Induction Mapping of the 3D-Modulated Spin Texture of Skyrmions in Thin Helimagnets

Envisaged applications of skyrmions in magnetic memory and logic devices crucially depend on the stability and mobility of these topologically non-trivial magnetic textures in thin films. We present for the first time quantitative maps of the magnetic induction that provide evidence for a 3D modulation of the skyrmionic spin texture. The projected in-plane magnetic induction maps as determined from in-line and off-axis electron holography carry the clear signature of Bloch skyrmions. However, the magnitude of this induction is much smaller than the values expected for homogeneous Bloch skyrmions that extend throughout the thickness of the film. This finding can only be understood, if the underlying spin textures are modulated along the out-of-plane z direction. The projection of (the in-plane magnetic induction of) helices is further found to exhibit thickness-dependent lateral shifts, which show that this z modulation is accompanied by an (in-plane) modulation along the x and y directions

Demographische Entwicklung im Freistaat Sachsen: Analyse und Strategien zum Bevölkerungsrückgang auf dem Arbeitsmarkt. Gutachten im Auftrag der Sächsischen Staatskanzlei

Die Studie geht in zwei Schritten vor: Im ersten Teil werden die Konsequenzen des Bevölkerungswandels auf den Arbeitsmarkt in Sachsen aufgezeigt. Für diesen Zweck wird ein Referenzszenario des sächsischen Arbeitsmarktes bis 2020 entwickelt. Es zeigt sich, dass sich die Arbeitsmärkte je nach Qualifikation der Arbeitskräfte sehr unterschiedlich entwickeln. Ohne Gegenmaßnahmen können hoch qualifizierte Arbeitskräfte schon in wenigen Jahren zum knappen Faktor werden, der die Wachstumschancen im Freistaat restringiert. Für die gering qualifizierten Arbeitskräfte ist durch den demographischen Wandel jedoch auch auf lange Sicht keine Entspannung zu erkennen.Der zweite Teil der Studie nimmt die Nachwuchslücke bei qualifizierten Arbeitskräften zum Ausgangspunkt und entwickelt mögliche Gegenstrategien und Anpassungsmaßnahmen für die Landespolitik. Die Studie identifiziert drei Felder, auf denen die Landesregierung aktiv werden kann und soll: Zuwanderung, Erwerbsbeteiligung und Humankapitalbildung. Die Untersuchung quantifiziert auch – so weit möglich – die einzelnen Politikmaßnahmen. Während die Neuausrichtung der Zuwanderungspolitik und die Aktivierung von Erwerbspotenzial kurz- und mittelfristig Wirkung zeigen, ist die Bildung von neuem Humankapital als eher langfristige Strategie angelegt. Zusammen können diese Antwortstrategien helfen, die Ausstattung Sachsens mit der knappen Ressource Humankapital langfristig zu sichern. Ein innovativer Standort mit hoch qualifizierten Arbeitskräften schafft auch Nachfrage nach gering qualifizierten Arbeitskräften. Angesichts der hohen Arbeitslosigkeit bei Geringqualifizierten, die auch durch den demographischen Wandel nicht wesentlich abgebaut wird, ist allerdings eine tief greifende Reform des Niedriglohnsektors unumgänglich

Overexpression of Hepatocyte Chemerin-156 Lowers Tumor Burden in a Murine Model of Diethylnitrosamine-Induced Hepatocellular Carcinoma

The tumor inhibitory potential of the highly active chemerin-156 isoform was described in orthotopic models of hepatocellular carcinoma (HCC). The majority of HCC arises in the fibrotic liver, which was not reproduced in these studies. Here, a potential therapeutic activity of chemerin-156 was evaluated in diethylnitrosamine (DEN)-induced liver cancer, which mimics fibrosis-associated HCC. Mice were infected with adeno-associated virus (AAV) six months after DEN injection to overexpress chemerin-156 in the liver, and animals injected with non-recombinant-AAV served as controls. Three months later, the animals were killed. Both groups were comparable with regard to liver steatosis and fibrosis. Of note, the number of very small tumors was reduced by chemerin-156. Anyhow, the expression of inflammatory and profibrotic genes was similar in larger tumors of control and chemerin-156-AAV-infected animals. Although genes with a role in lipid metabolism, like 3-hydroxy-3-methylglutaryl-coenzym-A--reductase, were overexpressed in tumors of animals with high chemerin-156, total hepatic cholesterol, diacylglycerol and triglyceride levels, and distribution of individual lipid species were normal. Chemerin-156-AAV-infected mice had elevated hepatic and systemic chemerin. Ex vivo activation of the chemerin receptor chemokine-like receptor 1 increased in parallel with serum chemerin, illustrating the biological activity of the recombinant protein. In the tumors, chemerin-155 was the most abundant variant. Chemerin-156 was not detected in tumors of the controls and was hardly found in chemerin-156-AAV infected animals. In conclusion, the present study showed that chemerin-156 overexpression caused a decline in the number of small lesions but did not prevent the growth of pre-existing neoplasms

XTraQue: traceability for product line systems

Product line engineering has been increasingly used to support the development and deployment of software systems that share a common set of features and are developed based on the reuse of core assets. The large number and heterogeneity of documents generated during the development of product line systems may cause difficulties to identify common and variable aspects among applications, and to reuse core assets that are available under the product line. In this paper, we present a traceability approach for product line systems. Traceability has been recognised as an important task in in software system development. Traceability relations can improve the quality of the product being developed and reduce development time and cost. We present a rule-based approach to support automatic generation of traceability relations between feature-based object-oriented documents. The traceability rules used in our work are classified into two groups namely (a) direct rules, which support the creation of traceability relations that do not depend on the existence of other relations, and (b) indirect rules, which require the existence of previously generated relations. The documents are represented in XML and the rules are represented in an extension of XQuery. A prototype tool called XTraQue has been implemented. This tool, together with a mobile phone product line case study, has been used to demonstrate and evaluate our work in various experiments. The results of these experiments are encouraging and comparable with other approaches that support automatic generation of traceability relations

Accumulation of cholesterol, triglycerides and ceramides in hepatocellular carcinomas of diethylnitrosamine injected mice

Background Dysregulated lipid metabolism is critically involved in the development of hepatocellular carcinoma (HCC). The respective metabolic pathways affected in HCC can be identified using suitable experimental models. Mice injected with diethylnitrosamine (DEN) and fed a normal chow develop HCC. For the analysis of the pathophysiology of HCC in this model a comprehensive lipidomic analysis was performed. Methods Lipids were measured in tumor and non-tumorous tissues by direct flow injection analysis. Proteins with a role in lipid metabolism were analysed by immunoblot. Mann-Whitney U-test or paired Student´s t-test were used for data analysis. Results Intra-tumor lipid deposition is a characteristic of HCCs, and di- and triglycerides accumulated in the tumor tissues of the mice. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha, lipoprotein lipase and hepatic lipase protein were low in the tumors whereas proteins involved in de novo lipogenesis were not changed. Higher rates of de novo lipogenesis cause a shift towards saturated acyl chains, which did not occur in the murine HCC model. Besides, LDL-receptor protein and cholesteryl ester levels were higher in the murine HCC tissues. Ceramides are cytotoxic lipids and are low in human HCCs. Notably, ceramide levels increased in the murine tumors, and the simultaneous decline of sphingomyelins suggests that sphingomyelinases were involved herein. DEN is well described to induce the tumor suppressor protein p53 in the liver, and p53 was additionally upregulated in the tumors. Conclusions Ceramides mediate the anti-cancer effects of different chemotherapeutic drugs and restoration of ceramide levels was effective against HCC. High ceramide levels in the tumors makes the DEN injected mice an unsuitable model to study therapies targeting ceramide metabolism. This model is useful for investigating how tumors evade the cytotoxic effects of ceramides

Short-term functional adaptation of aquaporin-1 surface expression in the proximal tubule, a component of glomerulotubular balance

Transepithelial water flow across the renal proximal tubule is mediated predominantly by aquaporin-1 (AQP1). Along this nephron segment, luminal delivery and transepithelial reabsorption are directly coupled, a phenomenon called glomerulotubular balance. We hypothesized that the surface expression of AQP1 is regulated by fluid shear stress, contributing to this effect. Consistent with this finding, we found that the abundance of AQP1 in brush border apical and basolateral membranes was augmented >2-fold by increasing luminal perfusion rates in isolated, microperfused proximal tubules for 15 minutes. Mouse kidneys with diminished endocytosis caused by a conditional deletion of megalin or the chloride channel ClC-5 had constitutively enhanced AQP1 abundance in the proximal tubule brush border membrane. In AQP1-transfected, cultured proximal tubule cells, fluid shear stress or the addition of cyclic nucleotides enhanced AQP1 surface expression and concomitantly diminished its ubiquitination. These effects were also associated with an elevated osmotic water permeability. In sum, we have shown that luminal surface expression of AQP1 in the proximal tubule brush border membrane is regulated in response to flow. Cellular trafficking, endocytosis, an intact endosomal compartment, and controlled protein stability are the likely prerequisites for AQP1 activation by enhanced tubular fluid shear stress, serving to maintain glomerulotubular balance

Hepatocyte expressed chemerin-156 does not protect from experimental non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is a rapidly growing liver disease. The chemoattractant chemerin is abundant in hepatocytes, and hepatocyte expressed prochemerin protected from NASH. Prochemerin is inactive and different active isoforms have been described. Here, the effect of hepatocyte expressed muChem-156, a highly active murine chemerin isoform, was studied in the methionine-choline deficient dietary model of NASH. Mice overexpressing muChem-156 had higher hepatic chemerin protein. Serum chemerin levels and the capability of serum to activate the chemerin receptors was unchanged showing that the liver did not release active chemerin. Notably, activation of the chemerin receptors by hepatic vein blood did not increase in parallel to total chemerin protein in patients with liver cirrhosis. In experimental NASH, muChem-156 had no effect on liver lipids. Accordingly, overexpression of active chemerin in hepatocytes or treatment of hepatocytes with recombinant chemerin did not affect cellular triglyceride and cholesterol levels. Importantly, overexpression of muChem-156 in the murine liver did not change the hepatic expression of inflammatory and profibrotic genes. The downstream targets of chemerin such as p38 kinase were neither activated in the liver of muChem-156 producing mice nor in HepG2, Huh7 and Hepa1-6 cells overexpressing this isoform. Recombinant chemerin had no effect on global gene expression of primary human hepatocytes and hepatic stellate cells within 24 h of incubation. Phosphorylation of p38 kinase was, however, increased upon short-time incubation of HepG2 cells with chemerin. These findings show that muChem-156 overexpression in hepatocytes does not protect from liver steatosis and inflammation

Collaborative and competitive strategies in the variability and resiliency of large-scale societies in Mesoamerica

Examinations of the variation and duration of past large-scale societies have long involved a conceptual struggle between efforts at generalization and the unraveling of specific trajectories. Although historical particulars are critical to understanding individual cases, there exist both scientific and policy rationales for drawing broader implications regarding the growing corpus of cross-cultural data germane to understanding variability in the constitution of human societies, past and present. Archaeologists have recently paid increased attention to successes and failures in communal-resource management over the long term, as articulated by the transdisciplinary theory on cooperation and collective action. In this article, we consider frameworks that have been traditionally employed in studies of the rise, diversity, and fall of large-scale preindustrial aggregations. We suggest that a comparative theoretical perspective that foregrounds collective-action problems, unaligned individual and group interests, and the social mechanisms that promote or hamper cooperation advances our understanding of variability in these early cooperative arrangements. We apply such a perspective to an examination of cities from pre-Columbian Mesoamerica to demonstrate tendencies for more collective systems to be larger and longer lasting than less collective ones, likely reflecting greater resiliency in the face of the ecological and cultural perturbations specific to the region and era

Melatonin Acts as an Antidepressant by Inhibition of the Acid Sphingomyelinase/Ceramide System

Background: Melatonin has been shown to have antidepressive effects. We tested whether melatonin inhibits the acid sphingomyelinase/ceramide system and mediates its antidepressive effects via inhibition of the acid sphingomyelinase and a reduction of ceramide in the hippocampus. Antidepressants such as amitriptyline and fluoxetine were previously shown to inhibit the acid sphingomyelinase/ceramide system, which mediates neurogenesis and behavioral changes induced by these drugs. Methods: The effect of melatonin on the activity of the acid sphingomyelinase prior to and after treatment with melatonin was determined in cultured neurons and in vivo in the hippocampus of mice by measuring the consumption of [14C] sphingomyelin. Ceramide was measured by DAG kinase assay and fluorescence microscopy of the hippocampus and of cultured neurons. Neurogenesis in the hippocampus was analyzed by in vivo labeling with bromodeoxyuridine. Behavior was assessed in standardized tests. Results: Melatonin treatment inhibited acid sphingomyelinase in vitro in cultured pheochromocytoma cells and in vivo in the hippocampus, which resulted in a reduction of ceramide in vitro and in vivo. The inhibition of the acid sphingomyelinase/ceramide system translated into increased neurogenesis in glucocorticosterone-stressed mice after treatment with melatonin, an effect that is abrogated in acid sphingomyelinase-deficient mice. Likewise, melatonin improved the depressive behavior of stressed mice, a therapeutic effect that was again absent in acid sphingomyelinase-deficient animals. Conclusion: These data indicate that the antidepressive effects of melatonin as well as the induction of neurogenesis triggered by this drug are mediated by an inhibition of the acid sphingomyelinase/ceramide system. This is the first study to identify melatonin as an inhibitor of the acid sphingomyelinase

Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics.

Mutations in the nuclear-encoded mitochondrial maintenance gene RRM2B are an important cause of familial mitochondrial disease in both adults and children and represent the third most common cause of multiple mitochondrial DNA deletions in adults, following POLG [polymerase (DNA directed), gamma] and PEO1 (now called C10ORF2, encoding the Twinkle helicase) mutations. However, the clinico-pathological and molecular features of adults with RRM2B-related disease have not been clearly defined. In this multicentre study of 26 adult patients from 22 independent families, including five additional cases published in the literature, we show that extra-ocular neurological complications are common in adults with genetically confirmed RRM2B mutations. We also demonstrate a clear correlation between the clinical phenotype and the underlying genetic defect. Myopathy was a prominent manifestation, followed by bulbar dysfunction and fatigue. Sensorineural hearing loss and gastrointestinal disturbance were also important findings. Severe multisystem neurological disease was associated with recessively inherited compound heterozygous mutations with a mean age of disease onset at 7 years. Dominantly inherited heterozygous mutations were associated with a milder predominantly myopathic phenotype with a later mean age of disease onset at 46 years. Skeletal muscle biopsies revealed subsarcolemmal accumulation of mitochondria and/or cytochrome c oxidase-deficient fibres. Multiple mitochondrial DNA deletions were universally present in patients who underwent a muscle biopsy. We identified 18 different heterozygous RRM2B mutations within our cohort of patients, including five novel mutations that have not previously been reported. Despite marked clinical overlap between the mitochondrial maintenance genes, key clinical features such as bulbar dysfunction, hearing loss and gastrointestinal disturbance should help prioritize genetic testing towards RRM2B analysis, and sequencing of the gene may preclude performance of a muscle biopsy