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Etablierung einer Co-Kultur aus Osteoblasten und Makrophagen zur Untersuchung des Einflusses von Bone Sialoprotein (BSP) und BSP-Antikörpern auf die Differenzierung zu Osteoklasten
Get PDFIV, 75 Seiten ; Illustrationen, Diagramm
Orientierende Untersuchungen zur Schimmelpilzbelastung bei Baumaßnahmen in der Universitätsmedizin Mainz
Get PDFIII, 47 Seiten ; Illustrationen, Diagramm
Gut dysbiosis is linked to severe steatosis and enhances its diagnostic performance in MASLD
Get PDFBackground Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease globally, with rising prevalence linked to metabolic syndrome (MetS). Excessive liver fat accumulation (steatosis) worsens disease progression and MASLD prognosis. Moreover, gut microbiota dysbiosis might promote steatosis, accelerating the disease progression to severe stages. Identifying gut microbiota signatures specific to steatosis severity might improve its diagnosis and inform personalised interventions in MASLD. This study aimed to characterise associations between gut microbiota composition and hepatic steatosis severity in a cohort of patients with MASLD/MetS. Ultimately, we aimed to assess the potential for microbiota features to enhance the diagnosis of severe steatosis.
Methods A cross-sectional cohort of 61 patients with MetS with extensive clinical history was recruited at different stages of MASLD. Transient elastography was used to evaluate liver fibrosis and steatosis severity. Participants’ faecal microbiota were profiled using 16S rRNA gene sequencing. Statistical analyses first identified correlations between microbiota profiles and patients’ phenotypes, while disentangling important confounders such as medication. Identified features were then used to build predictive models for diagnosing severe steatosis.
Results High steatosis severity was distinctly associated with a higher prevalence of the inflammation-associated Bacteroides 2 (Bact2)-enterotype, accompanied by a lower proportion of beneficial commensals (eg, Akkermansia) and a higher proportion of opportunistic bacteria (eg, Streptococcus). Patients harbouring a Bact2-enterotype reached severe steatosis at lower Fatty Liver Index (FLI) thresholds. Using Bact2-carrier status together with FLI in a predictive model significantly improved the classification of severe steatosis (accuracy 90%, receiver operating characteristics 96%) when compared with FLI alone.
Conclusion Gut microbiota composition and dysbiosis (defined as Bact2-enterotype) are distinctly associated with steatosis severity in MASLD/MetS. Patient stratification by microbiota composition enhances the diagnostic classification of severe steatosis in MASLD, suggesting a potential for personalised interventions in patients with microbiota dysbiosis
Barriers to suicide research are also barriers to suicide prevention : insights from conducting a mixed-methods project in oncology
Get PDFCancer patients are at risk for suicidal crises. There is a need for more research concerning specific risk/protective factors and knowledge about barriers and resources of prevention efforts in clinical practice. This contribution reports on difficulties during the realization of a research project that aimed to address these research gaps, among other approaches, via a patient survey and an interview study with healthcare professionals (HCPs). Throughout recruitment and implementation, we documented the barriers encountered and systematically analyzed them.
We identified three main categories of obstacles toward the research endeavor that also hold meaning for the efficacy of suicide prevention: First, suicidal thoughts and behaviors are not (allowed to be) an issue in oncology, subsuming the denial of their occurrence, the minimization of their relevance, the alleged appropriateness of the construct to oncology, and the rejection of responsibility; second, prevailing suicide myths, in particular of iatrogenic harm; and third, strong, negative emotional reactions undermining dialogue.
We interpret these experiences against previous considerations of dysregulated responses to suicidal patients in the healthcare setting and analyze their causes and functions. These findings highlight the urgent need for structured education on suicide prevention across medical disciplines, particularly in oncology. Addressing both knowledge gaps and emotional barriers among HCPs is crucial for fostering a proactive, evidence-based approach to suicide prevention. Future efforts should focus on integrating suicide risk assessment and intervention strategies into routine cancer care, alongside improved interdisciplinary collaboration and institutional support
Broader functional role of Meprin β in the murine brain and in the APP/V717I mouse model
Get PDFDie Alzheimer-Krankheit (AD) ist eine sich weltweit rasch ausbreitende Gesundheitskrise, deren Fallzahlen sich aufgrund der steigenden Lebenserwartung bis 2050 voraussichtlich mehr als verdoppeln werden. Früher fälschlicherweise als einfache senile Demenz diagnostiziert, wird AD heute durch eine Kombination aus klinischen Untersuchungen, Bildgebung des Gehirns (MRT, PET) und spezifischen Biomarkern wie Amyloid-beta (Aβ) und Tau diagnostiziert. Die Pathologie umfasst Neurodegeneration, die durch die Ansammlung fehlgefalteter Proteine und chronischer Entzündungen verursacht wird.
AD manifestiert sich hauptsächlich in zwei Formen: der seltenen, früh auftretenden familiären AD (FAD) und der weitaus häufigeren, spät auftretenden sporadischen AD. Die vorherrschende Erklärung, die Amyloid-Hypothese, geht davon aus, dass die Anhäufung von Aβ die primäre auslösende Ursache ist. Dieser toxische Prozess erfolgt über den amyloidogenen Stoffwechselweg der Verarbeitung des Amyloid-Vorläuferproteins (APP), dem der schützende nicht-amyloidogene Stoffwechelweg gegenübersteht. Dieser schützende Weg wird durch positive Lebensstilfaktoren wie gesunde Ernährung und regelmäßige Bewegung unterstützt.
Aktuelle Forschungsbemühungen gehen über Aβ und Tau hinaus und untersuchen die Rolle spezifischer Proteasen im Gehirn, wie z. B. Meprin β, welches als Risikofaktor für AD identifiziert wurde. Während aktuelle Therapien weitgehend nur eine Linderung der Symptome bieten, konzentrieren sich zukünftige Strategien auf Interventionen, die frühzeitig im Krankheitsverlauf auf die Kernpathologie abzielen können.
Hier berichten wir, dass die Überexpression von Meprin β das Lernverhalten von Mäusen auf verhaltensbezogener und elektrophysiologischer Ebene beeinflusst. Wir zeigen, dass die NMDA- und AMPA-Rezeptorlevel unverändert bleiben, wobei die N-Terminomik-Analyse Brevican als potenziellen Kandidaten für die beobachteten Effekte identifiziert. Gleichzeitig zeigt die Überexpression von Meprin β in einem AD-Mausmodell (APP/Ld) keine beobachtbaren Unterschiede im Lernverhalten. Die Analyse von löslichem Aβ im Kortex und Hippocampus ergab, dass Mäuse mit Meprin-β-Überexpression in einem APP/Ld-Hintergrund mehr Aβ produzieren als APP/Ld-Tiere. Die höheren Aβ-Spiegel führen nicht zur Bildung von Plaques, während wir eine intrazelluläre Akkumulation beobachten.Alzheimer's Disease (AD) is a rapidly growing global health crisis, with case numbers projected to more than double by 2050 due to increasing life expectancy. Historically misdiagnosed as simple senile dementia, AD is now diagnosed through a combination of clinical assessments, brain imaging (MRI, PET), and specific biomarkers like amyloid-beta (Aβ) and tau. Pathology involves neurodegeneration caused by the accumulation of misfolded proteins and chronic inflammation.
AD primarily manifests in two forms: the rare, early-onset familial AD (FAD), driven by gene mutations that lead to the overproduction of Aβ, and the far more common, late-onset sporadic AD, which results from the impaired clearance of Aβ from the brain. The dominant explanation, the amyloid hypothesis, posits that the accumulation of is the primary initiating pathological event. This toxic process occurs via the amyloidogenic pathway of amyloid precursor protein (APP) processing, which is contrasted by the protective non-amyloidogenic pathway. This protective pathway is supported by beneficial lifestyle factors, including healthy diets and regular exercise.
Current research efforts extend beyond Aβ and tau to explore the role of specific proteases in the brain, such as meprin β, which has been identified as a risk factor for AD. While current treatments largely offer only symptomatic relief, future strategies are focused on interventions that can target the core pathology early in the disease course to modify or prevent its progression.
Here, we report that the overexpression of meprin β affects learning in mice on the behavioral and electrophysiological level. We show that NMDA- and AMPA receptor levels are not altered, while N-terminomics analysis reveals brevican as a potential candidate to explain the observed effects. Simultaneously, overexpression of meprin β in an AD mouse model background (APP/Ld) shows no observable differences in learning and behavior. Analysis of soluble Aβ in the cortex and hippocampus revealed that meprin β-overexpressing mice in an APP/Ld background produce more Aβ than APP/Ld animals. The higher Aβ levels do not translate into the formation of plaques, whereas we observe intracellular accumulation.X, 139 Seiten ; Illustrationen, Diagramm
Die »neue Motette« im Quattrocento: Vielfalt und Formwandel der nicht-isorhythmischen Motetten 1400-1450 in ihrem soziokulturellen Kontext.
Get PDFEine Untersuchung der historischen Musikwissenschaft, die sich mit der Motettentransformation in der ersten Hälfte des 15. Jahrhunderts befasst.v, 268 Seiten ; Illustrationen, Note
Effects of surface charge of amphiphilic peptides on peptide–lipid interactions in the gas phase and in solution
Get PDFThe interactions between peptides and lipids are fundamental for many biological processes. Therefore, exploring the noncovalent interactions that govern these interactions has become increasingly important. Native mass spectrometry is a valuable technique for the characterization of specific peptide–lipid interactions. However, native mass spectrometry requires the transfer of the analyte into the gas phase, and noncovalent interactions driven by the hydrophobic effect might be distorted. We, therefore, address the importance of electrostatic interactions for the formation of peptide–lipid interactions. For this, we make use of the amphipathic, antimicrobial peptide LL-37 as well as a positively and a negatively charged variant thereof and study binding of a variety of lipids by native mass spectrometry. We found that the surface charge of the peptides affects the transfer of stable peptide–lipid complexes into the gas phase and that the ionization mode is important to observe these interactions. We further compare our findings observed in the gas phase with interactions formed in solution between the peptides and lipid monolayers using a Langmuir film balance. The two approaches deliver comparable results and reveal a clear trend in the lipid preferences of all variants for those lipids with opposite charge. Notably, the unmodified wild-type peptide was more flexible in the formation of peptide–lipid interactions. We conclude that native mass spectrometry is indeed well-suited to explore the interactions between peptides and lipids and that electrostatic interactions as expressed by the surface charge of the peptides play an important role in the formation and stabilization of peptide–lipid interactions
Laser system for precision spectroscopy of the ground state hyperfine splitting in muonic hydrogen
Get PDFThis thesis describes the laser system for the spectroscopy of the 1S HFS (1SF=1
1/2 -1SF=01/2 ) in muonic hydrogen (μH), pursued by the CREMA collaboration with its current experiment
HyperMu.
Muonic hydrogen is an atomic system formed by a muon (μ−), a negatively charged
unstable lepton with a lifetime of ∼2.2 μs, and a proton (p), much like the hydrogen atom
(eH). As the muon is ∼ 207 times more massive than the electron, the wavefunction of
the muon has a larger overlap with that of the nucleus, making its bound-state energy
levels characteristically perturbed by nuclear structure effects. A measurement of the 1S
HFS to about 1ppm in μH allows the determination of the nuclear structure contribution
to about 200 ppm. In a second step from this contribution, the Zemach radius and the
polarizability contribution can be deduced, assuming polarizability from theory or the
Zemach radius from ep scattering of eH.
The experiment is to be conducted at the Paul Scherrer Institute (PSI), Switzerland,
where a high-intensity continuous muon beam is available. The muons from the ΠE5
beamline are stopped within a H2 target (22K temperature, 0.5 bar pressure) to form μH.
After thermalization, these atoms are excited by the laser pulses that undergo multiple
reflections in a toroidal enhancement cell, placed in the H2 target, to increase the 1SF=0
1/2 -
1SF=1
1/2 transition probability. The lifetime of the 1SF=1
1/2 state is longer than that of the
muons, which makes the fluorescence from the deexcitation not a viable indicator of laser
excitation. An indirect detection scheme is designed based on diffusion of μH through
the H2 and the production of X-rays at its arrival at the target walls. The laser-excited μH
undergoing a collision with H2 molecules acquires a kinetic energy of 0.1 eV and diffuses
efficiently to the target walls coated with gold. The transfer of μ− from the μH to the Au
atom creates μAu in an excited state. The deexcitation of μAu generates characteristic
X-rays that are detected by X-ray detectors to indicate laser excitation. The resonance
curve of the HFS transition is obtained by plotting the number of μAu events versus the
frequency of the laser.
Simulations indicate that the laser pulses for the spectroscopy must have an energy
of 3 mJ with 100MHz frequency bandwidth at the predicted transition wavelength of
6.8 μm. Moreover, as the muons arrive stochastically within the target, the laser system
must be stochastically triggerable with an average repetition rate of >100 s−1. The
muon lifetime constrains the maximum pulse build-up time to be ∼1 μs. Generating such
high-energy pulses in the mid-infrared in such a short time and with adequate frequency
control is technologically challenging. We pursue a two-stage design that begins with
the generation of NIR 1030nm pulses, followed by a second stage that downconverts
the 1030nm pulses into the required 6.8μm pulses via nonlinear difference frequency
generation (DFG).
Pulses of 1030nm of 50 ns duration and energy 30 mJ are generated in a thin-disk oscillator
by the method of cavity dumping within <1 μs. These pulses are amplified to
the energy of 300 mJ by a thin-disk multipass amplifier (TDA). These 1030nm pulses
are used for pumping two optical parametric oscillators (OPO) operating at 2.1μm and
3.1μm wavelengths. The 2.1 μm-OPO converts the 1030nm pulse into pulses of wavelength
2.1μm and 1.9μm while the 3.1 μm-OPO converts the 1030nm pulse into pulses
of wavelength 3.1μm and 1.5 μm. In a similar process, the 2.1μm and 3.1μm pulses are amplified by 1030nm pulses to energies of 25 mJ and 3 mJ, respectively, in their respective
optical parametric amplifiers. The 6.8μm pulses are eventually obtained by difference
frequency generation of the 2.1μm pulse and the 3.1μm pulse. The TDO and
the two OPOs are injection-seeded and Pound-Drever-Hall (PDH) stabilized to ensure
single-frequency operation. While the wavelength of the 1030nm and 2.1μm pulses are
fixed, the wavelength of the 3.1μm pulses can be varied by changing the frequency of the
seed-laser. This allows the 6.8μm pulses to be scanned across the search range of 6798nm
- 6785nm of the 1S HFS in μH.
This thesis deals with the development of the 2.1 μm-OPO, the 2.1 μm-OPA, the 6.8 μm-
DFG stage and the frequency calibration of the 6.8μm pulses.
Chapter 1 of the thesis elaborates on the motivation of the experiment along with a
summary of the theoretical efforts parallel to the experiment. Details of the experimental
scheme are given, focusing on the aspects that constrain the requirements of the laser
system.
Chapter 2 of the thesis discusses the layout of the laser system under development,
designed to satisfy these requirements. A brief review of laser physics and nonlinear
optics, as well as the current status of the laser system, is provided.
Chapter 3 compiles the results on the 2.1μm-OPO and the implications on its variablefinesse
cavity layout. The effect of injection-seeding and PDH stabilization of the cavity
on the energy and stability is studied. Generation of 2.1μm pulses of energy 1 mJ of
average beam qualityM2 ∼ 1.12 with 5 mJ of input 1030nm pulse energy is demonstrated.
Chapter 4 describes the amplification of the 2.1μm pulses of 1 mJ energy by the 2.1 μm-
OPA to ∼5 mJ while providing a beam with average M2 of 1.56, for input 1030nm pulse
energy of 25 mJ from the TDO. Preliminary tests of the 2.1 μm-OPA with 1030nm pulses
of energy 95 mJ are shown to amplify the 2.1μm pulses to 22 mJ.
Chapter 5 focuses on the 6.8 μm-DFG stage that converts the 2.1μm pulses into 6.8μm
pulses. 300 μJ of 6.8μm is generated from 6 mJ of 2.1μm and 300 μJ of 3.1 μm-seed pulses.
The dependence of the nonlinear process on the orientation and temperature of the crystal,
as well as the frequency of the 6.8μm beam, is studied for optimum frequency and
energy control during the μH spectroscopy campaign.
Chapter 6 reports on the frequency calibration of the 6.8μm pulses. By absorption
spectroscopy in a H2O vapour cell, three resonances of H2O are studied for various pressures
between the range 0.1 mbar and 7 mbar. From a fit to the measured transition, the
centroid position and linewidth of the transitions are obtained. The obtained centroid positions
were all systematically deviating by 50MHz from the HITRAN value, indicating
the need to recheck the frequency calibration. From the linewidth, the upper limit of the
laser bandwidth was determined to be 110 MHz. This fulfils the minimum requirement
for the spectroscopy in μH.
In this thesis, we have demonstrated for the first time our ability to produce 6.8μm
pulses with the necessary frequency control. Energy scaling of the laser system will be
needed to reach 3 mJ energy at the 6.8μm wavelength, but the observed efficiency is
promising.119, 3 Seiten ; Illustrationen, Diagramm
Untersuchungen zur enantioselektiven Synthese von Cripowellin (Aglycon)
Get PDFKurzzusammenfassung
Cripowelline gehören zur Gruppe der Amaryllidaceae-Alkaloide und sind wegen ihrer vielfältigen Bioaktivität für die Entwicklung neuer Anwendungen in der Humanmedizin und in der Landwirtschaft von wissenschaftlichem und kommerziellem Interesse. Eine enantioselektive Synthese des Cripowellin-Aglycons stellt aufgrund der komplexen polyzyklischen Struktur eine erhebliche Herausforderung dar.
In dieser Arbeit wurden neue Syntheserouten wie die Eschenmoser Umlagerung als Schlüsselreaktion zum Aufbau des stereogenen Zentrums an der C-1 Position erprobt und auf ihre Selektivität hin kontrolliert. Darüber hinaus wurden geeignete Methoden zur Einführung eines Stickstoffatoms untersucht. Sowohl bei der Luche Reduktion als auch bei der folgenden Eschenmoser Umlagerung wurde das (S) Diastereomer stereoselektiv an der C-1-Position gebildet. Mit Hilfe der Kristallstrukturanalyse konnte die absolute Konfiguration der Stereozentren bestimmt werden. Der Azepinring konnte als Lactambildungs-Epoxid-Kaskade der Iodlactone zu den Oxiranyl-ε Lactamen als auch aus dem syn-Lacton zum Caprolactam aufgebaut werden. Der Einbau eines Stickstoffatoms gelang in Form eines Azid und Phthalimids.Abstract
Cripowellins belong to the group of Amaryllidaceae alkaloids and are of scientific and commercial interest for the development of new applications in human medicine and agriculture due to their diverse bioactivity. However, the complex polycyclic structure of the cripowellin aglycone poses a major challenge for enantioselective synthesis.
In this work, new synthesis routes as well as the Eschenmoser rearrangement were tested as a key reaction for building up the stereogenic center at the C-1 position and checked for their selectivity. Furthermore, suitable methods for introducing a nitrogen atom were investigated. In both, the Luche reduction and the subsequent Eschenmoser rearrange¬ment, the (S) diastereomer was formed stereospecifically at the C-1 position. X-ray structure analysis was used to determine the absolute configuration of the stereocenters. The azepine ring could be constructed as a lactam-forming epoxide cascade of the iodo lactones to the oxiranyl-ε lactams, as well as from the syn-lactone to the caprolactam. Incorporation of nitrogen was achieved via an azide and a phthalimide unit.xxiv, 351 Seiten ; Illustratione
Eulers Horizonte : Möglichkeiten und Grenzen seiner Arbeitsweise in der Mathematik
Get PDFDie Dissertation hat im weitesten Sinne verschiedene Beiträge des Mathematikers und Physikers Leonhard Euler (1707--1783) zum Gegenstand. Die behandelten Themen reichen von der Herausarbeitung seiner Mathematikphilosophie, über die Illustration seiner Arbeitsweise anhand ausgewählter Beispiele, weiter über von ihm vorweggenommene -- bewiesene sowie unbewiesene -- Entdeckungen bis hin zur Eruierung seiner mathematischen Grenzen und der Applikation seiner Ideen auf unterschiedlichste verwandte Fragestellungen.\\
Grundlage waren dabei zahlreiche Euler'sche Abhandlungen selbst, welche vom Verfasser von lateinischer und französischer Sprache ins Deutsche und Englische übertragen worden sind. Eulers Vorbild widerspiegelnd ist die Art der Präsentation eine, welche anderes als die heutzutage vorherrschende synthetisch--deduktive eher induktiv und explanatorisch vorgeht. Es war eines der Hauptanliegen der Arbeit, den Euler'schen Schaffensprozess zu präsentieren und anschließend kritisch zu evaluieren, was auf diese Weise erreicht wurde. \\
Neben bereits hinlänglich bekannten Euler'schen Ergebnissen wie der Lösung des Baseler Problems wurden auch in der Literatur weniger bis gar nicht diskutierte Aspekte wie etwa seine Auflösung der einfachen Differenzengleichung vermöge einer Differentialgleichung unendlicher Ordnung vorgestellt und diskutiert. Überdies sind gänzliche neue Ergebnisse wie die heuristische Derivation des Primzahlsatzes aus den Euler'schen Vorgaben und die psychologisch begründete Nicht--Entdeckung der komplexen Analysis von Euler in der Dissertation zu finden. \\
Insgesamt bietet die Arbeit eine Auswahl von Eulers bemerkenswerten Errungenschaften, mit welchen er die Mathematik bereichert hat, mitsamt ihrer Entstehungs-- bzw. Entdeckungsgeschichte, sodass ein neuer Beitrag zum tieferen Verständnis des Euler'schen Opus erreicht wurde. Zugleich ist mit dem Aufwerfen der Frage nach den Grenzen Leonhard Eulers ein bislang noch kaum in der Literatur besprochenes Themenfeld aufgeworfen worden.\\397 Seiten ; Illustratione