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1.
Breast Cancer Res ; 21(1): 76, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31248446

RESUMO

BACKGROUND: Atypical breast hyperplasias (AH) have a 10-year risk of progression to invasive cancer estimated at 4-7%, with the overall risk of developing breast cancer increased by ~ 4-fold. AH lesions are estrogen receptor alpha positive (ERα+) and represent risk indicators and/or precursor lesions to low grade ERα+ tumors. Therefore, molecular profiles of AH lesions offer insights into the earliest changes in the breast epithelium, rendering it susceptible to oncogenic transformation. METHODS: In this study, women were selected who were diagnosed with ductal or lobular AH, but no breast cancer prior to or within the 2-year follow-up. Paired AH and histologically normal benign (HNB) tissues from patients were microdissected. RNA was isolated, amplified linearly, labeled, and hybridized to whole transcriptome microarrays to determine gene expression profiles. Genes that were differentially expressed between AH and HNB were identified using a paired analysis. Gene expression signatures distinguishing AH and HNB were defined using AGNES and PAM methods. Regulation of gene networks was investigated using breast epithelial cell lines, explant cultures of normal breast tissue and mouse tissues. RESULTS: A 99-gene signature discriminated the histologically normal and AH tissues in 81% of the cases. Network analysis identified coordinated alterations in signaling through ERα, epidermal growth factor receptors, and androgen receptor which were associated with the development of both lobular and ductal AH. Decreased expression of SFRP1 was also consistently lower in AH. Knockdown of SFRP1 in 76N-Tert cells resulted altered expression of 13 genes similarly to that observed in AH. An SFRP1-regulated network was also observed in tissues from mice lacking Sfrp1. Re-expression of SFRP1 in MCF7 cells provided further support for the SFRP1-regulated network. Treatment of breast explant cultures with rSFRP1 dampened estrogen-induced progesterone receptor levels. CONCLUSIONS: The alterations in gene expression were observed in both ductal and lobular AH suggesting shared underlying mechanisms predisposing to AH. Loss of SFRP1 expression is a significant regulator of AH transcriptional profiles driving previously unidentified changes affecting responses to estrogen and possibly other pathways. The gene signature and pathways provide insights into alterations contributing to AH breast lesions.

2.
Nat Commun ; 10(1): 2164, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31092820

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease, characterised by increased expression of type I interferon (IFN)-regulated genes and a striking sex imbalance towards females. Through combined genetic, in silico, in vitro, and ex vivo approaches, we define CXorf21, a gene of hitherto unknown function, which escapes X-chromosome inactivation, as a candidate underlying the Xp21.2 SLE association. We demonstrate that CXorf21 is an IFN-response gene and that the sexual dimorphism in expression is magnified by immunological challenge. Fine-mapping reveals a single haplotype as a potential causal cis-eQTL for CXorf21. We propose that expression is amplified through modification of promoter and 3'-UTR chromatin interactions. Finally, we show that the CXORF21 protein colocalises with TLR7, a pathway implicated in SLE pathogenesis. Our study reveals modulation in gene expression affected by the combination of two hallmarks of SLE: CXorf21 expression increases in a both an IFN-inducible and sex-specific manner.


Assuntos
Cromossomos Humanos X/genética , Genes Ligados ao Cromossomo X/genética , Interferon Tipo I/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lúpus Eritematoso Sistêmico/genética , Regiões 3' não Traduzidas/genética , Adulto , Fatores Etários , Estudos de Casos e Controles , Feminino , Genes Ligados ao Cromossomo X/imunologia , Predisposição Genética para Doença , Humanos , Interferon Tipo I/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Regiões Promotoras Genéticas/genética , Fatores Sexuais , Receptor 7 Toll-Like/genética
3.
Artigo em Inglês | MEDLINE | ID: mdl-30314533

RESUMO

Silastic capsules are frequently used to study the physiologic effects of estrogen exposure in animal models. The Officeof Laboratory Animal Welfare requires the sterilization of nonpharmaceutical-grade compounds before use. We compared 2commonly used terminal sterilization methods-ionizing radiation (IR) and ethylene oxide (EO)-for their utility in sterilizingsilastic capsules containing 0.05 or 0.1 mg 17ß-estradiol (E2). E2-specific ELISA demonstrated that serum estrogen levelsdid not differ between mice implanted with 0.05-mg E2 capsules that were sterilized with IR or EO and those implanted withnonsterilized capsules. Likewise, mammary gland morphology and progesterone receptor expression and proliferation inmammary epithelium were similar among mice treated with E2 capsules, regardless of sterilization method, and pregnant day15 mice. In addition, IR-sterilized 0.1-mg E2 pellets provided high serum E2. We conclude that neither ionizing radiation norethylene oxide degraded E2 or the cellulose matrix, suggesting that these methods of sterilization are appropriate to provideeffective sterile hormone capsules for animal research.

5.
Hum Mol Genet ; 27(3): 421-429, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29177435

RESUMO

The omnigenic model of complex disease stipulates that the majority of the heritability will be explained by the effects of common variation on genes in the periphery of core disease pathways. Rare variant associations, expected to explain far less of the heritability, may be enriched in core disease genes and thus will be instrumental in the understanding of complex disease pathogenesis and their potential therapeutic targets. Here, using complementary whole-exome sequencing, high-density imputation, and in vitro cellular assays, we identify candidate core genes in the pathogenesis of systemic lupus erythematosus (SLE). Using extreme-phenotype sampling, we sequenced the exomes of 30 SLE parent-affected-offspring trios and identified 14 genes with missense de novo mutations (DNM), none of which are within the >80 SLE susceptibility loci implicated through genome-wide association studies. In a follow-up cohort of 10, 995 individuals of matched European ancestry, we imputed genotype data to the density of the combined UK10K-1000 genomes Phase III reference panel across the 14 candidate genes. Gene-level analyses indicate three functional candidates: DNMT3A, PRKCD, and C1QTNF4. We identify a burden of rare variants across PRKCD associated with SLE risk (P = 0.0028), and across DNMT3A associated with two severe disease prognosis sub-phenotypes (P = 0.0005 and P = 0.0033). We further characterise the TNF-dependent functions of the third candidate gene C1QTNF4 on NF-κB activation and apoptosis, which are inhibited by the p.His198Gln DNM. Our results identify three novel genes in SLE susceptibility and support extreme-phenotype sampling and DNM gene discovery to aid the search for core disease genes implicated through rare variation.

6.
Hum Mol Genet ; 26(5): 1003-1017, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28062664

RESUMO

Studies attempting to functionally interpret complex-disease susceptibility loci by GWAS and eQTL integration have predominantly employed microarrays to quantify gene-expression. RNA-Seq has the potential to discover a more comprehensive set of eQTLs and illuminate the underlying molecular consequence. We examine the functional outcome of 39 variants associated with Systemic Lupus Erythematosus (SLE) through the integration of GWAS and eQTL data from the TwinsUK microarray and RNA-Seq cohort in lymphoblastoid cell lines. We use conditional analysis and a Bayesian colocalisation method to provide evidence of a shared causal-variant, then compare the ability of each quantification type to detect disease relevant eQTLs and eGenes. We discovered the greatest frequency of candidate-causal eQTLs using exon-level RNA-Seq, and identified novel SLE susceptibility genes (e.g. NADSYN1 and TCF7) that were concealed using microarrays, including four non-coding RNAs. Many of these eQTLs were found to influence the expression of several genes, supporting the notion that risk haplotypes may harbour multiple functional effects. Novel SLE associated splicing events were identified in the T-reg restricted transcription factor, IKZF2, and other candidate genes (e.g. WDFY4) through asQTL mapping using the Geuvadis cohort. We have significantly increased our understanding of the genetic control of gene-expression in SLE by maximising the leverage of RNA-Seq and performing integrative GWAS-eQTL analysis against gene, exon, and splice-junction quantifications. We conclude that to better understand the true functional consequence of regulatory variants, quantification by RNA-Seq should be performed at the exon-level as a minimum, and run in parallel with gene and splice-junction level quantification.


Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Locos de Características Quantitativas/genética , RNA não Traduzido/genética , Processamento Alternativo/genética , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/biossíntese , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/genética , Mapeamento Cromossômico , Feminino , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Lúpus Eritematoso Sistêmico/patologia , Masculino , Polimorfismo de Nucleotídeo Único , Fator 1 de Transcrição de Linfócitos T/biossíntese , Fator 1 de Transcrição de Linfócitos T/genética
7.
Nat Genet ; 48(8): 940-946, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27399966

RESUMO

Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease. Genome-wide association studies (GWASs) have identified more than 50 loci as robustly associated with the disease in single ancestries, but genome-wide transancestral studies have not been conducted. We combined three GWAS data sets from Chinese (1,659 cases and 3,398 controls) and European (4,036 cases and 6,959 controls) populations. A meta-analysis of these studies showed that over half of the published SLE genetic associations are present in both populations. A replication study in Chinese (3,043 cases and 5,074 controls) and European (2,643 cases and 9,032 controls) subjects found ten previously unreported SLE loci. Our study provides further evidence that the majority of genetic risk polymorphisms for SLE are contained within the same regions across both populations. Furthermore, a comparison of risk allele frequencies and genetic risk scores suggested that the increased prevalence of SLE in non-Europeans (including Asians) has a genetic basis.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Humanos
8.
Arthritis Res Ther ; 16(3): R114, 2014 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-24886912

RESUMO

INTRODUCTION: The majority of the genetic variance of systemic lupus erythematosus (SLE) remains unexplained by the common disease-common variant hypothesis. Rare variants, which are not detectable by genome-wide association studies because of their low frequencies, are predicted to explain part of this "missing heritability." However, recent studies identifying rare variants within known disease-susceptibility loci have failed to show genetic associations because of their extremely low frequencies, leading to the questioning of the contribution of rare variants to disease susceptibility. A common (minor allele frequency = 17.4% in cases) nonsynonymous coding variant rs1143679 (R77H) in ITGAM (CD11b), which forms half of the heterodimeric integrin receptor, complement receptor 3 (CR3), is robustly associated with SLE and has been shown to impair CR3-mediated phagocytosis. METHODS: We resequenced ITGAM in 73 SLE cases and identified two previously unidentified, case-specific nonsynonymous variants, F941V and G1145S. Both variants were genotyped in 2,107 and 949 additional SLE cases, respectively, to estimate their frequencies in a disease population. An in vitro model was used to assess the impact of F941V and G1145S, together with two nonsynonymous ITGAM polymorphisms, A858V (rs1143683) and M441T (rs11861251), on CR3-mediated phagocytosis. A paired two-tailed t test was used to compare the phagocytic capabilities of each variant with that of wild-type CR3. RESULTS: Both rare variants, F941V and G1145S, significantly impair CR3-mediated phagocytosis in an in vitro model (61% reduction, P = 0.006; 26% reduction, P = 0.0232). However, neither of the common variants, M441T and A858V, had an effect on phagocytosis. Neither rare variant was observed again in the genotyping of additional SLE cases, suggesting that their frequencies are extremely low. CONCLUSIONS: Our results add further evidence to the functional importance of ITGAM in SLE pathogenesis through impaired phagocytosis. Additionally, this study provides a new example of the identification of rare variants in common-allele-associated loci, which, because of their extremely low frequencies, are not statistically associated. However, the demonstration of their functional effects adds support to their contribution to disease risk, and questions the current notion of dismissing the contribution of very rare variants on purely statistical analyses.


Assuntos
Antígeno CD11b/genética , Predisposição Genética para Doença/genética , Lúpus Eritematoso Sistêmico/genética , Mutação de Sentido Incorreto/genética , Animais , Sequência de Bases , Antígeno CD11b/imunologia , Células COS , Cercopithecus aethiops , Citometria de Fluxo , Frequência do Gene , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Antígeno de Macrófago 1/genética , Antígeno de Macrófago 1/imunologia , Mutação de Sentido Incorreto/imunologia , Fagocitose/genética , Fagocitose/imunologia , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
9.
J Neurosci ; 33(45): 17874-83, 2013 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-24198376

RESUMO

The adipocyte-derived hormone leptin acts in the brain to modulate the central driver of fertility: the gonadotropin releasing hormone (GnRH) neuronal system. This effect is indirect, as GnRH neurons do not express leptin receptors (LEPRs). Here we test whether GABAergic or glutamatergic neurons provide the intermediate pathway between the site of leptin action and the GnRH neurons. Leptin receptors were deleted from GABA and glutamate neurons using Cre-Lox transgenics, and the downstream effects on puberty onset and reproduction were examined. Both mouse lines displayed the expected increase in body weight and region-specific loss of leptin signaling in the hypothalamus. The GABA neuron-specific LEPR knock-out females and males showed significantly delayed puberty onset. Adult fertility observations revealed that these knock-out animals have decreased fecundity. In contrast, glutamate neuron-specific LEPR knock-out mice displayed normal fertility. Assessment of the estrogenic hypothalamic-pituitary-gonadal axis regulation in females showed that leptin action on GABA neurons is not necessary for estradiol-mediated suppression of tonic luteinizing hormone secretion (an indirect measure of GnRH neuron activity) but is required for regulation of a full preovulatory-like luteinizing hormone surge. In conclusion, leptin signaling in GABAergic (but not glutamatergic neurons) plays a critical role in the timing of puberty onset and is involved in fertility regulation throughout adulthood in both sexes. These results form an important step in explaining the role of central leptin signaling in the reproductive system. Limiting the leptin-to-GnRH mediators to GABAergic cells will enable future research to focus on a few specific types of neurons.


Assuntos
Neurônios GABAérgicos/metabolismo , Ácido Glutâmico/metabolismo , Leptina/metabolismo , Neurônios/metabolismo , Receptores para Leptina/metabolismo , Reprodução/fisiologia , Transdução de Sinais/fisiologia , Animais , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Knockout , Ovário/metabolismo , Hipófise/metabolismo , Receptores para Leptina/genética , Maturidade Sexual/fisiologia
10.
J Am Chem Soc ; 135(34): 12564-7, 2013 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-23931011

RESUMO

Imaging of nanomaterials in biological tissues provides vital information for the development of nanotherapeutics and diagnostics. Multiplexed imaging of different nanoparticles (NPs) greatly reduces costs, the need to use multiple animals, and increases the biodistribution information that can enhance diagnostic applications and accelerate the screening of potential therapeutics. Various approaches have been developed for imaging NPs; however, the readout of existing imaging techniques relies on specific properties of the core material or surface ligands, and these techniques are limited because of the relatively small number of NPs that can be simultaneously measured in a single experiment. Here, we demonstrate the use of laser desorption/ionization mass spectrometry (LDI-MS) in an imaging format to investigate surface chemistry dictated intraorgan distribution of NPs. This new LDI-MS imaging method enables multiplexed imaging of NPs with potentially unlimited readouts and without additional labeling of the NPs. It provides the capability to detect and image attomole levels of NPs with almost no interferences from biomolecules. Using this new imaging approach, we find that the intraorgan distributions of same-sized NPs are directly linked to their surface chemistry.


Assuntos
Ouro/farmacocinética , Nanopartículas Metálicas/química , Neoplasias Experimentais/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Animais , Ouro/administração & dosagem , Ouro/química , Nanopartículas Metálicas/administração & dosagem , Camundongos , Neoplasias Experimentais/diagnóstico , Distribuição Tecidual
11.
Cancer Cell Int ; 13: 74, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23883065

RESUMO

BACKGROUND: Transforming growth factor beta (TGFß) is transiently increased in the mammary gland during involution and by radiation. While TGFß normally has a tumour suppressor role, prolonged exposure to TGFß can induce an oncogenic epithelial to mesenchymal transition (EMT) program in permissive cells and initiate the generation of cancer stem cells. Our objective is to mimic the transient exposure to TGFß during involution to determine the persistent effects on premalignant mammary epithelium. METHOD: CDßGeo cells, a transplantable mouse mammary epithelial cell line, were treated in vitro for 14 days with TGFß (5 ng/ml). The cells were passaged for an additional 14 days in media without TGFß and then assessed for markers of EMT and transformation. RESULTS: The 14-day exposure to TGFß induced EMT and transdifferentiation in vitro that persists after withdrawal of TGFß. TGFß-treated cells are highly tumorigenic in vivo, producing invasive solid de-differentiated tumours (100%; latency 6.7 weeks) compared to control (43%; latency 32.7 weeks). Although the TGFß-treated cells have initiated a persistent EMT program, the stem cell population was unchanged relative to the controls. The gene expression profiles of TGFß-treated cells demonstrate de-differentiation with decreases in the expression of genes that define luminal, basal and stem cells. Additionally, the gene expression profiles demonstrate increases in markers of EMT, growth factor signalling, TGFß2 and changes in extra cellular matrix. CONCLUSION: This model demonstrates full oncogenic EMT without an increase in stem cells, serving to separate EMT markers from stem cell markers.

12.
J Sleep Res ; 22(6): 717-20, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23682639

RESUMO

Short sleep has been associated with cardiovascular risk. The aim of this study was to determine the impact of short-term sleep restriction on lipid profiles and resting blood pressure factors in young, normal-weight individuals (14 men, 13 women). Participants were randomized to five nights of either habitual (9 h) or short (4 h) sleep in a cross-over design separated by a 3-week washout period. There was no sleep × day interaction on lipid profile and blood pressure. Short-term sleep restriction does not alter lipid profiles and resting blood pressure in healthy, normal-weight individuals. The association between short sleep and increased cardiovascular risk reported in the epidemiological literature may be the result of long-term sleep restriction and poor lifestyle choices.


Assuntos
Peso Corporal , Dieta , Lipídeos/sangue , Privação do Sono/sangue , Privação do Sono/metabolismo , Adulto , Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/etiologia , Estudos Cross-Over , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sono/fisiologia , Privação do Sono/complicações , Privação do Sono/fisiopatologia , Fatores de Tempo
13.
Am J Hum Genet ; 92(1): 28-40, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-23261299

RESUMO

Reduced FCGR3B copy number is associated with increased risk of systemic lupus erythematosus (SLE). The five FCGR2/FCGR3 genes are arranged across two highly paralogous genomic segments on chromosome 1q23. Previous studies have suggested mechanisms for structural rearrangements at the FCGR2/FCGR3 locus and have proposed mechanisms whereby altered FCGR3B copy number predisposes to autoimmunity, but the high degree of sequence similarity between paralogous segments has prevented precise definition of the molecular events and their functional consequences. To pursue the genomic pathology associated with FCGR3B copy-number variation, we integrated sequencing data from fosmid and bacterial artificial chromosome clones and sequence-captured DNA from FCGR3B-deleted genomes to establish a detailed map of allelic and paralogous sequence variation across the FCGR2/FCGR3 locus. This analysis identified two highly paralogous 24.5 kb blocks within the FCGR2C/FCGR3B/FCGR2B locus that are devoid of nonpolymorphic paralogous sequence variations and that define the limits of the genomic regions in which nonallelic homologous recombination leads to FCGR2C/FCGR3B copy-number variation. Further, the data showed evidence of swapping of haplotype blocks between these highly paralogous blocks that most likely arose from sequential ancestral recombination events across the region. Functionally, we found by flow cytometry, immunoblotting and cDNA sequencing that individuals with FCGR3B-deleted alleles show ectopic presence of FcγRIIb on natural killer (NK) cells. We conclude that FCGR3B deletion juxtaposes the 5'-regulatory sequences of FCGR2C with the coding sequence of FCGR2B, creating a chimeric gene that results in an ectopic accumulation of FcγRIIb on NK cells and provides an explanation for SLE risk associated with reduced FCGR3B gene copy number.


Assuntos
Variações do Número de Cópias de DNA , Lúpus Eritematoso Sistêmico/genética , Receptores de IgG/genética , Mapeamento Cromossômico , Proteínas Ligadas por GPI/genética , Deleção de Genes , Predisposição Genética para Doença , Humanos , Células Matadoras Naturais/metabolismo , Polimorfismo de Nucleotídeo Único
14.
Sleep ; 35(11): 1503-10, 2012 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-23115399

RESUMO

STUDY OBJECTIVE: To determine the hormonal effects of reducing sleep duration under controlled feeding conditions. DESIGN: Randomized, crossover study. SETTING: Inpatient. PARTICIPANTS: Twenty-seven normal weight, 30- to 45-yr-old men and women habitually sleeping 7-9 hr/night. INTERVENTION: PARTICIPANTS WERE STUDIED UNDER TWO SLEEP CONDITIONS: short (4 hr in bed) or habitual (9 hr in bed) sleep. A controlled diet was provided for each 4-day study period. MEASUREMENTS AND RESULTS: Fasting blood samples were obtained daily and frequent blood samples were obtained throughout day 4. The main outcomes measures included glucose, insulin, leptin, ghrelin, adiponectin, total glucagon-like peptide 1 (GLP-1) and peptide YY(3-36) (PYY(3-36)) concentrations. Body weights were reduced by 2.2 ± 0.4 lb and 1.7 ± 0.4 lb during the habitual and short sleep phases, respectively (both P < 0.0001). There was no effect of sleep duration on glucose, insulin, and leptin profiles (all P > 0.05). Ghrelin and GLP-1 responses differed by sex. Short sleep increased fasting (P = 0.054) and morning (08:00-12:00) (P = 0.042) total ghrelin in men but not women. The reverse was observed for GLP-1: afternoon levels (12:30-19:00) were lower (P = 0.016) after short sleep compared with habitual sleep in women but not men. CONCLUSIONS: These data suggest that, in the context of negative energy balance, short sleep does not lead to a state of increased insulin resistance, but may predispose to overeating via separate mechanisms in men and women. CLINICAL TRIAL INFORMATION: Trial registration on http://www.clinicaltrials.gov. #NCT00935402.


Assuntos
Glicemia , Grelina/sangue , Privação do Sono/sangue , Adiponectina/sangue , Adulto , Peso Corporal , Estudos Cross-Over , Feminino , Humanos , Insulina/sangue , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Fatores Sexuais
15.
Am J Physiol Regul Integr Comp Physiol ; 303(9): R883-9, 2012 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-22972835

RESUMO

Sleep reduction is associated with increased energy intake and weight gain, though few studies have explored the relationship between sleep architecture and energy balance measures in the context of experimental sleep restriction. Fourteen males and 13 females (body mass index: 22-26 kg/m(2)) participated in a crossover sleep curtailment study. Participants were studied under two sleep conditions: short (4 h/night; 0100-0500 h) and habitual (9 h/night; 2200-0700 h), for 5 nights each. Sleep was polysomnographically recorded nightly. Outcome measures included resting metabolic rate (RMR), feelings of appetite-satiety, and ad libitum food intake. Short sleep resulted in reductions in stage 2 sleep and rapid eye movement (REM) sleep duration (P < 0.001), as well as decreased percentage of stage 2 sleep and REM sleep and increased slow wave sleep (SWS) percentage (P < 0.05). Linear mixed model analysis demonstrated a positive association between stage 2 sleep duration and RMR (P = 0.051). Inverse associations were observed between REM sleep duration and hunger (P = 0.031) and between stage 2 sleep duration and appetite for sweet (P = 0.015) and salty (P = 0.046) foods. Stage 2 sleep percentage was inversely related to energy consumed (P = 0.024). Stage 2 sleep (P = 0.005), SWS (P = 0.008), and REM sleep (P = 0.048) percentages were inversely related to fat intake, and SWS (P = 0.040) and REM sleep (P = 0.050) were inversely related to carbohydrate intake. This study demonstrates that changes in sleep architecture are associated with markers of positive energy balance and indicate a means by which exposure to short sleep duration and/or an altered sleep architecture profile may lead to excess weight gain over time.


Assuntos
Metabolismo Energético/fisiologia , Homeostase/fisiologia , Privação do Sono/fisiopatologia , Fases do Sono/fisiologia , Sono REM/fisiologia , Sono/fisiologia , Adulto , Apetite/fisiologia , Metabolismo Basal/fisiologia , Estudos Cross-Over , Ingestão de Alimentos/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/fisiopatologia , Avaliação de Resultados (Cuidados de Saúde) , Polissonografia , Fatores de Tempo
16.
Ann Rheum Dis ; 71(12): 2028-34, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22586164

RESUMO

OBJECTIVES: The rs1143679 variant of ITGAM, encoding the R77H variant of CD11b (part of complement receptor 3; CR3), is among the strongest genetic susceptibility effects in human systemic lupus erythematosus (SLE). The authors aimed to demonstrate R77H function in ex-vivo human cells. METHODS: Monocytes/monocyte-derived macrophages from healthy volunteers homozygous for either wild type (WT) or 77H CD11b were studied. The genotype-specific expression of CD11b, and CD11b activation using conformation-specific antibodies were measured. Genotype-specific differences in iC3b-mediated phagocytosis, adhesion to a range of ligands and the secretion of cytokines following CR3 ligation were studied. The functionality of R77H was confirmed by replicating findings in COS7 cells expressing variant-specific CD11b. RESULTS: No genotype-specific difference in CD11b expression or in the expression of CD11b activation epitopes was observed. A 31% reduction was observed in the phagocytosis of iC3b opsonised sheep erythrocytes (sRBC(iC3b)) by 77H cells (p=0.003) and reduced adhesion to a range of ligands: notably a 24% reduction in adhesion to iC3b (p=0.014). In transfected COS7 cells, a 42% reduction was observed in phagocytosis by CD11b (77H)-expressing cells (p=0.004). A significant inhibition was seen in the release of Toll-like receptor 7/8-induced pro-inflammatory cytokines from WT monocytes when CR3 was pre-engaged using sRBC(iC3b), but no inhibition in 77H monocytes resulting in a significant difference between genotypes (interleukin (IL)-1ß p=0.030; IL-6 p=0.029; tumour necrosis factor alpha p=0.027). CONCLUSIONS: The R77H variant impairs a broad range of CR3 effector functions in human monocytes. This study discusses how perturbation of this pathway may predispose to SLE.


Assuntos
Antígeno CD11b/genética , Antígeno CD11b/imunologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Antígeno de Macrófago 1/imunologia , Monócitos/imunologia , Adulto , Animais , Antígeno CD11b/química , Células COS , Adesão Celular/imunologia , Cercopithecus aethiops , Citocinas/metabolismo , Fibroblastos/citologia , Expressão Gênica/imunologia , Predisposição Genética para Doença/genética , Variação Genética , Genótipo , Homozigoto , Humanos , Antígeno de Macrófago 1/química , Macrófagos/citologia , Macrófagos/imunologia , Monócitos/citologia , Fagocitose/imunologia , Conformação Proteica , Estrutura Terciária de Proteína
17.
Metabolism ; 61(10): 1347-52, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22538118

RESUMO

Evidence suggests that ginger consumption has anti-inflammatory, anti-hypertensive, glucose-sensitizing, and stimulatory effects on the gastrointestinal tract. This study assessed the effects of a hot ginger beverage on energy expenditure, feelings of appetite and satiety and metabolic risk factors in overweight men. Ten men, age 39.1±3.3 y and body mass index (BMI) 27.2±0.3 kg/m(2), participated in this randomized crossover study. Resting state energy expenditure was measured using indirect calorimetry and for 6h after consumption of a breakfast meal with or without 2 g ginger powder dissolved in a hot water beverage. Subjective feelings of satiety were assessed hourly using visual analog scales (VAS) and blood samples were taken fasted and for 3 h after breakfast consumption. There was no significant effect of ginger on total resting energy expenditure (P=.43) or respiratory quotient (P=.41). There was a significant effect of ginger on thermic effect of food (ginger vs control=42.7±21.4 kcal/d, P=.049) but the area under the curve was not different (P=.43). VAS ratings showed lower hunger (P=.002), lower prospective food intake (P=.004) and greater fullness (P=.064) with ginger consumption versus control. There were no effects of ginger on glucose, insulin, lipids, or inflammatory markers. The results, showing enhanced thermogenesis and reduced feelings of hunger with ginger consumption, suggest a potential role of ginger in weight management. Additional studies are necessary to confirm these findings.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Alimentos , Gengibre , Resposta de Saciedade/efeitos dos fármacos , Termogênese/efeitos dos fármacos , Adulto , Área Sob a Curva , Proteína C-Reativa/análise , Estudos Cross-Over , Grelina/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Sobrepeso , Projetos Piloto
18.
Am J Clin Nutr ; 95(4): 818-24, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22357722

RESUMO

BACKGROUND: Epidemiologic evidence shows an increase in obesity concurrent with a reduction in average sleep duration among Americans. Although clinical studies propose that restricted sleep affects hormones related to appetite, neuronal activity in response to food stimuli after restricted and habitual sleep has not been investigated. OBJECTIVE: The objective of this study was to determine the effects of partial sleep restriction on neuronal activation in response to food stimuli. DESIGN: Thirty healthy, normal-weight [BMI (in kg/m²): 22-26] men and women were recruited (26 completed) to participate in a 2-phase inpatient crossover study in which they spent either 4 h/night (restricted sleep) or 9 h/night (habitual sleep) in bed. Each phase lasted 6 d, and functional magnetic resonance imaging was performed in the fasted state on day 6. RESULTS: Overall neuronal activity in response to food stimuli was greater after restricted sleep than after habitual sleep. In addition, a relative increase in brain activity in areas associated with reward, including the putamen, nucleus accumbens, thalamus, insula, and prefrontal cortex in response to food stimuli, was observed. CONCLUSION: The findings of this study link restricted sleep and susceptibility to food stimuli and are consistent with the notion that reduced sleep may lead to greater propensity to overeat.


Assuntos
Alimentos , Neurônios/metabolismo , Prosencéfalo/fisiopatologia , Privação do Sono/fisiopatologia , Adulto , Estudos Cross-Over , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Cidade de Nova Iorque , Especificidade de Órgãos , Hipernutrição/etiologia , Prosencéfalo/metabolismo , Recompensa , Privação do Sono/metabolismo
19.
Adv Child Dev Behav ; 40: 209-41, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21887963

RESUMO

This chapter examines children's learning through careful attention and participation in the ongoing activities of their community. This form of learning, which has been called learning through Intent Community Participation, seems to be especially common in Mesoamerican Indigenous communities. In these communities, children are integrated into the everyday work and lives of adults and their learning may not be the central focus. We contrast this pattern with that of middle-class European American communities where children are segregated from the primary adult functions of the community. In middle-class communities and schools, children are often encouraged to engage in abstract lessons where their attention is explicitly directed to specific events. In contrast, learning through keen attention and observation may rely on learning through attention to instructions not specifically directed to the learner. Studies demonstrate Mesoamerican Indigenous children's ability to learn through simultaneous and open attention to overheard or observed activities. This form of learning is supported through multiple modalities of communication and interaction. Motivation to learn stems from the learner's inclusion into the major activities and goals of the community. Implications of research and future directions for the study of learning through keen observation are discussed.


Assuntos
Atenção , Comunicação , Características Culturais , Socialização , Adolescente , Adulto , Criança , Pré-Escolar , Comportamento Cooperativo , Comparação Transcultural , Grupo com Ancestrais do Continente Europeu/psicologia , Família/psicologia , Humanos , Índios Norte-Americanos/psicologia , Lactente , Poder Familiar/psicologia , Características de Residência , Meio Social , Facilitação Social
20.
Am J Clin Nutr ; 94(2): 410-6, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21715510

RESUMO

BACKGROUND: Evidence suggests a relation between short sleep duration and obesity. OBJECTIVE: We assessed energy balance during periods of short and habitual sleep in normal-weight men and women. DESIGN: Fifteen men and 15 women aged 30-49 y with a body mass index (in kg/m(2)) of 22-26, who regularly slept 7-9 h/night, were recruited to participate in this crossover inpatient study. All participants were studied under short (4 h/night) and habitual (9 h/night) sleep conditions, in random order, for 5 nights each. Food intake was measured on day 5, and energy expenditure was measured with the doubly labeled water method over each period. RESULTS: Participants consumed more energy on day 5 during short sleep (2813.6 ± 593.0 kcal) than during habitual sleep (2517.7 ± 593.0 kcal; P = 0.023). This effect was mostly due to increased consumption of fat (20.7 ± 37.4 g; P = 0.01), notably saturated fat (8.7 ± 20.4 g; P = 0.038), during short sleep. Resting metabolic rate (short sleep: 1455.4 ± 129.0 kcal/d; habitual sleep: 1486.5 ± 129.5 kcal/d; P = 0.136) and total energy expenditure (short sleep: 2589.2 ± 526.5 kcal/d; habitual sleep: 2611.1 ± 529.0 kcal/d; P = 0.832) did not differ significantly between sleep phases. CONCLUSIONS: Our data show that a reduction in sleep increases energy and fat intakes, which may explain the associations observed between sleep and obesity. If sustained, as observed, and not compensated by increased energy expenditure, the dietary intakes of individuals undergoing short sleep predispose to obesity. This trial is registered at clinicaltrials.gov as NCT00935402.


Assuntos
Ingestão de Energia , Metabolismo Energético , Sono , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Fatores de Tempo
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