Who knows what when? : The information content of pre-IPO market prices : [Version March/June 2002]

To resolve the IPO underpricing puzzle it is essential to analyze who knows what when during the issuing process. In Germany, broker-dealers make a market in IPOs during the subscription period. We examine these pre-issue prices and find that they are highly informative. They are closer to the first price subsequently established on the exchange than both the midpoint of the bookbuilding range and the offer price. The pre-issue prices explain a large part of the underpricing left unexplained by other variables. The results imply that information asymmetries are much lower than the observed variance of underpricing suggests

Who knows what when? : the information content of pre-IPO market prices : [Version Mai 2004]

To resolve the IPO underpricing puzzle it is essential to analyze who knows what when during the issuing process. In Germany, broker-dealers make a market in IPOs during the subscription period. We examine these pre-issue prices and find that they are highly informative. They are closer to the first price subsequently established on the exchange than both the midpoint of the bookbuilding range and the offer price. The pre-issue prices explain a large part of the underpricing left unexplained by other variables. The results imply that information asymmetries are much lower than the observed variance of underpricing suggests

Computationally modeling interactions and dynamics to promote the understanding of protein function

Understanding the structural and functional properties of molecular interactions on atomic-level is fundamental to elucidate biochemical phenomena such as protein interactions, protein-ligand binding, and enzymatic activities. For this purpose, molecular modeling provides a powerful toolkit allowing the observation of molecular interactions in silico through an approximation of the physics of Nature. In this work, we show how various methods of molecular modeling can be applied to analyze and understand different biological systems. Depending on the biological problem to be solved, molecular modeling was performed either on static structures or by considering their dynamic properties. The basis for modeling were atomically-accurate crystal structures; if necessary, model generation was combined with homology modeling and molecular dynamics to account for mutational and conformational changes. In order to derive valuable insights from those models, their structural compositions were studied: By performing small-molecule docking, structure alignments, electrostatic surface calculations, analyses of intermolecular cavities and visual inspection, biological problems were studied qualitatively. The significance of our results was then substantiated through quantifying binding energies, interaction energies, and the spatial distribution of atoms. A profound understanding of molecular interactions can be demonstrated via protein engineering, i.e. the targeted modification or design of proteins. So far, most computational protocols have used rigid structures for design which is a simplification because a protein’s structure is more accurately specified by a conformational ensemble. As part of this work, a framework for computational protein design was developed that allows existing design protocols to make use of multiple design states, e.g. structural ensembles. An in silico assessment simulating ligand-binding design made clear that this new multi-state approach generates more reliably native-like sequences than a single-state approach. As a proof-of-concept, de novo retro-aldolase activity was introduced into a scaffold protein and nine variants were characterized experimentally. All variants displayed measurable catalytic activity, testifying to a high success rate for this novel concept of multi-state enzyme design

Physikalisch-mechanische Eigenschaften von CAD/CAM-PMMA Werkstoffen nach Alterung in verschiedenen flüssigen Aufbewahrungsmedien

Vergleich von vier industriell hergestellten CAD/CAM-PMMA Werkstoffen und einer Kontrollgruppe bei Alterung (Zeitraum bis zu 180 Tagen) in vier verschiedenen Lagerungsmedien (dest. Wasser, 0,9% Kochsalzlösung, künstl. Speichel, natürl. Speichel). Prüfparameter: Martenshärte, Vickershärte, EIT, Rauigkeit, Wasseraufnahme, Löslichkeit. Statistische Auswertung mit Hilfe von SPSS deskriptiv (Mittelwert, Standardabweichung (SD), 95% Konfidenzintervall (CI), Minimum, Median und Maximum; Kolmogorov-Smirnov und Shapiro-Wilk-Test) und 3-/2- oder 1-Wege ANOVA Testreihen (p < 0,05, post-hoc-Tests). Ergebnisse: CAD/CAM-PMMA Werkstoffe signifikant bessere Härteparameter als Kontrollgruppe, Lagerungszeit signifikanten negativen Einfluss auf Prüfparameter, Art des Lagerungsmediums keinen signifikanten Einfluss, Kontrollgruppe signifikant geringste Löslichkeit

Who knows what when? The Information content of pre-IPO market prices

To resolve the IPO underpricing puzzle it is essential to analyze who knows what when during the issuing process. In Germany, broker-dealers make a market in IPOs during the subscription period. We examine these pre-issue prices and find that they are highly informative. They are closer to the first price subsequently established on the exchange than both the midpoint of the bookbuilding range and the offer price. The pre-issue prices explain a large part of the underpricing left unexplained by other variables. The results imply that information asymmetries are much lower than the observed variance of underpricing suggests

Increase of the mean inner Coulomb potential in Au clusters induced by surface tension and its implication for electron scattering

Electron holography in a transmission electron microscope was applied to measure the phase shift induced by Au clusters as a function of the cluster size. Large phase shifts Df observed for small Au clusters cannot be described by the well-known equation Df=C_E V_0 t (C_E: interaction constant, V_0: mean inner Coulomb potential (MIP) of bulk gold, t: cluster thickness). The rapid increase of the Au MIP with decreasing cluster size derived from Df, can be explained by the compressive strain of surface atoms in the cluster

Rosetta:MSF: a modular framework for multi-state computational protein design

Computational protein design (CPD) is a powerful technique to engineer existing proteins or to design novel ones that display desired properties. Rosetta is a software suite including algorithms for computational modeling and analysis of protein structures and offers many elaborate protocols created to solve highly specific tasks of protein engineering. Most of Rosetta's protocols optimize sequences based on a single conformation (i.e. design state). However, challenging CPD objectives like multi-specificity design or the concurrent consideration of positive and negative design goals demand the simultaneous assessment of multiple states. This is why we have developed the multi-state framework MSF that facilitates the implementation of Rosetta's single-state protocols in a multi-state environment and made available two frequently used protocols. Utilizing MSF, we demonstrated for one of these protocols that multi-state design yields a 15% higher performance than single-state design on a ligand-binding benchmark consisting of structural conformations. With this protocol, we designed de novo nine retro-aldolases on a conformational ensemble deduced from a (beta alpha)(8)-barrel protein. All variants displayed measurable catalytic activity, testifying to a high success rate for this concept of multi-state enzyme design

Corticotropin-stimulated steroid profiles to predict shock development and mortality in sepsis: From the HYPRESS study

Rationale Steroid profiles in combination with a corticotropin stimulation test provide information about steroidogenesis and its functional reserves in critically ill patients. Objectives We investigated whether steroid profiles before and after corticotropin stimulation can predict the risk of in-hospital death in sepsis. Methods An exploratory data analysis of a double blind, randomized trial in sepsis (HYPRESS [HYdrocortisone for PRevention of Septic Shock]) was performed. The trial included adult patients with sepsis who were not in shock and were randomly assigned to placebo or hydrocortisone treatment. Corticotropin tests were performed in patients prior to randomization and in healthy subjects. Cortisol and precursors of glucocorticoids (17-OH-progesterone, 11-desoxycortisol) and mineralocorticoids (11-desoxycorticosterone, corticosterone) were analyzed using the multi-analyte stable isotope dilution method (LC–MS/MS). Measurement results from healthy subjects were used to determine reference ranges, and those from placebo patients to predict in-hospital mortality. Measurements and main results Corticotropin tests from 180 patients and 20 volunteers were included. Compared to healthy subjects, patients with sepsis had elevated levels of 11-desoxycorticosterone and 11-desoxycortisol, consistent with activation of both glucocorticoid and mineralocorticoid pathways. After stimulation with corticotropin, the cortisol response was subnormal in 12% and the corticosterone response in 50% of sepsis patients. In placebo patients (n = 90), a corticotropin-stimulated cortisol-to-corticosterone ratio > 32.2 predicted in-hospital mortality (AUC 0.8 CI 0.70–0.88; sensitivity 83%; and specificity 78%). This ratio also predicted risk of shock development and 90-day mortality. Conclusions In this exploratory analysis, we found that in sepsis mineralocorticoid steroidogenesis was more frequently impaired than glucocorticoid steroidogenesis. The corticotropin-stimulated cortisol-to-corticosterone ratio predicts the risk of in-hospital death. Trial registration Clinical trial registered with www.clinicaltrials.gov Identifier: NCT00670254. Registered 1 May 2008, https://clinicaltrials.gov/ct2/show/NCT00670254

MAPKinase inhibition after failure of immune checkpoint blockade in patients with advanced melanoma – an evaluation of the multicenter prospective skin cancer registry ADOREG

Objectives: Forty to sixty percent of patients with advanced melanoma show primary resistance to PD-1-based immunotherapy, 30-40% of initial responders also progress. Here, we evaluated the outcome of second-line targeted therapy (TT) after progression on PD-1-based immune checkpoint inhibition (ICI) in BRAFV600-mutated melanoma. In addition, we report data on the activity of re-exposure with PD-1-based regimes. Methods: Patients with advanced (non- resectable stage III or IV, AJCC 2017, 8th edition) melanoma progressing on PD-1-based ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line BRAF plus MEK inhibition were identified from the prospective multicenter skin cancer registry ADOREG. Results: We identified 108 patients with unresectable stage III or stage IV melanoma progressing on first-line ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line combined BRAF/MEK inhibition. Seventy- three percent of the cohort presented with primary PD-1 resistant disease. Median progression-free survival ( PFS) on ICI was 2.6 (95% CI 2.2-2.9) months. Median PFS on subsequent TT was 6.6 (95% CI 5.4 -7.8) months. Median OS from start of second-line TT was 16.0 (95% CI 11.2-20.8) months. The 3-year PFS and OS rates on second-line TT were 16% and 30%. The objective response rate (ORR) and disease control rate (DCR) to TT were 42.6% and 55.6%. In patients with brain metastases, the ORR and DCR were 31.4% and 43.1%. Patients without brain metastases showed an ORR and DCR of 52.6% and 66.7%, respectively. Response to first-line ICI was associated with a numerically higher ORR and DCR to second-line TT and improved OS on TT. Twenty-three patients received third-line ICI of whom two patients showed an objective response. Conclusions: BRAF plus MEK inhibition shows meaningful activity and outcome in patients with advanced melanoma resistant to anti-PD-1- based immunotherapy. Rates of long- term benefit and survival in our study were similar to those reported for treatment-naive patients receiving first-line MAPKi