Circadian regulation of renal function and potential role in hypertension.

PURPOSE OF REVIEW: Previous studies have shown that a variety of specific renal functions exhibit circadian oscillations. This review aims to provide an update on the molecular mechanisms underlying circadian rhythms in the kidney, and to discuss how dysregulation of circadian rhythms can interfere with kidney function. RECENT FINDINGS: The molecular mechanism responsible for generating and maintaining circadian rhythms has been unraveled in great detail. This mechanism, known as the circadian clock, drives circadian oscillation in expression levels of a large number of renal mRNA transcripts. Several proteins critically involved in renal homeostatic functions have been shown to exhibit significant circadian oscillation in their expression levels or in their posttranslational modifications. In transgenic mouse models, disruption of circadian clock activity results in dramatic changes in the circadian pattern of urinary sodium and potassium excretion and causes significant changes in arterial blood pressure. A growing amount of evidence suggests that dysregulation of circadian rhythms is associated with the development of hypertension and accelerated progression of chronic kidney disease and cardiovascular disease in humans. Chronotherapy studies have shown that the efficacy of antihypertensive medication is greatly dependent on the circadian time of drug administration. SUMMARY: Recent research points to the major role of circadian rhythms in renal function and in control of blood pressure.

Monitoring and failure mechanism interpretation of an unstable slope in Southern Switzerland based on terrestrial laser scanner

We present the application of terrestrial laser scanning (TLS) for the monitoring and characterization of an active landslide area in Val Canaria (Ticino, Southern Swiss Alps). At catchment scale, the study area is affected by a large Deep Seated Gravitational Slope Deformation (DSGSD) area presenting, in the lower boundary, several retrogressive landslides active since the 1990s. Due to its frequent landslide events this area was periodically monitored by TLS since 2006. Periodic acquisitions provided new information on 3D displacements at the bottom of slope and the detection of centimetre to decimetre level scale changes (e.g. rockfall and pre-failure deformations). In October 2009, a major slope collapse occured at the bottom of the most unstable area. Based on the comparison between TLS data before and after the collapse, we carried out a detailed failure mechanism analysis and volume calculation.

Virological and immunological responses to efavirenz or boosted lopinavir as first-line therapy for patients with HIV.

BACKGROUND: Efavirenz and lopinavir boosted with ritonavir are both recommended as first-line therapies for patients with HIV when combined with two nucleoside reverse transcriptase inhibitors. It is uncertain which therapy is more effective for patients starting therapy with an advanced infection. METHODS: We estimated the relative effect of these two therapies on rates of virological and immunological failure within the Swiss HIV Cohort Study and considered whether estimates depended on the CD4(+) T-cell count when starting therapy. We defined virological failure as either an incomplete virological response or viral rebound after viral suppression and immunological failure as failure to achieve an expected CD4(+) T-cell increase calculated from EuroSIDA statistics. RESULTS: Patients starting efavirenz (n=660) and lopinavir (n=541) were followed for a median of 4.5 and 3.1 years, respectively. Virological failure was less likely for patients on efavirenz, with the adjusted hazard ratio (95% confidence interval) of 0.63 (0.50-0.78) then multiplied by a factor of 1.00 (0.90-1.12) for each 100 cells/mm(3) decrease in CD4(+) T-cell count below the mean when starting therapy. Immunological failure was also less likely for patients on efavirenz, with the adjusted hazard ratio of 0.68 (0.51-0.91) then multiplied by a factor of 1.29 (1.14-1.46) for each 100 cells/mm(3) decrease in CD4(+) T-cell count below the mean when starting therapy. CONCLUSIONS: Virological failure is less likely with efavirenz regardless of the CD4(+) T-cell count when starting therapy. Immunological failure is also less likely with efavirenz; however, this advantage disappears if patients start therapy with a low CD4(+) T-cell count.

Characterization of the molecular mechanisms of insulin exocytosis and of their adaptation to physiopathological conditions

Résumé large public Le glucose est une source d'énergie essentielle pour notre organisme, indispensable pour le bon fonctionnement des cellules de notre corps. Les cellules β du pancréas sont chargées de réguler l'utilisation du glucose et de maintenir la glycémie (taux de glucose dans le sang) à un niveau constant. Lorsque la glycémie augmente, ces dernières sécrètent l'insuline, une hormone favorisant l'absorption, l'utilisation et le stockage du glucose. Une sécrétion insuffisante d'insuline provoque une élévation anormale du taux de glucose dans le sang (hyperglycémie) et peut mener au développement du diabète sucré. L'insuline est sécrétée dans le sang par un mécanisme particulier appelé exocytose. Une meilleure compréhension de ce mécanisme est nécessaire dans l'espoir de trouver des nouvelles thérapies pour traiter les 170 millions de personnes atteintes de diabète sucré à travers le monde. L'implication de diverses protéines, comme les SNAREs ou Rabs a déjà été démontrée. Cependant leurs mécanismes d'action restent, à ce jour, peu compris. De plus, l'adaptation de la machinerie d'exocytose à des conditions physiopathologiques, comme l'hyperglycémie, est encore à élucider. Le but de mon travail de thèse a été de clarifier le rôle de deux protéines, Noc2 et Tomosyn, dans l'exocytose ; puis de déterminer les effets d'une exposition prolongée à un taux élevé de glucose sur l'ensemble des protéines de la machinerie d'exocytose. Noc2 est un partenaire potentiel de deux Rabs connues pour leur implication dans les dernières étapes de l'exocytose, Rab3 et Rab27. Grâce à l'étude de différents mutants de Noc2, j'ai montré que l'interaction avec Rab27 permet à la protéine de s'associer avec les organelles de la cellule β contenant l'insuline. De plus, en diminuant sélectivement l'expression de Noc2, j'ai déterminé l'importance de cette protéine pour le bon fonctionnement du processus d'exocytose et le relâchement de l'insuline. Quant à Tomosyn, une protéine interagissant avec les protéines SNAREs, j'ai démontré son importance dans la sécrétion d'insuline en diminuant de manière sélective son expression dans les cellules β. Ensuite, grâce à une combinaison d'approches moléculaires et de microscopie, j'ai mis en évidence le rôle de Tomosyn dans les dernières étapes de l'exocytose. Enfin, puisque la sécrétion d'insuline est diminuée lors d'une hyperglycémie prolongée, j'ai analysé l'adaptation de la machinerie d'exocytose à ces conditions. Ceci m'a permis de découvrir que l'expression de quatre protéines essentielles pour le processus d'exocytose, Noc2, Rab3, Rab27 et Granuphilin, est fortement diminuée lors d'une hyperglycémie chronique. L'ensemble de ces données met en évidence l'importance de Noc2 et Tomosyn dans la sécrétion d'insuline. L'inhibition, par un taux élevé de glucose, de l'expression de Noc2 et d'autres protéines indispensables pour l'exocytose suggère que ce phénomène pourrait contribuer au développement du diabète sucré. Résumé L'exocytose d'insuline, en réponse au glucose circulant dans le sang, est la fonction principale de la cellule β. Celle-ci permet de stabiliser le taux de glucose sanguin (glycémie). Le diabète de type 2 est caractérisé par une glycémie élevée due, principalement, à un défaut de sécrétion d'insuline en réponse au glucose. La compréhension des mécanismes qui contrôlent l'exocytose d'insuline est essentielle pour clarifier les causes du diabète sucré. Plusieurs composants impliqués dans ce processus ont été identifiés. Ceux-ci incluent les SNAREs Syntaxin-1, VAMP2 et SNAP25 et les GTPases Rab3 et Rab27 qui jouent un rôle dans les dernières étapes de l'exocytose. Pendant mon travail de thèse, j'ai étudié le rôle de Noc2, un des partenaires de Rab3 et Rab27, dans l'exocytose d'insuline. Nous avons déterminé que Noc2 s'associe aux granules de sécrétion d'insuline grâce à son interaction avec Rab27. La diminution de l'expression de Noc2 dans la lignée cellulaire β INS-1E, par ARN interférence, influence négativement la sécrétion d'insuline stimulée par différents sécrétagogues et prouve que cette protéine Noc2 est essentielle pour l'exocytose d'insuline. L'interaction avec Munc13, une protéine impliquée dans l'arrimage des vésicules, suggère que Noc2 participe au recrutement des granules d'insuline à la membrane plasmique. Ensuite, j'ai analysé l'adaptation de la machinerie d'exocytose à des concentrations supraphysiologiques de glucose. Le niveau d'expression de Rab3 et Rab27 et de leurs effecteurs Granuphilin/S1p4 et Noc2 est fortement diminué par une exposition prolongée des cellules β à haut glucose. L'effet observé est en relation avec l'induction de l'expression de ICER, un facteur de transcription surexprimé dans des conditions d'hyperglycémie et également dans des modèles génétiques de diabète de type 2. La surexpression de ICER dans des cellules INS-1E diminue l'expression de Rab3, Rab27, Granuphilin/Slp4 et Noc2 et par conséquent l'exocytose d'insuline. Ainsi, l'induction de ICER, après une exposition prolongée à haut glucose, régule négativement l'expression de protéines essentielles pour l'exocytose et altère la sécrétion d'insuline. Ce mécanisme pourrait contribuer au dysfonctionnement de l'exocytose d'insuline dans le diabète de type 2. Dans la dernière partie de ma thèse, j'ai investigué le rôle de la protéine Tomosyn-1 dans la formation du complexe SNARE. Cette protéine a une forte affinité pour Syntaxin-1 et contient un domaine SNARE. Tomosyn-1 est concentrée dans les régions cellulaires enrichies en granules de sécrétion. La diminution sélective de l'expression de Tomosyn-1 induit une réduction de l'exocytose stimulée par différents sécrétagogues. Cet effet est dû à un défaut de fusion des granules avec la membrane plasmique. Ceci nous indique que Tomosyn-1 intervient dans une phase importante de la préparation des vésicules à la fusion, qui est nécessaire à l'exocytose. Abstract: Insulin exocytosis from pancreatic β-cells plays a central role in blood glucose homeostasis. Diabetes mellitus is a complex metabolic disorder characterized by secretory dysfunctions in pancreatic β-cells and release of amounts of insulin that are inappropriate to maintain blood glucose concentration within normal physiological ranges. To define the causes of β-cell failure a basic understanding of the molecular mechanisms that control insulin exocytosis is essential. Some of the molecular components involved in this process have been identified, including the SNARE proteins VAMP2, Syntaxin-1 and SNAP25 and the two GTPases, Rab3 and Rab27, that regulate the final steps of insulin secretion. I first investigated the role of Noc2, a potential Rab3 and Rab27 partner, in insulin secretion. I found that Noc2 associates with Rab27 and is recruited by this GTPase on insulin- containing granules. Silencing of the Noc2 gene by RNA interference led to a strong impairment in the capacity of the β-cell line INS-1E to respond to secretagogues, indicating that appropriate levels of the protein are essential for insulin exocytosis. I also showed that Noc2 interacts with Munc13, a protein that controls vesicle priming, suggesting a possible involvement of Noc2 in the recruitment of secretory granules at the plasma membrane. In the second part of my thesis, I investigated the adaptation of the molecular machinery of exocytosis to physiopathological conditions. I found that the expression of Rab3, Rab27 and of their effectors Granuphilin/Slp4 and Noc2 is dramatically decreased by chronic exposure of β-ce1ls to supraphysiological glucose levels. The observed glucotoxic effect is a consequence of the induction of ICER, a transcriptional repressor that is increased by prolonged hyperglycemia and in genetic models of type 2 diabetes. Overexpression of ICER reduced Granuphilin, Noc2, Rab3 and Rab27 levels and inhibited exocytosis. These results suggest that the presence of inappropriate levels of ICER diminishes the expression of a group of proteins essential for exocytosis and contributes to defective insulin release in type 2 diabetes. In the last part of my thesis, I focused my attention on the role of Tomosyn-1, a Syntaxin-1 binding protein possessing a SNARE-like motif, in the control of SNARE complex assembly. I found that Tomosyn-1 is concentrated in cellular compartments enriched in insulin-containing secretory granules. Silencing of Tomosyn-1 did not affect the number of secretory granules docked at the plasma membrane but decreased their release probability, resulting in a reduction in stimulus-induced insulin exocytosis. These findings suggest that Tomosyn-1 is involved in a post-docking event that prepares secretory granules for fusion and is necessary to sustain exocytosis in response to insulin secretagogues.

Spine bone texture assessed by trabecular bone score (TBS) predicts osteoporotic fractures in men: The Manitoba Bone Density Program.

INTRODUCTION: One quarter of osteoporotic fractures occur in men. TBS, a gray-level measurement derived from lumbar spine DXA image texture, is related to microarchitecture and fracture risk independently of BMD. Previous studies reported the ability of spine TBS to predict osteoporotic fractures in women. Our aim was to evaluate the ability of TBS to predict clinical osteoporotic fractures in men. METHODS: 3620 men aged ≥50 (mean 67.6years) at the time of baseline DXA (femoral neck, spine) were identified from a database (Province of Manitoba, Canada). Health service records were assessed for the presence of non-traumatic osteoporotic fracture after BMD testing. Lumbar spine TBS was derived from spine DXA blinded to clinical parameters and outcomes. We used Cox proportional hazard regression to analyze time to first fracture adjusted for clinical risk factors (FRAX without BMD), osteoporosis treatment and BMD (hip or spine). RESULTS: Mean followup was 4.5years. 183 (5.1%) men sustain major osteoporotic fractures (MOF), 91 (2.5%) clinical vertebral fractures (CVF), and 46 (1.3%) hip fractures (HF). Correlation between spine BMD and spine TBS was modest (r=0.31), less than correlation between spine and hip BMD (r=0.63). Significantly lower spine TBS were found in fracture versus non-fracture men for MOF (p<0.001), HF (p<0.001) and CVF (p=0.003). Area under the receiver operating characteristic curve (AUC) for incident fracture discrimination with TBS was significantly better than chance (MOF AUC=0.59, p<0.001; HF AUC=0.67, p<0.001; CVF AUC=0.57, p=0.032). TBS predicted MOF and HF (but not CVF) in models adjusted for FRAX without BMD and osteoporosis treatment. TBS remained a predictor of HF (but not MOF) after further adjustment for hip BMD or spine BMD. CONCLUSION: We observed that spine TBS predicted MOF and HF independently of the clinical FRAX score, HF independently of FRAX and BMD in men. Studies with more incident fractures are needed to confirm these findings.

Surgery for unruptured arteriovenous malformations of the brain is better than conservative management for selected cases : a prospective cohort study

Object. The aim of this study was to identify patients who are likely to benefit from surgery for unruptured brain arterriovenous malformations (ubAVMs). Methods. The authors' database was interrogated for the risk and outcome of hemorrhage after referral and the out- come from surgery. Furthermore, the outcome from surgery incorporated those cases excluded from surgery because of perceived greater risk (sensitivity analysis). Finally, a comparison was made for the authors' patients between the natural history and surgery. Data were collected for 427 consecutively enrolled patients with ubAVMs in a database that in- cluded patients who were conservatively managed. Kaplan-Meier analysis was performed on patients observed for more than 1 day to determine the risk of hemorrhage. Variables that may influence the risk of first hemorrhage were assessed using Cox proportional hazard regression models and Kaplan-Meier life table analyses from referral until the first occur- rence of the following: hemorrhage, treatment, or last review. The outcome from surgery (leading to a new permanent neurological deficit with last review modified Rankin Scale [mRS] score > 1) was determined. Further sensitivity analy- sis was made to predict risk from surgery for the total ubAVM cohort by incorporating outcomes of surgical cases as well as cases excluded from surgery because of perceived risk, and assuming an adverse outcome for these excluded cases. Results. A total of 377 patients with a ubAVM were included in the analysis of the risk of hemorrhage. The 5-year risk of hemorrhage for ubAVM was 11.5%. Hemorrhage resulted in an mRS score > 1 in 14 cases (88% [95% CI 63%-98%]). Patients with Spetzler-Ponce Class A ubAVMs treated by surgery (n = 190) had a risk from surgery of 1.6% (95% CI 0.3%-4.8%) for a permanent neurological deficit leading to an mRS score > 1 and 0.5% (95% CI< 0.1%-3.2%) for a permanent neurological deficit leading to an mRS score > 2. Patients with Spetzler-Ponce Class B ubAVMs treated by surgery (n = 107) had a risk from surgery of 14.0% (95% CI 8.6%-22.0%) for a permanent neurological deficit leading to an mRS score > 1. Sensitivity analysis of Spetzler-Ponce Class B ubAVMs, including those in patients excluded from surgery, showed that the true risk for surgically eligible patients may have been as high as 15.6% (95% CI 9.9%-23.7%) for mRS score > 1, had all patients who were perceived to have a greater risk experienced an adverse outcome. Patients with Spetzler-Ponce Class C ubAVMs treated by surgery (n = 44) had a risk from surgery of 38.6% (95% CI 25.7%-53.4%) for a permanent neurological deficit leading to an mRS score >1. Sensitivity analysis of Class C ubAVMs, including those harbored by patients excluded from surgery, showed that the true risk for surgically eligible patients may have been as high as 60.9% (95% CI 49.2%-71.5%) for mRS score > 1, had all patients who were perceived to have a greater risk experienced an adverse outcome. Conclusion. Surgical outcomes for Spetzler-Ponce Class ubAVMs are better than those for conservative management.

Differential associations of personal and general just-world beliefs with the Five-Factor and HEXACO models of personality.

Recent literature evidences differential associations of personal and general just-world beliefs with constructs in the interpersonal domain. In line with this research, we examine the respective relationships of each just-world belief with the Five-Factor and the HEXACO models of personality in one representative sample of the working population of Switzerland and one sample of the general US population, respectively. One suppressor effect was observed in both samples: Neuroticism and emotionality was positively associated with general just-world belief, but only after controlling for personal just-world belief. In addition, agreeableness was positively and honesty-humility negatively associated with general just-world belief but unrelated to personal just-world belief. Conscientiousness was consistently unrelated to any of the just-world belief and extraversion and openness to experience revealed unstable coefficients across studies. We discuss these points in light of just-world theory and their implications for future research taking both dimensions into account.

Impact of the early use of immunomodulators or TNF antagonists on bowel damage and surgery in Crohn's disease.

BACKGROUND: The impact of early treatment with immunomodulators (IM) and/or TNF antagonists on bowel damage in Crohn's disease (CD) patients is unknown. AIM: To assess whether 'early treatment' with IM and/or TNF antagonists, defined as treatment within a 2-year period from the date of CD diagnosis, was associated with development of lesser number of disease complications when compared to 'late treatment', which was defined as treatment initiation after >2 years from the time of CD diagnosis. METHODS: Data from the Swiss IBD Cohort Study were analysed. The following outcomes were assessed using Cox proportional hazard modelling: bowel strictures, perianal fistulas, internal fistulas, intestinal surgery, perianal surgery and any of the aforementioned complications. RESULTS: The 'early treatment' group of 292 CD patients was compared to the 'late treatment' group of 248 CD patients. We found that 'early treatment' with IM or TNF antagonists alone was associated with reduced risk of bowel strictures [hazard ratio (HR) 0.496, P = 0.004 for IM; HR 0.276, P = 0.018 for TNF antagonists]. Furthermore, 'early treatment' with IM was associated with reduced risk of undergoing intestinal surgery (HR 0.322, P = 0.005), and perianal surgery (HR 0.361, P = 0.042), as well as developing any complication (HR 0.567, P = 0.006). CONCLUSIONS: Treatment with immunomodulators or TNF antagonists within the first 2 years of CD diagnosis was associated with reduced risk of developing bowel strictures, when compared to initiating these drugs >2 years after diagnosis. Furthermore, early immunomodulators treatment was associated with reduced risk of intestinal surgery, perianal surgery and any complication.

The First International Workshop on Warning Criteria for Active Slides: technical issues, problems and solutions for managing early warning systems

Early warning systems (EWSs) rely on the capacity to forecast a dangerous event with a certain amount of advance by defining warning criteria on which the safety of the population will depend. Monitoring of landslides is facilitated by new technologies, decreasing prices and easier data processing. At the same time, predicting the onset of a rapid failure or the sudden transition from slow to rapid failure and subsequent collapse, and its consequences is challenging for scientists that must deal with uncertainties and have limited tools to do so. Furthermore, EWS and warning criteria are becoming more and more a subject of concern between technical experts, researchers, stakeholders and decision makers responsible for the activation, enforcement and approval of civil protection actions. EWSs imply also a sharing of responsibilities which is often averted by technical staff, managers of technical offices and governing institutions. We organized the First International Workshop on Warning Criteria for Active Slides (IWWCAS) to promote sharing and networking among members from specialized institutions and relevant experts of EWS. In this paper, we summarize the event to stimulate discussion and collaboration between organizations dealing with the complex task of managing hazard and risk related to active slides.

Trabecular bone score in kidney transplant recipients.

UNLABELLED: It is uncertain whether bone mineral density (BMD) can accurately predict fracture in kidney transplant recipients. Trabecular bone score (TBS) provides information independent of BMD. Kidney transplant recipients had abnormal bone texture as measured by lumbar spine TBS, and a lower TBS was associated with incident fractures in recipients. INTRODUCTION: Trabecular bone score (TBS) is a texture measure derived from dual energy X-ray absorptiometry (DXA) lumbar spine images, providing information independent of bone mineral density. We assessed characteristics associated with TBS and fracture outcomes in kidney transplant recipients. METHODS: We included 327 kidney transplant recipients from Manitoba, Canada, who received a post-transplant DXA (median 106 days post-transplant). We matched each kidney transplant recipient (mean age 45 years, 39 % men) to three controls from the general population (matched on age, sex, and DXA date). Lumbar spine (L1-L4) DXA images were used to derive TBS. Non-traumatic incident fracture (excluding hand, foot, and craniofacial) (n = 31) was assessed during a mean follow-up of 6.6 years. We used multivariable linear regression models to test predictors of TBS, and multivariable Cox proportional hazard regression was used to estimate hazard ratios (HRs) per standard deviation decrease in TBS to express the gradient of risk. RESULTS: Compared to the general population, kidney transplant recipients had a significantly lower lumbar spine TBS (1.365 ± 0.129 versus 1.406 ± 0.125, P < 0.001). Multivariable linear regression revealed that receipt of a kidney transplant was associated with a significantly lower mean TBS compared to controls (-0.0369, 95 % confidence interval [95 % CI] -0.0537 to -0.0202). TBS was associated with fractures independent of the Fracture Risk Assessment score including BMD (adjusted HR per standard deviation decrease in TBS 1.64, 95 % CI 1.15-2.36). CONCLUSION: Kidney transplant recipients had abnormal bone texture as assessed by TBS and a lower lumbar spine TBS was associated with fractures in recipients.

From Regional Landslide Detection to Site-Specific Slope Deformation Monitoring and Modelling Based on Active Remote Sensors

Landslide processes can have direct and indirect consequences affecting human lives and activities. In order to improve landslide risk management procedures, this PhD thesis aims to investigate capabilities of active LiDAR and RaDAR sensors for landslides detection and characterization at regional scales, spatial risk assessment over large areas and slope instabilities monitoring and modelling at site-specific scales. At regional scales, we first demonstrated recent boat-based mobile LiDAR capabilities to model topography of the Normand coastal cliffs. By comparing annual acquisitions, we validated as well our approach to detect surface changes and thus map rock collapses, landslides and toe erosions affecting the shoreline at a county scale. Then, we applied a spaceborne InSAR approach to detect large slope instabilities in Argentina. Based on both phase and amplitude RaDAR signals, we extracted decisive information to detect, characterize and monitor two unknown extremely slow landslides, and to quantify water level variations of an involved close dam reservoir. Finally, advanced investigations on fragmental rockfall risk assessment were conducted along roads of the Val de Bagnes, by improving approaches of the Slope Angle Distribution and the FlowR software. Therefore, both rock-mass-failure susceptibilities and relative frequencies of block propagations were assessed and rockfall hazard and risk maps could be established at the valley scale. At slope-specific scales, in the Swiss Alps, we first integrated ground-based InSAR and terrestrial LiDAR acquisitions to map, monitor and model the Perraire rock slope deformation. By interpreting both methods individually and originally integrated as well, we therefore delimited the rockslide borders, computed volumes and highlighted non-uniform translational displacements along a wedge failure surface. Finally, we studied specific requirements and practical issues experimented on early warning systems of some of the most studied landslides worldwide. As a result, we highlighted valuable key recommendations to design new reliable systems; in addition, we also underlined conceptual issues that must be solved to improve current procedures. To sum up, the diversity of experimented situations brought an extensive experience that revealed the potential and limitations of both methods and highlighted as well the necessity of their complementary and integrated uses.

IMP2 provides an alternative to LIN28B for LET-7 target gene protection and glioma stem cell maintenance

Glioblastoma multiforme (GBM) is the most frequent and lethal primary brain tumor in adults. Accumulating evidence suggests that tumors comprise a hierarchical organization that is, at least partially, not genetically driven. Cells that reside at the apex of this hierarchy are commonly referred to as cancer stem cells (CSCs) and are believed to largely contribute to recurrence and therapeutic failure. Although the complexity of epigenetic regulation of the genome precludes prediction as to which epigenetic changes dominate CSC specification in different cancer types, the ability of microRNAs (miRNAs) to fine-tune expression of entire gene networks places them among prime candidates for establishing CSC properties. In this study we characterized the miRNA expression profile of primary GBM grown either under conditions that enrich for GSCs or their differentiated non-tumorigenic progeny (DGCs). Although, we identified a subset of miRNAs that was strongly differentially expressed between GSCs and DGCs, we observed that in GSCs both let-7 and, paradoxically, their target genes are highly expressed, suggesting protection against let-7 action. Using PAR-CLIP we show that insulin-like growth factor-2 mRNA-binding protein 2 (IMP2) provides a mechanism for let-7 target gene protection that represents an alternative to LIN28A/B, which abrogates let-7 biogenesis in normal embryonic and certain malignant stem cells. By direct binding to miRNA recognition elements, IMP2 protects its targets from let-7 mediated decay. Importantly, depletion of IMP2 in GSCs strongly impairs their self- renewal properties and tumorigenicity in vivo, a phenotype that can be rescued by expression of LIN28B, suggesting that IMP2 mainly contributes to GSC maintenance by protecting let-7 target genes from silencing. Using mouse models, we show that depletion of IMP2 in neural stem cells (NSCs) induces let-7 target gene down-regulation, impairs their clonogenic capacity, and affects differentiation. Taken together, our observations describe a novel regulatory function of IMP2 in the let-7 axis whereby it supports GSC and NSC specification. Résumé (Français) Le glioblastome (GBM) est la tumeur primaire maligne du cerveau la plus fréquente. De nombreuses études ont démontré l'existence d'une organisation hiérarchique des cellules cancéreuses liée à des mécanismes épigénétiques. Les cellules qui se trouvent au sommet de cette hiérarchie sont appelées cellules souches cancéreuses (CSC), et contribuent à l'échec thérapeutique. Bien que la complexité des régulateurs épigénétiques permette difficilement de prédire quel mécanisme contribue le plus aux propriétés des CSC, la capacité des microRNAs (miRNAs) de réguler des réseaux entiers de gènes, les placent comme des candidats de premiers choix. Ici, nous avons caractérisé le profil d'expression des miRNAs dans des tumeurs primaires de GBM cultivées dans des conditions qui enrichissent soit pour les CSC, soit pour leur contrepartie de cellules cancéreuses différences (CCD). De manière surprenante et paradoxale la famille de miRNA let-7 et leurs gènes cibles étaient hautement exprimés dans les CSC, suggérant un mécanisme de protection contre l'action des let-7. Avec l'aide de la technologie PAR-CLIP, nous démontrons que la protéine IMP2, protège les mRNAs de l'action des let-7 et représente une alternative à Lin28A/B, qui d'ordinaire réprime fortement la maturation des let-7 dans les cellules souches embryonnaires et divers cancers. En se liant à la région ciblée par les let-7, IMP2 protège ses transcrits de l'action de cette classe de microRNA qui est tumoro-supressive. La déplétion d'IMP2 dans des CSC de GBM réduit fortement leur clonogénicité in vitro et leur tumorigénicité in vivo. Ceci peut être reversé en introduisant Lin28B dans des CSC de GBM, suggérant qu'IMP2 exerce ses fonctions pro-tumorigéniques en modulant l'axe let-7. Avec l'aide de modèles murins, nous observons que la déplétion de IMP2 dans les cellules souches neurales (CSN) induit une baisse de leur clonogénicité et des cibles des miRNAs let-7, suggérant une conservation de ce mécanisme entre les CSC de GBM et les CSN. En résumé, nos observations définissent une nouvelle fonction de IMP2 dans l'axe let-7 par lequel il contribue au maintien des propriétés des CSC et des CSN.

Asymptotic analysis of stock price densities and implied volatilities in mixed stochastic models

In this paper, we obtain sharp asymptotic formulas with error estimates for the Mellin con- volution of functions de ned on (0;1), and use these formulas to characterize the asymptotic behavior of marginal distribution densities of stock price processes in mixed stochastic models. Special examples of mixed models are jump-di usion models and stochastic volatility models with jumps. We apply our general results to the Heston model with double exponential jumps, and make a detailed analysis of the asymptotic behavior of the stock price density, the call option pricing function, and the implied volatility in this model. We also obtain similar results for the Heston model with jumps distributed according to the NIG law.

Mechanistic population Models in Biology: Model Derivation and Application

In general, models of ecological systems can be broadly categorized as ’top-down’ or ’bottom-up’ models, based on the hierarchical level that the model processes are formulated on. The structure of a top-down, also known as phenomenological, population model can be interpreted in terms of population characteristics, but it typically lacks an interpretation on a more basic level. In contrast, bottom-up, also known as mechanistic, population models are derived from assumptions and processes on a more basic level, which allows interpretation of the model parameters in terms of individual behavior. Both approaches, phenomenological and mechanistic modelling, can have their advantages and disadvantages in different situations. However, mechanistically derived models might be better at capturing the properties of the system at hand, and thus give more accurate predictions. In particular, when models are used for evolutionary studies, mechanistic models are more appropriate, since natural selection takes place on the individual level, and in mechanistic models the direct connection between model parameters and individual properties has already been established. The purpose of this thesis is twofold. Firstly, a systematical way to derive mechanistic discrete-time population models is presented. The derivation is based on combining explicitly modelled, continuous processes on the individual level within a reproductive period with a discrete-time maturation process between reproductive periods. Secondly, as an example of how evolutionary studies can be carried out in mechanistic models, the evolution of the timing of reproduction is investigated. Thus, these two lines of research, derivation of mechanistic population models and evolutionary studies, are complementary to each other.

Survival analysis of female dogs with mammary tumors after mastectomy: epidemiological, clinical and morphological aspects

Abstract: Mammary gland tumors are the most common type of tumors in bitches but research on survival time after diagnosis is scarce. The purpose of this study was to investigate the relationship between survival time after mastectomy and a number of clinical and morphological variables. Data was collected retrospectively on bitches with mammary tumors seen at the Small Animal Surgery Clinic Service at the University of Brasília. All subjects had undergone mastectomy. Survival analysis was conducted using Cox's proportional hazard method. Of the 139 subjects analyzed, 68 died and 71 survived until the end of the study (64 months). Mean age was 11.76 years (SD=2.71), 53.84% were small dogs. 76.92% of the tumors were malignant, and 65.73% had both thoracic and inguinal glands affected. Survival time in months was associated with age (hazard rate ratios [HRR] =1.23, p-value =1.4x10-4), animal size (HRR between giant and small animals =2.61, p-value =0.02), nodule size (HRR =1.09, p-value =0.03), histological type (HRR between solid carcinoma and carcinoma in a mixed tumor =2.40, p-value =0.02), time between diagnosis and surgery (TDS, with HRR =1.21, p-value =2.7x10-15), and the interaction TDS*follow-up time (HRR =0.98, p-value =1.6x10-11). The present study is one of the few on the subject matter. Several important covariates were evaluated and age, animal size, nodule size, histological type, TDS and TDS*follow up time were identified as significantly associated to survival time.