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Burkitt's lymphoma (BL) is a highly aggressive form of B-cell non-Hodgkin's lymphoma. The clinical outcome in children with BL has improved over the last years but the prognosis for adults is still poor, highlighting the need for novel treatment strategies. Here, we report that the combinational treatment with the Smac mimetic BV6 and TRAIL triggers necroptosis in BL when caspases are blocked by zVAD.fmk (TBZ treatment). The sensitivity of BL cells to TBZ correlates with MLKL expression. We demonstrate that necroptotic signaling critically depends on MLKL, since siRNA-induced knockdown and CRISPR/Cas9-mediated knockout of MLKL profoundly protect BL cells from TBZ-induced necroptosis. Conversely, MLKL overexpression in cell lines expressing low levels of MLKL leads to necroptosis induction, which can be rescued by pharmacological inhibitors, highlighting the important role of MLKL for necroptosis execution. Importantly, the methylation status analysis of the MLKL promoter reveals a correlation between methylation and MLKL expression. Thus, MLKL is epigenetically regulated in BL and might serve as a prognostic marker for treatment success of necroptosis-based therapies. These findings have crucial implications for the development of new treatment options for BL.
It has been suggested that the existence of a non-Gaussian fixed point in general relativity might cure the ultraviolet problems of this theory. Such a fixed point is connected to an effective running of the gravitational coupling. We calculate the effect of the running gravitational coupling on the black hole production cross section in models with large extra dimensions.
The upcoming high energy experiments at the LHC are one of the most outstanding efforts for a better understanding of nature. It is associated with great hopes in the physics community. But there is also some fear in the public, that the conjectured production of mini black holes might lead to a dangerous chain reaction. In this Letter we summarize the most straightforward arguments that are necessary to rule out such doomsday scenarios.
Background: The factors driving the late phase of COVID-19 are still poorly understood. However, autoimmunity is an evolving theme in COVID-19’s pathogenesis. Additionally, deregulation of human retroelements (RE) is found in many viral infections, and has also been reported in COVID-19.
Results: Unexpectedly, coronaviruses (CoV) – including SARS-CoV-2 – harbour many RE-identical sequences (up to 35 base pairs), and some of these sequences are part of SARS-CoV-2 epitopes associated to COVID-19 severity. Furthermore, RE are expressed in healthy controls and human cells and become deregulated after SARS-CoV-2 infection, showing mainly changes in long interspersed nuclear element (LINE1) expression, but also in endogenous retroviruses.
Conclusion: CoV and human RE share coding sequences, which are targeted by antibodies in COVID-19 and thus could induce an autoimmune loop by molecular mimicry.
Our understanding of human biology and disease is based on the last millennia’s gain of knowledge, which has been exponentially accelerated since the invention of optical and "biochemical" microscopes like transcriptomics and other omics technologies.
In order to broaden our knowledge of an important human transcription factor, T-Cell Acute Lymphocytic Leukemia 1 (TAL1), some of these technologies were used.
TAL1’s gene or promoter structure is altered in about 20-30% of T-ALL. In addition, there is an increase in TAL1 expression in ca. 60% of pediatric and about 45% of adult T-ALL. Physiologically, TAL1 is an indispensable factor in hematopoiesis: in the murine knockout model, blood cells vanish in the early embryonic period. In addition, the TF is also relevant in adult erythropoiesis.
Accordingly, the identification of novel TAL1 target genes was significant both for clinical reasons and in order to understand the hematopoietic functions.
We performend a combined RNA- and ChIPseq approach. After a lentiviral mediated knockdown in K562 cells RNAseq was performed using the Illumina high-throughput method. Overall, the RNAseq yielded one billion good quality sequencing fragments. They made identification of up- and downregulated transcripts as well as associated biological processes, cellular components, molecular function and dominant KEGG signaling pathways possible. Furthermore, more than 2-fold altered coding transcripts and lncRNA were analyzed for relevant TAL1-binding in the transcription start area. There were 3205 significantly altered coding transcripts and 5136 significantly altered lncRNA. By integrating an Encode TAL1-ChIPseq in K562 cells (using a cutoff fold change of 2x) a relevant TAL1 binding could be detected with 71 coding and 416 lncRNA genes.
The combination of RNA- and ChIPseq yields a wealth of relevant results. Accordingly, TAL1 has complex pro- and anti-malignant effects in all areas of oncogenesis like described by Hanahan and Weinberg. Various interactions with target genes and signaling cascades in inter alia proliferation (e.g. HEMGN, MYC, AHI1, YPEL3, BTG2), angiogenesis (e.g. EGFL7, LTBP3), apoptosis (e.g. BCL3, BCL2A1, BMF), immune evasion (e.g. CMTM6) and inflammation (e.g. IL23 and PTGS1) have been revealed, thus complementing the knowledge about pro- and anti-oncogenic effects of TAL1. In addition, it was possible to identify target genes relevant for erythropoiesis and possible osteogenesis. Concerning lncRNA, interesting potential effectors have been identified. However, they still need to be functionally characterized. Relating the results to Virchow’s first description of leukemia as "white blood" the role of TAL1 in leukemia’s genesis but also in erythropoiesis has been confirmed and extended, thus contributing to explain Virchow’s observation: "...therefore, when I speak of white blood, I mean in fact a blood in which the proportion between the red and colorless (in white) blood corpuscles is reversed ...” (Virchow R. Weisses Blut. Frorieps Notizen 1845;36:151-156).
Highligthts
• Marburg virus infects and replicates in primary human proximal tubular cells (PTC).
• Transcriptome analyses at multiple time points revealed a profound inflammatory response by IFNα, -y and TNFα signaling.
• Among the strongly downregulated gene sets were targets of the transcription factors MYC and E2F, the G2M checkpoint, as well as oxidative phosphorylation.
• Importantly, the downregulated factors comprise PGC-1α, a key factor in mitochondrial biogenesis and renal energy homeostasis, to be substantially downregulated in MARV-infected PTC.
• Our results suggest inflammation-induced changes in tubular energy metabolism as a possible factor in MARV-associated tubular dysfunction.
Abstract
Marburg virus, a member of the Filoviridae, is the causative agent of Marburg virus disease (MVD), a hemorrhagic fever with a case fatality rate of up to 90 %. Acute kidney injury is common in MVD and is associated with increased mortality, but its pathogenesis in MVD remains poorly understood. Interestingly, autopsies show the presence of viral proteins in different parts of the nephron, particularly in proximal tubular cells (PTC). These findings suggest a potential role for the virus in the development of MVD-related kidney injury. To shed light on this effect, we infected primary human PTC with Lake Victoria Marburg virus and conducted transcriptomic analysis at multiple time points. Unexpectedly, infection did not induce marked cytopathic effects in primary tubular cells at 20 and 40 h post infection. However, gene expression analysis revealed robust renal viral replication and dysregulation of genes essential for different cellular functions. The gene sets mainly downregulated in PTC were associated with the targets of the transcription factors MYC and E2F, DNA repair, the G2M checkpoint, as well as oxidative phosphorylation. Importantly, the downregulated factors comprise PGC-1α, a well-known factor in acute and chronic kidney injury. By contrast, the most highly upregulated gene sets were those related to the inflammatory response and cholesterol homeostasis. In conclusion, Marburg virus infects and replicates in human primary PTC and induces downregulation of processes known to be relevant for acute kidney injury as well as a strong inflammatory response.
Mesenchymal stromal/stem cells and their derivates are the most promising cell source for cell therapies in regenerative medicine. The application of extracellular vesicles (EVs) as cell-free therapeuticals requires particles with a maximum regenerative capability to enhance tissue and organ regeneration. The cargo of mRNA and microRNA (miR) in EVs after hypoxic preconditioning has not been extensively investigated. Therefore, the aim of our study was the characterization of mRNA and the miR loading of EVs. We further investigated the effects of the isolated EVs on renal tubular epithelial cells in vitro. We found 3131 transcripts to be significantly regulated upon hypoxia. Only 15 of these were downregulated, but 3116 were up-regulated. In addition, we found 190 small RNAs, 169 of these were miRs and 21 were piwi-interacting RNAs (piR). However, only 18 of the small RNAs were significantly altered, seven were miRs and 11 were piRs. Interestingly, all seven miRs were down-regulated after hypoxic pretreatment, whereas all 11 piRs were up-regulated. Gene ontology term enrichment and miR-target enrichment analysis of the mRNAs and miR were also performed in order to study the biological background. Finally, the therapeutic effect of EVs on human renal tubular epithelial cells was shown by the increased expression of three anti-inflammatory molecules after incubation with EVs from hypoxic pretreatment. In summary, our study demonstrates the altered mRNA and miR load in EVs after hypoxic preconditioning, and their anti-inflammatory effect on epithelial cells.
Background/Aims: Middle East respiratory syndrome coronavirus (MERS-CoV) and Marburg virus (MARV) are among the World Health Organization’s top 8 emerging pathogens. Both zoonoses share nonspecific early symptoms, a high lethality rate, and a reduced number of specific treatment options. Therefore, we evaluated extracorporeal virus and glycoprotein (GP) elimination by lectin affinity plasmapheresis (LAP).
Methods: For both MERS-CoV (pseudovirus) as well as MARV (GPs), 4 LAP devices (Mini Hemopurifiers, Aethlon Medical, San Diego, CA, USA) and 4 negative controls were tested. Samples were collected every 30 min and analyzed for reduction in virus infectivity by a flow cytometry-based infectivity assay (MERS-CoV) and in soluble GP content (MARV) by an immunoassay.
Results: The experiments show a time-dependent clearance of MERS-CoV of up to 80% within 3 h (pseudovirus). Up to 70% of MARV-soluble GPs were eliminated at the same time. Substantial saturation of the binding resins was detected within the first treatment hour.
Conclusion: MERS-CoV (pseudovirus) and MARV soluble GPs are eliminated by LAP in vitro. Considering the high lethality and missing established treatment options, LAP should be evaluated in vivo. Especially early initiation, continuous therapy, and timed cartridge exchanges could be of importance.
Patients with neuroendocrine tumors (NET) often go through a long phase between onset of symptoms and initial diagnosis. Assessment of time to diagnosis and pre-clinical pathway in patients with gastroenteropancreatic NET (GEP-NET) with regard to metastases and symptoms. Retrospective analysis of patients with GEP-NET at a tertiary referral center from 1984 to 2019; inclusion criteria: Patients ≥18 years, diagnosis of GEP-NET; statistical analysis using non-parametrical methods. Four hundred eighty-six patients with 488 tumors were identified; median age at first diagnosis (478/486, 8 unknown) was 59 years; 52.9% male patients. Pancreatic NET: 143/488 tumors; 29.3%; small intestinal NET: 145/488 tumors, 29.7%. 128/303 patients (42.2%) showed NET specific and 122/486 (25%) patients other tumor-specific symptoms. 222/279 patients had distant metastases at initial diagnosis (187/222 liver metastases). 154/488 (31.6%) of GEP-NET were incidental findings. Median time from tumor manifestation (e.g., symptoms related to NET) to initial diagnosis across all entities was 19.5 (95% CI: 12–28) days. No significant difference in patients with or without distant metastases (median 73 vs 105 days, P = .42). A large proportion of GEP-NET are incidental findings and only about half of all patients are symptomatic at the time of diagnosis. We did not find a significant influence of the presence of metastases on time to diagnosis, which shows a large variability with a median of <30 days.
Introduction: Scarce data exist for therapy regimens other than somatostatin analogues (SSA) and peptide receptor radiotherapy (PRRT) for siNET. We analyzed real world data for differences in survival according to therapy. Patients and methods: Analysis of 145 patients, diagnosed between 1993 and 2018 at a single institution, divided in treatment groups. Group (gr.) 0: no treatment (n = 10), gr 1: TACE and/or PRRT (n = 26), gr. 2: SSA (n = 32), gr. 3: SSA/PRRT (n = 8), gr. 4: chemotherapy (n = 8), gr. 5: not metastasized (at diagnosis), surgery only (n = 53), gr. 6 = metastasized (at diagnosis), surgery only (n = 10). Results: 45.5% female, median age 60 years (range, 27–84). A total of 125/145 patients with a resection of the primary tumor. For all patients, 1-year OS (%) was 93.8 (95%-CI: 90–98), 3-year OS = 84.3 (CI: 78–90) and 5-year OS = 77.5 (CI: 70–85). For analysis of survival according to therapy, only stage IV patients (baseline) that received treatment were included. Compared with reference gr. 2 (SSA only), HR for OS was 1.49 (p = 0.47) for gr. 1, 0.72 (p = 0.69) for gr. 3, 2.34 (p = 0.19) for gr. 4. The 5 y OS rate of patients whose primary tumor was resected (n = 125) was 73.1%, and without PTR was 33.3% (HR: 4.31; p = 0.003). Individual patients are represented in swimmer plots. Conclusions: For stage IV patients in this analysis (limited by low patient numbers in co. 3/4), multimodal treatment did not significantly improve survival over SSA treatment alone. A resection of primary tumor significantly improves survival.
Background/aims: Hepatocellular carcinoma (HCC) is a leading indication for liver transplantation (LT) worldwide. Early identification of patients at risk for HCC recurrence is of paramount importance since early treatment of recurrent HCC after LT may be associated with increased survival. We evaluated incidence of and predictors for HCC recurrence, with a focus on the course of AFP levels.
Methods: We performed a retrospective, single-center study of 99 HCC patients who underwent LT between January 28th, 1997 and May 11th, 2016. A multi-stage proportional hazards model with three stages was used to evaluate potential predictive markers, both by univariate and multivariable analysis, for influences on 1) recurrence after transplantation, 2) mortality without HCC recurrence, and 3) mortality after recurrence.
Results: 19/99 HCC patients showed recurrence after LT. Waiting time was not associated with overall HCC recurrence (HR = 1, p = 0.979). Similarly, waiting time did not affect mortality in LT recipients both with (HR = 0.97, p = 0.282) or without (HR = 0.99, p = 0.685) HCC recurrence. Log10-transformed AFP values at the time of LT (HR 1.75, p = 0.023) as well as after LT (HR 2.07, p = 0.037) were significantly associated with recurrence. Median survival in patients with a ratio (AFP at recurrence divided by AFP 3 months before recurrence) of 0.5 was greater than 70 months, as compared to a median of only 8 months in patients with a ratio of 5.
Conclusion: A rise in AFP levels rather than an absolute threshold could help to identify patients at short-term risk for HCC recurrence post LT, which may allow intensification of the surveillance strategy on an individualized basis.
Background and Aims. Systemic treatment with sorafenib has been the standard of care (SOC) in patients with advanced Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) for more than a decade. TACE has been reported to allow better local tumor control in selected patients with BCLC stage C HCC. Methods. A retrospective analysis of patients with BCLC stage C HCC that were treated with sorafenib and TACE was conducted; they were compared to BCLC stage C patients treated either with TACE or sorafenib in the same period of time outside a clinical trial. Results. A total of 201 patients with BCLC stage C were identified, who were treated with either sorafenib and TACE (group A; n = 54), sorafenib (group B; n = 82) or TACE (group C; n = 65). No significant difference in baseline characteristics was observed. Time to progression was 7.0 months (95% CI: 4.3–9.7), 4.1 months (95% CI: 3.6–4.7) and 5.0 months (95% CI: 2.9–7.1) in groups A, B and C, respectively, and overall survival was 16.5 months (95% CI: 15.0–18.1), 8.4 months (95% CI: 6.0–10.8) and 10.5 months (95% CI: 7.5–13.6), respectively (group A vs. group B: p < 0.001; group A vs. group C: p = 0.0023). Adverse events of grade 3/4 occurred in 34% of patients in group A. Conclusions. Although sorafenib is a SOC in patients with BCLC stage C HCC, TACE is frequently used as an additional locoregional treatment in selected patients. This combined approach resulted in a significant overall survival benefit in selected patients, although randomized trials have not yet proven this benefit.
Immunosuppression is a typical hallmark of cancer and frequently includes perturbations of the NKG2D tumor recognition system as well as impaired signaling by other activating NK cell receptors. Several in vitro studies suggested that sustained engagement of the NKG2D receptor, as it is occurring in the tumor microenvironment, not only impairs expression and function of NKG2D but also impacts signaling by other activating NK receptors. Here, we made use of a transgenic mouse model of ubiquitous NKG2D ligand expression (H2-Kb-MICA mice) to investigate consequences of chronic NKG2D engagement in vivo for functional responsiveness by other activating NK receptors such as NKp46 and Ly49D. Unexpectedly, we found no evidence for an impairment of NKp46 expression and function in H2-Kb-MICA mice, as anticipated from previous in vitro experiments. However, we observed a marked downregulation and dysfunction of the activating receptor Ly49D in activated NK cells from H2-Kb-MICA mice. Ly49D shares the adaptor proteins DAP10 and DAP12 with NKG2D possibly explaining the collateral impairment of Ly49D function in situations of chronic NKG2D engagement. Altogether, our results demonstrate that persistent engagement of NKG2D in vivo, as often observed in tumors, can selectively impair functions of unrelated NK receptors and thereby compromise NK responsiveness to third-party antigens.
Background and aims: Patients with gastric cancer often show signs of malnutrition. We sought to evaluate the influence of sarcopenia in patients with locally advanced, not metastasized, gastric or gastro-esophageal junction (GEJ) cancer undergoing curative treatment (perioperative chemotherapy and surgery) on morbidity and mortality in order to identify patients in need for nutritional intervention.
Patients and methods: Two-centre study, conducted in the Frankfurt University Clinic and Krankenhaus Nordwest (Frankfurt) as part of the University Cancer Center Frankfurt (UCT). 47/83 patients were treated in the FLOT trial (NCT01216644). Patients´ charts were reviewed for clinical data. Two consecutive CT scans were retrospectively analyzed to determine the degree of sarcopenia. Survival was calculated using the Kaplan-Meier method, multivariate analysis was performed using the Cox regression.
Results: 60 patients (72.3%) were male and 23 (27.7%) female. 45 patients (54.2%) had GEJ type 1–3 and 38 (45.8%) gastric tumors, respectively. Sarcopenic patients were significantly older than non-sarcopenic patients (mean age 65.1 years vs. 59.5 years, p = 0.042), terminated the chemotherapy significantly earlier (50% vs. 22.6%, p = 0.037) and showed higher Clavien-Dindo scores, indicating more severe perioperative complications (score ≥3 43.3 vs. 17.0%, p = 0.019). Sarcopenic patients had a significantly shorter survival than non-sarcopenic patients (139.6 ± 19.5 [95% CI, 101.3–177.9] vs. 206.7 ± 13.8 [95% CI, 179.5–233.8] weeks, p = 0.004). Multivariate Cox regression analysis showed that, besides UICC stage, sarcopenia significantly influenced survival.
Conclusion: Sarcopenia is present in a large proportion of patients with locally advanced gastric or GEJ cancer and significantly influences tolerability of chemotherapy, surgical complications and survival.
Background: The aim of this meta-analysis was to evaluate efficacy and safety of first-line chemotherapy with or without a monoclonal antibody in elderly patients ( ≥ 70 years) with metastatic colorectal cancer (mCRC), since they are frequently underrepresented in clinical trials.
Results: Individual data from 10 studies were included. From a total of 3271 patients, 604 patients (18%) were ≥ 70 years (median 73 years, range 70–88). Of these, 335 patients were treated with a bevacizumab-based first-line regimen and 265 were treated with chemotherapy only. The median PFS was 8.2 vs. 6.5 months and the median OS was 16.7 vs. 13.0 months in patients treated with and without bevacizumab, respectively. The safety profile of bevacizumab in combination with first-line chemotherapy did not differ from published clinical trials.
Materials and Methods: PubMed and Cochrane Library searches were performed on 29 April 2013 and studies published to this date were included. Authors were contacted to request progression-free survival (PFS), overall survival (OS) data, patient data on treatment regimens, age, sex and potential signs of toxicity in patients ≥ 70 years of age.
Conclusions: This meta-analysis suggests that the addition of bevacizumab to standard first-line chemotherapy improves clinical outcome in elderly patients with mCRC and is well tolerated.
Die autosomal rezessive Erkrankung Ataxia teleangiectasia ist durch eine stark erhöhte Inzidenz von Krebs charakterisiert. Das verantwortliche Genprodukt, das bei AT verändert, beziehungsweise funktionsuntüchtig ist, spielt eine entscheidende Rolle in der Zellzykluskontrolle, der DNA Reparatur und der Apoptose nach einem Doppelstrangbruch, der durch ionisierende Strahlung oder ROS induziert wurde. Neueste Studien haben gezeigt, dass n-3 PUFA, wie z.B. Eicosapentaensäure (EPA), in der Lage sind, Zellproliferation zu unterdrücken und Tumorwachstum durch Zellzyklusstopp und das Auslösen von Apoptose zu verhindern. Das Ziel dieser Arbeit war, den Einfluss von EPA auf die Entwicklung des Tumors bei Atm Knock-out Mäusen zu untersuchen. Folglich wurde im Verlauf dieser Studie die Latenzzeit der Tumorentstehung nach EPA Behandlung der Tiere analysiert. Aufgrund erhöhten oxidativen Stresses bei AT und der Auswirkung von ROS auf die Tumorinzidenz bei Atm Knock-out Mäusen, untersuchten wir ebenfalls die DNA-Oxidation der Versuchstiere. EPA zeigte keinen Effekt auf die Latenz der Tumorentstehung bei Atm defizienten Mäusen. Erklärungen für den negativen Effekt können in der eingesetzten Konzentration der PUFA oder dem genetischen Hintergrund der Erkrankung diskutiert werden. Die Bestimmung von oxidierter DNA legt aber die Vermutung nahe, dass EPA den oxidativen Stress bei AT verstärkt und der antiproliferative und chemopräventative Effekt der früheren in vitro Untersuchungen hierdurch nicht zum Tragen kommt. Eine Kombination von EPA und Antioxidantien ist möglicherweise eine Strategie um die Tumorenstehung im Atm Mausmodell zu inhibieren und Präventive Therapie für die Patienten zu entwickeln.
Herzforschung meets KI
(2024)
Moderne Methoden der Künstlichen Intelligenz (KI) spielen in der Wissenschaft eine immer größere Rolle. Wie Forscher des Exzellenzclusters Cardio-Pulmonary Institute (CPI) KI in der Herzbildgebung nutzen, zeigte Professor Eike Nagel im Rahmen der Bürgeruniversität der Goethe-Universität. Er leitet das Institut für experimentelle und translationale kardiovaskuläre Bildgebung am Fachbereich Medizin und forscht an der Entwicklung verbesserter Behandlungsmöglichkeiten für Herz-Kreislauf-Erkrankungen. Mit dem Ziel, seine Forschung für alle Menschen zugänglich und verständlicher zu machen, lud Prof. Nagel interessierte Bürger*innen am 10. Mai in sein Institut ein.
Exercise interventions in mental disorders have evidenced a mood-enhancing effect. However, the association between physical activity and affect in everyday life has not been investigated in adult individuals with ADHD, despite being important features of this disorder. As physical activity and affect are dynamic processes in nature, assessing those in everyday life with e-diaries and wearables, has become the gold standard. Thus, we used an mHealth approach to prospectively assess physical activity and affect processes in individuals with ADHD and controls aged 14–45 years. Participants wore accelerometers across a four-day period and reported their affect via e-diaries twelve times daily. We used multilevel models to identify the within-subject effects of physical activity on positive and negative affect. We split our sample into three groups: 1. individuals with ADHD who were predominantly inattentive (n = 48), 2. individuals with ADHD having a combined presentation (i.e., being inattentive and hyperactive; n = 95), and 3. controls (n = 42). Our analyses revealed a significant cross-level interaction (F(2, 135.072)=5.733, p = 0.004) of physical activity and group on positive affect. In details, all groups showed a positive association between physical activity and positive affect. Individuals with a combined presentation significantly showed the steepest slope of physical activity on positive affect (slope_inattentive=0.005, p<0.001; slope_combined=0.009, p<0.001; slope_controls=0.004, p = 0.008). Our analyses on negative affect revealed a negative association only in the individuals with a combined presentation (slope=-0.003; p = 0.001). Whether this specifically pronounced association in individuals being more hyperactive might be a mechanism reinforcing hyperactivity needs to be empirically clarified in future studies.
Der menschliche Knochen besitzt, als Folge einer Verletzung oder eines chirurgischen Eingriffs, eine große Fähigkeit zur Reparatur und Regeneration. Die Knochenheilung beinhaltet ein komplexes Zusammenspiel von Zellen, Wachstumsfaktoren, Zytokinen sowie der extrazellulären Matrix (Hoerth et al. 2014). Nichtsdestotrotz führt ein Knochenbruch zu einer dramatischen Veränderung der mechanischen Belastbarkeit an der Verletzungsstelle. Der Abstand zwischen den beiden Frakturenden bildet einen entscheidenden Faktor in der Knochenheilung. Hier wird zwischen der primären, der osteonalen Knochenheilung und der sekundären, der kallusformierenden Knochenheilung unterschieden. Umso größer der Frakturspalt ist, desto größer wird die Instabilität, die Heilungsverzögerung und damit auch die Gefahr einer Pseudoarthrose (Hoerth et al., 2014; Marsell et Einhorn, 2011).
Große diaphysale Defekte werden meistens durch Traumata, Infektionen oder Tumore bedingt. Sie werden als critical size defects (CSD) bezeichnet, wenn eine chirurgische Intervention zur Heilung notwendig ist (Rosset et al., 2014). Langstreckige Knochendefekte stellen immer noch eine sehr große Herausforderung in der rekonstruktiven Chirurgie dar. Deswegen ist die Untersuchung und Weiterentwicklung von implantierbaren biomedizinischen Materialien bei der Behandlung von CSD eine wichtige Aufgabe.
Im Augenblick ist die häufigste Behandlungsmethode großer diaphysaler Defekte die Autologe Spongiosaplastik (ASP) und wird als Goldstandart der Therapie bezeichnet. Jedoch stehen die autologen Knochenmaterialien nur begrenzt zur Verfügung und verursachen viele Entnahmemorbiditäten. Darüber hinaus gibt es allogene, xenogene und synthetische Knochentransplantate. Dennoch ist noch keine der Therapiemöglichkeiten so ausgereift, dass die ASP dadurch ersetzt werden könnte. Die allogenen und xenogenen Materialien sind von der Menge unbegrenzt, besitzen aber eine niedrigere Biokompatibilität, höhere Infektionsgefahr und schlechtere Ergebnisse in der Langzeitwirkung (Wang et al., 2014).
Ein weiterer Nachteil gegenüber der ASP besteht darin, dass die synthetischen Knochenersatzmaterialien keine osteoinduktiven und osteogenen Eingenschaften besitzen. Eine Möglichkeit diese Qualitäten zu erhalten ist, sie mit Zellsuspensionen, wie z.B. bone marrow mononuclear cells (BMC), zu kombinieren und somit zu versuchen ein ausgereiftes Therapiekonzept zu entwickeln.
Zugleich beschreibt Masquelet et al. (2000) eine neue Technik, ein zweistufiges Verfahren zur Rekonstruktion von Knochendefekten. Es wird eine biologisch aktive Membran induziert, welche verschiedene Wachstumsfaktoren (wie z.B. VEGF, TGF beta1, BMP-2) sezerniert, die osteoinduktiv wirksam sind. Mit diesem operativen Verfahren wurden bereits gute klinische Ergebnisse bei Knochendefekten nach Tumorresektionen und Traumata erzielt.
Das Ziel dieser Studie ist es einen anorganischen Knochenersatzstoff von Heraeus Herafill unter Verwendung der induzierten Membrantechnik nach Masquelet am Rattenfemur zu testen. Die Forschung erfolgt dabei unter der Hypothese, dass die Korngröße des Knochenersatzmaterials Herafill in Kombination mit BMC-Besiedelung Einfluss auf die Heilung eines kritischen Knochendefekts hat.
Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB. Methods: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan–Meier method. Log-rank tests, χ2 tests, and t-tests were performed to detect significant differences between both cohorts. Results: The median OS of the overall population was 16 months (95% CI 13.4–23.7) and the median PFS, 2.8 months (95% CI 2.5–3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts. Conclusion: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only.
This is the 22. article in our series Trouble on the Far-Right.
Changing political and economic situations generate new types of political protagonists – the far right is no exception here. Whether its structures and organizational forms endure, whether they diffuse (trans)nationally, whether their models prove successful, depends on various factors. A model that is currently about to serve as a flagship for the far right in Europe is the neo-fascist movement / party CasaPound. So why is this organizational model within the far right in Italy and Europe so successful?
My contribution is intended to shed light on the hybridity of CasaPound and the resulting force for the renewal of fascism. To carry out my argument, I will first describe the evolution of CasaPound from a movement to a party. Then I will discuss strategies and practices in terms of organizational and ideological hybridization, to finally outline the European dimension of the self-proclaimed „fascists of the third millennium“...
Functional modules of metabolic networks are essential for understanding the metabolism of an organism as a whole. With the vast amount of experimental data and the construction of complex and large-scale, often genome-wide, models, the computer-aided identification of functional modules becomes more and more important. Since steady states play a key role in biology, many methods have been developed in that context, for example, elementary flux modes, extreme pathways, transition invariants and place invariants. Metabolic networks can be studied also from the point of view of graph theory, and algorithms for graph decomposition have been applied for the identification of functional modules. A prominent and currently intensively discussed field of methods in graph theory addresses the Q-modularity. In this paper, we recall known concepts of module detection based on the steady-state assumption, focusing on transition-invariants (elementary modes) and their computation as minimal solutions of systems of Diophantine equations. We present the Fourier-Motzkin algorithm in detail. Afterwards, we introduce the Q-modularity as an example for a useful non-steady-state method and its application to metabolic networks. To illustrate and discuss the concepts of invariants and Q-modularity, we apply a part of the central carbon metabolism in potato tubers (Solanum tuberosum) as running example. The intention of the paper is to give a compact presentation of known steady-state concepts from a graph-theoretical viewpoint in the context of network decomposition and reduction and to introduce the application of Q-modularity to metabolic Petri net models.
Motivation: Arabidopsis thaliana is a well-established model system for the analysis of the basic physiological and metabolic pathways of plants. Nevertheless, the system is not yet fully understood, although many mechanisms are described, and information for many processes exists. However, the combination and interpretation of the large amount of biological data remain a big challenge, not only because data sets for metabolic paths are still incomplete. Moreover, they are often inconsistent, because they are coming from different experiments of various scales, regarding, for example, accuracy and/or significance. Here, theoretical modeling is powerful to formulate hypotheses for pathways and the dynamics of the metabolism, even if the biological data are incomplete. To develop reliable mathematical models they have to be proven for consistency. This is still a challenging task because many verification techniques fail already for middle-sized models. Consequently, new methods, like decomposition methods or reduction approaches, are developed to circumvent this problem.
Methods: We present a new semi-quantitative mathematical model of the metabolism of Arabidopsis thaliana. We used the Petri net formalism to express the complex reaction system in a mathematically unique manner. To verify the model for correctness and consistency we applied concepts of network decomposition and network reduction such as transition invariants, common transition pairs, and invariant transition pairs.
Results: We formulated the core metabolism of Arabidopsis thaliana based on recent knowledge from literature, including the Calvin cycle, glycolysis and citric acid cycle, glyoxylate cycle, urea cycle, sucrose synthesis, and the starch metabolism. By applying network decomposition and reduction techniques at steady-state conditions, we suggest a straightforward mathematical modeling process. We demonstrate that potential steady-state pathways exist, which provide the fixed carbon to nearly all parts of the network, especially to the citric acid cycle. There is a close cooperation of important metabolic pathways, e.g., the de novo synthesis of uridine-5-monophosphate, the γ-aminobutyric acid shunt, and the urea cycle. The presented approach extends the established methods for a feasible interpretation of biological network models, in particular of large and complex models.
CROWDFUNDING PLATFORMS HAVE BECOME A VALUABLE ALTERNATIVE TO TRADITIONAL SOURCES OF FINANCING. HOWEVER, SOME PHENOMENA ON CROWDFUN DING PLATFORMS CAUSE UNDESIRABLE EXTERNAL EFFECTS THAT CAN ADVERSELY INFLUENCE THE FUNDING SUCCESS OF PROJECTS. ONE SUCH PHENOMENON IS PROJECT OVERFUNDING. IN ORDER TO INTERNALIZE THE EXTERNALITIES OF OVER FUNDING, WE PROPOSE A FUNDING REDISTRIBUTION APPROACH FOR IMPROVING OVERALL FUNDING RESULTS. TO EVALUATE THIS CONCEPT, WE DEVELOP AND DEPLOY AN AGENT-BASED MODEL.
Crowdfunding platforms offer project initiators the opportunity to acquire funds from the Internet crowd and, therefore, have become a valuable alternative to traditional sources of funding. However, some processes on crowdfunding platforms cause undesirable external effects that influence the funding success of projects. In this context, we focus on the phenomenon of project overfunding. Massively overfunded projects have been discussed to overshadow other crowdfunding projects which in turn receive less funding. We propose a funding redistribution mechanism to internalize these overfunding externalities and to improve overall funding results. To evaluate this concept, we develop and deploy an agent-based model (ABM). This ABM is based on a multi-attribute decision-making approach and is suitable to simulate the dynamic funding processes on a crowdfunding platform. Our evaluation provides evidence that possible modifications of the crowdfunding mechanisms bear the chance to optimize funding results and to alleviate existing flaws.
Die Tagungsreihe ECLE – Economy, Criminal Law, Ethics – steht für die im Einklang mit der Frankfurter Schule des Strafrechts stehende Überzeugung, dass moderne strafrechtliche Fragen, die einen Bezug zur Wirtschaft aufweisen, nicht durch das Recht alleine zu beantworten sind. Vielmehr sind die Perspektiven der Kriminalwissenschaften, der Ökonomie, der Politik und der Ethik mit der Praxis von Wirtschaftsstrafrecht und -strafverfahren zu konfrontieren und im Wege einer fächer- und länderübergreifenden Diskussion anzugehen. In ihrer zehnten Ausgabe stand das Thema „Wirtschaftsstrafrecht und Systeme“ im Mittelpunkt.
Die Tagungsreihe wird von Prof. Dr. Matthias Jahn, Eberhard Kempf, Prof. Dr. Cornelius Prittwitz und Dr. Charlotte Schmitt-Leonardy organisiert.
Ökosystem statt Nutzwald
(2011)
The transporter associated with antigen processing (TAP1/2) translocates cytosolic peptides of proteasomal degradation into the endoplasmic reticulum (ER) lumen. A peptide-loading complex of tapasin, major histocompatibility complex class I, and several auxiliary factors is assembled at the transporter to optimize antigen display to cytotoxic T-lymphocytes at the cell surface. The heterodimeric TAP complex has unique N-terminal domains in addition to a 6 + 6-transmembrane segment core common to most ABC transporters. Here we provide direct evidence that this core TAP complex is sufficient for (i) ER targeting, (ii) heterodimeric assembly within the ER membrane, (iii) peptide binding, (iv) peptide transport, and (v) specific inhibition by the herpes simplex virus protein ICP47 and the human cytomegalovirus protein US6. We show for the first time that the translocation pore of the transporter is composed of the predicted TM-(5-10) of TAP1 and TM-(4-9) of TAP2. Moreover, we demonstrate that the N-terminal domains of TAP1 and TAP2 are essential for recruitment of tapasin, consequently mediating assembly of the macromolecular peptide-loading complex.
Schönheit liegt auch in der Wissenschaft im Auge des Betrachters. So wie Eltern ihre Sprösslinge schön finden, schwärmen auch Forscher wie Mike Heilemann und Ivan Dikic von ihren Bildern fluoreszierender Bakterien. Doch wenn sie es auf das Cover einer Fachzeitschrift schaffen wollen, nehmen sie die Hilfe wissenschaftlicher Illustratorinnen wie Ella Marushchenko in Anspruch.
Im ersten Projekt der vorliegenden Arbeit wurden CD - 1 Mäuse mit drei unterschiedlichen Diäten für zwei Wochen ad libitum gefüttert. Die Diäten bestanden aus zwei kohlenhydratarmen, fettreichen Diäten und einer Standard Haltungsdiät. Die kohlenhydratarmen, fettreichen Diäten enthielten entweder Triheptanoin (dreifach mit Heptanoat verestertes Glycerol) oder Soja - Öl als Fettkomponente (jeweils 35 % der Gesamtkalorien). Nach zwei Wochen wurde ein ischämischer Schlaganfall für 90 min. mithilfe eines Silikonfadens induziert. Die Leber, das Blut und das Gehirn wurden nach dem Schlaganfall entnommen und die Konzentrationen der Metabolite β - Hydroxybutyrat, Glukose, Laktat und Citrat wurden mit der zuvor etablierten GC - MS-Methode ermittelt. Unter gleichen Bedingungen wurde eine Mikrodialysestudie durchgeführt.
Bei den Tieren, die die kohlenhydratarmen, fettreichen Diäten erhielten, konnte in den Leber - und Hirnhomogenaten, im Plasma sowie im Mikrodialysat eine Ketose festgestellt werden. Die BHB Konzentrationen durch eine Soja Diät erreichten im Leberhomogenat bis zu 4 mM, im Plasma bis zu 1,5 mM, im Hirnhomogenat bis zu 1,5 mM und im Mikrodialysat bis zu 30 µM. Um eine Aussage treffen zu können, ob das Gehirn die von der Leber produzierten Ketonkörper als Energiesubstrate nutzen kann, wurde eine Folgestudie (unter gleichen Bedingungen) durchgeführt. Bei dieser Studie wurde der Zeitpunkt der Gewebeentnahme 60 min. nach Entfernen des Fadens (Reperfusion) gewählt. In den Leber – und Hirnhomogenaten konnten erniedrigte Konzentrationen des Ketonkörpers BHB nachgewiesen werden. Die nicht operierten Tiere, die eine fettreiche Diät erhielten, hatten erhöhte Konzentrationen an Citrat in den genannten Geweben. Durch den Abbau des Ketonkörpers BHB können bei Verstoffwechslung in Geweben außerhalb der Leber, zwei Moleküle Acetyl - CoA gebildet werden. Diese gebildeten Acetyl - CoA Moleküle können in den Citratzyklus eingespeist werden.
Um diesen Befund mechanistisch besser verstehen zu können, wurde den Mäusen Propranolol (ein unselektiver β - Blocker) verabreicht, und zwar kurz nachdem der Faden die mittlere Zerebralarterie verschlossen hatte. Als Folge blieb bei den fettreich gefütterten Tieren die zuvor beobachtete Ketose, aus. Daraus wurde geschlossen, dass die auftretende Ketose bei den fettreich gefütterten Tieren durch adrenerge β - Rezeptoren vermittelt wurde. Zusammengefasst kann eine fettreiche bzw. ketogene Ernährung im Falle einer Ischämie die Versorgung des Gehirns durch die Bildung von Ketonkörper gewährleisten.
Die zu beobachtende hepatische Ketogenese aus dem ersten Projekt hat die Frage entstehen lassen, ob eine akute Gabe von β - Hydroxybutyrat (BHB) bei Entfernen des Fadens schützende Effekte auf das Verhalten bzw. die Mitochondrien als Kraftwerke der Zelle hat. Hierzu wurde BHB bei Reperfusion gegeben und die Wirkungen dieser Einmalgabe nach 24 h untersucht. Als erster Schritt wurde der Nachweis erbracht, dass eine exogene Gabe von BHB das Gehirn erreicht. Im zweiten Schritt wurde das Verhalten der Mäuse nach 24 h untersucht. Hierbei erbrachte die Gabe von BHB eine signifikante Verbesserung der sensorischen und motorischen Fähigkeiten der Mäuse. Die metabolischen Veränderungen nach 24 h wurden erneut in Leberhomogenaten und Plasma vermessen. Eine Einzelgabe von BHB bewirkte eine milde Ketose auch 24 h nach Reperfusion der mittleren Zerebralarterie. Um eine detailliertere Erkenntnis über die Wirkung von BHB zu erlangen, wurden die Mitochondrien als potentielles Ziel für BHB in den Fokus genommen. Die Einmalgabe von BHB verhinderte ein Absinken der Komplex – II Aktivität. Außerdem kann die Aktivität der Citratsynthase unter der Gabe von BHB erhalten werden, sodass die Mitochondrien vor allem im wichtigen Zeitraum nach der Reperfusion geschützt werden. Im Rahmen der Untersuchungen der Mitochondrien wurden unterschiedliche Substrateinflüsse auf die Respiration der isolierten Mitochondrien getestet. Bei Zugabe von BHB, Oxalacetat + Acetat oder Citrat zu dem Respirationsmedium stieg die Respiration der Mitochondrien an. Im Falle von Glukose, Propranolol oder Acetat wird die Respiration verringert. Bei Zugabe von Laktat, verbleibt die Respiration auf Ausgangsniveau. Abschließend ist festzustellen, dass die Einzelgabe von BHB nach 24 h das Verhalten der Mäuse verbessert, eine milde Ketose induziert, sowie Mitochondrien und die Citratsynthase gegen ischämische Ereignisse schützt.
Um die in dieser Arbeit gezeigten Daten über metabolische Veränderungen zeigen zu können, musste eine vorherige Etablierung der GC – MS Analytik vollzogen werden. Auf der einen Seite musste die Probenvorbereitung, aber auch die gesamte Vermessung der Proben aufgebaut werden. Es wurden insgesamt 11 Analyte in vier unterschiedlichen Kompartimenten quantifiziert. Die Nachweisgrenze lag bei diesen 11 Analyten bei 0,01 - 1 ng/µl, was einer umgerechneten Stoffmengenkonzentration von 0,5 - 10 µM entspricht. Mithilfe dieser Methode können optional weitere Substanzen aus verschiedenen Geweben zugänglich gemacht werden. Diese Arbeit bietet hierzu eine Anleitung, wie die Etablierung erfolgen kann. Im Rahmen der Probenvorbereitung wurden alle Schritte systematisch verbessert. Dazu wurden Wiederholungsmessungen für unterschiedliche Modalitäten vollzogen. Die Abundance und die Zeitbeständigkeit waren die wesentlichen Beurteilungskriterien. So wurden die Daten für die Extraktionseffektivität, die Lösungsmittelabhängigkeit der Silylierung, der Zusatz von Hünig - Base sowie die Temperatur und Zeitabhängigkeit der Silylierung in dieser Arbeit erarbeitet. Die Quantifizierung wurde anhand von internen Standardverbindungen durchgeführt. Die jeweiligen Response – Faktoren blieben über die gesamte Zeit nach der Etablierung konstant und erlaubten die Quantifizierung mit geringen Fehlern. Die Beurteilung der ermittelten Daten über die Validierung wurden anhand von geltenden Regelwerken der pharmazeutischen Industrie entschieden. Es wurde ein Protokoll entwickelt, das im Rahmen der universitären Forschung eine vertrauenswürdige Aussage über Veränderungen von Metabolitenspiegeln in vielen Geweben der Maus und der Ratte geben kann.
BACKGROUND: Ketone bodies are known to substitute for glucose as brain fuel when glucose availability is low. Ketogenic diets have been described as neuroprotective. Similar data have been reported for triheptanoin, a fatty oil and anaplerotic compound. In this study, we monitored the changes of energy metabolites in liver, blood, and brain after transient brain ischemia to test for ketone body formation induced by experimental stroke.
METHODS AND RESULTS: Mice were fed a standard carbohydrate-rich diet or 2 fat-rich diets, 1 enriched in triheptanoin and 1 in soybean oil. Stroke was induced in mice by middle cerebral artery occlusion for 90 minutes, followed by reperfusion. Mice were sacrificed, and blood plasma and liver and brain homogenates were obtained. In 1 experiment, microdialysis was performed. Metabolites (eg glucose, β-hydroxybutyrate, citrate, succinate) were determined by gas chromatography-mass spectrometry. After 90 minutes of brain ischemia, β-hydroxybutyrate levels were dramatically increased in liver, blood, and brain microdialysate and brain homogenate, but only in mice fed fat-rich diets. Glucose levels were changed in the opposite manner in blood and brain. Reperfusion decreased β-hydroxybutyrate and increased glucose within 60 minutes. Stroke-induced ketogenesis was blocked by propranolol, a β-receptor antagonist. Citrate and succinate were moderately increased by fat-rich diets and unchanged after stroke.
CONCLUSIONS: We conclude that brain ischemia induces the formation of β-hydroxybutyrate (ketogenesis) in the liver and the consumption of β-hydroxybutyrate in the brain. This effect seems to be mediated by β-adrenergic receptors.
Eine überlebenswichtige Eigenschaft von Mensch und Tier ist es, sich bei Gefahr durch eine Schreckreaktion in Sicherheit zu bringen. Doch woran erkennt ein Organismus, in welcher Situation es „sinnvoll“ wäre, sich zu erschrecken und welche Eigenschaften sensorischer Stimuli tragen zu dem Gefahreneindruck bei? Bei plötzlich eintretenden, lauten auditorischen Reizen kann es zur Auslösung der akustischen Schreckreaktion kommen. Dies führt bei Menschen, aber auch bei kleineren Säugetieren zu einer reflexartigen Kontraktion der Nacken-, Gesichts- und Skelettmuskulatur. Die Erforschung der akustisch evozierten Schreckreaktion (ASR) dient dem besseren Verständnis der neurobiologischen Grundlagen sensorischer Verarbeitung. Modulationen der ASR mithilfe von Präpulsen (Präpulsinhibition) ermöglichen Einblicke in die Funktion der Kochlea, des Hörnervs, der Hirnstammstrukturen und anderer beteiligter Gehirnregionen.
In dieser Arbeit wurden kurzzeitige Änderungen von Frequenz oder Intensität des akustischen Hintergrundes als neuartige Präpulse untersucht. Die Bedeutung verschiedener Reizparameter dieser Präpulse wurde in der vorliegenden Arbeit zum ersten Mal systematisch erforscht. Um zu prüfen, welche Präpulsstimulationen eine Inhibition der ASR auslösen können, wurde eine Reihe von Parametern umfassend getestet. In einem weiteren Schritt wurde analysiert, ob es mithilfe von gezielten Änderungen von Frequenz oder Intensität möglich sein könnte, Unterscheidungsschwellen, oder gar Hörschwellen von Versuchstieren zu bestimmen.
Die Experimente zur Modulation der ASR wurden mit weiblichen Sprague Dawley-Ratten durchgeführt. Dabei wurde eine Vielzahl von Verhaltensparadigmen untersucht. Dazu zählten Präpulse mit unterschiedlichem Frequenzgehalt und variabler Dauer. Zusätzlich wurden neuartige Paradigmen etabliert, um die Fähigkeit zur Frequenz- und Intensitätsdiskriminierung zu untersuchen. Hierbei wurde der Frequenzgehalt oder die Intensität einer kontinuierlichen Hintergrundstimulation verändert, um eine Präpulswirkung zu erzeugen. Um die Möglichkeiten der Bestimmung von Hörschwellen mittels der Präpulsinhibition (PPI) zu ergründen, wurde die Intensität von Präpulsen systematisch verändert. Die so generierten Schwellenwerte wurden durch die Messung früher akustisch evozierter Hirnstammpotenziale verifiziert. Schließlich sollten, unter Zuhilfenahme der Signaldetektionstheorie, aus den erhobenen Daten diverse Schwellen bestimmt werden: Für die Intensitätsänderungen der Präpulse in Stille wurden Hörschwellen bestimmt, während bei Änderungen der Frequenz und Intensität Unterscheidungsschwellen bestimmt werden sollten.
Mit steigender Größe eines Frequenzsprungs in einer kontinuierlichen Hintergrundstimulation war eine stärkere Inhibition der ASR feststellbar; ein Effekt, der stark von der Hintergrundfrequenz abhängig war. Bei einer Stimulation mit 8 kHz konnten signifikant höhere Inhibitionswerte erzielt werden als mit 16 kHz. Bei der Untersuchung des Zeitablaufs der Stimulation ergab sich, dass eine abgesetzte Stimulation mit einer Abweichung von 80 ms Dauer bis 50 ms vor dem Schreckreiz für die höchsten Inhibitionen sorgte.
Die durch eine Intensitätsänderung einer kontinuierlichen Hintergrundstimulation ausgelöste PPI hing primär von der Größe und Richtung des Intensitätssprungs ab. Mit zunehmender Sprunggröße stiegen die Inhibitionswerte an. Eine Erhöhung der Hintergrundintensität um 10 dB hatte einen signifikanten Einfluss auf die Inhibitionswerte. Auch hier zeigte sich eine höhere Sensitivität in Form von höheren Inhibitionen für Stimuli mit einer Hintergrundfrequenz von 8 kHz als für alle anderen getesteten Hintergrundfrequenzen.
Die Bestimmung von Hörschwellen mittels intensitätsabhängiger PPI wies im Vergleich mit den elektrophysiologisch bestimmten Hörschwellen ein heterogenes Bild mit starken individuellen Schwankungen auf: Bei etwa der Hälfte der Tiere waren die Hörschwellen beider Messungen sehr vergleichbar, bei den übrigen Tieren konnten mittels PPI für eine oder mehrere Frequenzen keine aussagekräftigen Hörschwellen erzielt werden. Die elektrophysiologisch bestimmten Hörschwellen waren am sensitivsten, während PPI-Stimulationen signifikant höher waren. Außerdem bewirkten PPI-Stimulationen mit Reintönen signifikant sensitivere Hörschwellen im Vergleich zu einem Schmalbandrauschen.
Für die Bestimmung der Unterscheidungsschwellen von Frequenzänderungen konnte beobachtet werden, dass die Tiere auf Frequenzsprünge hin zu niedrigeren Frequenzen signifikant sensibler reagierten, als hin zu Aufwärtssprüngen (-1.2 bzw. +4.5%). Bei der Intensitätsunterscheidung hingegen konnte beobachtet werden, dass die Tiere signifikant sensitiver auf Intensitätserhöhungen als auf Erniedrigungen reagierten (-5.9 bzw. +2.7 dB).
Zusammenfassend konnte in der vorliegenden Arbeit festgestellt werden, dass die PPI zur Bestimmung von absoluten Hörschwellen starken Schwankungen unterlag, sodass diese Methode nur eingeschränkt als Alternative zu operanter Konditionierung oder elektrophysiologischen Ableitungen in Frage kommt. Des Weiteren erzeugten bereits kleine Änderungen des Frequenzgehalts oder der Intensität einer Hintergrundstimulation eine robuste PPI. Somit können reflexbasierte Messungen mit überschwelligen Stimuli genutzt werden, um Unterscheidungsschwellen in Versuchstieren zu bestimmen. Diese Herangehensweise stellt also eine vielversprechende Methode dar, um Hörstörungen zu untersuchen, die nach einem Schalltrauma auftreten können. In einem nächsten Schritt könnte sie zur weiteren Charakterisierung von verstecktem Hörverlust beitragen.
Modellierung der klimatischen Habitateignung verschiedener krankheitsübertragender Vektorarten
(2018)
Der Klimawandel hat einen starken Einfluss auf die Verbreitungsgebiete von Arten. Infolgedessen kann sich das Verbreitungsgebiet von Arten verschieben, einschränken oder ausweiten. Bei thermophilen Arten wird vermutet, dass sie von den klimatischen Änderungen profitieren und sie sich wahrscheinlich ausbreiten werden. Eine solche Ausbreitung, wozu auch die Einwanderung von gebietsfremden Arten zählt, hätte nicht nur zahlreiche Konsequenzen für diese Ökosysteme, sondern könnte sich auch zu einem ernsten Gesundheitsrisiko entwickeln, wenn es sich bei den einwandernden Neobiota um Vektorarten handelt.
Stechmücken und Sandmücken, als blutsaugende Insekten, zählen zu den bekanntesten Vektorarten. Sie sind in der Lage, eine Vielzahl von Infektionskrankheiten wie das Denguefieber oder das Gelbfieber, aber auch protozoische Parasiten wie "Leishmania"-Arten zu übertragen. Als thermophile Arten sind viele dieser Vektoren aktuell in ihrer Verbreitung weitgehend auf tropische und subtropische Gebiete beschränkt. Eine Einwanderung in gemäßigtere Gebiete kann zu einer Einschleppung der durch sie übertragenden Erreger führen und damit zum Ausbruch von Infektionskrankheiten. Aufgrund der medizinischen Relevanz dieser Arten ist es essentiell, die räumliche Verbreitung, sowie die abiotischen Ansprüche der Vektorarten zu kennen, um deren mögliche Ausbreitung nachzuvollziehen.
Vor diesem Hintergrund beschäftigte sich die vorliegende kumulative Dissertation mit den klimawandelinduzierten Änderungen der Habitateignung verschiedener medizinisch relevanter Vektorarten. Dabei wurden die zwei invasiven Stechmückenarten "Aedes albopictus" (I-III) und "Aedes japonicus" (III), sowie zehn in Europa bereits vorkommende Sandmückenarten der Gattung "Phlebotomus" (IV), untersucht. Die Arbeit basiert auf vier (ISI-) Publikationen. Unter Verwendung ökologischer Nischenmodellierung wurden geeignete Gebiete unter aktuellen und zukünftigen Klimabedingungen bestimmt. Um dabei sowohl räumliche als auch zeitliche Aspekte zu berücksichtigen, wurden mehrere räumliche Skalen (Deutschland und Europa), sowie Zeitperioden (2030, 2050 und 2070) betrachtet. Des Weiteren wurden verschiedene Ansätze (einzelne Algorithmen und Ensemble-Modelle) zur Modellierung der Habitateignung verwendet.
Die Ergebnisse dieser Dissertation zeigen eine zukünftige klimawandelbedingte Ausweitung der geeigneten Gebiete für viele der betrachteten Vektorarten. So konnte gezeigt werden, dass die Habitateignung für "Aedes albopictus" in Deutschland (I) und in Europa (III) zukünftig deutlich zunimmt. Auch für die Sandmückenarten "Phlebotomus alexandri", "Phlebotomus neglectus", "Phlebotomus papatasi", "Phlebotomus perfiliewi" und "Phlebotomus tobbi" konnte eine deutliche Zunahme der klimatisch geeigneten Gebieten projiziert werden (IV).
Lediglich Arten, wie die Asiatische Buschmücke "Aedes japonicus" (III) und auch kältetolerantere Sandmücken, wie "Phlebotomus ariasi" und "Phlebotomus mascittii" (IV) scheinen weniger von diesen klimatischen Veränderungen zu profitieren und könnten in Zukunft sogar aktuell geeignete Gebiete verlieren (klimawandelinduzierte Arealverkleinerung). Bei "Aedes japonicus" konnte dies auf eine engeren Nische mit einem Optimum bei vergleichsweise niedrigen Temperaturen zurückgeführt werden (III).
Am Beispiel von "Aedes albopictus" wurden ferner Umweltfaktoren identifiziert, die die Verbreitung der Art limitieren (II). Als wärmeliebende Art spielen bei "Aedes albopictus" in Mitteleuropa insbesondere die niedrigen Temperaturen eine Rolle, während in Zukunft die Sommertrockenheit in Südeuropa zunehmend eine Rolle spielen könnte.
Nischenmodellierung stellt trotz ihrer vereinfachenden Annahmen und Unsicherheiten, eine hilfreiche Methode zur Untersuchung klimawandelinduzierter Arealverschiebungen dar. Mit Hilfe der Modellierungsergebnisse konnten Gebiete mit einem hohen Etablierungsrisiko für die Vektorarten identifiziert werden, welche daher im Fokus künftiger Überwachungsprogramme stehen sollten. In Zukunft könnten mehr Vektorarten geeignete Bedingungen in Mitteleuropa finden, wodurch die Vektordiversität zunehmen wird. Dadurch könnte auch das Risiko für einen Ausbruch der durch die Vektoren übertragenen Krankheiten steigen.
Auch wenn das Vorhandensein eines kompetenten Vektors eine unerlässliche Voraussetzung für den Ausbruch einer Infektionskrankheit darstellt, gibt es noch weitere Faktoren, wie das Vorhandensein des Erregers. In Bezug auf die Risikoabschätzung vektorassoziierter Krankheiten sollten neben der Verbreitung des Vektors und des Erregers auch die abiotischen Bedingungen für die Entwicklung des Erregers berücksichtigt werden. Neben neu eingewanderten Arten sollten zudem auch die heimischen Arten in Bezug auf ihre Vektorkompetenz untersucht werden, da diese ebenfalls als potentielle Vektoren dienen und somit das Gesundheitsrisiko weiter erhöhen könnten.
The genus Ebolavirus comprises some of the deadliest viruses for primates and humans and associated disease outbreaks are increasing in Africa. Different evidence suggests that bats are putative reservoir hosts and play a major role in the transmission cycle of these filoviruses. Thus, detailed knowledge about their distribution might improve risk estimations of where future disease outbreaks might occur. A MaxEnt niche modelling approach based on climatic variables and land cover was used to investigate the potential distribution of 9 bat species associated to the Zaire ebolavirus. This viral species has led to major Ebola outbreaks in Africa and is known for causing high mortalities. Modelling results suggest suitable areas mainly in the areas near the coasts of West Africa with extensions into Central Africa, where almost all of the 9 species studied find suitable habitat conditions. Previous spillover events and outbreak sites of the virus are covered by the modelled distribution of 3 bat species that have been tested positive for the virus not only using serology tests but also PCR methods. Modelling the habitat suitability of the bats is an important step that can benefit public information campaigns and may ultimately help control future outbreaks of the disease.
Das Ziel der vorliegenden Arbeit war, zu analysieren, welche Einflussgrößen sich auf die Kryotransferergebnisse positiv oder negativ auswirken können, um somit Paaren, die über kryokonservierte Zellen verfügen, am effektivsten zu einem gemeinsamen Kind zu verhelfen.
Untersucht wurde, ob das Alter der Patientinnen, die Art der Befruchtung, die Anzahl der übertragenen Embryonen und die Zyklusvorbereitung einen Unterschied auf die Entwicklungs- und Implantationsfähigkeit menschlicher Eizellen sowie auf die Schwangerschaftsrate nach Kryokonservierung und Auftauen im Pronucleus-Stadium aufwiesen.
In der vorliegenden Studie wurden 126 Patientinnen mit ungewollter Kinderlosigkeit, die zwischen 2002 und 2004 am Universitätsklinikum Frankfurt am Main in Behandlung waren, aufgenommen. Das Durchschnittsalter der Patientinnen lag bei 33,3 Jahren. Von 226 durchgeführten Kryotransferzyklen resultierten die Pronukleus-Eizellen bei 34 Kryotransferzyklen aus einer In-vitro-Fertilisation (IVF) und bei 192 Zyklen aus einer intrazytoplasmatischen Spermieninjektion (ICSI).
Es wurde festgestellt, dass in der vorliegenden Studie die erzielte Erfolgsrate, gemessen an der relativ geringen Schwangerschaftsrate, deutlich niedriger lag als beim deutschen IVF-Register. Das Resultat muss jedoch auch unter dem Aspekt der schlechten Ergebnisse der IVF-/ICSI-Therapie in der untersuchten Gruppe betrachtet werden.
Die Ergebnisse der Kryotherapie sind dagegen mit den Zahlen anderer Reproduktionszentren vergleichbar, die derzeit eine Effektivität von durchschnittlich 19,12 % erreichen (DIR 2007) (23).
Bei der Untersuchung wurde jeweils nur der erste und zweite Kryotransferzyklus pro Patientin ausgewertet, damit die Voraussetzung zur Untersuchung der Einflüsse anamnestischer Faktoren gleich war.
Durch ICSI befruchtete Eizellen führten nach Kryokonservierung seltener zu einer Schwangerschaft (11,59%) als nach IVF (16,66%), beim Primärtransfer war das Ergebnis weniger verschieden (9,41% und 7,40%).
Die Vorbereitung des Kryotransferzylus war insofern relevant, als das der Transfer im spontanen Zyklus bezüglich der Schwangerschaftsrate am erfolgreichsten war (13,79%). Der Transfer in einem artifiziellen Zyklus, also nach Stimulation aus einer Kombination von HMG mit FSH, der alleinigen Verabreichung beider Medikamente oder nach dem Kaufmann-Schema, erbrachte dagegen nur eine geringe Schwangerschaftsrate von 6,45%.
Signifikante Unterschiede wiesen die im Punktionszyklus verwendeten Medikamente zur ovariellen Stimulation hinsichtlich der Degenerationsrate nach dem Auftauen der PN-Stadien auf, die nach HMG-Stimulation niedriger (19,35%) als nach FSH-Stimulation (30,82%) war, die Schwangerschaftsrate wies allerdings keine deutlichen Unterschiede auf (11,90% und 13,08%).
Das Alter der Patientinnen hatte wider Erwarten in der vorliegenden Untersuchung keinen eindeutigen Einfluss auf die Schwangerschaftsrate.
Die Resultate bestätigten, dass ein Transfer von maximal drei erlaubten Embryonen die besten Ergebnisse erzielte (19,6 %), hingegen bei einem Transfer von zwei Embryonen ein Ergebnis von nur 5,5 % vorlag. Dieses Ergebnis spricht, wie bereits bei anderen Forschungsergebnissen postuliert, für einen Transfer von drei Embryonen und sollte somit angestrebt werden.
Es lässt sich zusammenfassen, dass die Ergebnisse der Kryotransferbehandlungen in Bezug auf die untersuchten Parameter, wie spontan/hormonelle Kryotransferzyklen, IVF- oder ICSI- Behandlung und Alter, nur geringe Unterschiede aufwiesen.
Einen signifikanten Einfluss auf die Erfolgsrate hatten jedoch die Anzahl der transferierten Embryonen und die verschiedenen Stimulationsmedikamente auf die Degeneration der Oozyten.
Die vorliegende Arbeit hat gezeigt, dass die Kryokonservierung die Effizienz der reproduktionsmedizinischen Behandlung nachweislich erhöht. Darüber hinaus plädiert sie für ein Überdenken des deutschen Embryonenschutzgesetzes, um somit den Frauen eine hohe Anzahl von Behandlungszyklen zu ersparen.
In order to promote the accessibility of biodiversity data in historic and contemporary literature, we introduce a new interdisciplinary project called BIOfid (FID=Fachinformationsdienst, a service for providing specialized information). The project aims at a mobilization of data available in print only by combining digitization of scientific biodiversity literature with the development of innovative text mining tools for complex, eventually semantic searches throughout the complete text corpus. A major prerequisite for the development of such search tools is the provision of sophisticated anatomy ontologies on the one hand, and of complete lists of species names (currently considered valid as well as all synonyms) at a global scale on the other hand. In the initial stage, we chose examples from German publications of the past 250 years dealing with the geographic distribution and ecology of vascular plants (Tracheophyta), birds (Aves), as well as moths and butterflies (Lepidoptera) in Germany. These taxa have been prioritized according to current demands of German research groups (about 50 sites) aiming at analyses and modeling of distribution patterns and their changes through time. In the long term, we aim at providing data and open source software applicable for any taxon and geographic region. For this purpose, a platform for open access journals for long-term availability of professional e-journals will be established. All generated data will also be made accessible through GFBio (German Federation for Biological Data). BIOfid is supported by the LIS-Scientific Library Services and Information Systems program of the German Research Foundation (DFG).
Über einen Schriftsteller und seinen Körper : Aris Fioretos wird neuer Frankfurter Poetikdozent
(2024)
To reconstruct ocean circulation changes during specific periods of Earth history, benthic and planktic foraminifera were used as proxies in the different parts of this thesis. Both studied time periods, the Late Cretaceous and the early Pleistocene, are characterized by long-term climate cooling and major changes in ocean circulation. The first part of this thesis concentrated in the Late Cretaceous. During the Late Cretaceous long-term cooling phase, benthic foraminiferal δ18O values show a positive shift lasting about 1.5 Myr (71.5–70 Ma). This shift can be observed on a global scale and has become known as the Campanian-Maastrichtian Boundary Event (CMBE). It is proposed that this δ18O excursion is influenced either by changing intermediate- to deep-water circulation or by temporal build-up of Antarctic ice sheets. Benthic foraminiferal assemblage counts from a southern high-latitudinal site near Antarctica (ODP Site 690) are analyzed to test if the influence of the CMBE on the benthic species composition. One of the two discussed hypotheses for the causation of the δ18O transition is a change in intermediate- to deep-water circulation from low-latitude to high-latitude water masses. This change would result in cooler temperatures, higher oxygen concentration, and possibly lower organic-matter flux at the seafloor, causing a major benthic foraminiferal assemblage change. Another possible explanation of the δ18O transition of the CMBE is significant ice formation on Antarctica. However no major benthic foraminiferal assemblage change would be expected in this case. The benthic foraminiferal assemblage of Site 690 shows a separation of the studied succession into two parts with significantly different species composition. The older part (73.0–70.5 Ma) is dominated by species, which are typical for lower bottom water oxygen concentration and more common in low-latitude assemblages. Species dominating the younger part (70.0–68.0 Ma) are indicators for well-oxygenated bottom waters and more common in high-latitude assemblages. This change in the benthic foraminiferal assemblages is interpreted to represent a shift of low-latitude toward high-latitude dominated intermediateto deep-water sources. A change in oceanic circulation was therefore at least a major component of the CMBE. The Pacific Ocean contributed significantly to the climatic development during the Late Cretaceous cooling period. The contribution of ocean circulation changes in the Pacific Ocean to the Late Cretaceous climatic development in general and the CMBE and Mid-Maastrichtian Event (MME) in particular, however, is poorly understood. Previously measured high resolution planktic and benthic stable isotope data and a neodymium (Nd) isotope record from the Pacific ODP Site 1210 (Shatsky Rise, tropical Pacific Ocean) for the Campanian to Maastrichtian (69.5 to 72.5 Ma) are used to reconstruct changes in surface- and bottom water temperatures as well as changes in the source region of deep- to intermediate waters [see Appendix 4; Jung et al. 2013]. The results of the benthic foraminiferal δ18O and Nd isotope records in combination with Nd isotope records from other studies indicate changes in the intensity of intermediate- to deep ocean circulation in the tropical Pacific across the Campanian-Maastrichtian interval [see Appendix 4; Jung et al. 2013]. During the early Maastrichtian (72.5 to 69.5 Ma), a three-million-year-long period of cooler conditions and a simultaneous change towards less radiogenic Nd isotope signatures is interpreted to represent a period of increased admixture and northward flow of deep waters from the Southern Ocean (Southern Component Water, SCW). This change was probably caused by an intensified formation of deep waters in the Southern Ocean. This was reduced again during the MME (69.5 to 68.5 Ma). This early Maastrichtian cold interval is similar to the CMBEδ13C fall and succeeding δ13C rise towards the MME and is therefore also interpreted to represent tectonically forced, long-term changes in the global carbon cycle and thus a tectonic forcing of the early Maastrichtian climate cooling. Overall, the Campanian-Maastrichtian Nd and stable isotope records of Shatsky Rise indicate changes in ocean circulation that are paralleled by global warming and cooling periods. The fluctuating strength of SCW contribution in the tropical Pacific points towards an increased respectively weakened ocean circulation, which is probably related to the strength of deep-water formation in the Southern Ocean [see Appendix 4; Jung et al. 2013]. For this study, the analysis of benthic foraminiferal assemblages of Site 1210 is carried out for the same time interval (69.5 to 72.5 Ma) as Nd and stable isotopes to evaluate the influence of intermediate- to deep ocean circulation changes on the benthic foraminiferal community. The possible reaction of benthic foraminiferal assemblages is compared to the results of stable isotope and neodymium isotopes. The observed changes in species abundances only partly reflect the circulation changes reconstructed with Nd and stable oxygen istopes. For example, Stensioina spp., Aragonia spp. and Lenticulina spp., cold-water preferring species, start to be increasingly abundant at the beginning of enhanced influence of SCW. However, their abundance pattern does not follow the varying strength of the cold SCW influence at Shatsky Rise. Other species prefer lesser oxygen concentrations and warmer bottom water, e.g. Paralabamina spp. and Globorotalites spp. Paralabamina spp. has its highest relativ abundance at the beginning of the studied succession, where the influence of SCW is small. However, this taxa occurs throughout the record, even though the influence of SCW increases. Globorotalites spp. is even most abundance after the CMBE, where bottom waters are till cold and influenced by SCW. This leads to the conclusion that the varying strength of SCW in the tropical Pacific at Shatsky Rise through the studied interval is not facilitating a significant faunal turnover as has been observed at the South Atlantic Site 690 (Chapter 3). These results of the benthic foraminiferal assemblage analysis suggest a rather minor influence of the SCW on the major environmental factors that are generally influencing benthic foraminiferal communities (e.g., oxygen concentration, organic matter flux to the sea floor, bottom-water temperature). The second major part of this thesis focused on the late Pliocene-earliest Pleistocene. The late Pliocene is characterized by a long-term global cooling trend resulting in a major increase of Arctic ice sheets from around 3 Ma onwards, culminating in the Plio-Pleistocene intensification of the Northern Hemisphere glaciation. At around 2.7 Ma, large amplitude glacial-interglacial excursions (~1‰ δ18O in benthic foraminiferal calcite) in benthic oxygen isotopes can be observed. Marine isotope stage (MIS) 100 at around 2.55 Ma is the first glacial, when widespread ice rafted debris has been found in sediments in the North Atlantic Ocean. To gain a deeper understanding of the climatic evolution of the latest Pliocene-early Pleistocene, it is necessary to improve the reconstructions of North Atlantic paleohydrography, as the North Atlantic provides a key region for global climate. The consequences of the intensification of Northern Hemisphere on the early Pleistocene North Atlantic thermocline stratification and intermediate waters are still poorly understood. However, surface hydrography, the history of the thermocline and development of North Atlantic intermediate waters are well-studied for the Last Glacial Maximum (LGM). These well-known mechanisms responsible for the LGM in comparison with the present-day interglacial North Atlantic are used as an analogue for te early Pleistocene glacialinterglacials cycles. In this study, suborbitally resolved stable oxygen and carbon isotope and Mg/Ca records are measured from a deep-dwelling planktic foraminifera (Globorotaliacrassaformis) from Integrated Ocean Drilling Program Site U1313 (North Atlantic, 41°N) covering marine oxygen isotope stages MIS 103 to 95 (early Pleistocene, 2.6 to 2.4 Ma). The results are interpreted to represent a change in intermediate-water masses on glacialinterglacial timescales. During glacials geochemical records in G. crassaformis (~500–1000 m) bear the imprint of Glacial North Atlantic Intermediate Water (GNAIW), while during interglacials this species reflects the signature of the influence of Mediterranean Outflow Water (MOW) in combination with the subtropical gyre. The comparison of this data with the published records from G. ruber from the same samples facilitates the reconstruction of glacial-interglacial stratification changes of the upper water column at Site U1313. The results show that larger gradients of temperature, salinity and δ13C prevailed during glacials, suggesting a stronger stratification of the upper water column. This can be seen to indicate glacial-interglacial changes in ntermediate water masses in the North Atlantic similar to those reconstructed for the latest Pleistocene. As an additional proxy, the clumped isotope paleothermometer is applied for the Late Cretaceous study as well as for the early Pleistocene. This proxy is commonly assumed to be independent of other factors than temperature. Clumped isotopes are measured for the Late Cretaceous Site 690 on the planktic foraminiferal species Archaeoglobigerina australis and compared to already existing stable oxygen isotopes of this species. This is assumed to enable the reconstruction of paleotemperature independent of ice volume and therefore contribute to the long-lasting discussion whether there was a temporal ice build-up on Antarctic during the Campanian-Maastrichtian cooling period. For the early Pleistocene, the planktic foraminiferal species G. crassaformis is used from Site U1313 from MIS 99 (interglacial) and MIS 98 (glacial). This provides the opportunity to separate ice volume, salinity and temperature effects on the measured δ18O record of G. crassaformis. The results of the clumped isotope measurements reveal comparatively large standard errors. For the Late Cretaceous the standard error of the clumped isotope measurements proved too large to allow any conclusions on the temperature component on the δ18O record of A. australis. For the early Pleistocene, the temperature difference is also too small to be reconstructed with the standard error of the clumped isotope measurements in this study. Measuring many replicates of one sample would minimize the standard error considerably. However, the amount necessary to measure replicates cannot be gained for either time period, as almost all foraminifera were picked from the respective samples. It is concluded that the respective questions may be solved with a different method of clumped isotope analysis requiring less sample material. This method is, for example, available at the ETH Zurich.
The formation of terrestrial planets was a complex process which begun in the very early stage of the Solar System in the protoplanetary disk (PPD). Chondrites are fragments of planet precursors, which have never experienced differentiation and can help to reconstruct the first processes leading to planet formation. The main components of chondrites are chondrules, calcium-aluminum-rich inclusions (CAIs), amoeboid olivine aggregates (AOAs), metals and fine-grained material. Each of these components formed by a complex mechanism involving aggregation and/or melting. Previous research has already provided an overall view of the formation of these objects, however, there are still open questions regarding the aggregation behavior of particles, the heating mechanism(s) and the thermal history of CAIs, AOAs and chondrules. For instance, the involvement of flash-heating events and electrostatics in the aggregation and melting of these objects has been a keen topic of discussion.
The aim of this doctoral thesis was to develop and carry out an experiment to study various early Solar System processes under long-term microgravity. In the project with the acronym EXCISS (Experimental Chondrule Formation aboard the ISS), free-floating, 126(23)µm-sized Mg2SiO4 dust particles were exposed to electric fields and electric discharges.
The experimental set-up was installed inside a 10x10x15 cm3-sized container and consisted of an arc generation unit connected to the sample chamber, a camera with an optical system, a power supply unit with lithium-ion batteries and the EXCISS mainboard with a Raspberry Pi Zero and mass storage devices. The sample chamber was manufactured from quartz glass and the experiments were filmed. The complete experiment container was subsequently returned to the Goethe University and the samples were analyzed with scanning electron microscopy, electron backscatter diffraction and synchrotron micro-CT.
Video analysis has shown that particles, which were agitated by electric discharges, align in chains within the electric field with their longest axis parallel to the electric field lines. Consequently, electric fields could have influenced the inner structure and porosity of particle aggregates in the PPD.
The discharge experiments produced fused aggregates and individual melt spherules.
The fused aggregates share many morphological characteristics with natural fluffy-type CAIs and some igneous CAIs found in chondrites. Consequently, CAIs could have formed by the aggregation of particles with various degrees of melting. Further, a small amount of melting could have supplied the required stability for such fractal structures to have survived transportation and aggregation to, and subsequent compaction within, developing planetesimals.
Some initial particles were completely melted by the arc discharges and formed melt spherules. The newly formed olivines crystallized with a preferred orientation of the [010] axis perpendicular to the surface of the spherule. Similar preferred orientations have been found in natural chondrules. However, the microstructure differs from the results of previous experiments on Earth, which show, for example, crystal settling on one side of the sample because of the influence of gravity. Furthermore, the melt spherules show evidence for an interaction of the melt with the surrounding hot gas. Therefore, microgravity experiments with more advanced experimental parameters bear great potential for future chondrule formation experiments.
In order to gain further insights into early solar system aggregation processes, we carried out an experiment on board the International Space Station, which allowed us to study the behavior of dust particles exposed to electric arc discharges under long-term microgravity. The experiment led to the formation of robust, elongated, fluffy aggregates, which were studied by scanning electron microscopy, electron backscatter diffraction, and synchrotron micro-computed tomography. The morphologies of these aggregates strongly resemble the typical shapes of fractal fluffy-type calcium-aluminum-rich inclusions (CAIs). We conclude that a small amount of melting could have supplied the required stability for such fractal structures to have survived transportation and aggregation to and compaction within planetesimals. Other aggregates produced in our experiment have a massy morphology and contain relict grains, likely resulting from the collision of grains with different degrees of melting, also observed in some natural CAIs. Some particles are surrounded by igneous rims, which remind in thickness and crystal orientation of Wark–Lovering rims; another aggregate shows similarities to disk-shaped CAIs. These results imply that a (flash-)heating event with subsequent aggregation could have been involved in the formation of different morphological CAI characteristics.
Chondrules are thought to play a crucial role in planet formation, but the mechanisms leading to their formation are still a matter of unresolved discussion. So far, experiments designed to understand chondrule formation conditions have been carried out only under the influence of terrestrial gravity. In order to introduce more realistic conditions, we developed a chondrule formation experiment, which was carried out at long-term microgravity aboard the International Space Station. In this experiment, freely levitating forsterite (Mg2SiO4) dust particles were exposed to electric arc discharges, thus simulating chondrule formation via nebular lightning. The arc discharges were able to melt single dust particles completely, which then crystallized with very high cooling rates of >105 K h−1. The crystals in the spherules show a crystallographic preferred orientation of the [010] axes perpendicular to the spherule surface, similar to the preferred orientation observed in some natural chondrules. This microstructure is probably the result of crystallization under microgravity conditions. Furthermore, the spherules interacted with the surrounding gas during crystallization. We show that this type of experiment is able to form spherules, which show some similarities with the morphology of chondrules despite very short heating pulses and high cooling rates.
Staphylococcus aureus proteins Sbi and Efb recruit human plasmin to degrade complement C3 and C3b
(2012)
Upon host infection, the human pathogenic microbe Staphylococcus aureus (S. aureus) immediately faces innate immune reactions such as the activated complement system. Here, a novel innate immune evasion strategy of S. aureus is described. The staphylococcal proteins surface immunoglobulin-binding protein (Sbi) and extracellular fibrinogen-binding protein (Efb) bind C3/C3b simultaneously with plasminogen. Bound plasminogen is converted by bacterial activator staphylokinase or by host-specific urokinase-type plasminogen activator to plasmin, which in turn leads to degradation of complement C3 and C3b. Efb and to a lesser extend Sbi enhance plasmin cleavage of C3/C3b, an effect which is explained by a conformational change in C3/C3b induced by Sbi and Efb. Furthermore, bound plasmin also degrades C3a, which exerts anaphylatoxic and antimicrobial activities. Thus, S. aureus Sbi and Efb comprise platforms to recruit plasmin(ogen) together with C3 and its activation product C3b for efficient degradation of these complement components in the local microbial environment and to protect S. aureus from host innate immune reactions.
Highlights
• MRI and ultrasound provided significant correlations between findings suggestive of vasculitis and the final diagnosis.
• Careful selection of available imaging techniques is warranted considering the time course, location, and clinical history.
• Considering its moderate diagnostic power to distinguish tracer uptake, a holistic view of PET/CT findings is essential.
Abstract
Purpose: To assess the diagnostic value of different imaging modalities in distinguishing systemic vasculitis from other internal and immunological diseases.
Methods: This retrospective study included 134 patients with suspected vasculitis who underwent ultrasound, magnetic resonance imaging (MRI), or 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) between 01/2010 and 01/2019, finally consisting of 70 individuals with vasculitis. The main study parameter was the confirmation of the diagnosis using one of the three different imaging modalities, with the adjudicated clinical and histopathological diagnosis as the gold standard. A secondary parameter was the morphological appearance of the vessel affected by vasculitis.
Results: Patients with systemic vasculitis had myriad clinical manifestations with joint pain as the most common symptom. We found significant correlations between different imaging findings suggestive of vasculitis and the final adjudicated clinical diagnosis. In this context, on MRI, vessel wall thickening, edema, and diameter differed significantly between vasculitis and non-vasculitis groups (p < 0.05). Ultrasound revealed different findings that may serve as red flags in identifying patients with vasculitis, such as vascular occlusion or halo sign (p = 0.02 vs. non-vasculitis group). Interestingly, comparing maximal standardized uptake values from PET/CT examinations with vessel wall thickening or vessel diameter did not result in significant differences (p > 0.05).
Conclusions: We observed significant correlations between different imaging findings suggestive of vasculitis on ultrasound or MRI and the final adjudicated diagnosis. While ultrasound and MRI were considered suitable imaging methods for detecting and discriminating typical vascular changes, 18F-FDG PET/CT requires careful timing and patient selection given its moderate diagnostic accuracy.
Objectives: To investigate the diagnostic accuracy of color-coded contrast-enhanced dual-energy CT virtual noncalcium (VNCa) reconstructions for the assessment of lumbar disk herniation compared to unenhanced VNCa imaging.
Methods: A total of 91 patients were retrospectively evaluated (65 years ± 16; 43 women) who had undergone third-generation dual-source dual-energy CT and 3.0-T MRI within an examination interval up to 3 weeks between November 2019 and December 2020. Eight weeks after assessing unenhanced color-coded VNCa reconstructions for the presence and degree of lumbar disk herniation, corresponding contrast-enhanced portal venous phase color-coded VNCa reconstructions were independently analyzed by the same five radiologists. MRI series were additionally analyzed by one highly experienced musculoskeletal radiologist and served as reference standard.
Results: MRI depicted 210 herniated lumbar disks in 91 patients. VNCa reconstructions derived from contrast-enhanced CT scans showed similar high overall sensitivity (93% vs 95%), specificity (94% vs 95%), and accuracy (94% vs 95%) for the assessment of lumbar disk herniation compared to unenhanced VNCa images (all p > .05). Interrater agreement in VNCa imaging was excellent for both, unenhanced and contrast-enhanced CT (κ = 0.84 vs κ = 0.86; p > .05). Moreover, ratings for diagnostic confidence, image quality, and noise differed not significantly between unenhanced and contrast-enhanced VNCa series (all p > .05).
Conclusions: Color-coded VNCa reconstructions derived from contrast-enhanced dual-energy CT yield similar diagnostic accuracy for the depiction of lumbar disk herniation compared to unenhanced VNCa imaging and therefore may improve opportunistic retrospective lumbar disk herniation assessment, particularly in case of staging CT examinations.
Key Points
• Color-coded dual-source dual-energy CT virtual noncalcium (VNCa) reconstructions derived from portal venous phase yield similar high diagnostic accuracy for the assessment of lumbar disk herniation compared to unenhanced VNCa CT series (94% vs 95%) with MRI serving as a standard of reference.
• Diagnostic confidence, image quality, and noise levels differ not significantly between unenhanced and contrast-enhanced portal venous phase VNCa dual-energy CT series.
• Dual-source dual-energy CT might have the potential to improve opportunistic retrospective lumbar disk herniation assessment in CT examinations performed for other indications through reconstruction of VNCa images.
This prospective study sought to evaluate potential savings of radiation dose to medical staff using real-time dosimetry coupled with visual radiation dose feedback during angiographic interventions. For this purpose, we analyzed a total of 214 angiographic examinations that consisted of chemoembolizations and several other types of therapeutic interventions. The Unfors RaySafe i2 dosimeter was worn by the interventionalist at chest height over the lead protection. A total of 110 interventions were performed with real-time radiation dosimetry allowing the interventionalist to react upon higher x-ray exposure and 104 examinations served as the comparative group without real-time radiation monitoring. By using the real-time display during interventions, the overall mean operator radiation dose decreased from 3.67 (IQR, 0.95–23.01) to 2.36 μSv (IQR, 0.52–12.66) (−36%; p = 0.032) at simultaneously reduced operator exposure time by 4.5 min (p = 0.071). Dividing interventions into chemoembolizations and other types of therapeutic interventions, radiation dose decreased from 1.31 (IQR, 0.46-3.62) to 0.95 μSv (IQR, 0.53-3.11) and from 24.39 (IQR, 12.14-63.0) to 10.37 μSv (IQR, 0.85-36.84), respectively, using live-screen dosimetry (p ≤ 0.005). Radiation dose reductions were also observed for the participating assistants, indicating that they could also benefit from real-time visual feedback dosimetry during interventions (−30%; p = 0.039). Integration of real-time dosimetry into clinical processes might be useful in reducing occupational radiation exposure time during angiographic interventions. The real-time visual feedback raised the awareness of interventionalists and their assistants to the potential danger of prolonged radiation exposure leading to the adoption of radiation-sparing practices. Therefore, it might create a safer environment for the medical staff by keeping the applied radiation exposure as low as possible.
Background: Dual-source dual-energy computed tomography (DECT) offers the potential for opportunistic osteoporosis screening by enabling phantomless bone mineral density (BMD) quantification. This study sought to assess the accuracy and precision of volumetric BMD measurement using dual-source DECT in comparison to quantitative CT (QCT). Methods: A validated spine phantom consisting of three lumbar vertebra equivalents with 50 (L1), 100 (L2), and 200 mg/cm3 (L3) calcium hydroxyapatite (HA) concentrations was scanned employing third-generation dual-source DECT and QCT. While BMD assessment based on QCT required an additional standardised bone density calibration phantom, the DECT technique operated by using a dedicated postprocessing software based on material decomposition without requiring calibration phantoms. Accuracy and precision of both modalities were compared by calculating measurement errors. In addition, correlation and agreement analyses were performed using Pearson correlation, linear regression, and Bland-Altman plots. Results: DECT-derived BMD values differed significantly from those obtained by QCT (p < 0.001) and were found to be closer to true HA concentrations. Relative measurement errors were significantly smaller for DECT in comparison to QCT (L1, 0.94% versus 9.68%; L2, 0.28% versus 5.74%; L3, 0.24% versus 3.67%, respectively). DECT demonstrated better BMD measurement repeatability compared to QCT (coefficient of variance < 4.29% for DECT, < 6.74% for QCT). Both methods correlated well to each other (r = 0.9993; 95% confidence interval 0.9984–0.9997; p < 0.001) and revealed substantial agreement in Bland-Altman plots. Conclusions: Phantomless dual-source DECT-based BMD assessment of lumbar vertebra equivalents using material decomposition showed higher diagnostic accuracy compared to QCT.