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BACKGROUND: Micro-RNAs (miRNA) are attributed to the systems biological role of a regulatory mechanism of the expression of protein coding genes. Research has identified miRNAs dysregulations in several but distinct pathophysiological processes, which hints at distinct systems-biology functions of miRNAs. The present analysis approached the role of miRNAs from a genomics perspective and assessed the biological roles of 2954 genes and 788 human miRNAs, which can be considered to interact, based on empirical evidence and computational predictions of miRNA versus gene interactions.
RESULTS: From a genomics perspective, the biological processes in which the genes that are influenced by miRNAs are involved comprise of six major topics comprising biological regulation, cellular metabolism, information processing, development, gene expression and tissue homeostasis. The usage of this knowledge as a guidance for further research is sketched for two genetically defined functional areas: cell death and gene expression. Results suggest that the latter points to a fundamental role of miRNAs consisting of hyper-regulation of gene expression, i.e., the control of the expression of such genes which control specifically the expression of genes.
CONCLUSIONS: Laboratory research identified contributions of miRNA regulation to several distinct biological processes. The present analysis transferred this knowledge to a systems-biology level. A comprehensible and precise description of the biological processes in which the genes that are influenced by miRNAs are notably involved could be made. This knowledge can be employed to guide future research concerning the biological role of miRNA (dys-) regulations. The analysis also suggests that miRNAs especially control the expression of genes that control the expression of genes.
Background: In addition to controlled post-translational modifications proteins can be modified with highly reactive compounds. Usually this leads to a compromised functionality of the protein. Methylglyoxal is one of the most common agents that attack arginine residues. Methylglyoxal is also regarded as a pro-oxidant that affects cellular redox homeostasis by contributing to the formation of reactive oxygen species. Antioxidant enzymes like catalase are required to protect the cell from oxidative damage. These enzymes are also targets for methylglyoxal-mediated modification which could severely affect their catalytic activity in breaking down reactive oxygen species to less reactive or inert compounds.
Results: Here, bovine liver catalase was incubated with high levels of methylglyoxal to induce its glycation. This treatment did not lead to a pronounced reduction of enzymatic activity. Subsequently methylglyoxal-mediated arginine modifications (hydroimidazolone and dihydroxyimidazolidine) were quantitatively analysed by sensitive nano high performance liquid chromatography/electron spray ionisation/tandem mass spectrometry. Whereas several arginine residues displayed low to moderate levels of glycation (e.g., Arg93, Arg365, Arg444) Arg354 in the active centre of catalase was never found to be modified.
Conclusions: Bovine liver catalase is able to tolerate very high levels of the modifying α-oxoaldehyde methylglyoxal so that its essential enzymatic function is not impaired.
Electronic supplementary material: The online version of this article (doi:10.1186/s13104-015-1793-5) contains supplementary material, which is available to authorized users.
Mitochondrial complex I (NADH:ubiquinone oxidoreductase) is a key enzyme in cellular energy metabolism and provides approximately 40% of the proton-motive force that is utilized during mitochondrial ATP production. The dysregulation of complex I function--either genetically, pharmacologically, or metabolically induced--has severe pathophysiological consequences that often involve an imbalance in the production of reactive oxygen species (ROS). Slow transition of the active (A) enzyme to the deactive, dormant (D) form takes place during ischemia in metabolically active organs such as the heart and brain. The reactivation of complex I occurs upon reoxygenation of ischemic tissue, a process that is usually accompanied by an increase in cellular ROS production. Complex I in the D-form serves as a protective mechanism preventing the oxidative burst upon reperfusion. Conversely, however, the D-form is more vulnerable to oxidative/nitrosative damage. Understanding the so-called active/deactive (A/D) transition may contribute to the development of new therapeutic interventions for conditions like stroke, cardiac infarction, and other ischemia-associated pathologies. In this review, we summarize current knowledge on the mechanism of A/D transition of mitochondrial complex I considering recently available structural data and site-specific labeling experiments. In addition, this review discusses in detail the impact of the A/D transition on ROS production by complex I and the S-nitrosation of a critical cysteine residue of subunit ND3 as a strategy to prevent oxidative damage and tissue damage during ischemia-reperfusion injury. This article is part of a Special Issue entitled Respiratory complex I, edited by Volker Zickermann and Ulrich Brandt.
Biomass burning impacts vegetation dynamics, biogeochemical cycling, atmospheric chemistry, and climate, with sometimes deleterious socio-economic impacts. Under future climate projections it is often expected that the risk of wildfires will increase. Our ability to predict the magnitude and geographic pattern of future fire impacts rests on our ability to model fire regimes, either using well-founded empirical relationships or process-based models with good predictive skill. A large variety of models exist today and it is still unclear which type of model or degree of complexity is required to model fire adequately at regional to global scales. This is the central question underpinning the creation of the Fire Model Intercomparison Project - FireMIP, an international project to compare and evaluate existing global fire models against benchmark data sets for present-day and historical conditions. In this paper we summarise the current state-of-the-art in fire regime modelling and model evaluation, and outline what lessons may be learned from FireMIP.
Vimentin is currently used to differentiate between malignant renal carcinomas and benign oncocytomas. Recent reports showing Vimentin positive oncocytomas seriously question the validity of this present diagnostic approach. Vimentin 3 is a spliced variant and ends with a unique C-terminal ending after exon 7 which differentiates it from the full length version that has 9 exons. Therefore, the protein size is different; the full length Vimentin version has a protein size of ~57 kDa and the truncated version of ~47 kDa. We designed an antibody, called Vim3, against the unique C-terminal ending of the Vimentin 3 variant. Using immune histology, immune fluorescence, Western blot, and qRT-PCR analysis, a Vim3 overexpression was detectable exclusively in oncocytoma, making the detection of Vim3 a potential specific marker for benign kidney tumors. This antibody is the first to clearly differentiate benign oncocytoma and the mimicking eosinophilic variants of the RCCs. This differentiation between malignant and benign RCCs is essential for operative planning, follow-up therapy, and patients' survival. In the future the usage of Vimentin antibodies in routine pathology has to be applied with care. Consideration must be given to Vimentin specific binding epitopes otherwise a misdiagnosis of the patients' tumor samples may result.
Since Mobile Virtual Assistants are rising in popularity and come with most new smartphones out of the box and theoretical work in the field is hard to come by, a test is in order to establish the status quo of development. We did a manual test on six different Mobile Virtual Assistants in the categories Voice Recognition, Online Search, Phone Control and Natural Conversation and the results show that Siri is currently the best Mobile Virtual Assistant on the market with a success rate of 65.8% on average over all four categories.
Electronic states with non-trivial topology host a number of novel phenomena with potential for revolutionizing information technology. The quantum anomalous Hall effect provides spin-polarized dissipation-free transport of electrons, while the quantum spin Hall effect in combination with superconductivity has been proposed as the basis for realizing decoherence-free quantum computing. We introduce a new strategy for realizing these effects, namely by hole and electron doping kagome lattice Mott insulators through, for instance, chemical substitution. As an example, we apply this new approach to the natural mineral herbertsmithite. We prove the feasibility of the proposed modifications by performing ab-initio density functional theory calculations and demonstrate the occurrence of the predicted effects using realistic models. Our results herald a new family of quantum anomalous Hall and quantum spin Hall insulators at affordable energy/temperature scales based on kagome lattices of transition metal ions.
We discuss applications of a recently developed method for model reduction based on linear response theory of weakly coupled dynamical systems. We apply the weak coupling method to simple stochastic differential equations with slow and fast degrees of freedom. The weak coupling model reduction method results in general in a non-Markovian system; we therefore discuss the Markovianization of the system to allow for straightforward numerical integration. We compare the applied method to the equations obtained through homogenization in the limit of large timescale separation between slow and fast degrees of freedom. We numerically compare the ensemble spread from a fixed initial condition, correlation functions and exit times from a domain. The weak coupling method gives more accurate results in all test cases, albeit with a higher numerical cost.
The Central Nigerian Nok Culture has been well known for its elaborate terracotta sculptures and evidence of iron metallurgy since its discovery by British archaeologist Bernard Fagg in the 1940s. With a date in the first millennium BCE, both, sculptures and ironworking, belong to the earliest of their kind in sub-Saharan Africa. After a period of destruction of Nok sites by looting, scientific research resumed in 2006, when a team of archaeologists from Goethe University in Germany started to explore different Nok Culture aspects, one of which focused on chronology. Establishing a chronology for the Nok Culture employed two approaches: a comprehensive pottery analysis based on decoration and form elements and a wealth of radiocarbon dates from a large number of excavated sites. This volume presents the radiocarbon dates and the methods, data and results of the chronological pottery analysis, conducted within the scope of a dissertation project completed in 2015. Combining the two strands of information, a chronology emerges, dividing the Nok Culture into three phases from the middle of the second millennium BCE to the last centuries BCE and defining seven pottery groups that can be arranged to some extent in a chronological order.
The degradation of cytosol-invading pathogens by autophagy, a process known as xenophagy, is an important mechanism of the innate immune system. Inside the host, Salmonella Typhimurium invades epithelial cells and resides within a specialized intracellular compartment, the Salmonella-containing vacuole. A fraction of these bacteria does not persist inside the vacuole and enters the host cytosol. Salmonella Typhimurium that invades the host cytosol becomes a target of the autophagy machinery for degradation. The xenophagy pathway has recently been discovered, and the exact molecular processes are not entirely characterized. Complete kinetic data for each molecular process is not available, so far. We developed a mathematical model of the xenophagy pathway to investigate this key defense mechanism. In this paper, we present a Petri net model of Salmonella xenophagy in epithelial cells. The model is based on functional information derived from literature data. It comprises the molecular mechanism of galectin-8-dependent and ubiquitin-dependent autophagy, including regulatory processes, like nutrient-dependent regulation of autophagy and TBK1-dependent activation of the autophagy receptor, OPTN. To model the activation of TBK1, we proposed a new mechanism of TBK1 activation, suggesting a spatial and temporal regulation of this process. Using standard Petri net analysis techniques, we found basic functional modules, which describe different pathways of the autophagic capture of Salmonella and reflect the basic dynamics of the system. To verify the model, we performed in silico knockout experiments. We introduced a new concept of knockout analysis to systematically compute and visualize the results, using an in silico knockout matrix. The results of the in silico knockout analyses were consistent with published experimental results and provide a basis for future investigations of the Salmonella xenophagy pathway.
Author Summary
Salmonellae are Gram-negative bacteria, which cause the majority of foodborne diseases worldwide. Serovars of Salmonella cause a broad range of diseases, ranging from diarrhea to typhoid fever in a variety of hosts. In the year 2010, Salmonella Typhi caused 7.6 million foodborne diseases and 52 000 deaths, and Salmonella enterica was responsible for 78.7 million diseases and 59 000 deaths. After invasion of Salmonella into host epithelial cells, a small fraction of Salmonella escapes from a specialized intracellular compartment and replicates inside the host cytosol. Xenophagy is a host defense mechanism to protect the host cell from cytosolic pathogens. Understanding how Salmonella is recognized and targeted for xenophagy is an important subject of current research. To the best of our knowledge, no mathematical model has been presented so far, describing the process of Salmonella Typhimurium xenophagy. Here, we present a manually curated and mathematically verified theoretical model of Salmonella Typhimurium xenophagy in epithelial cells, which is consistent with the current state of knowledge. Our model reproduces literature data and postulates new hypotheses for future investigations.