Evidence for transcript networks composed of chimeric RNAs in human cells.

The classic organization of a gene structure has followed the Jacob and Monod bacterial gene model proposed more than 50 years ago. Since then, empirical determinations of the complexity of the transcriptomes found in yeast to human has blurred the definition and physical boundaries of genes. Using multiple analysis approaches we have characterized individual gene boundaries mapping on human chromosomes 21 and 22. Analyses of the locations of the 5' and 3' transcriptional termini of 492 protein coding genes revealed that for 85% of these genes the boundaries extend beyond the current annotated termini, most often connecting with exons of transcripts from other well annotated genes. The biological and evolutionary importance of these chimeric transcripts is underscored by (1) the non-random interconnections of genes involved, (2) the greater phylogenetic depth of the genes involved in many chimeric interactions, (3) the coordination of the expression of connected genes and (4) the close in vivo and three dimensional proximity of the genomic regions being transcribed and contributing to parts of the chimeric RNAs. The non-random nature of the connection of the genes involved suggest that chimeric transcripts should not be studied in isolation, but together, as an RNA network.

Does Semantic Context Benefit Speech Understanding through "Top-Down" Processes? Evidence from Time-resolved Sparse fMRI.

When speech is degraded, word report is higher for semantically coherent sentences (e.g., her new skirt was made of denim) than for anomalous sentences (e.g., her good slope was done in carrot). Such increased intelligibility is often described as resulting from "top-down" processes, reflecting an assumption that higher-level (semantic) neural processes support lower-level (perceptual) mechanisms. We used time-resolved sparse fMRI to test for top-down neural mechanisms, measuring activity while participants heard coherent and anomalous sentences presented in speech envelope/spectrum noise at varying signal-to-noise ratios (SNR). The timing of BOLD responses to more intelligible speech provides evidence of hierarchical organization, with earlier responses in peri-auditory regions of the posterior superior temporal gyrus than in more distant temporal and frontal regions. Despite Sentence content × SNR interactions in the superior temporal gyrus, prefrontal regions respond after auditory/perceptual regions. Although we cannot rule out top-down effects, this pattern is more compatible with a purely feedforward or bottom-up account, in which the results of lower-level perceptual processing are passed to inferior frontal regions. Behavioral and neural evidence that sentence content influences perception of degraded speech does not necessarily imply "top-down" neural processes.

Evidence against a direct role of klotho in insulin resistance.

The klotho gene may be involved in the aging process. Klotho is a coactivator of FGF23, a regulator of phosphate and vitamin D metabolism. It has also been reported to be downregulated in insulin resistance syndromes and paradoxically to directly inhibit IGF-1 and insulin signaling. Our aim was to study klotho's regulation and effects on insulin and IGF-1 signaling to unravel this paradox. We studied klotho tissue distribution and expression by quantitative real-time polymerase chain reaction and Western blotting in obese Zucker rats and high-fat fed Wistar rats, two models of insulin resistance. Klotho was expressed in kidneys but at much lower levels (<1.5%) in liver, muscle, brain, and adipose tissue. There were no significant differences between insulin resistant and control animals. We next produced human recombinant soluble klotho protein (KLEC) and studied its effects on insulin and IGF-1 signaling in cultured cells. In HEK293 cells, FGF23 signaling (judged by FRS2-alpha and ERK1/2 phosphorylation) was activated by conditioned media from KLEC-producing cells (CM-KLEC); however, IGF-1 signaling was unaffected. CM-KLEC did not inhibit IGF-1 and insulin signaling in L6 and Hep G2 cells, as judged by Akt and ERK1/2 phosphorylation. We conclude that decreased klotho expression is not a general feature of rodent models of insulin resistance. Further, the soluble klotho protein does not inhibit IGF-1 and/or insulin signaling in HEK293, L6, and HepG2 cells, arguing against a direct role of klotho in insulin signaling. However, the hypothesis that klotho indirectly regulates insulin sensitivity via FGF23 activation remains to be investigated.

Radiolarian biostratigraphic evidence for a Late Jurassic age of the El Tambor group ophiolites (Guatemala)

We present a radiolarian biostratigraphic study of the metacherts of the El Tambor Group ophiolites (South Motagua Unit), Guatemala. The ophiolite sequence comprises MOR pillow metabasalts, massive metabasalts, metacherts and micaschists. The age of the studied metacherts is referable to the Late Jurassic (Oxfordian-Kimmeridgian). The radiolarian assemblage described in this paper is the first Jurassic finding in the ophiolitic MOR succession of the Motagua zone and represents a valuable tool to constrain the geodynamic evolution of the Caribbean area. A review of the ages of Jurassic rocks associated with the ophiolites from the Caribbean area is also reported.

Evidence for a role of sphingosine-1 phosphate in cardiovascular remodelling in Fabry disease.

AIMS: A hallmark of Fabry disease is the concomitant development of left-ventricular hypertrophy and arterial intima-media thickening, the pathogenesis of which is thought to be related to the presence of a plasmatic circulating growth-promoting factor. We therefore characterized the plasma of patients with Fabry disease in order to identify this factor. METHODS AND RESULTS: Using a classical biochemical strategy, we isolated and identified sphingosine-1 phosphate (S1P) as a proliferative factor present in the plasma of patients with Fabry disease. Plasma S1P levels were significantly higher in 17 patients with Fabry disease compared with 17 healthy controls (225 +/- 40 vs. 164 +/- 17 ng/mL; P = 0.005). There was a positive correlation between plasma S1P levels and both common carotid artery intima-media thickness and left-ventricular mass index (r(2) = 0.47; P = 0.006 and r(2) = 0.53; P = 0.0007, respectively). In an experimental model, mice treated with S1P developed cardiovascular remodelling similar to that observed in patients with Fabry disease. CONCLUSION: Sphingosine-1 phosphate participates in cardiovascular remodelling in Fabry disease. Our findings have implications for the treatment of cardiovascular involvement in Fabry disease.

No evidence for immune priming in ants exposed to a fungal pathogen.

There is accumulating evidence that invertebrates can acquire long-term protection against pathogens through immune priming. However, the range of pathogens eliciting immune priming and the specificity of the response remain unclear. Here, we tested if the exposure to a natural fungal pathogen elicited immune priming in ants. We found no evidence for immune priming in Formica selysi workers exposed to Beauveria bassiana. The initial exposure of ants to the fungus did not alter their resistance in a subsequent challenge with the same fungus. There was no sign of priming when using homologous and heterologous combinations of fungal strains for exposure and subsequent challenges at two time intervals. Hence, within the range of conditions tested, the immune response of this social insect to the fungal pathogen appears to lack memory and strain-specificity. These results show that immune priming is not ubiquitous across pathogens, hosts and conditions, possibly because of immune evasion by the pathogen or efficient social defences by the host.

Normal kinetics of intestinal glucose absorption in the absence of GLUT2: evidence for a transport pathway requiring glucose phosphorylation and transfer into the endoplasmic reticulum.

Glucose is absorbed through the intestine by a transepithelial transport system initiated at the apical membrane by the cotransporter SGLT-1; intracellular glucose is then assumed to diffuse across the basolateral membrane through GLUT2. Here, we evaluated the impact of GLUT2 gene inactivation on this transepithelial transport process. We report that the kinetics of transepithelial glucose transport, as assessed in oral glucose tolerance tests, was identical in the presence or absence of GLUT2; that the transport was transcellular because it could be inhibited by the SGLT-1 inhibitor phlorizin, and that it could not be explained by overexpression of another known glucose transporter. By using an isolated intestine perfusion system, we demonstrated that the rate of transepithelial transport was similar in control and GLUT2(-/-) intestine and that it was increased to the same extent by cAMP in both situations. However, in the absence, but not in the presence, of GLUT2, the transport was inhibited dose-dependently by the glucose-6-phosphate translocase inhibitor S4048. Furthermore, whereas transport of [(14)C]glucose proceeded with the same kinetics in control and GLUT2(-/-) intestine, [(14)C]3-O-methylglucose was transported in intestine of control but not of mutant mice. Together our data demonstrate the existence of a transepithelial glucose transport system in GLUT2(-/-) intestine that requires glucose phosphorylation and transfer of glucose-6-phosphate into the endoplasmic reticulum. Glucose may then be released out of the cells by a membrane traffic-based pathway similar to the one we previously described in GLUT2-null hepatocytes.

Durcissement des lois sociales et santé des migrants forcés: trois ans après (a Loi sur l'asile (LAsi) [Social policy hardening and forced immigrant's health: 3 years after the Asylum Law (LAsi)'s introduction].

In the canton de Vaud, General Practioners (GPs) caring for asylum seekers under the "aide d'urgence" regime can ask for an adaptation of their housing conditions, by filling out a specific form and addressing it to the medical commission responsible for advising the EVAM (the housing institution for asylum seekers) on these issues. The forms addressed to the commission are indicative of a worrisome state of health in this population, especially for mental health. More than 70% report at least one psychiatric diagnosis. Most frequent are anxiety and depressive disorders, as well as many posttraumatic stress disorders, associated with traumatic events both in the country of origin and in Switzerland. Adapting the housing conditions, based on vulnerabilities that the GP has specifically documented, may contribute to improve the health of the most vulnerable asylum seekers.

Health care supply, payment system and medical practice : evidence from obstetric practice

ABSTRACTA significant share of deliveries are performed by Cesarian section (C-section) in Europe and in many developed and developing countries. The aims of this thesis are to highlight the non medical, especially economic and financial, incentives that explain the use of C-section, as well as the medical consequences of C-section on women's health, in regard with other factors of ob¬stetrical care quality such as hospital concentration. Those diagnoses enable us to exhibit ways of improvement of obstetrical care quality in France. Our analysis focus on two countries, France and Switzerland. In the first part of the thesis, we show the influence of two non medical factors on the C-section use, namely the hospital payment system on the one hand and the obstetricians behaviour, especially their demand for leisure, on the other hand. With French data on the year 2003, we show firstly that the fee-for-service payment system of private for profit hospitals induces a higher probability of using C-section. Obstetricians play also a preeminent role in the decision to use a C-section, as the probability of a C-section rises with the number of obstetricians. We then focus on a French reform introduced in 2004, to investigate the impact of Prospective Payment System on obstetric practise. We show that the rise of C-section rate between 2003 and 2006 is mainly caused by changes in hospitals and patients features. Obstetricians practises do not vary a lot for patients with the same risk code. In the mean time however, the number of women coded with a high risk rises. This can be caused by improvements in the quality of coding, obstetricians chosing codes that match better the real health state of their patients. Yet, it can also show that obstetricians change their coding practises to justify the use of certain practises, such as C-section, with no regard to the health state of patients. Financial factors are not the only non medical fac¬tors that can influence the resort to C-section. Using Shelton Brown ΠΙ identification strategy, we focus on the potential impact of obstetricians leisure preference on the use of C-section. We use the distributions of days and hours of delivering and the types of C-section - planned or emergency C-sections - to show that the obstetricians demand for leisure has a significant impact on the resort to C-section, but only in emergency situations. The second part of the thesis deals with some ways to improve obstetric care quality. We use on the one hand swiss and french data to study the impact of C-section on the patients' probability of having an obstetric complication and on the other hand the influence of hospital concentration on the quality of obstetric care. We find the same results as former medical studies about the risks entailed by C-section on obstetric complications.These results prove women ought to be better informed of the medical consequences of C-section and that the slowing of C-section use should be a priority of public health policy. We finally focus on another way to improve obstetric care quality, that is hospital lmarket concentration. We investigate the impact of hospital concentration by integrating the Herfindahl-Hirschman index in our model, on health care quality, measured by the HCUP indicator. We find that hospital concentration has a negative impact on obstetric care quality, which undermines today's policy of hospital closings in France.JEL classification: 112; 118Keywords: Hospital; C-section; Payment System; Counterfactual Estimation; Quality of Care.RÉSUMÉUne part importante des accouchements sont réalisés par césarienne en Europe et dans de nom¬breux pays développés ou en développement. Les objectifs de cette thèse sont de mettre en évidence les déterminants non médicaux, notamment économiques et financiers, expliquant le développe¬ment de cette pratique, ainsi que ses conséquences sur la santé des femmes après Γ accouchement, en lien avec d'autres facteurs comme la concentration locale des structures hospitalières. Les résul¬tats exposés dans cette thèse éclairent les perspectives et voies d'amélioration de la qualité des soins en obstétriques.Notre analyse se concentre sur deux pays : la France et la Suisse. Dans la première partie de la thèse, nous mettons en évidence l'influence de deux déterminants non médicaux sur l'emploi de la césarienne : le système de paiement des hôpitaux d'une part, et le comportement des médecins obstétriciens d'autre part. En étudiant des données françaises de 2003, nous montrons d'abord que le financement à l'acte des établissements privés engendre une hausse de la proba¬bilité de pratiquer une césarienne. Le rôle de l'obstrétricien paraît également déterminant dans la décision d'opérer une césarienne, la probabilité d'employer cette technique augmentant avec le nombre d'obstétriciens. Nous nous intéressons ensuite à l'impact de la mise en place en 2004 du système de paiement prospectif sur l'évolution des pratiques obstétricales entre 2003 et 2006 en France. La hausse du taux de recours à la césarienne entre 2004 et 2006 peut ainsi être principa¬lement imputée aux évolutions des caractéristiques des hôpitaux et des patients, les pratiques des obstétriciens, pour un même codage de la situation du patient, variant peu. Dans le même temps cependant, les pratiques de codage des patients parles obstétriciens évoluent fortement, les femmes étant de plus en plus nombreuses à porter des codes correspondant à des situations à risques. Cette évolution peut indiquer que la qualité du codage en 2006 s'est améliorée par rapport à 2004, le codage correspondant de plus en plus à la situation réelle des patientes. H peut aussi indiquer que les pratiques de codage évoluent pour justifier un recours accru à la césarienne, sans lien avec l'état réel des patientes. Les facteurs financiers ne sont pas les seuls facteurs non médicaux à pouvoir expliquer le recours à la césarienne : nous nous intéressons, en suivant la stratégie d'identifica¬tion de Shelton Brown m, à l'impact potentiel de la demande de loisir des médecins obstétriciens sur la pratique de la césarienne. En utilisant la distribution des jours et heures d'accouchement, et en distinguant les césariennes planifiées de celles effectuées en urgence, nous constatons que la demande de loisir des obstétriciens influence significativement le recours à la césarienne, mais uni¬quement pour les interventions d'urgence. La deuxième partie de la thèse est consacrée à l'étude de la qualité des soins en obstétriques. Nous utilisons des données suisses et françaises pour analyser d'une part l'impact de la césarienne sur la survenue de complications obstétricales et d'autre part l'impact de la concentration des soins sur la qualité des soins en obstétrique. Nons confirmons les résultats antérieurs de la littérature médicale sur la dangerosité de la césarienne comme facteur de complications obstétricales. Ces conclusions montrent que les femmes ont besoin d'être informées des conséquences de la césarienne sur leur santé et que le ralentissement de l'augmentation de la pratique de la césarienne devrait être un objectif de la politique publique de santé. Nous nous in¬téressons à un autre facteur d'amélioration des soins en obstrétique, l'organisation des hôpitaux et particulièrement leur concentration. Nous estimons ainsi l'effet de la concentration sur la qualité des soins obstétriques en intégrant l'indice de Herfindahl-Hirschman dans notre modèle, la qualité des soins étant mesurée à l'aide de l'indicateur HCUP. Nous constatons que la concentration des naissances a un impact négatif sur la qualité des soins en obstétrique, résultat qui va dans le sens contraire des politiques de fermeture d'hôpitaux menées actuellement en France. JEL classification : 112 ; 118Mots-clés : Hôpital ; Césarienne ; Système de paiement ; Contrefactuels ; Qualité des soins, sur la qualité des soins en obstétrique.