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Anti-TNFα and anti-IL-1β monoclonal antibodies preserve BV-2 microglial homeostasis under hypoxia by mitigating inflammatory reactivity and ATF4/MAPK-mediated apoptosis
Get PDFThe disruption of microglial homeostasis and cytokine release are critical for neuroinflammation post-injury and strongly implicated in retinal neurodegenerative diseases like glaucoma. This study examines microglial responses to chemical hypoxia induced by cobalt chloride (CoCl2) in BV-2 murine microglial cells, focusing on signaling pathways and proteomic alterations. We assessed the protective effects of monoclonal antibodies against TNFα and IL-1β. CoCl2 exposure led to decreased cell viability, reduced mitochondrial membrane potential, increased lactate dehydrogenase release, elevated reactive oxygen species generation, and activation of inflammatory pathways, including nitric oxide synthase (iNOS), STAT1, and NF-κB/NLRP3. These responses were significantly mitigated by treatment with anti-TNFα and anti-IL-1β, suggesting their dual role in reducing microglial damage and inhibiting inflammatory reactivity. Additionally, these treatments reduced apoptosis by modulating ATF4 and the p38 MAPK/caspase-3 pathways. Label-free quantitative mass spectrometry-based proteomics and Gene Ontology revealed that CoCl2 exposure led to the upregulation of proteins primarily involved in endoplasmic reticulum and catabolic processes, while downregulated proteins are associated with biosynthesis. Anti-TNFα and anti-IL-1β treatments partially restored the proteomic profile toward normalcy, with network analysis identifying heat shock protein family A member 8 (HSPA8) as a central mediator in recovery. These findings offer insights into the pathogenesis of hypoxic microglial impairment and suggest potential therapeutic targets
Einfluss eines einjährigen, individualisierten, internetgestützen Sportprogrammes auf die Körperzusammensetzung, das Inflammationsgeschehen und die Lungenfunktion von Menschen mit zystischer Fibrose
Get PDFvii, [116] Seiten ; Illustrationen, Diagramm
Kann KI bei der Analyse von Realienbezeichnungen unterstützen? : Ein Versuch am Beispiel von drei Gedichten des französischen Revolutionsdichters Eugène Pottier
Get PDFIn diesem Aufsatz soll der Frage nachgegangen werden, ob das LLM-Tool Nemotron Ultra 253B bei der Extraktion von Realienbezeichnungen aus sozialen Gedichten aus dem Umfeld der Pariser Commune sowie bei deren korrekter Einordnung im politischen und historischen Kontext einen Mehrwert bieten kann. Trotz der erwarteten Schwierigkeiten in Bezug auf Realienbezeichnungen im Kontext der Pariser Commune und der bei LLM-Tools bekannten ‚Halluzinationen‘ wurde die Aufgabe insgesamt zufriedenstellend gelöst: Die Realienbezeichnungen in den Gedichten wurden fast vollständig korrekt identifiziert, wenngleich zusätzlich wiederkehrend anhand einzelner Textzeilen ohne Realienbezeichnungen historische Hintergründe erklärt wurden. Ungenauigkeiten sowie teils gravierende Fehler in der Analyse der Realienbezeichnungen erinnern aber daran, dass Daten, die durch das LLM-Tool generiert werden, einer genauen Prüfung unterzogen werden müssen. Tendenziöse Einordnungen der Geschehnisse durch das Tool lassen sich möglicherweise darauf zurückführen, dass diese nicht nur im Internet häufig von Personen beschrieben werden, die der Pariser Commune nahestehen und dabei eine gewisse Objektivität fehlen lassen. Das LLM-Tool kann nicht nur bei der Extraktion der Realienbezeichnungen nützlich sein, sondern z. B. auch, bei entsprechender Aufgabenstellung, zur Stärkung von Reflexions- und Recherchefähigkeiten der Studierenden eingesetzt werden.57 Seite
Tracking detector and Møller Polarimeter for the P2 experiment
Get PDFThe primary aim of the P2 experiment is to determine the weak mixing angle sin^2(θ_w) precisely. The experiment will take place at the Mainz Energy Recovery Superconducting Accelerator (MESA), which will provide a beam of electrons with alternating longitudinal polarization and energy of 155 MeV and a current of 150 μA. These conditions enable a targeted relative uncertainty of 0.14 % on sin^2(θ_w) at low four-momentum transfer of Q^2 = 4.5 × 10^−3 GeV^2. This high precision allows for a sensitive search for physics beyond the Standard Model of Elementary Particle Physics.
In the experiment, the parity-violating asymmetry will be measured by integrating Cherenkov detectors. Additionally, a tracking detector will determine the four-momentum transfer Q^2 of electrons scattered in the liquid hydrogen target and reconstruct individual electron tracks for systematic studies. The tracking detector will employ High Voltage Monolithic Active Pixel Sensors (HV-MAPS), a novel technology designed to minimize the material budget and thus reduce multiple scattering. A major challenge is represented by the high electron scattering rate into the tracking detector acceptance, reaching approximately 100 GHz. This demands additional requirements on the data acquisition system and the radiation hardness of all used materials and components.
The value of the electroweak mixing angle will be extracted from the parity-violating rate asymmetry measured in the experiment. The measured asymmetry is directly proportional to the beam polarization. Long-term scattering asymmetry measurements at the Mainz Microtron MAMI have shown that beam polarization can fluctuate by up to 10 % during a typical run. To ensure the required accuracy in the asymmetry measurements, beam polarization must be monitored regularly, ideally continuously, with a precision of ≤0.5 %. Møller polarimetry using a low-density gaseous atomic hydrogen target is the only suitable technique to meet these stringent requirements. A concept for this type of polarimeter, known as the Hydro-Møller polarimeter, was originally proposed by V. Luppov and E. Chudakov. This setup allows for online, non-destructive beam monitoring. However, the gaseous target introduces significant technological challenges that must be addressed. As an interim solution, a Møller polarimeter, which will initially use a conventional solid iron target and operate in discontinuous mode until the hydrogen target is ready, is currently under consideration.169 Seiten ; Illustrationen, Diagramm
Psychosocial work stress, resilience and the risk of tinnitus : results from a population-based cohort study
Get PDFBackground and Objectives: Tinnitus is a common symptom in otolaryngologic practice. Although its pathophysiology is multifactorial and remains mostly unclear, it can be correlated to stress and psychological comorbidities. The aim of this study was to assess the correlation between the occurrence of tinnitus and psychosocial work stress (measured using the German COPSOQ-III, a validated instrument) in a large working population. Materials and Methods: The Gutenberg Health Study is a single-center, prospective, observational cohort study. Participants of working age were included and surveyed using the German COPSOQ-III; they were interviewed regarding the occurrence of tinnitus (yes/no) and stratified according to their resilience (measured using the Brief Resilient Coping Scale). Results: A total of 4933 participants of working age were included in the study cohort, in which tinnitus was reported with a prevalence of 26.3%. Participants with tinnitus answered more negatively in all COPSOQ scales, although not all differences were statistically significant. The scales Emotional Demands, Work Privacy Conflicts, Work Environment/Physical Demands and Insecurity over Working Conditions showed especially high differences in means. In addition, all effect scales showed significant differences between participants with and without tinnitus. The prevalence of tinnitus decreased with increasing resilience. Conclusions: Tinnitus is a symptom highly correlated with psychosocial work stress. As such, it represents a significant health burden within the working community
Measurement report : Influence of particle density on secondary ice production by graupel and frozen drop collisions
Get PDFCollision-induced fragmentation of atmospheric ice particles is a crucially important but understudied secondary ice production mechanism in clouds. We present a laboratory study dedicated to fragmentation due to graupel–graupel and frozen drop–frozen drop collisions and the role of these collisions in augmenting the ice particle concentration in clouds. For this, graupel particles of different sizes and densities were created utilizing dry growth conditions in a cold chamber at −7 and −15 °C using a setup that simulates the natural rotation and tumbling motion of freely falling graupel. Ice spheres, as proxies for frozen drops and ice pellets, were generated by freezing purified water in 3D-printed spherical molds. We conducted collision experiments inside the cold chamber utilizing a fall tube that ensures the central and repeatable collision of ice particles at different collision kinetic energies. The number of fragments generated in the collisions was analyzed, following a theoretical framework, as a function of the collision kinetic energy. The detection limit of our experiments was 30 µm; thus, fragments with sizes lower than 30 µm could not be detected. The observed number of fragments varied between 1 and 20 and was, thus, comparable to or higher than the number of fragments resulting from drop freezing experiments. Our results revealed a strong dependency of the fragment number on the density of the colliding ice particles, which can be attributed to the particles' structure. The sizes of the fragments that we detected were in the submillimeter range for graupel and up to 3 mm for ice spheres. Another set of experiments, focusing on the multiple collision of graupel revealed that the number of fragments generated decreases significantly and approaches zero when a particle undergoes more than three collisions in a row
Understanding GABAergic synapse diversity and its implications for GABAergic pharmacotherapy
Get PDFDespite the substantial contribution of disruptions in GABAergic inhibitory neurotransmission to the etiology of psychiatric, neurodevelopmental, and neurodegenerative disorders, surprisingly few drugs targeting the GABAergic system are currently available, partly due to insufficient understanding of circuit-specific GABAergic synapse biology. In addition to GABA receptors, GABAergic synapses contain an elaborate organizational protein machinery that regulates the properties of synaptic transmission. Until recently, this machinery remained largely unexplored, but key methodological advances have now led to the identification of a wealth of new GABAergic organizer proteins. Notably, many of these proteins appear to function only at specific subsets of GABAergic synapses, creating a diversity of organizer complexes that may serve as circuit-specific targets for pharmacotherapies. The present review aims to summarize the methodological developments that underlie this newfound knowledge and provide a current overview of synapse-specific GABAergic organizer complexes, as well as outlining future avenues and challenges in translating this knowledge into clinical applications
Relevance queries for interval data
Get PDFA wide range of applications manage large collections of interval data. For instance, temporal databases manage validity intervals of objects or versions thereof, while in probabilistic databases attribute values of records are associated with confidence or uncertainty intervals. The main search operation on interval data is the retrieval of data intervals that intersect (i.e., overlap with) a query interval (e.g., find records which were valid in September 2020, find temperature readings with non-zero probability to be within [24, 26] degrees). As query results could be many, we need mechanisms that filter or order them based on how relevant they are to the query interval. We define alternative relevance scores between a data and a query interval based on their (relative) overlap. We define relevance queries, which compute only a subset of the most relevant intervals that intersect a query. Then, we propose a framework for evaluating relevance queries that can be applied on popular domain-partitioning interval indices (interval tree and HINT). We present experiments on real datasets that demonstrate the efficiency of our framework over baseline approaches
Pulsed inhibition of corticospinal excitability by the thalamocortical sleep spindle
Get PDFThalamocortical sleep spindles, i.e., oscillatory bursts at ∼12–15 Hz of waxing and waning amplitude, are a hallmark feature of non-rapid eye movement (NREM) sleep and believed to play a key role in memory reactivation and consolidation. Generated in the thalamus and projecting to neocortex and hippocampus, they are phasically modulated by neocortical slow oscillations (80 Hz). This hierarchical cross-frequency nesting, where slower oscillations group faster ones into certain excitability phases, may enable phase-dependent plasticity in the neocortex, and spindles have thus been considered windows of plasticity in the sleeping brain. However, the assumed phasic excitability modulation had not yet been demonstrated for spindles. Utilizing a recently developed real-time spindle detection algorithm, we applied spindle phase-triggered transcranial magnetic stimulation (TMS) to the primary motor cortex (M1) hand area to characterize the corticospinal excitability profile of spindles via motor evoked potentials (MEP). MEPs showed net suppression during spindles, driven by a “pulse of inhibition” during its falling flank with no inhibition or facilitation during its peak, rising flank, or trough. This unidirectional (“asymmetric”) modulation occurred on top of the general sleep-related inhibition during spindle-free NREM sleep and did not extend into the refractory post-spindle periods. We conclude that spindles exert “asymmetric pulsed inhibition" on corticospinal excitability. These findings and the developed real-time spindle targeting methods enable future studies to investigate the causal role of spindles in phase-dependent synaptic plasticity and systems memory consolidation during sleep by repetitively targeting relevant spindle phases