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Fehlgeschlagene Technologieeinführungsprojekte, ungenutzte Potenziale, fehlerhafte Technologieanwendungen – zehn Jahre nach der Einführung des Begriffs „Industrie 4.0“ scheitern noch viele Technologieprojekte in der Implementierungsphase. Nicht bedachte Risiken, veränderte Risikoprofile im Zusammenhang mit neuen digitalen Technologien sowie falsch gewählte Mitigationsstrategien sind oftmals der Grund dafür. Basierend auf einer Studie, in der 359 Industrie-4.0-Anwendungsfälle untersucht und mehr als 50 Expertengespräche geführt worden sind, hat die Otto-von-Guericke Universität Magdeburg gefördert durch die FUNK-Stiftung die neuen Anforderungen im Zuge der veränderten Risikoprofile durch die Digitalisierung untersucht und Handlungsempfehlungen für ein zukünftiges Risikomanagement erarbeitet.

Sexual conflict is the conflict between the evolutionary interests of individuals of different sexes. Sexual conflict may result in sexually antagonistic coevolution, producing sex-specific adaptations that are involved in cooperation and conflict concerning sex and other mating-relevant aspects between individual men and women. Sexual conflict is studied in many species; however, human long-term relationship maintenance provides a special case. The current chapter introduces the concept of sexual conflict and considers sexual conflict in the context of species-specific and species-typical long-term relationship maintenance. Different expressions of this include phenomena such as parental investment conflict, relationship satisfaction, intercourse frequency in couples, mate retention tactics, jealousy, infidelity, threat to the relationship, breakup, and forgiveness. Evolutionary psychology theory and empirical findings from studies of these phenomena will be presented and discussed within a metanarrative of how human evolved psychology influences contemporary romantic relationships.

Both practitioners and scholars emphasise the benefits of Industry 4.0 (I4.0) technology implementation, such as increased transparency and the availability of real-time data in operations processes. Current literature on I4.0 technologies tends to overemphasise the positive impact and transformational capabilities of digital technologies while there is little focus on evaluating potential risks associated with their adoption in industrial operations. An understanding of how supply chain risks are perceived in digitalisation projects within industrial operations and an understanding of decision-makers' responses to different types of risks has important managerial implications. Current literature, however, lacks systematic empirical evidence on the implementation of I4.0 applications and related risk factors. This study aims to address this research gap by exploring the relationship between I4.0 technologies and supply chain risks based on empirical evidence from 300 case studies of industrial practice in Germany and fifty-three interviews with relevant managers from selected use cases and with general experts in this field. Our findings show that digital technologies are frequently adopted to address certain existing supply chain risks but that their implementation introduces new sources of risks (e.g. cyber risks). Based on qualitative data analysis and drawing on Normal Accident Theory, we propose a framework to explicate the drivers and contingency factors of new sources of supply chain risks in the context of Industry 4.0 technologies. Practical recommendations are provided for supply chain managers to guide the process of managing supply chain risks based on the technological life cycle.

Digitalization and the transformation of industry into Industry 4.0 is changing the character of production logistics substantially. New Logistics 4.0 technologies are largely enabling automated decision-making by machines. Human decisions are nevertheless still required. Research shows, however, that human decisions are often more biased and less rational than most logistics models assume. Decision makers and decision support system designers therefore need to understand the influence of the so-called cognitive biases on the human decision-making process. We contribute to the scholarship on this issue by combining the literature streams of logistics and cognitive biases. We demonstrate the influence of cognitive biases on human decision-making based on typical decisions in logistics and derive initial hypotheses.

Over the past years, supply chains have become more complex, widespread, and interlinked - in particular, due to increasing digitalization. Nevertheless, companies face substantial maturity differences regarding the implementation of digitalization technologies, which causes several risks for buyer-supplier relationships (BSRs). Managing these risks within BSRs requires human decision-making in various steps. However, research shows that human decisions are often biased which can negatively affect risk management. We contribute to this issue by combining a systematic literature review on I4.0 maturity in BSRs and cognitive biases with practice insights from discussions with experts to derive first guidelines for supplier risk management, considering I4.0 maturity differences.

We identified and characterized a series of pyrazole amides as potent, selective Ca v 3.1-blockers. This series culminated with the identification of pyrazole amides 5a and 12d , with excellent potencies and/or selectivities toward the Ca v 3.2- and Ca v 3.3-channels. This compound displays poor DMPK properties, making its use difficult for in vivo applications. Nevertheless, this compound as well as analogous ones are well-suited for in vitro studies.

A series of dihydropyrazole derivatives was developed as potent, selective, and brain-penetrating T-type calcium channel blockers. An optimized derivative, compound 6c, was advanced to in vivo studies, where it demonstrated efficacy in the WAG/Rij rat model of generalized nonconvulsive, absence-like epilepsy. Compound 6c was not efficacious in the basolateral amygdala kindling rat model of temporal lobe epilepsy, and it led to prolongation of the PR interval in ECG recordings in rodents.

Background: Species-specific point-of-care tests (POCT) permit a rapid analysis of canine C-reactive protein (CRP), enabling veterinarians to include CRP in clinical decisions. Aim of the study was to evaluate a novel POCT for canine CRP (Point Stripâ TM Canine CRP Assay) run on a small in-house-analyzer (Point Reader TM V) using lithium heparin plasma and to compare assay performance to an already established canine CRP assay (Gentian Canine CRP Immunoassay) run on two different bench top analyzers serving as reference methods (ABX Pentra 400, AU 5800). Linearity was assessed by stepwise dilution of plasma samples with high CRP concentrations. Limit of quantification (LoQ) was determined by repeated measurements of samples with low CRP concentrations. Coefficient of variation (CV) at low (10-50 mg/l), moderate (50-100 mg/l), and high (100-200 mg/l) CRP concentrations was investigated as well as possible interferences. Method comparison study was performed using 45 samples of healthy and diseased dogs. Quality criteria were fulfilled if the total observed error (TEobs=2CV%+bias%) was below the minimal total allowable error of 44.4% (TE min). Additionally, a reference range (n =60 healthy dogs) was established. Results: Linearity was present at CRP concentrations of 10-132 mg/l (≙ 361 mg/l CRP with reference method) with a LoQ set at 10 mg/l. At moderate to high CRP concentrations, intra- and inter-assay CVs were< =8% and

We identified and characterized a series of pyrazole amides as potent, selective Ca

Despite the availability of numerous antiepileptic drugs, 20-30% of epileptic patients are pharmacoresistant with seizures not appropriately controlled. Consequently, new strategies to address this unmet medical need are required. T-type calcium channels play a key role in neuronal excitability and burst firing, and selective triple T-type calcium channel blockers could offer a new way to treat various CNS disorders, in particular epilepsy. Herein we describe the identification of new 1,4-benzodiazepines as brain penetrant and selective triple T-type calcium channel blockers. From racemic hit 4, optimization work led to the preparation of pyridodiazepine 31c with improved physicochemical properties, solubility, and metabolic stability. The racemic mixture was separated by chiral preparative HPLC, and the resulting lead compound (3R,5S)-31c showed promising efficacy in the WAG/Rij-rat model of generalized nonconvulsive absence-like epilepsy.

We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.

We describe the discovery and optimization of new, brain-penetrant T-type calcium channel blockers. We present optimized compounds with excellent efficacy in a rodent model of generalized absence-like epilepsy. Along the fine optimization of a chemical series with a pharmacological target located in the CNS (target potency, brain penetration, and solubility), we successfully identified an Ames negative aminopyrazole as putative metabolite of this compound series. Our efforts culminated in the selection of compound 20, which was elected as a preclinical candidate.

Despite the availability of numerous antiepileptic drugs, 20–30% of epileptic patients are pharmacoresistant with seizures not appropriately controlled. Consequently, new strategies to address this unmet medical need are required. T-type calcium channels play a key role in neuronal excitability and burst firing, and selective triple T-type calcium channel blockers could offer a new way to treat various CNS disorders, in particular epilepsy. Herein we describe the identification of new 1,4-benzodiazepines as brain penetrant and selective triple T-type calcium channel blockers. From racemic hit 4, optimization work led to the preparation of pyridodiazepine 31c with improved physicochemical properties, solubility, and metabolic stability. The racemic mixture was separated by chiral preparative HPLC, and the resulting lead compound (3R,5S)-31c showed promising efficacy in the WAG/Rij-rat model of generalized nonconvulsive absence-like epilepsy.