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The combined effect of ultraviolet (UV) light soaking and self-assembled monolayer deposition on the work function (WF) of thin ZnO layers and on the efficiency of hole injection into the prototypical conjugated polymer poly(3-hexylthiophen-2,5-diyl) (P3HT) is systematically investigated. It is shown that the WF and injection efficiency depend strongly on the history of UV light exposure. Proper treatment of the ZnO layer enables ohmic hole injection into P3HT, demonstrating ZnO as a potential anode material for organic optoelectronic devices. The results also suggest that valid conclusions on the energy-level alignment at the ZnO/organic interfaces may only be drawn if the illumination history is precisely known and controlled. This is inherently problematic when comparing electronic data from ultraviolet photoelectron spectroscopy (UPS) measurements carried out under different or ill-defined illumination conditions.
Background:
Anti-TNFα monoclonal antibodies (mAbs) are a well-established treatment for patients with Crohn’s disease (CD). However, subtherapeutic concentrations of mAbs have been related to a loss of response during the first year of therapy1. Therefore, an appropriate dosing strategy is crucial to prevent the underexposure of mAbs for those patients. The aim of our study was to assess the impact of different dosing strategies (fixed dose or body size descriptor adapted) on drug exposure and the target concentration attainment for two different anti-TNFα mAbs: infliximab (IFX, body weight (BW)-based dosing) and certolizumab pegol (CZP, fixed dosing). For this purpose, a comprehensive pharmacokinetic (PK) simulation study was performed.
Methods:
A virtual population of 1000 clinically representative CD patients was generated based on the distribution of CD patient characteristics from an in-house clinical database (n = 116). Seven dosing regimens were investigated: fixed dose and per BW, lean BW (LBW), body surface area, height, body mass index and fat-free mass. The individual body size-adjusted doses were calculated from patient generated body size descriptor values. Then, using published PK models for IFX and CZP in CD patients2,3, for each patient, 1000 concentration–time profiles were simulated to consider the typical profile of a specific patient as well as the range of possible individual profiles due to unexplained PK variability across patients. For each dosing strategy, the variability in maximum and minimum mAb concentrations (Cmax and Cmin, respectively), area under the concentration-time curve (AUC) and the per cent of patients reaching target concentration were assessed during maintenance therapy.
Results:
For IFX and CZP, Cmin showed the highest variability between patients (CV ≈110% and CV ≈80%, respectively) with a similar extent across all dosing strategies. For IFX, the per cent of patients reaching the target (Cmin = 5 µg/ml) was similar across all dosing strategies (~15%). For CZP, the per cent of patients reaching the target average concentration of 17 µg/ml ranged substantially (52–71%), being the highest for LBW-adjusted dosing.
Conclusion:
By using a PK simulation approach, different dosing regimen of IFX and CZP revealed the highest variability for Cmin, the most commonly used PK parameter guiding treatment decisions, independent upon dosing regimen. Our results demonstrate similar target attainment with fixed dosing of IFX compared with currently recommended BW-based dosing. For CZP, the current fixed dosing strategy leads to comparable percentage of patients reaching target as the best performing body size-adjusted dosing (66% vs. 71%, respectively).
The termprocess modelis widely used, but rarely agreed upon. This paper proposes a framework for characterizing and building cognitive process models. Process models model not only inputs and outputs but also model the ongoing information transformations at a given level of abstraction. We argue that the following dimensions characterize process models: They have a scope that includes different levels of abstraction. They specify a hypothesized mental information transformation. They make predictions not only for the behavior of interest but also for processes. The models' predictions for the processes can be derived from the input, without reverse inference from the output data. Moreover, the presumed information transformation steps are not contradicting current knowledge of human cognitive capacities. Lastly, process models require a conceptual scope specifying levels of abstraction for the information entering the mind, the proposed mental events, and the behavior of interest. This framework can be used for refining models before testing them or after testing them empirically, and it does not rely on specific modeling paradigms. It can be a guideline for developing cognitive process models. Moreover, the framework can advance currently unresolved debates about which models belong to the category of process models.
In the comment on "Varves of the Dead Sea sedimentary record." Quaternary Science Reviews 215 (Ben Dor et al., 2019): 173-184. by R. Bookman, two recently published papers are suggested to prove that the interpretation of the laminated sedimentary sequence of the Dead Sea, deposited mostly during MIS2 and Holocene pluvials, as annual deposits (i.e., varves) is wrong. In the following response, we delineate several lines of evidence which coalesce to demonstrate that based on the vast majority of evidence, including some of the evidence provided in the comment itself, the interpretation of these sediments as varves is the more likely scientific conclusion. We further discuss the evidence brought up in the comment and its irrelevance and lack of robustness for addressing the question under discussion.
Aldehyde oxidases (AOXs) are a small group of enzymes belonging to the larger family of molybdo-flavoenzymes, along with the well-characterized xanthine oxidoreductase. The two major types of reactions that are catalyzed by AOXs are the hydroxylation of heterocycles and the oxidation of aldehydes to their corresponding carboxylic acids. Different animal species have different complements of AOX genes. The two extremes are represented in humans and rodents; whereas the human genome contains a single active gene (AOX1), those of rodents, such as mice, are endowed with four genes (Aox1-4), clustering on the same chromosome, each encoding a functionally distinct AOX enzyme. It still remains enigmatic why some species have numerous AOX enzymes, whereas others harbor only one functional enzyme. At present, little is known about the physiological relevance of AOX enzymes in humans and their additional forms in other mammals. These enzymes are expressed in the liver and play an important role in the metabolisms of drugs and other xenobiotics. In this review, we discuss the expression, tissue-specific roles, and substrate specificities of the different mammalian AOX enzymes and highlight insights into their physiological roles.
Broad and unspecific use of antibiotics accelerates spread of resistances. Sensitive and robust pathogen detection is thus important for a more targeted application. Bacteriophages contain a large repertoire of pathogen-binding proteins. These tailspike proteins (TSP) often bind surface glycans and represent a promising design platform for specific pathogen sensors. We analysed bacteriophage Sf6 TSP that recognizes the O-polysaccharide of dysentery-causing Shigella flexneri to develop variants with increased sensitivity for sensor applications. Ligand polyrhamnose backbone conformations were obtained from 2D H-1,H-1-trNOESY NMR utilizing methine-methine and methine-methyl correlations. They agreed well with conformations obtained from molecular dynamics (MD), validating the method for further predictions. In a set of mutants, MD predicted ligand flexibilities that were in good correlation with binding strength as confirmed on immobilized S. flexneri O-polysaccharide (PS) with surface plasmon resonance. In silico approaches combined with rapid screening on PS surfaces hence provide valuable strategies for TSP-based pathogen sensor design.
Do all roads lead to Rome?
(2020)
Content website providers have two main goals: They seek to attract consumers and to keep them on their websites as long as possible. To reach potential consumers, they can utilize several online channels, such as paid search results or advertisements on social media, all of which usually require a substantial marketing budget. However, with rising user numbers of online communication tools, website providers increasingly integrate social sharing buttons on their websites to encourage existing consumers to facilitate referrals to their social networks. While little is known about this social form of guiding consumers to a content website, the study proposes that the way in which consumers reach a website is related to their stickiness to the website and their propensity to refer content to others. By using a unique clickstream data set of a video-on-demand website, the study compares consumers referred by their social network to those consumers arriving at the website via organic search or social media advertisements in terms of stickiness to the website (e.g., visit length, number of page views, video starts) and referral likelihood. The results show that consumers referred through social referrals spend more time on the website, view more pages, and start more videos than consumers who respond to social media advertisements, but less than those coming through organic search. Concerning referral propensity, the results indicate that consumers attracted to a website through social referrals are more likely to refer content to others than those who came through organic search or social media advertisements. The study offers direct insights to managers and recommends an increase in their efforts to promote social referrals on their websites.
The COVID-19 virus has hit Germany as unexpectedly as other European countries. For a few weeks, Germans thought that COVID-19 was an issue for Asian states and not for their country. Although Germany continues to be affected by the coronavirus, the situation is nowhere as dire as it was in Britain, Italy or Spain. The race to lift restrictions in Germany began in May, and by early June, the country may be back to normal. Germany, with its enormous financial resources and a well-equipped medical sector, appears to be better placed than other economies to weather the storm.
Germany as a leading power
(2020)
Better land stewardship is needed to achieve the Paris Agreement's temperature goal, particularly in the tropics, where greenhouse gas emissions from the destruction of ecosystems are largest, and where the potential for additional land carbon storage is greatest. As countries enhance their nationally determined contributions (NDCs) to the Paris Agreement, confusion persists about the potential contribution of better land stewardship to meeting the Agreement's goal to hold global warming below 2 degrees C. We assess cost-effective tropical country-level potential of natural climate solutions (NCS)-protection, improved management and restoration of ecosystems-to deliver climate mitigation linked with sustainable development goals (SDGs). We identify groups of countries with distinctive NCS portfolios, and we explore factors (governance, financial capacity) influencing the feasibility of unlocking national NCS potential. Cost-effective tropical NCS offers globally significant climate mitigation in the coming decades (6.56 Pg CO(2)e yr(-1) at less than 100 US$ per Mg CO(2)e). In half of the tropical countries, cost-effective NCS could mitigate over half of national emissions. In more than a quarter of tropical countries, cost-effective NCS potential is greater than national emissions. We identify countries where, with international financing and political will, NCS can cost-effectively deliver the majority of enhanced NDCs while transforming national economies and contributing to SDGs. This article is part of the theme issue 'Climate change and ecosystems: threats, opportunities and solutions'.
In nature, plants are constantly exposed to many transient, but recurring, stresses. Thus, to complete their life cycles, plants require a dynamic balance between capacities to recover following cessation of stress and maintenance of stress memory. Recently, we uncovered a new functional role for macroautophagy/autophagy in regulating recovery from heat stress (HS) and resetting cellular memory of HS inArabidopsis thaliana. Here, we demonstrated that NBR1 (next to BRCA1 gene 1) plays a crucial role as a receptor for selective autophagy during recovery from HS. Immunoblot analysis and confocal microscopy revealed that levels of the NBR1 protein, NBR1-labeled puncta, and NBR1 activity are all higher during the HS recovery phase than before. Co-immunoprecipitation analysis of proteins interacting with NBR1 and comparative proteomic analysis of annbr1-null mutant and wild-type plants identified 58 proteins as potential novel targets of NBR1. Cellular, biochemical and functional genetic studies confirmed that NBR1 interacts with HSP90.1 (heat shock protein 90.1) and ROF1 (rotamase FKBP 1), a member of the FKBP family, and mediates their degradation by autophagy, which represses the response to HS by attenuating the expression ofHSPgenes regulated by the HSFA2 transcription factor. Accordingly, loss-of-function mutation ofNBR1resulted in a stronger HS memory phenotype. Together, our results provide new insights into the mechanistic principles by which autophagy regulates plant response to recurrent HS.
Kurzarbeitergeld
(2020)
Das Kurzarbeitergeld (nachfolgend: KuG) ist eines der wichtigsten Instrumente zur Überwindung der aktuellen Corona-Krise. Der Staat übernimmt einen Teil der Lohnkosten und hilft so, gleichzeitig Arbeitsplätze zu erhalten und die Unternehmen zu entlasten. Kurzarbeit ist die vorübergehende Kürzung der betriebsüblichen normalen Arbeitszeit wegen Mangels an Arbeit bei entsprechender Minderung der Entgeltansprüche. Das KuG ersetzt den Teil des Entgelts, der in Folge des Arbeitsausfalls nicht erarbeitet und ausgezahlt werden kann. Ohne KuG läge das Wirtschaftsrisiko beim Arbeitgeber. Könnte er seine Mitarbeiter wegen der Corona-Krise nicht beschäftigen, würde er nach § 615 Satz 1 BGB den vollen Annahmeverzugslohn schulden. Davon entlastet ihn das Instrument der Kurzarbeit. Das KuG deckt die sog. „Nettoentgeltdifferenz“ zwischen dem bisherigen „Soll-Entgelt“ und dem nach Reduzierung von Arbeitszeit verbleibenden „Ist- Entgelt“ in Höhe von 60 % bzw. bei Arbeitnehmern mit Kindern 67 % ab. Schon in der Finanzkrise 2008/2009 hat sich das KuG hervorragend bewährt, damit Unternehmen ihre Belegschaft behalten können, um nach Ende der Krise wieder voll „durchzustarten“.
Alcohol use disorder (AUD) is the most common substance use disorder worldwide. Although dopamine-related findings were often observed in AUD, associated neurobiological mechanisms are still poorly understood. Therefore, in the present study, we investigate D2/3 receptor availability in healthy participants, participants at high risk (HR) to develop addiction (not diagnosed with AUD), and AUD patients in a detoxified stage, applying F-18-fallypride positron emission tomography (F-18-PET). Specifically, D2/3 receptor availability was investigated in (1) 19 low-risk (LR) controls, (2) 19 HR participants, and (3) 20 AUD patients after alcohol detoxification. Quality and severity of addiction were assessed with clinical questionnaires and (neuro)psychological tests. PET data were corrected for age of participants and smoking status. In the dorsal striatum, we observed significant reductions of D2/3 receptor availability in AUD patients compared with LR participants. Further, receptor availability in HR participants was observed to be intermediate between LR and AUD groups (linearly decreasing). Still, in direct comparison, no group difference was observed between LR and HR groups or between HR and AUD groups. Further, the score of the Alcohol Dependence Scale (ADS) was inversely correlated with D2/3 receptor availability in the combined sample. Thus, in line with a dimensional approach, striatal D2/3 receptor availability showed a linear decrease from LR participants to HR participants to AUD patients, which was paralleled by clinical measures. Our study shows that a core neurobiological feature in AUD seems to be detectable in an early, subclinical state, allowing more individualized alcohol prevention programs in the future.
„Zur rechten Zeit“ ist ein flüssig geschriebenes, gut lesbares und an ein breites Publikum gerichtetes Sachbuch. Es will die Geschichte der Bundesrepublik „unter dem Eindruck der gegenwärtigen rechten Konjunktur anders denn als gängige Erfolgsgeschichte“ (S. 10) erzählen. Die Autorinnen und Autoren sind nicht bestrebt, das Erfolgsnarrativ radikal zu dekonstruieren und damit den Forschungsertrag der Zeitgeschichtsschreibung zu ignorieren, wohl aber rekonstruieren sie Abschattungen und Brüche, die zeigen, dass der Prozess weniger geradlinig war als häufig angenommen – und dass seine Ergebnisse nicht irreversibel sind.
Both climate change and land use regimes affect the viability of populations, but they are often studied separately. Moreover, population viability analyses (PVAs) often ignore the effects of large environmental gradients and use temporal resolutions that are too coarse to take into account that different stages of a population's life cycle may be affected differently by climate change. Here, we present the High-resolution Large Environmental Gradient (HiLEG) model and apply it in a PVA with daily resolution based on daily climate projections for Northwest Germany. We used the large marsh grasshopper (LMG) as the target species and investigated (1) the effects of climate change on the viability and spatial distribution of the species, (2) the influence of the timing of grassland mowing on the species and (3) the interaction between the effects of climate change and grassland mowing. The stageand cohort-based model was run for the spatially differentiated environmental conditions temperature and soil moisture across the whole study region. We implemented three climate change scenarios and analyzed the population dynamics for four consecutive 20-year periods. Climate change alone would lead to an expansion of the regions suitable for the LMG, as warming accelerates development and due to reduced drought stress. However, in combination with land use, the timing of mowing was crucial, as this disturbance causes a high mortality rate in the aboveground life stages. Assuming the same date of mowing throughout the region, the impact on viability varied greatly between regions due to the different climate conditions. The regional negative effects of the mowing date can be divided into five phases: (1) In early spring, the populations were largely unaffected in all the regions; (2) between late spring and early summer, they were severely affected only in warm regions; (3) in summer, all the populations were severely affected so that they could hardly survive; (4) between late summer and early autumn, they were severely affected in cold regions; and (5) in autumn, the populations were equally affected across all regions. The duration and start of each phase differed slightly depending on the climate change scenario and simulation period, but overall, they showed the same pattern. Our model can be used to identify regions of concern and devise management recommendations. The model can be adapted to the life cycle of different target species, climate projections and disturbance regimes. We show with our adaption of the HiLEG model that high-resolution PVAs and applications on large environmental gradients can be reconciled to develop conservation strategies capable of dealing with multiple stressors.