CYR61 and alphaVbeta5 integrin cooperate to promote invasion and metastasis of tumors growing in preirradiated stroma.

Radiotherapy is widely used to treat human cancer. Patients locally recurring after radiotherapy, however, have increased risk of metastatic progression and poor prognosis. The clinical management of postradiation recurrences remains an unresolved issue. Tumors growing in preirradiated tissues have an increased fraction of hypoxic cells and are more metastatic, a condition known as tumor bed effect. The transcription factor hypoxia inducible factor (HIF)-1 promotes invasion and metastasis of hypoxic tumors, but its role in the tumor bed effect has not been reported. Here, we show that tumor cells derived from SCCVII and HCT116 tumors growing in a preirradiated bed, or selected in vitro through repeated cycles of severe hypoxia, retain invasive and metastatic capacities when returned to normoxia. HIF activity, although facilitating metastatic spreading of tumors growing in a preirradiated bed, is not essential. Through gene expression profiling and gain- and loss-of-function experiments, we identified the matricellular protein CYR61 and alphaVbeta5 integrin as proteins cooperating to mediate these effects. The anti-alphaV integrin monoclonal antibody 17E6 and the small molecular alphaVbeta3/alphaVbeta5 integrin inhibitor EMD121974 suppressed invasion and metastasis induced by CYR61 and attenuated metastasis of tumors growing within a preirradiated field. These results represent a conceptual advance to the understanding of the tumor bed effect and identify CYR61 and alphaVbeta5 integrin as proteins that cooperate to mediate metastasis. They also identify alphaV integrin inhibition as a potential therapeutic approach for preventing metastasis in patients at risk for postradiation recurrences.

Hyperhidrosis: a new and often early symptom in Fabry disease. International experience and data from the Fabry Outcome Survey.

Hypohidrosis is a classic feature of Fabry disease; in contrast, hyperhidrosis has only been rarely described. The aim of the study is to characterise the baseline descriptive data on hyperhidrosis (frequency, age at onset, sex ratio and outcome with and without enzyme replacement therapy) in hemizygous male and heterozygous female patients with Fabry disease. We describe case histories of five patients with Fabry disease and hyperhidrosis seen at three different centres. We have also analysed a cohort of 21 paediatric patients in the UK and a large European cohort of patients enrolled in the Fabry Outcome Survey (FOS). Five patients (three female, two male) with hyperhidrosis were originally identified, although each had additional symptoms related to Fabry disease. The age at onset of hyperhidrosis was less than 18 years in four cases. In the cohort of 21 paediatric patients (12 female, nine male), one female had hyperhidrosis; the age at onset of this symptom was 11 years. In the FOS cohort, 66 of 714 patients with Fabry disease had hyperhidrosis (44 of 369 females, 11.9%; 22 of 345 males, 6.4%). The female predominance was observed in seven of nine countries from which data were analysed. Hyperhidrosis is an increasingly recognised feature of the Fabry disease phenotype. It is more prevalent in females than in males and often appears in childhood or adolescence. The efficacy of enzyme replacement therapy on this recently recognised symptom should be assessed.

Transforming personal experience and emotions through education to cultural diversity: an interplay between unicity and genericity

When subjects studied at school are close to societal discourses and to the students' social identities, when they have high emotional resonance, is it possible to enable the students to distance themselves from their emotions and personal experience, and to conceptualise them? Examining the relation between emotion and learning through the lens of socio-cultural psychology, the aim of our study was to shed light on "secondarisation" processes, that is, processes that transform personal experience and emotions into conceptualised forms of thinking. We analysed 85 video-recorded lessons in education for cultural diversity involving 12 teachers (of primary and secondary schools). Having identified episodes in which emotions were put into words or personal experience was reported, we analysed the use of pronouns (taken as indicators of secondarisation processes) and found a recurrent pattern: "the unicity-genericity routine". We illustrate the functioning of this routine with various excerpts taken from lessons in education for diversity taught in the classes of two teachers in primary school. The results show that the interplay between unicity and genericity works as a discursive resource for the development of secondarisation processes.

Congenital heart defects in Europe: prevalence and perinatal mortality, 2000 to 2005.

BACKGROUND: This study determines the prevalence of Congenital Heart Defects (CHD), diagnosed prenatally or in infancy, and fetal and perinatal mortality associated with CHD in Europe. METHODS AND RESULTS: Data were extracted from the European Surveillance of Congenital Anomalies central database for 29 population-based congenital anomaly registries in 16 European countries covering 3.3 million births during the period 2000 to 2005. CHD cases (n=26 598) comprised live births, fetal deaths from 20 weeks gestation, and terminations of pregnancy for fetal anomaly (TOPFA). The average total prevalence of CHD was 8.0 per 1000 births, and live birth prevalence was 7.2 per 1000 births, varying between countries. The total prevalence of nonchromosomal CHD was 7.0 per 1000 births, of which 3.6% were perinatal deaths, 20% prenatally diagnosed, and 5.6% TOPFA. Severe nonchromosomal CHD (ie, excluding ventricular septal defects, atrial septal defects, and pulmonary valve stenosis) occurred in 2.0 per 1000 births, of which 8.1% were perinatal deaths, 40% were prenatally diagnosed, and 14% were TOPFA (TOPFA range between countries 0% to 32%). Live-born CHD associated with Down syndrome occurred in 0.5 per 1000 births, with > 4-fold variation between countries. CONCLUSION: Annually in the European Union, we estimate 36 000 children are live born with CHD and 3000 who are diagnosed with CHD die as a TOFPA, late fetal death, or early neonatal death. Investing in primary prevention and pathogenetic research is essential to reduce this burden, as well as continuing to improve cardiac services from in utero to adulthood.

Chroma binary similarity and local alignment applied to cover song identification

We present a new technique for audio signal comparison based on tonal subsequence alignment and its application to detect cover versions (i.e., different performances of the same underlying musical piece). Cover song identification is a task whose popularity has increased in the Music Information Retrieval (MIR) community along in the past, as it provides a direct and objective way to evaluate music similarity algorithms.This article first presents a series of experiments carried outwith two state-of-the-art methods for cover song identification.We have studied several components of these (such as chroma resolution and similarity, transposition, beat tracking or Dynamic Time Warping constraints), in order to discover which characteristics would be desirable for a competitive cover song identifier. After analyzing many cross-validated results, the importance of these characteristics is discussed, and the best-performing ones are finally applied to the newly proposed method. Multipleevaluations of this one confirm a large increase in identificationaccuracy when comparing it with alternative state-of-the-artapproaches.

A non-interventional phase IV Belgian survey to assess the antiviral effectiveness of pegylated interferon-alpha-2b and ribavirin treatment according to the stage of liver fibrosis in previously untreated patients with genotype 1/4/5/6 chronic hepatitis C (PRACTICE).

BACKGROUND AND STUDY AIMS: This was an observational, non-interventional, multicenter, phase IV study, in patients with genotype 1/4/5/6 chronic hepatitis C (CHC). The primary objectives were to evaluate SVR in patients with no or minimal fibrosis (METAVIR F0-F1) versus well established fibrosis (F2-F4), and to estimate response on Weeks 12, 24 and 48 on treatment in previously untreated patients with genotypes 1/4/5/6 CHC. PATIENTS AND METHODS: 538 patients treated with pegylated interferon alfa 2b 1.5 mcg/kg in combination with ribavirin 800-1200 mg/day were enrolled in 55 sites in Belgium and Luxembourg, 505 being considered for the analysis. 40% of the patients were female and 60% male, the average age was 47.5 years, 10.5% were 65 or older. RESULTS: SVR was observed in 35% of the patients, EVR in 68%, of which pEVR in 33% and cEVR in 35%. SVR was observed in 43% of the low fibrosis group (F0, F1) and 30% of the high fibrosis group (F2, F3, F4) (p = 0.005). SVR rates were 34% for genotype 1, 37% for genotype 4, and 47% for genotype 5 (NS). Multivariate analysis showed that EVR and baseline METAVIR score are independent prognostic factors for SVR. CONCLUSIONS: This trial confirms that fibrosis stage and early viral response are the most important key-factors to predict sustained response, suggesting that the earlier patients are treated, the better the outcome. Non-invasive techniques enable us to closely monitor progression of fibrosis, allowing a better selection of patients for antiviral treatment in the DAA-era.

A novel and divergent role of granzyme a and B in resistance to helminth infection.

Granzyme (gzm) A and B, proteases of NK cells and T killer cells, mediate cell death, but also cleave extracellular matrices, inactivate intracellular pathogens, and induce cytokines. Moreover, macrophages, Th2 cells, regulatory T cells, mast cells, and B cells can express gzms. We recently reported gzm induction in human filarial infection. In this study, we show that in rodent filarial infection with Litomosoides sigmodontis, worm loads were significantly reduced in gzmA×B and gzmB knockout mice during the whole course of infection, but enhanced only early in gzmA knockout compared with wild-type mice. GzmA/B deficiency was associated with a defense-promoting Th2 cytokine and Ab shift, enhanced early inflammatory gene expression, and a trend of reduced alternatively activated macrophage induction, whereas gzmA deficiency was linked with reduced inflammation and a trend toward increased alternatively activated macrophages. This suggests a novel and divergent role for gzms in helminth infection, with gzmA contributing to resistance and gzmB promoting susceptibility.

Global transcriptional programs in peripheral nerve endoneurium and DRG are resistant to the onset of type 1 diabetic neuropathy in Ins2 mice.

While the morphological and electrophysiological changes underlying diabetic peripheral neuropathy (DPN) are relatively well described, the involved molecular mechanisms remain poorly understood. In this study, we investigated whether phenotypic changes associated with early DPN are correlated with transcriptional alterations in the neuronal (dorsal root ganglia [DRG]) or the glial (endoneurium) compartments of the peripheral nerve. We used Ins2(Akita/+) mice to study transcriptional changes underlying the onset of DPN in type 1 diabetes mellitus (DM). Weight, blood glucose and motor nerve conduction velocity (MNCV) were measured in Ins2(Akita/+) and control mice during the first three months of life in order to determine the onset of DPN. Based on this phenotypic characterization, we performed gene expression profiling using sciatic nerve endoneurium and DRG isolated from pre-symptomatic and early symptomatic Ins2(Akita/+) mice and sex-matched littermate controls. Our phenotypic analysis of Ins2(Akita/+) mice revealed that DPN, as measured by reduced MNCV, is detectable in affected animals already one week after the onset of hyperglycemia. Surprisingly, the onset of DPN was not associated with any major persistent changes in gene expression profiles in either sciatic nerve endoneurium or DRG. Our data thus demonstrated that the transcriptional programs in both endoneurial and neuronal compartments of the peripheral nerve are relatively resistant to the onset of hyperglycemia and hypoinsulinemia suggesting that either minor transcriptional alterations or changes on the proteomic level are responsible for the functional deficits associated with the onset of DPN in type 1 DM.

Phylogenetic relatedness and proboscis length contribute to structuring bumblebee communities in the extremes of abiotic and biotic gradients

Aim To improve our understanding of how biological communities assemble, we investigated changes in bumblebee communities in space along an elevation gradient. We assessed how much deterministic abiotic and biotic factors shape community assembly. We focused on proboscis length (influencing the species' dietary regime) and phylogenetic relatedness to investigate if competition and environmental filtering occur in more and less productive climates, respectively. Location Western Swiss Alps. Methods We recorded bumblebee species in 149 plots along a 1800-m wide elevation gradient. We contrasted two major clades of bumblebees, a short-tongued and a long-tongued clade. We calculated the phylogenetic and proboscis-length diversity of the bumblebee communities and compared these observed data with a random distribution to detect clustering likely to be caused by environmental filtering or overdispersion likely to be caused by competition. We compared the prevalence of clustered and overdispersed communities along the gradients of plant species richness (biotic) and temperature (abiotic). Results Under colder conditions, where plant species richness is lower and floral resources are scarcer, the clade with shorter proboscides prevails over the clade with longer proboscides, and communities are functionally and phylogenetic clustered. Under warmer conditions, we found phylogenetic but not functional overdispersion in communities. Main conclusions We show for the first time a strong correlation between phylogenetic relatedness, proboscis length and species distribution along temperature and plant richness gradients shaping bumblebee communities. The low temperatures and low levels of plant species richness limit the dispersal of the species from the long-tongued clade, which have more specialized diets, into high-elevation areas. Competition under warmer conditions may produce communities composed of less closely related species that share distinct ecological preferences. Our empirical results corroborate theoretical expectation as well as experiments on the prevalence of deterministic processes in the most severe and most productive parts of environmental gradients.

The hourglass and the early conservation models--co-existing patterns of developmental constraints in vertebrates.

Developmental constraints have been postulated to limit the space of feasible phenotypes and thus shape animal evolution. These constraints have been suggested to be the strongest during either early or mid-embryogenesis, which corresponds to the early conservation model or the hourglass model, respectively. Conflicting results have been reported, but in recent studies of animal transcriptomes the hourglass model has been favored. Studies usually report descriptive statistics calculated for all genes over all developmental time points. This introduces dependencies between the sets of compared genes and may lead to biased results. Here we overcome this problem using an alternative modular analysis. We used the Iterative Signature Algorithm to identify distinct modules of genes co-expressed specifically in consecutive stages of zebrafish development. We then performed a detailed comparison of several gene properties between modules, allowing for a less biased and more powerful analysis. Notably, our analysis corroborated the hourglass pattern at the regulatory level, with sequences of regulatory regions being most conserved for genes expressed in mid-development but not at the level of gene sequence, age, or expression, in contrast to some previous studies. The early conservation model was supported with gene duplication and birth that were the most rare for genes expressed in early development. Finally, for all gene properties, we observed the least conservation for genes expressed in late development or adult, consistent with both models. Overall, with the modular approach, we showed that different levels of molecular evolution follow different patterns of developmental constraints. Thus both models are valid, but with respect to different genomic features.

Spatio-temporal transcript profiling of rice roots and shoots in response to phosphate starvation and recovery.

Using rice (Oryza sativa) as a model crop species, we performed an in-depth temporal transcriptome analysis, covering the early and late stages of Pi deprivation as well as Pi recovery in roots and shoots, using next-generation sequencing. Analyses of 126 paired-end RNA sequencing libraries, spanning nine time points, provided a comprehensive overview of the dynamic responses of rice to Pi stress. Differentially expressed genes were grouped into eight sets based on their responses to Pi starvation and recovery, enabling the complex signaling pathways involved in Pi homeostasis to be untangled. A reference annotation-based transcript assembly was also generated, identifying 438 unannotated loci that were differentially expressed under Pi starvation. Several genes also showed induction of unannotated splice isoforms under Pi starvation. Among these, PHOSPHATE2 (PHO2), a key regulator of Pi homeostasis, displayed a Pi starvation-induced isoform, which was associated with increased translation activity. In addition, microRNA (miRNA) expression profiles after long-term Pi starvation in roots and shoots were assessed, identifying 20 miRNA families that were not previously associated with Pi starvation, such as miR6250. In this article, we present a comprehensive spatio-temporal transcriptome analysis of plant responses to Pi stress, revealing a large number of potential key regulators of Pi homeostasis in plants.

Cognitive behavioural therapy for obesity and binge eating associated to antipsychotic drugs

Background and Aims: Overweight, obesity and binge eating disorder are commonly reported in persons with severe mental disorders. Particularly, antipsychotic drugs (AP) induce weight gain in up to half of the patients. The aim of the present study is to confirm a previous study results on a larger sample of patients, to assess the impact of the interventions on other relevant dimensions of eating and weight related cognitions as well as to assess potential clinical indicators of outcomes such as AP drug, concomitant treatment with lithium or carbamazepine, psychiatric diagnostic, binge eating and severity of cognitive distortions. Method: A controlled study (12-week CBT vs. B N E) was carried out on 99 patients treated with an AP and who have gained weight following this treatment. Binge eating symptomatology, eating and weight-related cognitions, as well as weight and body mass index were assessed before treatment, at 12 weeks and at 24 weeks. Results: The findings confirms usefulness and effectiveness of the proposed CBT program on the treatment of binge symptomatology, cognitive distortions and obesity in patients treated with AP. Reduction of binge symptoms and maladapted cognitions appeared early, whereas the effect on weight appeared later during the follow up observation. No differences on outcomes were found across pharmacotherapy characteristics, diagnostic categories, binge eating nor severity of cognitive distortions. Conclusion: The proposed CBT treatment is useful for patients suffering from weight gain associated with AP treatments indeed when a concomitant treatment with lithium or valproate was given.

T cell receptor delta gene rearrangement and T early alpha (TEA) expression in immature alpha beta lineage thymocytes: implications for alpha beta/gamma delta lineage commitment.

Mature T cells comprise two mutually exclusive lineages expressing heterodimeric alpha beta or gamma delta antigen receptors. During development, beta, gamma, and delta genes rearrange before alpha, and mature gamma delta cells arise in the thymus prior to alpha beta cells. The mechanism underlying commitment of immature T cells to the alpha beta or gamma delta lineage is controversial. Since the delta locus is located within the alpha locus, rearrangement of alpha genes leads to deletion of delta. We have examined the rearrangement status of the delta locus immediately prior to alpha rearrangement. We find that many thymic precursors of alpha beta cells undergo VDJ delta rearrangements. Furthermore, the same cells frequently coexpress sterile T early alpha (TEA) transcripts originating 3' of C delta and 5' of the most upstream J alpha, thus implying that individual alpha beta lineage cells undergo sequential VDJ delta and VJ alpha rearrangements. Finally, VDJ delta rearrangements in immature alpha beta cells appear to be random, supporting models in which alpha beta lineage commitment is determined independently of the rearrangement status at the TCR delta locus.

GLUT8 subcellular localization and absence of translocation to the plasma membrane in PC12 cells and hippocampal neurons.

GLUT8 is a high-affinity glucose transporter present mostly in testes and a subset of brain neurons. At the cellular level, it is found in a poorly defined intracellular compartment in which it is retained by an N-terminal dileucine motif. Here we assessed GLUT8 colocalization with markers for different cellular compartments and searched for signals, which could trigger its cell surface expression. We showed that when expressed in PC12 cells, GLUT8 was located in a perinuclear compartment in which it showed partial colocalization with markers for the endoplasmic reticulum but not with markers for the trans-Golgi network, early endosomes, lysosomes, and synaptic-like vesicles. To evaluate its presence at the plasma membrane, we generated a recombinant adenovirus for the expression of GLUT8 containing an extracellular myc epitope. Cell surface expression was evaluated by immunofluorescence microscopy of transduced PC12 cells or primary hippocampal neurons exposed to different stimuli. Those included substances inducing depolarization, activation of protein kinase A and C, activation or inhibition of tyrosine kinase-linked signaling pathways, glucose deprivation, AMP-activated protein kinase stimulation, and osmotic shock. None of these stimuli-induced GLUT8 cell surface translocation. Furthermore, when GLUT8myc was cotransduced with a dominant-negative form of dynamin or GLUT8myc-expressing PC-12 cells or neurons were incubated with an anti-myc antibody, no evidence for constitutive recycling of the transporter through the cell surface could be obtained. Thus, in cells normally expressing it, GLUT8 was associated with a specific intracellular compartment in which it may play an as-yet-uncharacterized role.

Early Jurassic to Early late Cretaceous radiolarians from the Santa Rosa accretionary complex (Northwestern Costa Rica)

In the circum-Pacific ophiolitic belts, when no other biogenic constituents are found, radiolarians have the potential to provide significant biostratigraph- ic information. The Santa Rosa Accretionary Complex, which crops out in several half-windows (Carrizal, Sitio Santa Rosa, Bahia Nancite, Playa Naranjo) along the south shores of the Santa Elena Peninsula in northwestern Costa Rica, is one of these little-known ophiolitic mélanges. It contains various oceanic assemblages of alkaline basalt, radiolarite and polymictic breccias. The radiolarian biochronology presented in this work is mainly based by correlation on the biozonations of Carter et al. (2010), Baumgartner et al. (1995b), and O'Dogherty (1994) and indicate an Early Jurassic to early Late Cretaceous (early Pliensbachian to earliest Turonian) age for the sediments associated with oceanic basalts or recovered from blocks in breccias or megabreccias. The 19 illus- trated assemblages from the Carrizal tectonic window and Sitio Santa Rosa contain in total 162 species belonging to 65 genera. The nomenclature of tecton- ic units is the one presented by (Baumgartner and Denyer, 2006). This study brings to light the Early Jurassic age of a succession of radiolarite, which was previously thought to be of Cretaceous age, intruded by alkaline basalts sills (Unit 3). The presence of Early Jurassic large reworked blocks in a polymictic megabreccia, firstly reported by De Wever et al. (1985) is confirmed (Unit 4). Therefore, the alkaline basalt associated with the radiolarites of these two units (and maybe also Units 5 and 8) could be of Jurassic age. In the Carrizal tectonic window, Middle to early Late Jurassic radiolarian chert blocks associ- ated with massive tholeitic basalts and Early Cretaceous brick-red ribbon cherts overlying pillow basalts are interpreted as fragments of a Middle Jurassic oceanic basement accreted to an Early Cretaceous oceanic Plate, in an intra-oceanic subduction context. Whereas, the knobby radiolarites and black shales of Playa Carrizal are indicative of a shallower middle Cretaceous paleoenvironment. Other remnants of this oceanic basin are found in Units 2, 6, and 7, which documented the rapid approach of the depocentre to a subduction trench during the late Early Cretaceous (Albian-Cenomanian), to possibly early Late Cretaceous (Turonian).