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Recently described rhizolutin and collinolactone isolated from Streptomyces Gç 40/10 share the same novel carbon scaffold. Analyses by NMR and X-Ray crystallography verify the structure of collinolactone and propose a revision of rhizolutins stereochemistry. Isotope-labeled precursor feeding shows that collinolactone is biosynthesized via type I polyketide synthase with Baeyer–Villiger oxidation. CRISPR-based genetic strategies led to the identification of the biosynthetic gene cluster and a high-production strain. Chemical semisyntheses yielded collinolactone analogues with inhibitory effects on L929 cell line. Fluorescence microscopy revealed that only particular analogues induce monopolar spindles impairing cell division in mitosis. Inspired by the Alzheimerprotective activity of rhizolutin, we investigated the neuroprotective effects of collinolactone and its analogues on glutamate-sensitive cells (HT22) and indeed, natural collinolactone displays distinct neuroprotection from intracellular oxidative stress.
Few unfocused factories outperform competitors, but Focus is elusive because the environment is constantly evolving and this requires changes to a factory’s key tasks. So how can focus be achieved and sustained? We present insights derived from an historical analysis of the German Hewlett-Packard server plant which went through a series of Focus changes over the years. Using this example, we provide clues for the right timing of Focus changes and discuss critical structural and infrastructural changes required during the Focus transitions, as well as cross-functional coordination and leadership challenges. Our assertion is that production operations constitute a system that can adapt to disruptive Change by using the levers of manufacturing policies to stay focused on a limited but absolutely essential task which creates a strategic advantage.
The reduced research and development (R&D) efficiency, strong competition from generics, increased cost pressure from payers, and an increased biological complexity of new target indications have resulted in a rethinking and a change from a traditional and more closed R&D model in the pharmaceutical industry toward the new paradigm of open innovation. In the past years, pharmaceutical companies have broadened their external networks toward research collaborations with academic institutes, technology providers, or codevelopment partners. To fulfill the demand to reduce timelines and costs, research-based pharmaceutical companies started to outsource R&D activities. In addition, internal R&D processes were adjusted to the more open R&D model and new processes such as alliance management were established. The corporate frontier of pharmaceutical companies became permeable and more open. As a result, the focus of pharmaceutical R&D expanded from a purely internal toward a mixed internal and external model. Today, the U.S. pharmaceutical company Eli Lilly may have established the most open model toward external innovation, as it has integrated its innovation processes with its business model. Other companies are following this more open R&D model with newer concepts such as new frontier sciences, drug discovery alliances, private public partnerships, innovation incubators, virtual R&D, crowdsourcing, open source innovation, and innovation camps.
AbstractThrough their procyclical behavior, loan loss provisions have been determined as one of the factors that contribute to financial instability during a crisis. IFRS 9 was introduced in 2018 with an expected credit loss model replacing the incurred loss model of IAS 39 to mitigate the effect in the future. Our study aims to analyze loan loss provisions of major banks in the Eurozone to determine for the first time if the implementation of IFRS 9, as intended by regulators, has a dampening effect on procyclicality, especially during the stressed situation under COVID‐19. We analyze 51 banks from 12 countries of the European Monetary Union using 2856 firm‐year observations. While no robust evidence of less procyclicality can be found after the implementation of IFRS 9 until the pandemic, we find evidence that loan loss provisions moved countercyclical during 2020, indicating an alleviating effect at the beginning of the exogenous shock.
Clinical development is historically the phase in which a potential new medicine is being tested in phase 2 and phase 3 patient trials to demonstrate the new molecules' efficacy and safety to support the regulatory approval of drugs by health authorities. This relatively focused approach has been considerably expanded by a number of forces from within the pharmaceutical industry and equally important by changes in the healthcare systems. The need to identify the optimal patient population, showstoppers leading to discontinuation of clinical programs, the silent but constant removal of surrogate endpoints for registration, and the increased demand for real-life data which are used to demonstrate the patients' benefit and which have an ever-increasing role for pricing and reimbursement negotiations are today an integral part of this phase.
This chapter will review both the nuts and bolts of clinical development but also recent developments in this area which shape the environment and how the different players have reacted and what options might need to be explored in the future.
Block-copolyesters of polyethylene terephthalate (PET) and polyethylene naphthalate (PEN) were synthesized via reactive extrusion. The influence of processing parameters on the material properties on a molecular scale like degree of trans-esterification, block length, and degree of randomness were investigated. The varied process factors were extrusion temperature and rotational speed. The effects of process parameter variation were investigated by 1H-NMR-spectroscopy. The experimental results show a clear dependence of the molecular properties on the processing conditions. By using statistical experimental design (DoE), it was possible to prepare defined copolyesters from PET and PEN without addition of further chemicals. With a degree of randomness between 0.05 and 0.5, the presence of an actual copolyester was confirmed when appropriate extrusion conditions were applied. The reactive extrusion process was confirmed to be suitable to produce defined block-copolyesters in a predictable and reproducible way. It was possible to produce designed sequence lengths, which could be adjusted within a range of 11–136 repeating units in the case of PET and, in the case of PEN, of 2.5–26. The produced materials can be used as barrier materials or barrier coatings to protect substrates against molecular oxygen and water vapour, e.g., in organic photovoltaic applications or food packaging. The described method is a one-pot alternative method to the previously described chemical recycling pathway.
Ethylene terephthalate and ethylene naphthalate oligomers of defined degree of polymerization were synthesized via chemical recycling of the parent polymers. The oligomers were used as defined building blocks for the preparation of novel block-co-polyesters having tailored sequence compositions. The sequence lengths were systematically varied using Design of Experiments. The dispersive surface energy and the specific desorption energy of the co-polymers were determined by inverse gas chromatography. The study shows that polyethylene terephthalate-polyethylene naphthalate (PET-PEN) block-co-polyesters of defined sequence lengths can be prepared. Furthermore, the specific and dispersive surface energies of the obtained block-co-polyesters showed a linear dependence on the oligomer molecular weight and it was possible to regulate and control their interfacial properties. In contrast, with the corresponding random-block-co-polyesters no such dependence was found. The synthesized block-co-polyesters could be used as polymeric modifying agents for stabilizing PET-PEN polymer blends.
Poly(dimethylsiloxane) can be covalently coated with ultrathin NCO-sP(EO-stat-PO) hydrogel layers which permit covalent binding of cell adhesive moieties, while minimizing unspecific cell adhesion on non-functionalized areas. We applied long term uniaxial cyclic tensile strain (CTS) and revealed (a) the preservation of protein and cell-repellent properties of the NCO-sP(EO-stat-PO) coating and (b) the stability and bioactivity of a covalently bound fibronectin (FN) line pattern. We studied the adhesion of human dermal fibroblast (HDFs) on non-modified NCO-sP(EO-stat-PO) coatings and on the FN. HDFs adhered to FN and oriented their cell bodies and actin fibers along the FN lines independently of the direction of CTS. This mechanical long term stability of the bioactive, patterned surface allows unraveling biomechanical stimuli for cellular signaling and behavior to understand physiological and pathological cell phenomenon. Additionally, it allows for the application in wound healing assays, tissue engineering, and implant development demanding spatial control over specific cell adhesion.
Science-based analysis for climate action: how HSBC Bank uses the En-ROADS climate policy simulation
(2021)
In 2018, the Intergovernmental Panel on Climate Change (IPCC, 2018) found that rapid decarbonization and net negative greenhouse gas (GHG) emissions by mid-century are required to "hold the increase in global average temperature to well below 2°C above pre-industrial levels and pursue efforts to limit the temperature increase to 1.5°C," as stipulated by the Paris Agreement (UNFCCC, 2015, p. 2). Meeting these goals reduces physical climate-related risks from, for example, sea-level rise, ocean acidification, extreme weather, water shortages, declining crop yields, and other impacts. These impacts threaten our economy, security, health, and lives.
At the same time, policies to mitigate these harms by rapidly reducing GHG emissions can create transition risks for businesses - for example, stranded assets and loss of market value for fossil fuel producers and firms dependent on fossil energy (Carney, 2019). Rapid decarbonization requires an unprecedented energy transition (IEA, 2021a) driven by and affecting economic players including businesses, asset managers, and investors in all sectors and all countries (Kriegler et al., 2014).
However, GHG emissions are not falling rapidly enough to meet the goals of the Paris Agreement (Holz et al., 2018). The UNFCCC, 2021 found that the emissions reductions pledged by all nations as of early 2021 "fall far short of what is required, demonstrating the need for Parties to further strengthen their mitigation commitments under the Paris Agreement" (2021, p. 5). Businesses are faring no better. Despite high-profile calls to action from influential firms such as BlackRock (Fink, 2018, 2021), corporate action to meet climate goals has thus far fallen short (e.g. the Right, 2019 analysis of the German DAX 30 companies' emissions targets by NGO "right."). Instead of implementing climate strategies that might mitigate the risks, managers are often caught up in "firefighting" and capability traps that erode the resources needed for ambitious climate action (Sterman, 2015). Firms may also exaggerate environmental accomplishments, leading to greenwashing (Lyon and Maxwell, 2011); implement policies that are vague, rely on unproven offsets, or are not climate neutral (e.g. Sterman et al., 2018); or simply take no action at all (Delmas and Burbano, 2011; Sterman, 2015).
Adding to the confusion are difficulties evaluating the effectiveness of different climate policies. Misperceptions include wait-and-see approaches (Dutt and Gonzalez, 2012; Sterman, 2008), underestimating time delays and ignoring the unintended consequences of policies (Sterman, 2008), and beliefs in "silver bullet" solutions (Gilbert, 2009; Kriegler et al., 2013; Shackley and Dütschke, 2012). These beliefs arise in part because the climate–energy system is a high-dimensional dynamic system characterized by long time delays, multiple feedback loops, and nonlinearities (Sterman, 2011), while even simple systems are difficult for people to understand (Booth Sweeney and Sterman, 2000; Cronin et al., 2009; Kapmeier et al., 2017). Although senior executives might receive briefings on climate change, simply providing more information does not necessarily lead to more effective action (Pearce et al., 2015; Sterman, 2011).
Alternatively, interactive approaches to learning about climate change and policies to mitigate it can trigger climate action (Creutzig and Kapmeier, 2020). Decision-makers require tools and methods grounded in science that enable them to learn for themselves how a low-carbon economy can be achieved and how climate policies condition physical and transition risks. The system dynamics climate–energy simulation En-ROADS (Energy-Rapid Overview and Decision Support; Jones et al., 2019b), codeveloped by the climate think-tank Climate Interactive and the MIT Sloan Sustainability Initiative, provides such a tool.
Here we show how En-ROADS helps HSBC Bank U.S.A., the American subsidiary of U.K.-based multinational financial services company HSBC Holdings plc, focus its global sustainability strategy on activities with higher impact and relevance, communicate and implement the strategy, understand transition risks, and better align the strategy with global climate goals. We show how the versatility and interactivity of En-ROADS increases its reach throughout the organization. Finally, we discuss challenges and lessons learned that may be helpful to other organizations.
Das Erkennen und Steuern von Risiken wird in einem turbulenten und dynamischen Umfeld von Unternehmen immer wichtiger. Neue Regularien wie Basel II, Solvency II und vor allem die aktuellen Reglementierungen vieler Staaten aufgrund der aktuellen Finanzmarktkrise führen zu einem verstärkten Einsatz von Instrumenten des Risikomanagements auch außerhalb von Banken und Versicherungen. Die Kenntnis der rechtlichen Vorgaben (Basel II, DRS, SolvV und MaRisk), der risikotheoretischen Grundlagen und deren Mess- und Frühwarnmethoden (Szenario, Delphi) ist für Unternehmen aus diesem Grund weiterhin eminent wichtig.Über die Grundlagen des Risikomanagements hin zu Risikocontrolling und -steuerung (d.h. der Identifikation und Messung von Risiken) beschäftigt sich dieser Praxisleitfaden zum Risikomanagement darüber hinaus auch mit dem Thema Risikovorsorge und -abwälzung durch Derivate, das für die Planung eines Risikomanagements im Unternehmen von enormer Bedeutung ist. Abschließend wird ein Fallbeispiel einer erfolgreichen Risikomanagement-Implementierung betrachtet. Schritt für Schritt soll damit nicht nur die konkrete Implementierung demonstriert sondern darüber hinaus gezeigt werden, dass solch eine Einführung möglich und sinnvoll ist.