Dynamic collective theory of odd-a nuclei

The unified model and the collective giant-dipole-resonance model are unified. The resulting energy spectrum and the transition probabilities are derived. A new approximate selection rule involving the symmetry of the γ vibrations is established. It is verified that the main observable features in the photon-absorption cross section are not influenced by the odd particle, despite the considerably richer spectrum of states as compared to even-even nuclei

Static theory of the giant quadrupole resonance in deformed nuclei

The modes and frequencies of the giant quadrupole resonance of heavy deformed nuclei have been calculated. The quadrupole operator is computed and the absorption cross section is derived. The quadrupole sum rule is discussed, and the relevant oscillator strengths have been evaluated for various orientations of the nucleus. The giant quadrupole resonances have energies between 20 and 25 MeV. The total absorption cross section is about 20% of the giant dipole absorption cross section. Of particular interest is the occurrence of the quadrupole mode which is sensitive to the nuclear radius in a direction of approximately θ=(1/4)π from the symmetry axis. This may give information on the details of the nuclear shape

Die C–H-Aktivierung als Werkzeug in der Totalsynthese von HDAC-Inhibitoren und Totalsynthese von Myxoprincomid

Diese Doktorarbeit beschäftigt sich mit dem Aufbau cyclotetrapeptidischer HDAC-Inhibitoren unter Verwendung moderner Synthesemethoden, wie der C–H-Aktivierung und der MattesonHomologisierung. Macrocyclische HDAC-Inhibitoren (HDACi) zeichnen sich durch hohe Antitumoraktivitäten aus und sind somit interessant für die pharmazeutische Wirkstoffforschung. Charakteristisch ist vor allem deren Zinkbindungsmotiv, das häufig aus einer 2-Amino-9,10-epoxy-8- oxodecansäure (Aeo) besteht. Eine neuartige Synthese einer Aeo-Vorstufe wird in dieser Arbeit beschrieben und anhand der Totalsynthesen der beiden HDAC-Inhibitoren WF-3161 und HC-Toxin auf Anwendbarkeit in der HDACi-Synthese geprüft. In diesem Zusammenhang wird außerdem eine neue Methode zur Aminal-C–H-Aktivierung beschrieben, die es auf indirektem Wege ermöglicht Peptide mit acidem Amidproton umzusetzen. Der myxobakterielle Naturstoff Myxoprincomid wurde 2012 von Müller et al. aus Myxococcus xanthus isoliert. Da Myxoprincomid nur in äußerst geringen Mengen vom Myxobakterium produziert wird, wurde eine Totalsynthese entwickelt, die die Synthese einer größeren Menge des Naturstoffs ermöglichte. Mit dem synthetisierten Naturstoff wurden weitere biologische Tests durchgeführt, mit denen eine biologische Aktivität gefunden werden sollte.This PhD-Work deals with the application of C–H activation and Matteson homologation reactions in the total synthesis of cyclotetrapeptide HDAC-inhibitors (HDACi). Macrocyclic HDAC-inhibitors show a high activity against tumor cells and are therefore interesting for the field of pharmaceutical drug development. Many HDAC-inhibitors contain a 2-amino-9,10-epoxy-8-oxodecanoic acid (Aeo) moiety which is responsible for their zinc-binding properties. This work describes the development of a new synthetic route towards an Aeo-precursor and its application in the total syntheses of the HDACi WF-3161 and HC-toxin. In this context, the development of C–H activations with aminals as key intermediates is described. This new method allows the conversion of peptides containing acidic amide protons, which could not be used in C–H activation reactions so far. The myxobacterial natural product Myxoprincomide was isolated by Müller et al. in 2012. It is produced in tiny amounts by Myxococcus xanthus making it difficult to carry out broad biological testings. The herein described total synthesis of myxoprincomide allows the synthesis of a significant amount of this natural product in order to expand the biological activity data

Total synthesis and biological evaluation of histone deacetylase inhibitor WF-3161

A novel synthesis of the naturally occurring HDAC inhibitor WF-3161 is described. Key steps include the Matteson homologation to generate the stereogenic centres in the side chain, and Pdcatalysed C–H functionalisation to connect the side chain to the peptide backbone. WF-3161 was found to be highly selective for HDAC1, whereas no activity was observed towards HDAC6. High activity was also found against the cancer cell line HL-60

Methodology for the Geometric Layout of a Mechanically Fully Variable Valve Train with Two Synchronously Rotating Cam Disks

New engine concepts such as Miller, HCCI or highly diluted combustion offer great potential for further optimization of ICEs in terms of fuel economy and pollutant emissions. However, the development of such concepts requires a high degree of variability in the control of gas exchange, characterized by variability in valve spread, maximum valve lift and – ideally independent of these two variables – in valve opening time. In current series variable valvetrains, valve lift and opening duration are usually directly dependent one from the other. In the ideal case, however, engine concepts such as Miller require a fully flexible variation of the closing time of the intake valve while still maintaining the same intake opening time. Here, a methodology for the geometric layout of fully variable valve trains with significantly extended functionalities is presented. In this concept, the control of the valve opening and closing events is distributed to two synchronously rotating cam disks. This geometric separation allows to vary the valve opening duration at constant maximum valve lift by varying the phase offset between the two disks. On the other hand, the geometric properties of the system can be used to vary the maximum valve lift at the constant valve opening and/or valve closing (depending on the layout), as well as for switching additional valve events on or off. The methodology presented here includes the computer-aided and partially automated generation of the characteristic geometric features of the system and the kinematic simulation and evaluation of the concept. By kinematic simulation, various possible resulting valve lift curves can be evaluated and optimized by adapting the geometry and the motion rules. The subsequent investigations on a component test bench serve to assess the newly developed concept with respect to functionality, required drive torque, stiffness and speed capability, thus proving its technical feasibility

Total synthesis of Myxoprincomide, a secondary metabolite from Myxococcus xanthus

Myxoprincomide, a secondary metabolite of the myxobacterium Myxococcus xanthus DK 1622, is synthesised for the first time. The central, unusual α-ketoamide is generated at the end of the synthesis to avoid side reactions during the synthesis of this rather reactive subunit. Nevertheless, the synthetic natural product is obtained as an isomeric mixture. Detailed analytical investigations show that the identical isomeric mixture is found in the isolated natural product

Acute Chloroform Ingestion Successfully Treated with Intravenously Administered N-acetylcysteine

Chloroform, a halogenated hydrocarbon, causes central nervous system depression, cardiac arrhythmias, and hepatotoxicity. We describe a case of chloroform ingestion with a confirmatory serum level and resultant hepatotoxicity successfully treated with intravenously administered N-acetylcysteine (NAC). A 19-year-old man attempting suicide ingested approximately 75 mL of chloroform. He was unresponsive and intubated upon arrival. Intravenously administered NAC was started after initial stabilization was complete. His vital signs were normal. Admission laboratory values revealed normal serum electrolytes, AST, ALT, PT, BUN, creatinine, and bilirubin. Serum ethanol level was 15 mg/dL, and aspirin and acetaminophen were undetectable. The patient was extubated but developed liver function abnormalities with a peak AST of 224 IU/L, ALT of 583 IU/L, and bilirubin level reaching 16.3 mg/dL. NAC was continued through hospital day 6. Serum chloroform level obtained on admission was 91 μg/mL. The patient was discharged to psychiatry without known sequelae and normal liver function tests. The average serum chloroform level in fatal cases of inhalational chloroform poisoning was 64 μg/mL, significantly lower than our patient. The toxicity is believed to be similar in both inhalation and ingestion routes of exposure, with mortality predominantly resulting from anoxia secondary to central nervous system depression. Hepatocellular toxicity is thought to result from free radical-induced oxidative damage. Previous reports describe survival after treatment with orally administered NAC, we report the first use of intravenously administered NAC for chloroform ingestion. Acute oral ingestion of chloroform is extremely rare. Our case illustrates that with appropriate supportive care, patients can recover from chloroform ingestion, and intravenously administered NAC may be of benefit in such cases

A Unifying Mechanism for Mitochondrial Superoxide Production during Ischemia-Reperfusion Injury.

Ischemia-reperfusion (IR) injury occurs when blood supply to an organ is disrupted--ischemia--and then restored--reperfusion--leading to a burst of reactive oxygen species (ROS) from mitochondria. It has been tacitly assumed that ROS production during IR is a non-specific consequence of oxygen interacting with dysfunctional mitochondria upon reperfusion. Recently, this view has changed, suggesting that ROS production during IR occurs by a defined mechanism. Here we survey the metabolic factors underlying IR injury and propose a unifying mechanism for its causes that makes sense of the huge amount of disparate data in this area and provides testable hypotheses and new directions for therapies.Work in our laboratories is supported by the Medical Research Council (UK) and the British Heart Foundation. E.T.C. is supported by a Human Frontiers Science Program fellowship.This is the author accepted manuscript. The final version is available from Cell Press via http://dx.doi.org/10.1016/j.cmet.2015.12.00