Search

3d printing is capable of providing dose individualization for pediatric medicines and translating the precision medicine approach into practical application. In pediatrics, dose individualization and preparation of small dosage forms is a requirement for successful therapy, which is frequently not possible due to the lack of suitable dosage forms. For precision medicine, individual characteristics of patients are considered for the selection of the best possible API in the most suitable dose with the most effective release profile to improve therapeutic outcome. 3d printing is inherently suitable for manufacturing of individualized medicines with varying dosages, sizes, release profiles and drug combinations in small batch sizes, which cannot be manufactured with traditional technologies. However, understanding of critical quality attributes and process parameters still needs to be significantly improved for this new technology. To ensure health and safety of patients, cleaning and process validation needs to be established. Additionally, adequate analytical methods for the in-process control of intermediates, regarding their printability as well as control of the final 3d printed tablets considering any risk of this new technology will be required. The PolyPrint consortium is actively working on developing novel polymers for fused deposition modeling (FDM) 3d printing, filament formulation and manufacturing development as well as optimization of the printing process, and the design of a GMP-capable FDM 3d printer. In this manuscript, the consortium shares its views on quality aspects and measures for 3d printing from drug-loaded filaments, including formulation development, the printing process, and the printed dosage forms. Additionally, engineering approaches for quality assurance during the printing process and for the final dosage form will be presented together with considerations for a GMP-capable printer design.

Mobility in the sense of the International Classification of Functioning, Disability and Health ICF-CY is an important prerequisite for participation in everyday life. The present study aims to show to what extent a movement promotion program in kindergarten has an effect on mobility behavior. Methods: The sample consists of 46 boys and 34 girls (age 4.51 ± .98 years) from one regular and one physical education kindergarten. The MobiScreen 4-6 was performed. Group differences were examined using a t-test, and multiple linear regression analysis was used to examine the effects of the predictors kindergarten affiliation, age, sex, born premature, sports club membership, and number of sports hours in the club. Results: Total time shows a strong multiple coefficient of R = .75 with an explained variance of R² = .57; total score also shows strong values of R = .59 and R² = .35. Age and sports club membership are the strongest predictors for both variables. Conclusions: Since raw values are analyzed for total time and score, the high influence of age is obvious. The effect of sports club membership indicates that the children may be better supported in their free time than in the concept of physical education kindergarten. Therefore, the concept of the physical education kindergarten should be reviewed and standardized.

Phosphorylation-dependent interactions play crucial regulatory roles in all domains of life. Forkhead-associated (FHA) and von Willebrand type A (vWA) domains are involved in several phosphorylation-dependent processes of multiprotein complex assemblies. Although well-studied in eukaryotes and bacteria, the structural and functional contexts of these domains are not yet understood in Archaea. Here, we report the structural base for such an interacting pair of FHA and vWA domain-containing proteins, ArnA and ArnB, in the thermoacidophilic archaeon Sulfolobus acidocaldarius, where they act synergistically and negatively modulate motility. The structure of the FHA domain of ArnA at 1.75 Å resolution revealed that it belongs to the subclass of FHA domains, which recognizes double-pSer/pThr motifs. We also solved the 1.5 Å resolution crystal structure of the ArnB paralog vWA2, disclosing a complex topology comprising the vWA domain, a β-sandwich fold, and a C-terminal helix bundle. We further show that ArnA binds to the C terminus of ArnB, which harbors all the phosphorylation sites identified to date and is important for the function of ArnB in archaellum regulation. We also observed that expression levels of the archaellum components in response to changes in nutrient conditions are independent of changes in ArnA and ArnB levels and that a strong interaction between ArnA and ArnB observed during growth on rich medium sequentially diminishes after nutrient limitation. In summary, our findings unravel the structural features in ArnA and ArnB important for their interaction and functional archaellum expression and reveal how nutrient conditions affect this interaction.

Background Texture-related factors such as consistency, vascularity, and adherence vary considerably in meningioma and are thought to be linked with surgical resectability and morbidity. However, data analyzing the true impact of meningioma texture on the surgical management is sparse. Methods Patients with intracranial meningioma treated between 08/2014 and 04/2018 at our institution were prospectively collected for demographics, clinical presentation, histology, and surgical treatment with related morbidity and extend of resection. Tumor characteristics were reported by the surgeon using a standardized questionnaire including items such as tumor consistency, homogeneity, vascularization, and adherence to surrounding neurovascular structure and analyzed for their impact surgical outcome parameters using univariate and logistic regression analyses. Results Tumor texture-related parameters of 300 patients (72.3% female) with meningioma were analyzed. Meningioma localizations were grouped into 3 different cohorts namely convexity, skull base, and posterior. Postoperative occurrence of a neurological deficit (transient 23.0%; permanent 6.1%) was associated with the duration of surgery (P = .001), size of tumor (P = .046), tumor vascularization (P = .015), and adherence to neurovascular structures (P = .002). Coherently, the duration of surgery (mean 230.99 ± 101.33 min) was associated with size of tumor (P < .0001), vascularization (P < .0001), and adherence (P < .0001). Similar associations were recapitulated in subgroup analyses of different tumor localizations. Noteworthy, tumor rigidity had no significant impact on time of surgery and neurological outcome. Conclusions Our analysis demonstrates that tumor texture has an impact on the surgical management of meningioma and provides data that tumor vascularization and adherence are significant factors influencing surgical outcome whereas the influence of tumor consistency has less impact than previously thought.

Many cell death pathways, including apoptosis, regulated necrosis and ferroptosis are relevant for neuronal cell death and share common mechanisms such as the formation of reactive oxygen species (ROS). However, which molecular signaling pathways contribute to related pathologies and how they are interconnected remains elusive.Here, we present the role of cofilin1 in regulating mitochondrial functions and neuronal impairment. Cofilin1 deletion in neuronal HT22 cells exerted increased mitochondrial resilience, assessed by quantification of mitochondrial ROS production, mitochondrial membrane potential and ATP levels. HT22 cells deficient for cofilin1 exhibited a profound glycolytic shift to meet their energy demand in conditions of erastin and glutamate toxicity, whereas control cells were metabolically impaired and underwent ferroptosis and oxytosis, respectively. Further, cofilin1 was confirmed as a key player in glutamate-mediated excitotoxicity in primary cortical neurons isolated from cofilin1flx/flx, CaMKIIα-Cre knock-out mice. Mitochondrial respiration and cell viability were significantly preserved in cofilin1-/- primary neurons under conditions of excitotoxicity.Using isolated mitochondria and recombinant cofilin1, we provide a further link to toxicity-related mitochondrial impairment mediated by oxidized cofilin1. Wildtype cofilin1 directly affected the mitochondrial membrane potential, mitochondrial ROS accumulation and mitochondrial respiration. The detrimental impact of cofilin1 on mitochondria depends on oxidation of cysteine residues at positions 139 and 147.Our findings show that the actin-regulating protein cofilin1 acts as a redox sensor in oxidative cell death pathways of ferroptosis and oxytosis, and also promotes glutamate excitotoxicity. Oxidized cofilin1 links ROS accumulation to mitochondrial demise and neuronal cell death. Protective effects by cofilin1 inhibition are particularly attributed to preserved mitochondrial integrity and function. Thus, interfering with the oxidation and pathological activation of cofilin1 may offer an effective therapeutic strategy in neurodegenerative diseases.

This article deals with multiple address in crossover literature and media. It focusses on the structures and strategies of multiple address, and contrasts that concept with ›double address‹ and other related terms. The concept of multiple address, and therefore of crossover literature and media, can be properly comprehended only when analysed within the context of literary market strategies and the use of the term in public discourse. This article gives a number of examples from literature and audiovisual media, which establish multiple address as a prolific concept for literary and media studies. With the help of this concept a group of texts and other media which has emerged and developed since the late nineteenth century is rendered visible and can be identified as a distinct genre of fiction. This article therefore responds to and contradicts the common view that multiple address and crossover are synonymous with fantasy and merely catchphrases of publishers and distributors. Twilight, Tintenherz, The Hunger Games und – auch 20 Jahre nach Erstpublikation des ersten Bandes ist an ihm kein Vorbeikommen – Harry Potter: Wir kennen sie alle, die großen kommerziellen Erfolge der Literaturbranche der Gegenwart. Seit dem durchschlagenden Erfolg von J.K. Rowlings Romanserie um den Zauberlehrling ist der Markt geradezu überschwemmt von seriellen Erzählungen, die im öffentlichen Diskurs als Fantasyerzählungen wahrgenommen beziehungsweise beschrieben werden. Deren Popularität dokumentieren seit nunmehr 20 Jahren in Deutschland die Jahresbestsellerlisten des Spiegel: Während im Jahr 2000 die deutschen Übersetzungen der ersten drei Harry Potter-Bände die Plätze 1 bis 3 belegen (vgl. Der Spiegel 2000, S. 206), ist auch das postHarry Potter-Deutschland diese Art von Romanserien nicht leid. Im Jahr 2008 finden sich unter den meistverkauften Romanen unter anderem Cornelia Funkes TintenherzTrilogie (2003–2007), Stephenie Meyers Bis(s)-Romane (2005–2009), Bände von Christopher Paolinis Eragon (2004–2011), der Romanserie House of Night (2009–2014) des Mutter-und-Tochter-Teams Casts, Kerstin Giers Liebe geht durch alle Zeiten- (2009–2010) und Silber-Serien (2013–2015) und Suzanne Collins’ Die Tribute von Panem (2008–2010) (vgl. Der Spiegel 2009, S. 131). Die ehemals der Allgemeinliteratur vorbehaltene Belletristik-Bestsellerliste des Spiegel kann sich Romanen nicht länger erwehren, die LeserInnen in den Kinder- und Jugendbuchabteilungen ihrer Buchhandlungen finden können. ...

The tumor-suppressor cylindromatosis (CYLD) is a deubiquitinating enzyme and key regulator of cell proliferation and inflammation. A genome-wide siRNA screen linked CYLD to receptor interacting protein-1 (RIP1) kinase-mediated necroptosis; however, the exact mechanisms of CYLD-mediated cell death remain unknown. Therefore, we investigated the precise role of CYLD in models of neuronal cell death in vitro and evaluated whether CYLD deletion affects brain injury in vivo. In vitro, downregulation of CYLD increased RIP1 ubiquitination, prevented RIP1/RIP3 complex formation, and protected neuronal cells from oxidative death. Similar protective effects were achieved by siRNA silencing of RIP1 or RIP3 or by pharmacological inhibition of RIP1 with necrostatin-1. In vivo, CYLD knockout mice were protected from trauma-induced brain damage compared to wild-type littermate controls. These findings unravel the mechanisms of CYLD-mediated cell death signaling in damaged neurons in vitro and suggest a cell death-mediating role of CYLD in vivo.

Einkaufen, Kochen, Waschen, Telefonieren. All das gehört zu einer selbstständigen Lebensführung. Mit dem Tölzer Screening der Handlungsplanung in den erweiterten ADLs können Ergotherapeuten bereits in der Klinik einschätzen, ob Klienten ihren Alltag zu Hause wieder bewerkstelligen können.

Ferroptosis has been defined as an oxidative and iron-dependent pathway of regulated cell death that is distinct from caspase-dependent apoptosis and established pathways of death receptor-mediated regulated necrosis. While emerging evidence linked features of ferroptosis induced e.g. by erastin-mediated inhibition of the Xc- system or inhibition of glutathione peroxidase 4 (Gpx4) to an increasing number of oxidative cell death paradigms in cancer cells, neurons or kidney cells, the biochemical pathways of oxidative cell death remained largely unclear. In particular, the role of mitochondrial damage in paradigms of ferroptosis needs further investigation. In the present study, we find that erastin-induced ferroptosis in neuronal cells was accompanied by BID transactivation to mitochondria, loss of mitochondrial membrane potential, enhanced mitochondrial fragmentation and reduced ATP levels. These hallmarks of mitochondrial demise are also established features of oxytosis, a paradigm of cell death induced by Xc- inhibition by millimolar concentrations of glutamate. Bid knockout using CRISPR/Cas9 approaches preserved mitochondrial integrity and function, and mediated neuroprotective effects against both, ferroptosis and oxytosis. Furthermore, the BID-inhibitor BI-6c9 inhibited erastin-induced ferroptosis, and, in turn, the ferroptosis inhibitors ferrostatin-1 and liproxstatin-1 prevented mitochondrial dysfunction and cell death in the paradigm of oxytosis. These findings show that mitochondrial transactivation of BID links ferroptosis to mitochondrial damage as the final execution step in this paradigm of oxidative cell death., Graphical abstract fx1, Highlights • CRISPR Bid knockout reveals a pivotal role for BID in oxidative death. • BID links ferroptosis to mitochondrial demise in neurons. • Mitochondrial damage determines cell death in oxytosis and ferroptosis.

As the main tool for the achievement of the proper functioning of the internal market, the Union is focused on the process of harmonization. The role of harmonization in the EU’s internal market is to remove barriers to trade and to facilitate free movement of goods, persons, services, and capital (as well as payment). This can be achieved in many ways, including through the adoption of harmonization, i.e., approximation measures, such as directives and regulations. The established CJEU case law confirms that the aim of harmonization measures is to ‘reduce disparities between legal systems.’ This aim’s realization very often depends upon the form of the chosen harmonization measure and the level of harmonization the measure is based on (e.g., minimum, maximum, full (targeted) harmonization). However, today, we are faced with changes in the regulatory approach of the EU legislator and these changes are greatly affecting the process of harmonization. Due to the increased level of harmonization, EU directives are starting to appear and function more like EU regulations, and vice versa. Because of numerous optional clauses, clauses of minimal harmonization, and the so- called ‘opening clauses’, EU regulations are not reducing but enabling ‘disparities between legal systems.’ As an example, authors are analyzing the EU’s General Data Protection Regulation (GDPR) containing more than 69 opening clauses, which play an important role in the process of harmonization and present an instrument of interplay between EU law and Member States’ laws. Therefore, it remains to be answered within the lines of this paper whether the role of opening clauses is in compliance with the aim of harmonization in the EU law.

Abstract Pseudomonads are among the most common bacteria in soils, limnic ecosystems, and human, animal, or plant host environments, including intensively studied species such as Pseudomonas aeruginosa, P. putida, or P. fluorescens. Various gene expression systems are established for some species, but there is still a need for a simple system that is suitable for a wide range of pseudomonads and that can be used for physiological applications, i.e., with a tuning capacity at lower expression levels. Here, we report the establishment of the anthranilate-dependent PantA promoter for tunable gene expression in pseudomonads. During studies on P. fluorescens, we constructed an anthranilate-inducible AntR/PantA-based expression system, named pUCP20-ANT, and used GFP as reporter to analyze gene expression. This system was compared with the rhamnose-inducible RhaSR/PrhaB-based expression system in an otherwise identical vector background. While the rhamnose-inducible system did not respond to lower inducer concentrations and always reached high levels over time when induced, expression levels of the pUCP20-ANT system could be adjusted to a range of distinct lower or higher levels by variation of anthranilate concentrations in the medium. Importantly, the anthranilate-inducible expression system worked also in strains of P. aeruginosa and P. putida and therefore will be most likely useful for physiological and biotechnological purposes in a wide range of pseudomonads. Key points • We established an anthranilate-inducible gene expression system for pseudomonads. • This system permits tuning of gene expression in a wide range of pseudomonads. • It will be very useful for physiological and biotechnological applications.

Die Arbeit widmet sich auf unterschiedlichen Ebenen der Problematik der Energiearmut und vereint dabei verbraucher-, sozial- und zivilrechtliche Fragestellungen. Die Richtlinie 2009/72 des Europäischen Parlaments und des Rates vom 13. Juli 2009 über gemeinsame Vorschriften für den Elektrizitätsbinnenmarkt und zur Aufhebung der Richtlinie 2003/54/EG enthielt bereits 2009 einen konkreten Umsetzungsauftrag zur Bekämpfung von Energiearmut. Die Mitgliedstaaten sollten dazu u.a. ein Konzept entwickeln, das sich auf verletzliche VerbraucherInnen und ihren Schutz vor Stromsperrungen bezieht. Durch die Nachfolgerichtlinie (EU) 2019/944 wird dieser Umsetzungsauftrag bekräftigt. Inwieweit die bestehenden Regelungen im Sozial-, Zivil-und Kartellrecht bereits einen hinreichenden Schutz vor Energiearmut – insbesondere im Hinblick auf die europäischen Vorgaben und den Schutz verletzlicher VerbraucherInnen - gewährleisten, wird innerhalb dieser Arbeit untersucht. Ausgehend von diesem Ergebnis werden rechtspolitische und rechtliche Überlegungen zum Schutz vor Energiearmut in einem Policy Mix zusammengefasst.

OBJECTIVE Texture-related factors such as consistency, vascularity and adherence vary considerably in meningioma and are thought to be linked with surgical resectability and morbidity. However, data analyzing the true impact of meningioma texture on the surgical management is sparse. METHODS Patients with intracranial meningioma treated between 08/2014-04/2018 were prospectively collected for demographics and surgical treatment with related morbidity and extend of resection (EOR). Tumor characteristics were reported by the surgeon using a standardized questionnaire including items such as tumor rigidity, homogeneity, vascularization and adherence to surrounding neurovascular structure and analyzed for their impact on EOR and neurological outcome using multivariate regression analyses. RESULTS 296 patients (214 female (72.3%) with intracranial meningiomas were included with a mean age of 60.4 years. 23% of patients had a transient and 6.1% permanent neurological deficits and three patients (1.1%) died. The occurrence of a neurological deficit was associated with duration of surgery (p = 0.013) and tumor adherence to neurovascular structures (p = 0.014). Similar associations were observed in subgroup analyses of different tumor localizations (e.g. convexity and skull base). With regard to EOR, the tumor adherence (p < 0.001) and recurrent surgery (p = 0.001) were found as independent predictors for subtotal resection. Noteworthy, the tumor rigidity had no significant impact on the morbidity or EOR. CONCLUSION Our analysis supports the notion that tumor texture has an impact on the surgical management of meningioma and provides sound data that tumor adherence is a significant factor influencing neurological outcome and EOR. In contrast, the influence of tumor rigidity has less impact than previously thought. Preoperative prediction of tumor texture is therefore required for optimized risk assessment.

Organisms have evolved motility organelles that allow them to move to favorable habitats. Cells integrate environmental stimuli into intracellular signals to motility machineries to direct this migration. Many motility organelles are complex surface appendages that have evolved a tight, hierarchical regulation of expression. In the crenearchaeon Sulfolobus acidocaldarius, biosynthesis of the archaellum is regulated by regulatory network proteins that control expression of archaellum components in a phosphorylation-dependent manner. A major trigger for archaellum expression is nutrient starvation, but although some components are known, the regulatory cascade triggered by starvation is poorly understood. In this work, we identify the starvation-induced Ser/Thr protein kinase ArnS (Saci_1181) which is located proximally to the archaellum operon. Deletion of arnS results in reduced motility, though the archaellum is properly assembled. Therefore, our experimental and modelling results indicate that ArnS plays an essential role in the precisely controlled expression of archaellum components during starvation-induced motility in Sulfolobus acidocaldarius. Furthermore we combine in vivo experiments and mathematical models to describe for the first time in archaea the dynamics of key regulators of archaellum expression. This article is protected by copyright. All rights reserved.

We address the widely studied question of ‘When does it pay to be green?’ by theorizing that environmental corporate social responsibility (CSR) is a specific form of knowledgeable decision-making....

In natural environments microorganisms encounter extreme changes in temperature, pH, osmolarities and nutrient availability. The stress response of many bacterial species has been described in detail, however, knowledge in Archaea is limited. Here, we describe the cellular response triggered by nutrient limitation in the thermoacidophilic crenarchaeon Sulfolobus acidocaldarius. We measured changes in gene transcription and protein abundance upon nutrient depletion up to 4 h after initiation of nutrient depletion. Transcript levels of 1118 of 2223 protein coding genes and abundance of approximately 500 proteins with functions in almost all cellular processes were affected by nutrient depletion. Our study reveals a significant rerouting of the metabolism with respect to degradation of internal as well as extracellular-bound organic carbon and degradation of proteins. Moreover, changes in membrane lipid composition were observed in order to access alternative sources of energy and to maintain pH homeostasis. At transcript level, the cellular response to nutrient depletion in S. acidocaldarius seems to be controlled by the general transcription factors TFB2 and TFEβ. In addition, ribosome biogenesis is reduced, while an increased protein degradation is accompanied with a loss of protein quality control. This study provides first insights into the early cellular response of Sulfolobus to organic carbon and organic nitrogen depletion.

Autor_innen wie Daniel Kehlmann, Bernhard Schlink oder Julia Franck sind seit etlichen Jahren nicht mehr aus dem deutschsprachigen – und auch internationalen – Literaturbetrieb wegzudenken, ihre Romane werden immer wieder auf den Bestsellerlisten des Spiegel geführt. Bestsellerliteratur hatte lange Zeit in Literaturkritik und -wissenschaft einen schwierigen Stand. Anerkennende, wenn nicht sogar begeisterte Diskursmeinungen zu den oben genannten Schriftsteller_innen und weiteren sprechen aber eine andere Sprache: Der Bestseller scheint in der Literaturkritik anzukommen.Wer Bestseller-Phänomene aus dem allgemeinliterarischen mit solchen aus dem kinder- und jugendliterarischen System vergleicht, stellt aber fest, dass dieses auf den Bestseller bezogene Umdenken nur partiell stattgefunden hat. Die Crossover-Literatur, die ein generationenübergreifendes Publikum adressiert, wird im Gegenteil Gegenstand von Debatten, die einen gesellschaftlichen Kompetenzverlust, eine gesellschaftliche Infantilisierung befürchten.Ausgehend von Moritz Baßlers Beobachtungen zum Populären Realismus wird deutlich, dass Populärer Realismus und Crossover-Literatur Strategien teilen, die ihre (internationale) Popularität bedingen und an denen sich ein systemübergreifendes Instrumentarium der Bestseller-Forschung ansetzen ließe. Diskursanalytisch wird aber ebenso deutlich, dass in der Wertung dennoch ein Unterschied gemacht wird. Dieser diskursiv getroffene Unterschied kann nicht losgelöst betrachtet werden von einer Perspektive auf Kindheit und Jugend in unserer Gesellschaft und muss im Kontext verstanden werden einer Diskurstradition, die Kinder- und Jugendliteratur seit Jahrhunderten mindere literarische Wertigkeit unterstellt.

In response to a variety of environmental cues, prokaryotes can switch between a motile and a sessile, biofilm-forming mode of growth. The regulatory mechanisms and signaling pathways underlying this switch are largely unknown in archaea but involve small winged helix-turn-helix DNA-binding proteins of the archaea-specific Lrs14 family. Here, we study the Lrs14 member AbfR1 of Sulfolobus acidocaldarius. Small-angle X-ray scattering data are presented, which are consistent with a model of dimeric AbfR1 in which dimerization occurs via an antiparallel coiled coil as suggested by homology modeling. Furthermore, solution structure data of AbfR1-DNA complexes suggest that upon binding DNA, AbfR1 induces deformations in the DNA. The wing residues tyrosine 84 and serine 87, which are phosphorylated in vivo, are crucial to establish stable protein-DNA contacts and their substitution with a negatively charged glutamate or aspartate residue inhibits formation of a nucleoprotein complex. Furthermore, mutation abrogates the cellular abundance and transcription regulatory function of AbfR1 and thus affects the resulting biofilm and motility phenotype of S. acidocaldarius. This work establishes a novel wHTH DNA-binding mode for Lrs14-like proteins and hints at an important role for protein phosphorylation as a signal transduction mechanism for the control of biofilm formation and motility in archaea.