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Sugarcane, the world's most harvested crop by tonnage, has shaped global history, trade and geopolitics, and is currently responsible for 80% of sugar production worldwide1. While traditional sugarcane breeding methods have effectively generated cultivars adapted to new environments and pathogens, sugar yield improvements have recently plateaued2. The cessation of yield gains may be due to limited genetic diversity within breeding populations, long breeding cycles and the complexity of its genome, the latter preventing breeders from taking advantage of the recent explosion of whole-genome sequencing that has benefited many other crops. Thus, modern sugarcane hybrids are the last remaining major crop without a reference-quality genome. Here we take a major step towards advancing sugarcane biotechnology by generating a polyploid reference genome for R570, a typical modern cultivar derived from interspecific hybridization between the domesticated species (Saccharum officinarum) and the wild species (Saccharum spontaneum). In contrast to the existing single haplotype ('monoploid') representation of R570, our 8.7 billion base assembly contains a complete representation of unique DNA sequences across the approximately 12 chromosome copies in this polyploid genome. Using this highly contiguous genome assembly, we filled a previously unsized gap within an R570 physical genetic map to describe the likely causal genes underlying the single-copy Bru1 brown rust resistance locus. This polyploid genome assembly with fine-grain descriptions of genome architecture and molecular targets for biotechnology will help accelerate molecular and transgenic breeding and adaptation of sugarcane to future environmental conditions.
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Genoma de Planta , Poliploidia , Saccharum , Cromossomos de Plantas/genética , Genoma de Planta/genética , Haplótipos/genética , Hibridização Genética/genética , Melhoramento Vegetal , Saccharum/classificação , Saccharum/genética , Biotecnologia , Padrões de Referência , DNA de Plantas/genéticaRESUMO
Four new psammaplysin derivatives (1-4) with fatty acyl substituents, designated irciniaplysins A-D, and three known psammaplysins (5-7) were isolated from a marine sponge Ircinia sp. Their structures were elucidated using extensive spectroscopic analyses. The positions of the double bonds and the branch points of the fatty acyl side chains were determined by GC-MS analysis of their fatty acid methyl ester (FAME) derivatives. Irciniaplysins A (1) and B (2) contained an unusual long-chain fatty acyl substituent with a 5,9-diene unit. The isolated compounds were evaluated for their cytotoxic activity against the human colorectal carcinoma (HCT 116) cells, however, none of these compounds showed significant activity.
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Progression of metabolic dysfunction-associated steatites liver disease (MASLD) to steatohepatitis (MASH) is driven by stress-inducing lipids that promote liver inflammation and fibrosis, and MASH can lead to cirrhosis and hepatocellular carcinoma. Previously, we showed coordinated defenses regulated by transcription factors, nuclear factor erythroid 2-related factor-1 (Nrf1) and -2 (Nrf2), protect against hepatic lipid stress. Here, we investigated protective effects of hepatocyte Nrf1 and Nrf2 against MASH-linked liver fibrosis and tumorigenesis. Male and female mice with flox alleles for genes encoding Nrf1 (Nfe2l1), Nrf2 (Nfe2l2), or both were fed a MASH-inducing diet enriched with high fat, fructose, and cholesterol (HFFC) or a control diet for 24-52 weeks. During this period, hepatocyte Nrf1, Nrf2, or combined deficiency for ~7 days, ~7 weeks, and ~35 weeks was induced by administering mice hepatocyte-targeting adeno-associated virus (AAV) expressing Cre recombinase. The effects on MASH, markers of liver fibrosis and proliferation, and liver tumorigenesis were compared to control mice receiving AAV-expressing green fluorescent protein. Also, to assess the impact of Nrf1 and Nrf2 induction on liver fibrosis, HFFC diet-fed C57bl/6J mice received weekly injections of carbon tetrachloride, and from week 16 to 24, mice were treated with the Nrf2-activating drug bardoxolone, hepatocyte overexpression of human NRF1 (hNRF1), or both, and these groups were compared to control. Compared to the control diet, 24-week feeding with the HFFC diet increased bodyweight as well as liver weight, steatosis, and inflammation. It also increased hepatocyte proliferation and a marker of liver damage, p62. Hepatocyte Nrf1 and combined deficiency increased liver steatosis in control diet-fed but not HFFC diet-fed mice, and increased liver inflammation under both diet conditions. Hepatocyte Nrf1 deficiency also increased hepatocyte proliferation, whereas combined deficiency did not, and this also occurred for p62 level in control diet-fed conditions. In 52-week HFFC diet-fed mice, 35 weeks of hepatocyte Nrf1 deficiency, but not combined deficiency, resulted in more liver tumors in male mice, but not in female mice. In contrast, hepatocyte Nrf2 deficiency had no effect on any of these parameters. However, in the 15-week CCL4-exposed and 24-week HFFC diet-fed mice, Nrf2 induction with bardoxolone reduced liver steatosis, inflammation, fibrosis, and proliferation. Induction of hepatic Nrf1 activity with hNRF1 enhanced the effect of bardoxolone on steatosis and may have stimulated liver progenitor cells. Physiologic Nrf1 delays MASLD progression, Nrf2 induction alleviates MASH, and combined enhancement synergistically protects against steatosis and may facilitate liver repair.
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Hepatócitos , Fator 2 Relacionado a NF-E2 , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Camundongos , Hepatócitos/metabolismo , Masculino , Feminino , Progressão da Doença , Camundongos Endogâmicos C57BL , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado Gorduroso/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Cirrose Hepática/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Fator 1 Relacionado a NF-E2/metabolismo , Fator 1 Relacionado a NF-E2/genética , Fator 1 Nuclear Respiratório/metabolismo , Fator 1 Nuclear Respiratório/genética , Dieta Hiperlipídica/efeitos adversos , Fígado/metabolismo , Fígado/patologia , HumanosRESUMO
Hepatocyte stress signaling has been established to alter glucose metabolism and impair systemic glucose homeostasis. In contrast, the role of stress defenses in the control of glucose homeostasis is less understood. Nuclear factor erythroid 2 related factor-1 (NRF1) and -2 (NRF2) are transcription factors that promote stress defense and can exert hepatocyte stress defense programming via complementary gene regulation. To identify whether there are independent or complementary roles of these factors in hepatocytes on glucose homeostasis, we investigated the effect of adult-onset, hepatocyte-specific deletion of NRF1, NRF2, or both on glycemia in mice fed 1-3 weeks with a mildly stressful diet enriched with fat, fructose, and cholesterol. Compared to respective control, NRF1 deficiency and combined deficiency reduced glycemia, in some cases resulting in hypoglycemia, whereas there was no effect of NRF2 deficiency. However, reduced glycemia in NRF1 deficiency did not occur in the leptin-deficient mouse model of obesity and diabetes, suggesting hepatocyte NRF1 support defenses that counteract hypoglycemia but does not promote hyperglycemia. Consistent with this, NRF1 deficiency was associated with reduced liver glycogen and glycogen synthase expression as well as marked alteration to circulating level of glycemia-influencing hormones, growth hormone and insulin-like growth factor-1 (IGF1). Overall, we identify a role for hepatocyte NRF1 in modulating glucose homeostasis, which may be linked to liver glycogen storage and the growth hormone/IGF1 axis.
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Hipoglicemia , Glicogênio Hepático , Camundongos , Animais , Glicogênio Hepático/metabolismo , Fator 1 Nuclear Respiratório/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , Glucose/metabolismo , Hipoglicemia/metabolismo , Hormônio do Crescimento/metabolismoRESUMO
BACKGROUND: Multiplex tests allow for measurement of allergen-specific IgE responses to multiple extracts and molecular allergens and have several advantages for large cohort studies. Due to significant methodological differences, test systems are difficult to integrate in meta-analyses/systematic reviews since there is a lack of datasets with direct comparison. We aimed to create models for statistical integration of allergen-specific IgE to peanut/tree nut allergens from three IgE test platforms. METHODS: Plasma from Canadian and Austrian children/adolescents with peanut/tree nut sensitization and a cohort of sensitized, high-risk, pre-school asthmatics (total n = 166) were measured with three R&D multiplex IgE test platforms: Allergy Explorer version 1 (ALEX) (Macro Array Dx), MeDALL-chip (Mechanisms of Development of Allergy) (Thermo Fisher), and EUROLINE (EUROIMMUN). Skin prick test (n = 51) and ImmunoCAP (Thermo Fisher) (n = 62) results for extracts were available in a subset. Regression models (Multivariate Adaptive Regression Splines, local polynomial regression) were applied if >30% of samples were positive to the allergen. Intra-test correlations between PR-10 and nsLTP allergens were assessed. RESULTS: Using two regression methods, we demonstrated the ability to model allergen-specific relationships with acceptable measures of fit (r2 = 94%-56%) for peanut and tree nut sIgE testing at the extract and molecular-level, in order from highest to lowest: Ara h 2, Ara h 6, Jug r 1, Ana o 3, Ara h 1, Jug r 2, and Cor a 9. CONCLUSION: Our models support the notion that quantitative conversion is possible between sIgE multiplex platforms for extracts and molecular allergens and may provide options to aggregate data for future meta-analysis.
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Alérgenos , Hipersensibilidade a Amendoim , Adolescente , Antígenos de Plantas , Arachis , Áustria , Canadá , Criança , Humanos , Imunoglobulina E , NozesRESUMO
BACKGROUND: Preschool children with recurrent wheezing suffer high morbidity. It is unclear whether objective measures of asthma control, such as pulmonary function tests (PFTs), provide additional information to the clinical assessment. METHODS: We recruited children between 3 and 6 years old, with a history of recurrent wheezing in the preceding year and treated for acute wheezing exacerbation in the emergency department (ED) into an observational cohort study. Children attended two outpatient visits: the first study visit within five days of discharge from the ED and the second study visit 12 weeks after the ED visit. We performed standardized symptom score (test for respiratory and asthma control in kids (TRACK)), multiple breath washout (MBW), spirometry, and clinical assessment at both visits. RESULTS: Seventy-four children, mean (standard deviation (SD)) age of 4.32 years (0.84), attended both visits. Paired FEV0.75 and lung clearance index (LCI) measurements at both time points were obtained in 37 and 34 subjects, respectively. Feasibility for all tests improved at visit 2 and was not age-dependent. At the second study visit, a third had controlled asthma based on the TRACK score, and the mean lung clearance index (LCI) improved from 9.86 to 8.31 (P = .003); however, 46% had an LCI in the abnormal range. FEV0.75 z-score improved from -1.66 to -1.17 (P = .05) but remained in the abnormal range in 24%. LCI was abnormal in more than half of the children with "well-controlled" asthma based on the TRACK score. There was no correlation between PFT measures and TRACK scores at either visit. CONCLUSIONS: Lung clearance index demonstrates a persistent deficit post-exacerbation in a large proportion of preschoolers with recurrent wheezing, highlighting that symptom scores alone may not suffice for monitoring these children.
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Asma , Sons Respiratórios , Asma/diagnóstico , Pré-Escolar , Humanos , Recém-Nascido , Pulmão , Testes de Função Respiratória , EspirometriaRESUMO
Universal screening for colorectal cancer (CRC) is recommended for individuals 50-75 years of age, but screening uptake is suboptimal and African Americans have suffered persistent racial disparities in CRC incidence and deaths. We compared a culturally tailored fictional narrative and an engaging expert interview on the ability to increase intentions to be screened for CRC among African American women. In a post-only experiment, women (N = 442) in face-to-face listening groups in African American churches heard audio recordings of either a narrative or an expert interview. Questionnaires were completed immediately afterward and 30 days later. Women who heard narratives reported stronger intentions to be screened with a home stool blood test than women who heard the interview; the effect lasted at least 30 days. Culturally tailored, fictional narratives appear to be an effective persuasive strategy for reducing racial disparities in CRC outcomes.
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Negro ou Afro-Americano , Colonoscopia , Neoplasias Colorretais/diagnóstico , Conhecimentos, Atitudes e Prática em Saúde , Promoção da Saúde , Intenção , Idoso , Competência Cultural , Detecção Precoce de Câncer , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Processes shaping the distribution of foliar fungal endophyte species remain poorly understood. Despite increasing evidence that these cryptic fungal symbionts of plants mediate interactions with pathogens and herbivores, there remain basic questions regarding the extent to which dispersal limitation and host specificity might shape fungal endophyte community composition in rainforests. To assess the relative importance of spatial pattern and host specificity, we isolated fungi from a sample of mapped trees in lowland Papua New Guinea. Sequences of the internal transcribed spacer (ITS) region were obtained for 2079 fungal endophytes from three sites and clustered into molecular operational taxonomic units (MOTUs) at 95% similarity. Multivariate analyses suggest that host affinity plays a significant role in structuring endophyte community composition whereas there was no evidence of endophyte spatial pattern at the scale of tens to hundreds of metres. Differences in endophyte communities between sampled trees were weakly correlated with variation in foliar traits but not with tree species relatedness. The dominance of relatively few generalist endophytes and the presence of a large number of rare MOTUs was a consistent observation at three sites separated by hundreds of kilometres and regional turnover was low. Host specificity appears to play a relatively weak but more important role than dispersal limitation in shaping the distribution of fungal endophyte communities in New Guinea forests. Our results suggest that in the absence of strong ecological gradients and host turnover, beta diversity of endophyte communities could be low in large areas of contiguous forest.
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Biodiversidade , Endófitos/classificação , Fungos/classificação , Floresta Úmida , Árvores/microbiologia , DNA Fúngico , DNA Espaçador Ribossômico/genética , Endófitos/genética , Fungos/genética , Dados de Sequência Molecular , Nova Guiné , Filogenia , Folhas de Planta/microbiologia , Análise EspacialRESUMO
Cigar smoking is increasingly common among adolescents who perceive cigars as less harmful than cigarettes. This perception of reduced harm is especially true for cigars that are user-modified by removing the tobacco binder through a process called 'freaking'. Little is known about 'freaking' and this multi-study, mixed-methods analysis sought to understand better the rationale and prevailing beliefs about this smoking practice using YouTube videos. In Study 1, we conducted a descriptive content analysis on the characteristics of 26 randomly sampled cigar product modification (CPM) videos posted during 2006-10. In Study 2, a thematic analysis was performed on the transcripts of commentary associated with each video to characterize viewers' comments about video content. Study 1 results revealed that 90% of videos illustrated a four-step CPM technique: 'Loosening the tobacco'; 'Dumping the tobacco'; 'Removing the cigar binder' and 'Repacking the tobacco'. Four themes related to the purpose of CPM were also derived from video content: 'Easier to smoke' (54%), 'Beliefs in reduction of health risks' (31%), 'Changing the burn rate' (15%) and 'Taste enhancement' (12%). Study 2 results concerning the content characteristics of video comments were categorized into three themes: 'Disseminating information/answering questions' (81%), 'Seeking advice/asking questions' (69%) and 'Learning cigar modification techniques' (35%). Favorable comments were more common (81%) compared to unfavorable (58%) and comment content suggested low-risk perceptions and poor understanding of smoking harms. These findings highlight a novel means for youth to access information concerning CPM that may have important implications for tobacco control policy and prevention.
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Conhecimentos, Atitudes e Prática em Saúde , Internet , Fumar/etnologia , Produtos do Tabaco , Gravação de Videoteipe , Adolescente , Negro ou Afro-Americano , Fatores Etários , Criança , Feminino , Educação em Saúde , Humanos , Disseminação de Informação , Masculino , PercepçãoRESUMO
OBJECTIVE: Excess cholesterol storage can induce the formation of cholesterol crystals in hepatocyte lipid droplets. Such crystals distinguish metabolic dysfunction associated steatohepatitis (MASH) from simple steatosis and may underlie its pathogenesis by causing cell damage that triggers liver inflammation. The mechanism linking cholesterol excess to its crystallization in lipid droplets is unclear. As cholesteryl esters localize to and accumulate in lipid droplets more readily than unesterified free cholesterol, we investigated whether cholesterol esterification by sterol O-acyltransferase (SOAT), also known as acyl co-A cholesterol acyltransferase (ACAT), is required for hepatocyte lipid droplet crystal formation. METHOD: Cholesterol crystals were measured in cholesterol loaded Hep3B hepatocytes, RAW264.7 macrophages, and mouse liver using polarizing light microscopy. We examined the effect of blocking SOAT activity on crystal formation and compared these results to features of cholesterol metabolism and the progression to intracellular crystal deposits. RESULTS: Cholesterol loading of Hep3B cells caused robust levels of lipid droplet localized crystal formation in a dose- and time-dependent manner. Co-treatment with SOAT inhibitors and genetic ablation of SOAT1 blocked crystal formation. SOAT inhibitor also blocked crystal formation in low density lipoprotein (LDL) treated Hep3B cells, acetylated LDL treated RAW 264.7 macrophages, and in the liver of mice genetically predisposed to hepatic cholesterol overload and in mice with cholesterol enriched diet-induced MASH. CONCLUSION: SOAT1-mediated esterification may underlie cholesterol crystals associated with MASH by concentrating it in lipid droplets. These findings imply that inhibiting hepatocyte SOAT1 may be able to alleviate cholesterol associated MASH. Moreover, that either a lipid droplet localized cholesteryl ester hydrolase is required for cholesterol crystal formation, or the crystals are composed of cholesteryl ester.
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Colesterol , Hepatócitos , Gotículas Lipídicas , Esterol O-Aciltransferase , Animais , Humanos , Masculino , Camundongos , Colesterol/metabolismo , Ésteres do Colesterol/metabolismo , Cristalização , Esterificação , Hepatócitos/metabolismo , Gotículas Lipídicas/metabolismo , Fígado/metabolismo , Fígado/patologia , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Esterol O-Aciltransferase/metabolismo , Esterol O-Aciltransferase/genéticaRESUMO
BACKGROUND: The residential segregation of black populations, often in areas of high-economic disadvantage and low social status, may play a crucial role in the observed racial inequities in sexually transmitted disease rates. METHODS: An ecological analysis of 2005 to 2009 average gonorrhea rates was performed across 277 US metropolitan statistical areas (MSAs). The black isolation index and Gini index of income inequality were used as proxy measures for racial and economic residential segregation respectively, derived from 2005 to 2009 US Census estimates. We used logistic regression modeling to produce estimates of odds ratios (ORs) and 95% confidence intervals (CIs) for the association between the segregation indices, both independently and in combination, on gonorrhea rates in MSAs. Effect measure modification was assessed by calculating the relative excess risk due to interaction between the 2 indices. RESULTS: Compared with MSAs with low levels of racial segregation, MSAs with high levels of racial segregation had increased odds of high gonorrhea rates (adjusted OR, 3.37; 95% CI, 1.23-9.21). Similarly, higher levels of income inequality predicted higher gonorrhea rates, although this association did not persist after adjustment for potential confounders (adjusted OR, 1.54; 95% CI, 0.74-3.24). In combined models, the influence of racial residential segregation on gonorrhea rates was stronger than that of income inequality-based segregation; there was no evidence of additivity or a multiplicative interaction. CONCLUSIONS: Residential segregation by race or income equality may be a key component in the perpetuation of high rates of gonorrhea and other sexually transmitted diseases among black populations in the United States.
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Gonorreia/epidemiologia , Racismo/estatística & dados numéricos , Características de Residência/estatística & dados numéricos , População Urbana/estatística & dados numéricos , Negro ou Afro-Americano , Feminino , Disparidades nos Níveis de Saúde , Habitação , Humanos , Renda , Masculino , Fatores Socioeconômicos , Estados Unidos/epidemiologiaRESUMO
Acute respiratory distress syndrome (ARDS) poses a major challenge in intensive care settings. The main underlying causes of ARDS are trauma, pancreatitis, and pulmonary manifestation of systemic inflammatory response syndrome/sepsis.Lemierre syndrome represents a nearly forgotten entity arising from oropharyngeal infections with Fusobacterial species, and it is of renewed and increasing interest because of evolving antibiotic resistances.We report two cases of young female patients afflicted by Lemierre syndrome with additional severe ARDS and present an overview of the current literature.
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Fusobacterium necrophorum/isolamento & purificação , Síndrome de Lemierre/microbiologia , Síndrome do Desconforto Respiratório/microbiologia , Feminino , Humanos , Síndrome de Lemierre/complicações , Síndrome de Lemierre/diagnóstico , Síndrome de Lemierre/terapia , Pessoa de Meia-Idade , Síndrome do Desconforto Respiratório/diagnóstico , Síndrome do Desconforto Respiratório/terapia , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto JovemRESUMO
High density lipoproteins (HDL) promote homeostasis and counteract stressful tissue damage that underlie cardiovascular and other diseases by mediating reverse cholesterol transport, reducing inflammation, and abrogating oxidative damage. However, metabolically stressful conditions associated with atherosclerosis can impair these effects. Hepatocytes play a major role in the genesis and maturation of circulating HDL, and liver stress elicits marked regulatory changes to circulating HDL abundance and composition, which affect its functionality. The mechanisms linking liver stress to HDL function are incompletely understood. In this study, we sought to determine whether stress defending transcription factors nuclear factor erythroid 2 related factor-1 (Nrf1) and -2 (Nrf2) promote hepatocyte production of functional HDL. Using genetically engineered mice briefly fed a mild metabolically stressful diet, we investigated the effect of hepatocyte-specific deletion of Nrf1, Nrf2, or both on circulating HDL cholesterol, protein composition, and function. Combined deletion, but not single gene deletion, reduced HDL cholesterol and apolipoprotein A1 levels as well as the capacity of HDL to accept cholesterol undergoing efflux from cultured macrophages and to counteract tumor necrosis factor α-induced inflammatory effect on cultured endothelial cells. This coincided with substantial alteration to the HDL proteome, which correlated with liver gene expression profiles of corresponding proteins. Thus, our findings show complementary actions by hepatocyte Nrf1 and Nrf2 play a role in shaping HDL abundance and composition to promote production of functionally viable HDL. Consequently, our study illuminates the possibility that enhancing stress defense programming in the liver may improve atheroprotective and perhaps other health promoting actions of HDL.
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Hepatic cholesterol overload promotes steatohepatitis. Insufficient understanding of liver stress defense impedes therapy development. Here, we elucidate the role of stress defense transcription factors, nuclear factor erythroid 2 related factor-1 (NRF1) and -2 (NRF2), in counteracting cholesterol-linked liver stress. Using a diet that increases liver cholesterol storage, expression profiles and phenotypes of liver from mice with hepatocyte deficiency of NRF1, NRF2, or both are compared with controls, and chromatin immunoprecipitation sequencing is undertaken to identify target genes. Results show NRF1 and NRF2 co-regulate genes that eliminate cholesterol and mitigate inflammation and oxidative damage. Combined deficiency, but not deficiency of either alone, results in severe steatohepatitis, hepatic cholesterol overload and crystallization, altered bile acid metabolism, and decreased biliary cholesterol. Moreover, therapeutic effects of NRF2-activating drug bardoxolone require NRF1 and are supplemented by NRF1 overexpression. Thus, we discover complementary gene programming by NRF1 and NRF2 that counteract cholesterol-associated fatty liver disease progression.
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Fator 2 Relacionado a NF-E2 , Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , Colesterol/metabolismo , Regulação da Expressão Gênica , Fígado/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse OxidativoRESUMO
Hepatocellular carcinoma (HCC) is a major public health concern that is promoted by obesity and associated liver complications. Onset and progression of HCC in obesity is a multifactorial process involving complex interactions between the metabolic and immune system, in which chronic liver damage resulting from metabolic and inflammatory insults trigger carcinogenesis-promoting gene mutations and tumor metabolism. Moreover, cell growth and proliferation of the cancerous cell, after initiation, requires interactions between various immunological and metabolic pathways that provide stress defense of the cancer cell as well as strategic cell death escape mechanisms. The heterogenic nature of HCC in addition to the various metabolic risk factors underlying HCC development have led researchers to focus on examining metabolic pathways that may contribute to HCC development. In obesity-linked HCC, oncogene-induced modifications and metabolic pathways have been identified to support anabolic demands of the growing HCC cells and combat the concomitant cell stress, coinciding with altered utilization of signaling pathways and metabolic fuels involved in glucose metabolism, macromolecule synthesis, stress defense, and redox homeostasis. In this review, we discuss metabolic insults that can underlie the transition from steatosis to steatohepatitis and from steatohepatitis to HCC as well as aberrantly regulated immunometabolic pathways that enable cancer cells to survive and proliferate in the tumor microenvironment. We also discuss therapeutic modalities targeted at HCC prevention and regression. A full understanding of HCC-associated immunometabolic changes in obesity may contribute to clinical treatments that effectively target cancer metabolism.
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The onset of mammalian maternal care is associated with plasticity in neural processing of infant-related sensory stimuli; however, little is known about sensory plasticity associated with fatherhood. We quantified behavioral and neural responses of virgin males and new fathers to olfactory and auditory stimuli from young, unfamiliar pups in the biparental California mouse (Peromyscus californicus). Each male was exposed for 10 min to one of four combinations of a chemosensory stimulus (pup-scented or unscented cotton [control]) and an auditory stimulus (pup vocalizations or white noise [control]). Behavior did not differ between fathers and virgins during exposure to sensory stimuli or during the following hour; however, males in both groups were more active both during and after exposure to pup-related stimuli compared to control stimuli. Fathers had lower expression of Fos in the main olfactory bulbs (MOB) but higher expression in the medial preoptic area (MPOA) and bed nucleus of the stria terminalis medial division, ventral part (STMV) compared to virgins. Lastly, males had higher Fos expression in MPOA when exposed to pup odor compared to control stimuli, and when exposed to pup odor and pup calls compared to pup calls only or control stimuli. These findings suggest that the onset of fatherhood alters activity of MOB, MPOA and STMV and that pup odors and vocalizations have additive or synergistic effects on males' behavior and MPOA activation.
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Comportamento Paterno , Peromyscus , Animais , Comportamento Animal , Pai , Humanos , Masculino , Odorantes , Área Pré-ÓpticaRESUMO
This review discusses molecular motors that use the microfilament and microtubule cytoskeletal systems in filamentous fungi. There has been an explosion in our knowledge of kinesins over the past year, because of the integration of genetic and biochemical data. The recognition of possible interactions between septation genes and cytokinesis has also advanced our understanding of microfilament-based cytoskeletal systems. We review recent findings on microfilament motors, including conventional and unconventional myosins, and the microtubule motors of the kinesin family and cytoplasmic dynein. The roles that these molecules play in hyphal morphogenesis and organelle transport provide an insight into cytoskeletal-based transport systems.
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Dineínas/fisiologia , Fungos/citologia , Cinesinas/fisiologia , Miosinas/fisiologia , Citoesqueleto/metabolismoRESUMO
BACKGROUND: Although the efficacy and safety of extensive endomucosal resection (EMR) in eradicating Barrett's esophagus (BE) harbouring early neoplasia have been established, factors predicting efficacy remains unclear. AIM: To determine the complete eradication rate of Barrett's esophagus with high-grade intraepithelial neoplasia (HGIN) or intramucosal carcinoma (IMC), safety, and factors predicting complete eradication by EMR. METHODS: Patients with histological confirmation of Barrett's HGIN/IMC were prospectively identified. EMR was performed using Duette multiband ligator or cap technique by a single operator (NEM). RESULTS: 99 patients (81 males) with median age 67 years [interquartile range (IQR) 60-77 years] and median Barrett's length 4 cm (IQR 2-6 cm) were included. Of 628 index EMRs [mean 6.3, median 5 (IQR 3-8)], 23% showed IMC, 58.5% showed HGIN, and 16% showed low-grade dysplasia only. A median of 8 EMR resections per patient (IQR 6-16, 1,064 resections in 89 patients) resulted in complete eradication of BE harboring neoplasia in 49.4% and eradication of HGIN/IMC in 81% (BE <5 cm subgroup: 65% complete eradication and 91% HGIN eradication) at median follow-up of 18 months (range 6-27 months). On univariate analysis, focal dysplasia (P = 0.003) and Barrett's length <5 cm (P = 0.001) were predictors of complete BE eradication. Barrett's length <5 cm was the only significant predictor [odds ratio (OR) 3.4, standard error (SE) 0.11, P = 0.0006] on multiple logistic regression analysis. Strictures developed in 27% and major bleeding in 2% with no procedure-related perforations or mortality. CONCLUSIONS: Extensive EMR for removal of BE with early neoplasia is safe. Outcomes for complete BE eradication are modest at 49.4% and eradication of high-grade dysplasia at 81%. Barrett's length <5 cm is the only significant predictor of complete response.
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Esôfago de Barrett/cirurgia , Carcinoma in Situ/cirurgia , Neoplasias Esofágicas/cirurgia , Esofagoscopia , Idoso , Esôfago de Barrett/complicações , Esôfago de Barrett/patologia , Carcinoma in Situ/complicações , Neoplasias Esofágicas/complicações , Esôfago/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-OperatóriasRESUMO
BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) remains a challenge for endoscopists in patients with surgically altered anatomy of the upper gastrointestinal tract. Double-balloon enteroscopes (DBEs) have revolutionized the ability to access the small bowel. The indication for its therapeutic use is expanding to include ERCP for patients who have undergone small bowel reconstruction. Most of the published experiences in DBE-assisted ERCP have used conventional double-balloon enteroscopes that are 200 cm in length, which do not permit use of the standard ERCP accessories. The authors report their experience with DBE-assisted ERCP using a 'short' DBE in patients with surgically altered anatomy. METHODS: A retrospective review of patients with previous small bowel reconstruction who underwent ERCP with a 'short' DBE at the Centre for Therapeutic Endoscopy and Endoscopic Oncology (Toronto, Ontario) between February 2007 and November 2008 was performed. RESULTS: A total of 20 patients (10 men) with a mean age of 57.9 years (range 26 to 85 years) underwent 29 sessions of ERCP with a DBE. Six patients underwent Billroth II gastroenterostomy, seven patients Roux-en-Y hepaticojejunostomy, five patients Roux-en-Y gastrojejunostomy, one patient Roux-en-Y esophagojejunostomy and one patient a Whipple's operation with choledochojejunostomy. Some patients (n=12 [60%]) underwent previous attempts at ERCP in which the papilla of Vater or bilioenteric anastomosis could not be reached with either a duodenoscope or pediatric colonoscope. All procedures were performed with a commercially available DBE (working length 152 cm, distal end diameter 9.4 mm, channel diameter 2.8 mm). The procedures were performed under conscious sedation with intravenous midazolam, fentanyl and diazepam, except in one patient in whom general anesthesia was administered. Either the papilla of Vater or bilioenteric anastomosis was reached in 25 of 29 cases (86.2%) in a mean duration of 20.8 min (range 5 min to 82 min). Bile duct cannulation was successful in 24 of 25 cases in which the papilla or bilioenteric anastomosis was reached. Therapeutic interventions were successful in 15 patients (24 procedures) including sphincterotomy (n=7), stone extraction (n=9), biliary dilation (n=8), stent placement (n=9) and stent removal (n=8). The mean total duration of the procedures was 70.7 min (range 30 min to 117 min). There were no procedure-related complications. CONCLUSION: DBEs enable successful diagnostic and therapeutic ERCP in patients with a surgically altered anatomy of the upper gastrointestinal tract. It is a safe, feasible and less invasive therapeutic option in this group of patients. Standard 'long' DBEs have limitations of long working length and the need for modified ERCP accessories. 'Short' DBEs are equally as effective in reaching the target limb as standard 'long' DBEs, and overcomes some limitations of long DBEs to result in high success rates for endoscopic therapy.