Spectrophotometric assay for dapE-encoded N-succinyl-L,L-di aminopimelic acid desuccinylase, a potential antibiotic target

The previously most widely used DapE assay monitors amide bond cleavage of the L,L-SDAP substrate spectrophotometrically at 225 nm.1 This assay is straightforward and reliable for structurally simple inhibitors, but it cannot be used to test potential inhibitors that absorb strongly in the UV region, precluding its use in testing many preferred medicinal chemistry leads and analogs. Ninhydrin-based assays provide ease of application and reliability to detect primary amino groups such as that formed upon the hydrolysis of L,L-SDAP. We synthesized N6-methylated and N6-acetylated L,L-SDAP derivatives to prevent ninhydrin side reactions in the assay and also tested them as viable substrates for the Haemophilus influenza DapE (HiDapE) used in the assay. The data showed that the N-methylated derivative was both less reactive with ninhydrin and also was a better suited substrate for the HiDapE. In addition to the development of the assay itself we have also used a high throughput coupled screening to identify a number of lead HiTS (Figure 2) that show binding potential to DapE. These compounds will be tested as inhibitors themselves, while also being the basis for potential derivatives. The synthesis of analogs of these derivatives will be guided by structure activity relationships (SAR) as well as Lipinski’s rule of five, a general guide for predicting orally activity of potential drugs

Physical Characteristics and Morphology of Platinum Nanocrystals on Single Crystal Strontium Titanate

Eight nanometer platinum films were fabricated via electron beam deposition upon (001) strontium titanate (STO) substrates at ambient temperature then annealed at a range of temperatures in a reducing, oxidizing, or neutral environment. The evolution of platinum film dewetting and forming distinct nanocrystals was examined with XRD, AFM, and SEM. The initial deposition showed no crystallinity for the film. Upon annealing, a (001) cube on cube epitaxy was expected due to similar lattice parameters. However, an initial weak polycrystalline Pt (111) peak formed, which then transformed into (111) texture and eventually epitaxy. This (111) epitaxial relationship was observed in all annealing environments. The oxidizing environment suffered from significant platinum loss due to the sublimation of PtO2 at high temperatures, which as not seen in other environments. Secondary crystal growth from the STO substrate was seen in oxidizing and reducing environments and possibly indicated the in-plane epitaxy of the particles. Surface terminations of SrOx were found via AES despite etching to ensure a TiO2 termination, indicating migration of Ti atoms, most likely into the bulk platinum. The formation of (111) platinum epitaxy along with an SrOx termination in various environments indicates the substrate-platinum interactions are the predominant factor in determining platinum crystallinity and other features of the system

Studies of targeted treatment in RET mutant thyroid cancers

The societal burden of thyroid cancer is increasing, with both incidence and mortality on the rise. Mutations in the REarranged during Transfection (RET) gene are found in both the papillary and medullary subtype. There are significant limitations in current targeted treatment regimens of thyroid cancer, including the absence of a prolonged therapeutic response and severe toxicities. The goal of this project was to identify alternative strategies for the development of targeted treatments for this malignancy. This thesis demonstrates that constitutive activation of RET was associated with increased activation of mTOR, which was inhibited with the dual mTOR inhibitor INK128. The tolerability and efficacy of combining a RET kinase inhibitor together with the mTOR inhibitor was demonstrated in a murine model. Treatment of thyroid cancer cell lines with the HSP90 inhibitor AUY922, resulted in increased apoptosis. Tumour associated macrophages (TAMs), found in the microenvironment, were shown to play a pivotal role in thyroid cancer development. Following genetic ablation of TAMs in mouse models, there was profound remodelling of the tumour stroma with less extrathyroidal invasion and tumour cell proliferation. This thesis has identified novel therapeutic mechanisms for treatment of thyroid cancer which may lead to clinical trials, and better patient outcomes

Studies of targeted treatment in RET mutant thyroid cancers

The societal burden of thyroid cancer is increasing, with both incidence and mortality on the rise. Mutations in the REarranged during Transfection (RET) gene are found in both the papillary and medullary subtype. There are significant limitations in current targeted treatment regimens of thyroid cancer, including the absence of a prolonged therapeutic response and severe toxicities. The goal of this project was to identify alternative strategies for the development of targeted treatments for this malignancy. This thesis demonstrates that constitutive activation of RET was associated with increased activation of mTOR, which was inhibited with the dual mTOR inhibitor INK128. The tolerability and efficacy of combining a RET kinase inhibitor together with the mTOR inhibitor was demonstrated in a murine model. Treatment of thyroid cancer cell lines with the HSP90 inhibitor AUY922, resulted in increased apoptosis. Tumour associated macrophages (TAMs), found in the microenvironment, were shown to play a pivotal role in thyroid cancer development. Following genetic ablation of TAMs in mouse models, there was profound remodelling of the tumour stroma with less extrathyroidal invasion and tumour cell proliferation. This thesis has identified novel therapeutic mechanisms for treatment of thyroid cancer which may lead to clinical trials, and better patient outcomes

Indigene Psychologie in China - "Dekolonisierungsbewegung" oder Morgendämmerung einer neuen chinesischen Wissenschaftsdisziplin?

"Seit den späten 1990er-Jahren widmet sich eine wachsende Zahl chinesischer Wissenschaftler der Sinisierung des Faches Psychologie respektive der Indigenen Psychologie in China. Seither sind in Abgrenzung sowohl zur amerikanischen akademischen Psychologie als auch zur taiwanesischen Indigenen Psychologie (本土心理学 bentu xinlixue) unterschiedliche Forschungsansätze sowie eine eigene Terminologie entstanden. Der folgende Artikel stellt eine erste Bestandsaufnahme des Themas Indigene Psychologie in China dar." (Autorenreferat)"Linked to social and economic reforms since the 1990s a growing number of Chinese psychologists has been engaged in the sinization of psychology and indigenous psychology in China. To distance their theories from American academic psychology as well as Taiwanese indigenous psychology more and more indigenous approaches have been formed and technical terms have been coined. Whether this process can be understood as cultural integration of the psychological field in China or whether it is an indigenization movement based on the claim of self-assertion against the universalism of Western, particularly American, psychology has to be proved by intensive reading of the literature almost entirely written in Chinese. The following article is intended as an initial stocktaking of Indigenous Psychology in China." (author's abstract

Custeio Sequência na produção de hortaliças produzidas em sistema hidropônico no município de Presidente Médici –RO, Amazônia legal, Brasil

Trabalho de Conclusão de Curso apresentado à Fundação Universidade Federal de Rondônia Câmpus Professor Francisco Gonçalves Quiles, como parte dos requisitos, para obtenção do título de Bacharel em Ciências Contábeis sob a orientação da Profa. M.ª Liliane Maria Nery Andrade.Este trabalho evidencia o mapeamento do processo produtivo de hortaliças produzidas em sistema de hidroponia e o seu custeamento sem a utilização de rateios através da aplicação do método do Custeio Sequência. Sendo assim, o custo foi apurado a partir da tradução do mapeamento de cada fase do processo em eventos mensuráveis tais como: material (insumos, semente e adubo), mão de obra, energia, depreciação e água, apurados pela demanda de consumo horário de cada um destes. Foi realizada uma pesquisa de natureza aplicada, de campo e a observação direta, utilizada para realizar o mapeamento do processo e o cálculo dos tempos para realização de cada evento; a entrevista semiestruturada foi utilizada na etapa seguinte para identificação dos custos. Os resultados confirmam a eficácia do Custeio Sequência como método de mensuração sem utilização de rateio e sem ferir princípio contábil

Die perioperative suprapubische Harnableitung in der Urogynäkologie. Eine retrospektive Untersuchung

Die postoperative Blasenentleerungsstörung kann in Abhängigkeit der durchgeführten Operation nach urogynäkologischen Eingriffen eine häufige Begleiterscheinung sein und eine Harnableitung notwendig machen. Dabei herrscht kein Konsens, ob diese mittels transurethralem Dauerkatheter, intermittierendem transurethralen Katheterismus, oder suprapubischem Blasenkatheter erfolgen soll. In nahezu allen Fällen ist die Blasenentleerungsstörung passager, seltenst persistiert sie. Im Rahmen unserer Erhebung untersuchten wir retrospektiv die Daten von N=4463 Patientinnen, die in dem Zeitraum vom 01.06.2005 bis 31.01.2013 an der UFK Tübingen wegen BIK, Descensus genitalis, oder einer Kombination aus beiden Erkrankungen operiert wurden. Zusätzlich wurden die Daten von N=35 Patientinnen, welche wegen vesikovaginaler oder urethrovaginaler Fisteln operiert wurden analysiert. Wir konnten feststellen, dass bei gewissen Eingriffen eine postoperative Blasenentleerungsstörung von etwa 5 Tagen zu erwarten ist. Je nach Kombination mit weiteren Eingriffen kann diese interindividuell unterschiedlich lange fortbestehen. Neben einem intermittierenden transurethralen Kathetersimus wäre also eine suprapubische Harnableitung für diese Eingriffe wegen der Dauer der Blasenentleerungsstörung und den Vorteilen eines SPK wie der Option eines Blasentrainings der Patientin von Vorteil. Die aktuelle Studienlage legt zudem einen höheren Patientenkomfort im Vergleich zu anderen Harnableitungsverfahren nahe. Namentlich wäre bei folgenden Eingriffen die suprapubische Katheteranlage von Vorteil: Die vordere Kolporrhaphie vor allem in Kombination mit vaginalen Eingriffen im hinteren und mittleren Beckenbodenkompartiment oder/ und TVT-Anlage, die spannungsfreie Netzeinlage im vorderen Kompartiment in Kombination mit einer TVT-Anlage. Für andere Eingriffe, wie isolierte hintere Kolporrhaphie, Kolposuspension oder Sakropexie scheint die suprapubische Harnableitung nur in Ausnahmefällen indiziert. Bei den Fisteloperationen von voroperierten Patientinnen ist die Anlage eines SPK unter Umständen mit hohen Risiken für eine Darmverletzung verbunden, und sollte daher gegebenenfalls laparoskopisch assistiert erfolgen. In Ausnahmefällen sind ausgedehnte Voroperationen auch als Kontraindikation für die Anlage eines suprapubischen Katheters zu sehen. Die Schlußfolgerungen unserer Studie können in die Patientenaufklärungsgespräche integriert werden. Wesentliche Limitationen bestehen in dem eher explorativen Design der Studie mit unterschiedlichen Patientenzahlen in den verschiedenen Kategorien, Untergruppen, und Operationsgruppen sowie in der begrenzten Erfassbarkeit weiterer Parameter wie der Patientenzufriedenheit. Auf eventuelle volkswirtschaftliche Fragestellungen, wie der ökonomischsten Form der Harnableitung wurde nicht eingegangen, wobei sicherlich eine kürzere Hospitalisierungsdauer weniger Kosten verursacht, und diese durch eine optimale Therapie der postoperativen Blasenentleerungsstörung am ehesten erreicht werden kann