New 2D-Experiments and Numerical Simulations on Stress-state-dependence of Ductile Damage and Failure

AbstractThe paper deals with a series of new experiments and corresponding numerical simulations to be able to study the effect of stress state on damage and failure behavior of ductile metals. The material behavior is modeled by a continuum approach based on free energy functions defined in damaged and corresponding fictitious undamaged configurations leading to elastic material laws which are affected by damage. Inelastic behavior of ductile materials is modeled by continuum plasticity and continuum damage model, respectively. The present approach takes into account the effect of stress state on damage and failure conditions expressed in terms of the stress intensity, the stress triaxiality and the Lode parameter. Previous studies have shown that it will not be possible to propose the stress-state-dependent functions for damage and failure criteria only based on tests with uniaxially loaded specimens. Therefore, new experiments with carefully designed and two-dimensionally loaded specimens have been developed. Corresponding numerical simulations of these tests show that they cover a wide range of stress states allowing validation of stress-state-dependent functions for the damage criterion and evolution laws for the damage strains

Signal Incongruence and Its Consequences: A Study of Media Disapproval and CEO Overcompensation

We draw on the signaling and infomediary literatures to examine how media evaluations of CEO overcompensation (a negative cue associated with selfishness and greed) are affected by the presence of corporate philanthropy (a positive cue associated with altruism and generosity). In line with our theory on signal incongruence, we find that firms engaged in philanthropy receive more media disapproval when they overcompensate their CEO, but they are also more likely to decrease CEO overcompensation as a response. Our study contributes to the signaling literature by theorizing about signal incongruence, and to infomediary and corporate governance research by showing that media disapproval can lead to lower executive compensation. We also reconcile two conflicting views on firm prosocial behavior by showing that, in the presence of incongruent cues, philanthropy can simultaneously enhance and damage media evaluations of firms and CEOs. Taken together, these findings shed new light on the media as agents of external corporate governance for firms and open new avenues for research on executive compensation

Genetische Untersuchungen zur α-Synuklein-Expression

Das SNCA-Gen bzw. sein Genprodukt aSYN wurden auf mehreren verschiedenen Ebenen mit dem IPS, der MSA und der DLB in Verbindung gebracht. Sie definieren die Erkrankungsgruppe der Synukleinopathien. Für die Pathogenese dieser Erkrankungen scheint besonders die Gendosis entscheidend zu sein. Dies gilt insbesondere für die häufigste Erkrankung unter den Synukleinopathien, dem sporadisch auftretenden IPS. Folglich erscheint die Untersuchung der Genexpression wichtig, um die Ursache dieser Erkrankungen besser zu verstehen und daraus zukünftig kausale Therapien ableiten zu können. Ein wesentlicher Vorgang der Genexpression ist die Transkription, die durch die Bindung von TF an den Promotorbereich initiiert wird. Doch gerade zu diesem Vorgang existieren bislang nur wenige Studien, die zudem alle an speziellen Zellsystemen und nicht an menschlichen Hirnzellen durchgeführt wurden. Diese Arbeit sollte daher die Transkription genauer charakterisieren und untersuchen, inwieweit sich die bisherigen Erkenntnisse auf menschliche Hirnzellen übertragen lassen. Dabei wurden in einem ersten Schritt durch den Einsatz von Western Blots und IP die potentiellen TF C/EBPβ, GATA2 und ZSCAN21 durch klassische Proteinnachweisverfahren in menschlichen Hirnzellen verschiedener Regionen nachgewiesen. Daraus leitete sich ab, dass diese TF tatsächlich an der Genregulation in vielen verschiedenen Hirnzellen beteiligt sein dürften. In einem zweiten Schritt war es dann nötig, den komplexen Promotorbereich von SNCA besser zu charakterisieren. Dies gelang durch den Einsatz eines bioinformatischen Programms, mit dessen Hilfe auch potentielle Bindungsstellen für die drei untersuchten TF identifiziert werden konnten. Anschließend konnten diese potentiellen Bindungsstellen durch den Einsatz von ChIP Assays auf ihre funktionelle Relevanz untersucht werden. Die für GATA2 und ZSCAN21 identifizierten Bindungsstellen wurden dann mittels EMSAs genauer charakterisiert. Aus diesen Ergebnissen lässt sich ableiten, dass GATA2 und ZSCAN21 tatsächlich die Genexpression von SNCA in menschlichen Hirnzellen verschiedenster Areale regulieren, auch wenn für GATA2 eine andere Bindungsstelle als bisher angenommen identifiziert wurde. Außerdem kann aus den Ergebnissen der ChIP Assays geschlossen werden, dass C/EBPβ nicht als direkter TF für SNCA fungiert. C/EBPβ könnte über eine Protein-Protein-Interaktion mit GATA2 eine Enhancer-Funktion inne haben und auf diese Weise auf die Genexpression einwirken. Durch die Identifikation von GATA2 und ZSCAN21 als TF für SNCA sowie deren Bindungsstellen im Promotorbereich konnte durch diese Arbeit weiteres geleistet werden: Das Screening nach SNPs in den identifizierten TF-Bindungsstellen bei Patienten, die an einem IPS leiden, lieferte wichtige Erkenntnisse für die Beantwortung der Frage, über welchen Mechanismus SNPs, die mit einem erhöhten Risiko einhergehen, an einem IPS zu erkranken, das Erkrankungsrisiko modulieren. Es wird angenommen, dass diese SNPs die Genexpression erhöhen. Da durch den Einsatz von Schmelzkurvenanalysen und der anschließenden Sequenzierung von DNA-Proben mit auffälligen Schmelzkurven keine SNPs in diesen Bereichen nachgewiesen werden konnten und auch die Suche nach annotierten SNPs für diese Bereiche keine hinreichenden Erkenntnisse lieferte, muss davon ausgegangen werden, dass diese SNPs die Genexpression nicht über eine Veränderung der TF-Bindungsstellen regulieren. Vielmehr kommen weitere Mechanismen in Betracht. Zukünftig muss die Genexpression von SNCA noch besser verstanden werden. Es gilt, weitere regulatorische Elemente zu identifizieren und bisher bekannte besser zu charakterisieren. Wie aus dieser Arbeit ersichtlich wurde, müssen alle künftigen Ergebnisse auch in menschlichen Hirnzellen verifiziert werden. Gelingt dies und wird zusätzlich die physiologische Rolle von aSYN besser verstanden, so bestünde erstmals die Möglichkeit, über Medikamente, die gegen die identifizierten TF von SNCA gerichtet sind, die Genexpression zu verringern und eine kausale Therapie für die Synukleinopathien zu etablieren

Instabilities in the transient response of muscle

We investigate the isometric transient response of muscle using a quantitative stochastic model of the actomyosin cycle based on the swinging lever-arm hypothesis. We first consider a single pair of filaments, and show that when values of parameters such as the lever-arm displacement and the crossbridge elasticity are chosen to provide effective energy transduction, the T2 curve (the tension recovered immediately after a step displacement) displays a region of negative slope. If filament compliance and the discrete nature of the binding sites are taken into account, the negative slope is diminished, but not eliminated. This implies that there is an instability in the dynamics of individual half-sarcomeres. However, when the symmetric nature of whole sarcomeres is taken into account, filament rearrangement becomes important during the transient: as tension is recovered, some half-sarcomeres lengthen while others shorten. This leads to a flat T2 curve, as observed experimentally. In addition, we investigate the isotonic transient response and show that for a range of parameter values the model displays damped oscillations, as recently observed in experiments on single muscle fibers. We conclude that it is essential to consider the collective dynamics of many sarcomeres, rather than the dynamics of a single pair of filaments, when interpreting the transient response of muscle.Comment: 11 pages, 11 figures, Submitted to Biophysical Journa

Somatostatin receptor PET/CT in restaging of typical and atypical lung carcinoids

Background To assess the role of somatostatin receptor (SR) PET/CT using Ga-68 DOTATOC or DOTATATE in staging and restaging of typical (TC) and atypical (AC) lung carcinoids. Methods Clinical and PET/CT data were retrospectively analyzed in 27 patients referred for staging (N = 5; TC, N = 4; AC, N = 1) or restaging (N = 22; TC, N = 8; AC, N = 14). Maximum standardized uptake value (SUVmax) of SR-positive lesions was normalized to the SUVmax of the liver to generate SUVratio; SR PET was compared to contrast-enhanced (ce) CT. The classification system proposed by Rindi et al. (Endocr Relat Cancer. 2014;21(1):1-16, 2014) was used for classification of patients in TC and AC groups. Results Only 18/27 patients were found to have metastases on PET/CT. Of the 186 lesions, 101 (54.3 %) were depicted on both PET and CT, 53 (28.5 %) lesions only on CT, and 32 (17.2 %) only on PET. SUVratio of lesions was significantly higher in AC as compared to TC (p < 0.001). In patients referred for restaging, additional findings on PET lead to upstaging with change in management strategy in 5/22 (22.7 %) patients (AC, N = 5; TC, N = 1). In four patients (all AC) referred for restaging and in one patient (TC) referred for staging, additional findings on CT missed on PET lead to correct staging. Conclusions Typical and atypical carcinoid patients have complex patterns of metastases which make it necessary to combine functional SR PET and contrast- enhanced CT for appropriate restaging. In patients referred for restaging SR, PET may have a relevant impact on treatment strategy in up to 22.7 of patients with typical and atypical lung carcinoids

Relationships between auditory event-related potentials and mood state, medication, and comorbid psychiatric illness in patients with bipolar disorder

BACKGROUND: Patients with bipolar disorder (BD) exhibit aberrations in auditory event-related potentials (ERPs), although the relationships between these measures and mood state at testing, comorbid psychiatric illness, presence of psychotic features, and medication usage are unclear. The purpose of this study was to investigate the relationships between these factors and auditory ERP measures in BD patients. METHODS: An auditory 'oddball' discrimination task was used to elicit ERPs from 69 patients with type I BD and 52 healthy controls. Patients were placed into subgroups based upon their mood state at testing (euthymic or symptomatic), and ANOVA was used to compare amplitude and peak latency measures from the N100, P200, N200, and P300 ERP components across subgroups. Multiple regression was used to investigate relationships between ERP measures and comorbid psychiatric diagnosis, history of psychotic features, and medication status. RESULTS: Relative to healthy control participants, euthymic and symptomatic BD patients exhibited reduced P300 and P200 amplitude, but ERP measures did not differ among BD patients on the basis of mood status. A history of a comorbid anxiety disorder was associated with reduced N200 peak latency, but prolonged P300 peak latency among BD patients. No other relationships between clinical variables and ERP measures were significant. CONCLUSIONS: The results suggest that disrupted auditory attention may be observed in BD patients regardless of their mood state at testing, medication status, or history of psychosis. These results extend previous findings, and provide further evidence for aberrations in the P300 ERP as an endophenotype for BD

Diffusion-weighted magnetic resonance imaging using a preclinical 1 T PET/MRI in healthy and tumor-bearing rats

Background: Hybrid positron emission tomography and magnetic resonance imaging (PET/MRI) scanners are increasingly used for both clinical and preclinical imaging. Especially functional MRI sequences such as diffusionweighted imaging (DWI) are of great interest as they provide information on a molecular level, thus, can be used as surrogate biomarkers. Due to technical restrictions, MR sequences need to be adapted for each system to perform reliable imaging. There is, to our knowledge, no suitable DWI protocol for 1 Tesla PET/MRI scanners. We aimed to establish such DWI protocol with focus on the choice of b values, suitable for longitudinal monitoring of tumor characteristics in a rat liver tumor model. Material and methods: DWI was first performed in 18 healthy rat livers using the scanner-dependent maximum of 4 b values (0, 100, 200, 300 s/mm2). Apparent diffusion coefficients (ADC) were calculated from different b value combinations and compared to the reference measurement with four b values. T2-weighted MRI and optimized DWI with best agreement between accuracy, scanning time, and system performance stability were used to monitor orthotopic hepatocellular carcinomas (HCC) in five rats of which three underwent additional 2-deoxy-2-(18F)fluoro-D-glucose(FDG)-PET imaging. ADCs were calculated for the tumor and the surrounding liver parenchyma and verified by histopathological analysis. Results: Compared to the reference measurements, the combination b = 0, 200, 300 s/mm2 showed the highest correlation coefficient (rs = 0.92) and agreement while reducing the acquisition time. However, measurements with less than four b values yielded significantly higher ADCs (p < 0.001). When monitoring the HCC, an expected drop of the ADC was observed over time. These findings were paralleled by FDG-PET showing both an increase in tumor size and uptake heterogeneity. Interestingly, surrounding liver parenchyma also showed a change in ADC values revealing varying levels of inflammation by immunohistochemistry. Conclusion: We established a respiratory-gated DWI protocol for a preclinical 1 T PET/MRI scanner allowing to monitor growth-related changes in ADC values of orthotopic HCC liver tumors. By monitoring the changes in tumor ADCs over time, different cellular stages were described. However, each study needs to adapt the protocol further according to their question to generate best possible results