin pathway in the nephrotoxic nephritis model, which is another model of crescentic glomerulonephritis. METHODS: Nephrotoxic nephritis was induced in wild type and mannan-binding lectin-associated serine protease-2 deficient mice. Diseases were assessed by quantifying glomerular crescents and macrophages, in addition to albuminuria and serum creatinine. RESULTS: There was no difference between wild type and MASP-2 deficient mice in any of the histological or biochemical parameters of disease assessed. In addition, there was no difference in the humoral immune response to sheep IgG. CONCLUSION: These data show that the lectin pathway of complement activation is not required for the development of crescentic glomerulonephritis in the nephrotoxic nephritis model, reinforcing previous findings in the anti-myeloperoxidase model.
Assuntos
Glomerulonefrite/imunologia , Lectinas/imunologia , Animais , Ativação do Complemento , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The role of paclitaxel-coated balloons has been established in the coronary and peripheral arterial circulations with recent interest in the use of paclitaxel-coated balloons to improve patency rates following angioplasty of arteriovenous fistulas. To assess the efficacy of paclitaxel-coated angioplasty balloons to prolong the survival time of target lesion primary patency in arteriovenous fistulas, we designed an investigator-led multi-center randomized controlled trial with follow up time variable for a minimum of one year. Patients with an arteriovenous fistula who were undergoing an angioplasty for a clinical indication were included but patients with one or more lesions outside the treatment segment were excluded. Following successful treatment with a high-pressure balloon, 212 patients were randomized. In the intervention arm, the second component was insertion of a paclitaxel-coated balloon. In the control arm, an identical procedure was followed, but using a standard balloon. The primary endpoint was time to loss of clinically driven target lesion primary patency. Primary analysis showed no significant evidence for a difference in time to end of target lesion primary patency between groups: hazard ratio 1.18 with a 95% confidence interval of 0.78 to 1.79. There were no significant differences for any secondary outcomes, including patency outcomes and adverse events. Thus, our study demonstrated no evidence that paclitaxel-coated balloons provide benefit, following standard care high-pressure balloon angioplasty, in the treatment of arteriovenous fistulas. Hence, in view of the benefit suggested by other trials, the role of paclitaxel-coated angioplasty balloons remains uncertain.
Assuntos
Angioplastia com Balão , Fístula Arteriovenosa , Derivação Arteriovenosa Cirúrgica , Fármacos Cardiovasculares , Angioplastia com Balão/efeitos adversos , Derivação Arteriovenosa Cirúrgica/efeitos adversos , Materiais Revestidos Biocompatíveis , Humanos , Paclitaxel/efeitos adversos , Diálise Renal/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Grau de Desobstrução VascularRESUMO
The 3D organization of the genome changes concomitantly with expression changes during hematopoiesis and immune activation. Studies have focused either on lamina-associated domains (LADs) or on topologically associated domains (TADs), defined by preferential local chromatin interactions, and chromosome compartments, defined as higher-order interactions between TADs sharing functionally similar states. However, few studies have investigated how these affect one another. To address this, we mapped LADs using Lamin B1-DamID during Jurkat T-cell activation, finding significant genome reorganization at the nuclear periphery dominated by release of loci frequently important for T-cell function. To assess how these changes at the nuclear periphery influence wider genome organization, our DamID data sets were contrasted with TADs and compartments. Features of specific repositioning events were then tested by fluorescence in situ hybridization during T-cell activation. First, considerable overlap between TADs and LADs was observed with the TAD repositioning as a unit. Second, A1 and A2 subcompartments are segregated in 3D space through differences in proximity to LADs along chromosomes. Third, genes and a putative enhancer in LADs that were released from the periphery during T-cell activation became preferentially associated with A2 subcompartments and were constrained to the relative proximity of the lamina. Thus, lamina associations influence internal nuclear organization, and changes in LADs during T-cell activation may provide an important additional mode of gene regulation.
Assuntos
Cromossomos Humanos/metabolismo , Elementos Facilitadores Genéticos , Lamina Tipo B/metabolismo , Ativação Linfocitária , Proteínas de Neoplasias/metabolismo , Membrana Nuclear/metabolismo , Linfócitos T/metabolismo , Cromossomos Humanos/genética , Humanos , Células Jurkat , Lamina Tipo B/genética , Proteínas de Neoplasias/genética , Membrana Nuclear/genética , Linfócitos T/citologiaRESUMO
V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA) is a negative checkpoint regulator of T cells. We assessed VISTA deficient mice in the murine nephrotoxic nephritis models of acute and chronic immune-complex mediated glomerulonephritis. We show that VISTA deficiency protects from crescentic glomerulonephritis, with no effect on the nephritogenic adaptive immune response. The early neutrophil influx was unaffected but proteinuria was reduced suggesting a reduction in neutrophil activation. In vivo, there was reduced neutrophil degranulation in VISTA deficienct mice and, in vitro, VISTA-deficient neutrophils had an impaired response to immune complexes but not to fMLP or PMA. Mice with a genetic deficiency of neutrophils due to myeloid-specific deletion of myeloid cell leukemia 1 (Mcl-1) were also protected from crescentic glomerulonephritis, indicating an essential role for neutrophils. Therefore, VISTA deficiency inhibits neutrophil activation by immune complexes and neutrophil-dependent crescentic glomerulonephritis. This suggests that VISTA is a therapeutic target for inflammatory disease. However, this would need to be balanced against a potential enhancing effect on autoimmunity.
Assuntos
Complexo Antígeno-Anticorpo/imunologia , Glomerulonefrite/imunologia , Glomérulos Renais/patologia , Proteínas de Membrana/deficiência , Neutrófilos/imunologia , Animais , Modelos Animais de Doenças , Adjuvante de Freund/administração & dosagem , Adjuvante de Freund/imunologia , Glomerulonefrite/sangue , Glomerulonefrite/patologia , Humanos , Glomérulos Renais/imunologia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Proteína de Sequência 1 de Leucemia de Células Mieloides/deficiência , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Ativação de Neutrófilo , Neutrófilos/metabolismoRESUMO
OBJECTIVE: In Brazil, the most common method of controlling outbreaks of arbovirus is by the use of chemical sprays, which kill the insect vector, Aedes aegypti. The main objective of this study was to evaluate the resistance of Ae. aegypti to the insecticide, malathion, in situ. The location of this study was the municipality of Foz do Iguaçu, in the state of Paraná, Brazil. METHODS: Ultra-low-volume (ULV) fogging equipment was used, by vehicle, to apply the insecticide in situ, and mosquito populations after treatment were compared with those of control areas. The resistance of strains collected from the municipality was compared to the Rockefeller strain under laboratory conditions. RESULTS: We found 220 adult female specimens and 7423 eggs of Ae. aegypti in the areas subjected to UBV treatment, whereas 245 adult females and 10 557 eggs were found in the control areas. The UBV treatment area showed no significant difference compared to the control area, for all the indices. Mortality of the Rockefeller colony varied more quickly when there were slight variations in malathion concentration than the Foz do Iguaçu population.
OBJECTIF: Au Brésil, la méthode la plus courante de lutte contre les épidémies d'arbovirus consiste à utiliser des pulvérisations chimiques qui tuent l'insecte vecteur, Aedes aegypti. L'objectif principal de cette étude était d'évaluer la résistance de Ae. aegypti à l'insecticide, le malathion, in situ. Le lieu de cette étude était la municipalité de Foz do Iguaçu, dans l'état du Paraná, au Brésil. MÉTHODES: Un équipement de brumisation à très faible volume (ULV) a été utilisé, par véhicule, pour appliquer l'insecticide in situ et les populations de moustiques après le traitement ont été comparées à celles des zones témoins. La résistance des souches collectées dans la municipalité a été comparée à la souche Rockefeller dans des conditions de laboratoire. RÉSULTATS: Nous avons trouvé 220 spécimens femelles adultes et 7.423 Åufs d'Ae. aegypti dans les zones soumises au traitement ULV, alors que 245 femelles adultes et 10.557 Åufs ont été trouvés dans les zones témoins. La zone de traitement ULV n'a montré aucune différence significative par rapport à la zone témoin, pour tous les indices. La mortalité de la colonie de Rockefeller variait plus rapidement lorsqu'il y avait de légères variations dans la concentration de malathion que la population de Foz do Iguaçu.
Assuntos
Aedes/efeitos dos fármacos , Dengue/prevenção & controle , Resistência a Inseticidas , Inseticidas/farmacologia , Malation/farmacologia , Mosquitos Vetores/efeitos dos fármacos , Animais , Brasil/epidemiologia , Incidência , Controle de MosquitosRESUMO
BACKGROUND: To demonstrate that studies on induction of labour should be analyzed by parity as there is a significant difference in the labour outcome among induced nulliparous and multiparous women. METHODS: Obstetric outcome, specifically caesarean section rates, among induced term nulliparous and multiparous women without a previous caesarean section were analyzed in this cross-sectional study using the Robson 10 group classification for the year 2016. RESULTS: In the total number of 8851 women delivered in 2016, the caesarean section rates among nulliparous women in spontaneous and induced labour, Robson groups 1 and 2A, were 7.84% (151/1925) and 32.63% (437/1339) respectively and among multiparous (excluding those women with a previous caesarean section), Robson group 3 and 4A were 1%(24/2389) and 4.37% (44/1005), respectively. Pre labour caesarean rates for nulliparous and multiparous women, Robson groups 2B and 4B (Robson M, Fetal Matern Med Rev, 12; 23-39, 2001) were 3.91% (133/3397) and 2.86% (100/3494), of the respective single cephalic cohort at term. CONCLUSION: The data suggests that studies on induction of labour should be analyzed by parity as there is a significant difference between nulliparous and multiparous women.