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A recent in-vivo experiment has shown that force can be transmitted between the gastrocnemius and the hamstring muscles due to a direct tissue continuity. However, it remains unclear if this mechanical interaction is affected by the stiffness of the structural connection. This study therefore aimed to investigate the impact of the knee angle on myofascial force transmission across the dorsal knee. A randomized, cross-over study was performed, including n = 56 healthy participants (25.36 ± 3.9 years, 25 females). On two separate days, they adopted a prone position on an isokinetic dynamometer (knee extended or 60° flexed). In each condition, the device moved the ankle three times from maximal plantarflexion to maximal dorsal extension. Muscle inactivity was ensured using EMG. High-resolution ultrasound videos of the semimembranosus (SM) and the gastrocnemius medialis (GM) soft tissue were recorded. Maximal horizontal tissue displacement, obtained using cross-correlation, was examined as a surrogate of force transmission. SM tissue displacement was higher at extended (4.83 ± 2.04 mm) than at flexed knees (3.81 ± 2.36 mm). Linear regression demonstrated significant associations between (1) SM and GM soft tissue displacement (extended: R2 = 0.18, p = 0.001; flexed: R2 = 0.17, p = 0.002) as well as (2) SM soft tissue displacement and ankle range of motion (extended: R2 = 0.103, p = 0.017; flexed: R2 = 0.095, p = 0.022). Our results further strengthen the evidence that local stretching induces a force transmission to neighboring muscles. Resulting remote exercise effects such as increased range of motion, seem to depend on the stiffness of the continuity.
Trial registration: DRKS (Deutsches Register Klinischer Studien), registration number DRKS00024420, first registered 08/02/2021, https://drks.de/search/de/trial/DRKS00024420.
MicroRNAs (miRNAs) are critical post-transcriptional regulators in many biological processes. They act by guiding RNA-induced silencing complexes to miRNA response elements (MREs) in target mRNAs, inducing translational inhibition and/or mRNA degradation. Functional MREs are expected to predominantly occur in the 3' untranslated region and involve perfect base-pairing of the miRNA seed. Here, we generate a high-resolution map of miR-181a/b-1 (miR-181) MREs to define the targeting rules of miR-181 in developing murine T-cells. By combining a multi-omics approach with computational high-resolution analyses, we uncover novel miR-181 targets and demonstrate that miR-181 acts predominantly through RNA destabilization. Importantly, we discover an alternative seed match and identify a distinct set of targets with repeat elements in the coding sequence which are targeted by miR-181 and mediate translational inhibition. In conclusion, deep profiling of MREs in primary cells is critical to expand physiologically relevant targetomes and establish context-dependent miRNA targeting rules.
In the deep-sea, the interaction between benthic fauna and substrate mainly occurs through bioturbational processes which can be preserved as traces (i.e., lebensspuren). Lebensspuren are common features of deep seafloor landscapes and usually more abundant than the organism that produce them (i.e., tracemakers), rendering them promising proxies to infer biodiversity. The density and diversity relationships between lebensspuren and benthic fauna are to the present day unclear and contradicting hypotheses have been proposed suggesting negative, positive, or even null correlations. To test these hypotheses, in this study lebensspuren, tracemakers (specific epibenthic fauna that produce these traces), degrading fauna (benthic fauna that can erase lebensspuren), and fauna in general were characterized taxonomically at eight deep-sea stations in the Kuril Kamchatka Trench area. No general correlation (over-all study area) could be observed between diversities of lebensspuren, tracemakers, degrading fauna and fauna. However, a diversity correlation was observed between specific stations, showing both negative and positive correlations depending on: 1) the number of unknown tracemakers (especially significant for dwelling lebensspuren); and 2) the lebensspuren with multiple origins; and 3) tracemakers that can produce different lebensspuren. Lebensspuren and faunal density were not correlated. However, lebensspuren density was either positively or negatively correlated with tracemaker densities, depending on the lebensspuren morphotypes. A positive correlation was observed for resting lebensspuren (e.g., ophiuroid impressions, Actinaria circular impressions), while negative correlations were observed for locomotion-feeding lebensspuren (e.g., echinoid trails). In conclusion, lebensspuren diversity may be a good proxy for tracemaker biodiversity when the lebensspuren-tracemaker tandem can be reliable characterized; and lebensspuren-density correlations vary depending the specific lebensspuren residence time, tracemaker density and associated behaviour (rate of movement), but on a global scale abiotic and other biotic 42 factors may also play an important role.
Samples of Crustacea and Annelida (Polychaeta, Sipuncula, and Hirudinea) were collected in the Bering Sea and the northwestern Pacific Ocean during scientific cruise SO-249 BERING in 2016. Biological samples were collected from 32 locations by the team on-board RV Sonne using a chain bag dredge at depths ranging between 330–5,070 m, and preserved in 96% ethanol. Specimens were morphologically identified to the lowest taxonomic level possible using a Leica M60 stereomicroscope. The generated data here comprise taxonomic information as well as annotated bathymetric and biogeographic information from a total of 78 samples (26 Crustacea, 47 Polychaeta, 4 Sipuncula, and 1 Hirudinea). The dataset was prepared following Darwin Core Biodiversity standards for FAIR data sharing based on Ocean Biodiversity Information System (OBIS) and Global Biodiversity Facility (GBIF) guidelines. The standardised digitised data were then mobilised to both OBIS and GBIF under CC BY 4.0 licence to publicly share and adopt the data. As records of these important marine taxa from bathyal and abyssal depths are sparse, especially from the deep Bering Sea, the herein generated and digitised data aid in filling existing knowledge gaps on their diversity and distribution in that region. As part of the “Biogeography of the NW Pacific deep-sea fauna and their possible future invasions into the Arctic Ocean” (BENEFICIAL) project, this dataset thus not only increases our knowledge in re-assessing and uncovering the deep-sea diversity of these taxa, but also serves policy and management sectors by providing first-hand data for global report assessments.
A Large Ion Collider Experiment (ALICE) is a high-energy physics experiment, designed to study heavy ion collisions at the European Organization for Nuclear Research (CERN)Large Hadron Collider (LHC). ALICE is built to study the fundamental properties of matter as it existed shortly after the big bang. This requires reading out millions of sensors with high frequency, enabling high statistics for physics analysis, resulting in a considerable computing demand concerning network throughput and processing power. With the ALICE Run 3 upgrade [14], requirements for a High Throughput Computing
(HTC) online processing cluster increased significantly, due to more than an order of magnitude more data than in Run 2, resulting in a processing input rate of up to 900 GB/s. Online (real-time) event reconstruction allows for the compression of the data stream to 130 GB/s, which is stored on disk for physics analysis.
This thesis presents the implementation of the ALICE Event Processing Node (EPN) compute farm, to cope with the Run 3 online computing challenges. Building a Data Centre tailored to ALICE requirements for the Run 3 and Run 4 EPN farm. Providing the operational conditions for a dynamic compute environment of a High Performance Computing (HPC) cluster, with significant load changes in a short time span, when starting or stopping a data-taking run. EPN servers provide the required computing resources for online reconstruction and data compression. The farm includes network connectivity towards First Level Processors (FLPs), requiring reliable throughput of 900 GB/s between FLPs and EPNs and connectivity from the internal InfiniBand network to the CERN Exabyte Object Storage (EOS) Ethernet network, with more than 100 GB/s.
The results of operating the EPN computing infrastructure during the first year of Run 3 LHC collisions are described in the context of the ALICE experiment. The EPN farm was delivering the expected performance for ALICE data-taking. Data Centre environmental conditions remained stable during the last more than two years, in particular during starting and stopping runs, which include significant changes in IT load. Several unforeseen external circumstances lead to increasing demands for the Online Offline System (O2). Higher data rates than anticipated required network performance to exceed the initial design specifications, for the throughput between FLPs and EPNs. In particular, the high throughput from an internal EPN InfiniBand network towards the storage Ethernet network was one of the challenges to overcome.
This thesis is concerned with the investigation of static and dynamic properties of quantum Heisenberg paramagnets in the absence of a magnetic field and therefore for vanishing magnetization. For this purpose a new formulation of the spin functional renormalization group (SFRG) is employed. The first manifestations of the SFRG were developed by Krieg and Kopietz, motivated by the FRG approach to ordinary field theories and the older works of Vaks, Larkin and Pikin on diagrammatic methods for spin operators.
The main idea is to study quantum spin systems by considering the evolution of correlation functions under a continuous deformation of the interaction between magnetic moments, starting from a solvable limit. This leads to nonperturbative results for quantities like the spin-spin correlation function. After a basic introduction to the phenomena and concomitant problems discussed in this thesis, a detailed description of the SFRG method in its initial formulation is given in the second chapter. We start with the generating functional of connected imaginary-time spin-correlation functions GΛ [h], for which an exact flow equation is derived. A particular issue, already pointed out by Krieg and Kopietz, arises here, namely the singular non-interacting limit of its subtracted Legendre transform ΓΛ [m]. As a consequence the initial condition of that functional does not have a proper series expansion in powers of m. This prevents us from working directly within a pure one-particle irreducible (1-PI) parametrization of the correlation functions, as is often done in the context of field theories. Thus motivated, we develop a workaround explicitly tailored to paramagnets, which provides us with a functional that has a well-behaved Legendre transform. The new approach is based on a different treatment of fluctuations at zero and finite frequencies, analogous to a previous hybrid formulation for the symmetry-broken phase. Certain properties, considered to be highly relevant for isotropic paramagnets, as well as previous observations, already made in the study of simpler spin systems like the Ising model, serve as additional justifications for choosing this construction.
In the third chapter our new method is assessed by calculating the dynamic susceptibility G(k, iω) and thus the dynamic structure factor S(k, ω) in the symmetric phase. For this purpose an approximate integral equation for the dynamic polarization function Π̃(k, iω) was derived. This equation results from a truncation of the hierarchy of flow equations and contains static quantities, that are assumed to be known from another source. Our first application is the high-temperature limit T → ∞ in d ≤ 3 dimensions. Salient features, believed to be part of the spin dynamics in isotropic Heisenberg magnets are also exhibited by our solution, like (anomalous) diffusion in a suitable hydrodynamic limit. Moreover we obtain the same order of magnitude for the diffusion coefficient D as in experiments and other theoretical calculations. Other aspects do not entirely agree with previous approaches.
Afterwards we continue by investigating systems close to the critical point Tc. Dynamic scaling forms for Π̃(k, iω) and S(k, ω), which, like spin diffusion, are postulated on the basis of quite general physical arguments, are reproduced. Agreement of the line-shapes 2with neutron scattering experiments at T = Tc is found to be satisfying, with deviations for ω → 0, that may be attributed to the simplicity of the approximation, like at infinite temperature.
Finally, we focus our attention on the thermodynamic properties of isotropic Heisenberg paramagnets by calculating the static susceptibility G(k). For this purpose we employ simple truncation schemes of the flow equations for the static self-energy ΣΛ (k) and four-spin vertex ΓΛ , together with a basic ansatz for the dynamic polarization Π̃(k, iω) in quantum systems. As a result we obtain transition temperatures Tc of three-dimensional nonfrustrated magnets within an accuracy of 5 percent compared to established benchmark values from Quantum Monte Carlo and high temperature expansion series. We conclude this chapter by giving an outlook on the application of our method to frustrated systems, which may require a combined non-trivial calculation of static and dynamic properties.
The longitudinal and transverse spin transfers to Λ (Λ¯¯¯¯) hyperons in polarized proton-proton collisions are expected to be sensitive to the helicity and transversity distributions, respectively, of (anti-)strange quarks in the proton, and to the corresponding polarized fragmentation functions. We report improved measurements of the longitudinal spin transfer coefficient, DLL, and the transverse spin transfer coefficient, DTT, to Λ and Λ¯¯¯¯ in polarized proton-proton collisions at s√ = 200 GeV by the STAR experiment at RHIC. The data set includes longitudinally polarized proton-proton collisions with an integrated luminosity of 52 pb−1, and transversely polarized proton-proton collisions with a similar integrated luminosity. Both data sets have about twice the statistics of previous results and cover a kinematic range of |ηΛ(Λ¯¯¯¯)| < 1.2 and transverse momentum pT,Λ(Λ¯¯¯¯) up to 8 GeV/c. We also report the first measurements of the hyperon spin transfer coefficients DLL and DTT as a function of the fractional jet momentum z carried by the hyperon, which can provide more direct constraints on the polarized fragmentation functions.
Einleitung: Allergisches Asthma bronchiale ist eine chronische Atemwegserkrankung, deren Prävalenz zunimmt. Angesichts der immensen gesellschaftlichen und individuellen Belastung durch Asthma ist es dringend erforderlich, neue Strategien zur Behandlung der Krankheit zu entwickeln. Immunologisch ist allergisches Asthma durch ein Ungleichgewicht zwischen TH2-Zellen und TH1-Zellen gekennzeichnet, das durch regulatorische T-Zellen (Tregs) reguliert wird. Tregalizumab ist ein monoklonaler IgG-Antikörper, der Tregs selektiv aktiviert. Ziel der vorliegenden Arbeit war es daher, die Wirkung von Tregalizumab auf die allergeninduzierte allergische Entzündung bei Patienten mit Hausstaubmilbenallergie anhand eines bronchialen Provokationsmodells zu untersuchen.
Methoden: In einer prospektiven, randomisierten, doppelblinden und placebokontrollierten Studie wurden 42 Probanden mit allergischem Asthma und Hausstaubmilbenallergie zwölf Wochen lang mit Tregalizumab 100 mg oder Placebo behandelt. Bronchiale Provokation mit HSM wurde vor (V4) und nach (V17) Tregalizumab-Gabe durchgeführt. Induziertes Sputum (Visite V5, V16, V18) und peripheres Blut (Visite V4, V5, V18) wurden entnommen und Zelldifferenzierung, Zytokine und Transkriptionsfaktoren wurden durch Mikroskopie, Durchflusszytometrie bzw. RT-PCR bewertet.
Ergebnisse: Sowohl in der Verum- als auch in der Placebogruppe zeigte sich zwischen Visite V5 (24 Stunden nach Provokation) und vier Wochen nach Provokation bei Visite V16 (p<0,05) ein signifikanter Rückgang des Anteils eosinophiler Granulozyten (wie auch des ECP-Levels). Interessanterweise konnte bei V18 (24 Stunden nach Provokation) nur in der Placebogruppe ein signifikanter Anstieg beobachtet werden (p<0,01). Die Konzentration des TH-2-Zytokins IL-5 nahm zwischen V5 und V16 in der Verumgruppe signifikant ab (p<0,05). Zwischen V16 und V18 konnte wiederum nur in der Placebogruppe ein signifikanter Anstieg festgestellt werden (p<0,01). Dieser spätere Effekt wurde auch auf Protein- und Transkriptionsebene und im peripheren Blut sowie bei der Expression des Transkriptionsfaktors FoxP3 gefunden. Auf der Ebene der TH-1-Zytokine konnten keine signifikanten Veränderungen festgestellt werden.
Diskussion: Der Anteil eosinophiler Granulozyten, die Konzentration von IL-5 in Blut und Sputum sowie die Konzentration von ECP im Sputum haben sich als gute Parameter zur Beurteilung der Entzündungsreaktion bei unseren Studienteilnehmern erwiesen. Wir haben gezeigt, dass allergische Entzündungen, die durch das Provokationsmodell verursacht wurden, durch die analysierten Parameter im Sputum, aber auch im Blut gut überwacht werden konnten. Ein klinischer Effekt von Tregalizumab konnte in dieser Studie jedoch nicht festgestellt werden und dieses Ergebnis stimmt gut mit der Analyse der Entzündungsparameter im induzierten Sputum überein.
Cell-free (CF) synthesis with highly productive E. coli lysates is a convenient method to produce labeled proteins for NMR studies. Despite reduced metabolic activity in CF lysates, a certain scrambling of supplied isotope labels is still notable. Most problematic are conversions of 15N labels of the amino acids L-Asp, L-Asn, L-Gln, L-Glu and L-Ala, resulting in ambiguous NMR signals as well as in label dilution. Specific inhibitor cocktails suppress most undesired conversion reactions, while limited availability and potential side effects on CF system productivity need to be considered. As alternative route to address NMR label conversion in CF systems, we describe the generation of optimized E. coli lysates with reduced amino acid scrambling activity. Our strategy is based on the proteome blueprint of standardized CF S30 lysates of the E. coli strain A19. Identified lysate enzymes with suspected amino acid scrambling activity were eliminated by engineering corresponding single and cumulative chromosomal mutations in A19. CF lysates prepared from the mutants were analyzed for their CF protein synthesis efficiency and for residual scrambling activity. The A19 derivative “Stablelabel” containing the cumulative mutations asnA, ansA/B, glnA, aspC and ilvE yielded the most useful CF S30 lysates. We demonstrate the optimized NMR spectral complexity of selectively labeled proteins CF synthesized in “Stablelabel” lysates. By taking advantage of ilvE deletion in "Stablelabel", we further exemplify a new strategy for methyl group specific labeling of membrane proteins with the proton pump proteorhodopsin.
We investigate the thermodynamic geometry of the quark-meson model at finite temperature, T, and quark number chemical potential, μ. We extend previous works by the inclusion of fluctuations exploiting the functional renormalization group approach. We use recent developments to recast the flow equation into the form of an advection-diffusion equation. We adopt the local potential approximation for the effective average action. We focus on the thermodynamic curvature, R, in the (μ,T) plane, in proximity of the chiral crossover, up to the critical point of the phase diagram. We find that the inclusion of fluctuations results in a smoother behavior of R near the chiral crossover. Moreover, for small μ, R remains negative, signaling the fact that bosonic fluctuations reduce the capability of the system to completely overcome the fermionic statistical repulsion of the quarks. We investigate in more detail the small μ region by analyzing a system in which we artificially lower the pion mass, thus approaching the chiral limit in which the crossover is actually a second order phase transition. On the other hand, as μ is increased and the critical point is approached, we find that R is enhanced and a sign change occurs, in agreement with mean field studies. Hence, we completely support the picture that R is sensitive to a crossover and a phase transition, and provides information about the effective behavior of the system at the phase transition.
We reanalyze some critical exponents of the 𝑂(𝑁) model within the functional renormalization group (FRG) approach in the local potential approximation (LPA). We use recent advances which are based on the observation that the FRG flow equation in LPA can be put into the form of an advection-diffusion equation. This allows to employ well-tested hydrodynamical algorithms for its solution to better estimate various sources of errors. Our results complement previous results for the critical exponents obtained within the FRG approach in LPA and compare favorably with those obtained via other methods.
Polyunsaturated fatty acids (PUFAs) play essential roles in mediating inflammation and its resolution. PUFA metabolites generated by the cytochrome P450 (CYP) - soluble epoxide hydrolase (sEH) axis are known to regulate macrophage activation/polarization but little is known about their role in the resolution of inflammation. Monocytes were isolated from murine bone marrow or human peripheral blood and differentiated to naïve macrophages (M0). Thereafter cells were polarized using LPS and IFNγ (M1), IL-4 (M2a), or TGFβ1 (M2c). Gene expression was analyzed by RNA sequencing, RT-qPCR and Western blotting. Phagocytosis of zymosan and oxo-LDL were also assessed in vitro. Zymosan-induced peritonitis combined with immune cell profiling was used to evaluate the resolution of inflammation in vivo. The expression of sEH was comparable in M0, M1 and M2a macrophages but markedly elevated in M2c polarized cells. The increase in sEH expression elicited by TGFβ relied on the TGFβ receptor ALK5 and the phosphorylation of SMAD2, which was able to bind to the sEH promoter. In macrophages lacking sEH, M2c polarization was incomplete and characterized by lower levels of pro-resolving phagocytosis associated receptors (Tlr2 and Mrc1), as well as higher levels of the pro-inflammatory markers; Nlrp3, IL-1β and TNFα. Fitting with the failure to upregulate phagocytosis associated receptors, the uptake of zymosan and ox-LDL was less efficient in M2c macrophages from sEH-/- mice. The latter animals also demonstrated a retarded resolution of inflammation (zymosan-induced peritonitis) in vivo with fewer resident macrophages and recruited macrophages. PUFA profile analysis indicated decreased sEH substrates e.g., 11, 12-EET, as well as increased sEH products e.g., 11, 12-DHET, indicating an increased sEH activity in M2c macrophages. Taken together, our data indicates that sEH expression is required for the effective M2c polarization of macrophages and thus the resolution of inflammation.
The thermodynamic properties of the interacting particle–antiparticle boson system at high temperatures and densities were investigated within the framework of scalar and thermodynamic mean-field models. We assume isospin (charge) density conservation in the system. The equations of state and thermodynamic functions are determined after solving the self-consistent equations. We study the relationship between attractive and repulsive forces in the system and the influence of these interactions on the thermodynamic properties of the bosonic system, especially on the development of the Bose–Einstein condensate. It is shown that under “weak” attraction, the boson system has a phase transition of the second order, which occurs every time the dependence of the particle density crosses the critical curve or even touches it. It was found that with a “strong” attractive interaction, the system forms a Bose condensate during a phase transition of the first order, and, despite the finite value of the isospin density, these condensate states are characterized by a zero chemical potential. That is, such condensate states cannot be described by the grand canonical ensemble since the chemical potential is involved in the conditions of condensate formation, so it cannot be a free variable when the system is in the condensate phase.
The STAR experiment at RHIC reports new measurements of jet quenching based on the semi-inclusive distribution of charged-particle jets recoiling from direct photon (γdir) and neutral pion (π0) triggers in p+p and central Au+Au collisions at √sNN=200 GeV, for triggers in the range 9<EtrigT<20 GeV. The datasets have integrated luminosities of 3.9 nb−1 for Au+Au and 23 pb−1 for p+p collisions. Jets are reconstructed using the anti-kT algorithm with resolution parameters R=0.2 and 0.5. The large uncorrelated jet background in central Au+Au collisions is corrected using a mixed-event approach, which enables precise charged-particle jet measurements at low transverse momentum pchT,jet and large R. Recoil-jet distributions are reported in the range pchT,jet<25 GeV. Comparison of the distributions measured in p+p and Au+Au collisions reveals strong medium-induced jet yield suppression for R=0.2, with markedly less suppression for R=0.5. These data provide new insight into the mechanisms underlying jet quenching, and the angular dependence of medium-induced jet-energy transport.
The differential cross section for Z0 production, measured as a function of the boson's transverse momentum (pT), provides important constraints on the evolution of the transverse momentum dependent parton distribution functions (TMDs). The transverse single spin asymmetry (TSSA) of the Z0 is sensitive to one of the polarized TMDs, the Sivers function, which is predicted to have the opposite sign in p+p →W/Z+X from that which enters in semi-inclusive deep inelastic scattering. In this Letter, the STAR Collaboration reports the first measurement of the Z0/γ∗ differential cross section as a function of its pT in p+p collisions at a center-of-mass energy of 510 GeV, together with the Z0/γ∗ total cross section. We also report the measurement of Z0/γ∗ TSSA in transversely polarized p+p collisions at 510 GeV.
The attention on the protein PURA has increased recently following the discovery of the rare PURA Syndrome. This neurodevelopmental disorder is caused by de novo mutations in the PURA gene. Notably, our collaborators could show that the protein PURA can bind DNA and RNA in vitro. As a result, I was motivated to explore PURA's cellular RNAbinding activity. Furthermore, I inquired on the connection of PURA-RNA binding to the cellular effect of a reduction of functional PURA as present in PURA Syndrome patients.
To investigate the binding of PURA and the impact of PURA de ciency on cellular RNA and protein expression, I performed an integrative computational analysis of multimodal data from complementary high-throughput experiments. An essential component was the examination of UV Crosslinking and immunoprecipitation (CLIP) experiments, which can query the global RNA-binding behaviour of a given protein in a cellular context. As the processing and analysis of CLIP data are rather complex, I introduce an automated command line tool for the processing of CLIP data named racoon_clip as part of this dissertation. Therefore, this dissertation comprises two major segments. Firstly, I describe the implementation and usage of racoon clip for CLIP data analysis. Secondly, I discuss my research on the protein PURA, demonstrating its global RNA-binding properties, the effects of PURA depletion and its association with neuronal functions and P-bodies, among others.
racoon_clip is a command line application that I have developed for processing of individualnucleotide resolution CLIP (iCLIP) and enhanced CLIP (eCLIP) experiments - two of the most commonly used types of CLIP experiments - in a comparable and user-friendly way.
For this, I built racoon_clip as an automated work how that encompasses all CLIP processing steps from raw data to single-nucleotide resolution crosslink events. racoon_clip is available as a command line tool that users can run with a single command. The work how is implemented with Snakemake work how management providing computational advantage tages including parallelisation, scalability and portability of the work how. The main task of racoon_clip is to extract single-nucleotide crosslink events from iCLIP, iCLIP2, eCLIP and similar data types. To strike a balance between being highly customisable and easy to use, racoon_clip supplies pre-set options for the most common types of experiments.
Additionally, it is possible for users to create a custom setup of barcode and adapter architectures, which allows them to use the software for other types of CLIP data. While accounting for the different architectures in the reads, the performed central processing steps remain the same. This leads to a high degree of comparability between the different experiment types, which I demonstrate in the exemplary processing of U2AF2 iCLIP and eCLIP data. Taken together, I am confident that racoon_clip will be beneficial to numerous researchers interested in RNA-Protein interactions as it offers easily accessible processing for CLIP data and enhances the comparability of multiple CLIP datasets across di erent experiment types.
In the second part of this dissertation, I focus on the cellular function of the RNAbinding protein PURA. Through in-depth computational analysis of one iCLIP data set of endogenous PURA and two iCLIP data sets of overexpressed PURA in HeLa cells, I establish that PURA is a global RNA-binding protein. It preferentially binds RNAs in either the coding sequence (CDS) or the 3' untranslated region (3'UTR) of mature protein-coding transcripts by recognising a Purine-rich degenerated sequence motif. Even though overexpression of PURA results in less specific binding behaviour, the same overall binding patterns as from endogenous PURA persist. Overall characteristics of PURA binding remain similar in three distinct PURA iCLIP data sets with and without PURA overexpression.
To learn about the molecular consequences of a depletion of functional PURA in a cellular context, I used a 50% reduction of PURA in HeLa cells as a model for the heterozygous loss of PURA in PURA Syndrome and evaluated its impact on global RNA and protein expression. The results demonstrate that PURA depletion globally a ects RNA and protein expression. Additionally, I integrate PURA RNA binding with the changes in expression of RNAs and proteins in the context of PURA depletion. This reveals 234 targets of PURA that are bound by PURA and are impacted at both RNA and protein levels by the PURA protein. RNAs that are bound by PURA or change in abundance upon PURA depletion are enriched in neuronal development factors, RNA lifecycle regulators, and mitochondrial factors, among others. Consistent with a possible role of PURA in neuronal transport, there is considerable overlap between PURA bound transcripts and transcripts, that are transported to the dendritic end of neurons.
Notably, there is a link between PURA and P-bodies, as documented by the enrichment of PURA-bound RNAs in both the P-body and stress granule transcriptome. Further, PURA was found by our collaborators to be localised within P-bodies and P-body numbers were strongly reduced in cells that are depleted of PURA. This absence might be attributed to the downregulation of the proteins encoded by the PURA targets LSM14A and DDX6 as both of them were previously identified as essential for P-body formation.
Overall, the reduction of P-body numbers in PURA depletion, the neuronal function of PURA, and its association with mitochondria and RNA lifecycle regulation may indicate the cellular foundation of both PURA Syndrome and related neuronal diseases.
In summary, I present a versatile and user-friendly computational tool for the analysis of CLIP data. Subsequently, I conduct a thorough computational analysis of CLIP and other high-throughput data in the context of the RNA-binding protein PURA, which offers valuable insights into the cellular functions of PURA. These insights advance our understanding of the impact of PURA loss in PURA Syndrome and other disease contexts.
Anthropogenic activities have a major impact on our planet and rapidly drive biodiversity loss in ecosystems at a global scale. Particularly over the last century, rising CO2 emissions significantly raised global temperatures and increased the intensity and frequency of droughts and heatwaves. Additionally, agricultural land use and fossil fuel combustion contribute to the continuous release of nitrogen (N) and phosphorus (P) into ecosystems worldwide through extensive fertilization and deposition from the atmosphere. It is important to understand how these rapid changes affect the evolution of plant populations and their adaptive potential. Adaptation by natural selection (i.e., adaptive evolution) within a few generations is an essential process as a response to rapid environmental changes. Rapid evolution of plant populations can be detected by using the so-called resurrection approach. Here, diaspores (i.e., seeds) from a population are collected before (ancestors) and after (descendants) a potential selection pressure (e.g., consecutive years of drought or changes in nutrient supply). Comparing phenotypes of ancestors and descendants in a common environment such as an outside garden, greenhouse, or climate chamber, may then reveal evolutionary changes. Ideally, plants are first grown in a common environment for an intermediate refresher generation to reduce parental and storage effects.
The aim of this thesis was to investigate the occurrence of adaptive evolution in natural plant populations in response to rapidly changing environments over the past three decades. I conducted three experiments using the resurrection approach to generate comprehensive data on the adaptive processes that acted on three plant populations from three different species over the last three decades. Furthermore, I filled knowledge gaps in plant evolutionary ecology and conceptually developed the resurrection approach further.
In Chapter I, I performed a novel approach by testing for adaptive evolution in natural plant populations using the resurrection approach in combination with in-situ transplantations. I cultivated seedlings from ancestors (23 – 26 years old) and contemporary descendants of three perennial species (Melica ciliata, Leontodon hispidus and Clinopodium vulgare) from calcareous grasslands in the greenhouse and In Chapter III, I assessed the reproducibility of phenotypic differences between genotypes among three different growth facilities (climate chamber, greenhouse, and outdoor garden). I also evaluated differences in phenotypic expression between plants grown after one vs. two intermediate generations (i.e., refresher generations). I performed this experiment within the framework of the resurrection approach and compared ancestors and descendants of the same population of Leontodon hispidus.
I observed very strong differences among plants growing in the different growth facilities. I found a significant interaction between the growth facility and the temporal origin (ancestors vs. descendants): descendants had significantly larger rosettes than ancestors only in the greenhouse and they flowered significantly later than ancestors exclusively in the climate chamber. I did not find significant differences between intermediate generations within the growth facilities. Overall, Chapter III shows that the use of a particular experimental system can dictate the presence and magnitude of phenotypic differences. This implies that absence of evidence is not evidence of absence when it comes to investigating genetically based trait differentiation among plant origins (in space or time). Experimental systems should be carefully designed to provide meaningful conditions, ideally mimicking the environmental conditions of the population’s origins. Finally, growing a second intermediate generation did not impact the genetic differences of ancestors and descendants within the environments, supporting the idea that only one intermediate generation may be sufficient to reduce detectable parental and storage effects.
The resurrection approach allows a better understanding of rapid plant adaptation, but some limitations deserve to be highlighted. I only studied one population per species, and Chapters II and III only focus on one population of L. hispidus, which is also hampering generalizations, as adaptive potential can vary greatly among populations of the same species. I only compared the ancestral genotypes to one descendant sample with a long time span in between (26 – 28 years), which makes it hard to pinpoint the selection agents that caused the genetic differentiation among the sampling years. Hence, closely monitoring biotic and abiotic factors of the studied populations between the ancestral and descendant sampling in future studies, would make identifying the responsible selection pressures more precise. I also recommend sampling multiple populations over consecutive years to improve the robustness of results and make generalizations more approachable.Furthermore, combining the resurrection approach with other methods such as in-situ transplantations will be valuable to offset the limitation that adaptations cannot be proven under artificial conditions (e.g., in the greenhouse).
We present cross sections for the reaction e+e−→K0SK0L at center-of-mass energies ranging from 3.51 GeV to 4.95 GeV using data samples collected in the BESIII experiment, corresponding to a total integrated luminosity of 26.5 fb−1. The ratio of neutral-to-charged kaon form factors at large momentum transfers (12 GeV2<Q2<25 GeV2) is determined to be 0.21±0.01, which indicates a small but significant effect of flavor-SU(3) breaking in the kaon wave function, and consequently excludes the possibility that flavor-SU(3) breaking is the primary reason for the strong experimental violation of the pQCD prediction |F(π±)|/|F(K±)|=f2π/f2K, where F(π±) and F(K±) are the form factors, and fπ and fK are the decay constants of charged pions and kaons, respectively. We also observe a significant signal for the charmless decay ψ(3770)→K0SK0L for the first time. Within a 1σ contour of the likelihood value, the the branching fraction for ψ(3770)→K0SK0L is determined to be B=(2.63+1.40−1.59)×10−5, and the relative phase between the continuum and ψ(3770) amplitudes is ϕ=(−0.39+0.05−0.10)π. The branching fraction is in good agreement with the S- and D-wave charmonia mixing scheme proposed in the interpretation of the "ρπ puzzle" between J/ψ and ψ(3686) decays.
Mitochondria perform essential energetic, metabolic and signalling functions within the cell. To fulfil these, the integrity of the mitochondrial proteome has to be preserved. Therefore, each mitochondrial subcompartment harbours its own system for protein quality control. However, if the capacity of mitochondrial chaperones and proteases is overloaded, mitochondrial misfolding stress (MMS) occurs. Upon this stress condition, mitochondria communicate with the nucleus to increase the transcription of nuclear encoded mitochondrial chaperones and proteases. This proteotoxic stress pathway was termed the mitochondrial unfolded protein response (UPRmt) aiming at restoring protein homeostasis. Despite being discovered over 25 years ago, the signalling molecules released by stressed mitochondria as well as the corresponding receptor and transcription factor remain poorly understood. With this study, we aimed at characterising the underlying signalling events and mechanisms of how mitochondria react to misfolded proteins. First, we aimed to establish different methods to induce MMS that triggers the transcriptional induction of mitochondrial chaperones and proteases detected by quantitative polymerase chain reaction. We were able to induce UPRmt signalling by overexpression of an aggregation-prone protein and by knock-down or inhibition of mitochondrial protein quality control components. To study the signalling in a time-resolved manner, we focused on the usage of the mitochondrial HSP90 inhibitor GTPP and the mitochondrial LONP1 protease inhibitor CDDO.
Early time point RNA sequencing analysis of cells stressed with GTPP or CDDO revealed upregulated genes in response to oxidative stress. Indeed, measurements of mitochondrial superoxide with the fluorescent dye MitoSOX showed increased levels of reactive oxygen species (ROS) upon MMS induction. In contrast, there was no induction of mitochondrial chaperones and proteases when combining MMS with antioxidants. Compartment-specific targeting of the hydrogen peroxide sensor HyPer7 revealed increased ROS levels in the intermembrane space and matrix of mitochondria, followed by elevated ROS levels in the cytosol at later time points. The importance of cytosolic ROS for the signalling was supported by preventing UPRmt induction with an inhibitor blocking the outer mitochondrial membrane pore. Thus, ROS were identified as an essential UPRmt signal.
To understand which cytosolic factor is modified by ROS, redox proteomics was performed. Here, reversible changes on cysteine residues of the HSP40 co-chaperone DNAJA1 were observed upon MMS. Consequently, transcriptional induction of UPRmt genes was abolished by DNAJA1 knock-down. To understand the function of DNAJA1 during UPRmt signalling, quantitative interaction proteomics upon MMS revealed an increased binding to mitochondrial proteins and its interaction partner HSP70. Immunoprecipitation confirmed a ROS-dependent interaction between HSP40 and HSP70. Increased binding to mitochondrial proteins represented a cytosolic interaction of DNAJA1 with mitochondrial precursor proteins, whose accumulation was confirmed by western blot. Moreover, a fluorescent protein targeted to mitochondria accumulated in the cytosol during GTPP treatment, confirming a reduced import efficiency upon MMS. Preventing the accumulation of precursors by a translation inhibitor or depletion of a general mitochondrial transcription factor resulted in reduced UPRmt activation. Thus, DNAJA1 is essential for UPRmt signalling, since its oxidation by mitochondrial ROS and its enhanced recruitment to mitochondrial precursors allows the integration of both MMS-induced signals.
To link these findings to an increased transcription of mitochondrial chaperones and proteases, we screened for transcription factors accumulating in the nucleus upon MMS by cellular fractionation mass spectrometry. We demonstrated that specifically HSF1 accumulates in nuclei of cells stressed with GTPP or CDDO. Depletion of HSF1 by knock-down or knock-out resulted in the abrogation of the UPRmt-specific transcriptional response. HSF1 activation was visualised by nuclear accumulation on western blot, a process inhibited by ROS and precursor suppression. Moreover, DNAJA1 depletion prevented HSF1 activation. Ultimately, we proved by immunoprecipitation that the inhibitory interaction between HSF1 and HSP70 is reduced upon MMS.
Thus, we conclude that MMS increases mitochondrial ROS that are released into the cytosol. In addition, the import efficiency is reduced upon MMS, resulting in the accumulation of non-imported mitochondrial precursor proteins in the cytosol. Both signals are recognised via DNAJA1 oxidation and substrate binding. The concurrent recruitment of HSP70 to DNAJA1 results in the loss of the inhibitory HSP70-HSF1 interaction. Thus, active HSF1 can migrate to the nucleus to initiate transcription of mitochondrial chaperones and proteases. These findings are in accordance with observations in yeast, where mistargeted mitochondrial proteins activate cellular stress responses. Our results highlight a surprising interconnection and dependence of the mitochondrial and the cytosolic proteostasis network, in which the UPRmt is activated by a combination of two mitochondria-specific proteotoxic stress signals.
The theoretical and experimental investigation of exotic hadrons like tetraquarks is an important branch of modern elementary particle physics. In this thesis I investigate different four-quark systems using lattice QCD and search for evidence of stable tetraquark states or resonances.
Lattice QCD as a non-perturbative approach to QCD allows an accurate and reliable determination of the masses of strongly bound hadrons.
However, most tetraquarks appear as weakly bound states or resonances, which makes a theoretical investigation using lattice QCD difficult due to the finite spatial volume. A rigorous treatment of such systems is feasible using the so-called Lüscher method. This allows to calculate the scattering amplitude based on the finite-volume energy spectrum determined in a lattice QCD calculation. Similarly to the analysis of experimental data, this scattering amplitude can be used to determine the binding energies of bound states or the masses and decay widths of resonances in the infinite volume.
In my work I calculate the low-energy energy spectra of different four-quark systems and use - if necessary - the Lüscher method to determine the masses of potential tetraquark states.
I focus on systems consisting of two heavy antiquarks and two light quarks, where at least one of the heavy antiquarks is a bottom quark.
Even though such tetraquarks have not yet been experimentally detected, they are considered promising candidates for particles that are stable with respect to the strong interaction.
A decisive step for successfully calculating low-lying energy levels for such four-quark systems is a carefully chosen set of creation operators, which represent the physical states most accurately. In addition to operators that generate a local structure where all four quarks are located at the same space-time point, I also use so-called scattering operators that resemble two spatially separated mesons. These scattering operators turned out to be relevant for successfully determining the lowest energy levels and are therefore essential, especially if a Lüscher analysis is carried out.
In my work, I considered two different lattice setups to study the four-quark systems $\bar{b}\bar{b}ud$ with $I(J^P)=0(1^+) $, $\bar{b}\bar{b}us$ with $J^P=1^+ $ and $\bar{b}\bar{c}ud$ with $I(J^P)=0(0^+) $ and $I(J^P)=0(1^+) $ and to predict potential tetraquark states. In both setups, I considered scattering operators. While in the first setup I used them only as annihilation operators, in the second setup they were included both as creation and annihilation operators. Additionally, in the second lattice setup, I performed a simplified investigation of the $\bar{b}\bar{b}ud$ system with $I(J^P)=0(1^-) $, which is a potential candidate for a tetraquark resonance. The results of the investigation of the mentioned four-quark systems can be summarized as follows:
For the $ \bar{b}\bar{b}ud $ four-quark system with $ I(J^P)=0(1^+) $ I found a deeply bound ground state slightly more than $ 100\,\textrm{MeV} $ below the lowest meson-meson threshold. The existence of a corresponding $\bar{b}\bar{b}ud$ tetraquark in the infinite volume was confirmed using a Lüscher analysis and possible systematic errors due to the use of lattice QCD were taken into account.
Similar results were obtained for the $ \bar{b}\bar{b}us $ four-quark system with $ J^P=1^+ $. Again, I found a ground state well below the lowest meson-meson threshold, but slightly weaker bound than for the $ \bar{b}\bar{b}ud $ system. Effects due to the finite volume turned out to be negligible for this system, as already predicted for the $ \bar{b}\bar{b}ud $ system. \item For the $ \bar{b}\bar{c}ud $ four-quark systems with $ (J^P)=0(0^+) $ and $ (J^P)=0(1^+) $ I was able to rule out the existence of a deeply bound tetraquark states based on the energy spectrum in the finite volume. However, by means of a scattering analysis using the Lüscher method, I found evidence a broad resonance for both channels.
In the case of the $ \bar{b}\bar{b}ud $ four-quark system with $ I(J^P)=0(1^-) $, I could neither confirm the existence of a resonance, nor rule out its existence with certainty.
In particular, my investigations showed that the results of the two different lattice simulations are consistent. The theoretical prediction of the bound tetraquark states $\bar{b}\bar{b}ud$ and $\bar{b}\bar{b}us$ as well as the tetraquark resonances in the $\bar{b}\bar{c}ud$ system in this work represent an important contribution to the future experimental search for exotic hadrons and can support the discovery of previously unobserved particles.
Impact of pectin dietary supplementation on experimental food allergy via gut microbiota modulation
(2023)
In recent years, dietary fibers gained focus in regard of their immune-modulatory effects and the potentially beneficial effect on allergies. The dietary fiber and prebiotic pectin is able to promote growth and activity of beneficial bacteria and thereby induce modulation of different immune responses. However, structurally different types of pectin might promote different immune-modulatory responses and to date the optimal pectin type for induction of beneficial health effects is not identified. Furthermore, it is still unclear, whether pectins provide a beneficial effect on certain allergies, such as food allergy.
Having this in consideration, this study examined the immune-modulatory effects of structurally different pectins on naive as well as peach allergic mice. Furhtermore, the impact of dietary pectin supplementation on composition and diversity of the murine gut microbiota was determined.
This study showed that dietary pectin intervention was able to suppress allergy-related Th2 responses considering humoral and cellular immune responses. Only apple-derived high-methoxyl pectin revealed an impact on total IgA levels and affected the microbial richness. Furthermore, it is not known whether the effects observed with the two pectins are caused by modulations of the bacterial composition or induced at least partly by direct interaction with the immune cells. Further studies are required to fully understand the mechanisms underlying the immune-modulatory capacities of different pectins.
Finally, the obtained results generated evidence that dietary pectin intervention can beneficially modulate the immune response in healthy mice and – at least partially – suppress allergy-related immune responses in a model of food allergy, depending on the structural characteristics of the used pectin.
Bioactive small molecules are used in many research areas as important tools to uncover biological pathways, interpret phenotypic changes, deconvolute protein functions and explore new therapeutic strategies in disease relevant cellular model systems. To unlock the full potential of these small molecules and to ensure reliability of results obtained in cellular assays, it is crucial to understand the properties of these small molecules. These properties encompass their activity and potency on their designated target(s), their selectivity towards unintended off-targets and their phenotypic effects in a cellular system. Approved drugs often engage with multiple targets, which can be beneficial for some applications such as treatment of cancer where several pathways need to be inhibited for treatment efficacy. However, targeting multiple key proteins in diverse pathways also increases the possibility for unspecific or unwanted side effects. For many drugs the entire target space that they modulate is not known. This makes it difficult to use these drugs for target deconvolution or functional assays with the aim to understand the underlying biological processes. In contrast to drugs, for mechanistic studies, a good alternative are chemical tool compounds so called chemical probes that are usually exclusively selective as well as chemogenomic compounds, that inhibit several targets but have narrow selectivity profiles. Because they are mechanistic tools, chemical tool compounds must meet stringent quality criteria and they are therefore well characterized in terms of their potency, selectivity and cellular on-target activity. To ensure that an observed phenotypic effect caused by a compound can be attributed to the described target(s), it is essential to study also properties of chemical tools leading to unspecific cellular effects. There are a variety of unspecific effects that can be caused by physiochemical compound properties that can interfere with phenotypic assays as well as functional compound evaluations. One of these effects is low solubility causing toxicity or intrinsic fluorescence potentially interfering with assay readouts. But unanticipated cellular responses can also arise from unspecific binding, accumulation in cellular compartments or damage caused to organelles such as mitochondria or the cytoskeleton that can result in the induction of diverse forms of cell death.
In this study, we investigated the influence of a variety of small molecules on distinct cell states, by establishing and validating high-content imaging assays, which we called Multiplex assay. This assay portfolio enabled us to detect different cellular responses using diverse fluorescent reporters, such as the influence of a compound on cell viability, induction of cell death programs and modulation of the cell cycle. Additionally, general compound properties such as precipitation and intrinsic fluorescence were simultaneously detected. The assay is adaptable to assess other cellular properties of interest, such as mitochondrial health, changes in cytoskeletal morphology or phospholipidosis. A significant advantage of the assay is that we are using live cells, so we can capture dynamic cellular changes and fluctuations that can be crucial for the understanding of cellular responses.
This bachelor thesis developed a pipeline for automatic processing of scanned hospital letters: HospLetExtractor. Hospital letters can contain valuable information about potential adverse drug reactions and useful case information relevant to pharmacovigilance. To make this data accessible, this thesis presents a pipeline consisting of image pre-processing, optical character recognition and post-processing. Pre-processing deskews the images, removes lines and rectangles, reduces noise and applies super-resolution. For the post-processing a spell checking system was set up including a newly built word frequency dictionary for german medical terms based on a created corpus of german medical texts. Furthermore, classical and deep learning models for the classification of hospital letters were compared, in which the transformer-based models performed best. In order to train and test the models, a new gold standard was created. By making these medical documents accessible for automatic analysis, hopefully a contribution can be made to expand the scope of pharmacovigilance.
The main focus of this thesis is the application of the nonperturbative Functional Renormalization Group (FRG) to the study of low-energies effective models for Quantum Chromodynamics (QCD). The study of effective field theories and models is crucial for our understanding of physics, especially when we deal with fundamental interaction theories like QCD. In particular, the ultimate goal is the understanding of the critical properties of these models in such a way that we can have an insight on the actual critical phenomena of QCD, with a special focus on its chiral phase transition. The choice of the FRG method derives from the fact that it belongs to the class of functional non-perturbative methods and has also the advantage of linking physics at different energy scales. These features make FRG perfectly compatible with the task of studying non-perturbative phenomena and in particular phase transitions, like the ones expected for strongly interacting matter. However, the functional nature of the FRG approach and of the Wetterich equation has a consequence that its exact resolution is hardly possible, and an ansatz for the effective action is generally needed. In this work we choose to adopt the local-potential approximation (LPA), which prescribes to stop at zeroth order in the expansion in derivative operators of the quantum effective action, including only the quantum effective potential. In this work we exploited the key observation that the FRG flow equation can be cast, for specific models and truncation schemes, in the form of an advection-diffusion, possibly with a source term. This type of equation belongs to the class of problems faced in the context of viscous hydrodynamics. Therefore, an innovative approach to the solution of the FRG flow equation consists in the choice of a method developed specifically for the resolution of this class of hydrodynamic equations. In particular, the Kurganov-Tadmor finite-volume scheme is adopted. Throughout this work we apply this scheme to the study of different physical systems, showing the reliability and the flexibility of this approach.
In the first part of the thesis, we discuss the well-known O(N) model, using the hydrodynamic formulation to solve the FRG flow equation in the LPA truncation. We focus on the study of the critical behaviour of the system and calculate the corresponding critical exponents. Particular attention is given to the error estimation in the extraction of critical exponents, which is a needed and not widely explored aspect. The results are well compatible with others in the literature, obtained with different perturbative and nonperturbative methods, which validates the procedure. In the second part of the thesis, we introduce the quark-meson model as a low-energy effective model for QCD, with a specific focus on its chiral symmetry-breaking pattern and the subsequent dynamical quark-mass generation. The LPA flow equation is of the advection-diffusion type, with an extra source contribution which is due to the inclusion of fermionic degrees of freedom. We thus adopt the developed numerical techniques to derive the phase diagram of the model, which is in agreement with the one obtained with other techniques in the literature.
We also follow another possible way for the study of the critical properties of the quark-meson model: the so-called thermodynamic geometry. This approach is based on the interpretation of the parameter space of the system as a differential manifold. One can then obtain relevant information about the phase transitions from the Ricci scalar. We studied the chiral crossover investigating the behavior of the Ricci scalar up to the critical point, featuring a peaking behavior in the presence of the crossover. We then repeated this analysis in the chiral limit, where the phase transition is expected to be of second order. Via this geometric technique it is possible to have a different view on the chiral phase transition of QCD. This is the case since this approach is based on the calculation of quantities which are influenced by higher-order momenta of the thermodynamic potential, thus allowing for a more comprehensive analysis of the phase transition.
Finally, we exploit the numerical advancement to face the issue of the regulator choice in the FRG calculations. This is one of the most delicate issues which arise when using approximations to solve the FRG flow equation and deserves extensive investigation. In particular, we performed a vacuum parameter study and used the RG consistency requirement to determine the impact of the choice of the regulator on the physical observables and on the phase diagram of the model. Via this study we develop a systematic method to comparison the results obtained via different regulators. We show the importance of the choice of an appropriate UV cutoff in the determination of UV-independent IR observables and, consequently, the impact on the latter that the truncation of the effective average action and the choice of the regulator have.
Diese Versuchsreihe beschäftigte sich mit der Fragestellung, ob günstige Handelsmarken- Zigaretten mehr Feinstaub als teure Markenzigaretten emittieren. Dabei wurde der Passivrauch untersucht, welcher durch das Verrauchen verschiedener Zigarettenmarken entstand. Feinstaub stellt heutzutage den wichtigsten einzelnen gesundheitsschädlichen Faktor in Innenräumen dar. Das Augenmerk liegt dabei hauptsächlich auf den feinen Partikeln (PM2,5, PM1). Tumore, chronische Atemwegserkrankungen und eine erhöhte Mortalität stellen nur einen Teil der massiven gesundheitlichen Folgen durch Feinstaub dar. Vulnerable Bevölkerungsgruppen wie Kinder und alte Personen sind besonders durch Passivrauch gefährdet. Die Ergebnisse der Versuchsreihe dienen als Grundlage, um den gesundheitsschädlichen Einfluss des Passivrauchs zu interpretieren. Günstige Handelsmarken-Zigaretten weisen, unter anderem wegen des beständig ansteigenden Zigarettenpreises als auch der anhaltenden Inflation in Deutschland, einen wachsenden Marktanteil auf. Daher müssen sie auch weiterhin in wissenschaftlichen Untersuchungen mit einbezogen werden.
Drei teure sowie drei günstige Zigarettenmarken wurden miteinander und mit der Referenzzigarette 3R4F der Universität Kentucky verglichen. Zu den teuren Marken zählten Marlboro, Camel und Nil. Die günstigeren Handelsmarken-Zigaretten waren Giants, Goldfield und Jakordia. Die Rauchpumpe „Automatic environmental tobacco smoke emitter“ (AETSE) ermöglichte in einem definierten Raum der abgeschlossenen Rauchkammer, Passivrauch zu erzeugen, ohne die menschliche Gesundheit zu gefährden. Ein standardisiertes Rauchprotokoll garantierte dabei reproduzierbare und vergleichbare Ergebnisse. Das Laser Aerosolspektrometer (LAS) Modell 1.109 der Firma Grimm wies eine Messspanne von 0,25 μm bis 32 μm auf. So konnte der Feinstaub gemessen und gruppiert werden. Obwohl der Versuchsaufbau nicht vollkommen realitätsgetreu war, entstand ein adäquater Vergleich der Feinstaubemissionen von (Handels-)Markenzigaretten.
PM10 und PM2,5 wurden erhoben, weil sie die von der EU und WHO standardisierten Messwerte für die Luftverschmutzung durch Feinstaub sind. Die Messung von PM1 rechtfertigt sich durch die stärker gesundheitsschädigende Komponente von Partikeln dieser Größenordnung. Für diese drei Größenfraktionen wurden die mittlere Konzentration Cmean sowie die Area Under The Curve (AUC) ermittelt. Die AUC stellt dabei die Höhe der Gesamtexposition durch Feinstaub dar.
Die Ergebnisse dieser Versuchsreihe zeigen, dass PM1 den größten Anteil der Feinstaubemission der getesteten Zigaretten ausmachte. Alle Zigarettenmarken haben in einem abgeschlossenen Raum Feinstaubmengen in gesundheitsgefährdender Menge produziert. Die Handelsmarke Jakordia emittierte beim Verrauchen generell weniger Feinstaub als alle anderen Zigarettenmarken. Im Allgemeinen konnte kein Unterschied zwischen den günstigen Handels- und den teuren Markenzigaretten festgestellt werden. Es ist wissenschaftlich belegt, dass sich jede Feinstaubkonzentration negativ auf die Gesundheit auswirkt. Die Ergebnisse können dementsprechend in Gänze unter dem Gesichtspunkt der Gesundheitsschädlichkeit eingestuft werden.
Aufgrund veralteter und unspezifischer, beziehungsweise fehlender Angaben zu den Inhaltsstoffen der einzelnen Zigarettensorten, konnte die Ursache der Unterschiede zwischen Jakordia und den anderen Marken nicht geklärt werden. Die Zigarettenhersteller müssen verpflichtet werden, die detaillierten Zusammensetzungen der Tabakprodukte den Behörden wie dem BMEL oder dem Bundesgesundheitsministerium zugänglich zu machen. Dies wäre ein wichtiger Bestandteil für die zukünftige Forschung und Risikobewertung der verschiedenen Inhalts- und Zusatzstoffe.
Tobacco smoke-associated particulate matter emissions in a car cabin using the TAPaC platform
(2023)
Zigarettenrauch enthält bis zu 5000 Inhaltsstoffe, von denen mindestens 250 gesundheits-schädlich und 98 krebserregend sind. Der freigesetzte Feinstaub erreicht hohe Konzentrati-onen in Innenräumen und ist somit besonders schädlich für Passivraucher (z.B. Kinder).
Ziel war es eine Messplattform zu etablieren, mit dessen Hilfe die Feinstaubexposition durch Zigarettenrauch im Fahrzeuginnenraum unter unterschiedlichen ventilatorischen Szenarien untersucht werden konnte. Zudem sollte der Einfluss verschiedener Tabakprodukte auf die Feinstaubkonzentration getestet werden.
Im ersten Teil dieser Dissertation wird die neuartige TAPaC Messplattform (tobacco-associated particulate matter emissions inside a car cabin: establishment of a new measuring platform) vorgestellt. Sie erlaubt die Auswirkungen verschiedener ventilatorischer Sze-narien auf die Feinstaubemission von Zigarettenrauch im Auto besser beurteilen zu können. Da niemand gesundheitsschädlichem Tabakrauch ausgesetzt wird, kann sie ohne jegliche ethische Bedenken eingesetzt werden. Die Zigaretten werden hierbei einzeln auf der Beifahrerseite verraucht. Der beim Rauchen freigesetzte Feinstaub wird auf der Fahrerseite gemessen und in PM10 (Partikel mit einem aerodynamischen Durchmesser <10 µm), PM2,5 (Partikel mit einem aerodynamischen Durchmesser <2,5 µm), und PM1 (Partikel mit einem aerodynamischen Durchmesser <1 µm) unterteilt. Hierbei konnten unter der Verwendung von 3R4F Research Cigarettes extrem hohe Feinstaubmesswerte bei geschlossenen Fenstern und ausgeschalteter Lüftung nachgewiesen werden (PM10: 1608 µg/m3, PM2,5: 1583 µg/m3, PM1: 1133 µg/m3). Diese Daten stellen Durchschnittwerte nach 10-minütiger Messung dar. Auch konnte eine Reduktion der Feinstaubkonzentration (PM10: -70,8 bis -74,4%, PM2,5: -70,6 bis -74,3%, PM1: -64,0 bis -68,0%) durch den Einsatz der Lüftung nachgewiesen werden.
Der zweite Teil dieser Dissertation befasste sich maßgeblich mit dem Einfluss unterschiedlicher ventilatorischer Szenarien auf die Feinstaubkonzentrationen im Auto. Unter Verwen-dung von drei unterschiedlichen Zigarettenprodukten (3R4F Research Cigarettes, Marlboro Red, Marlboro Gold) wurden insgesamt 7 ventilatorische Szenarien (Condition C1b–C7b) getestet. Für alle Szenarien, mit Ausnahme von C1b, war die Autolüftung auf Stufe 2/4 ge-stellt und in Richtung der Windschutzscheibe gerichtet. Die Szenarien beinhalteten: Condition 1 (C1b) Fenster geschlossen, Autolüftung aus und externer Ventilator aus, Condition 2 (C2b) Fenster 10 cm geöffnet und externer Ventilator aus, Condition 3 (C3b) Fenster 10 cm geöffnet und externer Ventilator auf höchster Stufe (3/3) an, Condition 4 (C4b) Fenster halb geöffnet und externer Ventilator aus, Condition 5 (C5b) Fenster halb geöffnet und externer Ventilator auf höchster Stufe (3/3) an, Condition 6 (C6b) Fenster vollständig geöffnet und externer Ventilator aus und Condition 7 (C7b) Fenster vollständig geöffnet und externer Ventilator auf höchster Stufe (3/3) an.
Es zeigten sich besonders hohe Feinstaubkonzentrationen bei Zigaretten, welche ohne Ventilation bei geschlossenem Fenster verraucht wurden. Unabhängig von der verwendeten Marke war die Feinstaubbelastung nach 10 min unter C1b (PM10: 1272–1697 µg/m3, PM2,5: 1253–1659 µg/m3, PM1: 964–1263 µg/m3) deutlich höher als unter C2b (PM10: 67–84 µg/m3, PM2,5: 68–83 µg/m3, PM1: 66–79 µg/m3), C3b (PM10: 100–139 µg/m3, PM2,5: 99–138 µg/m3, PM1: 95–132 µg/m3), C4b (PM10: 84–94 µg/m3, PM2,5: 84–93 µg/m3, PM1: 81–89 µg/m3), C5b (PM10: 94–120 µg/m3, PM2,5: 93–119 µg/m3, PM1: 90–114 µg/m3), C6b (PM10: 155–196 µg/m3, PM2,5: 154–195 µg/m3, PM1: 148–184 µg/m3), und C7b (PM10: 74–99 µg/m3, PM2,5: 72–97 µg/m3, PM1: 69–93 µg/m3). Ebenfalls wurden Feinstaubspitzenwerte bei 4,5 min und 10 min ausgewertet. Bei 4,5 min konnte PM10 unter C2b–C7b um 81,6–93,3% im Vergleich zu C1b reduziert werden. Bei 10 min sogar um 92,9–99,3%. Die 3R4F Zigarette hatte die höchste Feinstaubemission gefolgt von Marlboro Rod und Marlboro Gold. Zudem zeigte sich, dass die Feinstaubemission auch von den Tabakinhaltsstoffen und dessen Konzentrationen abhängig ist.
Die Etablierung der neuen Messplattform ermöglicht die Erforschung von Feinstaubexpositionen durch Zigarettenrauch im Auto ohne potentiell gesundheitliche Folgen. In Zusammenschau der Daten ließ sich nach Öffnen des Fensters und unter Einflussnahme verschiedener ventilatorischer Einstellungen eine deutliche Reduktion der Feinstaubkonzentration im Auto feststellen. Nichtsdestotrotz bleibt die Feinstaubbelastung im Autoinnenraum zu hoch und übersteigt die Richtwerte der Air Quality Guidelines aus dem Jahre 2021 der WHO. Die experimentell untersuchten Belüftungsszenarien sind somit insuffizient, da sie nicht vor der toxischen Feinstaubexposition durch Passivrauch beim Autofahren schützen können.
A light scalar X0 or vector X1 particles have been introduced as a possible explanation for the (g−2)μ anomaly and dark matter phenomena.
Using (8.998±0.039)×109 $\jpsi$ events collected by the BESIII detector, we search for a light muon philic scalar X0 or vector X1 in the processes J/ψ→μ+μ−X0,1 with X0,1 invisible decays. No obvious signal is found, and the upper limits on the coupling g′0,1 between the muon and the X0,1 particles are set to be between 1.1×10−3 and 1.0×10−2 for the X0,1 mass in the range of 1<M(X0,1)<1000~MeV/c2 at 90% confidence level.
Using a data sample corresponding to an integrated luminosity of 11.3 fb−1 collected at center-of-mass energies from 4.23 to 4.70 GeV with the BESIII detector, we observe the process e+e− → π0π0ψ2(3823) for the first time with a statistical significance of 6.0 standard deviations. The ratio of average cross sections for e+e− → π0π0ψ2(3823) and π+π−ψ2(3823) is determined to be R = σ[e+e− → π0π0ψ2(3823)] σ[e+e−→π+π−ψ2(3823)] = 0.57 ± 0.14 ± 0.05, which is consistent with expectations from isospin symmetry. Here and below, the first uncertainties are statistical and the second are systematic. The mass of the ψ2(3823) is measured to be M[ψ2(3823)] = 3824.5±2.4±1.0 MeV/c2. Due to the limited data sample, an upper limit of 18.8 MeV at 90% confidence level is set on the intrinsic width of ψ2(3823).
Using an 𝑒+𝑒− collision data sample of (27.08±0.14)×108 𝜓(3686) events collected by the BESIII detector, we report the first observation of 𝜒𝑐𝐽→Ω−¯Ω+ (𝐽=0, 1, 2) decays with significances of 5.6𝜎, 6.4𝜎, and 18𝜎, respectively, where the 𝜒𝑐𝐽 mesons are produced in the radiative 𝜓(3686) decays. The branching fractions are determined to be ℬ(𝜒𝑐0→Ω−¯Ω+) = (3.51±0.54±0.29)×10−5, ℬ(𝜒𝑐1→Ω−¯Ω+)=(1.49±0.23±0.10)×10−5, and ℬ(𝜒𝑐2→Ω−¯Ω+)=(4.52±0.24±0.18)×10−5, where the first and second uncertainties are statistical and systematic, respectively.
Geometry is part of the core of mathematics. It has been relevant ever since people have interacted with nature and its phenomena. Geometry’s relevance to the teaching and learning of mathematics can be emphasized, too. Nevertheless, a current potential shift in the topics of mathematics education to the detriment of geometry might be emerging. That is, other topics related to mathematics are seeming to grow in importance in comparison to geometry. Despite this, or perhaps because of it, geometry is an important component of current research in mathematics education. In the literature review, we elaborate relevant foci on the basis of current conference proceedings. By means of about 50 journal articles, five main topics are elaborated in more detail: geometric thinking and practices, geometric contents and topics, teacher education in geometry, argumentation and proof in geometry, as well as the use of digital tools for the teaching and learning of geometry. Conclusions and limitations for current and future research on geometry are formulated at the end of the article. In particular, the transfer to the practices of geometric teaching is explored on the basis of the elaborated research findings in order to combine both aspects of the teaching and learning of geometry.
Biological membranes serve as physical barriers in cells and organelles, enabling the maintenance of chemical or ionic gradients that are essential for triggering various integral, peripheral, or lipid-anchored membrane proteins, necessary for their life-essential functions. The study of membrane proteins has unique challenges due to their hydrophobic nature, limited expression levels, and inherent flexibility. Single-particle analysis (SPA) enables the determination of high-resolution three-dimensional structures using minimal amounts of specimen without the need for crystallization. Additionally, cryogenic electron tomography (cryo-ET) and subtomogram averaging (StA) offer the ability to study membrane protein complexes, cellular architecture, and molecular interactions while preserving close-to-life conditions. With ongoing improvements in cryo-EM technologies, obtaining high-resolution structures of membrane proteins in vitro can allow people to understand their mechanisms and functions, and to facilitate the design and optimization of new therapeutic agents. Furthermore, there has been significant growth in the structural characterization of membrane proteins in situ, as studying biomolecules within their physiological context is an ultimate goal in structural biology for a comprehensive understanding of molecular networks in cells.
Due to the amphipathic nature of membrane proteins, their production, purification, and isolation pose significant challenges compared to soluble proteins. To maintain the membrane protein fold in an aqueous buffer after disrupting lipid membranes, the use of detergents, amphipols, lipid nanodiscs, saposin-lipoprotein (salipro), styrene-maleic acid co-polymer lipid particles (SMALPS) is common and often essential. A limitation of the membrane-mimetic systems is the absence of an actual lipid bilayer environment. To address this issue, membrane proteins can be reconstituted into liposomes, and this closed membrane environment closely mimics the physiological conditions of the proteins. The use of liposomes for structure determination is expected to significantly expand in the in vitro study of membrane proteins and membrane-associated proteins, particularly for capturing transient complexes in specific functional states.
Resolving the structures of membrane proteins in their native cellular context is considered the ideal approach for understanding their functions and associated molecular networks. While single-particle cryo-EM can achieve higher resolution than subtomogram averaging, it often requires at least partial purification of the target molecules from their native environment inside cells and tissues. By combining averaging tools on subvolumes obtained through cryo-ET, structures can currently be determined at resolutions of 10-30 Å. With ongoing advancements and refinements in cryo-ET methodologies, routine high-resolution structure determination in situ is poised to become a valuable tool for both structural and cell biologists in the long run, and the field holds great promise for further expanding our understanding of cellular structures and processes at the molecular level.
The main aim of this thesis is to further our knowledge of the structure and function of a small prokaryotic voltage-gated sodium ion channel, NaChBac in liposomes, and a large knob complex found on the surface of Plasmodium falciparum-infected human erythrocyte by cryo-ET and StA.
Chapter 2 presents the first StA map of the 120-kDa NaChBac embedded in liposomes under a resting membrane potential at a modest resolution of 16 Å. The approach presented in this study, which can be widely applied to cryo-EM analysis of membrane proteins, with a specific focus on membrane proteins with small soluble domains, lays the foundation for cryo-ET and StA of integral or peripheral membrane proteins whose functions are affected by transmembrane electrochemical gradients and/or membrane curvatures. Chapter 3 shows the first cryo-EM structure of the supramolecular knob complex in P. falciparum-infected human erythrocyte. While a previous study provided an overall architectural view of knobs using negative stain tomography, the in situ structure bridges this gap, guiding future investigations into the molecular composition and the role of these native knobs in Plasmodium infection and immunity.
This thesis opens up several promising lines for future studies of membrane proteins in vitro and in situ, where other membrane proteins can be studied in physiologically relevant environments. Already with the present generation of cryo-EM hardware and software, this thesis represents pioneering research in the field of membrane protein structural biology.
Using e+e− annihilation data corresponding to an integrated luminosity of 2.93 fb−1 taken at the center-of-mass energy s√=3.773~GeV with the BESIII detector, a joint amplitude analysis is performed on the decays D0→π+π−π+π− and D0→π+π−π0π0(non-η). The fit fractions of individual components are obtained, and large interferences among the dominant components of D0→a1(1260)π, D0→π(1300)π, D0→ρ(770)ρ(770) and D0→2(ππ)S are found in both channels. With the obtained amplitude model, the CP-even fractions of D0→π+π−π+π− and D0→π+π−π0π0(non-η) are determined to be (75.2±1.1stat.±1.5syst.)% and (68.9±1.5stat.±2.4syst.)%, respectively. The branching fractions of D0→π+π−π+π− and D0→π+π−π0π0(non-η) are measured to be (0.688±0.010stat.±0.010syst.)% and (0.951±0.025stat.±0.021syst.)%, respectively. The amplitude analysis provides an important model for binning strategy in the measurements of the strong phase parameters of D0→4π when used to determine the CKM angle γ(ϕ3) via the B−→DK− decay.
Using data samples with an integrated luminosity of 22.42 fb−1 collected by the BESIII detector operating at the BEPCII storage ring, we measure the cross sections of the $e^{+}e^{-}\rightarrow\etaJ/\psi$ process at center-of-mass energies from 3.808 to 4.951 GeV. Three structures are observed in the line shape of the measured cross sections. A maximum-likelihood fit with ψ(4040), two additional resonances, and a non-resonant component is performed. The mass and width of the first additional state are (4219.7±2.5±4.5)MeV/c2 and (80.7±4.4±1.4)MeV, respectively, consistent with the ψ(4230). For the second state, the mass and width are (4386±13±17)MeV/c2 and (177±32±13)MeV, respectively, consistent with the ψ(4360). The first uncertainties are statistical and the second ones are systematic. The statistical significance of ψ(4040) is 8.0σ and those for ψ(4230) and ψ(4360) are more than 10.0σ.
Using 15.6 fb−1 of e+e− collision data collected at twenty-four center-of-mass energies from 4.0 to 4.6 GeV with the BESIII detector, the helicity amplitudes of the process e+e−→π+π−ω are analyzed for the first time. Born cross section measurements of two-body intermediate resonance states with statistical significance greater than 5σ are presented, such as f0(500), f0(980), f2(1270), f0(1370), b1(1235)±, and ρ(1450)±. In addition, evidence of a resonance state in e+e−→π+π−ω production is found. The mass of this state obtained by line shape fitting is about 4.2 GeV/c2, which is consistent with the production of ψ(4160) or Y(4220).
The cross sections of the 𝑒+𝑒−→𝜙𝜂′ process at center-of-mass energies from 3.508 to 4.951 GeV are measured with high precision using 26.1 fb−1 data collected with the BESIII detector operating at the BEPCII storage ring. The cross sections are of the order of a few picobarn and decrease as the center-of-mass energy increases as 𝑠−𝑛/2 with 𝑛=4.35±0.14. This result is in agreement with the Nambu-Jona-Lasinio model prediction of 𝑛=3.5±0.9. In addition, the charmless decay 𝜓(3770)→𝜙𝜂′ is searched for by fitting the measured cross sections, yet no significant signal is observed. The upper limit of ℬ(𝜓(3770)→𝜙𝜂′) at the 90% confidence level is determined to be 2.3×10−5.
Evidence for the singly Cabibbo suppressed decay Λ+c→pπ0 is reported for the first time with a statistical significance of 3.7σ based on 6.0 fb−1 of e+e− collision data collected at center-of-mass energies between 4.600 and 4.843 GeV with the BESIII detector at the BEPCII collider. The absolute branching fraction of Λ+c→pπ0 is measured to be (1.56+0.72−0.58±0.20)×10−4, which distinctly exceeds the upper limit measured by Belle experiment. Combining with the branching fraction of Λ+c→nπ+, (6.6±1.3)×10−4, the ratio of the branching fractions of Λ+c→nπ+ and Λ+c→pπ0 is calculated to be 3.2+2.2−1.2. As an important input for the theoretical models describing the decay mechanisms of charmed baryons, our result indicates that the non-factorizable contributions play an essential role and their interference with the factorizable contributions should not be significant. In addition, the absolute branching fraction of Λ+c→pη is measured to be (1.63±0.31stat±0.11syst)×10−3, which is consistent with previous measurements.
The Ξ0 asymmetry parameters are measured using entangled quantum Ξ0 − Ξ¯ 0 pairs from a sample of ð448.1 2.9Þ × 106 ψð3686Þ events collected with the BESIII detector at BEPCII. The relative phase between the transition amplitudes of the Ξ0Ξ¯ 0 helicity states is measured to be ΔΦ ¼ −0.050 0.150 0.020 rad, which implies that there is no obvious polarization at the current level of statistics. The decay parameters of the Ξ0 hyperon ðαΞ0 ; αΞ¯ 0 ; ϕΞ0 ; ϕΞ¯ 0 Þ and the angular distribution parameter ½αψð3686Þ and ΔΦ are measured simultaneously for the first time. In addition, the CP asymmetry observables are determined to be AΞ0 CP ¼ ðαΞ0 þ αΞ¯ 0 Þ=ðαΞ0 − αΞ¯ 0 Þ ¼ −0.007 0.082 0.025 and ΔϕΞ0 CP ¼ ðϕΞ0 þ ϕΞ¯ 0 Þ=2 ¼ −0.079 0.082 0.010 rad, which are consistent with CP conservation.
We report a measurement of the cross section for the process e+e−→π+π−J/ψ around the X(3872) mass in search for the direct formation of e+e−→X(3872) through the two-photon fusion process. No enhancement of the cross section is observed at the X(3872) peak and an upper limit on the product of electronic width and branching fraction of X(3872)→π+π−J/ψ is determined to be Γee×B(X(3872)→π+π−J/ψ)<7.5×10−3eV at 90% confidence level under an assumption of total width of 1.19±0.21 MeV. This is an improvement of a factor of about 17 compared to the previous limit. Furthermore, using the latest result of B(X(3872)→π+π−J/ψ), an upper limit on the electronic width Γee of X(3872) is obtained to be <0.32eV at the 90% confidence level.
The raccoon is listed among the invasive alien species of EU concern requiring management actions. Projections of its global distribution have been mainly based on climatic variables so far. In this study, we aim to address the impact of land cover (LC) on the raccoon distribution in North America and Europe. First, we identified the LC types in which the observation sites are predominantly located to derive preferred LC types. Second, we used an ecological niche modelling (ENM) approach to evaluate the predictive power of climatic and LC information on the current distribution patterns of raccoons in both ranges. Raccoons seem to be more often associated to forested areas and mixed landscapes, including cropland and urban areas, but underrepresented in vegetation-poor areas, with patterns largely coinciding in both ranges. In order to compare the predictive power of climate variables and land cover variables, we conducted principal component analyses of all variables in the respective variable sets (climate variables and land cover variables) and used all PC variables that together explain 90% of the total variance in the respective set as predictors. Land cover only models resulted in patchy patterns in the projected habitat suitabilities and showed a higher performance compared to the climate only models in both ranges. In Europe, the land cover habitat suitability seems to exceed the current observed occurrences, which could indicate a further spread potential of the raccoon in Europe. We conclude that information on land cover types are important drivers, which explain well the spatial patterns of the raccoon. Consideration of land cover could benefit efforts to control invasive carnivores and contribute to better management of biodiversity, but also human and animal health.
Flow coefficients (v2 and v3) are measured in high-multiplicity p+Au, d+Au, and 3He+Au collisions at a center-of-mass energy of √sNN = 200 GeV using the STAR detector. The measurements are conducted using two-particle correlations with a pseudorapidity requirement of |η|< 0.9 and a pair gap of |Δη|>1.0. The primary focus of this paper is on the analysis procedures and methods employed, especially the subtraction of non-flow contributions. Four well-established non-flow subtraction methods are applied to determine vn, and their validity is verified using the HIJING event generator. The vn values are compared across the three collision systems at similar multiplicities, which allows for cancellation of final state effects and isolation of the impact of the initial geometry. While the v2 values display differences among these collision systems, the v3 values are largely similar, consistent with the expectations of subnucleon fluctuations in the initial geometry. The ordering of vn differs quantitatively from previous measurements obtained using two-particle correlations with a larger rapidity gap; this difference could be partially attributed to the effects of flow decorrelations in the rapidity direction.
We report a measurement of exclusive J/ψ photoproduction in Au+Au ultra-peripheral collisions at sNN−−−√=200 GeV using the STAR detector. For the first time, i) the rapidity correlation between J/ψ photoproduction and neutron emission from nuclear breakups has been experimentally measured; ii) nuclear suppression factors are measured for both the coherent and incoherent J/ψ production. At photon-nucleon center-of-mass energy of 25.0 GeV, the coherent and incoherent J/ψ cross sections of Au nuclei are found to be 71±10% and 36±7%, respectively, of that of free protons. The stronger suppression observed in the incoherent production provides a new experimental handle to study the initial-state parton density in heavy nuclei. Data are compared with theoretical models quantitatively.
We report a new measurement of the production of electrons from open heavy-flavor hadron decays (HFEs) at mid-rapidity (|y|< 0.7) in Au+Au collisions at sNN−−−√=200 GeV. Invariant yields of HFEs are measured for the transverse momentum range of 3.5<pT<9 GeV/c in various configurations of the collision geometry. The HFE yields in head-on Au+Au collisions are suppressed by approximately a factor of 2 compared to that in p+p collisions scaled by the average number of binary collisions, indicating strong interactions between heavy quarks and the hot and dense medium created in heavy-ion collisions. Comparison of these results with models provides additional tests of theoretical calculations of heavy quark energy loss in the quark-gluon plasma.
The financial sector plays an important role in financing the green transformation. Various regulatory initiatives in the EU aim to improve transparency in relation to the sustainability of financial products and the sustainability of economic activities of non-financial and financial undertakings. For credit institutions, the Green Asset Ratio (GAR) has been established by the European regulatory authorities as a key performance indicator (KPI) for measuring the proportion of Taxonomy-aligned on-balance-sheet exposure in relation to the total assets. The breakdown of the total GAR by type of counterparty, environmental objective and type of asset provides in-depth information about the sustainability profile of a credit institution. This information, which has not been available to date, may also initiate discussions between management and shareholders or other stakeholders regarding the future sustainability strategy of credit institutions. This paper provides an overview of the regulatory background and the method of calculating the GAR along different dimensions. Finally, the potential benefits and limitations of the GAR are discussed.
The linear and mode-coupled contributions to higher-order anisotropic flow are presented for Au+Au collisions at sNN−−−√ = 27, 39, 54.4, and 200 GeV and compared to similar measurements for Pb+Pb collisions at the Large Hadron Collider (LHC). The coefficients and the flow harmonics' correlations, which characterize the linear and mode-coupled response to the lower-order anisotropies, indicate a beam energy dependence consistent with an influence from the specific shear viscosity (η/s). In contrast, the dimensionless coefficients, mode-coupled response coefficients, and normalized symmetric cumulants are approximately beam-energy independent, consistent with a significant role from initial-state effects. These measurements could provide unique supplemental constraints to (i) distinguish between different initial-state models and (ii) delineate the temperature (T) and baryon chemical potential (μB) dependence of the specific shear viscosity ηs(T,μB).
Die radikale Prostatektomie (RP) stellt neben der Radiatio der Prostata den Goldstandard der Lokaltherapie des lokalisierten Prostatakarzinoms (PCa) dar. Neben der Erzielung einer postoperativen Tumorfreiheit (onkologisches Ergebnis), spielen die postoperativen, funktionellen Ergebnisse (z.B. Erektionsfähigkeit, Urin-Kontinenz) nach RP für die Patienten eine zentrale Rolle. Hierbei ist vor allem die (Wieder-) Erlangung der postoperativen Kontinenz hervorzuheben, da das Ausbleiben mit einem substantiellem Verlust der Lebensqualität einhergeht und eine deutliche Einschränkung im Alltag darstellt. Verschiedene Tumor- und Patientencharakteristika (pathologisches Tumorstadium, Body Mass Index [BMI], Alter, Prostatavolumen) wurden in vorangegangenen Publikationen als Faktoren identifiziert, die Einflüsse auf die Wiedererlangung der Kontinenz nach RP haben. Interessanterweise jedoch, wurde der Einfluss von Diabetes Mellitus auf die Kontinenz-Rate zum jetzigen Stand nur unzureichend und teils mit widersprüchlichen Ergebnissen untersucht. In Anbetracht der vorbekannten protrahierten Wundheilungsverläufe sowie Mikrozirkulationsstörungen und Neuropathie bei Diabetes mellitus Patienten, hat die jetzige Studie deshalb untersucht, ob das Vorliegen von Diabetes Mellitus einen Einfluss auf die postoperative Früh-Kontinenz bei PCa-Patienten hat, die eine RP erhalten haben.
Nach Vorliegen des Ethikkomitee-Beschluss erfolgte mit Hilfe der RP-Datenbank der Klinik für Urologie, Johann Wolfgang-Goethe-Universität die Patientenidentifizierung im Zeitraum von 2018 bis 2021. Hierbei wurden Patienten in die Studienkohorte eingeschlossen bei denen Informationen bezüglich der Früh-Kontinenz (30-90 Tage postoperativ) vorlagen. Kontinenz wurde definiert als die Verwendung von keiner bzw. einer Sicherheitsvorlage innerhalb eines Zeitraums von 24 Stunden. Neben Auswertung der Kontinenz-Raten hinsichtlich des Diabetes Mellitus Status, erfolgte die Zuhilfenahme von uni- und multivariablen logistische Regressionsanalysen um den Effekt von Diabetes Mellitus auf die Kontinenz zu untersuchen. Kovariablen beinhalteten das pathologisches Tumorstadium, BMI, Alter, OP-Verfahren und Durchführung einer Nerv-Erhaltung.
Innerhalb der Studienkohorte (n=142) lag eine Diabetes Mellitus Erkrankung bei 15 Patienten (11%) vor. Mit Ausnahme eines höheren BMI (Median: 28.6 vs 26.5 m2/kg; p=0.005) bei Diabetes Mellitus Patienten, bestanden keine signifikanten Unterschiede hinsichtlich Patienten und Tumorcharakteristika zwischen den beiden Gruppen (p>0.05). Die Früh-Kontinenz Rate war bei Diabetes Mellitus Patienten geringer im Vergleich zu der restlichen Studienkohorte (33 vs 63%; p=0.03). Dieser Unterschied spiegelte sich ebenfalls in der univariablen logistischen Regressionsanalyse wider, in der Diabetes Mellitus einen signifikanten Einfluss auf die Früh-Kontinenz aufwies (Odds Ratio [OR]: 0.29, 95%-KI [95%-Konfidenz Interval]: 0.09-0.99; p=0.03). Der signifikante Einfluss von Diabetes Mellitus blieb ebenfalls in der multivariablen logistischen Regressionsanalyse fortbestehen, nachdem weitere Kovariablen berücksichtigt wurden (OR: 0.26; 95%-KI: 0.07-0.86; p=0.03). Unter Berücksichtigung der Limitationen der vorliegenden Studie (retrospektives Studiendesign, limitierte Fallzahl) lassen die Ergebnisse darauf schließen, dass das Vorliegen einer Diabetes Mellitus Erkrankung einen negativen Einfluss auf die Wiedererlangung der Kontinenz zu einem frühen Zeitpunkt nach RP hat. Die vorliegenden Ergebnisse haben für den klinischen Alltag wichtige Implikationen. Im Rahmen der Aufklärung vor RP kann der Patient bezüglich seines individuellen Risikos einer verlängerten postoperativen Inkontinenz entsprechend aufgeklärt werden, um somit die Erwartungshaltung des Patienten realitätsgetreu zu adressieren. Betrachtet man den postoperativen Verlauf, legen die vorliegenden Ergebnisse nahe, dass Diabetes mellitus Patienten aufgrund Ihrer geringeren Früh-Kontinenz Rate von einer intensivierte Beckenboden-Training zur Wiedererlangung der Kontinenz besonders profitieren könnten.
Auf der Grundlage dieser Studie sollten multizentrische Studien mit einer umfangreicheren Kohortengröße erfolgen und den Einfluss von Diabetes Mellitus nicht nur auf die Früh-Kontinenz, sondern ebenfalls auf die langfristige Kontinenz (>12 Monate) zu untersuchen
Die folgenden Überlegungen zielen darauf ab, den Übergangscharakter der Erkenntnislehre Feuerbachs auszuweisen, die einerseits an die objektivistische Linie der empiristisch-sensualistischen Philosophie unter den französischen Materialisten anschließt und andererseits auf die ökologische Fundierung des menschlichen Bewusstseins und seiner Leistungen vorausweist, die seit dem letzten Drittel des neunzehnten Jahrhunderts in Philosophie und Wissenschaften Verbreitung gefunden und der aktuellen, in Philosophie und Neurowissenschaften vertretenen Embodiment-Forschung den Weg bereitet hat. So stehen Feuerbachs 'reformatorische' Bemühungen um eine Erneuerung der deutschsprachigen Philosophie nach dem Idealismus in einer bislang noch unbeachtet gebliebenen Fernbeziehung mit den Bemühungen der Gegenwart um eine Revision des klassischen Leib-Seele-Dualismus. Zur Veranschaulichung des Kerngehalts von Feuerbachs französischen Vorläufern greife ich zunächst auf die Radikalisierung des Empirismus einerseits durch den erkenntnistheoretischen Sensualismus und andererseits durch den physiologischen Materialismus zurück, indem ich exemplarisch Etienne Bonnot de Condillacs "Traité des sensations" und Julien Offray de La Mettrie's "L'Homme Machine" als realtypische Ausdrucksgestalten dieser französischen Entwicklungslinie darstelle (1). In einem zweiten Schritt zeige ich Gemeinsamkeiten und Differenzen Ludwig Feuerbachs im Verhältnis zu dieser sensualistischmaterialistischen Traditionslinie des empiristischen Philosophierens auf (2) und schließe damit, wie Feuerbachs Umformung dieser Tradition zugleich auf die Ökologisierung der Erkenntnistheorie um 1900 und vermittelt darüber auch auf die gegenwärtige Forschung zur Philosophie der Verkörperung vorausweist (3).
We investigate the early time dynamics of heavy ion collisions studying the time evolution of the energy-momentum tensor as well as energy-momentum correlations within a uniformly thermalizing holographic QGP. From these quantities, we suggest a far-from equilibrium definition of shear viscosity, which is a crucial property of QCD matter as it significantly determines the generation of elliptic flow already at early times. During an exemplary initial heating phase of the holographic QGP the shear viscosity of entropy density ratio decreases down to 60%, followed by an overshoot to 110% of the near-equilibrium value, η/s=1/(4π). Implications for the QCD QGP are discussed. Subsequently, we consider a holographic QGP which is Bjorken-expanding. Its energy-momentum tensor components have a known hydrodynamic attractor to which all time evolutions collapse independent of the initial conditions. Based on this, we propose a definition for a far from equilibrium speed of sound, and analytically compute its hydrodynamic attractor. Subjecting this Bjorken-expanding plasma to an external magnetic field and an axial chemical potential, we study the chiral magnetic effect far from equilibrium.
Assessing communicative accommodation in the context of large language models : a semiotic approach
(2023)
Recently, significant strides have been made in the ability of transformer-based chatbots to hold natural conversations. However, despite a growing societal and scientific relevancy, there are few frameworks systematically deriving what it means for a chatbot conversation to be natural. The present work approaches this question through the phenomenon of communicative accommodation/interactive alignment. While there is existing research suggesting that humans adapt communicatively to technologies, the aim of this work is to explore the accommodation of AI-chatbots to an interlocutor. Its research interest is twofold: Firstly, the structural ability of the transformer-architecture to support accommodative behavior is assessed using a frame constructed in accordance with existing accommodationtheories.
This results in hypotheses to be tested empirically. Secondly, since effective accommodation produces the same outcomes, regardless of technical implementation, a behavioral experiment is proposed. Existing quantifications of accommodation are reconciled,
extended, and modified to apply them to nonhuman-interlocutors. Thus, a measurement scheme is suggested which evaluates textual data from text-only, double-blind interactions between chatbots and humans, chatbots and chatbots and humans and humans. Using the generated human-to-human convergence data as a reference, the degree of artificial accommodation can be evaluated. Accommodation as a central facet of artificial interactivity can thus be evaluated directly against its theoretical paradigm, i.e. human interaction. In case that subsequent examinations show that chatbots effectively do not accommodate, there may be a new form of algorithmic bias, emerging from the aggregate accommodation towards chatbots but not towards humans. Thus, existing, hegemonic semantics could be cemented through chatbot-learning. Meanwhile, the ability to effectively accommodate would render chatbots vastly more susceptible to misuse.
Die vielgestaltige Kunst der europäischen Avantgarden hat besondere Dinge, Objekte oder Artefakte hervorgebracht, die hier ins Zentrum einer interdisziplinär erarbeiteten Sammlung historischer Fallstudien gerückt werden. Die Beiträge untersuchen aus Sicht der digitalen Gegenwart sprechende Gegenstände wie Hüte, Puppen, Bücher in print on demand, Fototexte, Audiokassetten und diverse Archivalien, zudem einzigartige kulturhistorische und künstlerische Produktionen, etwa das 'Michelin-Männchen', Hannah Höchs 'Hampelfrau' und Schreibautomaten. Eine neu akzentuierte Literaturgeschichte der Objekte zeichnet sich hier ab, zugleich eine andere Geschichte der Avantgarden von ihren Rändern her.
This work focused on the biosynthesis and characterization of esterified lipid mediators. Lipid mediators were generally thought to exert their effects as free molecules, and their esterification was regarded as a storage mechanism. However, more recent studies indicate that esterified lipid mediators are a distinct class of mediators. When this thesis started back in 2017, the idea of esterified lipids as a new class of mediators was relatively new so that respective compounds were either quite expensive or not commercially available at all. Therefore, a biosynthetic approach had to be established first to enable the study of the new lipid mediator class. Within the cell, esterified lipids are produced by activation and subsequent incorporation of polyunsaturated fatty acids. These steps are enzymatically catalyzed by members of the acyl-CoA synthetase family and the lysophosphatidylcholine acyltransferase family, respectively. Therefore, the enzymes acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 2 (LPCAT2) were selected for a biosynthetic approach due to their broad substrate acceptance.
In a first attempt, recombinant protein expression in E. coli was studied. While the expression and purification of C-terminally His6x-tagged ACSL4 resulted in a pure and active protein, the expression of LPCAT2 turned out quite troublesome. Although several expression and purification parameters were varied, including purification tags, buffer compositions, and chromatography strategies, successful purification of LPCAT2 was not achieved.
Instead, a second approach was studied. This time, stably transfected cells overexpressing ACSL4 and/or LPCAT2 were generated from the human embryonal kidney (HEK) 293T cell line. Stably transfected cell lines were characterized on protein level and regarding their oxylipin profile. After confirming the overexpression and functionality of the enzymes, lipoxygenases (LOs) were co-expressed in a doxycycline-inducible manner to prevent premature cell death due to increased oxidative stress. As a result, LO product formation was enhanced and enabled the investigation of specific oxylipins. Since increased lipid peroxidation is also a key component of the ferroptosis cell death mechanisms, cell lines were investigated towards their cell viability. Indeed, expression of ACSL4 and/or LPCAT2 promoted cell death when treated with the ferroptosis inducers erastin or RSL3, even in the absence of LO expression. Furthermore, analysis by laser scanning confocal microscopy revealed that the localization of 15-LO1 was altered in the presence of LPCAT2, similar to treatment with RSL3 in vector control cells.
In conclusion, a stable overexpression system of ACSL4 and/or LPCAT2 was successfully established in HEK293T cells, which enabled the synthesis and characterization of esterified oxylipins. Interestingly, characterization of the cell lines revealed a correlation with the cell death mechanism ferroptosis. Although the expression of ACSL4 has already been reported as a biomarker for ferroptosis, this is the first time that a potential connection of LPCAT2 with ferroptosis was demonstrated. As a result, this may provide new therapeutic options for ferroptosis-related pathologies such as neurodegeneration, autoimmune diseases, or tumorigenesis.