Fasting and postprandial plasma ghrelin levels are decreased in patients with liver failure previous to liver transplantation

[Abstract] Anorexia is a problem of paramount importance in patients with advanced liver failure. Ghrelin has important actions on feeding and weight homeostasis. Concentrations of ghrelin are controversial in liver cirrhosis. Our aim was to study fasting ghrelin and their response to an oral glucose tolerance test (OGTT) in liver failure patients and normal subjects. Methods We included 16 patients with severe liver failure prior to liver transplantation. As a control group we included 10 age- and BMI-matched healthy subjects. After an overnight fast, 75 g of oral glucose were administered; glucose, insulin, and ghrelin were obtained at baseline and at times 30, 60, 90, and 120 min, respectively. Results Fasting ghrelin (median and range) were statistically significantly lower for patients compared to the controls, 527 (377–971) pg/ml vs. 643 (523–2163) pg/ml, P = 0.045, for patients and controls, respectively. The area under the curve for total ghrelin post-OGTT were lower in end-stage liver failure patients than in the control group, 58815 (44730–87420) pg/ml min vs. 76560 (56160–206385) pg/ml min, for patients and controls, respectively, P = 0.027. Conclusions Ghrelin levels are significantly decreased both fasting and post-OGTT in patients with liver failure candidates for transplantation. Decreased ghrelin levels could contribute to anorexia in patients with cirrhosis.Instituto de Salud Carlos III; PI051024Instituto de Salud Carlos III; PI070413Xunta de Galicia; PS07/12Xunta de Galicia; PGIDT05PXIC91605PNXunta de Galicia; INCITE08ENA916110E

Bigger, Faster, Better? Rhetorics and Practices of Large-Scale Research in Contemporary Bioscience

publication-status: Publishedtypes: ArticleEditorial for Special Issu

Using C. elegans to decipher the cellular and molecular mechanisms underlying neurodevelopmental disorders

Prova tipográfica (uncorrected proof)Neurodevelopmental disorders such as epilepsy, intellectual disability (ID), and autism spectrum disorders (ASDs) occur in over 2 % of the population, as the result of genetic mutations, environmental factors, or combination of both. In the last years, use of large-scale genomic techniques allowed important advances in the identification of genes/loci associated with these disorders. Nevertheless, following association of novel genes with a given disease, interpretation of findings is often difficult due to lack of information on gene function and effect of a given mutation in the corresponding protein. This brings the need to validate genetic associations from a functional perspective in model systems in a relatively fast but effective manner. In this context, the small nematode, Caenorhabditis elegans, presents a good compromise between the simplicity of cell models and the complexity of rodent nervous systems. In this article, we review the features that make C. elegans a good model for the study of neurodevelopmental diseases. We discuss its nervous system architecture and function as well as the molecular basis of behaviors that seem important in the context of different neurodevelopmental disorders. We review methodologies used to assess memory, learning, and social behavior as well as susceptibility to seizures in this organism. We will also discuss technological progresses applied in C. elegans neurobiology research, such as use of microfluidics and optogenetic tools. Finally, we will present some interesting examples of the functional analysis of genes associated with human neurodevelopmental disorders and how we can move from genes to therapies using this simple model organism.The authors would like to acknowledge Fundação para a Ciência e Tecnologia (FCT) (PTDC/SAU-GMG/112577/2009). AJR and CB are recipients of FCT fellowships: SFRH/BPD/33611/2009 and SFRH/BPD/74452/2010, respectively

Rapid selection of cyclic peptides that reduce alpha-synuclein toxicity in yeast and animal models

Phage display has demonstrated the utility of cyclic peptides as general protein ligands but cannot access proteins inside eukaryotic cells. Expanding a new chemical genetics tool, we describe the first expressed library of head-to-tail cyclic peptides in yeast (Saccharomyces cerevisiae). We applied the library to selections in a yeast model of alpha-synuclein toxicity that recapitulates much of the cellular pathology of Parkinson's disease. From a pool of 5 million transformants, we isolated two related cyclic peptide constructs that specifically reduced the toxicity of human alpha-synuclein. These expressed cyclic peptide constructs also prevented dopaminergic neuron loss in an established Caenorhabditis elegans Parkinson's model. This work highlights the speed and efficiency of using libraries of expressed cyclic peptides for forward chemical genetics in cellular models of human disease

Genetic Diversity and Antimicrobial Resistance of Escherichia coli from Human and Animal Sources Uncovers Multiple Resistances from Human Sources

Escherichia coli are widely used as indicators of fecal contamination, and in some cases to identify host sources of fecal contamination in surface water. Prevalence, genetic diversity and antimicrobial susceptibility were determined for 600 generic E. coli isolates obtained from surface water and sediment from creeks and channels along the middle Santa Ana River (MSAR) watershed of southern California, USA, after a 12 month study. Evaluation of E. coli populations along the creeks and channels showed that E. coli were more prevalent in sediment compared to surface water. E. coli populations were not significantly different (P = 0.05) between urban runoff sources and agricultural sources, however, E. coli genotypes determined by pulsed-field gel electrophoresis (PFGE) were less diverse in the agricultural sources than in urban runoff sources. PFGE also showed that E. coli populations in surface water were more diverse than in the sediment, suggesting isolates in sediment may be dominated by clonal populations.Twenty four percent (144 isolates) of the 600 isolates exhibited resistance to more than one antimicrobial agent. Most multiple resistances were associated with inputs from urban runoff and involved the antimicrobials rifampicin, tetracycline, and erythromycin. The occurrence of a greater number of E. coli with multiple antibiotic resistances from urban runoff sources than agricultural sources in this watershed provides useful evidence in planning strategies for water quality management and public health protection

Judgment of the Humanness of an Interlocutor Is in the Eye of the Beholder

Despite tremendous advances in artificial language synthesis, no machine has so far succeeded in deceiving a human. Most research focused on analyzing the behavior of “good” machine. We here choose an opposite strategy, by analyzing the behavior of “bad” humans, i.e., humans perceived as machine. The Loebner Prize in Artificial Intelligence features humans and artificial agents trying to convince judges on their humanness via computer-mediated communication. Using this setting as a model, we investigated here whether the linguistic behavior of human subjects perceived as non-human would enable us to identify some of the core parameters involved in the judgment of an agents' humanness. We analyzed descriptive and semantic aspects of dialogues in which subjects succeeded or failed to convince judges of their humanness. Using cognitive and emotional dimensions in a global behavioral characterization, we demonstrate important differences in the patterns of behavioral expressiveness of the judges whether they perceived their interlocutor as being human or machine. Furthermore, the indicators of interest displayed by the judges were predictive of the final judgment of humanness. Thus, we show that the judgment of an interlocutor's humanness during a social interaction depends not only on his behavior, but also on the judge himself. Our results thus demonstrate that the judgment of humanness is in the eye of the beholder

Inhibition of CCN6 (WISP3) expression promotes neoplastic progression and enhances the effects of insulin-like growth factor-1 on breast epithelial cells

INTRODUCTION: CCN6/WISP3 belongs to the CCN (Cyr61, CTGF, Nov) family of genes that contains a conserved insulin-like growth factor (IGF) binding protein motif. CCN6 is a secreted protein lost in 80% of the aggressive inflammatory breast cancers, and can decrease mammary tumor growth in vitro and in vivo. We hypothesized that inhibition of CCN6 might result in the loss of a growth regulatory function that protects mammary epithelial cells from the tumorigenic effects of growth factors, particularly IGF-1. METHOD: We treated human mammary epithelial (HME) cells with a CCN6 hairpin short interfering RNA. RESULTS: CCN6-deficient cells showed increased motility and invasiveness, and developed features of epithelial-mesenchymal transition (EMT). Inhibition of CCN6 expression promoted anchorage-independent growth of HME cells and rendered them more responsive to the growth effects of IGF-1, which was coupled with the increased phosphorylation of IGF-1 receptor and insulin receptor substrate-1 (IRS-1). CONCLUSION: Specific stable inhibition of CCN6 expression in HME cells induces EMT, promotes anchorage-independent growth, motility and invasiveness, and sensitizes mammary epithelial cells to the growth effects of IGF-1

CDH1 promoter hypermethylation and E-cadherin protein expression in infiltrating breast cancer

BACKGROUND: The E-cadherin gene (CDH1) maps, at chromosome 16q22.1, a region often associated with loss of heterozygosity (LOH) in human breast cancer. LOH at this site is thought to lead to loss of function of this tumor suppressor gene and was correlated with decreased disease-free survival, poor prognosis, and metastasis. Differential CpG island methylation in the promoter region of the CDH1 gene might be an alternative way for the loss of expression and function of E-cadherin, leading to loss of tissue integrity, an essential step in tumor progression. METHODS: The aim of our study was to assess, by Methylation-Specific Polymerase Chain Reaction (MSP), the methylation pattern of the CDH1 gene and its possible correlation with the expression of E-cadherin and other standard immunohistochemical parameters (Her-2, ER, PgR, p53, and K-67) in a series of 79 primary breast cancers (71 infiltrating ductal, 5 infiltrating lobular, 1 metaplastic, 1 apocrine, and 1 papillary carcinoma). RESULTS: CDH1 hypermethylation was observed in 72% of the cases including 52/71 ductal, 4/5 lobular carcinomas and 1 apocrine carcinoma. Reduced levels of E-cadherin protein were observed in 85% of our samples. Although not statistically significant, the levels of E-cadherin expression tended to diminish with the CDH1 promoter region methylation. In the group of 71 ductal cancinomas, most of the cases of showing CDH1 hypermethylation also presented reduced levels of expression of ER and PgR proteins, and a possible association was observed between CDH1 methylation and ER expression (p = 0.0301, Fisher's exact test). However, this finding was not considered significant after Bonferroni correction of p-value. CONCLUSION: Our preliminary findings suggested that abnormal CDH1 methylation occurs in high frequencies in infiltrating breast cancers associated with a decrease in E-cadherin expression in a subgroup of cases characterized by loss of expression of other important genes to the mammary carcinogenesis process, probably due to the disruption of the mechanism of maintenance of DNA methylation in tumoral cells

Shared Pattern of Endocranial Shape Asymmetries among Great Apes, Anatomically Modern Humans, and Fossil Hominins

Anatomical asymmetries of the human brain are a topic of major interest because of their link with handedness and cognitive functions. Their emergence and occurrence have been extensively explored in human fossil records to document the evolution of brain capacities and behaviour. We quantified for the first time antero-posterior endocranial shape asymmetries in large samples of great apes, modern humans and fossil hominins through analysis of “virtual” 3D models of skull and endocranial cavity and we statistically test for departures from symmetry. Once based on continuous variables, we show that the analysis of these brain asymmetries gives original results that build upon previous analysis based on discrete traits. In particular, it emerges that the degree of petalial asymmetries differs between great apes and hominins without modification of their pattern. We indeed demonstrate the presence of shape asymmetries in great apes, with a pattern similar to modern humans but with a lower variation and a lower degree of fluctuating asymmetry. More importantly, variations in the position of the frontal and occipital poles on the right and left hemispheres would be expected to show some degree of antisymmetry when population distribution is considered, but the observed pattern of variation among the samples is related to fluctuating asymmetry for most of the components of the petalias. Moreover, the presence of a common pattern of significant directional asymmetry for two components of the petalias in hominids implicates that the observed traits were probably inherited from the last common ancestor of extant African great apes and Homo sapiens