Taxonomic studies on adult and larval ascidians from California

The primary purpose of this research is to further morphological studies on larval ascidians and to encourage greater reliance on larval structures in ascidian taxonomy. This may necessitate some revisions in current classifications, but it is hoped that such revisions will lead to a better understanding of the group. Some general considerations of ascidians are here included for the benefit of those who may not be familiar with them. All specimens used in this study were collected at the Pacific Marine Station area at Dillon Beach, California, during June, July, and August of 1957

Hvilken betydning har kontekst i matematikkoppgaver : et studie av matematikkoppgaver i PISA-undersøkelsen

Hvilken betydning har kontekst i matematikkoppgaver? Et studie av matematikkoppgaver i PISA-undersøkelsen. Hovedoppgaven tar utgangspunkt i matematikkoppgavene fra PISA-undersøkelsen, hvor enkelte av oppgavene er svært dårlig besvart. Er det slik at norske elever er svake i matematikk, eller kan det være noe med presentasjonen av oppgavene som gjorde at de norske elevene synes oppgavene var vanskelig. I hovedoppgaven sammenlignes resultater fra PISA-undersøkelsen med en undersøkelse foretatt på 112 elever fra 10. klasse

Intracellular trafficking of FGF1 endocytosed by its four tyrosine kinase receptors

Fibroblast growth factors and the four related high-affinity, tyrosine kinase fibroblast growth factor receptors are involved in the regulation of many key cellular responses in developmental and physiological processes. Irregularities in FGF-mediated signalling are implicated in several serious disorders such as cancer and various forms of dwarfism. Little is known about the fate of endocytosed fibroblast growth factors and their receptors and the main purpose of this project is to study and compare the intracellular trafficking of the fibroblast growth factor 1 and the four related tyrosine kinase fibroblast growth factor receptors upon internalization

Landscape and Rock Art. An archaeological landscape analysis regarding the distribution of rock art in Onsøy, Fredrikstad

This study analyses and discusses the distribution and placement of Bronze Age rock art localities in Onsøy, Fredrikstad. The preliminary focus is on the rock art localities’ relationship with the surrounding landscape, and how the distribution can be understood in relevance to the social life of Onsøy’s prehistoric population. The overall premise for this thesis is that rock art has emerged in a ritual or cosmological setting. However, the intent of the study is to present a deeper understanding of how rock art also represented an active social role in the prehistoric society of Onsøy. The study takes advantage of digital methods to investigate the rock art’s placement in the landscape, including predictive modelling, viewshed analysis, and cost-affordance analysis. By adding the two latter methods in addition to reconstructing the prehistoric landscape, a post-processual landscape view will be considered, focusing on perception. The results show that Bronze Age rock art is closely connected to the prehistoric coastline and communication paths in the landscape. The results also indicate that the localities in large are placed on low occurrences of bedrock, with low visibility in the holistic landscape. Therefore, I argue that the distribution of rock art localities in Onsøy can be seen as a manifestation of social memory, social identity and transmission of knowledge connected to prehistoric communication.Arkeologi mastergradsoppgaveARK35

Expression of the FGFR2c mesenchymal splicing variant in human keratinocytes inhibits differentiation and promotes invasion

The altered isoform switching of the fibroblast growth factor receptor 2 (FGFR2) and aberrant expression of the mesenchymal FGFR2c isoform in epithelial cells is involved in cancer progression. We have recently described that the ectopic expression of FGFR2c in normal human keratinocytes induces epithelial-mesenchymal transition and leads to invasiveness and anchorage-independent growth. Here, we extended our analysis to the effects of this FGFR2c forced expression on human keratinocyte differentiation and stratification. Our findings demonstrated that, differently from cells overexpressing the epithelial splicing variant FGFR2b, keratinocytes ectopically expressing FGFR2c are not able to form a monolayer and display decreased expression of early differentiation markers. This impaired ability to enter the differentiation program is related to the up-modulation of the transcription factor ΔNp63. In addition, FGFR2c-expressing keratinocytes undergo defective stratification and invasion of the collagen matrix in 3D organotypic cultures, further suggesting their tumorigenic potential. Taken together, our results support the hypothesis that the receptor switching and the consequent appearance of the mesenchymal FGFR2c variant in the epithelial context would drive early steps of carcinogenesis, unbalancing the p63/FGFR interplay, and altering the paracrine response to the microenvironment

Myocardial oxidative stress is increased in early reperfusion, but systemic antioxidative therapy does not prevent ischemia-reperfusion arrhythmias in pigs

BackgroundArrhythmias in the early phase of reperfusion after myocardial infarction (MI) are common, and can lead to hemodynamic instability or even cardiac arrest. Reactive oxygen species (ROS) are thought to play a key role in the underlying mechanisms, but evidence from large animal models is scarce, and effects of systemic antioxidative treatment remain contentious.MethodsMI was induced in 7 male and 7 female pigs (Norwegian landrace, 35–40 kg) by clamping of the left anterior descending artery (LAD) during open thorax surgery. Ischemia was maintained for 90 min, before observation for 1 h after reperfusion. Pigs were randomized 1:1 in an operator-blinded fashion to receive either i.v. N-acetylcysteine (NAC) from 70 min of ischemia and onwards, or 0.9% NaCl as a control. Blood samples and tissue biopsies were collected at baseline, 60 min of ischemia, and 5 and 60 min of reperfusion. ECG and invasive blood pressure were monitored throughout.ResultsThe protocol was completed in 11 pigs. Oxidative stress, as indicated by immunoblotting for Malondialdehyde in myocardial biopsies, was increased at 5 min of reperfusion compared to baseline, but not at 60 min of reperfusion, and not reduced with NAC. We found no significant differences in circulating biomarkers of myocardial necrosis, nor in the incidence of idioventricular rhythm (IVR), non-sustained ventricular tachycardia (NSVT), ventricular tachycardia (VT) or ventricular fibrillation (VF) between NAC-treated and control pigs during reperfusion.ConclusionMyocardial oxidation was increased early after reperfusion in a porcine model of MI, but systemic antioxidative treatment did not protect against reperfusion arrhythmias

Fibroblast growth factor 2 conjugated with monomethyl auristatin E inhibits tumor growth in a mouse model

Worldwide, cancer is the second leading cause of death. Regardless of the continuous progress in medicine, we still do not have a fully effective anti-cancer therapy. Therefore, the search for new targeted anti-cancer drugs is still an unmet need. Here, we present novel protein–drug conjugates that inhibit tumor growth in a mouse model of human breast cancer. We developed conjugates based on fibroblast growth factor (FGF2) with improved biophysical and biological properties for the efficient killing of cancer cells overproducing fibroblast growth factor receptor 1 (FGFR1). We used hydrophilic and biocompatible PEG4 or PEG27 molecules as a spacer between FGF2 and the toxic agent monomethyl auristatin E. All conjugates exhibited a cytotoxic effect on FGFR1-positive cancer cell lines. The conjugate with the highest hydrodynamic size (42 kDa) and cytotoxicity was found to efficiently inhibit tumor growth in a mouse model of human breast cancer

Clathrin- and Dynamin-Independent Endocytosis of FGFR3 – Implications for Signalling

Endocytosis of tyrosine kinase receptors can influence both the duration and the specificity of the signal emitted. We have investigated the mechanisms of internalization of fibroblast growth factor receptor 3 (FGFR3) and compared it to that of FGFR1 which is internalized predominantly through clathrin-mediated endocytosis. Interestingly, we observed that FGFR3 was internalized at a slower rate than FGFR1 indicating that it may use a different endocytic mechanism than FGFR1. Indeed, after depletion of cells for clathrin, internalization of FGFR3 was only partly inhibited while endocytosis of FGFR1 was almost completely abolished. Similarly, expression of dominant negative mutants of dynamin resulted in partial inhibition of the endocytosis of FGFR3 whereas internalization of FGFR1 was blocked. Interfering with proposed regulators of clathrin-independent endocytosis such as Arf6, flotillin 1 and 2 and Cdc42 did not affect the endocytosis of FGFR1 or FGFR3. Furthermore, depletion of clathrin decreased the degradation of FGFR1 resulting in sustained signalling. In the case of FGFR3, both the degradation and the signalling were only slightly affected by clathrin depletion. The data indicate that clathrin-mediated endocytosis is required for efficient internalization and downregulation of FGFR1 while FGFR3, however, is internalized by both clathrin-dependent and clathrin-independent mechanisms

Phosphatidylinositol 5-phosphate 4-kinase γ (PI5P4Kγ), a lipid signalling enigma.

The phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are an important family of enzymes, whose physiological roles are being teased out by a variety of means. Phosphatidylinositol-5-phosphate 4-kinase γ (PI5P4Kγ) is especially intriguing as its in vitro activity is very low. Here we review what is known about this enzyme and discuss some recent advances towards an understanding of its physiology. Additionally, the effects of the ATP-competitive inhibitor I-OMe Tyrphostin AG-538 on all three mammalian PI5P4Ks was explored, including two PI5P4Kγ mutants with altered ATP- or PI5P-binding sites. The results suggest a strategy for targeting non-ATP binding sites on inositol lipid kinases.We are very grateful to Dr A. Vandewalle (INSERM U773, Paris, France) for provision of the mpkCCD cell line. M.-L.G. was supported by the BBSRC (Grant RG65394) and J.H.C by the MRC (Grant RG64071).This is the final version of the article. It was first available from Elsevier via http://dx.doi.org/10.1016/j.jbior.2015.11.00

Strategies to inhibit FGFR4 V550L-driven rhabdomyosarcoma

Background: Rhabdomyosarcoma (RMS) is a paediatric cancer driven either by fusion proteins (e.g., PAX3-FOXO1) or by mutations in key signalling molecules (e.g., RAS or FGFR4). Despite the latter providing opportunities for precision medicine approaches in RMS, there are currently no such treatments implemented in the clinic. Methods: We evaluated biologic properties and targeting strategies for the FGFR4 V550L activating mutation in RMS559 cells, which have a high allelic fraction of this mutation and are oncogenically dependent on FGFR4 signalling. Signalling and trafficking of FGFR4 V550L were characterised by confocal microscopy and proteomics. Drug effects were determined by live-cell imaging, MTS assay, and in a mouse model. Results: Among recently developed FGFR4-specific inhibitors, FGF401 inhibited FGFR4 V550L-dependent signalling and cell proliferation at low nanomolar concentrations. Two other FGFR4 inhibitors, BLU9931 and H3B6527, lacked potent activity against FGFR4 V550L. Alternate targeting strategies were identified by RMS559 phosphoproteomic analyses, demonstrating that RAS/MAPK and PI3K/AKT are essential druggable pathways downstream of FGFR4 V550L. Furthermore, we found that FGFR4 V550L is HSP90- dependent, and HSP90 inhibitors efficiently impeded RMS559 proliferation. In a RMS559 mouse xenograft model, the pan-FGFR inhibitor, LY2874455, did not efficiently inhibit growth, whereas FGF401 potently abrogated growth. Conclusions: Our results pave the way for precision medicine approaches against FGFR4 V550L-driven RMS