Lipoxin agonists: turn right! to path of resolving neutrophil

An impressive array of cellular and molecular adaptive responses achieves homeostasis. The inflammatory reaction is an adaptive response triggered by an insult to culminate into the overt cardinal signs of inflammation, eventually leading to resolution and returning the organism back to its original centered state. This article focuses on some aspects of the lipoxin A4 signaling pathway during the resolution phase, to better understand molecular mechanisms by which a neutrophil directs an inflammatory reaction to switch off and resume homeostasis. Defining the resolution state of a neutrophil at the molecular level will aid in treatments of diseases that are associated with an exaggerated and uncontrolled inflammation.

The eusociality continuum

Eusocial societies are traditionally characterized by a reproductive division of labor, an overlap of generations, and cooperative care of the breeders' young. Eusociality was once thought to occur only in termites, ants, and some bee and wasp species, but striking evolutionary convergences have recently become apparent between the societies of these insects and those of cooperatively breeding birds and mammals. These parallels have blurred distinctions between cooperative breeding and eusociality, leading to calls for either drastically restricting or expanding wage of these terms. We favor the latter approach. Cooperative breeding and eusociality are not discrete phenomena, but rather form a continuum of fundamentally similar social systems whose main differences lie in the distribution of lifetime reproductive success among group members. Therefore we propose to array vertebrate and invertebrate cooperative breeders along a common axis, representing a standardized measure of reproductive variance, and to drop such (loaded) terms as ''primitive'' and ''advanced'' eusociality. The terminology we propose unites all occurrences of alloparental helping of kin under a single theoretical umbrella (e.g., Hamilton's rule). Thus, cooperatively breeding vertebrates can be regarded as eusocial, just as eusocial inverbrates are cooperative breeders. We believe this integrated approach will foster potentially revealing cross-taxon comparisons, which are essential to understanding social evolution in birds, mammals, and in sects.

Comparative transcriptomics of rice reveals an ancient pattern of response to microbial colonization.

Glomalean fungi induce and colonize symbiotic tissue called arbuscular mycorrhiza on the roots of most land plants. Other fungi also colonize plants but cause disease not symbiosis. Whole-transcriptome analysis using a custom-designed Affymetrix Gene-Chip and confirmation with real-time RT-PCR revealed 224 genes affected during arbuscular mycorrhizal symbiosis. We compared these transcription profiles with those from rice roots that were colonized by pathogens (Magnaporthe grisea and Fusarium moniliforme). Over 40% of genes showed differential regulation caused by both the symbiotic and at least one of the pathogenic interactions. A set of genes was similarly expressed in all three associations, revealing a conserved response to fungal colonization. The responses that were shared between pathogen and symbiont infection may play a role in compatibility. Likewise, the responses that are different may cause disease. Some of the genes that respond to mycorrhizal colonization may be involved in the uptake of phosphate. Indeed, phosphate addition mimicked the effect of mycorrhiza on 8% of the tested genes. We found that 34% of the mycorrhiza-associated rice genes were also associated with mycorrhiza in dicots, revealing a conserved pattern of response between the two angiosperm classes.

Biomarkers of human gastrointestinal tract regions.

Dysregulation of intestinal epithelial cell performance is associated with an array of pathologies whose onset mechanisms are incompletely understood. While whole-genomics approaches have been valuable for studying the molecular basis of several intestinal diseases, a thorough analysis of gene expression along the healthy gastrointestinal tract is still lacking. The aim of this study was to map gene expression in gastrointestinal regions of healthy human adults and to implement a procedure for microarray data analysis that would allow its use as a reference when screening for pathological deviations. We analyzed the gene expression signature of antrum, duodenum, jejunum, ileum, and transverse colon biopsies using a biostatistical method based on a multivariate and univariate approach to identify region-selective genes. One hundred sixty-six genes were found responsible for distinguishing the five regions considered. Nineteen had never been described in the GI tract, including a semaphorin probably implicated in pathogen invasion and six novel genes. Moreover, by crossing these genes with those retrieved from an existing data set of gene expression in the intestine of ulcerative colitis and Crohn's disease patients, we identified genes that might be biomarkers of Crohn's and/or ulcerative colitis in ileum and/or colon. These include CLCA4 and SLC26A2, both implicated in ion transport. This study furnishes the first map of gene expression along the healthy human gastrointestinal tract. Furthermore, the approach implemented here, and validated by retrieving known gene profiles, allowed the identification of promising new leads in both healthy and disease states.

THE CXCR7/CXCR4/CXCL12 AXIS IN HUMAN NEUROBLASTOMA: INVOLVEMENT IN MALIGNANT PROGRESSION

Le neuroblastome (NB) est la tumeur maligne solide extra-crânienne la plus fréquente chez le jeune enfant. L'évolution clinique est très hétérogène, et les NBs de haut risque échappent encore aux traitements les plus agressifs. Diverses études ont montré que les chimiokines et leurs récepteurs, particulièrement l'axe CXCR4/CXCL12, sont impliqués dans la progression tumorale. Dans le NB, l'expression de CXCR4 est corrélée à un pronostic défavorable. De récentes études ont identifié l'expression d'un autre récepteur, CXCR7, présentant une forte affinité pour le ligand CXCL12. Cependant, son implication potentielle dans l'agressivité des NBs reste encore inconnue. Notre étude a pour objectif d'analyser le rôle de CXCR7 dans le comportement malin du NB, et son influence sur la fonctionnalité de l'axe CXCR4/CXCL12. Les profils d'expression de CXCR7 et CXCL12 ont d'abord été évalués sur un large échantillonnage de tissus de NB, incluant des tissus de tumeurs primaires et de métastases, provenant de 156 patients. CXCL12 est fortement détecté dans les vaisseaux et le stroma des tumeurs. Contrairement à CXCR4, CXCR7 n'est que très faiblement exprimé par les tumeurs indifférenciées. Néanmoins, l'expression de CXCR7 augmente dans les tumeurs matures, et se trouve spécifiquement associée aux cellules neurales différentiées, telles que les cellules ganglionnaires. L'expression de CXCR7 est faiblement détectée dans un nombre réduit de lignées de NB, mais peut-être induite suite à des traitements avec des agents de différenciation in vitro. La surexpression de CXCR7, CXCR4 et une combinaison des deux récepteurs dans les lignées IGR-NB8 et SH-SY5Y a permis l'analyse de leur fonction respective. En réponse à leur ligand commun, chaque récepteur induit l'activation de la voie ERK 1/2, mais pas celle de la voie Akt. Contrairement à CXCR4, l'expression exogène de CXCR7 réduit fortement la prolifération des cellules de NB in vitro, et in vivo dans un modèle d'injection sous-cutanée de. souris immunodéprimées. CXCR7 altère également la migration des cellules induite par l'axe CXCR4/CXCL12. De plus, l'utilisation d'un modèle orthotopique murin a démontré que la croissance tumorale induite par CXCR4 peut être fortement retardée lorsque les deux récepteurs sont co-exprimés dans les cellules de NB. Aucune induction de métastases n'a pu être observée dans ce modèle. Cette étude a permis d'identifier un profil d'expression opposé et des rôles distincts pour CXCR7 et CXCR4 dans le NB. En effet, contrairement à CXCR4, CXCR7 présente des propriétés non tumorigéniques et peut être associé au processus de différenciation du NB. De plus, nos analyses suggèrent que CXCR7 peut réguler les mécanismes induits par CXCR4. Ces données ouvrent donc de nouvelles perspectives de recherche quant au rôle de l'axe CXCR7/CXCR4/CXCL12 dans la biologie des NBs. - Neuroblastoma (NB) is a typical childhood and heterogeneous neoplasm for which efficient targeted therapy for high-risk tumours is not yet identified. The chemokine CXCL12, and its receptors CXCR4 and CXCR7 have been involved in tumour progression and dissemination in various cancer models. In the context of NB, CXCR4 expression is associated to undifferentiated tumours and poor prognosis, while the role of CXCR7, the recently identified second CXCL12 receptor, has not yet been elucidated. In this report, CXCR7 and CXCL12 expression were evaluated using a tissue micro-array (TMA) including 156 primary and 56 metastatic NB tissues. CXCL12 was found to be highly associated to NB vascular and stromal structures. In opposite to the CXCR4 expression pattern, the neural-associated CXCR7 expression was extremely low in undifferentiated tumours, while its expression increased in maturated tissues and was specifically associated to the differentiated neural tumour cells. As determined by RT-PCR, CXCR7 expression was only found in a minority of NB cell lines. Moreover, its expression in two CXCR7-negative NB cell lines was further induce upon treatment with differentiation agents in vitro. The relative roles of the two CXCL12 receptors was further assessed by overexpressing individual CXCR7 or CXCR4 receptors, or a combination of both, in the IGR-NB8 and SH-SY5Y NB cell lines. In vitro functional analyses indicated that, in response to their common ligand, both receptors induced activation of ERK 1/2 cascade, but not Akt signaling pathway. CXCR7 strongly reduced in vitro growth, in contrast to CXCR4. Sub-cutaneous implantations of CXCR7-expressing NB cells showed that CXCR7 also drastically reduced in vivo growth. Moreover, CXCR7 impaired CXCR4-mediated chemotaxis, and altered CXCR4-mediated growth when CXCR4/CXCR7-expressing NB cells were engrafted orthotopically in mouse adrenal gland, a CXCL12-producing environment. In such model, CXCR7 alone, or in association with CXCR4, did not induce NB cell metastatic dissemination. In conclusion, the CXCL12 receptors, CXCR7 and CXCR4, revealed opposite expression patterns and distinct functional roles in NB. While CXCR4 favours NB growth and chemotaxis, CXCR7 elicits anti-tumorigenic properties and may be associated with NB differentiation. Importantly, CXCR7 may act as a negative modulator of CXCR4 signaling, further opening new research perspectives for the role of the global CXCR7/CXCR4/CXCL12 axis in NB.

Host and invader impact of transfer of the clc genomic island into Pseudomonas aeruginosa PAO1

Genomic islands, large potentially mobile regions of bacterial chromosomes, are a major contributor to bacteria evolution. Here, we investigated the fitness cost and phenotypic differences between the bacterium Pseudomonas aeruginosa PAO1 and a derivative carrying one integrated copy of the clc element, a 103-kb genomic island [and integrative and conjugative element (ICE)] originating in Pseudomonas sp. strain B13 and a close relative of genomic islands found in clinical and environmental isolates of P. aeruginosa. By using a combination of whole genome transcriptome profiling, phenotypic arrays, competition experiments, and biofilm formation studies, only few differences became apparent, such as reduced biofilm growth and fourfold stationary phase repression of genes involved in acetoin metabolism in PAO1 containing the clc element. In contrast, PAO1 carrying the clc element acquired the capacity to grow on 3-chlorobenzoate and 2-aminophenol as sole carbon and energy substrates. No fitness loss >1% was detectable in competition experiments between PAO1 and PAO1 carrying the clc element. The genes from the clc element were not silent in PAO1, and excision was observed, although transfer of clc from PAO1 to other recipient bacteria was reduced by two orders of magnitude. Our results indicate that newly acquired mobile DNA not necessarily invoke an important fitness cost on their host. Absence of immediate detriment to the host may have contributed to the wide distribution of genomic islands like clc in bacterial genomes

Defining the role of common variation in the genomic and biological architecture of adult human height.

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing.

Signal transducer and activator of transcription (STAT) 3 is a pleiotropic transcription factor with important functions in cytokine signaling in a variety of tissues. However, the role of STAT3 in the intestinal epithelium is not well understood. We demonstrate that development of colonic inflammation is associated with the induction of STAT3 activity in intestinal epithelial cells (IECs). Studies in genetically engineered mice showed that epithelial STAT3 activation in dextran sodium sulfate colitis is dependent on interleukin (IL)-22 rather than IL-6. IL-22 was secreted by colonic CD11c(+) cells in response to Toll-like receptor stimulation. Conditional knockout mice with an IEC-specific deletion of STAT3 activity were highly susceptible to experimental colitis, indicating that epithelial STAT3 regulates gut homeostasis. STAT3(IEC-KO) mice, upon induction of colitis, showed a striking defect of epithelial restitution. Gene chip analysis indicated that STAT3 regulates the cellular stress response, apoptosis, and pathways associated with wound healing in IECs. Consistently, both IL-22 and epithelial STAT3 were found to be important in wound-healing experiments in vivo. In summary, our data suggest that intestinal epithelial STAT3 activation regulates immune homeostasis in the gut by promoting IL-22-dependent mucosal wound healing.

Large-scale gene-centric analysis identifies novel variants for coronary artery disease.

Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10(-7)). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ∼4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.

Notch signaling is required for normal prostatic epithelial cell proliferation and differentiation.

Notch pathway is crucial for stem/progenitor cell maintenance, growth and differentiation in a variety of tissues. Using a transgenic cell ablation approach, we found in our previous study that cells expressing Notch1 are crucial for prostate early development and re-growth. Here, we further define the role of Notch signaling in regulating prostatic epithelial cell growth and differentiation using biochemical and genetic approaches in ex vivo or in vivo systems. Treatment of developing prostate grown in culture with inhibitors of gamma-secretase/presenilin, which is required for Notch cleavage and activation, caused a robust increase in proliferation of epithelial cells co-expressing cytokeratin 8 and 14, lack of luminal/basal layer segregation and dramatically reduced branching morphogenesis. Using conditional Notch1 gene deletion mouse models, we found that inactivation of Notch1 signaling resulted in profound prostatic alterations, including increased tufting, bridging and enhanced epithelial proliferation. Cells within these lesions co-expressed both luminal and basal cell markers, a feature of prostatic epithelial cells in predifferentiation developmental stages. Microarray analysis revealed that the gene expression in a number of genetic networks was altered following Notch1 gene deletion in prostate. Furthermore, expression of Notch1 and its effector Hey-1 gene in human prostate adenocarcinomas were found significantly down-regulated compared to normal control tissues. Taken together, these data suggest that Notch signaling is critical for normal cell proliferation and differentiation in the prostate, and deregulation of this pathway may facilitate prostatic tumorigenesis.

Changes in the transcriptional profile of transporters in the intestine along the anterior-posterior and crypt-villus axes.

BACKGROUND: The purpose of this work was to characterize the expression of drug and nutrient carriers along the anterior-posterior and crypt-villus axes of the intestinal epithelium and to study the validity of utilizing whole gut tissue rather than purified epithelial cells to examine regional variations in gene expression. RESULTS: We have characterized the mRNA expression profiles of 76 % of all currently known transporters along the anterior-posterior axis of the gut. This is the first study to describe the expression profiles of the majority of all known transporters in the intestine. The expression profiles of transporters, as defined according to the Gene Ontology consortium, were measured in whole tissue of the murine duodenum, jejunum, ileum and colon using high-density microarrays. For nine transporters (Abca1, Abcc1, Abcc3, Abcg8, Slc10a2, Slc28a2, Slc2a1, Slc34a2 and Slc5a8), the mRNA profiles were further measured by RT-PCR in laser micro-dissected crypt and villus epithelial cells corresponding to the aforementioned intestinal regions. With respect to differentially regulated transporters, the colon had a distinct expression profile from small intestinal segments. The majority (59 % for p cutoff < or = 0.05) of transporter mRNA levels were constant across the intestinal sections studied. For the transporter subclass "carrier activity", which contains the majority of known carriers for biologically active compounds, a significant change (p < or = 0.05) along the anterior-posterior axis was observed. CONCLUSION: All nine transporters examined in laser-dissected material demonstrated good replication of the region-specific profiles revealed by microarray. Furthermore, we suggest that the distribution characteristics of Slc5a8 along the intestinal tract render it a suitable candidate carrier for monocarboxylate drugs in the posterior portion of the intestine. Our findings also predict that there is a significant difference in the absorption of carrier-mediated compounds in the different intestinal segments. The most pronounced differences can be expected between the adjoining segments ileum and colon, but the differences between the other adjoining segments are not negligible. Finally, for the examined genes, profiles measured in whole intestinal tissue extracts are representative of epithelial cell-only gene expression.

Metodologia per a la generació de consens social en el desplegament d'infraestructures de telefonia mòbil

Aquest document de treball es centra específicament en el desenvolupament de la infraestructura de telefonia mòbil a Catalunya com a exemple de tecnologia amb profundes implicacions socials. Esdevé un intent inicial de definir les principals línies de recerca en aquest tema. El projecte que el sosté és emmarcat en el programa de recerca Negrisc, centrat a examinar la negociació del risc en les tecnologies de la informació i de la comunicació. Parteix d'una aproximació que reconeix la natura multidisciplinària del risc i que, per tant, exigeix una aproximació interdisciplinària al seu estudi i a la gestió subsegüent. Aquesta perspectiva emfatitza la necessitat d'integrar els punts de vista dels diferents stakeholders, incloent-hi el públic, en la gestió d'una tecnologia socialment controvertida. Aquest és un pas necessari per a permetre la generació d'algun tipus de consens en el cas del desenvolupament de la infraestructura de telefonia mòbil a Catalunya.

Low frequency of human papillomavirus detection in prostate tissue from individuals from Northern Brazil

The presence of human papillomavirus (HPV) was evaluated in 65 samples of prostate tumours and six samples of prostates with benign prostatic hyperplasia from individuals from Northern Brazil. We used a highly sensitive test, the Linear Array HPV Genotyping Test, to detect 37 high and low-risk HPV types. In this study, only 3% of tumour samples showed HPV infection. Our findings support the conclusion that, despite the high incidence of HPV infection in the geographic regions studied, HPV was not associated with a higher risk of prostate cancer. To our knowledge, this is the first study evaluating the frequency of HPV detection in prostatic tissue of individuals from Brazil.

Mutation screening of multiple genes in Spanish patients with autosomal recessive retinitis pigmentosa by targeted resequencing.

Retinitis Pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. RP is the leading cause of visual loss in individuals younger than 60 years, with a prevalence of about 1 in 4000. The molecular genetic diagnosis of autosomal recessive RP (arRP) is challenging due to the large genetic and clinical heterogeneity. Traditional methods for sequencing arRP genes are often laborious and not easily available and a screening technique that enables the rapid detection of the genetic cause would be very helpful in the clinical practice. The goal of this study was to develop and apply microarray-based resequencing technology capable of detecting both known and novel mutations on a single high-throughput platform. Hence, the coding regions and exon/intron boundaries of 16 arRP genes were resequenced using microarrays in 102 Spanish patients with clinical diagnosis of arRP. All the detected variations were confirmed by direct sequencing and potential pathogenicity was assessed by functional predictions and frequency in controls. For validation purposes 4 positive controls for variants consisting of previously identified changes were hybridized on the array. As a result of the screening, we detected 44 variants, of which 15 are very likely pathogenic detected in 14 arRP families (14%). Finally, the design of this array can easily be transformed in an equivalent diagnostic system based on targeted enrichment followed by next generation sequencing.

Evolutionary implications of a high selfing rate in the freshwater snail Lymnaea truncatula.

Self-compatible hermaphroditic organisms that mix self-fertilization and outcrossing are of great interest for investigating the evolution of mating systems. We investigate the evolution of selfing in Lymnaea truncatula, a self-compatible hermaphroditic freshwater snail. We first analyze the consequences of selfing in terms of genetic variability within and among populations and then investigate how these consequences along with the species ecology (harshness of the habitat and parasitism) might govern the evolution of selfing. Snails from 13 localities (classified as temporary or permanent depending on their water availability) were sampled in western Switzerland and genotyped for seven microsatellite loci. F(IS) (estimated on adults) and progeny array analyses (on hatchlings) provided similar selfing rate estimates of 80%. Populations presented a low polymorphism and were highly differentiated (F(ST) = 0.58). Although the reproductive assurance hypothesis would predict higher selfing rate in temporary populations, no difference in selfing level was observed between temporary and permanent populations. However, allelic richness and gene diversity declined in temporary habitats, presumably reflecting drift. Infection levels varied but were not simply related to either estimated population selfing rate or to differences in heterozygosity. These findings and the similar selfing rates estimated for hatchlings and adults suggest that within-population inbreeding depression is low in L. truncatula.