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miR-223 and NLRP3 Inflammasome: Molecular Regulators in Neuroendocrine Neoplasms and Liver Pathophysiology
No full textDie für diese Dissertation vorgestellten Projekte untersuchten die Rolle von miR-223 und NLRP3 in zwei unabhängigen Modellen. Das NLRP3-Inflammasom ist ein Multiproteinkomplex welcher an essentiellen Stelle Entzündungsaktivität reguliert. Während dessen Aktivierung pro-entzündliche Reaktionen fördert, ist bekannt, dass seine Regulierung durch Zytokine und microRNA-223 gesteuert wird. Ziel dieser Arbeit ist es, die Komplexität des NLRP3 Inflammasoms und dessen Regulation zu betrachten, und zu zeigen, wie Veränderungen an der Aktivität des Inflammasoms sich auf neuroendokrine Neoplasien und Fettlebererkrankungen auswirken kann. Bei Patienten mit neuroendokrinen Neoplasien (NEN) beobachteten wir eine signifikante Regulation der miR-223-Expression und der Expression entzündlicher Zytokine. Wir fanden Korrelationen zwischen miR-223-Spiegeln und dem Neutrophilen Adhäsionsmolekül CD15 bei Patienten mit NEN. Darüber hinaus war miR-223 zwischen Tumoren und deren Tumorumgebung reguliert. In vitro Untersuchungen zeigten, dass reduzierte Expression von miR-223 das NLRP3-Inflammasom aktiviert, Chromogranin A-beeinflusst und die Fragmentierung von CgA durch Plasminaktivität fördert. Der NLRP3-Inflammasom-Knockout in Kupffer-Zellen der Leber veränderte die zellulären Reaktionen in Bezug auf den Fettsäuretransporter CD36, aber auch MRC1/CD206, und beeinflusste die Fettsäureaufnahme in Ko-Kultur mit Hepatozyten. Die zellspezifische NLRP3 (ASC) Inflammasom-Defizienz in vivo veränderte ebenfalls die Entwicklung einer metabolisch assoziierten Steatohepatischen Lebererkrankung und reduzierte Steatose in der Leber nach 10 Wochen Gabe fettreicher Diät. Tiere mit spezifischen KC-Phänotypen wiesen erhöhte Triglyceridspiegel auf. Dieser Anstieg könnte wiederum durch miR-223 vermittelt worden sein, welches stark in Kupffer-Zellen exprimiert wird und den Fettsäurestoffwechsel in der Leber beeinflusst.The projects presented in this thesis explored the roles of miR-223 and NLRP3 in two distinct disease conditions. The NLRP3 inflammasome, a multiprotein complex known to mediate both health and disease. While promoting inflammatory responses, its regulation by cytokines and miR-223 has been widely studied across various pathologies. This thesis aims to elucidate the complexities of NLRP3 activity and regulation and to demonstrate how its manipulation impacts neuroendocrine neoplasms and fatty liver disease. In neuroendocrine neoplasm (NEN) patients, we previously observed significant regulation of miR-223 and inflammatory cytokine expression. We found correlations between miR-223 levels and the neutrophil adhesion molecule CD15. miR-223, was differentially regulated between tumors and their microenvironment. In vitro studies demonstrated that miR-223 knockdown activated the NLRP3 inflammasome, reduced Chromogranin A expression, and increased CgA fragments via plasmin activity. Supernatants from miR-223 knockdown cells activated neutrophils, altering intercellular interactions in co-culture. NLRP3 inflammasome knockout in Kupffer cells induced altered cellular responses regarding the fatty acid transporter CD36 but also MRC1/CD206 and affected fatty acid uptake in co-culture with hepatocytes. These Kupffer cells were unresponsive to both Palmitic as well as Oleic acids, which have been previously shown to affect cellular metabolisms distinctly. Cell-specific NLRP3 (ASC) inflammasome deficiency altered the global response of mice in a model of Metabolic Associated Steatotic Liver Disease, reducing liver steatosis after 10 weeks of diet. However, prolonged growth of these mice significantly altered KC phenotypes in the liver, increasing liver triglyceride levels. This increase may be mediated by miR-223, which is highly expressed by KCs and has been previously shown to influence fatty acid metabolism in the liver
Banale Täuschung und spektrale Autorschaft
No full textDie Arbeit widmet sich den Implikationen von Large Language Models (LLMs) wie ChatGPT auf Konzepte von Autorschaft. Der zentrale analytische Rahmen bildet das Konzept der banalen Täuschung von Simone Natale, welches beschreibt, wie illusionäre Funktionalität und Anthropomorphismen die Wahrnehmung von KI als intelligent ermöglichen.
Es wird dargelegt, dass LLMs Sprache auf Basis einer strukturalistischen Logik der langue nutzen, welche die Fähigkeit zur sprachlichen Kohärenz aus einem Differenzsystem zieht. Im Gegensatz zur menschlichen Kommunikation fehlt der maschinell generierten Poesie der lebensweltliche Bezug und die Intentionalität der parole, was in Bezug auf ein monolithisches Autorschaftsmodell zu einer repräsentativen Leerstelle führt.
Die Arbeit beleuchtet einige Facetten dieser Repräsentationskrise. Einerseits wird die Sinnkonstitution maßgeblich der lesenden Person zugeschrieben, die im performativen Akt der Lektüre Bewusstseinskorrelate synthetisiert und dadurch ästhetische Bedeutung generiert. Andererseits trägt das Interface als black box zur Täuschung bei, indem es technische Arbeitsprozesse verschleiert. Durch die echtzeitliche Interaktion erzeugt das Interface die Illusion einer „appresent presence“, in der ein technisches Anderes sozial interagiert, sich jedoch nie physisch materialisiert.
Zur Charakterisierung der LLM-Autorschaft führe ich abschließend das Konzept der spektralen Autorschaft ein. Dieses Konzept integriert die identifizierten Täuschungsmechanismen und fasst die Kreation künstlicher Poesie in einem Netzwerk technischer, medialer, psychosozialer und kunsthistorischer Bedingungen. Spektrale Autorschaft beruht auf einer Irritation des chronologischen Vektors, indem sie einen aktualisierenden Rückbezug der Vergangenheit durch Textspuren („Nicht-mehr“) mit der antizipierten, illusorischen Präsenz des Anderen („Noch-nicht“) im Augenblick der virtuellen Interaktion verschränkt.This paper examines the implications of large language models (LLMs) such as ChatGPT on concepts of authorship. The central analytical framework is Simone Natale's concept of banal deception, which describes how illusory functionality and anthropomorphism enable the perception of AI as intelligent.
It is argued that LLMs use language based on a structuralist logic of langue, which derives its capacity for linguistic coherence from a system of differences. In contrast to human communication, machine-generated poetry lacks the reference of a lived experience and intentionality of parole, which leads to a representative void in relation to a monolithic model of authorship.
The work highlights some aspects of this crisis of representation. On the one hand, the constitution of meaning is largely attributed to the reader, who synthesizes correlates of consciousness in the performative act of reading and thereby generates aesthetic meaning. On the other hand, the interface poses a black box by obscuring technical work processes. Through real-time interaction, the interface creates the illusion of an “appresent presence” in which a technical other interacts socially but never physically materializes.
To characterize LLM authorship, I conclude by introducing the concept of spectral authorship. This concept integrates the identified mechanisms of deception and summarizes the creation of artificial poetry in a network of technical, media, psychosocial, and art-historical conditions. Spectral authorship is based on an irritation of the chronological vector by intertwining an actualizing reference back to the past through textual traces (“no longer”) with the anticipated, illusory presence of the other (“not yet”) at the moment of virtual interaction
Directional syncretism without directional rules
No full textCertain patterns of directional syncretism, in particular bidirectional syncretism, have been argued to necessitate the power of directional rules that create a form dependency between two cells in a paradigm. The existence of such patterns, divergent bidirectional syncretism in particular, has been claimed to be fatal for the approach to syncretism adopted in Distributed Morphology that holds that (directional) syncretism always involves a retreat to less specific and therefore less marked exponents. In this paper, we will demonstrate that this is not the case. Apparently challenging cases of directional syncretism can be adequately handled on the view that impoverishment may have two outcomes: deletion of features or insertion of contextually unmarked values. Once this view is adopted, bidirectionality is no longer a problem. Furthermore, we argue that this view allows us to still maintain the claim that syncretism is universally markedness decreasing if markedness is defined over insertion contexts rather than exponents.Open Access funding enabled and organized by Projekt DEAL.HORIZON EUROPE European Research Councilhttp://dx.doi.org/10.13039/100019180Humboldt-Universität zu Berlin (1034)Peer Reviewe
a cross analysis from the SHARE project
No full textThe article processing charge was funded by the Open Access Publication Fund of Humboldt-Universität zu Berlin.Objective:
In the context of global aging, the burden of metabolic diseases and arthritis is escalating, necessitating a more comprehensive understanding of the associations between these diseases. As modifiable factor the effect of lifestyle on the progression of arthritis also needs to be considered. Thus, this study aimed to identify the associations of the number of metabolic diseases (MDs) and lifestyle factors, with Rheumatoid Arthritis (RA) and Osteoarthritis (OA).
Methods:
This is a cross analysis of data from European cohort collected between 2017 and 2021. The demographic information, lifestyle factors, and disease data were used for a prospective analysis to explore the impact of MDs on the prevalence of arthritis within the 4-year study period (n = 43,085). In addition, a cross-sectional analysis of 9th wave participants (n = 66,208) was conducted to investigate the relationship between lifestyle factors and arthritis. Cox regression and binary logistic regression models were employed to explore the relationships between various factors and arthritis.
Results:
About 6.52 % and 12.54 % participants developed RA and OA within the 4-year study period. Individuals with MDs exhibited a higher risk of new-onset arthritis compared to no-MDs participants. OA prevalence was positively associated with higher age, higher BMI, less physical activity (PA) and smoking. RA prevalence was positively associated with higher age, higher BMI and less PA.
Conclusion:
There is a causal relationship between the number of MDs and new-onset Rheumatoid Arthritis and Osteoarthritis. Arthritis prevention programs should consider metabolic diseases as well as lifestyle factors in patients at risk.Peer Reviewe
reforming German citizenship through the postmigrant framework
No full textThe article processing charge was funded by the Open Access Publication Fund of Humboldt-Universität zu Berlin.This paper critically examines Germany’s 2024 citizenship reform, designed to promote integration and pluralism through legal and societal transformations. We argue that the prevailing migration discourse in Germany reinforces a one-dimensional political framework, reducing migrants to single-issue subjects—either threats or victims, economic assets or social burdens. This approach to migration falls short of capturing Germany’s evolving socio-political landscape and its changing actors, including queer, feminist, and anti-racist migrant initiatives and cross-generational and multi-ethnic migrant organizations. Adopting an intersectional and postmigrant framework, we explore the dual narrative of increasing structural integration and simultaneously decreasing affective belonging. Here, we are interested in exploring the overlapping contexts of migration and racism in Germany with a perspective that accounts for the experiences of noncitizen migrants, citizen migrants, and nonmigrant racialized citizens. We center our work on the figure of the migrant, not to oversimplify the legal, social, and categorical complexities of this term, but rather to address the social and political conditions of exclusion and marginalization that intersect with race, belonging, and access to rights in Germany. This approach calls for a shift in policy discourse, one that recognizes the intricate interplay of factors shaping migration debates and embraces a postmigrant perspective, viewing migration as a dynamic, multilinear process that drives broader societal transformation.Peer Reviewe
Assessing economic impacts of future GLOFs in Nepal's Everest region under different SSP scenarios using three-dimensional simulations
No full textThe article processing charge was funded by the Open Access Publication Fund of Humboldt-Universität zu Berlin.This study investigates simulated glacial lake outburst floods (GLOFs) at five glacial lakes in the Everest region of Nepal using the three-dimensional model OpenFOAM. It presents the evolution of GLOF characteristics in the 21st century considering different moraine breach scenarios and two Shared Socioeconomic Pathways scenarios. The results demonstrate that in low-magnitude scenarios, the five lakes generate GLOFs that inundate between 0.35 and 2.23 km 2 of agricultural land with an average water depth of 0.9 to 3.58 m. These GLOFs reach distances of 59 to 84 km, affect 30 to 88 km of roads or trails, and inundate 183 to 1699 buildings with 1.2 to 4.9 m of water. In higher scenarios, GLOFs can extend over 100 km and also affect larger settlements in the foothills. Between 80 and 100 km of roads, 735 to 1989 houses and 0.85 to 3.52 km 2 of agricultural land could be inundated, with average water depths of up to 10 m. The high precision of the 3D flood modeling, with detailed simulations of turbulence and viscosity, provides valuable insights into 21st-century GLOF evolution, supporting more accurate risk assessments and effective adaptation strategies.Peer Reviewe
A Case Note of CJEU, Judgement 30 April 2025, St Kliment Ohridski Primary Private School EOOD v QX, C-429/24
No full textThe Court of Justice of the European Union’s judgement of 30 April 2025, on consumer protection in the context of private school contracts, centres on a triangular relationship between parents and private schools as contracting parties, and pupils as service recipients. The court classified parents as consumers while denying this status to pupils despite them being primary beneficiaries of the contract. Fundamental information asymmetries emerge as parents assume contractual obligations without comprehensive knowledge of daily educational delivery, while pupils remain legally invisible here despite being most affected by the service quality. The private schools’ informational advantage enables potential exploitation through fee inflation via unrequested services. This decision therefore highlights tensions between public law obligations and private consumer protection law.Peer Reviewe
Eine Rekonstruktion zielgruppenspezifischer Ansprache an-hand einer Programmanalyse der Berliner Frauenbildungs-einrichtungen Paula Panke e.V. und Flotte Lotte e.V.
No full textDie Arbeit befasst sich mit alleinerziehenden Frauen als Zielgruppe der Erwachsenenbil-dung, insbesondere im Kontext der Frauenbildung. Im Zentrum steht eine Programmana-lyse der Berliner Frauenbildungseinrichtungen Flotte Lotte e.V. und Paula Panke e.V., die im Längsschnitt, über einen Zeitraum von 26 Jahren (1996–2022) durchgeführt wurde. Die Programmanalyse untersucht die Zielgruppenansprache von Frauen mit Er-ziehungsverantwortung sowie spezifisch die Zielgruppenansprache alleinerziehender Frauen. Dabei wird sowohl quantitativ als auch qualitativ gearbeitet; die Kategorienent-wicklung erfolgt deduktiv und induktiv. Der Fokus liegt auf der Frage, wie die Zielgruppe durch die Anbieterinnen konstruiert und entlang welcher Kriterien sie differenziert wird. Auch die Wortwahl der Ankündigungstexte, die Themensetzung der Angebote sowie der organisationale Rahmen wird mit in die Analyse der Zielgruppenansprache einbezogen. Zusätzlich beschäftigt sich die Programmanalyse mit der Frage, inwiefern sich Elemente in den Angeboten wiederfinden lassen, die für die Konzeption von Frauenbildungsange-boten typisch sind. Ergänzend zu der Programmanalyse beleuchtet die Arbeit alleinerzie-hende Frauen aus einer multidimensionalen Perspektive. So geht sie auf mögliche Lern- und Bildungsanschlüsse ein, elaboriert die sozioökonomische Risikokonstellation, die in der Lebensform angelegt ist und zieht daraus Rückschlüsse für potenzielle Bildungskon-zeptionen. Die Arbeit unterstreicht immer wieder die Heterogenität der Zielgruppe allein-erziehender Frauen und verweist auf die Mehrdimensionalität dieser Lebensform im Le-bensverlauf. Darüber hinaus gibt die Arbeit Einblick in zentrale Aspekte der Frauenbil-dungsforschung, etwa deren Verankerung in der Frauenbewegung und die Prinzipien fe-ministischer Bildungsarbeit
a dual-purpose breed at risk
No full textThe article processing charge was funded by the Open Access Publication Fund of Humboldt-Universität zu Berlin.The German Black Pied cattle (DSN) is an endangered dual-purpose breed valued for its genetic diversity and high milk fat and protein content. However, due to competition with higher-yielding dairy breeds, the DSN population has declined, leading to its designation as an endangered breed. While previous research has focused on the milk production traits of DSN, this study aims to address meat traits to further understand the genetic determination of the dual-purpose characteristics of the breed. We conducted genome-wide association studies on 669 DSN bulls to identify genetic loci associated with birth weight, BW, and BW gain at different growth stages. Using imputed whole-genome sequencing data, we identified 14 quantitative trait loci across ten chromosomes. Significant associations were found for birth weight on chromosomes 5 and 18, for body weight at 3 weeks (BW3w) on chromosomes 3 and 16, for body weight at 7 months (BW7m) on chromosomes 3 and 10, and for body weight gain from birth or 3 weeks to 18 months (BWG0d-18m, BWG3w-18m) on chromosomes 4 and 7. Key positional candidate genes influencing muscle and fat tissue development included RERGL and LMO3 (identified for birth weight), MET and CAPZA2 (identified for BWG0d-18m) which are essential for skeletal muscle development and actin filament regulation, respectively, TLN2 (identified for BW7m), MYO1F and ADAMTS10 (identified for BWG3w-18m) which are critical for actin filament assembly, cytoskeletal function, and skeletal development, respectively. Candidate genes such as CPT2 (identified or BW3w) and VPS13C (identified or BW7m) are involved in lipid metabolism and mitochondrial function. Additionally, candidate genes such as IGSF3 (identified for BW7m), KLRC1 and members of the C-type lectin family (identified for birth weight) are associated with immune regulation, and thus, suggest a potential interplay between metabolism, immune function, and growth efficiency. These findings highlight the distinct genetic mechanisms underlying growth at various developmental stages, underscoring the importance of breed-specific genetic evaluations. The identified loci also overlap with previously reported loci for meat and production traits in other cattle breeds, underscoring their relevance and potential utility in DSN breeding strategies. This study provides a foundation for conservation and genomic breeding strategies to maintain the dual-purpose characteristics of DSN through optimising both meat and milk production.Peer Reviewe
Isospin-Breaking Corrections with Rome123 Method and C* Boundary Conditions
No full textDas Standardmodell der Teilchenphysik ist der aktuelle Stand der Technik zur Beschreibung der Wechselwirkungen zwischen Elementarteilchen, berücksichtigt jedoch einige Phänomene wie Gravitation und Dunkle Materie nicht. Die direkte Erforschung neuer Physik scheint mit aktuellen Experimenten nicht möglich zu sein, weshalb die Erfassung indirekter Hinweise an Bedeutung gewinnt. Ein vielversprechender Kandidat ist das anomale magnetische Moment des Myons. Das aktuelle experimentelle Ziel erfordert die Berücksichtigung hadronischer Beiträge. Diese werden durch die QCD beschrieben, die nur durch Lattice-QCD-Simulationen untersucht werden kann. Übliche QCD-Simulationen werden in der isosymmetrischen Näherung durchgeführt, aber die prozentuale Genauigkeit erfordert die Einbeziehung von Isospin-brechenden Effekten (IBE), was QED erfordert. Dies kann mit C*-Randbedingungen erreicht werden. Es gibt zwei Möglichkeiten, IBE zu berechnen: Eine besteht darin, QCD+QED zu simulieren, die andere, die sogenannte Rome123-Methode, darin, QED-Korrekturen perturbativ um isosymmetrische QCD-Erwartungswerte herum zu bewerten. Diese Arbeit präsentiert einige allgemeine Aspekte vollständiger QCD+QED-Simulationen und Ergebnisse der RC*-Kollaboration bezüglich der Abstimmungsstrategie und der Mesonenmassen. Der Schwerpunkt dieser Arbeit liegt auf der Untersuchung der Rome123-Methode und insbesondere der Sea-Quark-IBE. Wir stellen einige numerische Methoden zu deren Berechnung vor und präsentieren die Ergebnisse für 4-Flavour-verbesserte Wilson-Fermionen-Ensembles mit einer Pionmasse von 400 MeV, einem Gitterabstand von 0,05 fm und zwei Volumina. Wir geben auch einen Überblick über die theoretische Untersuchung des statistischen Fehlers dieser Größen und präsentieren die numerischen Ergebnisse zur Fehlerskala der Sea-Quark-IBE mit 3-Flavour-verbesserten Wilson-Fermionen-Ensembles mit 400 MeV Pionmasse für verschiedene Gitterabstände und verschiedene Volumina.The Standard Model of particle physics is the current state-of-the-art for describing the interactions between fundamental particles, but it does not account for some phenomena like Gravity and Dark Matter. Direct research for new physics seems not to be possible with current experiments, which is why the detection of indirect evidence is becoming important. One promising candidate is the anomalous magnetic moment of the muon. The current experimental goal requires considering hadronic contributions. These are described by QCD, which can only be probed by Lattice QCD simulations. Usual QCD simulations are performed in the isosymmetric approximation, but the percentage precision requires including isospin-breaking effects (IBE), which requires QED. This can be done with C* boundary conditions. There are two ways to compute IBE: one is to simulate QCD+QED, the other, called Rome123 method, is to evaluate QED corrections perturbatively around isosymmetric QCD expectation values. This thesis presents some general aspects of full QCD+QED simulations and results of the RC* collaboration concerning the tuning strategy and the meson masses. The main focus of this thesis is the study of the Rome123 method and, in particular, sea-quark IBE. We present some numerical methods to compute them, and the results for 4-flavour improved Wilson fermions ensembles with 400 MeV pion mass, 0.05 fm lattice spacing and two volumes. We also review the theoretical study of the statistical error of these quantities and present numerical results on the error scaling of the sea-quark IBE with 3-flavour improved Wilson fermions ensembles with 400 MeV pion mass, for different lattice spacings and volumes