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This paper studies the valuation of insurance contracts linked to financial markets, for example through interest rates or in equity-linked insurance products. We build upon the concept of insurance-finance arbitrage as introduced by Artzner et al. (Math Financ, 2024), extending their work by incorporating model uncertainty. This is achieved by introducing statistical uncertainty in the underlying dynamics to be represented by a set of priors P. Within this framework we propose the notion of robust asymptotic insurance-finance arbitrage(RIFA) and characterize the absence of such strategies in terms of the new concept of QP-evaluations. This nonlinear two-step evaluation ensures absence of RIFA. Moreover, it dominates all two-step evaluations, as long as we agree on the set of priors P. Our analysis highlights the role of QP-evaluations in terms of showing that all two-step evaluations are free of RIFA. Furthermore, we introduce a doubly stochastic model to address uncertainty for surrender and survival, utilizing copulas to define conditional dependence. This setting illustrates how the QP-evaluation can be applied for the pricing of hybrid insurance products, highlighting the flexibility and potential of the proposed approach.

The number of applications of self-assembled deoxyribonucleic acid (DNA) origami nanoparticles (DNA NPs) has increased drastically, following the development of a variety of single-stranded template DNA (ssDNA) that can serve as the scaffold strand. In addition to viral genomes, such as M13 bacteriophage and lambda DNAs, enzymatically produced ssDNA from various template sources is rapidly gaining traction and being applied as the scaffold for DNA NP preparation. However, separating fully formed DNA NPs that have custom scaffolds from crude assembly mixes is often a multistep process of first separating the ssDNA scaffold from its enzymatic amplification process and then isolating the assembled DNA NPs from excess precursor strands. Only then is the DNA NP sample ready for downstream characterization and application. In this work, we highlight a single-step purification of custom sequence- or M13-derived scaffold-based DNA NPs using photocleavable biotin tethers. The process only requires an inexpensive ultraviolet (UV) lamp, and DNA NPs with up to 90% yield and high purity are obtained. We show the versatility of the process in separating two multihelix bundle structures and a wireframe polyhedral architecture.

Supplemental Digital Content is Available in the Text.Hacke, C, Knuth, J, Bucher, M, Weisser, B, and Schmidt, T. CORE-CERT items as a minimal requirement for replicability of exercise interventions: results from application to exercise studies for breast cancer patients. J Strength Cond Res37(5): e346–e360, 2023—Exercise interventions have been demonstrated to be useful in the prevention and therapy for multiple different diseases. The Consensus on Exercise Reporting Template (CERT) has been developed as the reporting guideline for exercise studies. The main goals of CERT are to ensure completeness of reporting, to enable interpretation of exercise programs, and to allow extraction of data for meta-analyses and the development of guidelines. However, for clinicians, the most important aspect of good reporting might be the replicability of protocols for their patients. This study was designed to determine the core components of exercise interventions for breast cancer, which are considered as minimal requirement for replicability in practice. The original items of CERT were specified, subdivided, or extended by additional key items to develop a “CORE-CERT checklist.” The original CERT and our CORE-CERT were then applied to 29 exercise RCTs for breast cancer obtained from the most frequently cited and most recent meta-analyses in current guidelines. The reporting quality using both templates were examined. Mean original CERT score was 11 of 19 (59%) of completed items and 13 of 19 (68%) of reporting completeness for CORE-CERT. Reporting quality using CORE-CERT items was approximately 8% higher, indicating a more precise description of items in CORE-CERT. Differences concerned exercise dosage, nonexercise components, supervision, and description of each exercise. We propose a novel CORE-CERT guideline necessary for the replicability of exercise interventions in clinical practice. The application of CORE-CERT demonstrated a slightly better but still insufficient reporting quality of exercise interventions for breast cancer.

The DNA origami technique allows the precise synthesis of complex, biocompatible nanomaterials containing small molecules, biomolecules, and inorganic nanoparticles. The negatively charged phosphates in the backbone make DNA highly water-soluble and require salts to shield its electrostatic repulsion. DNA origamis are therefore not soluble in most organic solvents. While this is not problematic for applications in biochemistry, biophysics, or nanomedicine, other potential applications, processes, and substrates are incompatible with saline solutions, which include the synthesis of many nanomaterials, and reactions in templated synthesis, the operation of nanoelectronic devices, or semiconductor fabrication. To overcome this limitation, we coated DNA origami with amphiphilic poly(ethylene glycol) polylysine block copolymers and transferred them into various organic solvents including chloroform, dichloromethane, acetone, or 1-propanol. Our approach maintains the shape of the nanostructures and protects functional elements bound to the structure, such as fluorophores, gold nanoparticles, or proteins. The DNA origami polyplex micellization (DOPM) strategy hence enables solubilization or a phase transfer of complex structures into various organic solvents, which significantly expands the use of DNA origami for a range of potential applications and technical processes.

Electrical double-layer capacitance (CDL) measurements are among the key experiments in physical electrochemistry aimed to understand the properties of electrified solid/liquid interfaces. CDLserves as a critical parameter for developing physical models of electrochemical interfaces. Palladium (Pd) electrodes are among the most widely used functional materials in many applications, including (electro)catalysis. In this work, we report on double-layer capacitances of the basal plane Pd(111), Pd(100), and Pd(110) electrodes in aqueous HClO4electrolytes measured using electrochemical impedance spectroscopy. Importantly, we find that the CDLvalues estimated at the minima of the capacitance vs electrode potential curves can be correlated with the density-functional-theory (DFT)-calculated adsorption energies for water molecules and the coordination of electrode surface atoms. Our results thus suggest that it might be possible to find simple descriptors of the electrical double layer (EDL) analogous to those used for functional electrode materials. Taken together, such descriptors could be employed for efficient high-throughput screening of various electrode/electrolyte interfaces, such as in supercapacitor and electrocatalytic systems.

Byline: Thorsten. Schmidt, Marion. van Mackelenbergh, Daniela. Wesch, Christoph. Mundhenke It has been suggested that physical activity in breast cancer patients can not only improve quality of life. Influences on [...]

Machado-Joseph disease (MJD) is a fatal neurodegenerative disorder clinically characterized by prominent ataxia. It is caused by an expansion of a CAG trinucleotide in ATXN3, translating into an expanded polyglutamine (polyQ) tract in the ATXN3 protein, that becomes prone to misfolding and aggregation. The pathogenesis of the disease has been associated with the dysfunction of several cellular mechanisms, including autophagy and transcription regulation. In this study, we investigated the transcriptional modifications of the autophagy pathway in models of MJD and assessed whether modulating the levels of the affected autophagy-associated transcripts (AATs) would alleviate MJD-associated pathology. Our results show that autophagy is impaired at the transcriptional level in MJD, affecting multiple AATs, including Unc-51 like autophagy activating kinase 1 and 2 (ULK1 and ULK2), two homologs involved in autophagy induction. Reinstating ULK1/2 levels by adeno-associated virus (AAV)-mediated gene transfer significantly improved motor performance while preventing neuropathology in two in vivomodels of MJD. Moreover, in vitrostudies showed that the observed positive effects may be mainly attributed to ULK1 activity. This study provides strong evidence of the beneficial effect of overexpression of ULKhomologs, suggesting these as promising instruments for the treatment of MJD and other neurodegenerative disorders.

Die Beherrschung von Fertigungszeitspreizung bei gleichzeitiger Steigerung des Nutzungsgrades und die Einhaltung der Reihenfolge sind die Gestaltungsmerkmale eines Montagesystems für kundenindividuelle Produkte bei Großserienfertigung. Deren Umsetzung leistet einen wichtigen Beitrag in der Strategie eines Premium-Automobilunternehmens. In diesem Beitrag wird das Fließsystem gegen ein Montagesystem mit Standarbeitsplätzen ersetzt. Mit den erarbeiteten Sensitivitätsgraphen gelingt eine kritische Diskussion der möglichen strukturellen Anordnungen des Montagesystems bei hoher Qualität der eingangs formulierten Gestaltungsmerkmale.

Designing efficient electrocatalytic structures requires reliable guidelines. For this purpose, experimental approaches for the characterization of model electrodes in operandoconditions are valuable. Reporting in Joule, Agnoli et al. showcase the determination of site-specific reaction onset potentials and Tafel slopes by using electrochemical scanning tunneling microscopy.

In this paper, we develop a novel methodology for estimationof risk capital allocation. The methodology is rooted in the theory of risk measures. We work within a general, but tractable class of law-invariant coherent risk measures, with a particular focus on expected shortfall. We introduce the concept of faircapital allocations and provide explicit formulae for fair capital allocations in case when the constituents of the risky portfolio are jointly normally distributed. The main focus of the paper is on the problem of approximating fair portfolio allocations in the case of not fully known law of the portfolio constituents. We define and study the concepts of fair allocation estimators and asymptotically fair allocation estimators. A substantial part of our study is devoted to the problem of estimating fair risk allocations for expected shortfall. We study this problem under normality as well as in a nonparametric setup. We derive several estimators, and prove their fairness and/or asymptotic fairness. Last, but not least, we propose two backtesting methodologies that are oriented at assessing the performance of the allocation estimation procedure. The paper closes with a substantial numerical study of the subject and an application to market data.

ABSTRACTThe neonatal Fc receptor (FcRn) promotes antibody recycling through rescue from normal lysosomal degradation. The binding interaction is pH-dependent with high affinity at low pH, but not under physiological pH conditions. Here, we combined rational design and saturation mutagenesis to generate novel antibody variants with prolonged half-life and acceptable development profiles. First, a panel of saturation point mutations was created at 11 key FcRn-interacting sites on the Fc region of an antibody. Multiple variants with slower FcRn dissociation kinetics than the wildtype (WT) antibody at pH 6.0 were successfully identified. The mutations were further combined and characterized for pH-dependent FcRn binding properties, thermal stability and the FcγRIIIa and rheumatoid factor binding. The most promising variants, YD (M252Y/T256D), DQ (T256D/T307Q) and DW (T256D/T307W), exhibited significantly improved binding to FcRn at pH 6.0 and retained similar binding properties as WT at pH 7.4. The pharmacokinetics in human FcRn transgenic mice and cynomolgus monkeys demonstrated that these properties translated to significantly prolonged plasma elimination half-life compared to the WT control. The novel variants exhibited thermal stability and binding to FcγRIIIa in the range comparable to clinically validated YTE and LS variants, and showed no enhanced binding to rheumatoid factor compared to the WT control. These engineered Fc mutants are promising new variants that are widely applicable to therapeutic antibodies, to extend their circulation half-life with obvious benefits of increased efficacy, and reduced dose and administration frequency.

Supplemental Digital Content is available in the text.Nuclear localization of ataxin-3 plays a fundamental role in seeding aggregation and the pathology of spinocerebellar ataxia type 3 (SCA3). However, very few compounds that are able to modulate the nuclear transport of ataxin-3 have been identified. In our previous study, we found that divalproex sodium (DVS) reduced heat shock-induced nuclear localization of ataxin-3. However, the mechanism of DVS in the translocation of ataxin-3 still remains unknown. There is accumulating evidence that importins are regulated by acetylation, and histone deacetylase inhibitors can interrupt this process. With this in mind, we used cells coexpressing ataxin-3 and importin α1 (encoded by KNPA2) to probe whether ataxin-3 is the shuttling cargo of importins and whether DVS plays a role in the nuclear transport of ataxin-3 through the transport protein pathway. Here, we reported that importin α1 enhanced nuclear amount of ataxin-3 and increased the aggregate formation and that DVS restored it to the normal level. Importantly, ataxin-3 is shown to directly bind to importin α1. Moreover, DVS modulated the function of importin α1 likely by altering its localization. We believe that this study provides a proof of principle for addressing the mechanism of DVS and furthers our understanding of the role of importins in the nuclear accumulation of ataxin-3 in SCA3.

The field of structural DNA nanotechnology offers a wide range of design strategies with which to build structures with a desired aspect ratio, size, and shape. Compared with traditional close-packed DNA structures, triangulated wireframe structures require less material per surface or volume unit and improve the stability in biologically relevant conditions due to the reduced electrostatic repulsion. Herein, we expand the design space of the DNA single-stranded tile method to cover a range of anisotropic, finite, triangulated wireframe structures as well as a number of one-dimensional crystalline assemblies. These structures are composed of six-arm junctions with a single double helix as connecting edges that assemble in physiologically relevant salinities. For a reliable folding of the structures, single-stranded spacers 2–4 nucleotides long have to be introduced in the junction connecting neighboring arms. Coarse-grained molecular dynamics simulations using the oxDNA model suggests that the spacers prevent the stacking of DNA helices, thereby facilitating the assembly of planar geometries.

Surface enhanced Raman spectroscopy (SERS) measurements are conventionally performed using assemblies of metal nanostructures on a macro- to micro-sized substrate or by dispersing colloidal metal nanoparticles directly onto the sample of interest. Despite intense use, these methods allow neither the removal of the nanoparticles after a measurement nor a defined confinement of the SERS measurement position. So far, tip enhanced Raman spectroscopy is still the key technique in this regard but not adequate for various samples mainly due to diminished signal enhancement compared to other techniques, poor device fabrication reproducibility, and cumbersome experimental setup requirements. Here, we demonstrate that a rational combination of only four gold nanoparticles (AuNPs) on a DNA origami template, and single silicon nanowires (SiNWs) yield functional optical amplifier nanoprobes for SERS. These nanoscale SERS devices offer a spatial resolution below the diffraction limit of light and still a high electric field intensity enhancement factor (EF) of about 105despite of miniaturization.

Plasmonic waveguides consisting of metal nanoparticle chains can localize and guide light well below the diffraction limit, but high propagation losses due to lithography-limited large interparticle spacing have impeded practical applications. Here, we demonstrate that DNA-origami-based self-assembly of monocrystalline gold nanoparticles allows the interparticle spacing to be decreased to ∼2 nm, thus reducing propagation losses to 0.8 dB per 50 nm at a deep subwavelength confinement of 62 nm (∼λ/10). We characterize the individual waveguides with nanometer-scale resolution by electron energy-loss spectroscopy. Light propagation toward a fluorescent nanodiamond is directly visualized by cathodoluminescence imaging spectroscopy on a single-device level, thereby realizing nanoscale light manipulation and energy conversion. Simulations suggest that longitudinal plasmon modes arising from the narrow gaps are responsible for the efficient waveguiding. With this scalable DNA origami approach, micrometer-long propagation lengths could be achieved, enabling applications in information technology, sensing, and quantum optics.

The programmability of DNA enables constructing nanostructures with almost any arbitrary shape, which can be decorated with many functional materials. Moreover, dynamic structures can be realized such as molecular motors and walkers. In this work, we have explored the possibility to synthesize the complementary sequences to single-stranded gap regions in the DNA origami scaffold cost effectively by a DNA polymerase rather than by a DNA synthesizer. For this purpose, four different wireframe DNA origami structures were designed to have single-stranded gap regions. This reduced the number of staple strands needed to determine the shape and size of the final structure after gap filling. For this, several DNA polymerases and single-stranded binding (SSB) proteins were tested, with T4 DNA polymerase being the best fit. The structures could be folded in as little as 6 min, and the subsequent optimized gap-filling reaction was completed in less than 3 min. The introduction of flexible gap regions results in fully collapsed or partially bent structures due to entropic spring effects. Finally, we demonstrated structural transformations of such deformed wireframe DNA origami structures with DNA polymerases including the expansion of collapsed structures and the straightening of curved tubes. We anticipate that this approach will become a powerful tool to build DNA wireframe structures more material-efficiently, and to quickly prototype and test new wireframe designs that can be expanded, rigidified, or mechanically switched. Mechanical force generation and structural transitions will enable applications in structural DNA nanotechnology, plasmonics, or single-molecule biophysics.

Die Diagnose und die Therapie einer Krebserkrankung sind mit einer Einschränkung auf physischer und psychischer Ebene verbunden. Darüber hinaus stellen die Nebenwirkungen einen potenziell therapielimitierenden Faktor dar, der Dosisreduktion, Verzögerung oder gar Abbruch einer Therapie erfordern kann. Dies hat negative Folgen für das Outcome und die mittlere Überlebensdauer. Zahlreiche Untersuchungen zeigen, dass körperliche Trainingsprogramme bei onkologischen Patienten während der Akutphase nicht nur durchführbar, sondern auch empfehlenswert sind. Eine zeitnahe Einbindung der Bewegungstherapie in Form von Physio- und Sporttherapie dient u. a. dazu, Bewegungsmangel sowie therapieassoziierten Nebenwirkungen vorzubeugen. Des Weiteren sollen Ängste und Unsicherheiten gegenüber einer körperlichen Aktivität abgebaut werden. Die bisherige Datenlage beschreibt eine Verbesserung der motorischen Hauptfähigkeiten und der psychischen Parameter, ein besseres Vertragen der medizinischen Therapie sowie eine Reduktion der Nebenwirkungen. Insgesamt ist ein großer Wissensfundus über die Optionen einer körperlichen Aktivität für die verschiedenen Therapiephasen und Nebenwirkungen bei einigen Entitäten vorhanden. In der aktuellen S3-Leitlinie zum Mammakarzinom wurde das Thema „körperliche Aktivität“ aufgenommen, was den inzwischen erlangten Stellenwert der Thematik unterstreicht. The diagnosis and treatment of cancer is associated with impairment at the physical and at the psychological level. In addition, side effects are a potentially treatment-limiting factor that may necessitate dose reduction, delay, or even discontinuation of therapy, with negative consequences for outcome and mean survival time. Numerous studies have shown that physical training programs are not only practicable but also recommendable for oncologic patients during the acute phase. A timely integration of exercise therapy in the form of physiotherapy and sports therapy serves to prevent physical inactivity and reduce treatment-associated side effects. Furthermore, fears and uncertainties regarding physical activity should be reduced. Existing data describe an improvement of main motor skills and psychological parameters, as well as better tolerance of the medical therapy and a reduction in side effects. Overall, there is a great deal of knowledge regarding physical therapy options for the various treatment phases and side effects in some entities. The topic of physical activity is included in the current S3 guideline for breast cancer, which underscores the significance the topic has attained.

Multispecific antibodies have gained significant importance in a broad indication space due to their ability to engage multiple epitopes simultaneously and to thereby overcome therapeutic barriers. With growing therapeutic potential, however, the molecular complexity increases, thus intensifying the demand for innovative protein engineering and analytical strategies. A major challenge for multispecific antibodies is the correct assembly of light and heavy chains. Engineering strategies exist to stabilize the correct pairing, but typically individual engineering campaigns are required to arrive at the anticipated format. Mass spectrometry has proven to be a versatile tool to identify mispaired species. However, due to manual data analysis procedures, mass spectrometry is limited to lower throughputs. To keep pace with increasing sample numbers, we developed a high-throughput-capable mispairing workflow based on intact mass spectrometry with automated data analysis, peak detection, and relative quantification using Genedata Expressionist. This workflow is capable of detecting mispaired species of ∼1000 multispecific antibodies in three weeks and thus is applicable to complex screening campaigns. As a proof of concept, the assay was applied to engineering a trispecific antibody. Strikingly, the new setup has not only proved successful in mispairing analysis but has also revealed its potential to automatically annotate other product-related impurities. Furthermore, we could confirm the assay to be format-agnostic, as shown by analyzing several different multispecific formats in one run. With these comprehensive capabilities, the new automated intact mass workflow can be applied as a universal tool to detect and annotate peaks in a format-agnostic approach and in high-throughput, thus enabling complex discovery campaigns.

Plasmonic structures allow the manipulation of light with materials that are smaller than the optical wavelength. Such structures can consist of plasmonically active metal nanoparticles and can be fabricated through scalable bottom-up self-assembly on DNA origami templates. To produce functional devices, the precise and high-yield arrangement of each of the nanoparticles on a structure is of vital importance as the absence of a single particle can destroy the functionality of the entire device. Nevertheless, the parameters influencing the yield of the multistep assembly process are still poorly understood. To overcome this deficiency, we employed a test system consisting of a tubular six-helix bundle DNA origami with binding sites for eight oligonucleotide-functionalized gold nanoparticles. We systematically studied the assembly yield as a function of a wide range of parameters such as ionic strength, stoichiometric ratio, oligonucleotide linker chemistry, and assembly kinetics by an automated high-throughput analysis of electron micrographs of the formed heterocomplexes. Our optimized protocols enable particle placement yields up to 98.7% and promise the reliable production of sophisticated DNA-based multiparticle plasmonic devices for applications in photonics, optoelectronics, and nanomedicine.

During the irradiation of high molecular weight poly (tetrafluoroethylene) (PTFE) in presence of oxygen perfluoroalkyl (peroxy) radicals and functional groups are formed which allow chemical coupling reactions (cc = chemical compatibilized) with oils and plastics. The micropowder resulting from the irradiation of PTFE are used in base oils to improve the tribological properties significantly if oil molecules are covalently linked to primary PTFE particles in the oil dispersion. These oil-PTFE-cc-dispersions show primarily anti-wear (AW) properties. The use of additional reactive groups (e.g. phosphite groups) in the oil gives the dispersions extreme pressure (EP) properties additionally. This article demonstrates the usefulness of the oil-PTFE-cc-dispersions in rolling bearings and in ropes using phosphite-modified PTFE products as additive in lubricants. The investigations are completed by wear tests with different contact geometries. A model is shown to explain the effect of phosphite groups on 100Cr6 metallic surfaces.Keyword s: PTFE, high performance lubricant, oil-PTFE-cc dispersion

To simplify the designing of electronic components of forklift trucks with regard to their specific operating conditions, a test forklift truck was equipped with industrial-standard instruments to measure the occurring electrical and mechanical stresses. To assess the fatigue potential of the operating load conditions, the acquired measurement data were analyzed in the time and frequency domain and compared with each other with the aid of a rainflow counting algorithm. To compare the failure characteristics of the examined electronic components, fatigue tests were carried out on an electro-dynamic shaker. These experiments were performed on individual components of the electronic drive unit, which were stressed at the same time under typical operating electrical loads. Additionally, the influence of vibration and shock excitation were checked for the control behavior of these components.

This paper presents the development and mathematical implementation of a production scheduling model utilizing mixed-integer linear programming (MILP). A simplified model of a real-world multi-product batch plant constitutes the basis. The paper shows practical extensions to the model, resulting in a digital twin of the plant. Apart from sequential arrangement, the final model contains maintenance periods, campaign planning and storage constraints to a limited extend. To tackle weak computational performance and missing model features, a condensed mathematical formulation is introduced at first. After stating that these measures do not suffice for applicability in a restrained time period, a novel solution strategy is proposed. The overall non-iterative algorithm comprises a multi-step decomposition approach, which starts with a reduced scope and incrementally complements the schedule in multiple subproblem stages. Each of those optimizations holds less decision variables and makes use of warmstart information obtained from the predecessor model. That way, a first feasible solution accelerates the subsequent improvement process. Furthermore, the optimization focus can be shifted beneficially leveraging the Gurobi solver parameters. Findings suggest that correlation may exist between certain characteristics of the scheduling scope and ideal parameter settings, which yield potential for further investigation. Another promising area for future research addresses the concurrent multi-processing of independent MILPs on a single machine. First observations indicate that significant performance gains can be achieved in some cases, though sound dependencies were not discovered yet.

The recent financial crisis, responsible for massive accumulations of credit events, emphasizes the urgent need for adequate portfolio default models. Due to the high dimensionality of real credit portfolios, balancing flexibility and numerical tractability is of uttermost importance. To acknowledge this, a multivariate default model with interesting stylized properties is introduced in the following way: a non-decreasing shot-noise process serves as common stochastic clock. Individual default times are defined as the first-passage times of the common clock across independent exponentially distributed threshold levels. We obtain a default model which has a dynamic stochastic representation, contagion effects, a positive probability for joint defaults, the ability to separate univariate marginal laws from the dependence structure, and the option for efficient pricing routines under a “large homogeneous groups” assumption. Besides this, the model is well-suited for insurance portfolios which are subject to catastrophe risks and the pricing of catastrophe derivatives.The recent financial crisis, responsible for massive accumulations of credit events, emphasizes the urgent need for adequate portfolio default models. Due to the high dimensionality of real credit portfolios, balancing flexibility and numerical tractability is of uttermost importance. To acknowledge this, a multivariate default model with interesting stylized properties is introduced in the following way: a non-decreasing shot-noise process serves as common stochastic clock. Individual default times are defined as the first-passage times of the common clock across independent exponentially distributed threshold levels. We obtain a default model which has a dynamic stochastic representation, contagion effects, a positive probability for joint defaults, the ability to separate univariate marginal laws from the dependence structure, and the option for efficient pricing routines under a “large homogeneous groups” assumption. Besides this, the model is well-suited for insurance portfolios which are subject to catastrophe risks and the pricing of catastrophe derivatives.

Unternehmensindividuelle Ganzheitliche Produktionssysteme haben sich bereits in vielen Betrieben etabliert und leisten einen wichtigen Beitrag zur Sicherung des langfristigen Erfolgs. Wurde in der Vergangenheit meist die Umsetzung von Produktionssystemen in den direkten Bereichen der Produktion beschrieben, sollen in diesem Artikel die Notwendigkeit und die Vorgehensweise mit Fokus auf den indirekten Bereich dargestellt werden. Denn auch hier gilt es, vorhandene Potenziale aufzuspüren und unter Zuhilfenahme geeigneter Methoden einen Kontinuierlichen Verbesserungsprozess (KVP) voranzutreiben. Noch entscheidender ist es aber, dass ohne ein vertieftes Verständnis des Produktionssystems durch die indirekten Bereiche eine Umsetzung im direkten Bereich nicht in vollem Umfang gelingen kann.

Die Internationalisierung der Märkte führt auch bei gefestigten und breit aufgestellten mittelständischen Unternehmen zu größeren Auftrags- und Produktionsunsicherheiten. In Verbindung mit steigendem nationalen Konkurrenzdruck und den damit einhergehenden geringeren Margen können jene externen Faktoren eine strategische Neuausrichtung erzwingen. Dadurch leiten sich neue Anforderungen an die Aufbau- und Ablauforganisation eines Unternehmens ab. Die gesamte Fabrikstruktur muss daher mit dieser Entwicklung Schritt halten, um den entsprechenden Rahmen bereitstellen zu können. Unternehmen unterliegen demnach einem ständigen Transformationsprozess. Im vorliegenden Beitrag werden anhand eines Fallbeispiels die Auswirkungen eines spezifischen Wandlungsprozesses auf KMU untersucht. Schwerpunkt hierbei ist der Einfluss auf die Fabrikstruktur, wobei auch technologisch-organisatorische Aspekte diskutiert werden.

Die Verarbeitung von großen Datenmengen erzeugt in Unternehmen hohe Kosten durch Datenqualitätsprobleme. Im Jahr 2007 erklärte man daher das Data Management zum strategischen Thema der IT. Lösungen, um die Datenqualität messbar zu machen, wurden in den darauf folgenden vier Jahren konzipiert, auf- und ausgebaut. Für die Identifikation von Brandherden in den IT-Prozessen wurde ein Verfahren entwickelt. So konnten relevante Datenqualitätsdimensionen, Datenobjekte und Messregeln ausgewählt werden. Zur Durchführung der Messungen wurde eine IT-Plattform aufgebaut. Die Darstellung der Messergebnisse erfolgt durch ein adressatengerechtes Dashboard.

We report on a father and son with facioaudiosymphalangism syndrome, an alternative designation for multiple synostoses syndrome, type I. This syndrome includes synostosis, brachydactyly, craniofacial dysmorphic features, stapes fixation, hyperopia, and growth retardation. In contrast to the typical presentation, the height of the 10yearold son was above the 97th centile from the age of 3.5 years and he had markers of an activated bone metabolism. The father and son had a novel heterozygous missense mutation c.696C > G, p.Cys232Trp, in the NOGgene. While not yet described in human NOGrelated disorders, there is experimental evidence that suppression of noggin might accelerate osteogenesis, which could explain the phenotype in the family reported here. © 2010 WileyLiss, Inc.

Komplexe Produkte in wachsender Vielfalt, die Befriedigung individueller Kundenbedürfnisse bei steigendem Konkurrenzdruck und unsichere Märkte stellen eine Realität dar, die veränderte Ansprüche an eine effiziente Planung, Steuerung und Überwachung der Montageprozesse stellt. Um flexibel und schnell auf sich dynamisch ändernde Rahmenbedingungen reagieren und diese beherrschen zu können, benötigen die Unternehmen innovative Konzepte und Technologien. Insbesondere hinsichtlich des Ressourceneinsatzes sind wesentliche Flexibilitäts- und Produktivitätspotenziale vorhanden, die bisher noch nicht optimal ausgeschöpft werden. In diesem Artikel wird ein, an der TU Dresden entwickelter, simulationsbasierter Lösungsansatz für die optimierte operative Einsatzplanung des Montagepersonals präsentiert – ein hochkomplexes, so genanntes Multiressourcen-Einsatzproblem. Ferner stellen die Autoren ein Pilotprojekt sowie eine geeignete Montageorganisation zur Einführung einer getakteten Fliessmontage für Großbaugruppen vor.

For large-scale applications of hydrogen fuel cells, the sluggish kinetics of the oxygen reduction reaction (ORR) have to be overcome. So far, only platinum (Pt)-group catalysts have shown adequate performance and stability. A well-known approach to increase the efficiency and decrease the Pt loading is to alloy Pt with other metals. Still, for catalyst optimization, the nature of the active sites is crucial. In this work, electrochemical scanning tunneling microscopy (EC-STM) is used to probe the ORR active areas on Pt5Gd and Pt5Pr in acidic media under reaction conditions. The technique detects localized fluctuations in the EC-STM signal, which indicates differences in the local activity. The in situexperiments, supported by coordination–activity plots based on density functional theory calculations, show that the compressed Pt–lanthanide (111) terraces contribute the most to the overall activity. Sites with higher coordination, as found at the bottom of step edges or concavities, remain relatively inactive. Sites of lower coordination, as found near the top of step edges, show higher activity, presumably due to an interplay of strain and steric hindrance effects. These findings should be vital in designing nanostructured Pt–lanthanide electrocatalysts.

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Abstract: This article proposes a model for stock prices which incorporates shot-noise effects. This means, that sudden jumps in the stock price are allowed, but their effect may decline as time passes by. Our model is general enough to capture arbitrary effects of this type. Generalizing previous approaches to shot noise we in particular allow the decay to be stochastic. This model describes an incomplete market, so that the martingale measure is not unique. We derive the minimal martingale measure via continuous time methods. [Copyright &y& Elsevier]

The objective of this study was to evaluate a new approach to noninvasive magnetic resonance assessment of human pulmonary ventilation with aerosolized Gd-DTPA.

Intracellular aggregates commonly forming neuronal intranuclear inclusions are neuropathological hallmarks of spinocerebellar ataxia type 3 and of other disorders characterized by expanded polyglutamine‐(poly‐Q) tracts. To characterize cellular responses to these aggregates, we performed an immunohistochemical analysis of neuronal intranuclear inclusions in pontine neurons of patients affected by spinocerebellar ataxia type 3, using a panel of antibodies directed against chaperones and proteasome subunits. A subset of the neuronal intranuclear inclusions stained positively for the chaperones Hsp90α and HDJ‐2, a member of the Hsp40 family. Most neuronal intranuclear inclusions were ubiquitin positive, suggesting degradation by ubiquitin‐dependent proteasome pathways. Surprisingly, only a fraction of neuronal intranuclear inclusions were immunopositive for antibodies directed against subunits of the 20S proteolytic core, whereas most inclusions were stained by antibodies directed against subunits of the 11S and 19S regulatory particles. These results suggest that the proteosomal proteolytic machinery that actively degrades neuronal intranuclear inclusions is assembled in only a fraction of pontine neurons in end stage spinocerebellar ataxia type 3. The dissociation between regulatory subunits and the proteolytic core and the changes in subcellular subunit distribution suggest perturbations of the proteosomal machinery in spinocerebellar ataxia type 3 brains.

Expression of the cdc25Bgene is up-regulated late during cell cycle progression (S/G2). We have cloned the murine cdc25Bpromoter to identify elements involved in transcriptional regulation. A detailed structure-function analysis led to the identification of several elements that are located upstream of a canonical Inr motif at the site of transcription initiation and are involved in transcriptional activation and regulation. Activation of the promoter is largely mediated by NF-Y and Sp1/3 interacting with one and four proximal binding sites, respectively. In addition, NF-Y plays an essential role in cell cycle regulation in conjunction with a repressor element (cell cycle-regulated repressor) located ∼30 nucleotides upstream of the putative Inr element and overlapping a consensus TATA motif. The cell cycle-regulated repressor is unrelated to the previously described cell cycle-regulated repressor elements. Taken together, our observations suggest that expression of thecdc25Bgene is controlled through a novel mechanism of cell cycle-regulated transcription.AJ296019

We evaluate the diagnostic accuracy of magnetic resonance urography in children with suspected ectopic ureters and ureteroceles in duplex systems.

The oncoprotein Bcl-2 protects cells against apoptosis, but the exact molecular mechanism that underlies this function has not yet been identified. Studying H2O2-induced cell injury in Rat-1 fibroblast cells, we observed that Bcl-2 had a protective effect against the increase in cytosolic calcium concentration and subsequent cell death. Furthermore, overexpression of Bcl-2 resulted in an alteration of cellular glutathione status: the total amount of cellular glutathione was increased by about 60% and the redox potential of the cellular glutathione pool was maintained in a more reduced state during H2O2 exposure compared with non-Bcl-2-expressing controls. In our cytotoxicity model, disruption of cellular glutathione homoeostasis closely correlated with the pathological elevation of cytosolic calcium concentration. Stabilization of the glutathione pool by Bcl-2, N-acetylcysteine or glucose delayed the cytosolic calcium increase and subsequent cell death, whereas depletion of glutathione by DL-buthionine-(S,R)-sulphoximine, sensitized Bcl-2-transfected cells towards cytosolic calcium increase and cell death. We therefore suggest that the protection exerted by Bcl-2 against H2O2-induced cytosolic calcium elevation and subsequent cell death is secondary to its effect on the cellular glutathione metabolism.

Autosomal dominant spinocerebellar ataxias (SCA) form a group of clinically and genetically heterogeneous neurodegenerative disorders. The defect responsible for SCA3/Machado‐Joseph disease (MJD) has been identified as an unstable and expanded (CAG)ntrinucleotide repeat in the coding region of a novel gene of unknown function. The MJD1gene product, ataxin‐3, exists in several isoforms. We generated polyclonal antisera against an alternate carboxy terminus of ataxin‐3. This isoform, ataxin‐3c, is expressed as a protein of approximately 42 kDa in normal individuals but is significantly enlarged in affected patients confirming that the CAG repeat is part of the ataxin‐3c isoform and is translated into a polyglutamine stretch, a feature common to all known CAG repeat disorders. Ataxin‐3 like immunoreactivity was observed in all human brain regions and peripheral organs studied. In neuronal cells of control individuals, ataxin‐3c was expressed cytoplasmatically and had a somatodendritic and axonal distribution. In SCA3 patients, however, C‐terminal ataxin‐3c antibodies as well as antiataxin‐3 monoclonal antibodies (1H9) and anti‐ubiquitin antibodies detected intranuclear inclusions (NIs) in neuronal cells of affected brain regions. A monoclonal antibody, 2B6, directed against an internal part of the protein, barely detected these NIs implying proteolytic cleavage of ataxin‐3 prior to its transport into the nucleus. These findings provide evidence that the alternate isoform of ataxin‐3 is involved in the pathogenesis of SCA3/MJD. Intranuclear protein aggregates appear as a common feature of neurodegenerative polyglutamine disorders.

Huntington's disease (HD) is a neurodegenerative disorder caused by a (CAG)>37 repeat expansion in a novel gene of unknown function. Although the huntingtin gene is expressed in neuronal and non-neuronal tissues, the disease affects nerve cells of selected regional areas of the central nervous system. To gain insight into the regulation of the HD gene we analysed 1348 bp of the rat huntingtin promoter region. This region lacks a TATA and a CAAT box, is rich in GC content and has several consensus sequences for binding sites for SP1, PEA3, Sif and H2A. The stretch between nucleotides -56 and -206 relative to the first ATG is highly conserved between human and rodents and it harbours several potential binding sites for transcription factors. We analysed deletion mutants fused with the chloramphenicol acetyltransferase reporter gene in transfected, HD-expressing neuronal (NS20Y, NG108-15) and non-neuronal Chinese hamster ovary cell lines. Hence these cells should contain the required trans-acting factors necessary for HD gene expression. Partial deletion of the evolutionarily conserved part of the promoter significantly decreases the activity in both neuronal and non-neuronal cells, indicating that the core promoter activity is located between nucleotides -332 and -15. DNase I footprinting and electrophoretic mobility-shift assays were used to define the nucleotide positions and binding affinity of DNA–protein interactions.

ABSTRACTNext-generation multi-specific antibody therapeutics (MSATs) are engineered to combine several functional activities into one molecule to provide higher efficacy compared to conventional, mono-specific antibody therapeutics. However, highly engineered MSATs frequently display poor yields and less favorable drug-like properties (DLPs), which can adversely affect their development. Systematic screening of a large panel of MSAT variants in very high throughput (HT) is thus critical to identify potent molecule candidates with good yield and DLPs early in the discovery process. Here we report on the establishment of a novel, format-agnostic platform process for the fast generation and multiparametric screening of tens of thousands of MSAT variants. To this end, we have introduced full automation across the entire value chain for MSAT engineering. Specifically, we have automated the in-silico design of very large MSAT panels such that it reflects precisely the wet-lab processes for MSAT DNA library generation. This includes mass saturation mutagenesis or bulk modular cloning technologies while, concomitantly, enabling library deconvolution approaches using HT Sanger DNA sequencing. These DNA workflows are tightly linked to fully automated downstream processes for compartmentalized mammalian cell transfection expression, and screening of multiple parameters. All sub-processes are seamlessly integrated with tailored workflow supporting bioinformatics. As described here, we used this platform to perform multifactor optimization of a next-generation bispecific, cross-over dual variable domain-Ig (CODV-Ig). Screening of more than 25,000 individual protein variants in mono- and bispecific format led to the identification of CODV-Ig variants with over 1,000-fold increased potency and significantly optimized production titers, demonstrating the power and versatility of the platform.

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ABSTRACTMonoclonal antibodies (mAbs) are among the fastest growing and most effective therapies for myriad diseases. Multispecific antibodies are an emerging class of novel therapeutics that can target more than one tumor- or immune-associated modulators per molecule. The combination of different binding affinities and target classes, such as soluble or membrane-bound antigens, within multispecific antibodies confers unique pharmacokinetic (PK) properties. Numerous factors affect an antibody’s PK, with affinity to the neonatal Fc receptor (FcRn) a key determinant of half-life. Recent work has demonstrated the potential for humanized FcRn transgenic mice to predict the PK of mAbs in humans. However, such work has not been extended to multispecific antibodies. We engineered mAbs and multispecific antibodies with various Fc modifications to enhance antibody performance. PK analyses in humanized FcRn transgenic mouse (homozygous Tg32 and Tg276) and non-human primate (NHP) models showed that FcRn-binding mutations improved the plasma half-lives of the engineered mAbs and multispecific antibodies, while glycan engineering to eliminate effector function did not affect the PK compared with wild-type controls. Furthermore, results suggest that the homozygous Tg32 mouse model can replace NHP models to differentiate PK of variants during lead optimization, not only for wild-type mAbs but also for Fc-engineered mAbs and multispecific antibodies. This Tg32-mouse model would enable prediction of half-life and linear clearance of mAbs and multispecific antibodies in NHPs to guide the design of further pharmacology/safety studies in this species. The allometric exponent for clearance scaling from Tg32 mice to NHPs was estimated to be 0.91 for all antibodies.

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