Dynamic econometric analysis of insurance markets with imperfect information

Abbring, J.H. [Promotor

Better Safe than Sorry? Ex Ante and Ex Post Moral Hazard in Dynamic Insurance Data

This paper empirically analyzes moral hazard in car insurance using a dynamic theory of an insuree's dynamic risk (ex ante moral hazard) and claim (ex post moral hazard) choices and Dutch longitudinal micro data. We use the theory to characterize the heterogeneous dynamic changes in incentives to avoid claims that are generated by the Dutch experience-rating scheme, and their effects on claim times and sizes under moral hazard. We develop tests that exploit these structural implications of moral hazard and experience rating. Unlike much of the earlier literature, we find evidence of moral hazard.insurance;moral hazard;selection;state dependence;event-history analysis

Modelling mutational landscapes of human cancers in vitro

Experimental models that recapitulate mutational landscapes of human cancers are needed to decipher the rapidly expanding data on human somatic mutations. We demonstrate that mutation patterns in immortalised cell lines derived from primary murine embryonic fibroblasts (MEFs) exposed in vitro to carcinogens recapitulate key features of mutational signatures observed in human cancers. In experiments with several cancer-causing agents we obtained high genome-wide concordance between human tumour mutation data and in vitro data with respect to predominant substitution types, strand bias and sequence context. Moreover, we found signature mutations in well-studied human cancer driver genes. To explore endogenous mutagenesis, we used MEFs ectopically expressing activation-induced cytidine deaminase (AID) and observed an excess of AID signature mutations in immortalised cell lines compared to their non-transgenic counterparts. MEF immortalisation is thus a simple and powerful strategy for modelling cancer mutation landscapes that facilitates the interpretation of human tumour genome-wide sequencing data

Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially modulates TGFβ signalling and EMT

Ubiquitin-dependent mechanisms have emerged as essential regulatory elements controlling cellular levels of Smads and TGFß-dependent biological outputs such as epithelial–mesenchymal transition (EMT). In this study, we identify a HECT E3 ubiquitin ligase known as WWP2 (Full-length WWP2-FL), together with two WWP2 isoforms (N-terminal, WWP2-N; C-terminal WWP2-C), as novel Smad-binding partners. We show that WWP2-FL interacts exclusively with Smad2, Smad3 and Smad7 in the TGFß pathway. Interestingly, the WWP2-N isoform interacts with Smad2 and Smad3, whereas WWP2-C interacts only with Smad7. In addition, WWP2-FL and WWP2-C have a preference for Smad7 based on protein turnover and ubiquitination studies. Unexpectedly, we also find that WWP2-N, which lacks the HECT ubiquitin ligase domain, can also interact with WWP2-FL in a TGFß-regulated manner and activate endogenous WWP2 ubiquitin ligase activity causing degradation of unstimulated Smad2 and Smad3. Consistent with our protein interaction data, overexpression and knockdown approaches reveal that WWP2 isoforms differentially modulate TGFß-dependent transcription and EMT. Finally, we show that selective disruption of WWP2 interactions with inhibitory Smad7 can stabilise Smad7 protein levels and prevent TGFß-induced EMT. Collectively, our data suggest that WWP2-N can stimulate WWP2-FL leading to increased activity against unstimulated Smad2 and Smad3, and that Smad7 is a preferred substrate for WWP2-FL and WWP2-C following prolonged TGFß stimulation. Significantly, this is the first report of an interdependent biological role for distinct HECT E3 ubiquitin ligase isoforms, and highlights an entirely novel regulatory paradigm that selectively limits the level of inhibitory and activating Smads

Dynamics of notch pathway expression during mouse testis post-natal development and along the spermatogenic cycle

Articles in International JournalsThe transcription and expression patterns of Notch pathway components (Notch 1–3, Delta1 and 4, Jagged1) and effectors (Hes1, Hes2, Hes5 and Nrarp) were evaluated (through RT-PCR and IHC) in the mouse testis at key moments of post-natal development, and along the adult spermatogenic cycle. Notch pathway components and effectors are transcribed in the testis and expressed in germ, Sertoli and Leydig cells, and each Notch component shows a specific cell-type and timewindow expression pattern. This expression at key testis developmental events prompt for a role of Notch signaling in prepubertal spermatogonia quiescence, onset of spermatogenesis, and regulation of the spermatogenic cycle

Evaluation of the porous silicon capacitor as a moisture sensor for vacuum applications

A growing demand exists for inexpensive and reliable sensors for moisture detection in reduced pressure processing environments. Sandia`s Porous Silicon Capacitor (PSC) sensor appears to be an ideal candidate for this application. This sensor is a solid state device that detects moisture through changes in dielectric constant with water adsorption. Standard microelectronic fabrication techniques are used in its production affording low cost production and ready integration into complex sensor and electronic arrays. This sensor has previously been investigated for moisture detection in fluid streams, however, little effort has been placed on its behavior in a vacuum environment. Sandia`s Sensors in Vacuum (SIV) test facility has been employed to evaluate the performance characteristics of this sensor in vacuum. In addition, a vacuum-based study allows for a more controlled environment in which the intrinsic lower limit for moisture detection and response times to moisture changes can be easily determined quantitatively. This report describes the performance characteristics of a series of sensors from a single production lot. Calibration of these sensors to moisture levels from part per billion to part per hundred concentrations has been performed. The concentration-dependent sensitivity of these sensors is documented. The response time and drift characteristics of these sensors are also discussed. The investigation of a preliminary method for increasing the recovery time of the sensor after moisture exposure is presented. The role of hydrocarbon contamination, a potential problem in some vacuum schemes, is also evaluated. Specific recommendations are made on how to implement this sensor for vacuum applications

Estrogen Receptor Alpha Is Expressed in Mesenteric Mesothelial Cells and Is Internalized in Caveolae upon Freund's Adjuvant Treatment

Transformation of epithelial cells into connective tissue cells (epithelial-mesenchymal transition, EMT) is a complex mechanism involved in tumor metastasis, and in normal embryogenesis, while type II EMT is mainly associated with inflammatory events and tissue regenaration. In this study we examined type II EMT at the ultrastructural and molecular level during the inflammatory process induced by Freund's adjuvant treatment in rat mesenteric mesothelial cells. We found that upon the inflammatory stimulus mesothelial cells lost contact with the basal lamina and with each other, and were transformed into spindle-shaped cells. These morphological changes were accompanied by release of interleukins IL-1alpha, -1beta and IL-6 and by secretion of transforming growth factor beta (TGF-beta) into the peritoneal cavity. Mesothelial cells also expressed estrogen receptor alpha (ER-alpha) as shown by immunolabeling at the light and electron microscopical levels, as well as by quantitative RT-PCR. The mRNA level of ER-alpha showed an inverse correlation with the secretion of TGF-beta. At the cellular and subcellular levels ER-alpha was colocalized with the coat protein caveolin-1 and was found in the plasma membrane of mesothelial cells, in caveolae close to multivesicular bodies (MVBs) or in the membrane of these organelles, suggesting that ER-alpha is internalized via caveola-mediated endocytosis during inflammation. We found asymmetric, thickened, electron dense areas on the limiting membrane of MVBs (MVB plaques) indicating that these sites may serve as platforms for collecting and organizing regulatory proteins. Our morphological observations and biochemical data can contribute to form a potential model whereby ER-alpha and its caveola-mediated endocytosis might play role in TGF-beta induced type II EMT in vivo

Evolution of project planning tools in a matrix organization

Until recently, the Corporate Construction Program at Sandia was experiencing difficulties in managing projects: poor planning and cost estimating caused schedule and budget problems. The first step taken was a Microsoft {reg_sign} Project schedule that provides a standard template for scheduling individual construction projects. It is broken down according to the life cycle of the project and prevents the project team from leaving out an important item. A WBS (work breakdown structure) dictionary was also developed that describes how capital and operating funds are used to develop, design, construct, equip, and manage projects. We also developed a matrix chart that maps the planning guide against the major types of construction projects at Sandia. The guide, dictionary, and matrix chart offer enough flexibility that the project manager can make choices about how to structure work, yet ensure that all work rolls up to the cost categories and key DOE WBS elements. As requirements change, the tools can be updated; they also serve as training tools for new project team members

Extreme water levels, waves and coastal impacts during a severe tropical cyclone in northeastern Australia: a case study for cross-sector data sharing

Severe tropical cyclone (TC) Debbie made landfall on the northern Queensland coast of Australia on 27 March 2017 after crossing the Great Barrier Reef as a slow-moving Category 4 system. Groups from industry, government and academia collected coastal hazard and impact data before, during and after the event and shared these data to produce a holistic picture of TC Debbie at the coast. Results showed the still water level exceeded the highest astronomical tide by almost a metre. Waves added a further 16&thinsp;% to water levels along the open coast, and were probably unprecedented for this area since monitoring began. In most places, coastal barriers were not breached and as a result there was net offshore sand transport. If landfall had occurred 2&thinsp;h earlier with the high tide, widespread inundation and overwash would have ensued. This paper provides a case study of effective cross-sector data sharing in a natural hazard context. It advocates for a shared information platform for coastal extremes in Australia to help improve the understanding and prediction of TC-related coastal hazards in the future.</p

Down-Regulation of GEP100 Causes Increase in E-Cadherin Levels and Inhibits Pancreatic Cancer Cell Invasion

AIMS: Invasion and metastasis are major reasons for pancreatic cancer death and identifying signaling molecules that are specifically used in tumor invasion is of great significance. The purpose of this study was to elucidate the role of GEP100 in pancreatic cancer cell invasion and metastasis and the corresponding molecular mechanism. METHODS: Stable cell lines with GEP100 knocked-down were established by transfecting GEP100 shRNA vector into PaTu8988 cells and selected by puromycin. qRT-PCR and Western blot were performed to detect gene expression. Matrigel-invasion assay was used to detect cancer cell invasion in vitro. Liver metastasis in vivo was determined by splenic injection of indicated cell lines followed by spleen resection. Immunofluorescence study was used to detect the intracellular localization of E-cadherin. RESULTS: We found that the expression level of GEP100 protein was closely related to the invasive ability of a panel of 6 different human pancreatic cancer cell lines. Down-regulation of GEP100 in PaTu8988 cells significantly decreased invasive activity by Matrigel invasion assay, without affecting migration, invasion and viability. The inhibited invasive activity was rescued by over-expression of GEP100 cDNA. In vivo study showed that liver metastasis was significantly decreased in the PaTu8988 cells with GEP100 stably knocked-down. In addition, an epithelial-like morphological change, mimicking a mesenchymal to epithelial transition (MET) was induced by GEP100 down-regulation. The expression of E-cadherin protein was increased 2-3 folds accompanied by its redistribution to the cell-cell contacts, while no obvious changes were observed for E-cadherin mRNA. Unexpectedly, the mRNA of Slug was increased by GEP100 knock-down. CONCLUSION: These findings provided important evidence that GEP100 plays a significant role in pancreatic cancer invasion through regulating the expression of E-cadherin and the process of MET, indicating the possibility of it becoming a potential therapeutic target against pancreatic cancer