Potential of demand response for chlor-alkali electrolysis processes

Chlor-alkali electrolysis indicates significant demand response potential, accounting for over 2% of Germany’s total elec-tricity demand. To fully analyze this potential, digital models or digital twins are necessary. In this study, we use the IRPopt modeling framework to develop a digital model of an electrolysis process and examine the cost-optimal load shifting application in the day-ahead spot and balancing reserve market for various price scenarios (2019, 2030, 2040). We also investigate the associated CO2 emissions. Combined optimization at both markets results in greater and more robust cost savings of 16.1% but cannibalizes the savings that are possible through optimization separately at each market. In future scenarios, the shares of savings from spot and reserve market could potentially reverse. CO2 savings between 2.5% and 9.2% appear only through optimization at the spot market and could even turn negative if optimized solely at the reserve market

Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development

Background: CHD8 haploinsufficiency causes autism and macrocephaly with high penetrance in the human population. Chd8 heterozygous mice exhibit relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. The purpose of this study was to generate new, sub-haploinsufficient Chd8 mouse models to allow us to identify and study the functions of CHD8 during embryonic cortical development. Methods: To examine the possibility that certain phenotypes may only appear at sub-heterozygous Chd8 levels in the mouse, we created an allelic series of Chd8-deficient mice to reduce CHD8 protein levels to approximately 35% (mild hypomorph), 10% (severe hypomorph) and 0% (neural-specific conditional knockout) of wildtype levels. We used RNA sequencing to compare transcriptional dysregulation, structural MRI and brain weight to investigate effects on brain size, and cell proliferation, differentiation and apoptosis markers in immunostaining assays to quantify changes in neural progenitor fate. Results: Mild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia than heterozygotes. Over 2000 genes were dysregulated in mild hypomorphs, including autism-associated neurodevelopmental and cell cycle genes. We identify increased proliferation of non-ventricular zone TBR2+ intermediate progenitors as one potential cause of brain hyperplasia in these mutants. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, including evidence for p53 pathway upregulation. In contrast to mild hypomorphs, these mice displayed reduced brain size and increased apoptosis in the embryonic neocortex. Homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in pronounced brain hypoplasia, partly caused by p53 target gene derepression and apoptosis in the embryonic neocortex. Limitations Our findings identify an important role for the autism-associated factor CHD8 in controlling the proliferation of intermediate progenitors in the mouse neocortex. We propose that CHD8 has a similar function in human brain development, but studies on human cells are required to confirm this. Because many of our mouse mutants with reduced CHD8 function die shortly after birth, it is not possible to fully determine to what extent reduced CHD8 function results in autism-associated behaviours in mice. Conclusions: Together, these findings identify important, dosage-sensitive functions for CHD8 in p53 pathway repression, neurodevelopmental gene expression and neural progenitor fate in the embryonic neocortex. We conclude that brain development is acutely sensitive to reduced CHD8 expression and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage result in non-linear effects on gene transcription and brain growth. Shaun Hurley, Conor Mohan and Philipp Suetterlin have contributed equally to this work

Metabolic biomarker signature to differentiate pancreatic ductal adenocarcinoma from chronic pancreatitis

Objective Current non-invasive diagnostic tests can distinguish between pancreatic cancer (pancreatic ductal adenocarcinoma (PDAC)) and chronic pancreatitis (CP) in only about two thirds of patients. We have searched for blood-derived metabolite biomarkers for this diagnostic purpose. Design For a case-control study in three tertiary referral centres, 914 subjects were prospectively recruited with PDAC (n=271), CP (n=282), liver cirrhosis (n=100) or healthy as well as non-pancreatic disease controls (n=261) in three consecutive studies. Metabolomic profiles of plasma and serum samples were generated from 477 metabolites identified by gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry. Results A biomarker signature (nine metabolites and additionally CA19-9) was identified for the differential diagnosis between PDAC and CP. The biomarker signature distinguished PDAC from CP in the training set with an area under the curve (AUC) of 0.96 (95% CI 0.93-0.98). The biomarker signature cut-off of 0.384 at 85% fixed specificity showed a sensitivity of 94.9% (95% CI 87.0%-97.0%). In the test set, an AUC of 0.94 (95% CI 0.91-0.97) and, using the same cut-off, a sensitivity of 89.9% (95% CI 81.0%-95.5%) and a specificity of 91.3% (95% CI 82.8%-96.4%) were achieved, successfully validating the biomarker signature. Conclusions In patients with CP with an increased risk for pancreatic cancer (cumulative incidence 1.95%), the performance of this biomarker signature results in a negative predictive value of 99.9% (95% CI 99.7%-99.9%) (training set) and 99.8% (95% CI 99.6%-99.9%) (test set). In one third of our patients, the clinical use of this biomarker signature would have improved diagnosis and treatment stratification in comparison to CA19-9

Causa Simulata – Gesetzesumgehungen als Scheingeschäft

Gesetzesumgehungen werden von der herrschenden Ansicht unter dem deutschen Recht regelmäßig nicht als Scheingeschäft eingeordnet: Ein Umgehungsgeschäft sei in seinen intendierten Rechtsfolgen ernstgemeint, womit § 117 BGB keine Anwendung fände. Philipp Lerch stellt dieses Dogma in Frage. Insbesondere wird die Lehre von der Causa (Rechtsgrund) als qualifikationsentscheidendes, historisch gewachsenes Kriterium in ihrer historischen Dimension herausgearbeitet. Die Besonderheit von Umgehungskonstellationen wird in der Dissimulation einer rein fiktiven Causa gegenüber dem wirklich verfolgten Geschäftszweck identifiziert. Hierzu untersucht der Autor insbesondere die Rechtsnatur der Causa. Er kommt zu dem Schluss, dass eine solche Umgehungssituation rechtssystematisch mittels einer Anwendung der Lehre von der Simulation zu fassen ist. Hierdurch wird eine rechtliche Qualifikation erzwungen, die das dem geschäftlich verfolgten Zweck angemessene Normenregime Anwendung finden lässt.»Causa Simulata. Artificial Transactions as a Sham«: In cases of evasion of legal statutes, German scholars as well as the judiciary are opposing the idea of the transaction to be a sham. This doctrine is questioned by Philipp Lerch: What constitutes an evading transaction, was its sham regarding the ›Causa‹. Its transactional purpose was merely fake. The author therefore concludes that the doctrine of sham (Simulation, Scheingeschäft) under German law was to be applied under these circumstances

Das Grossherzogliche Hof-Opern-Theater : Grund- und Aufrisse der merkwürdigsten Gebäude der Residenz Darmstadt für Liebhaber der Bauwissenschaften besonders für Architekten und Bauhandwerker : erstes Heft

von Philipp Lerch und Georg Ritterkeine weiteren Hefte erschiene

Functional conformational motions in the turnover cycle of cholesterol oxidase

Reexamining experimental data of single-molecule fluorescence correlation spectroscopy for cholesterol oxidase, we find that the existing Michaelis–Menten models with dynamical disorder cannot explain strong correlations between subsequent turnover cycles revealed in the diagonal feature in the joint statistical distribution of adjacent “on” times of this enzyme. We suggest that functional conformational motions representing ordered sequences of transitions between a set of conformational substates are involved, along with equilibrium conformational fluctuations in the turnover cycle of cholesterol oxidase. A two-channel model of single-enzyme dynamics, including a slow functional conformational motion in one of the channels, is proposed that allows us to reproduce such strong correlations

Statistical tools for the detection of memory and conformational motions in single-enzyme kinetics

We have systematically applied the statistical methods memory landscape and difference distribution of on-times to five models of cholesterol oxidase. The memory landscape expresses the deviation from the Markov assumption. The difference distribution of on-times gives the non-Markovian part of the joint probability distribution of adjacent on-times. Both statistical tools allow an easy discrimination among the models, and therefore provide an answer to the question whether functional conformational motions are present in the turnover cycle of the enzyme. These statistical methods can be applied to any time series data from single-enzyme experiments

Mutual synchronization of molecular turnover cycles in allosteric enzymes III. Intramolecular cooperativity

In small micrometer volumes typical of living cells, regulatory molecules of enzymic reactions can diffuse so fast from one enzyme molecule to another that the diffusion time is much shorter than the turnover time of an enzyme. Under these conditions, a special kinetic regime of a molecular network is realized. We consider molecular networks formed by allosteric enzymes with several functional subunits, interactions between which are described by a sequential model of Koshland et al. with heterotropic or homotropic (positive and negative) cooperativities. Simple product-activated and product-inhibited reactions are investigated. We show that allosteric cross-molecular regulation and intramolecular cooperativity result in the development of coherent dynamics of enzyme molecules in such networks. Intermolecular synchronization of turnover cycles of different enzymes is accompanied by intramolecular synchronization of the dynamics of subunits belonging to the same molecules. Strong intramolecular correlations persist even at high intensity of thermal molecular fluctuations, when intermolecular synchronization is already absent

Hardening Javas Access Control by Abolishing Implicit Privilege Elevation

While the Java runtime is installed on billions of devices and servers worldwide, it remains a primary attack vector for online criminals. As recent studies show, the majority of all exploited Java vulnerabilities comprise incorrect or insufficient implementations of access-control checks. This paper for the first time studies the problem in depth. As we find, attacks are enabled by shortcuts that short-circuit Java's general principle of stack-based access control. These shortcuts, originally introduced for ease of use and to improve performance, cause Java to elevate the privileges of code implicitly. As we show, this creates many pitfalls for software maintenance, making it all too easy for maintainers of the runtime to introduce blatant confused-deputy vulnerabilities even by just appl ying normally semantics-preserving refactorings. How can this problem be solved? Can one implement Java's access control without shortcuts, and if so, does this implementation remain usable and efficient? To answer those questions, we conducted a tool-assisted adaptation of the Java Class Library (JCL), avoiding (most) shortcuts and therefore moving to a fully explicit model of privilege elevation. As we show, the proposed changes significantly harden the JCL against attacks: they effectively hinder the introduction of new confused-deputy vulnerabilities in future library versions, and successfully restrict the capabilities of attackers when exploiting certain existing vulnerabilities. We discuss usability considerations, and through a set of large-scale experiments show that with current JVM technology such a faithful implementation of stack-based access control induces no observable performance loss