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The subject of this thesis is the experimental investigation of the neutron-capture cross sections of the neutron-rich, short-lived boron isotopes 13B and 14B, as they are thought to influence the rapid neutron-capture process (r process) nucleosynthesis in a neutrino-driven wind scenario.
The 13;14B(n,g)14;15B reactions were studied in inverse kinematics via Coulomb dissociation at the LAND/R3B setup (Reactions with Relativistic Radioactive Beams). A radioactive beam of 14;15B was produced via in-flight fragmentation and directed onto a lead-target at about 500 AMeV. The neutron breakup of the projectile within the electromagnetic field of the target nucleus was investigated in a kinematically complete measurement. All outgoing reaction products were detected and analyzed in order to reconstruct the excitation energy.
The differential Coulomb dissociation cross sections as a function of the excitation energy were obtained and first experimental constraints on the photoabsorption and the neutron-capture cross sections were deduced. The results were compared to theoretical approximations of the cross sections in question. The Coulomb dissociation cross section of 15B into 14B(g.s.) + n was determined to be s(15B;14B(g:s:)+n) CD = 81(8stat)(10syst) mb ; while the Coulomb dissociation cross section of 14B into a neutron and 13B in its ground state was found to be s(14B;13B(g:s:)+n) CD = 281(25stat)(43syst) mb: Furthermore, new information on the nuclear structure of 14B were achieved, as the spectral shape of the differential Coulomb dissociation cross section indicates a halolike structure of the nucleus.
Additionally, the Coulomb dissociation of 11Be was investigated and compared to previous measurements in order to verify the present analysis. The corresponding Coulomb dissociation cross section of 11Be into 10Be(g.s.) + n was found to be 450(40stat)(54syst ) mb, which is in good agreement with the results of Palit et al.
One of the most important events in human history occurred during the Early Pleistocene: the dispersal of early hominins out of Africa and into Europe and Asia. In Western Europe, the earliest evidences of the genus Homo have been found in the Baza Basin, at the sites of Orce in the SE of the Iberian Peninsula. These sites contain fossils and lithic industry dated approximately as 1.4–1.3 Ma.While hominin remains and artifacts at Orce, as well as the accompanying fauna, have been extensively studied, the properties and evolution of the Early Pleistocene vegetation in the basin remain unknown. The general effect of climate change on the expansion of early hominins from Africa into Eurasia still remains unclear. It is not known if the Early Pleistocene climate changes and the development of glacials periods led to the extirpation of European communities, or if those communities were able to endure and persist through such adverse climatic periods. This open question highlights the need for climate and environmental analyses for the time before, during and after the first presence of Homo in Europe. This PhD thesis contributes to that need by the presentation of the first long pollen record of the Baza Basin, where the oldest hominin sites in Western Europe are found.
This work presents a contribution to the literature on methods in search of lowdimensional models that yield insight into the equilibrium and kinetic behavior of peptides and small proteins. A deep understanding of various methods for projecting the sampled configurations of molecular dynamics simulations to obtain a low-dimensional free energy landscape is acquired. Furthermore low-dimensional dynamic models for the conformational dynamics of biomolecules in reduced dimensionality are presented. As exemplary systems, mainly short alanine chains are studied. Due to their size they allow for performing long simulations. They are simple, yet nontrivial systems, as due to their flexibility they are rapidly interconverting conformers. Understanding these polypeptide chains in great detail is of considerable interest for getting insight in the process of protein folding. For example, K. Dill et al. conclude in their review [28] about the protein folding problem that "the once intractable Levinthal puzzle now seems to have a very simple answer: a protein can fold quickly and solve its large global optimization puzzle simply through piecewise solutions of smaller component puzzles".
The ALICE High-Level-Trigger (HLT) is a large scale computing farm designed and constructed for the purpose of the realtime reconstruction of particle interactions (events) inside the ALICE detector. The reconstruction of such events is based on the raw data produced in collisions inside the ALICE at the Large Hadron Collider. The online reconstruction in the HLT allows the triggering on certain event topologies and a significant data reduction by applying compression algorithms. Moreover, it enables a real-time verification of the quality of the data.
To receive the raw data from the various sub-detectors of ALICE, the HLT is equipped with 226 custom built FPGA-based PCI-X cards, the H-RORCs. The H-RORC interfaces the detector readout electronics to the nodes of the HLT farm. In addition to the transfer of raw data, 108 H-RORCs host 216 Fast-Cluster-Finder (FCF) processors for the Time-Projection-Chamber (TPC). The TPC is the main tracking detector of ALICE and contributes with up to 16 GB/s to over 90% of the overall data volume. The FCF processor implements the first of two steps in the data reconstruction of the TPC. It calculates the space points and their properties from charge clouds (clusters) created by charged particles traversing the TPCs gas volume. Those space points are not only the base for the tracking algorithm, but also allow for a Huffman-based data compression, which reduces the data volume by a factor of 4 to 6.
The FCF processor is designed to cope with any incoming data rate up to the maximum bandwidth of the incoming optical link (160 MB/s) without creating back-pressure to the detectors readout electronics. A performance comparison with the software implementation of the algorithm shows a speedup factor of about 20 compared with one AMD Opteron 6172 Core @ 2.1 GHz, the CPU type used in the HLT during the LHC Run1 campaign. Comparison with an Intel E5-2690 Core @ 3.0 GHz, the CPU type used by the HLT for the LHC Run2 campaign, results in a speedup factor of 8.5. In total numbers, the 216 FCF processors provide the computing performance of 4255 AMD Opteron cores or 2203 Intel cores of the previously mentioned type. The performance of the reconstruction with respect to the physics analysis is equivalent or better than the official ALICE Offline clusterizer. Therefore, ALICE data taking was switched in 2011 to FCF cluster recording and compression only, discarding the raw data from the TPC. Due to the capability to compress the clusters, the recorded data volume could be increased by a factor of 4 to 6.
For the LHC Run3 campaign, starting in 2020, the FCF builds the foundation of the ALICE data taking and processing strategy. The raw data volume (before processing) of the upgraded TPC will exceed 3 TB/s. As a consequence, online processing of the raw data and compression of the results before it enters the online computing farms is an essential and crucial part of the computing model.
Within the scope of this thesis, the H-RORC card and the FCF processor were developed and built from scratch. It covers the conceptual design, the optimisation and implementation, as well as the verification. It is completed by performance benchmarks and experiences from real data taking.
The Late Cretaceous is known to be mostly affected by warm periods interrupted temporarily by a number of cooling events. The reconstruction of the paleoclimatic conditions during a period of high concentration of CO2 in the atmosphere is of great importance for the creation of future climate models. We applied the recently developed method reconstructing the SST from the TEX86 (TetraEther indeX of tetraethers consisting of 86 carbon atoms).
The sample material used for the present study was obtained from the tropical Late Cretaceous southern Tethys upwelling system (Negev/Israel), lasting from the Late Santonian to the Early Maastrichtian (~ 85 to 68 Ma). On the core samples from the Shefela basin, representing the outer belt of the upwelling system and the outcrop profile from the open mine Mishor Rotem (Efe Syncline), representing the inner belt, various bulk geochemical and biomarker studies were performed in this thesis.
Derived from TEX86 data, a significant long-term SST cooling trend from 36.0 to 29.3 °C is recognized during the Late Santonian and the Early Campanian in the southern Tethys margin. This is consistent with the opening and deepening of the Equatorial Atlantic Gateway (EAG) and the intrusion of cooler deep water from the southern Atlantic Ocean influencing the global SSTs and also the Tethys Ocean. Furthermore, the cooler near shore SST usually found in modern upwelling systems could be verified in case of the ancient upwelling system investigated in the present study. The calculated mean SST in the inner belt (27.7 °C) represented in the Efe Syncline was 1.5 °C cooler in comparison to the more seaward located outer belt (Shefela basin).
Moreover, geochemical and biomarker analyses were used to identify both the accumulation of high amounts of phosphate in the PM and good preservation of organic matter (OM) in the lower part of the OSM section. Total organic carbon (TOC) contents are highly variable over the whole profile reaching from 0.6 % in the MM, to 24.5 % in the OSM. Total iron (TFe) varies from 0.1 % in the PM to 3.3 % in the OSM and total sulfur (TS) varies between 0.1 % in the MM and 3.4 % in the OSM. Different correlations of TS, TOC and TFe were used to identify the conditions during the deposition of the different facies types. Natural sulfurization was found to play a key role in the preservation of the OM particularly in the lower part of the OSM. Samples from the OSM and the PM were deposited under dysoxic to anoxic conditions and iron limitation lasted during the deposition of the OSM and the PM, which effected the incorporation of sulfur into OM.
Phosphorus is highly accumulated in the sediments of the PM with a mean proportion of 11.5 % total phosphorus (TP), which is drastically reduced to a mean value of 0.9 % in the OSM and the MM. From the correlation of the bulk geochemical parameters TOC/TOCOR ratio and TP a major contribution of sulfate reducing bacteria to the phosphate deposition is concluded. This interrelation has previously been investigated in recent coastal upwelling systems off Peru, Chile, California and Namibia. This was further supported by the analysis of branched and monounsaturated fatty acids indicating the occurrence of sulfate reducing and sulfide oxidizing bacteria during the deposition.
According to the results from the analysis of n-alkanes and C27- to C29-steranes up to 95 % of the OM was of marine origin.
Organic sulfur compounds (OSC) were a major compound class in the aromatic hydrocarbon fraction and n-Alkyl and isoprenoid thiophenes were the most abundant, with highest amounts found for 2-methyl-5-tridecyl-thiophene (28 µg/g TOC). The relatively high abundance of ββ-C35 hopanoid thiophenes and epithiosteranes is equivalent to an incorporation of sulfur during the early stages of diagenesis.
Moreover, the geochemical parameters δ13Corg, δ15Norg, C/N and the pristane/phytane (Pr/Ph) ratio, were studied for reconstruction of seafloor and water column depositional environments. The high C/N ratio along with relatively low values of δ15Norg (4 ‰ to 6 ‰) and δ13Corg (-29 ‰ to -28 ‰) are consistent with a significant preferential loss of nitrogen-rich organic compounds during diagenesis. Oxygen-depleted conditions lasted during the deposition of the PM and the bottom of the OSM, reflected by the low Pr/Ph ratio of 0.11–0.7. In the upper part of the OSM and the MM the conditions changed from anoxic to dysoxic or oxic conditions. This environmental trend is consistent with co-occurring foraminiferal assemblages in the studied succession and implies that the benthic species in the Negev sequence were adapted to persistent minimum oxygen conditions by performing complete denitrification as recently found in many modern benthic foraminifera.
Furthermore, the anammox process could have influenced the nitrogen composition of the sediments. In this anaerobically process nitrite and ammonia are converted to molecular nitrogen.
Proteostasis stressors that destabilize the cellular proteome, like heat shock, trigger transcription and translational reactions leading to the accumulation of heat shock proteins, also called molecular chaperones. During stress, induction of stress response genes is prioritized so that molecular chaperones and other stress response proteins are synthesized to cope with proteome misfolding and aggregation. In order to promote the selective translation of stress-specific genes, translation of others genes that are nonessential for cell survival has to stop. Nonessential protein-coding mRNAs accumulate in the cytosol with the associated proteins to form granular structures called stress granules (SG). These membrane-less organelles are thought to be involved in cell survival, mRNA stabilization and mRNA triage. They were proposed to form via the liquid-liquid phase separation which can be triggered by the high local concentration of RNA-binding proteins. mRNAs were long thought to simply play a scaffolding role by bringing RNA-binding proteins together and allowing their concentration and local aggregation. Recently, the active role of mRNAs in the SG assembly became apparent, too. For example, the spontaneous assembly of total yeast RNA into granules was observed, and these RNA granules showed a large overlap with SG transcriptome. Furthermore, cytosolic mRNAs can be released from polyribosomes under stress and be exposed to the cytosolic contents as free mRNAs. It has been suggested that this massive increase of free mRNA in the cytosol might overload the capacities of RNA-stabilizing proteins. The remaining free mRNA molecules would then become exposed to misfolded and aggregation-prone proteins and trigger granulation.
We investigated the role of free mRNAs in different stress conditions during the early and chronic phases of stress response and explored their involvement in SGs assembly and amlyoidogenesis. We identified and studied the interactome of a free mRNA probe incubated with heat shocked cell lysate by means of quantitative mass spectrometry. Proteomics analysis allowed us to identify 79 interactors of free mRNA. Among these interactors, we focused on the translation initiation factor eIF2α and on the RNA methyltransferase TRMT6/61A. Both interactions were verified biochemically, which confirmed that the association is enhanced in heat shocked lysate. In vitro reconstitution showed that free mRNA and TRMT6 interact directly. Ex vivo pulldowns revealed that eIF2α and TRMT6/61A interact under stress conditions and that this interaction is RNA-dependent.
TRMT6/61A is a tRNA methytransferase responsible for the methylation of the adenosine 58 at the position 1 producing m1A. However, also mRNAs have been recently found to be methylated by TRMT6/61A. Our bioinformatics analyses revealed that significantly more mRNAs enriched in SG contain the motif for methylation than SG-depleted mRNAs. We hypothesized that m1A methylation of mRNAs could constitute a tag for the mRNAs targeting to SGs. TRMT61A knock-down (KD) cell lines were generated using the CRISPR-Cas9 technique. In TRMT61A KD cells, m1A was significantly reduced on mRNAs, which correlated with an increased sensitivity of the cells to proteostasis stress. KD cells also showed defects in SG assembly. In heat shocked cells, an m1A motif-containing mRNA recovered better after returning to normal temperature than a control mRNA with mutated motif. In addition, we could isolate SGs and analyze their m1A and m6A content by mass spectrometry. While m6A content in SG mRNAs was very similar to cytosolic mRNAs, m1A was almost 8 times enriched in SGs. Thus, we could confirm experimentally the results of the bioinformatics analysis and directly support the hypothesis that m1A is a tag to direct mRNAs for sequestration. Finally, we compared amyloidogenesis in wild-type and TRMT61A KD cell lines. Cells with reduced levels of TRMT61A demonstrated an increased accumulation of transfected Aβ and an impaired aggregate clearance. Various assays led us to conclude that the lack of m1A deposition on mRNAs enhanced RNA co-aggregation with amyloids.
Based on our results, we propose a model explaining the fate of free mRNA during proteostasis stress. Upon polysome disassembly, free mRNA is released and becomes free to interact with other proteins, including the methyltransferase TRMT6/61A. TRMT6/61A methylates the freed mRNAs containing the cognate motif. The m1A tag then targets mRNAs to SGs promoting sequestration. Upon stress release, SGs disassemble, thus releasing rescued mRNAs which could now reenter translation and support cell recovery. On the other hand, non-sequestered mRNAs increasingly co-aggregate with aggregating proteins. Thus, deficiency of the N1-adenine methylation of mRNAs due to the lack of TRMT6/61A increases the amount of unpacked mRNAs. The deposition of m1A on mRNAs could then be a way to protect them during exposure to stress, to limit their co-aggregation with misfolded proteins and to allow a faster recovery upon stress release.
Interleukin-11 signaling is a global molecular switch between regeneration and scarring in zebrafish
(2022)
The two diametrically opposing outcomes after tissue damage are regeneration and fibrotic scarring. After injury, adult mammals predominantly induce fibrotic scarring, which most often leads to patient lethality. Fibrotic scarring is the deposition of excessive extracellular matrix that matures and hinders tissue function. The scarring response is mainly orchestrated by myofibroblasts, which arise only upon tissue damage, from various cellular origins, including tissue resident fibroblasts, endothelial cells and circulating blood cells. On the contrary, species like zebrafish, possess the remarkable capacity to regenerate their damaged tissues. After injury, instead of inducing a myofibroblast-mediated fibrogenic gene program, cells in these species undergo regenerative reprogramming at the transcriptional level to activate vital cellular processes needed for regeneration, including proliferation, dedifferentiation, and migration. Several pro-regenerative mechanisms have been identified to date. Most of them, if not all, are also important for tissue homeostasis and hence, are not injury specific. Therefore, the central aim of this study is to identify injury-specific mechanisms that not only induce regeneration, but also limit fibrotic scarring.
To test the notion that fibrotic scarring limits regeneration, I first compared the scarring response in the regenerative zebrafish heart after cryoinjury with what is known in the non-regenerative adult mouse heart. I found that zebrafish display ~10-fold less myofibroblast differentiation compared to adult mouse after cardiac injury. With these findings, I hypothesized that zebrafish employ mechanisms to actively suppress scarring response. Using a novel comparative transcriptomic approach coupled with genetic loss-of-function analyses, I identified that Interleukin-6 (Il-6) cytokine family-mediated Stat3 is one such pro-regenerative pathway in zebrafish.
Il-6 cytokine family consists of Il-6, Interleukin-11 (Il-11), Ciliary neurotrophic factor, Leukemia inhibitory factor, Oncostatin M, and Cardiotrophin-like cytokine factor 1. Il-6 family ligands signal through their specific receptors and a common receptor subunit (Il6st or Gp130). Using gene expression analyses after adult heart and adult caudal fin injuries in zebrafish, I identified that both the Il-11 cytokine encoding paralogous genes (il11a and il11b) are the highest expressed and induced among the Il-6 family cytokines. Hence, I chose Il-11 signaling as a candidate pathway for further analysis. To investigate the role of Il-11 signaling, I generated genetic loss-of-function mutants for both the ligand (il11a and il11b) and the receptor (il11ra) encoding genes. Using various tissue regeneration models across developmental stages in these mutants, I identified that Il-11/Stat3 signaling is indispensable for global tissue regeneration in zebrafish.
To investigate the cellular and molecular mechanisms by which Il-11 signaling promotes regeneration, I performed transcriptomics comparing the non-regenerative il11ra mutant hearts and fins with that of the wild types, respectively. I identified that Il-11 signaling orchestrates both global and tissue-specific aspects of regenerative reprogramming at the transcriptional level. In addition, I also found that impaired regenerative reprogramming in the il11ra mutant hearts and fins resulted in defective cardiomyocyte and osteoblast repopulation of the injured area, respectively.
On the other hand, by deep phenotyping the scarring response in il11ra mutant hearts and fins, I identified that Il-11 signaling limits myofibroblast differentiation. Furthermore, I found that cardiac endothelial cells and fibroblasts are one of the major responders to injury-induced Il-11 signaling. Using lineage tracing, I found that both the endothelial and fibroblast lineages in the non-regenerative il11ra mutants commit to a myofibroblast fate, spearheading the scarring response. In addition, using cell type specific manipulations, I showed that Il-11 signaling in cardiac endothelial cells allows cardiomyocyte repopulation of the injured area. Finally, using human endothelial cells in culture, I uncovered a novel feedback mechanism by which Il-11 signaling limits fibrogenic gene expression by inhibiting its parent activator and a master regulator of tissue fibrosis, TGF-β signaling.
Overall, I identified Interleukin-11/Stat3 signaling as the first global regulator of regeneration in zebrafish. Briefly, I showed that Interleukin-11 signaling promotes regeneration by regulating two crucial cellular aspects in response to injury – (1) it promotes regenerative reprogramming, thereby allowing cell repopulation of the injured area and (2) it limits mammalian-like fibrotic scarring by inhibiting myofibroblast differentiation and TGF-β signaling. Altogether, these zebrafish data, together with the contradicting mammalian data strongly indicate that the secrets of tissue regeneration lie downstream of IL-11 signaling, in the differences between regenerative and non-regenerative species. Furthermore, I establish the non-regenerative il11ra mutant as an invaluable zebrafish model to study mammalian tissue fibrosis.
This study investigates a historical event that occurred during the Indonesian Revolution as depicted in Indonesian historical films and argues that these films not only attempt to depict the past but also use the past as a means of social commentary, teaching moral insight, and historical reinforcement. The historical films selected are The Long March (Darah dan Do’a) (1950) and Mereka Kembali (1972). Both films deal with the Long March event experienced by the troops of the Siliwangi Division in 1948. These troops were previously assigned to infiltrate Yogyakarta and its surrounding areas. They were instructed to march back to their original base in West Java as a part of the military strategies to confront the Dutch during the Indonesian Revolution, also known as the Indonesian War of Independence. This event became known as the Long March of the Siliwangi Division. This study examines not only the representation of the past or the texts of the films but also the production process, which includes the motivations of the filmmakers and the public reception when the films were screened for the public at the time—in 1950 and 1972, respectively. This approach provides a broader and richer dimension, valuable insights into the behind-the-scenes process of making the selected historical films, and essential information about the public reception of the films. From the production point of view, there are two main reasons for making these historical films: personal reason and social engagement. Further, the military also plays a vital role in these historical film productions. From the historical representation aspect, these two films depict the events of the Long March of the Siliwangi Division as a journey full of various obstacles and difficulties, such as harsh terrain, lack of food, battles against the Dutch, and internal disputes with fellow Indonesians: Darul Islam. From the reception aspect, the audience’s point of view, these films provide several representations that meet their expectations about the Long March of the Siliwangi Division. However, the audience disagrees with some of the other representations. Finally, the study revealed that historical films are potential vehicles for telling, interpreting, entertaining, legitimating and preserving the past. In addition, this study has a vital implication for reopening the tradition of Indonesian film studies and reigniting attention to old films.
Concentration of multivariate random recursive sequences arising in the analysis of algorithms
(2006)
Stochastic analysis of algorithms can be motivated by the analysis of randomized algorithms or by postulating on the sets of inputs of the same length some probability distributions. In both cases implied random quantities are analyzed. Here, the running time is of great concern. Characteristics like expectation, variance, limit law, rates of convergence and tail bounds are studied. For the running time, beside the expectation, upper bounds on the right tail are particularly important, since one wants to know large values of the running time not taking place with possibly high probability. In the first chapter game trees are analyzed. The worst case runnig time of Snir's randomized algorithm is specified and its expectation, asymptotic behavior of the variance, a limit law with uniquely characterized limit and tail bounds are identified. Furthermore, a limit law for the value of the game tree under Pearl's probabilistic modell is proved. In the second chapter upper and lower bounds for the Wiener Index of random binary search trees are identified. In the third chapter tail bounds for the generation size of multitype Galton-Watson processes (with immigration) are derived, depending on their offspring distribution. Therefore, the method used to prove the tail bounds in the first chapter is generalized.