Die Umsetzung der Richtlinie über grenzüberschreitende Verschmelzungen ins deutsche Recht

Das 2. UmwG-ÄndG bringt hinsichtlich der grenzüberschreitenden Verschmelzung einen erheblichen Gewinn an Rechtssicherheit. Weil die §§ 122a ff. UmwG-E weitgehend eine getreue Umsetzung der IntVRiL darstellen, werden künftige transnationale Verschmelzungen erleichtert; dies jedenfalls dann, wenn auch die anderen EU-Mitgliedstaaten die Richtlinie alsbald umsetzen. Anders als bei innerstaatlichen Verschmelzungen sind die für die Arbeitnehmer wesentlichen Informationen nicht im Verschmelzungsvertrag bzw. -plan, sondern im Verschmelzungsbericht enthalten. Dementsprechend ist dieser nicht verzichtbar. Sofern ein Verhandlungsverfahren über die künftige Mitbestimmung nach MgVG stattfindet, können sich die Anteilseigner die Bestätigung der dort erzielten Ergebnisse vorbehalten (§ 122g Abs. 1 UmwG-E), wenn die Verhandlungen im Zeitpunkt der Zustimmung zur Verschmelzung noch nicht beendet sind. Für die Bestätigung können andere Beschlussmodalitäten vorgesehen werden als für den Verschmelzungsbeschluss selbst. § 122c Abs. 2 Nr. 11, 12 UmwG-E ist dahingehend teleologisch zu reduzieren, dass die dort geforderten Angaben entfallen können, wenn sie für die Umsetzung und bilanzielle Abbildung der Verschmelzung nach den beteiligten Rechtsordnungen nicht erforderlich sind. Eine Zustimmung der Anteilseigner ausländischer Rechtsträger zur Durchführung eines Spruchverfahrens wird regelmäßig nicht zu erlangen sein. In diesem Fall sind die Gesellschafter des deutschen übertragenden Rechtsträgers – abweichend von § 14 Abs. 2 UmwG – auf die Anfechtungsklage verwiesen. Findet demgegenüber ein Spruchverfahren statt, insbesondere weil alle beteiligten Rechtsordnungen ein solches vorsehen, wird die vom Gesetzgeber gewünschte Zuständigkeitskonzentration kaum je zu erreichen sein. Regelmäßig werden nämlich die Gerichte in den Sitzstaaten sowohl des übertragenden als auch des übernehmenden Rechtsträgers international zuständig sein. Die Vorschrift des § 6c SpruchG-E ist dahingehend teleologisch zu reduzieren, dass ein gemeinsamer Vertreter nur für solche Anteilseigner zu bestellen ist, deren Zustimmung nach § 122h Abs. 1 UmwG-E zur Durchführung des Spruchverfahrens erforderlich ist. Auch in den vom 2. UmwG-ÄndG nicht geregelten Fälle internationaler Umwandlungen (insbesondere Verschmelzung unter Beteiligung von Personengesellschaften und Spaltung) kann weitgehend auf die in §§ 122a ff. UmwG-E enthaltenen Rechtsgedanken zurückgegriffen werden

Immune Architecture of Colorectal Lung Metastases and Implications for Patient Survival

Background: Pulmonary metastases occur in 10-20% of patients with colorectal cancer and significantly influence long-term survival. In this study, the immunological architecture of colorectal lung in comparison to liver metastases and its impact on patient survival were examined. Methods: Specimens of patients with colorectal lung and liver metastases were stained for HE, CD4, CD8, CD20, CD68 and CD45RO. Besides histomorphological evaluation, immunohistochemical stainings were analyzed for the respective cell numbers separately for tumor area, infiltrative margin and distant lung or liver stroma. These findings were correlated with clinical data and patient outcome. Results: In colorectal lung (n = 69) in comparison to liver (n = 222) metastases, the immunological focus is located in the tumor region. A high CD4(+) cell infiltration of this area is associated with prolonged survival of patients after resection of colorectal lung metastases [103 +/- 33 (high) vs. 37 +/- 6 months (low); p = 0.0246]. Patients who were treated with preoperative chemotherapy did not show differences in immune infiltrates compared to chemotherapy-naive patients. Conclusion: Colorectal lung and liver metastases showed a distinct immunological architecture. A dense cell infiltration of colorectal lung metastases by CD4(+) cells was related to prolonged patient survival. Preoperative chemotherapy did not influence cellular immune infiltrates. (C) 2016 S. Karger AG, Base

Nutlin-3a-aa: Improving the Bioactivity of a p53/MDM2 Interaction Inhibitor by Introducing a Solvent-Exposed Methylene Group

Nutlin-3a is a reversible inhibitor of the p53/MDM2 interaction. We have synthesized the derivative Nutlin-3a-aa bearing an additional exocyclic methylene group in the piperazinone moiety. Nutlin-3a-aa is more active than Nutlin-3a against purified wild-type MDM2, and is more effective at increasing p53 levels and releasing transcription of p53 target genes from MDM2-induced repression. X-ray analysis of wild-type MDM2-bound Nutlin-3a-aa indicated that the orientation of its modified piperazinone ring was altered in comparison to the piperazinone ring of MDM2-bound Nutlin-3a, with the exocyclic methylene group of Nutlin-3a-aa pointing away from the protein surface. Our data point to the introduction of exocyclic methylene groups as a useful approach by which to tailor the conformation of bioactive molecules for improved biological activity.This work was generously supported by the Deutsche Forschungsgemeinschaft (BE 4572/3-1 to T.B.). We extend our thanks to Barbara Klüver, Katrin Eckhardt, Nadiya Brovchenko, and Domenique Herbstritt for experimental support. Parts of the data described in this manuscript have been published in the dissertation of Florian Nietzold (Leipzig University, 2019).31 In addition, this work was financially supported by the National Science Centre, Poland (NCN) under Grant Symphony 2014/12/W/NZ1/00457 (to T.A.H). We thank HZB for the allocation of synchrotron radiation beamtime. We acknowledge the MCB Structural Biology Core Facility (supported by the TEAM TECH CORE FACILITY/2017-4/6 grant from the Foundation for Polish Science) for valuable support. Open Access funding enabled and organized by Projekt DEAL

Impact of breakfast on daily energy intake - an analysis of absolute versus relative breakfast calories

<p>Abstract</p> <p>Objective</p> <p>The role of breakfast energy in total daily energy intake is a matter of debate. Acute feeding experiments demonstrated that high breakfast energy leads to greater overall intake supported by cross-sectional data of a free-living population. On the other hand, a large intraindividual analysis has indicated that a high proportion of breakfast to overall intake is associated with lower daily energy intake. To evaluate these apparently contradictory results in greater detail both ways of analysis were applied to the same data set of dietary records.</p> <p>Methods</p> <p>On an intraindividual basis total daily energy intake was related to the absolute values of breakfast energy intake or to the ratio of breakfast to overall intake, respectively. Food intake of 280 obese and 100 normal weight subjects was analyzed who recorded over 10 (obese) or 14 (normal weight) consecutive days, respectively.</p> <p>Results</p> <p>Increasing breakfast energy was associated with greater overall intake in normal weight and obese subjects. The increasing ratio of breakfast to total daily energy intake was associated with a significant reduction of overall intake on days where post-breakfast energy was significantly reduced. Correlational and multiple regression analysis support the concept that absolute breakfast calories have the strongest influence on daily energy intake.</p> <p>Conclusion</p> <p>Reduced breakfast energy intake is associated with lower total daily intake. The influence of the ratio of breakfast to overall energy intake largely depends on the post-breakfast rather than breakfast intake pattern. Therefore, overweight and obese subjects should consider the reduction of breakfast calories as a simple option to improve their daily energy balance.</p

Northern lights assay: a versatile method for comprehensive detection of DNA damage.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadDNA damage assays have various limitations in types of lesions detected, sensitivity, specificity and samples that can be analyzed. The Northern Lights Assay (NLA) is based on 2D Strandness-Dependent Electrophoresis (2D-SDE), a technique that separates nucleic acids based on length, strandness, structure and conformation changes induced by damage. NLA is run on a microgel platform in 20-25 min. Each specimen is analyzed in pairs of non-digested DNA to detect single- and double-stranded breaks (DSBs) and Mbo I-digested DNA to detect other lesions. We used NLA to evaluate DNA in solution and isolated from human cells treated with various genotoxic agents. NLA detected and distinguished between single- and DSBs, interstrand and intrastrand DNA crosslinks, and denatured single-stranded DNA. NLA was sufficiently sensitive to detect biologically relevant amount of DNA damage. NLA is a versatile, sensitive and simple method for comprehensive and simultaneous analysis of multiple types of damage, both in purified DNA and in DNA isolated from cells and body fluids. NLA can be used to evaluate DNA quality in biosamples, monitor complex molecular procedures, assess genotoxicity, diagnose genome instability, facilitate cancer theranostics and in basic nucleic acids research.University of Iceland Research Fund Landspitali University Hospital Research Fund Icelandic Center for Research Funds Lifeind ehf. University of Iceland Research Fun

Phosphorylation of capsaicinoid derivatives provides highly potent and selective inhibitors of the transcription factor STAT5b

Design approaches for inhibitors of protein–protein interactions are rare, but highly sought after. Here, we report that O-phosphorylation of simple derivatives of the natural products dihydrocapsaicin and N-vanillylnonanamide leads to inhibitors of the SH2 domain of the transcription factor STAT5b. The most potent molecule is obtained from dihydrocapsaicin in only three synthetic steps. It has submicromolar affinity for the SH2 domain of STAT5b (Ki = 0.34 μM), while displaying 35-fold selectivity over the highly homologous STAT5a (Ki = 13.0 μM). The corresponding pivaloyloxymethyl ester inhibits STAT5b with selectivity over STAT5a in human tumor cells. Importantly, it inhibits cell viability and induces apoptosis in human tumor cells in a STAT5-dependent manner. Our data validate O-phosphorylation of appropriately preselected natural products or natural product derivatives as a semirational design approach for small molecules that selectively inhibit phosphorylation-dependent protein–protein interaction domains in cultured human tumor cells

Phosphorylation of Capsaicinoid Derivatives Provides Highly Potent and Selective Inhibitors of the Transcription Factor STAT5b

Design approaches for inhibitors of protein–protein interactions are rare, but highly sought after. Here, we report that <i>O</i>-phosphorylation of simple derivatives of the natural products dihydrocapsaicin and <i>N</i>-vanillylnonanamide leads to inhibitors of the SH2 domain of the transcription factor STAT5b. The most potent molecule is obtained from dihydrocapsaicin in only three synthetic steps. It has submicromolar affinity for the SH2 domain of STAT5b (<i>K</i>_i = 0.34 μM), while displaying 35-fold selectivity over the highly homologous STAT5a (<i>K</i>_i = 13.0 μM). The corresponding pivaloyloxymethyl ester inhibits STAT5b with selectivity over STAT5a in human tumor cells. Importantly, it inhibits cell viability and induces apoptosis in human tumor cells in a STAT5-dependent manner. Our data validate <i>O</i>-phosphorylation of appropriately preselected natural products or natural product derivatives as a semirational design approach for small molecules that selectively inhibit phosphorylation-dependent protein–protein interaction domains in cultured human tumor cells

Space constraints govern fate of hematopoietic stem and progenitor cells in vitro

Deciphering exogenous cues that determine stem cell fate decisions is a persisting challenge of cell biology and bioengineering. In an effort to unravel the role of spatial constraints in the cell-instructive characteristics of bone marrow microenvironments, murine hematopoietic stem and progenitor cells (HSPC) were exposed to fibronectin-coated microcavities in vitro. Microcavity sizes were chosen to allow for the inclusion of either individual or multiple cells. Repopulation experiments using lethally irradiated mice showed that the maintenance of functional HSPC in culture critically depends on cavity dimensions. Short-term repopulating hematopoietic stem cells (ST-HSC) were found to be best supported within single-cell sized compartments while long-term repopulating HSC (LT-HSC) were maintained within both cavity sizes. In sum, the reported data reveal spatial restriction to be a simple but powerful means for directing HSPC fate ex vivo

The phenotype of cancer cell invasion controlled by fibril diameter and pore size of 3D collagen networks

The behavior of cancer cells is strongly influenced by the properties of extracellular microenvironments, including topology, mechanics and composition. As topological and mechanical properties of the extracellular matrix are hard to access and control for in-depth studies of underlying mechanisms in vivo, defined biomimetic in vitro models are needed. Herein we show, how pore size and fibril diameter of collagen I networks distinctively regulate cancer cell morphology and invasion. Three-dimensional collagen I matrices with a tight control of pore size, fibril diameter and stiffness were reconstituted by adjustment of concentration and pH value during matrix reconstitution. At first, a detailed analysis of topology and mechanics of matrices using confocal laser scanning microscopy, image analysis tools and force spectroscopy indicate pore size and not fibril diameter as the major determinant of matrix elasticity. Secondly, by using two different breast cancer cell lines (MDA-MB-231 and MCF-7), we demonstrate collagen fibril diameter - and not pore size - to primarily regulate cell morphology, cluster formation and invasion. Invasiveness increased and clustering decreased with increasing fibril diameter for both, the highly invasive MDA-MB-231 cells with mesenchymal migratory phenotype and the MCF-7 cells with amoeboid migratory phenotype. As this behavior was independent of overall pore size, matrix elasticity is shown to be not the major determinant of the cell characteristics. Our work emphasizes the complex relationship between structural-mechanical properties of the extracellular matrix and invasive behavior of cancer cells. It suggests a correlation of migratory and invasive phenotype of cancer cells in dependence on topological and mechanical features of the length scale of single fibrils and not on coarse-grained network properties

Rational development of Stafib-2: a selective, nanomolar inhibitor of the transcription factor STAT5b

The transcription factor STAT5b is a target for tumour therapy. We recently reported catechol bisphosphate and derivatives such as Stafib-1 as the first selective inhibitors of the STAT5b SH2 domain. Here, we demonstrate STAT5b binding of catechol bisphosphate by solid-state nuclear magnetic resonance, and report on rational optimization of Stafib-1 (Ki = 44 nM) to Stafib-2 (Ki = 9 nM). The binding site of Stafib-2 was validated using combined isothermal titration calorimetry (ITC) and protein point mutant analysis, representing the first time that functional comparison of wild-type versus mutant protein by ITC has been used to characterize the binding site of a small-molecule ligand of a STAT protein with amino acid resolution. The prodrug Pomstafib-2 selectively inhibits tyrosine phosphorylation of STAT5b in human leukaemia cells and induces apoptosis in a STAT5-dependent manner. We propose Pomstafib-2, which currently represents the most active, selective inhibitor of STAT5b activation available, as a chemical tool for addressing the fundamental question of which roles the different STAT5 proteins play in various cell processes