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.

Akt fosforila FoxG1 en cèl·lules de glioma

En un treball recent s’ha descrit l’amplificació del gen del factor de transcripció FoxG1, homòleg de l'oncogen víric aviar Qin, en mostres de meduloblastoma, un tipus de tumor cerebral que representa el 20% dels tumors cerebrals infantils malignes (Adesina et al.¸2007). El tumor cerebral més freqüent i agressiu en l’adult és el glioma, especialment la seva forma més maligna: el glioblastoma multiforme (glioma de grau IV segons la classificació de l'OMS). En aquest treball hem estudiat l'expressió proteica del factor de transcripció FoxG1, homòleg de l'oncogen víric aviar Qin, en mostres de glioma. Vam analitzar 15 mostres de glioma, detectant FoxG1 en 9 d’elles, i amb diferents nivells d’expressió. Intentant aprofundir en el coneixement de la funció i la regulació de FoxG1, vam estudiar si FoxG1 podia ser fosforilat. Vam detectar, tant per assaig cinasa com per espectrometria de masses, que FoxG1 és un substracte directe de la cinasa Akt, el principal efector de la via de PI3K (phosphoinositide 3-kinase). En la línia cel•lular de glioblastoma U373MG, vam observar que Akt endogen fosforila FoxG1 en un pèptid situat a l’extrem C-terminal del domini forkhead. Aquesta fosforilació és contrarestada per un inhibidor farmacològic de PI3K. Al contrari del que passa en FoxO on la fosforilació per Akt inhibeix l’activitat de FoxO promovent la seva exportació del nucli, la fosforilació de FoxG1 per Akt no promou cap canvi en la seva localització subcel•lular, i FoxG1 es manté nuclear. Actualment estem estudiant els efectes biològics de la fosforilació de FoxG1 per Akt.

El problema de una sensibilización del campo de la moralidad en la filosofia trascendental de Kant

La problemática de la investigación se plantea en el contexto de la filosofía trascendental de Kant, en relación al modo en que es en general posible para nosotros representarnos el ámbito de la moralidad. Nuestra comprensión natural o preteórica del funcionamiento del lenguaje parece llevarnos a entender el significado de nuestras palabras en términos de la relación que se establece entre el signo lingüístico y el objeto: nuestros términos lingüísticos están en el lugar del objeto extralingüístico a que refieren y que constituye su significado. A nuestro modo de ver, la afirmación kantiana relativa a que todo nuestro conocimiento comienza con la experiencia, es decir, con aquello que procede de los sentidos, parece estar apuntando a esta intuición fundamental. Ahora bien, la cuestión que cabe plantearse es: de acuerdo con este modelo de significación, ¿cuál es el significado de nuestros términos morales? Si, con Kant, aceptamos que el concepto de deber moral exige el cumplimiento (u omisión) incondicionado de una acción y que, precisamente por las exigencias de universalidad y necesidad que le son inherentes, tal concepto es inderivable de la experiencia, cabe preguntarse cuál es el significado del concepto de deber en sentido moral (y, en general, de los términos morales) y de qué manera somos capaces de representárnoslo. Mi investigación ha pretendido esclarecer precisamente en qué sentido debe entenderse la afirmación kantiana de que en la reflexión sobre la corrección moral de nuestras acciones, para representarnos las exigencias de universalidad y necesidad que son propias del concepto de deber moral, nos servimos analógicamente del concepto de naturaleza, así como analizar la plausibilidad de la propuesta kantiana misma.

The different types of internal hernia after laparoscopic Roux-En-Y gastric by-bass for morbid obesity : MDCT features : P5

Purpose: 1. To provide an overview of the different types of internal hernia (IH) occurring after laparoscopic Roux-en-Y gastric bypass (LRYGBP) performed for morbid obesity. 2. To describe the correspondent MDCT features in relation with the underlying anatomical landmarks in order to differentiate their localisation and to direct the surgeon during following laparoscopic closure of mesenteric defects. Methods and materials: LRYGBP performed for morbid obesity is associated with less perioperative complications, shorter hospital stay and a more rapid recovery compared with the open surgical procedure. However, a relatively high incidence of IH is seen that may be due to the laparoscopic approach, but also caused by rapid weight loss with consecutive loosening of the mesenteric sutures. Results: After briefly reviewing the surgical procedure of LRYGBP (ante- versus retrocolic) we describe the exact anatomical landmarks of the different types of IH occurring at any time after operation: They are caused by surgical defects either at the level of the transverse colon mesentery, at the Petersen's space, which represents an opening between the mesocolon and jejunal mesentery, or at the enteroenterostomy site. Typical MDCT features of each IH type in axial and coronal plane as well as targeted vascular reconstructions are demonstrated. Conclusion: Exact knowledge about underlying pathophysiology and anatomical landmarks is essential for distinguishing the different types of IH occurring after LRYGBP on MDCT, since radiological features are difficult to recognize and may even overlap. The radiologist should be aware of the potential anatomic sites to ensure subsequent straightforward laparoscopic exploration.

Vitamin D has a direct immunomodulatory effect on CD8+ T cells of patients with early multiple sclerosis and healthy control subjects.

Little is known on a putative effect of vitamin D on CD8+ T cells. Yet, these cells are involved in the immmunopathogenesis of MS. We assessed the cytokine profile of EBV-specific CD8+ T cells of 10 early MS patients and 10 healthy control subjects with or without 1,25(OH)(2)D(3) and found that, with 1,25(OH)(2)D(3), these cells secreted less IFN-γ and TNF-α and more IL-5 and TGF-β. CD4+ T cell depletion or even culture with CD8+ T cells only did not abolish the immunomodulatory effect of 1,25(OH)(2)D(3) on CD8+ T cells, suggesting that 1,25(OH)(2)D(3) can act directly on CD8+ T cells.

Estudi de la bassa de l'institut com un ecosistema

Treball de recerca realitzat per un alumne d'ensenyament secundari i guardonat amb un Premi CIRIT per fomentar l'esperit cientí­fic del Jovent l'any 2009. L'IES Sant Andreu té una bassa que fa tres anys es va omplir i que s'ha anat poblant de vegetals aquàtics provinents de Banyoles i altres basses naturals a part de la colonització natural pròpia de qualsevol ecosistema. L'estudi de la bassa com un ecosistema és un tema molt interessant ja que es fonamenta bàsicament en l'observació. El treball està estructurat en dues parts. La primera part s'encarrega de l'estudi de les característiques de l'aigua, aquesta part del treball és més experimental. La segona part consisteix en l'observació dels habitants de la bassa. En general el treball tracta de l'ecologia de la bassa de al llarg del semestre Juliol- Desembre 2009. S'han estudiat les característiques físico-químiques de l'aigua i els organismes aquàtics que l'habiten. També s'ha confeccionat un DVD que recull les observacions en viu dels microorganismes més representatius.

Estudi de la successió primària en esculls artificials en un port marítim

Treball de recerca realitzat per una alumna d'ensenyament secundari i guardonat amb un Premi CIRIT per fomentar l'esperit científic del Jovent l'any 2009. La llum i el temps són factors importants en tots els ecosistemes i especialment en ecosistemes aquàtics, ja que constitueixen variables ambientals que condicionen la seva evolució i equilibri. L’objectiu principal del treball de recerca és estudiar el desenvolupament de les successions primàries all llarg del temps en esculls artificials submergits en un ambient marí i observar les conseqüències de la incidència, directa o no, de la llum en aquests esculls pel que fa al desenvolupament de la successions primàries. Els resultats obtinguts demostren satisfactòriament que la incidència de la llum és un factor determinant en la constitució de les successions primàries en ambients marins. Per altra part, els resultats també demostren que el temps és un factor que actua condicionant la diversitat de les formes de vida que colonitzen aquests medis marins, concretament la diversitat s’incrementa amb el temps.

Optimització i implementació en Simulink de l'adquisició d'un senyal GPS amb blocs FFT

Aquest projecte es tracta de la optimització i la implementació de l’etapa d’adquisició d’un receptor GPS. També inclou una revisió breu del sistema GPS i els seus principis de funcionament. El procés d’adquisició s’ha estudiat amb detall i programat en els entorns de treball Matlab i Simulink. El fet d’implementar aquesta etapa en dos entorns diferents ha estat molt útil tant de cara a l’aprenentatge com també per la comprovació dels resultats obtinguts. El principal objectiu del treball és el disseny d’un model Simulink que es capaç d’adquirir una senyal capturada amb hardware real. En realitat, s’han fet dues implementacions: una que utilitza blocs propis de Simulink i l’altra que utilitza blocs de la llibreria Xilinx. D’aquesta manera, posteriorment, es facilitaria la transició del model a la FPGA utilitzant l’entorn ISE de Xilinx. La implementació de l’etapa d’adquisició es basa en el mètode de cerca de fase de codi en paral·lel, el qual empra la operació correlació creuada mitjançant la transformada ràpida de Fourier (FFT). Per aquest procés es necessari realitzar dues transformades (per a la senyal entrant i el codi de referència) i una antitransformada de Fourier (per al resultat de la correlació). Per tal d’optimitzar el disseny s’utilitza un bloc FFT, ja que tres blocs consumeixen gran part dels recursos d’una FPGA. En lloc de replicar el bloc FFT, en el model el bloc és compartit en el temps gràcies a l’ús de buffers i commutadors, com a resultat la quantitat de recursos requerits per una implementació en una FPGA es podria reduir considerablement.

Direct analysis of peptide binding to cell-associated MHC class I molecules.

Exogenously added synthetic peptides can mimic endogenously produced antigenic peptides recognized on target cells by MHC class I-restricted cytolytic T lymphocytes. While it is assumed that exogenous peptides associate with class I molecules on the target cell surface, direct binding of peptides to cell-associated class I molecules has been difficult to demonstrate. Using a newly developed binding assay based on photoaffinity labeling, we have investigated the interaction of two antigenic peptides, known to be recognized in the context of H-2Kd or H-2Db, respectively, with 20 distinct class I alleles on living cells. None of the class I alleles tested, with the exception of H-2Kd or H-2Db, bound either of the peptides, thus demonstrating the exquisite specificity of peptide binding to class I molecules. Moreover, peptide binding to cell-associated H-2Kd was drastically reduced when metabolic energy, de novo protein synthesis or protein egress from the endoplasmic reticulum was inhibited. It is thus likely that exogenously added peptides do not associate with the bulk of class I molecules expressed at the cell surface, but rather bind to short-lived molecules devoid of endogenous peptides.

Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma.

Peroxisome proliferator-activated receptors (PPARs) alpha and gamma are key regulators of lipid homeostasis and are activated by a structurally diverse group of compounds including fatty acids, eicosanoids, and hypolipidemic drugs such as fibrates and thiazolidinediones. While thiazolidinediones and 15-deoxy-Delta12, 14-prostaglandin J2 have been shown to bind to PPARgamma, it has remained unclear whether other activators mediate their effects through direct interactions with the PPARs or via indirect mechanisms. Here, we describe a novel fibrate, designated GW2331, that is a high-affinity ligand for both PPARalpha and PPARgamma. Using GW2331 as a radioligand in competition binding assays, we show that certain mono- and polyunsaturated fatty acids bind directly to PPARalpha and PPARgamma at physiological concentrations, and that the eicosanoids 8(S)-hydroxyeicosatetraenoic acid and 15-deoxy-Delta12,14-prostaglandin J2 can function as subtype-selective ligands for PPARalpha and PPARgamma, respectively. These data provide evidence that PPARs serve as physiological sensors of lipid levels and suggest a molecular mechanism whereby dietary fatty acids can modulate lipid homeostasis.

The impact of past direct-personal traumatic events on 12-month outcome in first episode psychotic mania: trauma and early psychotic mania.

OBJECTIVE: Past traumatic events have been associated with poorer clinical outcomes in people with bipolar disorder. However, the impact of these events in the early stages of the illness remains unclear. The aim of this study was to investigate whether prior traumatic events were related to poorer outcomes 12 months following a first episode of psychotic mania. METHODS: Traumatic events were retrospectively evaluated from patient files in a sample of 65 participants who had experienced first episode psychotic mania. Participants were aged between 15 and 28 years and were treated at a specialised early psychosis service. Clinical outcomes were measured by a variety of symptomatic and functioning scales at the 12-month time-point. RESULTS: Direct-personal traumatic experiences prior to the onset of psychotic mania were reported by 48% of the sample. Participants with past direct-personal trauma had significantly higher symptoms of mania (p=0.02), depression (p=0.03) and psychopathology (p=0.01) 12 months following their first episode compared to participants without past direct-personal trauma, with medium to large effects observed. After adjusting for baseline scores, differences in global functioning (as measured by the Global Assessment of Functioning scale) were non-significant (p=0.05); however, participants with past direct-personal trauma had significantly poorer social and occupational functioning (p=0.04) at the 12-month assessment with medium effect. CONCLUSIONS: Past direct-personal trauma may predict poorer symptomatic and functional outcomes after first episode psychotic mania. Limitations include that the findings represent individuals treated at a specialist early intervention centre for youth and the retrospective assessment of traumatic events may have been underestimated.

Les symbioses agro-industrielles en Afrique de l'Ouest : évaluation du potentiel d'une nouvelle stratégie pour un développement durable

RésuméCette thèse traite de l'utilisation des concepts de Symbiose Industrielle dans les pays en développement et étudie le potentiel de cette stratégie pour stimuler un développement régional durable dans les zones rurales d'Afrique de l'Ouest. En particulier, lorsqu'une Symbiose Industrielle est instaurée entre une usine et sa population alentour, des outils d'évaluation sont nécessaires pour garantir que le projet permette d'atteindre un réel développement durable. Les outils existants, développés dans les pays industrialisés, ne sont cependant pas complètement adaptés pour l'évaluation de projets dans les pays en développement. En effet, les outils sont porteurs d'hypothèses implicites propres au contexte socio-économique dans lequel ils ont été conçus.L'objectif de cette thèse est de développer un cadre méthodologique pour l'évaluation de la durabilité de projets de Symbiose Industrielle dans les pays en développement.Pour ce faire, je m'appuie sur une étude de cas de la mise en place d'une Symbiose Industrielle au nord du Nigéria, à laquelle j'ai participé en tant qu'observatrice dès 2007. AshakaCem, une usine productrice de ciment du groupe Lafarge, doit faire face à de nombreuses tensions avec la population rurale alentour. L'entreprise a donc décidé d'adopter une nouvelle méthode inspirée des concepts de Symbiose Industrielle. Le projet consiste à remplacer jusqu'à 10% du carburant fossile utilisé pour la cuisson de la matière crue (calcaire et additifs) par de la biomasse produite par les paysans locaux. Pour ne pas compromettre la fragile sécurité alimentaire régionale, des techniques de lutte contre l'érosion et de fertilisation naturelle des sols sont enseignées aux paysans, qui peuvent ainsi utiliser la culture de biomasse pour améliorer leurs cultures vivrières. A travers cette Symbiose Industrielle, l'entreprise poursuit des objectifs sociaux (poser les bases nécessaires à un développement régional), mais également environnementaux (réduire ses émissions de CO2 globales) et économiques (réduire ses coûts énergétiques). Elle s'ancre ainsi dans une perspective de développement durable qui est conditionnelle à la réalisation du projet.A travers l'observation de cette Symbiose et par la connaissance des outils existants je constate qu'une évaluation de la durabilité de projets dans les pays en développement nécessite l'utilisation de critères d'évaluation propres à chaque projet. En effet, dans ce contexte, l'emploi de critères génériques apporte une évaluation trop éloignée des besoins et de la réalité locale. C'est pourquoi, en m'inspirant des outils internationalement reconnus comme l'Analyse du Cycle de Vie ou la Global Reporting Initiative, je définis dans cette thèse un cadre méthodologique qui peut, lui, être identique pour tous les projets. Cette stratégie suit six étapes, qui se réalisent de manière itérative pour permettre une auto¬amélioration de la méthodologie d'évaluation et du projet lui-même. Au cours de ces étapes, les besoins et objectifs en termes sociaux, économiques et environnementaux des différents acteurs sont déterminés, puis regroupés, hiérarchisés et formulés sous forme de critères à évaluer. Des indicateurs quantitatifs ou qualitatifs sont ensuite définis pour chacun de ces critères. Une des spécificités de cette stratégie est de définir une échelle d'évaluation en cinq graduations, identique pour chaque indicateur, témoignant d'un objectif totalement atteint (++) ou pas du tout atteint (--).L'application de ce cadre méthodologique à la Symbiose nigériane a permis de déterminer quatre critères économiques, quatre critères socio-économiques et six critères environnementaux à évaluer. Pour les caractériser, 22 indicateurs ont été définis. L'évaluation de ces indicateurs a permis de montrer que le projet élaboré atteint les objectifs de durabilité fixés pour la majorité des critères. Quatre indicateurs ont un résultat neutre (0), et un cinquième montre qu'un critère n'est pas atteint (--). Ces résultats s'expliquent par le fait que le projet n'en est encore qu'à sa phase pilote et n'a donc pas encore atteint la taille et la diffusion optimales. Un suivi sur plusieurs années permettra de garantir que ces manques seront comblés.Le cadre méthodologique que j'ai développé dans cette thèse est un outil d'évaluation participatif qui pourra être utilisé dans un contexte plus large que celui des pays en développement. Son caractère générique en fait un très bon outil pour la définition de critères et indicateurs de suivi de projet en terme de développement durable.SummaryThis thesis examines the use of industrial symbiosis in developing countries and studies its potential to stimulate sustainable regional development in rural areas across Western Africa. In particular, when industrial symbiosis is instituted between a factory and the surrounding population, evaluation tools are required to ensure the project achieves truly sustainable development. Existing tools developed in industrialized countries are not entirely suited to assessing projects in developing countries. Indeed, the implicit hypotheses behind such tools reflect the socioeconomic context in which they were designed. The goal of this thesis is to develop a methodological framework for evaluating the sustainability of industrial symbiosis projects in developing countries.To accomplish this, I followed a case study about the implementation of industrial symbiosis in northern Nigeria by participating as an observer since 2007. AshakaCem, a cement works of Lafarge group, must confront many issues associated with violence committed by the local rural population. Thus, the company decided to adopt a new approach inspired by the concepts of industrial symbiosis.The project involves replacing up to 10% of the fossil fuel used to heat limestone with biomass produced by local farmers. To avoid jeopardizing the fragile security of regional food supplies, farmers are taught ways to combat erosion and naturally fertilize the soil. They can then use biomass cultivation to improve their subsistence crops. Through this industrial symbiosis, AshakaCem follows social objectives (to lay the necessary foundations for regional development), but also environmental ones (to reduce its overall CO2 emissions) and economical ones (to reduce its energy costs). The company is firmly rooted in a view of sustainable development that is conditional upon the project's execution.By observing this symbiosis and by being familiar with existing tools, I note that assessing the sustainability of projects in developing countries requires using evaluation criteria that are specific to each project. Indeed, using generic criteria results in an assessment that is too far removed from what is needed and from the local reality. Thus, by drawing inspiration from such internationally known tools as Life Cycle Analysis and the Global Reporting Initiative, I define a generic methodological framework for the participative establishment of an evaluation methodology specific to each project.The strategy follows six phases that are fulfilled iteratively so as to improve the evaluation methodology and the project itself as it moves forward. During these phases, the social, economic, and environmental needs and objectives of the stakeholders are identified, grouped, ranked, and expressed as criteria for evaluation. Quantitative or qualitative indicators are then defined for each of these criteria. One of the characteristics of this strategy is to define a five-point evaluation scale, the same for each indicator, to reflect a goal that was completely reached (++) or not reached at all (--).Applying the methodological framework to the Nigerian symbiosis yielded four economic criteria, four socioeconomic criteria, and six environmental criteria to assess. A total of 22 indicators were defined to characterize the criteria. Evaluating these indicators made it possible to show that the project meets the sustainability goals set for the majority of criteria. Four indicators had a neutral result (0); a fifth showed that one criterion had not been met (--). These results can be explained by the fact that the project is still only in its pilot phase and, therefore, still has not reached its optimum size and scope. Following up over several years will make it possible to ensure these gaps will be filled.The methodological framework presented in this thesis is a highly effective tool that can be used in a broader context than developing countries. Its generic nature makes it a very good tool for defining criteria and follow-up indicators for sustainable development.

Direct magnetic resonance arthrography of the wrist with axial traction: A feasibility study to assess joint cartilage.

PURPOSE: To assess the impact of axial traction during acquisition of direct magnetic resonance (MR) arthrography of the wrist with regard to joint space width and amount of contrast material between the opposing cartilage surfaces. MATERIALS AND METHODS: Fifteen consecutive patients (12 male, mean age 38.1 years) were included in this Institutional Review Board-approved prospective study. Three-compartment wrist MR arthrographies were performed between October and December 2009 on a 3 T unit using a fat-suppressed T1-weighted isotropic high-resolution volumetric interpolated breathhold examination (VIBE) sequence in the coronal plane, with and without axial traction (3 kg). Two radiologists measured radiocarpal (radioscaphoid, radiolunate) and midcarpal (lunocapitate, hamatolunate) joint space widths, with and without traction, and assessed the amount of contrast material between the opposing cartilage surfaces using a three-point scale: 0 = absence, 1 = partial, 2 = complete. RESULTS: With traction, joint space width increased significantly at the radioscaphoid (Delta = 0.78 mm, P < 0.01), radiolunate (Delta = 0.18 mm, P < 0.01), and lunocapitate (Delta = 0.45 mm, P < 0.01) spaces, and both observers detected significantly more contrast material between the cartilage surfaces. At the hamatolunate space, the differences in joint space width (Delta = 0.14 mm, P = 0.54) and amount of contrast material were not significant. CONCLUSION: Direct wrist MR arthrography with axial traction of 3 kg increases joint space width at the radiocarpal and lunocapitate spaces, and prompts better coverage of the articular cartilage by the contrast material. J. Magn. Reson. Imaging 2011;. (c) 2011 Wiley-Liss, Inc.