ГЕОХИМИЧЕСКИЕ МЕТКИ СОВМЕСТНОЙ СТРУКТУРНО-ВЕЩЕСТВЕННОЙ ЭВОЛЮЦИИ ЧЕХЛА И ФУНДАМЕНТА (СВЕКОФЕННИДЫ СЕВЕРНОГО ПРИЛАДОЖЬЯ, РОССИЯ)

Detailed studies of the deeply metamorphosed Early Precambrian rocks of the Northern Ladoga region allowed us to distinguish three deformation stages of the Svecofennian tectogenesis during which there occurred significant structural and compositional transformations of the "cover (Paleoproterozoic) – basement (Archean)" system. In addition to the structural-paragenetic analysis, which allowed to allocate transversal structural paragenesis in both floors, there are some other opportunities in the recognition of their-hosted granitoid veined bodies with a positive Eu anomaly. The rock varieties with this anomaly are always high in barium and do not show a direct correlation between the Eu anomaly and (La/Yb)n, Ca and Sr. This is contrary to the ideas about the occurrence of a positive Eu anomaly due to the substitution of divalent strontium by Eu++ and suggests that the formation of such rocks took place under the influence of deep reduced fluids. It was found that granitoids with a positive Eu anomaly were formed during the first and last stages of the structure evolution, with a predominance of brittle deformations and a deep-reduced fluid breakthrough. At the second stage, with the dominant manifestation of plastic deformations, when such fluids could be "blocked" within the system, there was a formation of granitoids with low barium concentrations and a negative Eu anomaly.Детальные исследования глубокометаморфизованных раннедокембрийских пород Северного Приладожья позволили выделить три этапа деформаций эпохи свекофеннского тектогенеза, в ходе которых произошли существенные структурно-вещественные преобразования системы «чехол (палеопротерозой) – фундамент (архей)». Помимо проведенного структурно-парагенетического анализа, позволившего выделять «сквозные» структурные парагенезы в обоих этажах, дополнительные возможности открываются при выделении вписанных в них гранитоидных жильных образований c выявленной положительной Eu-аномалией. Разности, имеющие эту аномалию, всегда обогащены барием и не показывают прямую корреляцию величины Eu-аномалии с (La/Yb)n, Ca и Sr. Это противоречит представлениям о причинах появления положительной Eu-аномалии за счет замещения двухвалентного стронция Eu++ и позволяет предположить, что формирование подобных пород происходило под влиянием глубинных восстановленных флюидов. Установлено, что гранитоиды с положительной Eu-аномалией формировались на первом и заключительном этапах эволюции структуры, когда преобладали хрупкие деформации и происходил прорыв глубинных восстановленных флюидов. На втором этапе, с доминирующим проявлением пластических деформаций, когда могла происходить «закупорка» таких флюидов внутри системы, формировались гранитоиды с низкими концентрациями бария и отрицательной Eu-аномалией

The Central-Bank Balance Sheet as an Instrument of Monetary Policy

While many analyses of monetary policy consider only a target for a short-term nominal interest rate, other dimensions of policy have recently been of greater importance: changes in the supply of bank reserves, changes in the assets acquired by central banks, and changes in the interest rate paid on reserves. We extend a standard New Keynesian model to allow a role for the central bank's balance sheet in equilibrium determination, and consider the connections between these alternative dimensions of policy and traditional interest-rate policy. We distinguish between "quantitative easing" in the strict sense and targeted asset purchases by a central bank, and argue that while the former is likely be ineffective at all times, the latter dimension of policy can be effective when financial markets are sufficiently disrupted. Neither is a perfect substitute for conventional interest-rate policy, but purchases of illiquid assets are particularly likely to improve welfare when the zero lower bound on the policy rate is reached. We also consider optimal policy with regard to the payment of interest on reserves; in our model, this requires that the interest rate on reserves be kept near the target for the policy rate at all times

Heparan Sulfate Proteoglycans Mediate Interstitial Flow Mechanotransduction Regulating MMP-13 Expression and Cell Motility via FAK-ERK in 3D Collagen

Interstitial flow directly affects cells that reside in tissues and regulates tissue physiology and pathology by modulating important cellular processes including proliferation, differentiation, and migration. However, the structures that cells utilize to sense interstitial flow in a 3-dimensional (3D) environment have not yet been elucidated. Previously, we have shown that interstitial flow upregulates matrix metalloproteinase (MMP) expression in rat vascular smooth muscle cells (SMCs) and fibroblasts/myofibroblasts via activation of an ERK1/2-c-Jun pathway, which in turn promotes cell migration in collagen. Herein, we focused on uncovering the flow-induced mechanotransduction mechanism in 3D.Cleavage of rat vascular SMC surface glycocalyx heparan sulfate (HS) chains from proteoglycan (PG) core proteins by heparinase or disruption of HS biosynthesis by silencing N-deacetylase/N-sulfotransferase 1 (NDST1) suppressed interstitial flow-induced ERK1/2 activation, interstitial collagenase (MMP-13) expression, and SMC motility in 3D collagen. Inhibition or knockdown of focal adhesion kinase (FAK) also attenuated or blocked flow-induced ERK1/2 activation, MMP-13 expression, and cell motility. Interstitial flow induced FAK phosphorylation at Tyr925, and this activation was blocked when heparan sulfate proteoglycans (HSPGs) were disrupted. These data suggest that HSPGs mediate interstitial flow-induced mechanotransduction through FAK-ERK. In addition, we show that integrins are crucial for mechanotransduction through HSPGs as they mediate cell spreading and maintain cytoskeletal rigidity.We propose a conceptual mechanotransduction model wherein cell surface glycocalyx HSPGs, in the presence of integrin-mediated cell-matrix adhesions and cytoskeleton organization, sense interstitial flow and activate the FAK-ERK signaling axis, leading to upregulation of MMP expression and cell motility in 3D. This is the first study to describe a flow-induced mechanotransduction mechanism via HSPG-mediated FAK activation in 3D. This study will be of interest in understanding the flow-related mechanobiology in vascular lesion formation, tissue morphogenesis, cancer cell metastasis, and stem cell differentiation in 3D, and also has implications in tissue engineering

Specific Syndecan-1 Domains Regulate Mesenchymal Tumor Cell Adhesion, Motility and Migration

Malignant mesothelioma is an asbestos induced cancer that is difficult to diagnose. Several studies have combined biomarkers to improve mesothelioma diagnosis, but with moderate success, and there is a need for new mesothelioma biomarkers. The tumour is often resistant to treatment and most patients will survive less than a year. An indicator of patient survival is the tumours growth pattern, which in turn is influenced by expressed proteoglycans. In this thesis work, we aim to improve the possibilities to diagnose malignant mesothelioma by combining biomarkers and by identifying new ones. We also investigate tumour driving mechanisms with focus on one of these suggested biomarkers, the cell-bound proteoglycan syndecan-1. We were able to construct a diagnostic two-step model based on biomarkers in patient material. By implementing a cut-off level and thereafter focusing on unresolved patients we combined hyaluronan and N-ERC/mesothelin (paper I), which significantly increased the diagnostic accuracy for malignant mesothelioma. To further improve diagnosis, we used mass spectrometry to find new biomarkers. We identified and validated galectin-1, which was excellent in discriminating mesotheliomas from adenocarcinomas (paper II). In the same study, we were also the first to describe aldo-keto reductase 1B10 as a novel prognostic mesothelioma biomarker. Syndecan-1 has been indicated as a marker for carcinomas. In paper I we describe how higher levels of syndecan-1 indicate the presence of a carcinoma over a mesothelioma. This was verified in paper II when syndecan-1 was identified as downregulated in fluids from mesothelioma patients compared to lung cancer patients. Paper III and paper IV focus on this proteoglycan. Malignant cell lines transfected with syndecan-1 and various truncated forms of syndecan-1 affected adhesion and migration, which are key features of cancer invasion (paper III). The results showed a domain- and cell type specific effect on the cells’ motility. Regulating syndecan-1 levels and analysing the global gene expression of mesothelioma cells made it evident that this proteoglycan has a strong influence on transforming growth factor β signalling and several growth factor pathways (paper IV). Links to cell migration and proliferation were furthermore identified, along with glycosaminoglycan modifying enzymes. These results can shed light on the complex role of syndecan-1 in invasion and growth of malignant mesenchymal cells. Taken together, this thesis work describes a complement to conventional mesothelioma diagnosis and identifies novel biomarkers. Furthermore, the potential biomarker syndecan-1 was shown to have an effect on cell motility and proliferation. These results increase our understanding of this aggressive malignancy