Global self-excited oscillations in a two-dimensional heated jet : a numerical simulation

The aim of this work was to develop a numerical methodology to gain insight in the low-density jet behaviour with a nonlinear approach. Numerical simulations are shown to differentiate convective and absolute instability regimes and to capture a self-excited global mode in an open flow : the 2D hot jet. The first part is devoted to numerical methodology and its validation on this unsteady problem which is known to be noise sensitive. The second part presents numerical results. They confirm theoretical and experimental results on the development of self-exited global oscillations of the jet column when the density ratio is lower than its critical value. The global mode and its associated Hopf bifurcation are identified

Unraveling the regulation of mTORC2 using logical modeling

Background The mammalian target of rapamycin (mTOR) is a regulator of cell proliferation, cell growth and apoptosis working through two distinct complexes: mTORC1 and mTORC2. Although much is known about the activation and inactivation of mTORC1, the processes controlling mTORC2 remain poorly characterized. Experimental and modeling studies have attempted to explain the regulation of mTORC2 but have yielded several conflicting hypotheses. More specifically, the Phosphoinositide 3-kinase (PI3K) pathway was shown to be involved in this process, but the identity of the kinase interacting with and regulating mTORC2 remains to be determined (Cybulski and Hall, Trends Biochem Sci 34:620-7, 2009). Method We performed a literature search and identified 5 published hypotheses describing mTORC2 regulation. Based on these hypotheses, we built logical models, not only for each single hypothesis but also for all combinations and possible mechanisms among them. Based on data provided by the original studies, a systematic analysis of all models was performed. Results We were able to find models that account for experimental observations from every original study, but do not require all 5 hypotheses to be implemented. Surprisingly, all hypotheses were in agreement with all tested data gathered from the different studies and PI3K was identified as an essential regulator of mTORC2. Conclusion The results and additional data suggest that more than one regulator is necessary to explain the behavior of mTORC2. Finally, this study proposes a new experiment to validate mTORC1 as second essential regulator

Zielgene der RAS-Onkoprotein-abhängigen Signaltransduktion

Die Entstehung und Progression maligner Tumoren ist ein mehrstufiger Prozeß, der auf einer Vielzahl genetischer Alterationen beruht. Essentielle Schritte sind die Aktivierung von Proto-Onkogenen und die Inaktivierung von Tumor-Suppressorgenen. Infolge dessen können die Zellen unabhängig von externen Wachstumssignalen ungebremst proliferieren, die Apoptose wird gehemmt, die Angiogenese wird aktiviert, und es kommt schließlich zur Metastasierung. Zu den bekanntesten Proto-Onkogenen, die in humanen Tumoren aktiviert werden, gehören die RAS Gene. Sie sind in einer Vielzahl von Tumoren mutiert und führen zu einer Stimulation der Proliferation. Um den Einfluß aktivierter RAS Onkogene auf die Regulation der Genexpression zu untersuchen wurden Genexpressionsprofile in Zellkultur-Modellen und humanen Tumoren erstellt. In einem Fibroblasten- und einem Epithelzell-basierten System konnten mehrere hundert, RAS-abhängig differenziell exprimierte Genen identifiziert werden. Aufgrund der bekannten Funktionen ihrer Genprodukte spielen sie eine wichtige Rolle im Verlust der Zellzyklus-Kontrolle, der Kontrolle der Signalübertragung, in der Angiogenese-Induktion sowie in der Invasion und damit Metastasierung. Die Zusammenhänge zwischen der Aktivierung bestimmter Signalkaskaden wie z.B. Raf-Mek-Erk oder PI-3K und der Expression von definierten Genmustern wurden hergestellt. Weiterhin konnte mit Hilfe von Microarray Analysen eine Vielzahl potentieller Tumormarker und Zielgene für therapeutische Intervention im Ovarialkarzinom identifiziert werden. Die Rolle der KlasseII Tumorsuppressor Gene Caveolin-1 und H-REV107-1 in humanen Ovarialkarzinomen wurde detailliert untersucht und ihre Rolle in der Regulation des Zellüberlebens nachgewiesen. Caveolin-1, ein negativer Regulator der RAS-abhängigen Signalübertragung, wird in über 80% der untersuchten humanen Ovarialkarzinome gehemmt. Hierbei spielen epigenetische Mechanismen eine Rolle, die jedoch nicht Caveolin-1 selbst, sondern einen unbekannten Regulator des Caveolin-1 Gens betreffen. Das H-REV107-1 Gen, ein Wachstumsregulator mit unbekannter Funktion wird in ca. 50% der untersuchten Ovarialkarzinome nicht mehr exprimiert. Ähnlich wie bei Caveolin-1, führt eine gezielte Expression des Gens in Tumorzellen zur Apoptose. Die Suche nach Interaktionspartnern des H-REV107-1 Gens führte zur Identifizierung der ubiquitär exprimierten Phosphatase2A (PP2A). Die Bindung zwischen H-REV107-1 und PP2A wurde weiter charakterisiert und ihre Rolle in der H-REV107-1 vermittelten Apoptose analysiert.Development and progression of human tumours is a multistep process depending on numerous genetic alterations. Essentiell steps herein are the mutational activation of oncogenes and the inactivation of tumour suppressor genes. As a result of these alterations, the cells acquire the potential of unlimited growth independent of external growth factor signals, apoptosis is diminished, angiogenesis is stimulated and finally metastasis can occur. Among the best known proto-oncogenes, mutated in a number of human tumours, are the RAS genes. To investigate the role of RAS oncogenes in transformation-related transcriptional alterations, expressionsprofiling was performed from cell culture models and human tumours. Several hundred genes were identified to be de-regulated in a RAS-dependent manner in a fibroblast and an epithelial cell-based model. The protein products encoded by these genes play important roles in the loss of cell cycle control, control of signal transduction, angiogenesis induction as well as invasion and metastasis. Groups of de-regulated genes could be assigned to distinct signaling pathways such as the Raf-Mek-Erk or the PI-3 kinase dependent pathways. In addition, a number of potential tumour markers and potential target structures for therapeutic intervention were identified in ovarian carcinomas with the help of microarray studies. The role of the class II tumor suppressor genes Caveolin-1 and H-REV107-1 in human ovarian carcinomas was further investigated and their role in the regulation of cell survival was demonstrated. Caveolin-1, a negative regulator of RAS-dependent signal transduction, is supressed in more than 80% of the ovarian carcinomas analysed. This suppression is mediated by epigenetic mechanisms which due not target Caveolin-1 itself but an unknown regulator of the Caveolin-1 gene. The H-Rev107-1 gene, a growth regulator with unknown function, is no longer expressed in nearly 50% of the ovarian carcinomas analysed. Similar to Caveolin-1, also re-expression of H-REV107-1 results in apoptosis in the tumour cells. The search for proteins interacting with H-REV107-1 led to the identification of the ubiquitously expressed phosphatase 2A (PP2A). The interaction between H-REV107-1 and PP2A was further characterised and its role in the H-REV107-1 mediated apoptosis investigated

Evaluating Uncertainty in Signaling Networks Using Logical Modeling

Systems biology studies the structure and dynamics of biological systems using mathematical approaches. Bottom-up approaches create models from prior knowledge but usually cannot cope with uncertainty, whereas top-down approaches infer models directly from data using statistical methods but mostly neglect valuable known information from former studies. Here, we want to present a workflow that includes prior knowledge while allowing for uncertainty in the modeling process. We build not one but all possible models that arise from the uncertainty using logical modeling and subsequently filter for those models in agreement with data in a top-down manner. This approach enables us to investigate new and more complex biological research questions, however, the encoding in such a framework is often not obvious and thus not easily accessible for researcher from life sciences. To mitigate this problem, we formulate a pipeline with specific templates to address some research questions common in signaling network analysis. To illustrate the potential of this approach, we applied the pipeline to growth factor signaling processes in two renal cancer cell lines. These two cell lines originate from similar tissue, but surprisingly showed a very different behavior toward the cancer drug Sorafenib. Thus our aim was to explore differences between these cell lines regarding three sources of uncertainty in one analysis: possible targets of Sorafenib, crosstalk between involved pathways, and the effect of a mutation in mammalian target of Rapamycin (mTOR) in one of the cell lines. We were able to show that the model pools from the cell lines are disjoint, thus the discrepancies in behavior originate from differences in the cellular wiring. Also the mutation in mTOR is not affecting its activity in the pathway. The results on Sorafenib, while not fully clarifying the mechanisms involved, illustrate the potential of this analysis for generating new hypotheses.Peer Reviewe

Jämför- och referensvärden från Svenskt Elfiskeregister

Rapporten utgörs av en mängd tabellerade jämför- och referensvärden, från elfiskeundersökningar spridda över landet åren 2008-2015. Materialet har delats in efter avrinningsområdets storlek, geografisk region samt typ av öringpopulation (strömlevande, insjövandrande, havsvandrande) eller laxpopulation (insjövandrande (Vänern) eller havsvandrande). Förslag ges (avsnitt 4) på hur man kan använda detta referensmaterial för att jämföra med sina egna elfiskeundersökningar. De tätheter som anges utgör beräknade tätheter från elfisken utförda i de olika regionerna, det vill säga fältdata korrigerade för fångsteffektivitet genom antingen upprepade utfisken eller skattade fångsteffektiviteter. Tätheterna visar inte på beräknad potential/produktion vid opåverkade förhållanden. Jämförvärdena och referensvärdena ger en jämförelse med motsvarande vatten idag, med den status de för tillfället har

Contrasting long-term trends in juvenile abundance of a widespread cold-water salmonid along a latitudinal gradient: effects of climate, stream size and migration strategy

A changing climate reshapes the range distribution of many organisms, and species with relatively low thermal optima, like many salmonids, are increasingly expected to face local population extinctions at lower latitudes. Understanding where and how fast these changes are happening is of pivotal importance for successful mitigation and conservation efforts.We used an extensive electrofishing database to explore temporal trends of juveniles of brown trout Salmo trutta in 218 locations from 174 Swedish streams, over the last 30 years (1991-2020). We hypothesized that 1) declines in abundance have occurred predominately in the warmer, southern regions, while increases have occurred in the colder, northern regions, 2) larger stream sizes may partly offset negative effects of climate, and 3) migrating and resident populations are affected differently by a warming climate.We found that abundance of brown trout juveniles generally declined in warmer regions especially in smaller streams (<= 6 m wide), while the abundance increased in colder regions. In larger streams, negative effects of higher temperatures were seemingly buffered, as we found lower rates of decline or even positive trends. The rate of change (i.e. the slopes of the trends in abundance) was more pronounced towards the climate extremes, and was on average zero in regions with a normal annual air temperature (average temperature over 30 year period) around 5-6 degrees C. Warmer climate had stronger effects on migrating compared to resident populations, suggesting that climate-induced loss of stream connectivity could be an additional factor that hinders recruitment in anadromous populations in a changing climate.Considering predictions of increasing temperatures and frequency of summer droughts, management of cold-water salmonid populations should focus on conserving and restoring riparian vegetation, wetlands, climate and thermal refugia, and habitat integrity overall. Such measures may, however, not suffice for small streams at lower latitudes, unless hydrological connectivity is maintained

Contrasting long-term trends in juvenile abundance of a widespread cold-water salmonid along a latitudinal gradient: effects of climate, stream size and migration strategy

A changing climate reshapes the range distribution of many organisms, and species with relatively low thermal optima, like many salmonids, are increasingly expected to face local population extinctions at lower latitudes. Understanding where and how fast these changes are happening is of pivotal importance for successful mitigation and conservation efforts. We used an extensive electrofishing database to explore temporal trends of juveniles of brown trout Salmo trutta in 218 locations from 174 Swedish streams, over the last 30 years (1991–2020). We hypothesized that 1) declines in abundance have occurred predominately in the warmer, southern regions, while increases have occurred in the colder, northern regions, 2) larger stream sizes may partly offset negative effects of climate, and 3) migrating and resident populations are affected differently by a warming climate. We found that abundance of brown trout juveniles generally declined in warmer regions especially in smaller streams (≤ 6 m wide), while the abundance increased in colder regions. In larger streams, negative effects of higher temperatures were seemingly buffered, as we found lower rates of decline or even positive trends. The rate of change (i.e. the slopes of the trends in abundance) was more pronounced towards the climate extremes, and was on average zero in regions with a normal annual air temperature (average temperature over 30 year period) around 5–6 °C. Warmer climate had stronger effects on migrating compared to resident populations, suggesting that climate-induced loss of stream connectivity could be an additional factor that hinders recruitment in anadromous populations in a changing climate. Considering predictions of increasing temperatures and frequency of summer droughts, management of cold-water salmonid populations should focus on conserving and restoring riparian vegetation, wetlands, climate and thermal refugia, and habitat integrity overall. Such measures may, however, not suffice for small streams at lower latitudes, unless hydrological connectivity is maintained.publishedVersio

Effects of RAF inhibitors on PI3K/AKT signalling depend on mutational status of the RAS/RAF signalling axis

Targeted therapies within the RAS/RAF/MEK/ERK signalling axis become increasingly popular, yet cross-talk and feedbacks in the signalling network lead to unexpected effects. Here we look systematically into how inhibiting RAF and MEK with clinically relevant inhibitors result in changes in PI3K/AKT activation. We measure the signalling response using a bead-based ELISA, and use a panel of three cell lines, and isogenic cell lines that express mutant forms of the oncogenes KRAS and BRAF to interrogate the effects of the MEK and RAF inhibitors on signalling. We find that treatment with the RAF inhibitors have opposing effects on AKT phosphorylation depending on the mutational status of two important oncogenes, KRAS and BRAF. If these two genes are in wildtype configuration, RAF inhibitors reduce AKT phosphorylation. In contrast, if BRAF or KRAS are mutant, RAF inhibitors will leave AKT phosphorylation unaffected or lead to an increase of AKT phosphorylation. Down-regulation of phospho-AKT by RAF inhibitors also extends to downstream transcription factors, and correlates with apoptosis induction. Our results show that oncogenes rewire signalling such that targeted therapies can have opposing effects on parallel pathways, which depend on the mutational status of the cell