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ZusammenfassungDeutsch: Als häufige genetisch bedingte neurodegenerative Erkrankung ist die Huntington-Krankheit eine Modellerkrankung – auch für die Gentherapie. Unter den unterschiedlichen Möglichkeiten ist die Entwicklung von Antisense-Oligonukleotiden am weitesten fortgeschritten. Als weitere Optionen auf Ebene der RNA stehen Mikro-RNAs und Modulatoren der RNA-Prozessierung (Spleißen) zur Verfügung, auf DNA-Ebene Zink-Finger-Proteine. Mehrere Produkte befinden sich in der klinischen Prüfung. Diese unterscheiden sich in Applikationsform und systemischer Verfügbarkeit, aber auch in der genauen Wirkung. Ein wichtiger Unterschied könnte darin liegen, ob alle Formen des Huntingtin-Proteins gleichermaßen von der Therapie angesprochen werden, oder ob sich die Therapie präferentiell gegen besonders toxische Formen wie das Exon1-Protein richtet. Die Ergebnisse der kürzlich abgebrochenen GENERATION HD1 Studie waren etwas ernüchternd, am ehesten aufgrund der nebenwirkungsbedingten Liquorzirkulationsstörung. Sie sind daher nur ein Schritt in der Entwicklung zu einer wirksamen Gentherapie gegen die Huntington-Krankheit.

Recently, Jennifer Saul (“Racial Figleaves, the Shifting Boundaries of the Permissible, and the Rise of Donald Trump”, 2017; “Racist and Sexist Figleaves”, 2021) has explored the use of what she calls “figleaves” in the discourse on race and gender. Following Saul, a figleaf is an utterance that, for some portion of the audience, blocks the conclusion that some other utterance, R, or the person who uttered R is racist or sexist. Such racial and gender figleaves are pernicious, says Saul, because, among other things, they can shift the boundaries of what is deemed acceptable to think or say. This paper expands on Saul’s picture in a threefold way: It is first argued that appeals to statistics can function as figleaves. It is then argued that—as far as figleaves go—there is reason to believe that statistics-as-figleaves are especially pernicious. Finally, the paper explores some strategies for counterspeech.

Zusammenfassung Martin Bräuer analysiert die Kurienreform und ihre bisherigen Auswirkungen. Er gibt einen Überblick über den bisherigen Stand der Reformen, die auf dem Dokument „Praedicate Evangelium“ fußen. Weiter wird ein Blick auf die Initiative #OutInChurch geworfen und deren konkrete Auswirkungen auf das kirchliche Arbeitsrecht – im November 2022 wurde eine neue Grundordnung dazu verabschiedet. Anschließend werden die verschiedenen Formate von Synodalität und vor allem der aktuelle Stand des deutschen Synodalen Weges analysiert. Am Ende gibt Daniel Lenski einen kurzen Überblick über den im Juni 2022 veranstalteten Katholikentag in Stuttgart.

The ligand-activated nuclear receptor peroxisome-proliferator-activated receptor-γ (PPARG or PPARγ) represents a potential target for a new generation of cancer therapeutics, especially in muscle-invasive luminal bladder cancer where PPARγ is a critical lineage driver. Here we disclose the discovery of a series of chloro-nitro-arene covalent inverse-agonists of PPARγ that exploit a benzoxazole core to improve interactions with corepressors NCOR1 and NCOR2.

ZusammenfassungBei der Beurteilung der gesundheitlichen Eignung zum Lenken eines Kraftfahrzeuges ist die öffentliche Sicherheit (Unfallprävention) das vorrangige Ziel. Der generelle Zugang zu Mobilität sollte jedoch nicht eingeschränkt werden, wenn kein besonderes Risiko für die öffentliche Sicherheit besteht. Für Menschen mit Diabetes mellitus sind im Führerscheingesetz (FSG) und in der Führerscheingesetz-Gesundheitsversorgung (FSG-GV) wichtige Aspekte zur Fahrsicherheit in Zusammenhang mit akuten und chronischen Komplikationen der Erkrankung geregelt. Zu den kritischen Komplikationen, die für die Verkehrssicherheit relevant sind, gehören schwere Hypoglykämie, ausgeprägte Hyperglykämie und Hypoglykämiewahrnehmungsstörung, sowie schwere Retinopathie und Neuropathie, weiters fortgeschrittene Nierenerkrankung und bestimmte kardiovaskuläre Manifestationen. Bei Verdacht auf Präsenz einer dieser Akutkomplikationen oder Folgeschäden ist eine genaue Evaluierung erforderlich.Darüber hinaus ist die individuelle antihyperglykämische Medikation auf vorhandenes Potenzial für Hypoglykämien zu überprüfen. Sulfonylharnstoffe, Glinide und Insulin gehören in diese Gruppe und sind daher automatisch mit der Auflage einer 5‑jährigen Befristung des Führerscheines assoziiert. Metformin, DPP-4-Hemmer (Dipeptidyl-Peptidase-4-Hemmer, Gliptine), SGLT2-Hemmer (Sodium-dependent-glucose-transporter‑2 inhibitors, Gliflozine), Glitazone und die zu injizierenden GLP-1 Analoga (GLP‑1 Rezeptor Agonisten) weisen kein Hypoglykämiepotential auf und sind daher nicht mit einer Befristung verbunden.Die FSG-GV gibt Spielraum für Interpretation, sodass im Folgenden spezifische Themen zur Fahrsicherheit für Menschen mit Diabetes mellitus aus fachärztlicher und verkehrsrelevanter Sicht aufgearbeitet wurden. Dieses Positionspapier dient zur Unterstützung von Personen, die mit dieser herausfordernden Materie befasst sind.

Die Entwicklungspsychologie beschreibt ontogenetische Prozesse, bei denen es um zeitlich überdauernde, aufeinander aufbauende Veränderungen menschlichen Erlebens und Verhaltens über die gesamte Lebensspanne geht. In diesem Artikel erläutern wir den Zusammenhang zwischen ontogenetischen und phylogenetischen Prozessen, die das zentrale Forschungsinteresse der Vergleichenden Psychologie darstellen. Untersuchungsgegenstand sind hierbei Gemeinsamkeiten und Unterschiede zwischen Menschen und verschiedenen Tierarten, die zum Beispiel Aufschluss über die Evolution von Kognition geben können. Hunde spielen dabei eine besondere Rolle: sie haben durch ihre lange Domestikationsgeschichte einzigartige Fähigkeiten in den Bereichen Kommunikation, Aufmerksamkeit und Kooperation erlangt. Durch die konvergente Entwicklung von Hund und Mensch durch den ähnlichen Selektionsdruck auf beide Spezies, kann man bei einigen dieser Eigenschaften sogar von menschenähnlichen Fähigkeiten sprechen. Developmental psychology describes ontogenetic processes that involve temporally persistent, sequential changes in human experience and behavior across the lifespan. In this article, we explain the relationship between ontogenetic and phylogenetic processes, which are the central research interest of comparative psychology. The targets of such investigations are similarities and differences between humans and various animal species, which can, for example, provide information about the evolution of cognition. Dogs play a special role in this context: Because of their long history of domestication, they have developed unique abilities in communication, attention, and cooperation. The convergent evolution of dogs and humans through similar selection pressures on both species allows us to even speak of human-like abilities in some of these characteristics.

Zusammenfassung In diesem Beitrag wird zunächst ein Blick auf die Geschichte und Entwicklung des Konfessionskundlichen Instituts von 1947 bis heute geworfen. Stand in den ersten Jahren und Jahrzehnten vor allem die römisch-katholische Kirche in Deutschland und Europa im Zentrum der Arbeit, so fächerten sich ab der zweiten Hälfte der sechziger Jahre die Aufgaben immer mehr auf. In einem zweiten Teil wird auf die Methoden der konfessionskundlichen Arbeit geschaut und dargelegt, wie heute diese Arbeit methodisch geschieht.

Von Transportaufträgen „per Zuruf„ bis zu vollständig digitalisierten Prozessen: Das Städtische Klinikum Dresden hat bei der Digitalisierung seiner Logistikprozesse einen weiten Weg zurückgelegt. Dieser war mitunter steinig, unterm Strich jedoch sehr erfolgreich – und ist noch lange nicht zu Ende.

Der Klimawandel und der hohe Grad an Automobilität ain der Stadt sind mit starken Umweltbelastungen verbunden. Ein deutliches Umsteuern mit dem Ziel einer resilienten Stadtentwicklung ist erforderlich. Das Quartier gilt hier als bedeutende räumliche Ebene für die Umsetzung einer sozial-ökologischen Transformation.

This paper studies why investors buy dividend-paying assets and how they time consumption accordingly. We combine administrative bank data linking customers’ consumption and income to portfolio data and survey responses on financial behavior. We find that private consumption is excessively sensitive to dividend income. Investors across wealth, income, and age distributions increase spending precisely around days of dividend receipt. Our results are at odds with a number of existing rational and behavioral explanations, such as financial constraints and impulsiveness. Instead, consumption responses reflect “planned” excess sensitivity, driven by investors who select dividend portfolios, anticipate dividend income, and plan consumption accordingly.

Dioxygenases catalyze stereoselective oxygen atom transfer in metabolic pathways of biological, industrial, and pharmaceutical importance, but their precise chemical principles remain controversial. The α-ketoglutarate (αKG)-dependent dioxygenase AsqJ synthesizes biomedically active quinolone alkaloids via desaturation and subsequent epoxidation of a carbon-carbon bond in the cyclopeptin substrate. Here, we combine high-resolution X-ray crystallography with enzyme engineering, quantum-classical (QM/MM) simulations, and biochemical assays to describe a peroxidic intermediate that bridges the substrate and active site metal ion in AsqJ. Homolytic cleavage of this moiety during substrate epoxidation generates an activated high-valent ferryl (Fe

The moon jellyfish Aurelia aurita is associated with a highly diverse microbiota changing with provenance, tissue, and life stage. While the crucial relevance of bacteria to host fitness is well known, bacteriophages have often been neglected. Here, we aimed to isolate virulent phages targeting bacteria that are part of the A. aurita-associated microbiota. Four phages (Pseudomonas phage BSwM KMM1, Citrobacter phages BSwM KMM2–BSwM KMM4) were isolated from the Baltic Sea water column and characterized. Phages KMM2/3/4 infected representatives of Citrobacter, Shigella, and Escherichia (Enterobacteriaceae), whereas KMM1 showed a remarkably broad host range, infecting Gram-negative Pseudomonas as well as Gram-positive Staphylococcus. All phages showed an up to 99% adsorption to host cells within 5 min, short latent periods (around 30 min), large burst sizes (mean of 128 pfu/cell), and high efficiency of plating (EOP > 0.5), demonstrating decent virulence, efficiency, and infectivity. Transmission electron microscopy and viral genome analysis revealed that all phages are novel species and belong to the class of Caudoviricetes harboring a tail and linear double-stranded DNA (formerly known as Siphovirus-like (KMM3) and Myovirus-like (KMM1/2/4) bacteriophages) with genome sizes between 50 and 138 kbp. In the future, these isolates will allow manipulation of the A. aurita-associated microbiota and provide new insights into phage impact on the multicellular host.

Observers can identify gender based on individual gait styles visually. Existing research showed that gender differences in gait kinematics mainly occur in the frontal and transverse planes and are influenced by various factors. This study adds to the existing work by analysing the kinematic features that distinguish gait styles influenced by gender and gait speeds. 29 females and 33 males without gait disorders took part in this study. A wireless IMU-based sensor system was used to collect 3D kinematic data at 60 Hz on a 15 m walkway at three different gait speeds. Statistical analysis was based on discrete parameters, principal component analysis (PCA), and support vector machines (SVM). Dissimilarities due to different gait speeds were analysed in transverse and frontal planes for the upper body and in the sagittal plane for the upper and lower body (p < 0.001 and Cohen’s d > 0.8). In joint angles (knees; transversal plane), segment orientation angles (upper body; frontal plane) and segment position (upper body; sagittal and frontal plane), statistically significant differences (p < 0.001 and Cohen’s d > 0.8) were observed for gender.Good classification accuracies for joint angles, segment orientation and segment positions of 97-100 % between gait speed and 77-87 % between gender groups were found. In this study, gender had less influence on gait kinematics than gait speed.:1. Introduction 2. Methods 3. Results 4. Discussion

We present a novel data-driven approach for synthesizing human gait motions with individual style characteristics and natural appearance. Our approach is based on the concept of a motion signature that captures the essential characteristic of an individual walking motion. For each joint angle our motion model consists of a shape template and feature functions that describe the variation of that shape with the stride length. For the synthesis of a walking motion, the feature functions are evaluated for a desired stride length. Then the templates are adapted to match the computed features and used as progressions for the joint angles of the skeleton. We demonstrate our data driven approach using motion data captured from 12 individuals. We report on an experiment showing that the synthesized motions have a natural appearance and maintain the individual style.:1. Introduction 2. Related Work 3. Preliminaries 3.1 Mathematics of motion 3.2 Walking motions 4. Data acquisition and analysis 5. Shape templates and feature functions 5.1 Definition of template functions 5.2 Continuous representation of template functions 5.3 Building the feature functions 6. Motion Generation 6.1 Adaption of template functions 6.2 Computing the poses 7 Experimental Results 7.1 Numerical Evaluation 7.2 User Study Acknowledgment References

Die Suche nach einem Standort für ein Endlager für hochradioaktive Abfälle in Deutschland ist eine vielseitige Herausforderung. Die verschiedenen Akteure im Prozess müssen laufend mit aktuellen und komplexen Informationen versorgt werden. Trotz unterschiedlicher Informationsangebote der beteiligten Akteure besteht der Bedarf nach einer zentralen Plattform, bei der auch Interaktion und eigenständiges Zusammenstellen von Informationen möglich ist. Da viele der Informationen, die für die Endlagersuche relevant sind, geographisch verortbar sind, bietet sich ein webbasiertes geographisches Informationssystem (WebGIS) als Ausgangspunkt für eine Plattform an. WebGIS Anwendungen werden bereits gezielt eingesetzt, um Bürger*innen in politischen Entscheidungsprozessen zu informieren oder sogar deren lokales Wissen in der Projektplanung zu berücksichtigen (bspw. in Planungsprozessen von Stromtrassen). Mit einem mehr stufigen transdisziplinären Forschungsansatz wurden gemeinsam mit verschiedenen Akteuren Aspekte erarbeitet, die für die Umsetzung eines WebGIS im Endlagerkontext relevant sind. Die Ergebnisse zeigen, dass durch ein solches System sowohl Expert*innen als auch Neueinsteiger*innen angesprochen werden können. Unter Berücksichtigung der Bedürfnisse beider Zielgruppen werden unter anderem Punkte wie die Transparenz sowie Niedrigschwelligkeit eines WebGIS und technischere Aspekte wie Möglichkeiten der Moderation von Inhalten diskutiert., The search for a repository for high-level radioactive waste (HLW) in Germany is a multifaceted challenge. The various actors in this process must be continuously provided with current and complex information. Despite different information offers and platforms of the involved (institutional) actors, there is a need for a central platform where interaction and independent compilation of information is possible. Since much of the information relevant to the site selection is geographically locatable, a web-based geographic information system (WebGIS) is a suitable starting point for a platform. WebGIS applications are already being used specifically to inform citizens in political decision-making processes or even to take their local knowledge into account in project planning (e.g. in planning processes for power lines). Using a multi-level transdisciplinary research approach, aspects relevant for the implementation of a WebGIS in the repository context were elaborated together with different stakeholders. The results show that such a system can address both experts and newcomers. Considering the needs of both target groups, points such as the transparency and low-threshold nature of a WebGIS and more technical aspects such as possibilities for moderating content are discussed.

Core temperature monitoring is indispensable to prevent children from perioperative thermal perturbations. Although nasopharyngeal measurements are commonly used in anesthesia and considered to reflect core temperature accurately, standardized target depths for probe insertion are unknown in children.Our primary goal was to determine a target depth of nasopharyngeal temperature probe insertion in children by measuring distances on magnetic resonance imaging (MRI). Secondary aims were to correlate these measurements with biometric variables and facial landmark-distances to derive formulas estimating target depth.We conducted a prospective observational study in children ≤12 years undergoing cranial MRI with anesthesia. We documented patient characteristics and measured the landmark-distances nostril-mandible, nostril-tragus, and philtrum-tragus on patient's faces. On MRI, the target point for the probe tip was considered to be the site of the nasopharyngeal mucosa with the closest proximity to the internal carotid artery. After its determination in the transverse axis and triangulation to the sagittal axis, we measured the distance to the nostril. This distance, defined as target insertion depth, was correlated with the patient characteristics and used for univariate and multiple linear regression analysis.One hundred twenty children with a mean age of 4.5 years were included. The target insertion depth ranged from 61.8 mm in infants to 89.8 mm in 12-year-old children. Height correlated best (ρ = 0.685, 95%-CI: [0.57-0.77]). The best-fit estimation in millimeters, "40.8 + height [cm] × 0.32,″ would lead to a placement in the target position in 67% of cases. A simplified approach by categories of 50-80, 80-110, 110-130, and130 cm height with target insertion depths of 60, 70, 80, and 85 mm, respectively, achieved similar probabilities.Height-based formulas could be a valuable proxy for the insertion depth of nasopharyngeal temperature probes. Further clinical trials are necessary to investigate their measurement accuracy.

Zusammenfassung Zunächst wird die katholische Synodalität historisch betrachtet und versucht, die Entwicklungslinien bis heute nachzuzeichnen. In einem weiteren Schritt werden die aktuell gültigen kirchenrechtlichen Bestimmungen und dazu alternative Formen angeschaut. Ein eigener Blick wird auf den Synodalen Weg in Deutschland geworfen und schließlich wird die Diskussion über Synodalität unter dem gegenwärtigen Papst dargestellt und analysiert. Dabei wird auch die aktuell bis 2023 terminierte „Synode für die ganze Kirche“ in den Blick genommen.

Genetic and morphological characteristics of AML patients and healthy donors used for miR-181a/b expression and RASSF1A protein analysis.

Western blot analysis of p53 protein in puromycin and gfp sorted miR-ZIP-expressing NB4 cells. GAPDH was used as internal control. Values below the blots represent the median {plus minus} SD from three independent experiments.

Primer sequences used for mRNA applification by qPCR.

Genetic and morphological characteristics of APL patients used for miR-181a/b expression analysis.

A, Apoptosis assay in NB4 cells 24h and 48h after application of As2O3 (1 µM). B, FACS analysis for CD11b expression in As2O3 treated NB4 cells 48h after application. C, qPCR analysis for C/EBPβ mRNA expression in NB4 cells after As2O3 application. D, Apoptosis assay in NB4 cells 48h after application of doxorubicin (0.01 µg/ml) with or without cytarabine (0.05 µM). E, qPCR analys for C/EBPβ mRNA expression in NB4 cells after doxorubicin and cytarabine application. For qPCR measurement GAPDH was used as control. Bars and values in the dot blots represent the median {plus minus} SD from three independent experiments.* p-value {less than or equal to} 0.05; ** p-value {less than or equal to} 0.01.

Dogs have an extraordinary relationship with humans. We understand, communicate, and cooperate remarkably with our dogs. But almost all we know about dog-human bonds, dog behaviour, and dog cognition is limited to Western, Educated, Industrialized, Rich, Democratic (WEIRD) societies. WEIRD dogs are kept for a variety of functions, and these can influence their relationship with their owner, as well as their behaviour and performance in problem-solving tasks. But are such associations representative worldwide? Here we address this by collecting data on the function and perception of dogs in 124 globally distributed societies using the eHRAF cross-cultural database. We hypothesize that keeping dogs for multiple purposes and/or employing dogs for highly cooperative or high investment functions (e.g., herding, guarding of herds, hunting) will lead to closer dog-human bonds: increased primary caregiving (or positive care), decreased negative treatment, and attributing personhood to dogs. Our results show that indeed, the number of functions associates positively with close dog-human interactions. Further, we find increased odds of positive care in societies that use herding dogs (an effect not replicated for hunting), and increased odds of dog personhood in cultures that keep dogs for hunting. Unexpectedly, we see a substantial decrease of dog negative treatment in societies that use watchdogs. Overall, our study shows the mechanistic link between function and the characteristics of dog-human bonds in a global sample. These results are a first step towards challenging the notion that all dogs are the same, and open questions about how function and associated cultural correlates could fuel departures from the ‘typical’ behaviour and social-cognitive skills we commonly associate with our canine friends. Results - Treatment of dogs and dog functions. - Treatment of dogs, subsistence, ecology, and nuisance parameters. Discussion - Increased affect and utility with multiple dog functions, but uneven effects across individual roles. - No evidence for positive care in societies that keep dogs for hunting. - Differential effects and potentially shifting pressures of utility versus affect. - Decreased negative treatment when dogs are kept for defence. - Distant dog‑human relationships with reliance on animal husbandry. - Complexities in dog‑human interactions. - Dog functions and dog‑human relationships: cultural and psychological perspectives. Methods - Data collection: eHRAF search and coding of variables. - Function and treatment of dogs. - Covariates for the treatment of dogs. - Phylogenetic and spatial dependence. - Statistical modelling.

Relying on aesthetic testimony seems problematic. For instance, it seems problematic for me to simply believe or assert that The Velvet Underground's debut album The Velvet Underground and Nico (1964) is amazing solely because you have told me so, even though I know you to be an honest and competent music critic. But why? After all, there do not seem to be similar reservations regarding testimony from many other domains. In this paper, I will argue that relying on aesthetic testimony seems problematic because we are attached to an ideal of aesthetic authenticity and feel that living up to this ideal is anathema to simply relying on aesthetic testimony.

The demand for novel antimicrobial compounds is rapidly growing due to the rising appearance of antibiotic resistance in bacteria; accordingly, alternative approaches are urgently needed. Antimicrobial peptides (AMPs) are promising since they are a naturally occurring part of the innate immune system and display remarkable broad-spectrum activity and high selectivity against various microbes. Marine invertebrates are a primary resource of natural AMPs. Consequently, cDNA expression (EST) libraries from the Cnidarian moon jellyfishAurelia auritaand the Ctenophore comb jellyMnemiopsis leidyiwere constructed inEscherichia coli. Cell-free size-fractionated cell extracts (< 3 kDa) of the two libraries (each with 29,952 clones) were consecutively screened for peptides preventing the biofilm formation of opportunistic pathogens using the crystal violet assay. The 3 kDa fraction of ten individual clones demonstrated promising biofilm-preventing activities againstKlebsiella oxytocaandStaphylococcus epidermidis. Sequencing the respective activity-conferring inserts allowed the identification of small ORFs encoding peptides (10 – 22 aa), which were subsequently chemically synthesized to validate their inhibitory potential. Biofilm-preventing effects againstK. oxytoca, Pseudomonas aeruginosa, S. epidermidis, andS. aureuswere verified for five synthetic peptides in a concentration-dependent manner, with peptide BiP_Aa_5 showing the strongest effects. The impact of BiP_Aa_2, BiP_Aa_5, and BiP_Aa_6 on dynamic biofilm formation ofK. oxytocawas further validated in microfluidic flow cells, demonstrating a significant reduction in biofilm thickness and volume by BiP_Aa_2 and BiP_Aa_5. Overall, the structural characteristics of the marine invertebrate-derived AMPs, their physicochemical properties, and promising anti-biofilm effects highlight them as attractive candidates for discovering new antimicrobials.

The associated diverse microbiome contributes to the overall fitness ofAurelia aurita, particularly to asexual reproduction. However, howA. auritamaintains this specific microbiome or reacts to manipulations is unknown. In this report, the response ofA. auritato manipulations of its native microbiome was studied by a transcriptomics approach. Microbiome-manipulated polyps were generated by antibiotic treatment and challenging polyps with a non-native, native, and potentially pathogenic bacterium. Total RNA extraction followed by RNAseq resulted in over 155 million reads used for ade novoassembly. The transcriptome analysis showed that the antibiotic-induced change and resulting reduction of the microbiome significantly affected the host transcriptome, e.g., genes involved in processes related to immune response and defense mechanisms were highly upregulated. Similarly, manipulating the microbiome by challenging the polyp with a high load of bacteria (2 × 107cells/polyp) resulted in induced transcription of apoptosis-, defense-, and immune response genes. A second focus was on host-derived quorum sensing interference as a potential defense strategy. Quorum Quenching (QQ) activities and the respective encoding QQ-ORFs ofA. auritawere identified by functional screening a cDNA-based expression library generated inEscherichia coli. Corresponding sequences were identified in the transcriptome assembly. Moreover, gene expression analysis revealed differential expression of QQ genes depending on the treatment, strongly suggesting QQ as an additional defense strategy. Overall, this study allows first insights intoA. aurita’sresponse to manipulating its microbiome, thus paving the way for an in-depth analysis of the basal immune system and additional fundamental defense strategies.

Climate change globally endangers certain marine species, but at the same time, such changes may promote species that can tolerate and adapt to varying environmental conditions. Such acclimatization can be accompanied or possibly even be enabled by a host’s microbiome; however, few studies have so far directly addressed this process. Here we show that acute, individual rises in seawater temperature and salinity to sub-lethal levels diminished host fitness of the benthicAurelia auritapolyp, demonstrated by up to 34 % reduced survival rate, shrinking of the animals, and almost halted asexual reproduction. Changes in the fitness of the polyps to environmental stressors coincided with microbiome changes, mainly within the phyla Proteobacteria and Bacteroidota. The absence of bacteria amplified these effects, pointing to the crucial importance of a balanced microbiota to cope with a changing environment. In a future ocean scenario, mimicked by a combined but milder rise of temperature and salinity, the fitness of polyps was severely less impaired, together with condition-specific changes in the microbiome composition. Our results show that the effects on host fitness correlate with the strength of environmental stress, while salt-conveyed thermotolerance might be involved. Further, a specific, balanced microbiome ofA. auritapolyps is essential for the host’s acclimatization. Microbiomes may provide a means for acclimatization, and microbiome flexibility can be a fundamental strategy for marine animals to adapt to future ocean scenarios and maintain biodiversity and ecosystem functioning.

The Cnidarian Aurelia aurita undergoes a complex life cycle alternating between the benthic polyp to the pelagic medusa. In absence of its natural microbiome, the asexual reproduction of this jellyfish is severely comprised, with limited strobilation and ephyrae release, whereas the recolonization of sterile polyps can restore this defect. Yet, the timing and molecular consequences of the microbiome during the strobilation process had not been investigated. Here, we demonstrate that a microbiota must be present at the polyp stage, before strobilation is initiated, to ensure normal asexual reproduction and a successful polyp-to-jellyfish transition. Addition of a microbiota at later stages of sterile animals failed to restore the defected process. Absence of a microbiome was accompanied with reduced transcription of developmental and strobilation genes. The transcription of strobilation genes was exclusively observed for native and recolonized polyps, pointing to the microbiome's impact on the strobilation process at the molecular level. Moreover, direct cell contact between the host and the bacteria was required for the generation of normal offspring. Overall, this study demonstrates that the timing of the host-microbe interaction in this developmental animal model is crucial, with the microbial impact being essential at the polyp stage, to ensure normal polyp-to-jellyfish transition.

Zusammenfassung Dieser Bericht wirft Schlaglichter auf die katholischen Kirchen, so auf die Enzyklika „Fratelli Tutti“, auf den weltweiten Synodalen Prozess und den deutschen Synodalen Weg als auch auf die versuchten Bischofsrücktritte in Deutschland und die „ökumenische Haftungsgemeinschaft“ aus der Sicht der Alt-Katholischen Kirche.

Mit Dünnschichtsensoren werden die Temperaturen, Kräfte und der Werkzeugverschleiß in Zerspanungsprozessen in unmittelbarer Nähe zur Wirkzone erfasst. Dadurch können zum einen analytische Modelle zur Beschreibung von Randschichtzuständen präzise kalibriert werden. Zum anderen kann mit den in-process erfassten Kenngrößen ein sogenannter Softsensor zur Regelung der Prozessstellgrößen implementiert werden, um gezielt Randzoneneigenschaften des Werkstücks einzustellen. Thin film sensors are used to record temperatures, forces and tool wear in machining processes in the immediate vicinity of the contact zone between tool and workpiece. On the one hand, this makes it possible to precisely calibrate analytical models for describing boundary layer conditions. On the other hand, the parameters recorded in-process can be used to implement a so-called soft sensor for controlling the process parameters in order to specifically adjust the properties of the subsurface layer of the workpiece.

Metal cutting is characterized by high temperatures at the tool-workpiece interface. Although valuable information could be provided by the temperature values, their direct measurement still presents a challenge due to the high contact pressure and the inaccessibility of the process kinematic. In this research work, the current state of thin-film sensors for measuring temperatures on the chip-tool interface has been analyzed with a focus on the measuring phenomena: thermoelectricity and thermoresistivity. Thin-film sensors placed on the cutting tools in or close to the tool-chip contact area are expected to obtain accurate temperature information at the expense of a short lifetime. New insights into thin-film sensors manufacturing, design and calibration are presented, and a new concept of a three-point thermoresistive thin-film sensor is proposed. During orthogonal cutting tests the workpiece deformations were measured through high-speed imaging and the process temperatures were measured with thin-film sensors. In order to validate the temperatures and to obtain the temperature distribution on the cutting edge, Finite Element simulations were carried out. Finally, the potential of using cutting tools with integrated thin-film sensors for in-situ characterization is investigated and a statement for its limitations and potential applications is given.

Peripheral T-cell lymphomas (PTCL) - especially angioimmunoblastic (AITL) and follicular TCL - have a dismal prognosis due to lack of efficient therapies, and patients` symptoms are often dominated by an inflammatory phenotype including fever, night sweats, weight loss and skin rash. In this study, we investigated the role of inflammatory granulocytes and activated cytokine signaling on PTCL-TFH (T-follicular helper type) disease progression and symptoms. We show, that ITK-SYK driven murine PTCLs and primary human PTCL-TFH xenografts both induce inflammation in mice including murine neutrophil expansion and massive cytokine release. Granulocyte/lymphoma interactions were mediated by positive autoregulatory cytokine loops involving INF-γ (CD4+malignant T-cells) and IL-6 (activated granulocytes), ultimately inducing broad JAK kinase activation (Jak1/2/3, Tyk2) in both cell types. Depletion of inflammatory granulocytes via antibodies (Ly6G), genetic granulocyte depletion (LyzM-Cre/MCL1flox/flox) or the deletion of IL-6 within microenvironmental cells blocked inflammatory symptoms, reduced lymphoma infiltration and enhanced mouse survival. Furthermore, unselective JAK kinase inhibitors (ruxolitinib) inhibited both, TCL progression and granulocyte activation in various PTCL mouse models. Our results support the important role of granulocyte-driven inflammation, cytokine-induced granulocyte/CD4+ TCL interactions and the requirement of an intact JAK/STAT signaling pathway for PTCL-TFH development, and support broad JAK kinase inhibition as an effective treatment strategy in early disease stages.

In this study, the interplay among the phospholipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) as a model membrane, the nonsteroidal anti-inflammatory drug naproxen, and the saponin β-aescin are investigated. The naproxen amount was fixed to 10 mol%, and the saponin amount varies from 0.0 to 1.0 mol%. Both substances are common ingredients in pharmaceutics; therefore, it is important to obtain deeper knowledge of their impact on lipid membranes. The size and properties of the DMPC model membrane upon naproxen and aescin addition were characterized with differential scanning calorimetry (DSC), small- and wide-angle X-ray scattering (SAXS, WAXS), and photon correlation spectroscopy (PCS) in a temperature-dependent study. The interaction of all substances was dependent on the lipid phase state, which itself depends on the lipid’s main phase transition temperature Tm. The incorporation of naproxen and aescin distorted the lipid membrane structure and lowers Tm. Below Tm, the DMPC–naproxen–aescin mixtures showed a vesicle structure, and the insertion of naproxen and aescin influenced neither the lipid chain–chain correlation distance nor the membrane thickness. Above Tm, the insertion of both molecules instead induced the formation of correlated bilayers and a decrease in the chain–chain correlation distance. The presented data clearly confirm the interaction of naproxen and aescin with DMPC model membranes. Moreover, the incorporation of both additives into the model membranes is evidenced.

Background Even though mandibular condyle fractures have a high clinical relevance, their treatment remains somewhat challenging. Open reduction and internal fixation are difficult due to narrow surgical approaches, poor overview during reduction, and a possible risk of facial nerve damage. In times of technical endeavors in surgery, there is a trend towards the usage of stable CAD-CAM-implants from additive manufacturing or titanium laser sintering. Up until now, there have not been any reports of fracture treatment of the mandibular condyle using this technique. Results and conclusion We present a workflow for virtual repositioning of the fractured mandibular condyle, to manufacture patient-specific implants for osteosynthesis with the intention of use of resorbable metal alloys in the future.

Monitoring peri-operative body temperature in children is currently mainly achieved through invasive devices. The Temple Touch Pro Temperature Monitoring System estimates core temperature noninvasively based on heat flux thermometry.To investigate the agreement of this noninvasive sensor against standard oesophageal core temperature.A prospective observational study.University hospital recruiting between April and July 2021.One hundred children (32 girls) aged 6 years or younger scheduled for noncardiac surgery, resulting in 6766 data pairs. Exclusion criteria were contraindication for the insertion of an oesophageal temperature probe, and procedures in which one of the measurement methods would interfere with the surgical field.Primary outcome was the agreement analysis by a Bland-Altman comparison with multiple measurements. Posthoc, we performed another agreement analysis after exclusion of a statistically determined equilibration time. Secondary outcomes were the temperature differences over time and subgroup analysis of hypothermic, normothermic and hyperthermic temperature ranges, age, sex and sensor's side by type III analysis of variance. Further, we correlated the sonographically determined depth of the artery with trueness.The mean difference was -0.07°C (95% CI -0.15 to +0.05) with limits of agreement of -1.00 and +0.85°C. After adjusting for an equilibration time of 13 min, the mean difference improved to -0.04°C (95% CI -0.08 to +0.01) with limits of agreement of -0.68 and +0.60°C. Concordance correlation coefficient was 0.83 (95% CI 0.82 to 0.84). Differences between the skin sensor and oesophageal reference increased over time by -0.05°C per hour. Subgroup analysis showed no clinically relevant differences. Depth of artery negatively correlated with trueness by 0.03°C per millimetre.Although the Temple Touch Pro sensor showed acceptable accuracy after allowing for an equilibration time, it still needs further investigation for routine use in children. This particularly affects accuracy in hypothermic ranges, imprecise positioning and applicability in children with immature or vulnerable skin.German Clinical Trials Register, identifier: DRKS00024703.

We propose heat machines that are nonlinear, coherent, and closed systems composed of few field (oscillator) modes. Their thermal-state input is transformed by nonlinear Kerr interactions into nonthermal (non-Gaussian) output with controlled quantum fluctuations and the capacity to deliver work in a chosen mode. These machines can provide an output with strongly reduced phase and amplitude uncertainty that may be useful for sensing or communications in the quantum domain. They are experimentally realizable in optomechanical cavities where photonic and phononic modes are coupled by a Josephson qubit or in cold gases where interactions between photons are transformed into dipole-dipole interacting Rydberg atom polaritons. This proposed approach is a step toward the bridging of quantum and classical coherent and thermodynamic descriptions.

Gain of chromosome 21 (Hsa21) is among the most frequent aneuploidies in leukemia. However, it remains unclear how partial or complete amplifications of Hsa21 promote leukemogenesis and why children with Down syndrome (DS) (ie, trisomy 21) are particularly at risk of leukemia development. Here, we propose that RUNX1 isoform disequilibrium with RUNX1A bias is key to DS-associated myeloid leukemia (ML-DS). Starting with Hsa21-focused CRISPR–CRISPR-associated protein 9 screens, we uncovered a strong and specific RUNX1 dependency in ML-DS cells. Expression of the RUNX1A isoform is elevated in patients with ML-DS, and mechanistic studies using murine ML-DS models and patient-derived xenografts revealed that excess RUNX1A synergizes with the pathognomonic Gata1s mutation during leukemogenesis by displacing RUNX1C from its endogenous binding sites and inducing oncogenic programs in complex with the MYC cofactor MAX. These effects were reversed by restoring the RUNX1A:RUNX1C equilibrium in patient-derived xenografts in vitro and in vivo. Moreover, pharmacological interference with MYC:MAX dimerization using MYCi361 exerted strong antileukemic effects. Thus, our study highlights the importance of alternative splicing in leukemogenesis, even on a background of aneuploidy, and paves the way for the development of specific and targeted therapies for ML-DS, as well as for other leukemias with Hsa21 aneuploidy or RUNX1 isoform disequilibrium.

Gain of chromosome 21 (Hsa21) is among the most frequent aneuploidies in leukemia. However, it remains unclear how partial or complete amplifications of Hsa21 promote leukemogenesis and why children with Down syndrome (DS) (ie, trisomy 21) are particularly at risk of leukemia development. Here, we propose that RUNX1 isoform disequilibrium with RUNX1A bias is key to DS-associated myeloid leukemia (ML-DS). Starting with Hsa21-focused CRISPR–CRISPR-associated protein 9 screens, we uncovered a strong and specific RUNX1 dependency in ML-DS cells. Expression of the RUNX1A isoform is elevated in patients with ML-DS, and mechanistic studies using murine ML-DS models and patient-derived xenografts revealed that excess RUNX1A synergizes with the pathognomonic Gata1s mutation during leukemogenesis by displacing RUNX1C from its endogenous binding sites and inducing oncogenic programs in complex with the MYC cofactor MAX. These effects were reversed by restoring the RUNX1A:RUNX1C equilibrium in patient-derived xenografts in vitro and in vivo. Moreover, pharmacological interference with MYC:MAX dimerization using MYCi361 exerted strong antileukemic effects. Thus, our study highlights the importance of alternative splicing in leukemogenesis, even on a background of aneuploidy, and paves the way for the development of specific and targeted therapies for ML-DS, as well as for other leukemias with Hsa21 aneuploidy or RUNX1 isoform disequilibrium.

Sprachliche und kommunikative Kompetenz ist, wenn auch mit unterschiedlichen Schwerpunkten, eines von vielen Lernzielen für Lernende in allen Bildungseinrichtungen von der Kindertageseinrichtung bis zur Universität. Gefordert wird unter anderem die Produktion von komplexen Diskurseinheiten auf bildungssprachlichem Niveau. Bildungssprache soll in diesem Zusammenhang als ein detaillierter, kontextentbundener verständlicher sowie begrifflich präziser (Morek und Heller 2012, S. 68). Sprachgebrauch mit dem übergeordneten Merkmal der Explizitheit (Feilke 2012) verstanden werden. Das Sprechen kann dabei unter anderem als Werkzeug der Wissensvermittlung (kommunikativ) und des Denkens (epistemisch) fungieren (Morek und Heller 2012). Wie bildungssprachliche Fähigkeiten vermittelt werden können, ist allerdings noch nicht abschließend geklärt (Feilke 2012). Hinzu kommt, dass sich zumindest bezüglich des mündlichen Sprachgebrauchs in Lehr- und Lernkontexten häufig wenig Gelegenheit zum Einüben längerer Redebeiträge bietet. Die Kommunikation über Texte erscheint hierfür schon aufgrund der Annahme geeignet, dass Texte eigentlich erst während der Rezeption von den Rezipient*innen konstruiert werden. Wir gehen mit Hausendorf et al. 2017 davon aus, dass Texte Lesbarkeitshinweise bereitstellen, die von den Rezipient*innen zur Konstruktion ihrer eigenen mentalen Modelle genutzt werden. Diese können als Ausgangspunkt für Gespräche mit längeren Redebeiträgen (epistemische Funktion) verwendet werden, in denen Bedeutungen immer wieder ausgehandelt werden (kommunikative Funktion). Solche Aushandlungen sind zwangsläufig kontextentbunden und fordern auch einen gewissen Grad an sprachlicher Explizitheit. Eine Möglichkeit ist die Verwendung literarischer Texte als Gesprächsanlass. Im Sinne eines erweiterten Textbegriffs (vgl. Staiger 2007) sollen darunter Texte in allen Medien verstanden werden, wie z. B. Bilderbücher, Computerspiele, Comics, Gedichte oder Filme. Die Offenheit literarischer Texte ermöglicht es, dass sie auf stets variierende Art interpretiert und verstanden werden können (vgl. Charlton und Sutter 2007). Dies entlastet die Interaktant*innen davon, eine „richtige Antwort“ geben zu müssen. In Anschluss- oder Begleitkommunikationen wie z.B. in Vorlesegesprächen (vgl. u.a. Wieler 1997, Spinner 2004, Gressnich et al. 2015) sind unterschiedliche Sichtweisen auf die Texte sogar ein erwünschter Effekt, der es auch Rezipient*innen mit sehr unterschiedlichen Wissensständen ermöglicht, sich über die Texte auszutauschen. Außerdem können die am Gespräch Teilnehmenden insofern voneinander lernen, als dass sie die unterschiedlichen Sichtweisen auf den Text nachvollziehen. Auch von der eigenen Deutung abweichende Äußerungen bergen ein großes Potenzial, weil sie dazu veranlassen, die eigene Haltung zum Text zu reflektieren, sie argumentierend zu verteidigen oder zu modifizieren (vgl. u.a. Spinner 2010, Preußer 2017, Heizmann 2019). Im vorliegenden Sammelband werden in elf Beiträgen unterschiedliche Perspektiven und verschiedene Erhebungs- und Auswertungskontexte, unter denen Gespräche über literarische Texte aktuell betrachtet werden, vorgestellt.

Ruinwahrscheinlichkeiten lassen sich in der Theorie als unendliche Summen von Faltungen darstellen. Die Berechnung der Faltungen von Zufallsvariablen gestaltet sich im Allgemeinen jedoch als sehr schwierig und ist mit hoher Komplexität verbunden. Daraus folgt, dass es in den meisten Fällen nicht möglich ist, Ruinwahrscheinlichkeiten exakt zu berechnen. Daher wird oft auf Approximationsverfahren zurückgegriffen, um an Näherungen für die Wahrscheinlichkeit des theoretischen Ruins zu gelangen. Das Ziel dieser Arbeit ist es die Fourier-Cosinus Methode für Ruinwahrscheinlichkeiten, die von Chau, Yam und Yang entwickelt wurde, vorzustellen und zu testen. Diese Methode hat den Vorteil, dass die Ruinwahrscheinlichkeiten mit geringem Aufwand angenähert werden können und für diese Approximation eine Fehlerschranke angegeben werden kann. Diese kann unter bestimmten Voraussetzungen sogar verbessert werden. Im ersten Kapitel dieser Diplomarbeit werden die wichtigsten mathematischen Grundlagen zur Ruintheorie zusammengefasst. Im zweiten Kapitel werden Lévy-Prozesse definiert und einige Eigenschaften dieser Prozesse näher beleuchtet. Das dritte Kapitel beschäftigt sich mit der Fourier-Transformation, die für die Fourier-Cosinus Methode, die dann im vierten Kapitel beschrieben wird, benötigt wird. Die Fehlerabschätzung der Approximation und die Verbesserung dieser Fehlerschranke erfolgt im fünften und sechsten Kapitel. Im Kapitel 7 wird die Fourier-Cosinus Methode erweitert, um auch im Falle einer statistischen Verteilungsfunktion zu einer Approximation zu gelangen. Kapitel 8 stellt eine Methode vor, um für Monotonie in der Approximationfunktion abhängig vom Anfangskapital zu sorgen. Abschließend wird im Kapitel 9 die Fourier-Cosinus Methode anhand eines Cramér-Lundberg Prozesses mit exponentialverteilten Einzelschäden, eines Risikoprozesses mit einem poissonverteilten Verlustprozess und eines Cramér-Lundberg Prozesses mit Gamma-verteilten Einzelschäden getestet., The probability of ruin can be represented in theory as infinite sums of convolutions. However, calculating the convolutions of random variables is generally very difficult and is associated with high complexity. This means that in most cases it is not possible to calculate the probability of ruin exactly. Therefore, approximation methods are often used to obtain approximations for the probability of theoretical ruin.The goal of this work is to present and test the Fourier-Cosine method for probability of ruin, developed by Chau, Yam and Yang. This method has the advantage that the probability of ruin can be approximated with less effort and that a margin of error can be given for this approximation. Under certain conditions, this margin of error can even be improved.In the first chapter of this diploma thesis, the most important mathematical basics of ruin theory are summarized. In the second chapter, Lévy processes are defined and some properties of these processes are examined in more detail. The third chapter deals with the Fourier transform, which is needed for the Fourier-Cosine method described in the fourth chapter. The error estimate of the approximation and the improvement of this margin of error are carried out in the fifth and sixth chapters. In chapter 7, the Fourier-Cosine method is extended to also approximate the case of a statistical distribution function. Chapter 8 introduces a method to ensure monotonicity in the approximation function depending on the initial capital. Finally, in chapter 9, the Fourier-Cosine method is tested using a Cramér-Lundberg process with exponentially distributed individual losses, a risk process with a Poisson-distributed loss process and a Cramér-Lundberg process with Gamma distributed individual losses.

Bei der Beurteilung der gesundheitlichen Eignung zum Lenken eines Kraftfahrzeuges ist die öffentliche Sicherheit (Unfallprävention) das vorrangige Ziel. Der generelle Zugang zu Mobilität sollte jedoch nicht eingeschränkt werden, wenn kein besonderes Risiko für die öffentliche Sicherheit besteht. Für Menschen mit Diabetes mellitus sind im Führerscheingesetz (FSG) und in der Führerscheingesetz-Gesundheitsversorgung (FSG-GV) wichtige Aspekte zur Fahrsicherheit in Zusammenhang mit akuten und chronischen Komplikationen der Erkrankung geregelt. Zu den kritischen Komplikationen, die für die Verkehrssicherheit relevant sind, gehören schwere Hypoglykämie, ausgeprägte Hyperglykämie und Hypoglykämiewahrnehmungsstörung, sowie schwere Retinopathie und Neuropathie, weiters fortgeschrittene Nierenerkrankung und bestimmte kardiovaskuläre Manifestationen. Bei Verdacht auf Präsenz einer dieser Akutkomplikationen oder Folgeschäden ist eine genaue Evaluierung erforderlich. Darüber hinaus ist die individuelle antihyperglykämische Medikation auf vorhandenes Potenzial für Hypoglykämien zu überprüfen. Sulfonylharnstoffe, Glinide und Insulin gehören in diese Gruppe und sind daher automatisch mit der Auflage einer 5‑jährigen Befristung des Führerscheines assoziiert. Metformin, DPP-4-Hemmer (Dipeptidyl-Peptidase-4-Hemmer, Gliptine), SGLT2-Hemmer (Sodium-dependent-glucose-transporter‑2 inhibitors, Gliflozine), Glitazone und die zu injizierenden GLP-1 Analoga (GLP‑1 Rezeptor Agonisten) weisen kein Hypoglykämiepotential auf und sind daher nicht mit einer Befristung verbunden. Die FSG-GV gibt Spielraum für Interpretation, sodass im Folgenden spezifische Themen zur Fahrsicherheit für Menschen mit Diabetes mellitus aus fachärztlicher und verkehrsrelevanter Sicht aufgearbeitet wurden. Dieses Positionspapier dient zur Unterstützung von Personen, die mit dieser herausfordernden Materie befasst sind. Public safety (prevention of accidents) is the primary objective in assessing fitness to drive a motor vehicle. However, general access to mobility should not be restricted if there is no particular risk to public safety. For people with diabetes mellitus, the Führerscheingesetz (Driving Licence Legislation) and the Führerscheingesetz—Gesundheitsverordnung (Driving Licence Legislation Health enactment) regulate important aspects of driving safety in connection with acute and chronic complications of the disease. Critical complications that may be relevant to road safety include severe hypoglycemia, pronounced hyperglycemia and hypoglycemia perception disorder as well as severe retinopathy and neuropathy, endstage renal disease and certain cardiovascular manifestations. If there is a suspicion of the presence of one of these complications, a detailed evaluation is required. In addition, the individual antihyperglycemic medication should be checked for existing potential for hypoglycemia. Sulfonylureas, glinides and insulin belong to this group and are therefore associated with the requirement of a 5-year limitation of the driver’s license. Other antihyperglycemic drugs without potential for hypoglycemia such as Metformin, SGLT‑2 inhibitors (Sodium-dependent-glucose-transporter‑2 inhibitors, gliflozins), DPP-4-inhibitors (Dipeptidyl-Peptidase inhibitors, gliptins), and GLP‑1 analogues (GLP‑1 rezeptor agonists) are not associated with such a time limitation. The relevant laws which regulate driving safety give room for interpretation, so that specific topics on driving safety for people with diabetes mellitus are elaborated from a medical and traffic-relevant point of view. This position paper is intended to support people involved in this challenging matter. Version of record