Unclicking of thioureas:Base catalyzed elimination of anilines and isothiocyanates from thioureas

Bisaromatic thioureas are widely used in e.g. asymmetric organocatalysis and considered to be robust compounds. Herein we show, in strong contrast to common notion, that thioureas dissociate to amines and isothiocyanates in a base catalyzed reaction under mild conditions. This 'unclicking' process can occur in the presence of weak organic bases even at moderate temperatures. The influence of the substituents at the aromatic rings of the thiourea on the regioselectivity of this unclicking process is also shown. (C) 2019 Published by Elsevier Ltd

Mapping and characterization of macro non-protein coding RNAs in human imprinted gene regions

Genomweite Transkriptomstudien haben unterschiedliche Klassen von Nicht-Protein-kodierenden (nk) RNS offenbart und Fragen nach der Komplexität und Regulation des Genoms aufgeworfen. Genomische Prägung, ein epigenetisches Phänomen das die Exprimierung eines Gens in diploiden Zellen auf ein von zwei elterlichen Chromosomen beschränkt, ist ein Modellsystem um die Funktion der makro oder langen nkRNAs zu studieren. Sechs gut erforschte geprägte Gen- Cluster enthalten jeweils eine makro nkRNS die zwischen Maus und Mensch konserviert ist. Weiters wurde gezeigt, dass die zwei murinen makro nkRNAs Airn und Kcnq1ot1 die Exprimierung aller Protein-kodierenden Gene in den jeweiligen Gen-Clustern Igf2r und Kcnq1 unterdrücken. Beim Menschen exprimieren 8 von 27 bekannten geprägten Gen-Regionen geprägte makro nkRNAs. Um herauszufinden ob makro nkRNAs ein universelles Merkmal von allen menschlichen geprägten Gen-Regionen sind, habe ich individuell entwickelte Human Imprinted Tiling Arrays (HIRTA) und RNA-Sequenzierungstechnologien verwendet. Durch Hybridisierung von cDNA von menschlichen Geweben (20 normale und 23 Krebsgewebe) habe ich gewebespezifische Exprimierungsprofile von menschlichen geprägten Regionen erhalten. Dadurch konnte ich 101 neue Transkripte kartieren von denen 95% durch einen bioinformatische Analyse als macro nkRNS bestätigt werden konnten. Die RNA-Sequenzierung von nicht-ribosomaler RNA einer Fibroblasten Zelllinie ergab 26,2 Millionen einmalig zugeordnete Sequenzfragmente. Damit konnte ich sowohl die Exprimierung bereits bekannter geprägter makro nkRNAs erfolgreich detektieren als auch die Exprimierung von 22/23 neuen makro nkRNAs bestätigen die ich mittels HIRTA gefunden habe. Sieben neue makro nkRNAs sind entwicklungsspezifisch reguliert wie ich mittels eines Differenzierungssystems in embryonalen Stammzellen zeigen konnte. Die weitere Charakterisierung von zehn makro nkRNAs hat gezeigt, dass 4/10 ausschliesslich im Zellkern vorliegen, 6/10 monoallelisch oder bevorzugt monoallelisch exprimiert werden und 2/10 einen CpG Insel Promoter haben der unterschiedlich stark auf den beiden elterlichen Chromosomen methyliert ist (DMR). Zusammengenommen habe ich Beweise für sechs neue geprägte makro nkRNAs. Weiters sind 22 der 101 neu kartierten Transkripte nur in Krebsgeweben exprimiert. Diese könnten einen wertvollen Startpunkt für weiterführende Biomarker Forschung darstellen. Weiters konnte ich zeigen, dass alle menschlichen geprägten Gen-Regionen zumindest je eine makro nkRNA exprimieren welche geprägt sein könnte und diese daher möglicherweise eine Rolle in der Genregulation unter normalen als auch krankhaften Zuständen beim Menschen spielt.Recent genome-wide transcriptome studies revealed diverse classes of non-protein-coding (nc)RNAs and raised questions about the complexity and regulation of the genome. Genomic imprinting (an epigenetic phenomenon that restricts gene expression to one of two parental alleles in diploid cells) is a model system to study the function of an unusual class of macro or long ncRNAs. Six well-studied imprinted gene clusters contain a macro ncRNA that are mainly conserved between mouse and human. Furthermore, the mouse Airn and Kcnq1ot1 macro ncRNAs have been shown to repress all protein-coding genes, respectively in the Igf2r and Kcnq1 imprinted gene clusters. In humans, 8 out of 27 known imprinted gene regions express imprinted macro ncRNAs. To determine if macro ncRNAs are universal features of all human imprinted gene regions I used a custom Human Imprinting Region Tilling Array (HIRTA) and RNA-seq technologies. By applying 20 normal and 23 cancer human samples to HIRTA, I obtained the tissue-specific expression profiles of human imprinted gene regions and based on these profiles I mapped 101 novel transcripts of which about 95% were confirmed as macro ncRNA using a bioinformatics approach. Using ribosomal RNA depleted RNA-seq in a fibroblast cell line, I obtained 26.2 million uniquely mapped reads, successfully detected the known imprinted macro ncRNAs and validated expression of 22/23 novel macro ncRNA transcripts detected by HIRTA. 7 novel macro ncRNAs were developmentally regulated in the human embryonic stem cells differentiation system. Characterization of 10 macro ncRNAs showed that 4/10 were exclusively nuclear localized, 6/10 had monoallelic or expression biased towards one parental allele and 2/10 had CpG island promoters that are differentially methylated regions (DMRs). Thus, I have partial evidence for 6 novel imprinted macro ncRNAs. Furthermore, 22 out of the 101 mapped transcripts were expressed exclusively in cancer samples and may represent a valuable starting point for biomarkers research. In summary, all human imprinted gene regions express at least one macro ncRNA that may be imprinted and potentially play a role in gene regulation in normal or disease conditions in human

Dynamic control of chiral space

Responsive molecular systems are systems, which upon external stimuli; produce observable changes of physical or chemical properties. Those changes are typically the result of configurational or conformational changes. They have recently gained a lot of interest in the scientific community in attempts to mimic dynamic functions in biological systems. One of the fascinating potential applications of responsive systems lies in catalysis. Inspired by Nature, novel responsive catalytic systems are built, which show analogy with allosteric regulation of enzymes. The design of responsive catalytic systems allows control of catalytic activity and selectivity. A major part of the research presented in this thesis deals with the design, synthesis and properties of novel responsive systems capable of dynamic control over catalytic functions. Apart from that, exploring the dynamic control of chiral space was pushed even further, by investigating the possibility of dynamic chiral anion binding.Overall, the research presented in this thesis contributes to the better understanding of how space restricted by chiral boundaries, can create a chiral environment at the molecular scale, and how this environment can be controlled in a dynamic fashion. Dynamic switching of such “chiral space” can e.g., be used to control the basic parameters of a catalytic function: activity and selectivity. Also, it could be used to switch the affinity towards anions, and even control the enantioselectivity in binding chiral anions

An indirect space-vector modulated three-phase AC-DC matrix converter for hybrid electric vehicles

This paper presents a bi-directional AC-DC matrix converter for the power supply systems of hybrid electric vehicles. Compared to conventional PWM rectifier and associated DC-DC converter, large DC bus capacitor banks are eliminated. The converter converts three-phase AC power into the desired DC output with higher energy density via a single power stage. A closed-loop control strategy based on indirect space vector modulation is proposed and the validity has been verified. The strategy ensures that the output voltage can be regulated tightly against different loads and wide input variation and high-quality input current can be achieved

A Review of Caveats in Statistical Nuclear Image Analysis

A large body of the published literature in nuclear image analysis do not evaluate their findings on an independent data set. Hence, if several features are evaluated on a limited data set over‐optimistic results are easily achieved. In order to find features that separate different outcome classes of interest, statistical evaluation of the nuclear features must be performed. Furthermore, to classify an unknown sample using image analysis, a classification rule must be designed and evaluated. Unfortunately, statistical evaluation methods used in the literature of nuclear image analysis are often inappropriate. The present article discusses some of the difficulties in statistical evaluation of nuclear image analysis, and a study of cervical cancer is presented in order to illustrate the problems. In conclusion, some of the most severe errors in nuclear image analysis occur in analysis of a large feature set, including few patients, without confirming the results on an independent data set. To select features, Bonferroni correction for multiple test is recommended, together with a standard feature set selection method. Furthermore, we consider that the minimum requirement of performing statistical evaluation in nuclear image analysis is confirmation of the results on an independent data set. We suggest that a consensus of how to perform evaluation of diagnostic and prognostic features is necessary, in order to develop reliable tools for clinical use, based on nuclear image analysis

REMISSION IS NOT ASSOCIATED WITH DRD2 RS1800497 AND DAT1 RS28363170 GENETIC VARIANTS IN MALE SCHIZOPHRENIC PATIENTS AFTER 6-MONTHS MONOTHERAPY WITH OLANZAPINE

Background: Symptomatic remission is an achievable goal in the treatment of schizophrenia. The type of antipsychotic medication and particular genetic variants of the dopaminergic system might be associated with remission. Potential pharmacogenetic markers of the treatment response to antipsychotic medication are missing. This study assessed the possible association between dopamine receptor type 2 (DRD2 rs1800497) and dopamine transporter (DAT1 rs28363170) gene variants with symptomatic remission in schizophrenia. Subjects and methods: Olanzapine (5-20 mg/d) monotherapy was administered for 6 months to 150 male Caucasian subjects with schizophrenia. Remission was evaluated according to "Remission in Schizophrenia Working Group" criteria. Genotyping was performed by PCR-RFLP. Results: Symptomatic remission was found in 31% of patients. DRD2 rs1800497 and DAT1 rs28363170 gene variants were not significantly associated with symptomatic remission. The limitations are a relatively small sample size of patients with schizophrenia (N=150), especially of group with symptomatic remission (N=45). However, the study had moderate but adequate sample sizes for most of the comparisons. Only two dopaminergic polymorphisms were analyzed, and plasma concentration of olanzapine was not determined. Conclusion: These results revealed a lack of association between DRD2 rs1800497 and DAT1 rs28363170 genetic variants and symptomatic remission in male patients treated with olanzapine, suggesting that these genetic variants could not be used to predict symptomatic remission to olanzapine monotherapy. Negative results should be further confirmed or rejected in the larger samples, including haplotype analyses, to detect clinically useful and easy obtainable pharmacogenetic markers that might predict therapeutic response or remission in schizophrenia

Robot-assisted laparoscopic prostatectomy in a 68-year-old patient with previous heart transplantation and pelvic irradiation

We report the case of a 68-year-old man who had previously undergone heart transplantation and pelvic irradiation for Hodgkin’s lymphoma and who was under active surveillance for prostate cancer. In response to his increased prostate-specific antigen levels and elevated Gleason score, he was offered robot-assisted laparoscopic prostatectomy