Publications Repository - Helmholtz-Zentrum Dresden-Rossendorf

Ion irradiation is a powerful tool to tune the properties of two-dimensional (2D) materials by
creating defects and introducing impurities. At the same time, efficient defect production and
especially ion implantation into 2D materials require a careful choice of ion energies, as when energies
are too low or too high, production of defects and implantation rate will be unsatisfactory low. As
for the bulk systems, various approaches have been employed to predict optimum ion energies for
specific tasks, but they not always can be directly applied to 2D materials. Here we carry out
ab-initio molecular dynamics (MD) and analytical potential (AP) MD simulations and compare the
results to those obtained with a simple binary collision approximation (BCA) model. We show
that when chemical interactions between the ions and target atoms are essential, as in the case
of B and N ion implantation into graphene, as compared to inert gas ions, the AP MD or the
BCA model are inadequate. We further suggest a modified BCA approach with the corrected
displacement threshold energies, which account for chemical interactions between the ion and target
atoms. The threshold energy can be obtained from first-principles calculations, and the modified
BCA model gives qualitatively and for some ions even quantitatively correct results for the energies
corresponding to the onset of defect production and substitution probabilities while being at same
time many orders of magnitude computationally less expensive than the first-principles MD. We
show that in any case the BCA and modified BCA calculations give the upper and lower bound on
the optimum ion energy.

Large Language Models (LLMs) have gained significant popularity in recent years for their ability to answer questions in various fields. However, these models have a tendency to "hallucinate" their responses, making it challenging to evaluate their performance. A major challenge is determining how to assess a model's certainty of its predictions and how it correlates with accuracy. In this work, we introduce an analysis for evaluating the performance of popular open-source LLMs, as well as gpt-3.5 Turbo, on multiple choice physics questionnaires. We focus on the relationship between answer accuracy and variability in topics related to physics. Our findings suggest that most models provide accurate replies in cases where they are certain, but this is by far not a general behavior. The relationship between accuracy and uncertainty exposes a broad horizontal bell-shaped distribution. We report how the asymmetry between accuracy and uncertainty intensifies as the questions demand more logical reasoning of the LLM agent while the same relationship remain sharp for knowledge retrieval tasks.

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The 78Se⁢(n,g)⁢79Se cross section has a high impact on the abundances of 78Se produced during the slow neutron capture process (s process) in massive stars. A measurement of the 78Se radiative neutron capture cross section has been performed at the Neutron Time-of-Flight facility at CERN using a set of liquid scintillation detectors that have been optimized for a low sensitivity to neutrons. We present resonance capture kernels up to 70 keV and cross section from 70 to 600 keV. Maxwellian-averaged cross section (MACS) values were calculated for stellar temperatures between kT=5 and 100 keV, with uncertainties between 4.6% and 5.8%. The new MACS values result in substantial decreases of 20–30% of 78Se abundances produced in the s process in massive stars and AGB stars. Massive stars are now predicted to produce subsolar 78Se/76Se ratios, which is expected since 76Se is an s-only isotope, while solar 78Se abundances have also contributions from other nucleosynthesis processes.

The 235U(n, f) reaction cross section was measured relative to neutron-proton elastic scattering for the first time in the energy region from 10 MeV to 440 MeV at the CERN n_TOF facility, extending the upper limit of the only previous measurement in the literature by more than 200 MeV. For neutron energies below 200 MeV, our results agree within one standard deviation with data in literature. Above 200 MeV, the comparison of model calculations to our data indicates the need to introduce a transient time in neutron-induced fission to allow the simultaneous description of (n, f) and (p, f) reactions.

Challenging neutron-capture cross-section measurements of small cross sections and samples with a very limited number of atoms require high-flux time-of-flight facilities. In turn, such facilities need innovative detection setups that are fast, have low sensitivity to neutrons, can quickly recover from the so-called -flash, and offer the highest possible detection sensitivity. In this paper, we present several steps towards such advanced systems. Specifically, we describe the performance of a high-sensitivity experimental setup at CERN n_TOF EAR2. It consists of nine sTED detector modules in a compact cylindrical configuration, two conventional used large-volume C6D6 detectors, and one LaCl3(Ce) detector. The performance of these detection systems is compared using 93Nb(, ) data. We also developed a detailed Geant4 Monte Carlo model of the experimental EAR2 setup, which allows for a better understanding of the detector features, including their efficiency determination. This Monte Carlo model has been used for further optimization, thus leading to a new conceptual design of a detector array, STAR, based on a deuterated-stilbene crystal array. Finally, the suitability of deuterated-stilbene crystals for the future STAR array is investigated experimentally utilizing a small stilbene-d12 prototype. The results suggest a similar or superior performance of STAR with respect to other setups based on liquid-scintillators, and allow for additional features such as neutron-gamma discrimination and a higher level of customization capability.

Asymptotic giant branch stars are responsible for the production of most of the heavy isotopes beyond Sr observed in the solar system. Among them, isotopes shielded from the r-process contribution by their stable isobars are defined as s-only nuclei. For a long time the abundance of 204Pb, the heaviest s-only isotope, has been a topic of debate because state-of-the-art stellar models appeared to systematically underestimate its solar abundance. Besides the impact of uncertainties from stellar models and galactic chemical evolution simulations, this discrepancy was further obscured by rather divergent theoretical estimates for the neutron capture cross section of its radioactive precursor in the neutron-capture flow, 204Tl (t1/2=3.78  yr), and by the lack of experimental data on this reaction. We present the first ever neutron capture measurement on 204Tl, conducted at the CERN neutron time-of-flight facility n_TOF, employing a sample of only 9 mg of 204Tl produced at the Institute Laue Langevin high flux reactor. By complementing our new results with semiempirical calculations we obtained, at the s-process temperatures of kT ≈8  keV and kT ≈30  keV, Maxwellian-averaged cross sections (MACS) of 580(168) mb and 260(90) mb, respectively. These figures are about 3% lower and 20% higher than the corresponding values widely used in astrophysical calculations, which were based only on theoretical calculations. By using the new 204Tl MACS, the uncertainty arising from the 204Tl⁢(n,gamma) cross section on the s-process abundance of 204Pb has been reduced from ∼30% down to +8%/−6%, and the s-process calculations are in agreement with the latest solar system abundance of 204Pb reported by K. Lodders in 2021.

Accelerator Mass Spectrometry (AMS) represents a single atom counting technique which allows the detection of radioisotopes at natural concentrations in our environment. Its high abundance sensitivity offers a variety of interdisciplinary applications in the fields of geosciences, environmental sciences or nuclear astrophysics. A new AMS facility, HAMSTER (Helmholtz AMS Tracing Environmental Radionuclides), will be installed at Helmholtz-Zentrum Dresden-Rossendorf (HZDR) in 2024. This facility will incorporate major recent technological developments which will open up new research areas.
With HAMSTER we will expand our measurement capabilities to new isotopes, including actinides, fission products and a number of additional new radionuclides. In this presentation, examples of our research portfolio will be presented, e.g. searches for traces on Earth of Supernovae and neutron star mergers, as well as new applications for studying past variations of solar and geomagnetic fields and also the distribution of releases of man-made radioactivity into our environment.

Earth is exposed to nearby cosmic events. Freshly produced radionuclides in the interstellar medium contain information about how and where the heavy elements are made in nature. The solar system moves through the interstellar medium (ISM) and collects interstellar dust particles that contain fresh nucleosynthetic signatures, including the radionuclides Fe-60 (t1/2=2.6 Myr) and Pu-244 (t1/2=81 Myr). These nuclides are incorporated into terrestrial archives over millions of years.
Detection of interstellar nuclides remains extremely challenging and so far was successful only with Accelerator Mass Spectrometry (AMS). Recent technical developments have seen an exceptional gain in measurement efficiency and sensitivity, in particular for actinides, including Pu-244 and more recently for Hf-182 (t1/2=9 Myr). On the other hand, very large accelerators with >10 million volts are required for the identification of small traces of interstellar Fe-60.
Recent data demonstrate a global Fe-60 influx and is evidence for exposure of Earth to recent (<10 Myr) supernova explosions. In addition, first evidence of ISM-Pu-244 presence in deep-sea archives, an actinide nuclide exclusively produced by the r-process, supports the hypothesis that the dominant heavy element r-process nucleosynthesis is rare.
Besides new data for the direct search for interstellar signatures I will also present preliminary results of recent laboratory measurements using AMS for understanding Fe-60 and Hf-182 production in massive stars - both nuclides predominantly produced via double neutron capture reactions.

The long-lived radionuclides Fe-60 (t1/2=2.6 Myr) and Hf-182 (t1/2=8.9 Myr) are sensitive monitors to the neutron environment under different stellar conditions. Production of both nuclides requires neutron fluxes high enough to compete with the decay of the shorter-lived nuclides Fe-59 (t1/2=44d) and Hf-181 (t1/2=42d) which separate Fe-60 and Hf-182 from stable isotopes Fe-58 and Hf-180. Such conditions are predicted for the s (slow neutron capture) process in massive stars only at their late burning phases, e.g., shortly before they end in a supernova, as well as in the r process (rapid neutron capture). The site and frequency of the r process is heavily debated and attributed either to some rare cases of supernovae or neutron star mergers.
On Earth, (n,α) reactions do not contribute to their natural production as the parent nuclides for both cases are not stable. Fission yields are also very low, consequently, both Fe-60 and Hf-182 are very rare on Earth. Accordingly, any presence of either nuclides on Earth may indicate signatures of interstellar influx with their nucleosynthesis within a time period of a few half-lives. Indeed, two distinct interstellar Fe-60 influxes had been found in terrestrial and lunar archives demonstrating recent (within 10 Myr) and ‘nearby’ supernova activity (<150 pc distance). No interstellar Hf-182 had been detected so far. This reflects either the expected low production yields of Hf-182 or a low interstellar influx into the solar system. However, more importantly, the difficulty to chemically extract and measure Hf-182 at the expected low concentrations in terrestrial archives makes detection of interstellar Hf-182 extremely challenging.
The production yields of both nuclides at astrophysical energies are not yet measured and predictions are highly uncertain. This is crucial not only for interpreting the supernova-produced Fe 60 data, but also for Hf-182, as both, s and r process may contribute to an interstellar signal, potentially still undetected in terrestrial or lunar archives.
In this contribution, we present new and precise data for both double neutron-capture reactions as well as give an outlook on Fe-60 production via 63Ni(n,α). Samples, highly enriched in Fe-58, Ni-62 and Hf-180, were irradiated at the nuclear reactor at the Institut Laue-Langevin (ILL), Grenoble, with a high, predominantly thermal, neutron flux. At the Atominstitut in Vienna, additional Fe-58 samples were exposed to a mix of thermal and epithermal neutrons extending the energy range to the astrophysical interesting keV-energies. The induced Fe-59 and Hf-181 activities were utilised as intrinsic monitors for the neutron fluence. After the decay of intermediate Fe-59, the produced Fe-60 was measured with AMS at the ANU. The number of Hf-182 nuclides, however – owing to the much higher capture cross sections – was high enough for a direct activity measurement of the irradiated sample without the need for AMS.
These new experimental data will provide important anchor points for a better understanding of heavy element nucleosynthesis in massive stars and explosive stellar environments.

new hexadentate picolinic-acid based bispidine ligand was attached to anti-FAP IgG4 target module
Radiolabelling with copper-64 and PET images in tumour-bearing mice

The degeneration of axon terminals before the soma, referred to as “dying back”, is a feature of Parkinson’s disease (PD). Axonal assays are needed to model early PD pathogenesis as well as identify protective therapeutics. We hypothesized that defects in axon lysosomal trafficking as well as injury repair might be important contributing factors to “dying back” pathology in PD. Since primary human PD neurons are inaccessible, we developed assays to quantify axonal trafficking and injury repair using induced pluripotent stem cell (iPSC)-derived neurons with LRRK2 G2019S, which is one of the most common known PD mutations, and isogenic controls. We observed a subtle axonal trafficking phenotype that was partially rescued by a LRRK2 inhibitor. Mutant LRRK2 neurons showed increased phosphorylated Rab10-positive lysosomes, and lysosomal membrane damage increased LRRK2-dependent Rab10 phosphorylation. Neurons with mutant LRRK2 showed a transient increase in lysosomes at axotomy injury sites. This was a pilot study that used two patient-derived lines to develop its methodology; we observed subtle phenotypes that might correlate with heterogeneity in LRRK2-PD patients. Further analysis using additional iPSC lines is needed. Therefore, our axonal lysosomal assays can potentially be used to characterize early PD pathogenesis and test possible therapeutics.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which currently lacks effective treatments. Mutations in the RNA-binding protein FUS are a common cause of familial ALS, accounting for around 4% of the cases. Understanding the mechanisms by which mutant FUS becomes toxic to neurons can provide insight into the pathogenesis of both familial and sporadic ALS. We have previously observed that overexpression of wild-type or ALS-mutant FUS in Drosophila motor neurons is toxic, which allowed us to screen for novel genetic modifiers of the disease. Using a genome-wide screening approach, we identified Protein Phosphatase 2A (PP2A) and Glycogen Synthase Kinase 3 (GSK3) as novel modifiers of FUS-ALS. Loss of function or pharmacological inhibition of either protein rescued FUS-associated lethality in Drosophila. Consistent with a conserved role in disease pathogenesis, pharmacological inhibition of both proteins rescued disease-relevant phenotypes, including mitochondrial trafficking defects and neuromuscular junction failure, in patient iPSC-derived spinal motor neurons (iPSC-sMNs). In FUS-ALS flies, mice, and human iPSC-sMNs, we observed reduced GSK3 inhibitory phosphorylation, suggesting that FUS dysfunction results in GSK3 hyperactivity. Furthermore, we found that PP2A acts upstream of GSK3, affecting its inhibitory phosphorylation. GSK3 has previously been linked to kinesin-1 hyperphosphorylation. We observed this in both flies and iPSC-sMNs, and we rescued this hyperphosphorylation by inhibiting GSK3 or PP2A. Moreover, increasing the level of kinesin-1 expression in our Drosophila model strongly rescued toxicity, confirming the relevance of kinesin-1 hyperphosphorylation. Our data provide in vivo evidence that PP2A and GSK3 are disease modifiers, and reveal an unexplored mechanistic link between PP2A, GSK3, and kinesin-1, that may be central to the pathogenesis of FUS-ALS and sporadic forms of the disease.

Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by the progressive loss of neurons mainly in the frontal and temporal lobes of the brain. Mutations (e.g., V337M, N297K) in the microtubule-associated protein TAU (MAPT) are responsible 5–20% of familial FTD cases and have been associated with defects in organelle trafficking that plays a critical role in the proper function of cells, including transport of essential molecules and degradation of waste products. Due to the critical role of TAU mutations in microtubule stabilization and organelle transportation, it is of great interest to study these molecular mechanisms to develop effective therapeutic strategies. Therefore, herein, we analyzed mitochondrial and lysosomal trafficking in disease-specific spinal motor neurons by using live cell imaging in undirected (uncompartmentalized) and directed (compartmentalized) cell culture systems. While V337M neurons only expressed 3R TAU, the N297K mutant neurons expressed both 3R and 4R TAU. Axonal trafficking was affected differentially in V337M and N297 MAPT mutated neurons. These findings suggest that the MAPT mutations V337M and N297K impaired axon physiology differentially, which highlights the need for mutation- and/or 3R/4R TAU-specific therapeutic approaches.

Diazabicyclic adamantan derivatives termed “bispidines” show a favorable CuII coordination chemistry. With the availability of the theranostic triple 61/64Cu/67Cu [1], bispidine ligands are in the focus as bifunctional chelators for radiopharmaceutical applications. They provide fast labeling at high molar activities under mild conditions and the resulting complexes exhibit a high thermodynamic stability.[2] However, a significant hepatic uptake has been observed for bispidine peptide conjugates. One possible cause could be the protonation of donor atoms in the acidic environment of tumor cells, leading to alterations of donor atom pattern and a change in the complex net charge accompanied by an accumulation in nontargeted organs. By increasing the basicity of the donor atoms, more stable complexes can be formed minimizing this effect.[3] The impact of different substituents leading to changes in the basicity have been observed in pentadentate bispidine ligands and were further explored in hexadentate ligands, which are known to form more stable complexes with CuII.[1,2]
Herein, electron-withdrawing or -donating groups were attached to the para-position of the pyridine substituents at the scaffold of the known hexadentate ligand N2Py4.[1,4] The new ligands were investigated with respect to complex stability and radiolabeling efficacy and furthermore characterized in terms of lipophilicity compared to the known copper bispidine complexes [CuII(N2Py4)]2+ and [CuII(bispa)]+1.[4] For this purpose, a fast gradient reversed-phased HPLC method was carried out on an immobilized artificial membrane (IAM) to determine the chromatographic hydrophobicity index (CHI). The index is derived from the retention time of compounds and provides information about the lipophilicity of the measured compound, which correlates with octanol/water partition coefficients.

The secure disposal of nuclear waste is of high societal concern, necessitating the development of deep geological repositories as a reliable solution. A key aspect of repository safety lies in understanding the far field, particularly the host rock, to predict the long-term behavior and migration of radionuclides within the geological environment from the deposit up to the ecosphere. This study addresses the specific challenges associated with crystalline host rocks.
Crystalline host rocks could be on the one hand of granitic composition and texture, but the term is also used for host rocks of metamorphic origin. While inside a large granitic intrusion there is little petrological variation expected, metamorphic rocks or the intrusion rim can exhibit complex structures in terms of structural geology as well as mineral composition, especially along potential fluid migration pathways. Consequently, this leads to a multitude of possible rock-
composition/fluid-composition interactions and thus significantly affects the retention potential of radionuclides as opposed to the simplified model of an isotropic, uniform granite. The results of the study will allow to determine which components of the host rock are important to be included
in geostatistical models which in turn serve as basis to estimate uncertainties of reactive transport through crystalline rocks.
Our study involves the development of Python code to feed chemical modelling software like PHREEQC or Geochemist’s Workbench© with varying mineral compositions and chemical conditions of the aqueous phase, following a specific Quasi-Monte-Carlo sampling scheme. The application of compositional data analysis principles is essential to guarantee a meaningful sampling of constraint concentration data, such as mineralogical rock compositions or element
concentrations in aqueous phases. Given that compositional data sum to a fixed total, each mineral content becomes a dependent variable in relation to the other contents. Recognizing and accounting for these interdependencies is crucial to ensuring the integrity of the sampling. The chemical modelling software relies on Surface Complexation Models (SCM) for each mineral phase to calculate the distribution coefficient (Kd-value) for the radionuclide (here: uranium) in the respective setting. Furthermore, a global sensitivity analysis is employed to investigate the complex interactions between mineralogical variations and radionuclide behavior. In this study, two techniques are employed namely, High-Dimensional Model Representation (HDMR) and Cumulative Sum of Univariate Nonlinear Regression (CUSUNORO) plots. The application of HDMR allows for a detailed investigation of high-dimensional parameter spaces, while CUSUNORO plots provide a visual representation of cumulative sensitivity effects.
This study presents a complete workflow of modelling how petrological variations in crystalline host rocks, including both granitic and metamorphic compositions, affects radionuclide retention. This approach advances the understanding of nuclear waste disposal and provides valuable tools for assessing the retention potential of radionuclides in diverse geological settings.

Analytical methods for inorganic chemistry are found to be differentially effective for specific combinations of target elements, sample matrices and concentration ranges. Consequently, it is a significant challenge to ensure that the results provided in element concentrations are independent of the analytical method employed on the sample matrix. In order to address this issue, reference materials are produced and certified. However, even with the most rigorous production and certification procedures, it remains challenging to accurately determine the "true" concentration values due to the combined effects of measurement protocols and sample matrix. In particular, when dealing with "normal" (non-reference) samples, these effects may introduce a bias into the measurements. When compiling measurements from different analytical approaches and time periods into consistent data sets for further data analysis these method induced biases present a significant challenge. To explore and quantify the extent of methods/matrix-specific offsets between measurement batches, we exploited chemical analysis data from the database for reference materials, GeoReM. The selected data sets from GeoREM of the standards AGV-1&2, BCR-1&2, BHVO-1&2, BIR-1, BRP-1, JA-2, JB-1, OU-6 and W-1&2 initially comprised 83,158 measurements. Following homogenisation and filtering of the samples to ensure robust statistical analysis, 55,413 measurements remained. The statistical analysis (ANOVA) shows that the most frequently occurring offsets between methods are LA-ICP-MS to ICP-MS, followed by XRF to ICP-MS and finally XRF to LA-ICP-MS.

Ensuring the safety for deep geological repositories for nuclear waste in crystlline host rock necessitates a comprehensive understanding of the far field and it's potential for radionuclide retention. In case of a repository leakage, radionuclides may get mobile and migrate through pathways in rock and aquifers. To asses the uncertainties in forcasting the migration of radionuclides it is essential to incorporate naturally occurring heterogeneities in rock composition and geological structures into the models, e.g. heterogeneities occurring near intrusion margins, tectonically influenced granitic bodies, or metamorphic formations like gneisses. This complexity significantly impacts the modeled radionuclide retention potential compared to simplistic isotropic granite models.
The SANGUR project (Systematic Sensitivity Analysis for Mechanistic Geochemical Models using Field Data from Crystalline Rock) aims to identify crucial parameters and their uncertainties essential for modeling radionuclide retention in crystalline rock. Our study presents a comprehensive workflow modeling how petrological variations in both granitic and metamorphic crystalline host rocks influence radionuclide retention. Utilizing Multinary Random Fields geostatistics, we simulate crystalline rocks based on analyzed spatial rock data to quantify uncertaintiesand to determine the appropriate model scale. The petrological variance is then considered for the chemical modeling through software such as PHREEQC or Geochemist's Workbench©: Surface Complexation Models (SCM) in chemical modeling software calculate partition coefficients (Kd values) for radionuclides, such as uranium, in diverse mineral environments in combination with varying aqueous phases. To enhance and simplify models, global sensitivity anlsysis is applied to determine critical features for radionuclide retention.

DREAMS, the DREsden AMS-facility, in operation since 2011 is based on a 6 MV Tandetron (manu-
factured by High Voltage Engineering Europa) and shared with other research groups at the Helmholtz-
Zentrum Dresden-Rossendorf (HZDR). DREAMS has been applied primarily in the measurement of cos-
mogenic isotopes. However, with radiocarbon not in the mix, a focal point has always been the routine
measurement of 10Be and 26Al. Over the years, we have improved the AMS facility in various aspects
for increased performance, particularly for these two isotopes. In this report we will give details on the
performance of our routine measurements over the past 12 years of operation with a focus on the impact of
methodological developments since 2021. We will present our recent investigations and improvements on
the performance of 10Be and 26Al measurements, highlight key challenges remaining, and point to potential
future optimisations. Finally, we have reinvestigated our in-house standard material for 26Al against the
standards provided by Nishiizumi (2004) -“KNSTD” to ensure compatibility of reported results with
exposure-age calculators such as CRONUS-Earth.

Accelerator Mass Spectrometry (AMS) is an ultrasensitive method for
detection of naturally or anthropogenically produced long-lived
radionuclides in our environment. Up to now we use the DREsden
AMS-facility (DREAMS) at the Helmholtz-Zentrum Dresden-Rossendorf
(HZDR). In operation since 2011 and based on a 6 MV Tandetron
(manufactured by High Voltage Engineering Europa), this accelerator
facility is shared with other research groups. A focus of DREAMS is the
measurement of the cosmogenic radionuclides Be and Al.
Over the years, we have improved the DREAMS measurement capabilities in
various aspects. One example is an improvement in the Be measurement efficiency by a factor of 1.4 [1].

Currently a second, dedicated AMS facility, HAMSTER (Helmholtz
Accelerator Mass Spectrometer Tracing Environmental Radionuclides), is
being set up at the Department of Accelerator Mass Spectrometry and
Isotope Research. HAMSTER is based on a 1-MV tandem accelerator from NEC
(National Electronics Corp.) and will have enhanced actinide
measurement capabilities. In addition, it is featuring a new ion cooler
we develop in cooperation with the University of Vienna [see talk of A.
Wieser] allowing laser-based isobar separation. In this presentation, I
will highlight present and future AMS capabilities at HZDR.
References:

[1] Lachner, J., et al. (2023) Nucl. Inst. Meth. B 535, 29.

During the last years the performance of DREAMS, the DREsden AMS-facility, at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) was improved in various aspects. The system is based on a 6 MV tandetron manufactured by High Voltage Engineering Europa (HVEE) and shared with various other groups at HZDR. This report will give detail on the performance of our routine measurements and an overview of the range of research topics of user projects at DREAMS. Moreover, we will present recent improvements and investigations on the performance of 10Be and 26Al measurements and highlight key challenges remaining, and potential future developments.

This paper presents a systematic study of the charge transport behavior of heavily doped n-type Ge layers with As and Sb. A nonequilibrium method ion implantation followed by milliseconds flash lamp annealing is applied to synthesize the n++ Ge layers (Ge:As and Ge:Sb). The resulting materials contain free electrons with a density above 3x10^19 /cm3 and mobility more than 220 cm2/(V s). Quantum corrections to the conductance in a magnetic field are observed at low temperatures. Weak localization persists up to 30 K in Ge:Sb, while only up to 10 K in Ge:As. Using the Hikami–Larkin–Nagaoka model to fit the magnetoconductance data, we obtain the phase coherence length l/ of the hyperdoped Ge samples in the range of 70–163 nm. This study may pave a way to explore possible applications for quantum technologies utilizing As- and Sb-hyperdoped Ge.

In this Letter, we employed atomic layer deposition (ALD) and flash lamp annealing (FLA) to form a wafer-scale ultra-shallow junction (USJ, ∼5 nm) in silicon.
The deep ultraviolet light is almost completely absorbed in the PN junction depletion region near the surface, resulting in a high collection efficiency of photogenerated carriers. The junction-based photodiode exhibits outstanding performances with internal quantum efficiency reaching ∼95% from 200 nm to 400 nm and a linear response to the UV light within a wide range of 0.4–10^3 μW.

We report on electroluminescence spectroscopy experiments demonstrating room-temperature light emission from heavily alloyed SiGe quantum dots, for which the light emission properties are enhanced by incorporated split-[110] self-interstitials. The quantum dots are formed during molecular beam epitaxy deposition of Si0.6Ge0.4 alloys on n-doped silicon-on-insulator substrates. To create the split-[110] self-interstitials the quantum dots were co-implantated in-situ using Si and Ge ions. The hybrid emitters were further embedded into the intrinsic region of a p-i-n diode structure to enable electrical pumping. Similar to previous theoretical results on unstrained Ge-based quantum dots containing these defects, radiative direct transitions are possible for these SiGe light emitters. However, in SiGe dots these transitions are not at the Brillouin zone center. Instead, first-principles calculations indicate that the presence of the split-[110] self-interstitial defect in strained and unstrained SiGe can lead to optically direct transitions in momentum space in the X-direction of the Brillouin zone.

Zinc oxide (ZnO) is a wide bandgap semiconductor that holds significant potential for various applications. However, most of the native point defects in ZnO like Zn interstitials typically cause an n-type conductivity. Consequently, achieving p-type doping in ZnO is challenging but crucial for comprehensive applications in the field of optoelectronics. In this work, we investigated the electrical and optical properties of ex situ doped p-type ZnO films. The p-type conductivity has been realized by ion implantation of group V elements followed by rapid thermal annealing (RTA) for 60 s or flash lamp annealing (FLA) on the millisecond time scale in nitrogen or oxygen ambience. The phosphorus (P)-doped ZnO films exhibit stable p-type doping with a hole concentration in the range of 10^14 to 10^18/cm^3, while antimony (Sb) implantation produces only n-type layers independently of the annealing procedure. Microstructural studies of Sb-doped ZnO show the formation of metallic clusters after ms range annealing and SbZn-oxides after RTA.

Thin films of silver-doped zinc oxide (SZO) were deposited at room temperature using a DC reactive magnetron co-sputtering technique using two independent Zn and Ag targets. The crystallographic structure, chemical composition and surface morphology of SZO films with different silver concentrations were correlated with the photocatalytic (PC) properties. The crystallization of the SZO films was made using millisecond range flash-lamp-annealing (FLA) treatments. FLA induces significant structural ordering of the wurtzite structure and an in-depth redistribution of silver, resulting in the formation of silver agglomerates. The wurtzite ZnO structure is observed for silver contents below 10 at.% where Ag is partially incorporated into the oxide matrix, inducing a decrease in the optical band-gap. Regardless of the silver content, all the as-grown SZO films do not exhibit any significant PC activity. The best PC response is achieved for samples with a relatively low Ag content (2–5 at.%) after FLA treatment. The enhanced PC activity of SZO upon FLA can be attributed to structural ordering and the effective band-gap narrowing through the combination of silver doping and the plasmonic effect caused by the formation of Ag clusters.

Modifying the energy band structure in heterostructured photocatalysts enhances charge separation efficiency and improves photoelectrochemical (PEC) performance by decreasing the charge transfer barrier. In this study, cobalt doping into WO3/TiO2 core/shell heterojunction nanorod arrays introduces versatile valence states of cobalt altering the oxygen coordination environment around W atoms in WO3, resulting in an increase in W5+ ions and oxygen vacancy defects in WO3 lattice, facilitating the water splitting reaction. Photogenerated electrons transfer easily from the WO3:Co shell to the TiO2 core due to the lower conduction band minimum (CBM) of WO3:Co shell. Moreover, photogenerated holes transfer from the TiO2 core to the WO3:Co shell efficiently due to the higher valence band maximum (VBM) of TiO2 core. The heterostructure has a high photogenerated carrier density (9.89 × 1018 cm-3), improving photoconversion efficiency (2.55 mA cm-2 at 1.23 V vs. RHE) and reducing charge recombination rates (6.51 × 10–4 s-1). Co doping increases the -OH bond on WO3/TiO2 surface, improves
its hydrophilicity, and is more conducive to the reaction in aqueous electrolyte. Additionally, the nanorod array
structure facilitates PEC reaction kinetics by providing open spaces for mass exchange. This work proposes a
feasible strategy for improving photogenerated charge transport and enhancing PEC by combining regulation of
the band structure of WO3/TiO2 heterostructures with morphology design.

We report the impact of flash-lamp-annealing (FLA) on the structural evolution of amorphous titania (TiO2) films produced by DC reactive magnetron sputtering. TiO2 films were grown at room-temperature at different oxygen partial pressure (PO2) and subsequently annealed as a function of the FLA energy density. X-ray diffraction confirms that FLA induces phase formation from the initial amorphous state with a general transition from anatase to rutile by increasing the FLA energy density (temperature). Interestingly, the transformation onset of anatase to rutile is achieved at lower energy densities for higher PO2. On the contrary, films with a highly resilient anatase phase can be produced at relatively low PO2. A detailed analysis of the pristine amorphous structure carried out by X-ray absorption near-edge structure indicates the role of oxygen sites in the observed phase transformation. In particular, oxygen vacancies seem to stabilize the anatase phase at high temperatures. The results show the relevance of subtle changes in the initial amorphous structure for phase selectivity in TiO2 films
upon FLA.

Fixed valve trays are increasingly considered in energy-intensive distillation columns, since they cope well with demanded partial load and overload scenarios. However, considering the vast number of possible valve arrangements and their respective impact on the complex vapor-liquid flow, the tray design is a challenging task in practice. Therefore, we aim at establishing a coarse-grid CFD approach that enables engineers to simulate two-phase flow scenarios on such trays at reasonable computational effort.

The approach is based on a morphology adaptive multifield two-fluid model, which allows for simulating resolved interfaces of continuous gas and liquid as well as dispersed phases, i.e. bubbles and droplets, within a single Eulerian framework. Additionally, the valves are emulated by local mass and momentum sources that are applied to cell zones, which result from a reasonable approximation of the valve geometry in the computational grid.

In the present contribution we demonstrate the simulation of the complex two-phase flow in a pilot scale setup of 1.2 m nominal diameter that exhibits 189 fixed valves and is operated with air and water. The simulated phase distribution is compared against three-dimensional experimental data obtained with a conductivity sensor array. Finally, we discuss capabilities and further perspectives of the suggested approach.

The Sichuan–Yunnan–Guizhou metallogenic province (SYGMP) includes > 400 Zn - Pb deposits and prospects, eight of which are large-scale deposits with large reserves of critical metals such as Cd and Ge, including the Huize Zn-Pb-Cd-Ge and Daliangzi Zn–Pb–Ge–Cd deposits. The newly discovered Zhugongtang Zn-Pb deposit is a super-large deposit with Zn–Pb reserves of > 3 Mt. Its geochemical features are similar to those of the Huize deposit, with similar sulfide δ34S values and concentrations of critical elements in sphalerite (e.g., Cd and Ge). However, the two deposits have different host strata, and it remains unclear as to whether they have similar oregenesis. In this study, δ114/110Cd values and major- and trace-element compositions of sphalerites collected from a drill-core and tunnels of the Zhugongtang deposit were determined in an investigation of metal sources. Drill-core samples were impure and exhibited strong correlation (R2 = 0.89) between Zn and Cd contents. For samples from mining tunnels, the Cd and Fe contents of selected sphalerites were positively correlated, especially yellow sphalerites (R2 = 0.76). Cadmium is likely hosted in sphalerite by the substitution mechanism of (Fe2+, Cd2+) ↔ Zn2+. The δ114/110Cd values of all samples ranged from - 0.43 ‰ to 0.06 ‰. Based on Zn/Cd ratios, and excluding geochemical processes that may have caused the variable Cd isotopic compositions, we suggest that the metal sources of the deposit were derived from the mixing of sedimentary and basement rocks. This model is supported by the strong relationship between the 114/110Cd and 1/Cd values of sphalerites from 11 typical Zn–Pb deposits in the SYGMP (R2 = 0.81). The quantification of metal contributions of source rocks indicates that deposits derived mainly from sedimentary rocks generally have relatively low sphalerite Ge contents and small Ge reserves, whereas those derived mainly from basement rocks have higher Ge contents and larger Ge reserves. This study provides a new model for explaining the enrichment of critical metals in Zn–Pb deposits of the SYGMP, thus extending the applications of Cd isotopes in hydrothermal systems

The newly discovered Danaopo algal limestone hosted Zn-Pb deposit (150 Mt ores @ an average of 3.06% Zn + Pb) is a representative and the second largest scale Zn-Pb deposit in the western Hunan-eastern Guizhou metallogenic belt (WHEGMB). In this study, the in-situ trace elements of sphalerite and C-O isotopes and rare earth elements of calcite were investigated in the Danaopo deposit, aiming to provide new insights into the mineralization potential of critical metals and origin of Zn-Pb deposits controlled by reef zone and Huayuan-Zhangjiajie regional fault at WHEGMB. The in-situ trace element researches show that the distribution of critical metals, including Cd (1520 to 11570 ppm), Ge (0.73 to 236 ppm), Ga (0.04 to 26.90 ppm), Tl (0.01 to 3.62 ppm), are inhomogeneous in sphalerite, in which Cd and Ge are over the standard of Chinese comprehensive utilization. The LA-ICP-MS elemental map and inter-element correlations imply that Cd and Ge enter the sphalerite lattice via the substitution of Zn2+ ↔ Cd2+ and 4Zn2+ ↔ Ge4+ + 2Fe2+ + □, respectively. Besides, the δ13CPDB (-3.93 to -0.12‰) values of the ore-stage calcites are plotted as a horizontal linear trend near the marine carbonate dissolution baseline, indicating that the carbon in hydrothermal fluids was mainly derived from the dissolution of Cambrian algal limestone. The measured δ18OSMOW (+14.58 to +21.19‰) and calculated δ18Ofluid (+5.23 to +9.95‰) values of these calcites overlap with oxygen isotopic compositions of the algal limestone (+18.76 to +23.87‰) and basinal hot brine (+4 to +10‰), respectively, implying that the oxygen was sourced from a binary mixing of ore-host rocks and basinal brine. In addition, the calcite REE data show that ΣREE concentration of Cal-Ⅰ (avg. 1.35 ppm) is lower than that of the Cal-Ⅱ (avg. 10.76 ppm), and REE distribution pattern of Cal-Ⅰ fall close to the field of ore-host rocks, while the Cal-Ⅱ are plotted between the ore-host and rocks from Proterozoic Banxi Group to Cambrian Niutitang Fm., which suggest that REE in Cal-Ⅰ was mainly sourced from the surrounding carbonate rocks, whilst Cal-Ⅱ have a mixed REE origin from wallrocks and underlying sedimentary and metamorphic basement rocks. Overall, based on our detailed deposit geology, sphalerite trace element, and calcite C-O and REE evidences, it was concluded that the Danaopo, with low-T and low fO2 reductive ore-forming fluid, belong to a typical Mississippi Valley-type Zn-Pb deposit.

Metal stable isotopes (e.g., Zn, Cd, and Cu) have been used to track metal sources in different types of hydrothermal systems. However, metal isotopic variations in sulphides could be triggered by various factors such as mineral precipitation and fluid mixing. Thus, tracking the metal sources of hydrothermal systems is still a big challenge for metal isotopes. In this study, we investigated the Cd isotopic systematics of sphalerite from the Nayongzhi Zn–Pb deposit, which is a Mississippi Valley‐type (MVT) deposit in the Sichuan–Yunnan–Guizhou mineralization province (SYGMP). We reinterpreted the published S isotope data for the SYGMP and found that the large S isotopic variations were controlled by Rayleigh fractionation between sulphide and reduced S. As such, a model that involves mixing of a metal‐rich fluid with a reduced S pool formed by thermochemical sulfate reduction (TSR) can explain the ore formation in the Nayongzhi deposit. Based on this model, no Cd isotopic fractionation was observed due to its low solubility in fluids during mixing, and thus the Cd isotopic variations of sphalerite were inherited from the source rocks. The large range of Zn/Cd ratios and uniform Cd isotopic compositions of the sulphides are similar to those of igneous rocks but different from those of sedimentary rocks, indicating that Zn and Cd were derived mainly from basement rocks (e.g., migmatite, gneiss, and granulite). Our results reaffirm that metal stable isotopes, particularly Cd isotope compositions of sphalerite, are powerful geochemical tracers for investigating the formation mechanisms of ore deposits.

Unraveling the precise mineralization age is vital to understand the geodynamic setting and ore-forming mechanism of the sediment-hosted Pb-Zn deposit; this has long been a challenge. The Sichuan-Yunnan-Guizhou (SYG) triangle in the southwestern margin of the Yangtze Block is a globally recognized carbonate-hosted Pb-Zn metallogenic province and also an essential part of the South China low-temperature metallogenic domain. This region has > 30 million tons (Mt) Zn and Pb resources and shows the enrichment of dispersed metals, such as Ga, Ge, Cd, Se, and Tl. During the past 2 decades, abundant data on mineralization ages of Pb-Zn deposits within the SYG triangle have been documented based on various radioisotopic dating methods, resulting in significant progress in understanding the geodynamic background and ore formation of Pb-Zn deposits hosted in sedimentary rocks at SYG triangle. This paper provides a comprehensive summary of the geochronological results and Pb-Sr isotopic data regarding Pb-Zn deposits in the SYG triangle, which identified two distinct Pb-Zn mineralization periods influencing the dynamic processes associated with the expansion and closure of the Paleo-Tethys Ocean in the western margin of the Yangtze Block. The predominant phase of Pb-Zn mineralization at SYG triangle spanned from the Middle Triassic to Early Jurassic (226–191 Ma), which was intensely correlated with the large-scale basin fluid transport triggered by the closure of the Paleo-Tethys Ocean and Indosinian orogeny. The secondary Pb-Zn mineralization phase occurred during the Late Devonian to Late Carboniferous and was controlled by extensional structures associated with the expansion of the Paleo-Tethys Ocean. Further investigation is necessary to clarify the occurrence and potential factors involved in the Pb-Zn mineralization events during the Late Devonian to Late Carboniferous.

Cambrian carbonate formations are widespread in the western Hunan-eastern Guizhou region (southwestern China), which hosts many Mississippi Valley-Type (MVT) lead–zinc (Pb-Zn) deposits. Regional Pb-Zn mineralization is well developed in the low-grade metamorphic rocks of the basal Proterozoic Banxi Group. The mineralization is associated with quartz veins and generally distributed along NE-trending fault zones. Moreover, these deposits have an extensive distribution and high grade, and are associated with Cu-Ag endowment. However, geological and geochemical research on these Pb-Zn vein-type deposits is relatively limited, and their relationship with the regional MVT mineralization remains unclear. The representative Xinhua deposit in Danzhai district is selected as the study subject. We conducted in situ trace element analyses on the sphalerite and chalcopyrite from the various metallogenic stages, and compared them with published sphalerite trace element data from the MVT Pb-Zn deposits in the western Hunan-eastern Guizhou metallogenic belt. Seven orebodies in Xinhua Pb-Zn deposit have been discovered so far, with a metal resource of over 120,000 metric tonnes of Zn + Pb. Field geology and microscopic petrography have revealed two mineralization stages: An earlystage black sphalerite (Sp-I) followed by reddish-brown sphalerite (Sp-II) mineralization, which corresponds to the main chalcopyrite mineralization stage, and a later-stage light-yellow sphalerite (Sp-III), Cu ore-barren mineralization.
LA-ICPMS data indicate that the sphalerite from Xinhua has similar trace element compositions to those from the MVT Pb-Zn deposits in the region. They are relatively enriched in Ga, Cd, and Ge, while depleted in Fe, Co, and Mn. Critical metal Ge and Ga are particularly enriched in sphalerite, especially in Sp-I (Ge max 937 ppm, Ga max 824 ppm). The substitution mechanism of Ge and Ga in sphalerite are likely 2Cu+ + Ge4+ ↔ 3Zn2+ and Cu+ + Ga3+ ↔ 2Zn2+. Indium and Sn are mainly present in Sp-I and Sp-III. Chalcopyrite contains Zn and Sn both exceeding 100 ppm. Contents of Se, Ag, In, and Sn in chalcopyrite are significantly higher than those in sphalerite. Calculation of the sphalerite trace element geothermometer (GGIMFis) suggests that the average sphalerite ore-forming temperatures are 164 ◦C (Sp-I), 156 ◦C (Sp-II), and 205 ◦C Sp-III), implying medium- to low-temperature mineralization. This indicates a possible influx of high-temperature, in-bearing fluid during the late-stage mineralization.
In summary, the faults-controlled vein-type Pb-Zn deposits (e.g., Xinhua) may have been products of the same Kwangsian orogeny as other strata bound MVT deposits, and the Xinhua deposit features two mineralization stages with multiple ore metal sources. During the ore-forming fluid ascent, some ore-forming materials may have precipitated in the fluid conduits. And exposed after the erosion of the shallower stratiform orebodies and strata. Consequently, the Xinhua Pb-Zn deposit represents the preserved ore-fluid conduit phase (in the basement strata) of the MVT mineralization.

The production of nuclear energy generates radioactive waste in various steps of the nuclear cycle: from mining, fuel preparation, irradiation of the fuel, to fuel reprocessing. Such waste has to be properly stored to ensure its isolation from the biosphere.
This talk will give an overview of the general aspects of the nuclear fuel cycle and the radioactive waste management.

Early results on the plasma deposition of dielectric thin films on acoustic wave (AW) activated substrates revealed a densification pattern arisen from the focusing of plasma ions and their impact on specific areas of the piezoelectric substrate. Herein, we extend this methodology to tailor the plasma deposition of metals onto AW-activated LiNbO3 piezoelectric substrates. Our investigation reveals the tracking of the initial stages of nanoparticle (NP) formation and growth during the submonolayer deposition of silver. We elucidate the specific role of AW activation in reducing particle size, enhancing particle circularity, and retarding NP agglomeration and account for the physical phenomena making these processes differ from those occurring on non-activated substrates. We provide a comparative analysis of the results obtained under two representative plasma conditions: diode DC sputtering and magnetron sputtering. In the latter case, the AW activation gives rise to a 2D pattern of domains with different amounts of silver and a distinct size and circularity for the silver NPs. This difference was attributed to the specific characteristics of the plasma sheath formed onto the substrate in each case. The possibilities of tuning the plasmon resonance absorption of silver NPs by AW activation of the sputtering deposition process are discussed.

Background Femoral bone metastases (FBM) or lesions (FBL) can lead to loss of mobility and independence due to
skeletal-related events (SRE), e.g. pain, deformity and pathological fractures. Aim of this study was to analyze effects of
radiotherapy and surgery, different surgical techniques and complications on disease-specific survival (DSS).
Methods Patients who underwent palliative therapy for FBM or FBL between 2014 and 2020 were retrospectively
analyzed. Chi-square test was used to detect intergroup differences. Survival was calculated using Kaplan-Meier
method, Cox regression and compared using log-rank test. Complications were evaluated using Chi-Square test.
Results 145 patients were treated for proximal femoral BM/BL or pathologic fractures (10 bilaterally). Three groups
were classified: surgery only (S, n = 53), surgery with adjuvant radiation (S + RT, n = 58), and primary radiation only (RT,
n = 44). Most common primary tumors were breast (n = 31), prostate (n = 27), and non-small cell lung cancer (n = 27).
47 patients underwent surgery for an impending, 61 for a manifest pathological fracture. There were no significant
differences in DSS between the 3 groups (S = 29.8, S + RT = 32.2, RT = 27.1 months), with the S + RT group having the
longest one-year survival. Local complications occurred in 25 of 145 patients after a mean interval of 9.9 months.
Conclusion Due to the steadily increasing incidence and survival of patients with FBM/FBL, indication for prevention
and treatment of painful and immobilizing SREs should be critically assessed. Surgical treatment should always be
performed with maximum stability and, whenever possible, adjuvant RT.

Artificial intelligence (AI) has made a tremendous impact in the space of healthcare, and proton therapy is not an exception. Proton therapy has witnessed growing popularity in oncology over recent decades, and researchers are increasingly looking to develop AI and machine learning tools to aid in various steps of the treatment planning and delivery processes. This review delves into the emergent role of AI in proton therapy, evaluating its development, advantages, intended clinical contexts, and areas of application. Through the analysis of 76 studies, we aim to underscore the importance of AI applications in advancing proton therapy and to highlight their prospective influence on clinical practices.

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Large magnetocaloric effects can be observed in materials with first-order magneto-structural phase transition. However, materials with large thermal hysteresis show a reduced effect in moderate fields (~2 T) because the external field is insufficient to induce a fully reversible transformation. The hysteresis can be overcome or even exploited by applying a second external stimulus. A multistimuli test bench has been built to demonstrate the multicaloric effect in FeRh alloy using a pulsed magnetic field up to 9 T and a uniaxial stress of up to 700 MPa. A cyclic multicaloric effect of ±2.5 K could be observed for a sequential application of a pulsed field of 3 T and a uniaxial stress of 700MPa. The interplay among external field strength, thermal hysteresis, and the transition width enables the use of pulsed magnetic fields and allows a decoupling of the applied magnetic field and the heat transfer process in the multi-stimuli cycle.

Remining the historic tailings for energy materials recovery using circular economy and sustainable chemistry approaches

“Circular economy in practice using process metallurgy

75. BHT – Freiberger Universitätsforum 2024, 05.06.2024, Freiberg, Deutschland

Electric micromobility, or e-scooters and e-bikes may offer an alternative to the use of private cars. These micromobility devices, while lighter and less resource-intensive than cars, still require different metals and minerals. In this paper, we build a dynamic material flow model for shared e-scooters and private e-bikes in Finland, with an emphasis on their batteries, as these contain many critical raw materials. Our aim is to quantify the future urban mining potential of micromo-bility. We use Weibull distributions to model the lifetimes of micromobility devices and their batteries and discrete-time Bass diffusion to model the uptake of e-bikes as an innovation. In our baseline scenario, the outflow of used e-scooter batteries will be approximately 25,400 units and the outflow of used e-bike batteries some 217,000 units annually. For both types of devices, the main drivers of uncertainty are battery lifetime and the volume of future sales.

ntroduction:

Accelerated brain ageing is associated with increased risks of dementia and mortality, and can be assessed
with machine learning and structural brain MRI data to determine the predicted age difference (brain-PAD)
between biological and chronological age[1]. Advanced brain-PAD approaches aim to increase accuracy and
sensitivity to specific pathologies by adding sequences able to assess cerebrovascular health, a contributor to
cognitive decline[2].
Improved brain-PAD accuracy, and classification of Alzheimer's Disease (AD) patients, were shown with
Cerebrovascular Brain-age by adding Arterial Spin Labeling (ASL) perfusion MRI to T1w and FLAIR data in a
single-site study[3,4]. Such a pre-trained model has, however, a limited value for data from different MRI
vendors or acquired with different parameters. While combining (ASL) studies is often a prerequisite to reach
sufficient sample sizes for machine learning, acquisition differences can lead to a systematic bias of brain-PAD.
The impact of commonly used harmonisation techniques on this bias is not sufficiently studied.

Keywords: Alzheimer's Disease, Arterial spin labelling, Blood-brain barrier, Biomarkers

Motivation: Blood-brain barrier (BBB) permeability changes may be implicated in Alzheimer’s Disease (AD) pathophysiology.

Goal(s): To investigate if the exchange time (Tex) of water across the BBB is associated with cognitive and amyloid status.

Approach: We measured Tex with a multi-echo arterial spin labeling MRI sequence in 116 adults older than 50 years and studied its association with cognition (cognitively normal vs mild cognitive impaired) and amyloid (A- vs A+) status.

Results: BBB water permeability is increased in A+ participants and in patients with MCI, compared to healthy controls

Impact: Our results suggest that multi-TE ASL MRI BBB water permeability can be used as a potential early imaging biomarker of AD pathophysiology.

Keywords: Tumors (Pre-Treatment), Arterial spin labelling

Motivation: Blood brain barrier arterial spin labeling (BBB-ASL) could assess BBB integrity. However, the assumption of homogeneous T2 in data fitting might be broken in gliomas.

Goal(s): To evaluate the BBB integrity in gliomas with regional tissue-specific T2.

Approach: A mono-exponential T2 fitting was used to obtain tissue-specific T2 values to estimate time of water exchange (Tex) and perfusion (CBF) in the tumor, normal-appearing white (NAWM), and gray matter (NAGM) using ExploreASL.

Results: Higher Tex in NAWM, and lower Tex in the tumor and NAGM were observed and the tumor heterogeneity was better depicted when tissue-specific T2 values were used.

Impact: Water exchange and perfusion maps are highly affected by the tissue T2 value used in BBB-ASL data processing. Applying tissue-specific T2 correction has resulted in a more reliable evaluation of BBB integrity in gliomas.

Keywords: Arterial Spin Labelling, Arterial spin labelling, Challenge; multi-PLD ASL

Motivation: The OSIPI ASL Challenge is a community initiative motivated by open science principles that aim to establish good practices in ASL image analysis and Cerebral Blood Flow (CBF) quantification.

Goal(s): The second ASL challenge's main goal is to provide a thorough comparison of existing post-processing pipelines focusing on Multi-PLD methodology.

Approach: The second roadmap will provide different datasets; a population dataset which will bring real variability to the challenge and synthetic data which allows straightforward ground truth comparison.

Results: The second edition of the ASL Challenge will contribute to gaining new insights into the potential sources of variability within the multi-PLD analysis pipeline.

Impact: Through the second edition of the ASL Challenge, we seek to enhance our understanding of multi-PLD analysis in the ASL community. Its success could establish a consensus on the processing of multi-PLD ASL data, positively influencing clinical and scientific practices.

Keywords: Arterial Spin Labelling, Perfusion, Arterial Spin Labelling, Normal Development

Motivation: There is lacking understanding of hemodynamic changes in children and their impact on MRI perfusion quantification.

Goal(s): We aim to investigate age-related hemodynamic changes in developing brain.

Approach: Perfusion parameters from single- and multi-delay Arterial Spin Labeling (ASL) MRI of MR-negative children are analyzed.

Results: We found significant age-dependent differences between perfusion quantification with single- and multi-delay approaches. ATT followed a non-linear distribution in age and was heterogeneous across vascular territories Our findings support the use of multi-delay ASL for improved perfusion assessment in children and provide better understanding of hemodynamic changes in developing brain.

Impact: This is the first study to investigate age-related arterial transit-time changes in children and their impact on perfusion quantification with perfusion MRI. Our findings prompt improved understanding of age-related perfusion changes and standardization of hemodynamic parameters in the pediatric cohort.

Motivation: Structural brain ageing models are associated with cognitive decline, and the addition of arterial spin labelling (ASL)-derived improved brain-age estimation accuracy, but the relation between cerebrovascular ageing and cognitive decline is not yet fully understood.

Goal(s): To assess the contribution of ASL in the relationship between brain-age estimates and cognitive decline.

Approach: Brain-age estimation accuracy and linear relationships with composite cognitive scores were compared between structural-only (T1w and FLAIR), ASL-only, and structural+ASL models.

Results: Combined structural and ASL brain-age models showed the highest accuracy and increased effect sizes with composite cognitive scores, however, ASL-only models showed unexpected relationships.

Impact: Combined structural-ASL brain-age models might present a surrogate biomarker in an earlier stage of cognitive decline, aiding in diagnosis and treatment monitoring. Possible mediation effects of ASL on the association of structural decline with cognitive domains should be investigated further.

Introduction
Mid-life cardiovascular and late-life structural cerebrovascular pathology play a major role in accelerating cognitive decline in normal aging and dementia. Cerebral blood flow (CBF) may be a critical intermediate biomarker of future cognitive decline, however our understanding of normal CBF variability and its relation with mid-life cardiovascular and late-life structural cerebrovascular parameters is limited. The MRC National Survey of Health and Development neuroimaging sub-study ‘Insight 46’ provides a unique opportunity to study the effects of cardiovascular and cerebrovascular health on CBF in a cohort with a fixed chronological age. We explored associations of life-long cardiovascular parameters and WMH volume with ASL MRI CBF in this cognitively healthy population-based sample.
Methods
3D T1-weighted, FLAIR, and pseudo-continuous ASL (labeling duration = 1800ms; post-labelling delay = 1800ms) data (3T) were acquired in 295 participants (Table 1). Clinical data included systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), pulse pressure (PP), and the Framingham Risk Score (FRS). MRI scans were processed with ExploreASL. Grey matter (GM), white matter (WM) and white matter hyperintensity (WMH) volume were segmented from the T1w and FLAIR images. ASL- derived partial volume-corrected CBF and the spatial coefficient of variation (sCoV) were obtained in whole-brain GM and WM. Linear regression models examined associations between life-long cardiovascular health (ages 43, 53, 60-64, 69, and 69-71 years), ASL metrics (at 69-71 years), and WMH load (at 69-71 years). Models were corrected for sex, and sex interactions were tested if applicable.
Results
While mid-life cardiovascular parameters were associated with late-life sCoV and CBF, the strongest associations were seen at 69-71 years. At this time point, higher SBP and MAP were associated with lower GM CBF in men (1A-B, β=-0.16,-0.28) and relatively stable GM CBF in women (1A-B, β=0.02,-0.02); higher DBP was associated with lower GM CBF (β=-0.18). Higher WMH volume was related to higher GM and WM CBF (2A-B, β=2.04,1.45), and lower GM and WM sCoV (2C-D, β=-0.04,0.05).
Discussion
These sex-dependent associations encourage further investigation into the potential mediatory role of CBF between mid-life cardiovascular and late-life structural decline of cerebrovascular health, leading to cognitive

The presence of open-volume defects, such as vacancies, can significantly alter the functional properties of a material, including its
structure and electronic transport. This study employs ion irradiation using inert ions (Ar+) and transition metal ions (Co+) at fluences
of 1012 – 1015 ions∙cm-2 to achieve systematic disorder in the multilayer structure of MAX-phase Cr2AlC. It is shown that the magnitude
of the paramagnetic response of Cr2AlC increases with ion fluence, regardless of the dopant used. A combination of isolated moments in
defect sites with J = ½ and magnetic clusters are used to explain this behavior. Low-temperature (< 30 K) resistivity measurements show
local minima and sudden up(down)-turns with decreasing temperature, which, together with unusual MR in this temperature range,
suggest the presence of quantum transport effects, such as the Kondo effect.

Introduction
Arterial spin labeling (ASL) MRI, a non-invasive technique for imaging perfusion, now allows studying BBB permeability. The DEveloping BBB-ASL as a non-Invasive Early biomarker of Alzheimer's Disease (DEBBIE-AD) multi-cohort study integrates this modified BBB-ASL technique in several healthy and diseased populations (Table 1) to study methodological and clinical research questions (Table 2) on the ability of BBB-ASL as an early AD biomarker.
Methods
DEBBIE-AD will enroll various cohorts with subjective cognitive decline, mild cognitive impairment, and AD dementia, as well as age-matched healthy controls, at seven sites (Table 1). Our newly developed BBB-ASL sequence — implemented with the vendor-independent MRI framework gammaSTAR — will be added to multiple MRI protocols. The BBB-ASL sequence combines time-encoded multi-post labeling delay pseudo-continuous ASL with a multi-echo 3D GRASE readout, allowing estimating CBF, ATT, and the BBB time of exchange (Tex). Data analyses will be conducted using ExploreASL. Beyond MRI standard sequences, including T1w, T2w, FLAIR, DWI, the DEBBIE clinical outcomes include amyloid-PET and blood and CSF fluid biomarkers (Table 1).
Expected Results
Preliminary testing of the BBB-ASL has been conducted on 3T systems (different Siemens Heathineers scanners) in different cohorts at multiple sites. Data processing with ExploreASL includes FSL-FABBER4 for quantification, allowing harmonized image processing. An example of the mean and standard deviation Tex maps of two DEBBIE cohorts is shown in Figure 1 to illustrate the similarities of the Tex patterns from two cohorts of similar-aged healthy adults from different sites.
Discussion
The DEBBIE-AD study aims to provide evidence on the ability of BBB-ASL to measure BBB permeability and demonstrate its utility in AD-related pathologies. The presented sequence may provide novel and unique insights into the staging of BBB permeability changes in groups at greater risk of developing AD, which may, in turn, provide new targets for treatment.

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In this work, we present the formation of superconducting phases of Ga-precipitates in hyperdoped SiGe with different ratios of Si/Ge composition. Using ion implantation and flash lamp annealing (FLA) in the millisecond range, we explore the coherent coupling of Ga network within the bulk instead at the SiO2/Si or SiO2/Ge interfaces. As the Si concentration in the alloy increases, but with an identical Ga concentration, the samples show a transition from a superconducting to a non-superconducting phase due to the change of the Ga solubility in the SiGe alloy. We found hyperdoped Si0.3Ge0.7 with 13 % of Ga shows superconducting transition temperature of 3.5 K, critical magnetic field of 1 T and a critical current of approximately 250 μA.

Background
Cyclooxygenase-2 (COX 2) and 5-lipoxygenase (5 LO) convert arachidonic acid to prostanoids and leukotrienes respectively. Both enzymes are involved in tumorigenesis and show overexpression in cancer which makes them promising targets for radioligands [1,2]. Herein, we present radioiodination of two dual COX 2/5 LO inhibitors featuring a closo-dicarbadodecaborane(12) moiety as metabolically stable phenyl mimetic and the results of preliminary in vitro and in vivo investigations.
Materials and Methods
Enzyme inhibition of I 1 and I 2 (Figure 1) was determined using a fluorescence-based COX assay. 1 and 2 were radioiodinated using chloramine T and purified by semipreparative HPLC followed by solid-phase extraction. Radiotracer formulations contained ascorbic acid (AA) or gentisic acid (GA). Stability in ethanol, isotonic saline (0.9% NaCl), phosphate-buffered saline pH 7.4 (PBS) and human plasma was investigated for up to 11 h. Cell uptake studies were performed using U87 glioblastoma, U87 COX 2–knockout, and A2058 melanoma cells. Distribution in U87 tumour-bearing NMRI nu/nu mice was investigated using single-photon emission computed tomography (SPECT).
Results
Radiosynthesis gave high radiochemical yield (41–67 %). Radiochemical purity (RCP) depended on addition of antioxidants (none 62–100 %, AA > 88 %, GA > 97 %). Formulations in EtOH were stable for more than 10 h at room temperature. In isotonic saline and PBS, radiodeiodination was decelerated by antioxidants. Radiotracers exhibited stability during incubation with human plasma (RCP > 95 % up to 5 h at 37°C with GA). Cell uptake was observed and partially blocked by inhibitors of COX 2 and 5 LO. A SPECT imaging pilot study showed tracer excretion via hepatobiliary and renal routes within 2 h, and thyroid uptake resulting mainly from residual [123I]iodide in the tracer formulation. Furthermore, [123I]I 2 formulated with AA, but not GA, showed uptake in the marginal region of COX 2-positive tumours 24 h after injection (maximum standardised uptake value SUVmax = 9.1).
Conclusions
Two radioiodinated closo-dicarbadodecaborane(12)-based COX 2/5 LO inhibitors were characterised in vitro and underwent first explorative SPECT studies in vivo. Interestingly, binding of [123I]I 2 at the marginal tumour region was observed in presence of AA but not GA, potentially indicating partial specificity by blocking COX-2 in GA-treated mice. Further investigations, such as an intact cell 5 LO assay and in vivo experiments, will allow to validate these initial observations and to assess the applicability of COX 2/5 LO inhibitors as tumour radiotracers.

Aim: Parkinson’s disease is caused by degeneration of nigro-striatal dopaminergic neurons and denervation of the target neurons in the neostriatum. The resulting disruption of dopaminergic modulation produces an imbalance between antagonistic pathways in the basal ganglia leading to rigidity, tremor, and bradykinesia [1]. One state-of-the-art treatment option is the so called deep-brain-stimulation (DBS), whereby an electrode is implanted to re-equilibrate the nervous pathways. Though highly effective, DBS is linked to a complex surgical procedure and can lead to adverse neurological effects [2,3]. The goal of this project is to enable a selective stimulation of striatal dopaminoceptive neurons from outside the brain through polymeric photovoltaic nanoparticles which are transported to the neostriatum using engineered M13 bacteriophage as nanocarrier. To monitor its biodistribution in the organism, the engineered bacteriophages are going to be radiolabeled.
Materials and methods: To allow the radiolabeling with a radiometal, a chelator has to be conjugated to the bacteriophage. Phage conjugates with different chelators were produced, but stability analysis by agarose gel electrophoresis revealed a significantly increased and unexpected aggregation of the radiolabeled conjugates, in comparison to the unconjugated phage, when incubated with 50% human serum. To address this problem and avoid aggregation, a chelator-free radiolabeling approach was chosen instead, by radioiodination of the tyrosine residues using [123I]NaI and Iodogen.
Results: The achieved radiochemical purity was > 96% and the molar activity was 11 MBq/pmol. Stability analysis using agarose gel electrophoresis indeed revealed a low aggregation in serum. C57BL mice were intravenously injected with ~ 30 MBq/mouse of [123I]I-M13 and imaged with SPECT/CT after 20 min, 40 min, 60 min and 18 h. A high amount of activity was observable in the heart of the mice over the whole duration of the experiment, indicating circulation of bacteriophages. In the necropsy after 18 h, a portion of 15% of the activity was still found in the blood. Another accumulation was observed in the lungs, however the signal originated from the blood circulation in the organ, which was confirmed by the necropsy. After 18 h, 5% of the activity was also found in the thyroid, indicating moderate deiodination over time. According to blood samples collected over time the biological half-life was calculated to be ~ 9 h.
Conclusion: In this study, for the first time the successful radioiodination of M13 bacteriophages using [123I]NaI is described. Using the radioiodinated M13, the biodistribution of the phages was studied in vivo and a striking long serum half-life of the [123I]I-M13 was discovered.

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Spin crossover (SCO) complexes have been shown to exhibit giant mechanocaloric effects. Due to the change of magnetization at the spin crossover transition, they are also expected to show magnetocaloric effects. However, experimental studies on the magnetocaloric properties in SCOs are scarce. Here, we have studied the magnetocaloric response in the SCO complex {Fe(L)₂}(BF₄)₂, {L = 2,6-di(pyrazol-1-yl)pyridine} using pulsed magnetic fields. We show that applying a magnetic field can induce a partial transformation from the low spin to the high spin state. We directly measure the adiabatic temperature change of the transformation for different initial sample temperatures and magnetic fields and compare them with calculations using the Clausius–Clapeyron equation. While we found a large change in entropy of 70 Jkg⁻¹K⁻¹ at 50 T, the corresponding temperature change of 1.5 K is small due to the weak dependence of the transformation temperature on the magnetic field. Our study enhances the knowledge of caloric effects in SCO complexes, which so far have mainly focused on mechanocaloric studies.

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es hat keine aussagefähiges Abstract vorgelegen

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We present comprehensive high magnetic field studies of the alternating weakly coupled ferroantiferromagnetic (FM-AFM) spin-1/2 chain compound Cu₂(OH)₃Br, with the structure of the natural mineral botallackite. Our measurements reveal a broad magnetization plateau at about half of the saturation value, strongly suggesting that the FM chain sublattice becomes fully polarized, while the AFM chain sublattice remains barely magnetized, in magnetic fields at least up to 50 T. We confirm a spin-reorientation transition for magnetic fields applied in the ac* plane, whose angular dependence is described in the framework of the mean-field theory. Employing high-field THz spectroscopy, we reveal a complex pattern of high-frequency spinon-magnon bound-state excitations. On the other hand, at lower frequencies we observe two modes of antiferromagnetic resonance, as a consequence of the long-range magnetic ordering.We demonstrate that applied magnetic field tends to suppress the long-range magnetic ordering; the temperature-field phase diagram of the phase transition is obtained for magnetic fields up to 14 T for three principal directions (a, b, c*).

The pressure and temperature conditions at which precipitation of diamond occurs from hydrocarbon mixtures is important for modelling the interior dynamics of icy planets. However, there is substantial disagreement from laboratory experiments, with those using dynamic compression techniques finding much more extreme conditions are required than in static compression. Here we report the time-resolved observation of diamond formation from statically compressed polystyrene, (C8H8)n, heated using the 4.5 MHz X-ray pulse trains at the European X-ray Free Electron Laser facility. Diamond formation is observed above 2,500 K from 19 GPa to 27 GPa, conditions representative of Uranus’s and Neptune’s shallow interiors, on 30 μs to 40 μs timescales. This is much slower than may be observed during the ∼10 ns duration of typical dynamic compression experiments, revealing reaction kinetics to be the reason for the discrepancy. Reduced pressure and temperature conditions for diamond formation has implications for icy planetary interiors, where diamond subduction leads to heating and could drive convection in the conductive ice layer that has a role in their magnetic fields.

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X-ray free electron laser (XFEL) sources coupled to high-power laser systems offer an avenue to study the structural dynamics of materials at extreme pressures and temperatures. The recent commissioning of the DiPOLE 100-X laser on the high energy density (HED) instrument at the European XFEL represents the state-of-the-art in combining x-ray diffraction with laser compression, allowing for compressed materials to be probed in unprecedented detail. Here, we report quantitative structural measurements of molten Sn compressed to 85(5) GPa and  ~3500 K. The capabilities of the HED instrument enable liquid density measurements with an uncertainty of ~1% at conditions which are extremely challenging to reach via static compression methods. We discuss best practices for conducting liquid diffraction dynamic compression experiments and the necessary intensity corrections which allow for accurate quantitative analysis. We also provide a polyimide ablation pressure vs input laser energy for the DiPOLE 100-X drive laser which will serve future users of the HED instrument.

We present in situ measurements of spectrally resolved X-ray scattering and X-ray diffraction from monocrystalline diamond samples heated with an intense pulse of heavy ions. In this way, we determine the samples’ heating dynamics and their microscopic and macroscopic structural integrity over a timespan of several microseconds. Connecting the ratio of elastic to inelastic scattering with state-of-the-art density functional theory molecular dynamics simulations allows the inference of average temperatures around 1300 K, in agreement with predictions from stopping power calculations. The simultaneous diffraction measurements show no hints of any volumetric graphitization of the material, but do indicate the onset of fracture in the diamond sample. Our experiments pave the way for future studies at the Facility for Antiproton and Ion Research, where a substantially increased intensity of the heavy ion beam will be available.

Die Therapie der Akuten Myeloischen Leukämie (AML) bleibt eine große Herausforderung. Intensive Chemotherapien und allogene hämatopoetische Stammzelltransplantationen bieten
manchen Patienten Heilungschancen, sind aber mit einer hohen Morbidität verbunden und kommen v.a. für ältere und morbide Patienten oft nicht infrage. Insbesondere die rezidiviert/
refraktäre AML weist weiterhin eine schlechte Prognose auf. Folglich ist der Bedarf an neuen innovativen und sicheren Therapieansätzen hoch. CAR T-Zellen konnten einen Durchbruch in
der Behandlung akuter lymphatischer Leukämien und Lymphome erzielen, sich aber bei der Behandlung der AML in klinischen Studien bislang nicht durchsetzen. Die Suche nach Ziel-
strukturen auf AML-Blasten erweist sich als schwierig, nicht zuletzt da deren Expression auf gesunden myeloischen Zellen mit einer Myelosuppression unter Therapie einhergehen kann.
Die UniCAR T-Zell-Therapie ist eine Adapter CAR-Plattform, welche innovative Lösungsansätze zur Therapie der AML offeriert. Das UniCAR-System basiert auf der Quervernetzung
von UniCAR T-Zellen mit Tumorzellen durch molekulare Adapter, sog. Targetmodule (TM). Da der UniCAR keine Tumorassoziierten Antigene, sondern das kurze E5B9-Peptidepitop des TM erkennt, ist das UniCAR-System in Abwesenheit der TM inaktiv. Dies erlaubt eine rasche, reversible Schaltbarkeit des Systems im Falle von Nebenwirkungen wie dem CRS oder der
Myelosuppression. Die TM vermitteln die spezifische Bindung an Zielstrukturen der AML. Zudem können durch Kombinationen von TM verschiedener Spezifität mehrere Zielstrukturen
der AML zeitgleich angegriffen werden. In der AG Bachmann wurden bereits scFv-basierte TM mit kurzer Halbwertszeit (HWZ) zur UniCAR T-Zell-Therapie der AML entwickelt. Beachtliche Ergebnisse konnten u. a. das CD33- und CD123-spezifische scFv TM zeigen, sodass Letzteres bereits in einer multizentrischen klinischen Phase 1 Studie evaluiert wird (NCT04230265). Eine weitere Zielstruktur der AML ist FLT3. Es handelt sich um eine Tyrosinkinase, welche von AML-Blasten überexprimiert wird. Darüber hinaus ist die interne Tandemduplikation von FLT3 eine der häufigsten Treibermutationen der AML, welche mit einer schlechten Prognose assoziiert ist. Dies macht FLT3 zu einem geeigneten Angriffspunkt der UniCAR T-Zell-Therapie. In dieser Arbeit wurden FLT3-spezifische TM verschiedener Größe für die UniCAR T-Zell-Therapie der AML entwickelt. Während kleine scFv-basierte TM aufgrund ihrer kurzen in vivo HWZ eine rasche Kontrolle von Nebenwirkungen ermöglichen, könnten sich größere HWZ-verlängerte TM für spätere Therapiephasen anbieten, in denen die AML-Blastenzahl und das Nebenwirkungs-Risiko wesentlich reduziert sind. Durch ihre verlängerten HWZ könnten die Abstände zwischen den TM-Infusionen verlängert werden, was ambulante Therapien ermöglichen könnte. In dieser Arbeit wurde eine Verlängerung der in vivo HWZ durch das Einfügen konstanter Domänen humaner IgG-Moleküle erreicht. So konnten zusätzlich zum FLT3-scFv TM mit kurzer HWZ ein FLT3-Minibody (Mb) TM, FLT3-IgG4 TM sowie FLT3-IgG4mut TM mit steigendem Molekulargewicht und somit längerer HWZ gebildet werden. Um deren Immunogenität im Patienten im Hinblick auf eine klinische Translation zu reduzieren, wurden alle FLT3-spezifischen TM humanisiert und funktionell mit den murinen TM verglichen. Es konnten erfolgreich murine und humanisierte FLT3-scFv TM, FLT3-Mb TM, FLT3-IgG4 TM und FLT3-IgG4mut TM kloniert und durch lentivirale Transduktion stabil in das Genom eukaryotischer Zelllinien eingebracht werden. Die von den Zelllinien exprimierten TM konnten durch Affinitätschromatografien in hoher Reinheit und Konzentration gewonnen werden. Im direkten in vitro Vergleich erwiesen sich die humanisierten FLT3 TM (huFLT3 TM) als funktionell gleichwertig zu den murinen Varianten. In weiteren Funktionalitätsstudien konnten die potenziell weniger immunogenen huFLT3 TM eingehender charakterisiert werden. Sämtliche huFLT3 TM erwiesen sich in vitro an verschiedenen AML-Zelllinien mit unterschiedlicher FLT3-Expression als sehr effektiv. Alle huFLT3 TM konnten spezifisch an FLT3+ AML-Zellen binden und im Folgenden UniCAR T-Zellen aktivieren. Diese setzten
daraufhin proinflammatorische Zytokine frei. UniCAR T-Zellen lysierten nach huFLT3 TM-vermittelter Quervernetzung spezifisch AML-Zellen bei geringen E:T-Verhältnissen, wofür
halbmaximale Wirkkonzentrationen der huFLT3 TM im picomolaren Bereich ermittelt wurden. Darüber hinaus konnten isolierte primäre AML-Blasten drei verschiedener AML-Patienten in
vitro durch die FLT3-spezifische UniCAR T-Zell-Therapie lysiert werden. Die höchste Effektivität konnte dabei das huFLT3-scFv TM erzielen. Bei der in vivo Behandlung von AML-
Tumoren im Mausmodell erwiesen sich das huFLT3-scFv TM sowie das huFLT3-IgG4 TM am wirksamsten. Letzteres konnte die Tumore binnen etwa einer Woche vollständig eradizieren.
Abschließend wurde durch PET-Untersuchungen die in vivo Pharmakokinetik der huFLT3 TM in einem immundefizienten murinen AML-Xenograftmodell evaluiert. Es konnte die sukzessive HWZ-Verlängerung im Blut für das huFLT3-Mb TM, das huFLT3-IgG4 TM und das huFLT3-IgG4mut TM entsprechend ihres steigenden Molekulargewichts im Vergleich zum huFLT3-scFv TM bestätigt werden. Alle huFLT3 TM reicherten sich hochspezifisch in den FLT3+ AML-Tumoren an und persistierten dort. Aufgrund dieser Eigenschaften könnten sich die TM evtl. auch durch Markierung mit geeigneten Radionukliden für eine Radioimmuntherapie eignen.
Insgesamt legt diese Doktorarbeit das Potenzial der neuen huFLT3 TM für die UniCAR T-Zell-Therapie der AML dar. Am wirksamsten erwiesen sich sowohl in vitro bei der Behandlung
primärer AML-Blasten als auch in vivo an AML-Tumoren im Mausmodell das huFLT3-scFv TM sowie das huFLT3-IgG4 TM als Vertreter eines huFLT3 TM mit kurzer und langer in vivo HWZ. Mit der erfolgreichen HWZ-Verlängerung der TM könnten langfristige UniCAR T-Zell-Erhaltungstherapien residualer AML-Blasten ermöglicht werden. Die in dieser Arbeit akquirierten
PET-Daten legen zudem die Eignung der huFLT3 TM für theranostische Ansätze nahe.

Femtosecond high-intensity laser pulses at intensities surpassing 1014 W/cm2 can generate a diverse range of functional surface nanostructures. Achieving precise control over the production of these functional structures necessitates a thorough understanding of the surface morphology dynamics with nanometer-scale spatial resolution and picosecond-scale temporal resolution. In this study, we show that single XFEL pulses can elucidate structural changes on surfaces induced by laser-generated plasmas using grazing-incidence small-angle X-ray scattering (GISAXS). Using aluminium-coated multilayer samples we distinguish between sub-picosecond (ps) surface morphology dynamics and subsequent multi-ps subsurface density dynamics with nanometer-depth sensitivity. The observed subsurface density dynamics serve to validate advanced simulation models representing matter under extreme conditions. Our findings promise to open new avenues for laser material-nanoprocessing and high-energy-density science.

Immunotherapy encompasses a wide array of strategies, spanning from cytokines to antibodies and their derivatives, extending to engineered immune cells. A highly promising
avenue in immunotherapy involves T or NK cell engineering to express chimeric antigen receptors (CARs), which redirect immune cells to specific antigens, triggering effector cell
activation and subsequent elimination of target cells. CAR technology has demonstrated significant therapeutic potential in both preclinical and clinical studies. This success
encourages the application of CAR-expressing immune effector cells for the treatment of GBM, a highly aggressive malignant brain tumor. Despite the success of CAR T cells, clinical trials have unveiled various toxicities and therapy-related adverse events in cancer patients. These side effects derive primarily from the inability to regulate the activity of CAR T cells post-administration and the expression of tumor-associated antigens (TAAs) on non-malignant cells, leading to the unspecific attack of healthy tissues. Additionally, effective targeting of solid tumors using CAR technology encounters challenges posed by the structural complexities, immunosuppressive microenvironment, and heterogeneity of the disease. To address these challenges, a novel modular and switchable CAR platform, named reversible CAR (RevCAR), has been developed by our group. Unlike conventional CARs, the RevCAR engineered effector cells that exhibits a peptide epitope (E7B6 or E5B9) in their extracellular domain (ECD) derived from the nuclear protein La-SS/B; instead of the scFv expressed on conventional CARs. This special modular design of RevCAR system is responsible for its switchability as it only interacts with target cancer cells through a RevTM, which simultaneously bind with one arm to the RevCAR epitope on effector cells and with the other arm to the TAA. This RevTM-induced cross-linkage facilitates the activation of the modified T cells, leading to the subsequent elimination of the tumor cells. Besides its safety mechanism, the system serves as a versatile platform for targeting multiple antigens by employing different RevTMs with distinct antigen specificities, thus overcoming tumor heterogeneity and antigen escape without the need to re-engineer T cells. Two formats of RevCAR T cells (RevCAR E5B9 and RevCAR E7B6) have been used in this thesis in order to target disialoganglioside (GD2) and/or epidermal growth factor receptor (EGFR) antigens that are overexpressed on GBM. For this purpose, GD2 and EGFR RevTMs were developed to redirect the corresponding RevCAR T cells towards tumor cells. In vitro functional tests have demonstrated a successful redirection of RevCAR T cells and therefore, a specific elimination of GBM cells and release of proinflammatory cytokines in an antigen-specific and RevTM concentration-dependent manner. While both RevTMs exhibited high killing efficiency, the half-maximal effective concentration (EC50) value for RevTM-5B9 was in the pM range, whereas RevTM-7B6 was in the nM range. In addition, also regarding the cytokine release the RevCAR-E5B9 system was superior compared to the RevCAR-E7B6 system. Following the successful application of OR-gated GBM targeting, I aimed to validate the concept of combinatorial targeting for more specific killing of GBM. Therefore, I employed the established Dual-RevCAR system, which follows the AND-gated targeting strategy. This novel framework includes a splitted version of the activation and costimulatory signaling domains into two RevCARs: the signaling (SIG) RevCARs that initiate the CD3 signal and the co-stimulatory (COS) RevCARs that initiate the CD28 signal. The full activation of the modified Dual-RevCAR T cells is only achieved through simultaneous cross-linking with cancer cells via two RevTMs upon recognition of two antigens. Through this combinatorial targeting of GBM cells displaying two TAAs, Dual-RevCARs reduce the risk of "on-target, off-tumor" toxicities. In this study, RevTMs against GD2 and EGFR were developed in different structures based on EGFR-nb (~45 KDa), GD2-scFv (~57 KDa) and GD2-IgG4 (~160 KDa), and they were linked to either 5B9- or 7B6-scFv. Structural different RevTMs provide different properties and biodistribution profiles for fast or retained elimination of RevTM. The performed functional analyses revealed that only in the simultaneous presence of RevTM GD2-5B9 or GD2-IgG4-5B9 and RevTM EGFR-7B6, Dual-RevCAR T cells significantly triggered the secretion of proinflammatory cytokines and efficiently eliminated GD2- and EGFR-expressing GBM cells in the nM range. This effect was completely absent using control cells lacking the expression of one or both TAAs, thereby indicating the precision targeting of Dual-RevCARs against GBM cells. Additionally, RevTM GD2 in the IgG4 and scFv formats were radiolabeled with 64Cu. Positron emission tomography (PET) analysis of the radiolabeled RevTM GD2 in tumor-bearing mice revealed that the different formats exhibits different pharmacokinetic profiles but both showed enrichment in GD2-expressing GBM cells, making them a suitable theranostic tool for GBM. Furthermore, I modified NK-92 cells with our RevCAR constructs to target GBM. NK-92 cell line can be used as “off-the-shelf” allogeneic therapy, which potentially lower the manufacturing costs and time, and reduce the likelihood of side effects due to their short lifespan. Due to the heterogenic nature of GBM, we decided to target an additional TAA, called fibroblast growth factor-inducible 14 (Fn14), which is overexpressed on GBM as indicated by previous studies. For this reason, Fn14-specific RevTMs were created to redirect the switchable RevCAR NK-92 cells, as well as RevCAR T cells, resulting in the specific killing of Fn14-expressing GBM cells in vitro and in vivo.
In conclusion, this thesis illustrates the significant potential of the switchable RevCAR system - as a mono or dual therapy - to specifically target different GBM cell models in a specific, safe and flexible manner.

Controlling the formation and stoichiometric content of the desired phases of materials has become of central interest for a variety of fields. The possibility of accessing metastable states by initiating reactions by X-ray-triggered mechanisms over ultrashort time scales has been enabled by the development of X-ray free electron lasers (XFELs). Utilizing the exceptionally high-brilliance X-ray pulses from the EuXFEL, we report the synthesis of a previously unobserved yttrium hydride under high pressure, along with nonstoichiometric changes in hydrogen content as probed at a repetition rate of 4.5 MHz using time-resolved X-ray diffraction. Exploiting non-equilibrium pathways, we synthesize and characterize a hydride in a Weaire–Phelan structure type at pressures as low as 125 GPa, predicted using a crystal structure search, with a hydrogen content of 4.0–5.75 hydrogens per cation, that is enthalpically metastable on the convex hull.

Das La Protein ist ein abundantes Protein, welches unter physiologischen Bedingungen im Zellkern lokalisiert ist. Dort ist es mit verschiedenen RNAs assoziiert und arbeitet einerseits
als Chaperone und stellt andererseits die korrekte Prozessierung der RNAs sicher. Außerhalb des Zellkerns ist das La Protein an der IRES-abhängigen Translation zellulärer
Proteine beteiligt, welche unter Bedingungen wie oxidativem Stress oder Apoptose auftritt. La ist allerdings nicht nur mit zellulären RNAs assoziiert, sondern auch mit viralen RNAs
und ist außerdem an der Translation viraler Proteine beteiligt. Abgesehen von der Möglichkeit der Re-lokalisation in das Cytoplasma wurde auch gezeigt, dass das La Protein
an die Zelloberfläche gelangen kann. Im Kontext der Krebstherapie wurde La als mögliches Zielantigen untersucht, weil es zum einen in maligne-transformierten Zellen überexprimiert ist und zum anderen wegen der Möglichkeit, die Re-lokalisation von La an die Zelloberfläche durch beispielsweise Bestrahlung oder Chemotherapie auszulösen. An der Zelloberfläche wäre das La Protein dann zugänglich für die Bindung durch La Antikörper (Ak). In der Gruppe von Prof. Bachmann wurden in den letzten Jahren verschiedene Ak gegen das La Protein charakterisiert. Die beiden bekanntesten dieser Ak, 5B9 und 7B6, erkennen jeweils kurze Peptid-Epitope. Die Interaktion dieser Ak mit den Peptid-Epitopen wurde verifiziert durch den Einsatz in immuntherapeutischen Ansätzen wie den Adapter-CAR Systemen UniCAR und RevCAR. Sowohl der 5B9 als auch der 7B6 Ak sind nicht in der Lage natives La Protein in Immunpräzipitations-experimenten zu erkennen, was bedeutet, dass die erkannten Epitope im nativen Protein kryptisch sind. Ein anderer La Ak, der von besonderem Interesse ist, ist der Ak 312B, welcher sowohl humanes als auch murines La Protein erkennt und demnach ein wirklicher Auto-Ak ist. Der 312B Ak erkennt ein Konformationsepitop, welches auch im nativen Protein zugänglich ist. Interessant an diesem Ak ist die geringe Anzahl an Mutationen in den variablen Regionen im Vergleich zu der vorhergesagten Keimbahnsequenz.
Im ersten Teil dieser Studie wurde der 312B Ak genauer untersucht, wobei besonderes Augenmerk auf die variablen Sequenzen des Ak gelegt wurde. Diese zeigen zum einen somatische Hypermutationen und zum anderen eingefügte N-Nukleotide, welche den Leserahmen und somit die Sequenz der CDR3 der schweren Ak-Kette bestimmen. Es wurde gezeigt, dass das Zurückmutieren der AS zurück zu der vorhergesagten Keimbahnsequenz, unter Beibehalten der N-Nukleotide, dazu führt, dass der erhaltene Keimbahn-312B Ak seine Reaktivität gegen La verliert. Das bedeutet, dass die Hypermutationen verantwortlich für die anti-La Reaktivität des 312B Ak sind. Durch das Rückmutieren der einzelnen AS des Keimbahn-312B Ak zu der Sequenz des urprünglichen Ak konnte gezeigt werden, dass der Austausch eines Asparaginsäure-Restes (D) in der CDR3 der schweren Kette gegen einen Tyrosin-Rest (Y) die anti-La Reaktivität wiederherstellt. Das resultierende Konstrukt konnte in Immunoblot Experimenten wieder sein Antigen erkennen. Mit Hilfe von Immunpräzipitation und ELISA konnte bestätig werden, dass diese eine D zu Y Mutation ausreichend ist, um die Bindungseigenschaften des reifen 312B Ak wiederherzustellen und dass diese Mutation einen wesentlichen Anteil an der anti-La Reaktivität dieses Ak trägt. Zusätzlich zur Charakterisierung des 312B Ak hat sich der zweite Teil dieser Arbeit mit den vier zuvor beschriebenen La Ak A3A9, A6F12, A1E5 und A9E9 befasst. Diese wurden in den 1980er Jahren etabliert, aber bisher nicht näher charakterisiert. Für diese Ak wurden zum einen die variablen Sequenzen identifiziert. Außerdem wurden die Bindeeigenschaften der Ak gegen humanes und murines La untersucht, wobei bestätigt wurde, dass alle Ak gegen humanes La reaktiv sind, allerdings nur der Ak A1E5 auch mit murinem Protein reagiert. In Immunpräzipitationsexperimenten wurde gezeigt, dass zwei der Ak, A3A9 und A9E9, natives La Protein erkennen, was bedeutet, dass diese Epitope im nativen Protein zugänglich sind. Um die Epitope der Ak zu bestimmen, wurden Immunoblot Experimente mit La-Deletionsmutanten durchgeführt, für eine genauere Bestimmung wurden die Ak zu der Firma PEPperPRINT geschickt. Für die Ak A3A9 und A6F12 konnten kurze Peptid-Epitope bestimmt werden, welche in der Linker-Region zwischen LaN und LaC,
beziehungsweise im RRM1 lokalisiert sind. Die Ak A1E5 und A9E9 erkennen jeweils Konformationsepitope, wobei das Epitop des Ak A1E5 im Bereich des RRM1 liegt und das
A9E9-Epitop in LaC lokalisiert ist. Da bekannt ist, dass manche der La Ak das Protein redox-abhängig erkennen, wurde auch für die vier in dieser Arbeit charakterisierten Ak die Redox-
Sensitivität untersucht. Die beiden Ak A3A9 und A6F12 zeigten keine redox-abhängigen Unterschiede in der Bindung an La. Für die Ak A1E5 und A9E9 konnte eine Redox-Sensitivität festgestellt werden, wobei der A1E5 Ak eine höhere Affinität zu oxidiertem La zeigt und der A9E9 Ak vorzugsweise an reduziertes La bindet. Weitere Experimente mit dem A9E9 Ak haben bestätigt, dass die Redox-Sensitivität durch die Cystein-Reste in LaC vermittelt wird. Für die beiden Ak A3A9 und A9E9, welche kurze Peptid-Epitope erkennen, wurde dann
getestet, ob sie auch für den Einsatz in einem Adapter-CAR System geeignet wären. Dafür wurden CARs entwickelt, welche extra-zellulär den anti-La scFv tragen, und Target Module
(TMs), die gegen das Tumorantigen PSMA gerichtet sind und das jeweilige La-Epitop-Tag tragen. Die neuen CARs wurden mit einer PSMA-positiven Zelllinie getestet, wobei beide
La CARs zusammen mit dem jeweiligen TM eine Lyse der Tumorzellen auslösen konnten. Beide CARs wurden auch für die Lyse von Tumorzellen, die La auf ihrer Oberfläche tragen,
eingesetzt. Dabei wurde eine unspezifische Lyse von La-gelabelten Zellen durch die A6F12 CARs beobachtet, die A3A9 CARs hingegen zeigten eine signifikante spezifische Lyse dieser Tumorzellen. Obwohl die neuen CARs in beiden Ansätzen eine Tumorzell-Lyse induzieren konnten, ist ein Adapter-CAR System einem direkten Targeting Ansatz vorzuziehen, da es sich besser kontrollieren lässt.
Zusammenfassend wurden in dieser Arbeit verschiedene La Ak charakterisiert. Es wurde gezeigt, dass die Reaktivität des 312B Ak hauptsächlich von einer AS-Mutation in der CDR3
der schweren Ak-Kette abhängt. Für die vier neuen Ak konnten die Sequenzen identifiziert und die Epitope bestimmt werden. Außerdem wurden die Bindungseigenschaften dieser Ak
untersucht. Des Weiteren wurden neue CARs entwickelt, die sowohl als Adapter CARs als auch für das direkte Targeting von La genutzt werden können.

H2O transforms to two forms of superionic (SI) ice at high pressures and temperatures, which contain highly mobile protons within a solid oxygen sublattice. Yet the stability field of both phases remains debated. Here, we present the results of an ultrafast X-ray heating study utilizing MHz pulse trains produced by the European X-ray Free Electron Laser to create high temperature states of H2O, which were probed using X-ray diffraction during dynamic cooling. We confirm an isostructural transition during heating in the 26-69 GPa range, consistent with the formation of SI-bcc. In contrast to prior work, SI-fcc was observed exclusively above ~50 GPa, despite evidence of melting at lower pressures. The absence of SI-fcc in lower pressure runs is attributed to short heating timescales and the pressure-temperature path induced by the pump-probe heating scheme in which H2O was heated above its melting temperature before the observation of quenched crystalline states, based on the earlier theoretical prediction that SI-bcc nucleates more readily from the fluid than SI-fcc. Our results may have implications for the stability of SI phases in ice-rich planets, for example during dynamic freezing, where the preferential crystallization of SI-bcc may result in distinct physical properties across mantle ice layers.

Immuntherapien zählen zu den vielversprechendsten neuartigen Ansätzen zur Behandlung von Krebserkrankungen. Ihr Ziel ist es, die Limitationen konventioneller Therapien zu überwinden, indem sie Zellen des Immunsystems reaktivieren und Tumorzellen auf diese Weise hoch spezifisch sowie effizient eliminieren. Dabei konnten insbesondere mit CAR T-Zellen enorme Fortschritte in der Immuntherapie liquider Tumorerkrankungen erzielt werden. CARs sind artifizielle Rezeptoren, die aus drei wesentlichen Komponenten aufgebaut sind: (i) eine Tumorantigen-bindende scFv-basierte EZD, (ii) eine TMD sowie (iii) eine intrazelluläre Signaldomäne. Letztere besteht häufig aus einer aktivierenden, signalgebenden (z. B. CD3z) sowie kostimulatorischen (z. B. CD28 oder CD137) Domäne. Die Ausstattung humaner T-Zellen mit CARs erlaubt die spezifische Erkennung von Tumorantigenen unabhängig vom endogenen TZR. Die Erkennung Zielantigen-präsentierender Tumorzellen resultiert in der spezifischen Aktivierung der CAR T-Zelle sowie die daraus folgende zytotoxische Elimination der Tumorzellen. Die klinische Zulassung von bislang sechs CAR T-Zellprodukten hat zur Entwicklung neuer, experimenteller CAR T-Zelltechnologien geführt, um u. a. die Expansion, Zytokinsekretion, Zytotoxizität und in vivo Persistenz von CAR T-Zellen zu optimieren. Dabei gibt es insbesondere auch großes Interesse an der Entwicklung sogenannter Adapter CAR Plattformen, um die Flexibilität, Tumor-spezifität sowie Kontrollierbarkeit von CAR T-Zelltherapien zu verbessern. Ziel dieser Ansätze ist es, die Tumorantigen-Bindedomäne von der intrazellulären Signaldomäne des CARs auf zwei Komponenten aufzuteilen, um die Aktivierung des CARs über Adaptermoleküle zu steuern. Adapter CARs, wie z. B. die in der AG Bachmann entwickelte UniCAR Plattform, weisen durch ihren modularen Aufbau wesentliche Vorteile, wie beispielsweise eine erhöhte Kontrollierbarkeit durch Dosierung der
Adaptermoleküle sowie Flexibilität in Hinblick auf die Antigenspezifität auf. Die entwickelten Ansätze nutzen allerdings mehrheitlich scFv-basierte Adapter CARs. Eine scFv-basierte EZD, wie sie auch in konventionellen CARs verwendet wird, kann zu tonischer Signalgebung führen. In der Folge werden CAR T-Zellen konstitutiv aktiviert und es kann im Patienten zu einer verringerten Persistenz der T-Zellen sowie Beeinträchtigung der antitumoralen Antwort kommen. Eine weitere Herausforderung der CAR T-Zelltherapie ist die Tumorspezifität. Die meisten Zielstrukturen von konventionellen sowie Adapter CARs sind TAAs. Diese werden in geringem Maß auch auf gesunden Zellen präsentiert, sodass die Anwendung von konventionellen und Adapter CAR T-Zellen ein Risiko für on target, off-tumor Toxizität birgt. Um die Tumorspezifität zu erhöhen, werden derzeit u. a. gated Targetingstrategien mit UND Logik evaluiert. Das Prinzip dieser Ansätze ist es, die signalgebende sowie kostimulatorische Domäne eines CARs auf zwei separate CARs mit unterschiedlicher Spezifität aufzuteilen und somit eine vollumfängliche Aktivierung von CAR T-Zellen nur dann zu vermitteln, wenn beide Zielantigene auf Tumorzellen präsentiert und erkannt werden. Der Erfolg dieser Ansätze wird durch den scFv-basierten CAR Aufbau jedoch durch gleich zwei Faktoren beeinträchtigt: einerseits limitiert die Größe der CAR Transgene die Transduktionseffizienz bei simultaner Ausstattung von T-Zellen mit zwei CARs, andererseits besteht weiterhin die Gefahr tonischer Signalgebung.
Unter Berücksichtigung dieser Kriterien wurde in der vorliegenden Dissertation die alternative, modulare RevCAR Plattform zum universellen Einsatz in der Tumorimmuntherapie entwickelt. Im Gegensatz zu konventionellen CARs oder UniCARs tragen RevCARs im extrazellulären Bereich keine scFv-Domäne, sondern eines der beiden Peptidepitope E5B9 oder E7B6. Beide Epitope stammen vom humanen nukleären La/SS-B Protein und resultieren durch ihre Länge von nur 10 bzw. 18 AS in einer signifikant verkürzten EZD in RevCARs. Damit einhergehend weisen RevCAR-kodierende Gene eine starke Reduktion im Vergleich zu Genen konventioneller scFv-basierter CARs auf. Es wurden E5B9- und E7B6-spezifische RevCAR Konstrukte mit CD3z Signaldomäne und CD28 KoD, sowie STOP RevCARs ohne intrazelluläre Signaldomäne als Kontrolle generiert. Zur Kreuzvernetzung RevCAR-armierter
T-Zellen mit TAA+ Tumorzellen bedarf es der Anwesenheit von Adaptermolekülen. Zu diesem Zweck wurden im Rahmen der Dissertation RevTMs generiert. RevTMs sind rekombinante bsAk, bei denen sich eine Bindedomäne jeweils gegen das RevCAR Peptidepitop E5B9 oder E7B6 richtet, während die andere Bindedomäne eines der beiden Prostatakarzinom-TAAs PSCA oder PSMA erkennt. Die RevTM-vermittelte Kreuzvernetzung von RevCAR-armierten T-Zellen mit TAA+ Tumorzellen resultiert in der spezifischen Aktivierung der RevCAR T-Zellen. Dies hat sowohl in vitro, als auch in vivo im Xenotransplantat-Mausmodell die effiziente zytotoxische Eliminierung von Tumorzellen zur Folge, welche strikt Peptidepitop- sowie TAA-spezifisch erfolgt. Zur Zytolyse der Tumorzellen nutzen RevCAR T-Zellen sowohl die Interaktion von Todesliganden wie TRAIL und FasL mit den entsprechenden Todesrezeptoren, als auch die Sekretion von Perforin und Granzym B. Darüber hinaus resultiert die spezifische Aktivierung der RevCAR T-Zellen in der Sekretion proinflammatorischer und proliferationsfördernder Zytokine. Die antitumorale Antwort der RevCAR T-Zellen ist dabei über die Dosierung der RevTM Konzentration ein- und ausschaltbar bzw. steuerbar. Durch die Gabe von RevTMs mit unterschiedlicher TAA-Spezifität kann die flexible RevCAR Plattformtechnologie für eine gated Targetingstrategie mit ODER Logik genutzt werden und ist darüber hinaus breit anwendbar gegen verschiedenste Tumorantigene und Tumorerkrankungen.
Zusätzlich zu den RevCARs E5B9-28/3z und E7B6-28/3z wurden auch Konstrukte mit CD137 KoD generiert, um zu evaluieren, in welchem Maß die Wahl der KoD die Funktionalität von RevCAR T-Zellen beeinflusst. RevCAR E5B9-137/3z und E7B6-137/3z T-Zellen konnten TAA+ Tumorzellen mit vergleichbarer Spezifität und Effizienz wie CD28-basierte RevCAR T-Zellen eliminieren. Insgesamt zeigten CD28- und CD137-basierte RevCAR T-Zellen in Hinblick auf T-Zell-Aktivierung sowie Differenzierung zu spezialisierten Gedächtnispopulationen und die Sekretion proinflammatorischer bzw. proliferationsfördernder Zytokine eine vergleichbare Funktionalität. Lediglich in Hinblick auf die Proliferation und Expansion der T-Zellen zeigten RevCARs mit CD28 KoD eine geringfügige Überlegenheit im Vergleich zu CD137-basierten RevCARs. Im Einsatz gegen solide Tumore wie dem Prostatakarzinom, welches im Rahmen der vorliegenden Dissertation im Fokus stand, ist die Wirksamkeit von CAR T-Zelltherapien u. a. durch das immunsuppressive Mikromilieu meist stark limitiert. Um dies zu überwinden, wurde die stärkere Kostimulation durch CD28 als vorteilhaft angesehen.
Trotz großer Erfolge ist die konventionelle CAR T-Zelltherapie oft mit lebensbedrohlichen Nebenwirkungen, wie z. B. on-target, off-tumor Effekten gegen gesundes Normalgewebe assoziiert. Um die Tumorspezifität der CAR T-Zelltherapie zu erhöhen, wurden gated Targetingstrategien nach dem Prinzip der UND Logik entwickelt. Dabei werden T-Zellen mit zwei unterschiedlichen CARs ausgestattet, sodass die Tumorzellen ausschließlich nach Erkennung von zwei unterschiedlichen Antigenen eliminiert werden. RevCARs zeichnen sich durch eine stark verkürzte EZD aus und basieren daher auf kurzen RevCAR-kodierenden Genen. Diese Voraussetzungen begünstigen die Generierung von dualen RevCAR T-Zellen (bzw. einer RevCAR Plattform) zum gated Targeting von Prostatakarzinomzellen nach dem Prinzip der UND Logik. Zu diesem Zweck wurden T-Zellen simultan mit zwei RevCARs unterschiedlicher Spezifität ausgestattet, die unterschiedliche Signale (einerseits die signalgebende CD3z und andererseits die kostimulatorische CD28 Domäne) vermitteln. Um das ideale SIG und COS Rezeptorpaar zu identifizieren, wurde eine Vielzahl unterschiedlicher RevCARs basierend auf verschiedenen Struktureinheiten neu generiert und in Kombination miteinander getestet.
Entscheidend war dabei, dass SIG und COS RevCARs keine Heterodimere bilden, um einen cross-talk zwischen beiden Rezeptoren zu verhindern und zu gewährleisten, dass das CD3z und CD28 Signal nach Erkennung unterschiedlicher Tumorantigene getrennt voneinander vermittelt werden. Gleichzeitig musste gewährleistet werden, dass eine komplette Aktivierung der RevCAR T-Zellen ausschließlich infolge beider Signale (und nicht bereits nach Vermittlung eines der beiden Signale allein) erfolgte. Hier erwies sich die schwächere Expression der SIG RevCARs infolge der Einführung der HiD des humanen IgG4 sowie der TMD vom humanen CD4 als vorteilhaft für die Implementierung der UND Logik. In dieser Arbeit ist es gelungen, eine neuartige RevCAR Plattform zum gated Targeting nach dem Prinzip der UND Logik am Beispiel des Prostatakarzinoms zu entwickeln. RevCAR T-Zellen mit dualer Spezifität
wurden sowohl durch Ko-Transduktion des COS und SIG RevCARs, als auch durch Transduktion eines bicistronischen Vektors, der gleichzeitig für COS und SIG RevCAR kodiert, generiert. Infolge des gated Targetings von PSCA und PMSA durch gleichzeitige RevTM-vermittelte Stimulation von COS und SIG RevCAR, zeigten bispezifische RevCAR T-Zellen eine gesteigerte Aktivierung, Zytotoxizität, Zytokinsekretion sowie Proliferation und Expansion. Dabei wurde beobachtet, dass die Generierung dualer E7B6-3z-E5B9-28 RevCAR T-Zellen infolge der Transduktion mit dem bicistronischen Vektor in einer verstärkten Expression des COS RevCARs resultiert. Dies wirkte sich vorteilhaft auf die strikte Implementierung der UND Logik aus. Duale E7B6-3z-E5B9-28 RevCAR T-Zellen wurden ausschließlich infolge des simultanen Targetings von PSCA und PSMA zu einer effizienten T-Zell-Aktivierung und
Zytokinsekretion sowie Tumorzellelimination angeregt. Die Analysen haben demonstriert, dass duale RevCAR T-Zellen entsprechend den Regeln der booleschen Algebra programmierbar sind und sich zur Anwendung einer gated Targetingstrategie mit UND Logik eignen. Zusammenfassend wurde in dieser Arbeit erstmalig die neue Adapter RevCAR Plattformtechnologie entwickelt, die ein- und ausschaltbar, vielseitig anwendbar und programmierbar ist, um eine effiziente, tumorspezifische und sichere personalisierte Immuntherapie von Tumorerkrankungen zu ermöglichen.

Resonant inelastic x-ray scattering (RIXS) is a widely used spectroscopic technique, providing access to the electronic structure and dynamics of atoms, molecules, and solids. However, RIXS requires a narrow bandwidth x-ray probe to achieve high spectral resolution. The challenges in delivering an energetic monochromated beam from an x-ray free electron laser (XFEL) thus limit its use in few-shot experiments, including for the study of high energy density systems. Here we demonstrate that by correlating the measurements of the self-amplified spontaneous emission (SASE) spectrum of an XFEL with the RIXS signal, using a dynamic kernel deconvolution with a neural surrogate, we can achieve electronic structure resolutions substantially higher than those normally afforded by the bandwidth of the incoming x-ray beam. We further show how this technique allows us to discriminate between the valence structures of Fe and Fe2O3, and provides access to temperature measurements as well as M-shell binding energies estimates in warm-dense Fe compounds.

Extensive efforts have been done in the area of immunotherapies to develop approaches that restore the ability of immune cells to recognize and eliminate malignant cells. These strategies range from the use of antibodies to the genetic modification of immune cells with cytotoxic potential. A strategy with great potential is T cell engineering with chimeric antigen receptors (CARs), which allows T cell redirection to recognize and eliminate cells expressing a certain tumor-associated antigen (TAA). Although CAR T cells have shown astonishing results in the treatment of CD19+ B-cell malignancies, their success targeting other TAAs has been overshadowed by life-threating adverse effects experienced by patients. Two main causes for such dangerous side-effects are the lack of control over the activity of the CAR T cells once they are administered to the patient and the fact that certain TAAs can also commonly be expressed on non-malignant cells. This results in an unspecific and uncontrolled ablation of healthy tissue. Aiming to address these relevant flaws of conventional CAR T cells and to develop a safer and more specific approach, the group of Prof. Bachmann and Dr. Feldmann developed the adaptor RevCAR system. Compared to conventional CAR T cells, RevCAR T cells do not display a scFv on their surface but a peptide epitope (E5B9 or E7B6) derived from the nuclear protein La-SS/B. Therefore, RevCAR T cells remain inert and their ability to recognize a cancer cell depends on the presence of a reverse target module (RevTM). The structure of a RevTM is similar to a bispecific antibody (bsAb), recognizing and binding
simultaneously to the peptide epitope on the RevCAR T cell and to a specific TAA. The crosslinking of cancer cells and RevCAR T cells mediated by the RevTM promotes the activation of
the modified T cells and the subsequent killing of the target cells. The RevCAR system represents a safer approach because the modified T cells can be reversely switched on and
off after their infusion into the patient, which allows the management of secondary effects upon their onset. Moreover, the targeted TAA can be easily exchanged by the administration of
different RevTMs without the need to re-engineer the T cells, which can be very practical if cancer cells downregulate the targeted TAA. Yet, the risk of “on-target, off-tumor” toxicities is
not completely circumvented by the RevCAR system. Aiming to increase the specificity of the CAR T cell killing potential towards tumor cells, multiple CAR technologies have been
developed, incorporating Boolean logic circuits (AND, OR, NOT). In this line of thought, the group of Prof. Bachmann and Dr. Feldmann further developed the RevCAR system to be
governed by an AND-gate Boolean logic. This new platform termed as Dual-RevCAR system incorporates two types of RevCARs: the signaling (SIG) RevCARs triggering the CD3 signal
and the co-stimulatory (COS) RevCARs triggering the CD28 signal. Only their simultaneous cross-linking with cancer cells via RevTMs can promote a full activation of the modified Dual-
RevCAR T cells. This allows a combinatorial targeting of tumor cells expressing two TAAs and should spare those cells lacking of a specific TAA expression pattern and thus reducing the
risk of “on-target, off-tumor” toxicities. The present work aims to demonstrate that the Dual-RevCAR system can be used for the targeting of hematological malignancies, like acute myeloid leukemia (AML), as well as, solid tumors like colorectal cancer (CRC). The AML-related antigens CD33 and CD123 were chosen as targets and existing anti-CD33 and anti-CD133 RevTMs were used. In vitro functional assays revealed that only the simultaneous presence of anti-CD33 and anti-CD123 RevTMs promoted the secretion of proinflammatory cytokines by Dual-RevCAR T cells and specific killing of CD33+ CD123+ cancer cells. Besides immortalized AML target cell lines, which have their limitations to recapitulate the high heterogenicity observed in samples of AML patients, Dual-RevCAR T cells were also able to eliminate AML patient-derived blasts following a true AND-gate targeting.
To further prove that the RevCAR system can also be used to precisely recognize and eliminate solid tumors, this thesis focuses also on the targeting of CRC. Since the structure of
the RevTMs has a direct effect on certain properties, such as biodistribution and pharmacokinetics, and considering that different formats could be useful at diverse time points
during treatment, a novel monomeric scFv-based and a homodimeric IgG4-based RevTMs targeting the carcinoembryonic antigen (CEA) were developed. In vitro and in vivo functional
assays showed that both RevTM formats successfully redirect RevCAR T cells towards CEA+ malignant cells in an antigen-specific and RevTM-dependent manner, which results in the
secretion of proinflammatory cytokines and killing of target cells. Although both RevTMs showed high efficiency in a dose-dependent manner, the EC50 value from RevTM CEA-IgG4-
7B6 was in the picomolar range, whereas the one from RevTM CEA-7B6 was in the nanomolar range. In addition, results demonstrate that the RevTM CEA-IgG4-7B6 promoted enhanced
cytokine secretion and a more robust effect in preventing tumor growth than the RevTM CEA-7B6. To further increase the precision of CRC targeting, a novel Dual-RevCAR system was
established targeting the epithelial cell adhesion molecule (EpCAM) in combination with CEA following an AND-gate logic. Therefore, two novel and structurally different anti-EpCAM
RevTMs were created: an IgG1-based and a minibody (Mb)-based format. In vitro and in vivo assays validated that only the simultaneous presence of RevTM CEA-IgG4-7B6 and either
anti-EpCAM RevTM triggered the specific elimination of CEA+ EpCAM+ malignant cells along with cytokine secretion. Moreover, phenotyping of Dual-RevCAR T cells after a first short-term challenge showed that the modified T cells mainly retained a non-exhausted TCM phenotype.
Taken together, this thesis demonstrates the remarkable potential of the Dual-RevCAR system to target diverse cancer entities following a true AND-gate Boolean logic, which represents a
safer approach circumventing off-target toxicities. Moreover, the adaptor nature of the system allows a quick switch on/off and a flexible targeting of different TAAs without re-engineering of
the T cells.

Optimizing grain boundary characteristics in polycrystalline materials can improve their properties. Many processing methods have been developed for grain boundary manipulation, including the use of intense radiation in certain applications. In this work, we used X-ray free electron laser pulses to irradiate single-crystalline bismuth selenide (Bi2Se3) and observed grain boundary formation and subsequent grain rotation in response to the X-ray radiation. Our observations with simultaneous transmission X-ray microscopy and X-ray diffraction demonstrate how intense X-ray radiation can rapidly change size and texture of grains.

Recently, we established the controllable modular UniCAR platform technology to advance the
efficacy and safety of CAR T cell therapy. The UniCAR system is composed of (i) target
modules (TMs) and (ii) UniCAR armed T cells. TMs are bispecific molecules that are able to
bind to the tumor cell surface and simultaneously to UniCAR T cells. For interaction with
UniCAR T cells, TMs contain a peptide epitope sequence which is recognized by UniCAR T
cells. So far, a series of TMs against a variety of tumor targets including against the prostate
stem cell antigen (PSCA) were constructed and functionally characterized. In order to facilitate
their purification all these TMs are expressed as recombinant proteins equipped with an oligo-
His-tag. The aim of the here presented manuscript was to learn whether or not the oligo-His-
tag of the TM influences the UniCAR system. For this purpose, we constructed TMs against
PSCA equipped with or lacking an oligo-His-tag. Both TMs were compared side by side
including for functionality and biodistribution. According to our data, an oligo-His-tag of a
UniCAR TM has only little if any effect on its binding affinity, in vitro and in vivo killing capability
and in vivo biodistribution.

Abstract
T-cell Acute Lymphoblastic Leukemia (T-ALL) is characterized by aggressive proliferation of
malignant T cells. It accounts for a pronounced percentage of around 25% of ALL in adult and
pediatric cases. Despite the advances in treatment, conventional T-ALL therapies like
chemotherapy remain with high relapse rates. Thus, there is the need for an alternative
treatments. CAR T cell therapy emerges as a promising approach, however faces its challenges
with T-ALL. In general, CAR T cell therapy associated with toxicities like cytokine release
syndrome (CRS) and neurotoxicity. In the case of treating T-ALL with CAR T cells, an
additional challenge is posed by tumor cells sharing surface markers with T cells, raising
further issues like fratricide and T cell aplasia. To overcome such limitations and risks posed
by conventional CAR T cell therapy, modular CAR T cell systems, for T-ALL in specific,
present a compelling treatment option as it may limit the fratricide, and mainly because it can
be switched off, thus long term destruction of T cells could be avoided. Therefore, the primary
aim of this thesis is to utilize the modular UniCAR T cell system to target CD7, a surface
antigen overexpressed in T-ALL. The objective is to evaluate the in vitro efficacy as a potential
therapeutic option for T-ALL. In this project, UniCAR T cells could be successfully redirected
towards CD7-expressing T-ALL cell lines via four different TMs; single chain fragment
variable (scFv)-based and IgG4-based; each with a murine version and a humanized version of
the TM. Purified TMs showed binding to CD7 on tumor cell lines and successful tumor cell
lysis was achieved with negligible fratricide. Given the results, the UniCAR T cell platform
confirms potential of targeting CD7 expressing tumor cells while also addressing the
limitations of conventional CAR T cell therapy. Offering a new scope of T-ALL targeted
therapy.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer. The survival rate of PDAC is
extremely low. For treatment of PDAC still an urgent unmet clinical need exists to develop novel
innovative treatment options. An improved understanding of the genetics of PDAC has lead to the new
targeted and immune based therapies that are available to improve the survival and quality of life. There
have been several advancements that have been made in the field of cancer immunotherapy in recent
years. The development of the chimeric antigen receptor (CAR) became a revolutionary idea in cancer
treatment. Exemplary treatment efficacy was showcased by the genetically engineer CAR-T cells given
to the patients by adoptive transfer. However, there are certain barriers such as severe life-threatening
toxicities such as Cytokine release syndrome (CRS) and Tumor lysis syndrom (TLS), antigen escape,
restricted trafficking, and limited tumor infiltration of the T-cells. To overcome these limitations,
adapter CAR-T cells were developed which specifically target the tumor cells in the presence of adapter
molecules. In this study the modular adapter UniCAR-T-cell system was employed which has been
preclinically validated and even shown successful anti-tumor responses in cancer patients.

In this study, we focused on the target antigen ICA512, also known as Islet cell autoantigen 512, which
belongs to a family of receptor-type protein tyrosine phosphatase (PTPs) associated with Type 1
diabetes are known to be expressed in pancreatic beta cells. Recent studies showed that any disruptions
in these regulatory pathways lead to uncontrolled cell growth in pancreatic and glioblastoma cancer
cells. Several monoclonal antibodies (mAbs) are available to target ICA512. Here we used the murine
mAb anti-ME1-ICA512 to generate a novel TM to target ICA512 on cancer cells by the UniCAR-T-
cell system and analyzed its functionality in vitro. Therefore, in this thesis the novel ICA512-specific,
IgG4-based UniCAR TM, named as anti-ICA512-IgG4-E5B9 TM, was cloned, produced and
characterized in vitro. For proof of concept, cancer cell lines were used as a robust cellular test model
that stably overexpress ICA512. It was shown that the anti-ICA512-IgG4-E5B9 TM specifically binds
to the ICA512-positive cancer cells as well as to the UniCAR-T cells. Remarkably, this study
demonstrate that the novel anti-ICA512-IgG4-E5B9 TM can specifically and efficiently redirect
UniCAR-T-cells to kill ICA512-expressing cancer cell lines in vitro. In principle, these data provide a
proof of concept that ICA512 cancer cells can be immunotherapeutically targeted by the UniCAR
approach and thus ICA512 might be a suitable target for tumor immunotherapy.

Der hohe Energiebedarf thermischer Trennverfahren erfordert eine stetige Weiterentwicklung der Einbauten, um den übergeordneten Zielen zur Energieeinsparung näher zu kommen. In Bodenkolonnen betrifft dies unter anderem Ventilböden mit Fixed Valves, bei denen im Gegensatz zu den in der Literatur bereits ausführlich untersuchten Siebböden noch großes Forschungspotential besteht.

Einen wichtigen Einfluss auf die Fluiddynamik von Böden hat das Strömungsverhalten der Flüssigkeit auf dem Boden, das maßgeblich durch die verschiedenen Bodenelemente beeinflusst wird. Die experimentelle Untersuchung der Strömung auf Kolonnenböden ist Bestandteil von einigen Untersuchungen in der Literatur, welche jedoch häufig nur auf qualitativen Beobachtungen des Strömungsverhaltens basieren.

Im Rahmen des IGF-Vorhabens "Werkzeuge und Methoden zur verbesserten fluiddynamischen Auslegung von Querstromböden mit Hochleistungsventilen" wurde am Helmholtz-Zentrum Dresden-Rossendorf (HZDR) ein Tracer-Feldsensor entwickelt, der mithilfe von 360 Leitfähigkeitssonden das Strömungsverhalten auf einer parallelen Ebene über dem Boden ortsaufgelöst erfassen kann. Die eigens dafür entwickelte Sondengeometrie ermöglicht eine zuverlässige Messung der auf dem Boden vorliegenden Flüssigkeitsströmung. Beim eingespeisten Tracer handelt es sich um eine Natriumsulfat-Lösung, die über eine entsprechende Vorrichtung über die ganze Breite des Schachts eingespeist wird. Basierend auf der anschließenden Auswertung lässt sich das Strömungsverhalten in Bezug auf die mittlere Punktverweilzeit, die mittlere Varianzverteilung sowie die unidirektionalen Geschwindigkeiten auf dem Boden charakterisieren.

Die Messungen wurden in einem Gas/Flüssig-Kolonnenversuchsstand am Lehrstuhl für Anlagen- und Prozesstechnik der TU München durchgeführt, der einen Durchmesser von 1,2 m aufweist und mit dem Stoffsystem Luft/Wasser betrieben wurde. Vermessen wurden verschiedene Konfigurationen von Sieb- und Fixed-Valve-Böden mit und ohne Push Valves, die unter Berücksichtigung von relevanten in der Industrie eingesetzten Ventiltypen ausgewählt wurden. Zusätzlich wurden Variationen in der Wehrhöhe und -geometrie durchgeführt.

Die Ergebnisse der Untersuchungen mit dem Tracer-Sensor ermöglichen detaillierte Aussagen zum Strömungsverhalten verschiedener Bodenkonfigurationen bei unterschiedlichen Belastungszuständen. Zudem konnten mit dem im letzten Jahr vorgestellten Sensor zur Messung der Phasenverteilung umfassende Untersuchungen zum Aufbau der Zweiphasenschicht durchgeführt werden. Durch die Verknüpfung der Messergebnisse beider Sensoren können abschließend wertvolle Aussagen zum fluiddynamischen Verhalten der untersuchten Böden getroffen werden.

A new AMS system called HAMSTER (Helmholtz Accelerator Mass Spectrometer Tracing Environmental Radionuclides) will be installed in Dresden-Rossendorf to expand the capabilities of radionuclide measurements at HZDR. It consists of a 1MV pelletron tandem accelerator and has a conventional ion source for classic AMS operation and two additional injection lines: One injection line holds an ion cooler for additional purposes of isobar suppression (Ion Linear Trap for Isobar Suppression ILTIS), the other is a SIMS (Secondary Ion Mass Spectrometer) moved from its original 6MV DREAMS facility to perform Super-SIMS measurements at the new machine.
The facility will be placed in a new building that holds space for the experimental area and control room of the AMS as well as for two
chemistry laboratories. Installation of the first injector beamline with the ILTIS is foreseen for early 2024 and we expect HAMSTER to be
in operation by summer. In this contribution we will introduce the surrounding infrastructure and layout of the new facility.

As nickel (Ni), cobalt (Co), and scandium (Sc) play crucial roles in driving essential technologies for sustainable energy and transportation, Indonesian laterites have emerged as prominent sources for these metals. In the present case study, new geological data on the laterites from Sebuku Island (SE Kalimantan, Indonesia) are presented.
The Sebuku ore deposits extend over an area of more than 30 km2 and contain a JORC-compliant resource of ~390 Mt at 42.5 wt.% Fe, 0.9 wt.% Ni, and 0.15 wt.% Co. Orebodies are mostly limonitic and oxide-dominated. They are formed by weathering of Jurassic-Cretaceous ophiolites. Despite mining has been underway since 2006 (primarily for iron ore), limited mineralogical and geochemical data exist, hindering the optimization of beneficiation processes and the recovery of critical metals.
Typical laterite profiles at Sebuku include a weathered bedrock composed of serpentinized dunites and harzburgites, overlain by a saprolite zone ranging from 0.2 to 7 meters thick, a yellow limonite zone spanning 2 to 8.5 meters, and a red-limonite zone measuring 1 to 3.5 meters thick. These soil horizons exhibit complex relationships among themselves, characterized by irregular boundaries, lenticular beds, and lateral variations.
X-ray diffraction (XRD) and mineral liberation analysis (MLA) data reveal a complex ore mineralogy, encompassing oxides and oxi-hydroxides such as goethite, gibbsite/bayerite, chromite, various iron oxides (maghemite, hematite, magnetite), manganese minerals (asbolane and lithiophorite), and silicates comprising serpentine/talc, chlorite, pyroxene, garnet, quartz, and smectites. Combined MLA, electron probe microanalysis (EPMA), and X-ray fluorence (XRF) allowed to determine the deportment of Ni, Co, and Sc in those minerals.
Based on these new findings, beneficiation strategies were developed, with the ultimate goal of enhancing the efficiency of the existing processing flowchart.

Indonesian laterites are a major global source of nickel (Ni) and cobalt (Co). Here, we present new geological data on the laterites from Sebuku Island (SE Kalimantan, Indonesia). The ore deposits at Sebuku extend over an area of more than 30 km2 and contain a resource of ~390 Mt at 42.5 wt.% Fe, 0.9 wt.% Ni, and 0.15 wt.% Co. They are mostly limonitic, oxide-dominant Fe-Ni-Co-rich bodies, which formed by weathering of Jurassic-Cretaceous ophiolites. Although the Fe ore has been mined since 2006, little mineralogical and geochemical data are available, which would allow for optimization of beneficiation and recovery of Ni, Co, and scandium (Sc).
Typical laterite profiles at Sebuku consist of: 1) weathered bedrock mainly composed of serpentinites overlain by 2) a 0.2-7 m-thick saprolite zone, 3) a 2-8.5 m-thick yellow limonite zone, and 4) a 1-3.5 m-thick red-limonite zone. These horizons show complex relationships between each other.
XRF analysis shows a decrease in Mg and Si and an increase in Fe moving upwards through the laterite profile. Scandium concentrations are locally high (up to ~120 ppm in some samples), highlighting its potential as a by-product. XRD and mineral liberation analysis (MLA) data show a complex ore assemblage, which includes oxides and (oxi)-hydroxides such as goethite, maghemite, hematite, magnetite, chromite, gibbsite/bayerite, and various Mn-minerals, and silicates consisting of serpentine, chlorite, talc, quartz, pyroxene, garnet, and smectites. Critical metal deportment was calculated through MLA, coupled with electron probe microanalysis (EPMA): Ni is hosted by various minerals, including goethite, Mn-hydroxides, Fe-oxides, serpentine, and smectites, whereas Co is mainly hosted by Mn-hydroxides. It is still unclear in which minerals Sc is primarily hosted.
On the basis of these results, new beneficiation concepts will be developed, which are ultimately aimed at improving the efficiency of the current processing flowsheet.

The Gorno mining district is an example of Mississippi Valley-type (MVT) deposit in the Italian Orobic Alps. It consists of stratabound Zn-Pb-Ag (± fluorite ± barite) mineralization extending for over ~100 km2. A complex series of dolomitization, silicification, brecciation, dissolution, and cementation phenomena affected the lower Carnian stratigraphic succession in the region. Here, high-grade sulfide ore is hosted in the basal portion of the Gorno Formation, consisting of a few meters-thick interval of clay-rich sediments known as “black shales”. Other major orebodies are hosted in the underlying peritidal limestones of the Breno and Calcare Metallifero Bergamasco formations. Mineralization types encompass replacements, dissolution cavity fillings, and breccia cements.

Microthermometry of primary fluid inclusions in dolomite, sphalerite, and fluorite, integrated with sphalerite trace-element geothermometry, allow to infer moderately hot formation temperatures. Moreover, fluid inclusion data (supported by Raman spectroscopy data) document the involvement of high-salinity brines and gaseous hydrocarbons in ore deposition. The isotopic values of carbon, oxygen, and strontium indicate that the ore fluid likely originated as seawater and modified through contact with the underlying Permian clastic sediments and/or with the metamorphic basement.

The association of sulfide bodies with organic-rich shales imply a notable role of organic carbon in ore deposition. Organic matter and associated hydrocarbons likely served as reactive barriers, leading to the reduction of the ore fluid and initiating the precipitation of sulfide minerals.