Calciumphosphat-Hohlpartikel als Indikator einer supramolekularen Selbstorganisation von Aminosäuren in Wasser sowie die Herstellung von Silber-dotiertem Hydroxylapatit

In dieser Arbeit wurde gezeigt, dass sich in Gegenwart der Aminosäuren O-Phospho-L-Tyrosin, L-Tyrosin, O-Phospho-L-Serin, L-Serin, und L-Alanin Calciumphosphat-Hohlpartikel herstellen lassen. Die Calciumphosphat-Hohlpartikel haben eine Größe zwischen 200 nm und 500 nm. Es wurde ebenfalls gezeigt, dass sich in Gegenwart der Dipeptide Serin-Tyrosin sowie Alanin-Tyrosin Calciumphosphat-Hohlpartikel mit einer Größe zwischen 200-300 nm herstellen lassen. Die Hohlpartikel bestehen aus einer Calciumphosphat-Schale, die sich aus kleinen 10 nm kleinen Calciumphosphat-Nanopartikeln aufbaut. Die Stärke der Schale liegt zwischen 10-30 nm. Mittels der Rasterkraftmikroskopie und der Kryo-Transmissionselektronenmikroskopie konnte bewiesen werden, dass die Partikel tatsächlich hohl vorliegen. Aus diesen Versuchen wird klar, dass die mit der Rasterelektronenmikroskopie beobachteten aufgebrochenen Partikel keine Trocknungsartefakte sind, sondern es sich in der Tat um hohle Strukturen handelt. Durch verschiedene Stabilitätstests konnte gezeigt werden, dass es sich bei den Hohlpartikeln um einen metastabilen Zustand handelt. Im zweiten Teil dieser Arbeit wurde eine supramolekulare Selbstorganisation von Aminosäuren bzw. Dipeptiden in Wasser gezeigt. Die Aminosäuren und Dipetide bilden Vesikel aus, die mittels der Nanoparticle Tracing Analysis und der Rasterkraftmikroskopie erstmals gezeigt werden konnten. Mittels der Elektrosprayionisations-Massenspektroskopie konnte eine pH-abhängige Clusterbildung von Aminosäuren nachgewiesen werden. Durch den Clusterbildungseffekt und NMR-Titration konnte gezeigt werden, dass es sich um eine elektrostatische Wechselwirkung zwischen einzelnen Aminosäuremolekülen bzw. Dipeptid¬molekülen handelt. Diese Wechselwirkung ist auf den zwitterionischen Charakter der Aminosäuren und Dipeptide zurückzuführen. Eine solche Selbstorganisation von Aminosäuren bzw. Dipeptiden wurde in der Literatur bisher nicht beschrieben. Aus den im zweiten Teil dieser Arbeit beobachteten Aminosäurevesikeln konnte ein Modell für den Bildungsmechanismus erstellt und so die Bildung der Calciumphosphat-Hohlpartikel erklärt werden. In diesem Modell fungieren die Aminosäurevesikel als Templat für die Bildung der Calciumphosphat-Hohlpartikel. Im letzten Teil dieser Arbeit wurde die Herstellung von Silber-dotiertem Hydroxylapatit gezeigt. Mit dem verwendeten kontinuierlichen Synthesever-fahren lässt sich Hydroxylapatit mit einem Silberanteil von bis zu 1,78 % Silber im Hydroxylapatit-Kristallgitter herstellen. Mittels Silber-Freisetzungsversuchen konnte gezeigt werden, dass bis zu 7,6 % von dem im Hydroxylapatit enthaltenen Silber über einen Zeitraum von 46 Tagen freigesetzt wurde. Eine Dialyseart, die noch getestet werden sollte, ist die Durchfluss-Dialyse, da es im menschlichen Organismus zu einem ständigen Austausch des Mediums um den verwendeten Apatit kommt. Durch Bakterientests mit E. coli konnte auch die gewünschte antibakterielle Wirkung des Hydroxylapatits nachgewiesen werden. Durch Zelltests mit HeLa-Zellen konnte gezeigt werden, dass der Silber-dotierte Hydroxylapatit nicht zelltoxisch ist. Mittels Calcinieren des entstandenen Silber-dotierten Hydroxylapatits bei 850 °C bzw. 1300 °C wurden alfa-Tricalciumphosphat und beta-Tricalciumphosphat mit einem Silberanteil von 1,71 Gew.-% und 0,20 Gew.-%Silber hergestellt. Aufgrund der antibakteriellen Wirkung des hergestellten Silber-dotierten Hydroxylapatits, könnte seine Anwendung vor allem im medizinischen Bereich, insbesondere in der Chirurgie, von Interesse sein

Zinc Deficiency

Zinc is an essential trace element for humans and plays a critical role both as a structural component of proteins and as a cofactor in about 300 enzymes. Zinc deficiency was, for example, reported to affect the immune response and the endocrine system and to induce and modify brain disorders. Besides hereditary zinc deficiency, zinc deficiency – at least in mild forms – is nowadays a very abundant health issue. Today, an estimated 20% of the population worldwide is at risk of developing zinc deficiency with a high number also in industrialized countries. The major risk factors to develop zinc deficiency in industrialized nations are aging and pregnancy. Mechanistic and behavioral studies on the effects of zinc deficiency have mainly been performed using animal models. However, in combination with the few studies on human subjects, a picture emerges that shows importance of adequate nutritional zinc supply for many processes in the body. Especially the immune system and brain development and function seem to be highly sensitive to zinc deficiency. Here, we provide an overview on the effects of zinc deficiency on different organ systems, biological processes, and the associations of zinc deficiency with pathologies observed in humans and animal models

Mary Ann and Robert Guenzler

This photograph, taken in 2013, was scanned and contributed by the Guenzlers for the IWU oral history project. Interview available at http://digitalcommons.iwu.edu/oral_hist/48/https://digitalcommons.iwu.edu/oralhistory_gallery/1088/thumbnail.jp

Mary Ann and Robert Guenzler

Mary Ann (Hagmeyer) and Robert Guenzler are members of the Class of 1953. Robert also graduated with a Masters in Music Education in 1956. Their daughter Marsha (Class of 1978) conducted this interview

Reductive Activation of Aryl Chlorides by Tuning the Radical Cation Properties of N ‐Phenylphenothiazines as Organophotoredox Catalysts

Aryl chlorides as substrates for arylations present a particular challenge for photoredox catalytic activation due to their strong C(sp$^2$)−Cl bond and their strong reduction potential. Electron-rich N-phenylphenothiazines, as organophotoredox catalysts, are capable of cleaving aryl chlorides simply by photoinduced electron transfer without the need for an additional electrochemical activation setup or any other advanced photocatalysis technique. Due to the extremely strong reduction potential in the excited state of the N-phenylphenothiazines the substrate scope is high and includes aryl chlorides both with electron-withdrawing and electron-donating substituents. We evidence this reactivity for photocatalytic borylations and phosphonylations. Advanced time-resolved transient absorption spectroscopy in combination with electrochemistry was the key to elucidating and comparing the unusual photophysical properties not only of the N-phenylphenothiazines, but also of their cation radicals as the central intermediates in the photocatalytic cycle. The revealed photophysics allowed the excited-state and radical-cation properties to be fine-tuned by the molecular design of the N-phenylphenothiazines; this improved the photocatalytic activity

Insights from the German Compassionate Use Program of Nintedanib for the Treatment of Idiopathic Pulmonary Fibrosis

Background: Nintedanib is approved for the treatment of idiopathic pulmonary fibrosis(IPF) and has been shown to slow disease progression by reducing annual lung function decline. Objective: To evaluate the results of a large cohort of IPF patients treated with nintedanib within a compassionate use program(CUP) in Germany(9 centers). Methods: Patients ( >= 40 years) were required to have a confirmed diagnosis of IPF, a forced vital capacity(FVC) >= 50% predicted ( pred.) and a carbon monoxide diffusing capacity(DLCO) 30-79% pred. and not to be eligible for pirfenidone treatment. Clinical data, pulmonary function tests and adverse events were recorded up to July 2015. Results: Sixty-two patients (48 male/14 female) with moderate IPF (FVC 64 +/- 17% pred. and DLCO 40 +/- 10% pred.) were treated with nintedanib. 77% of patients switched from pirfenidone (mean treatment duration 14 +/- 2 months) mostly due to disease progression (mean decline in FVC 7.4 +/- 3% pred. in the 6 months prior to nintedanib intake). Initiation of nintedanib treatment occurred 69 +/- 29 months after IPF diagnosis, and mean treatment duration was 8 +/- 4 months. Most patients (63%) stabilized 6 months after treatment start (mean FVC decline 3 +/- 1 vs. -17 +/- 2% in patients with disease progression;p < 0.01). The most common adverse events were diarrhea (63%) and weight loss (50%). Dose reduction occurred in 34% of cases and treatment discontinuation in 10%. Conclusion: Nintedanib treatment was generally well tolerated and was associated with FVC stabilization in the majority of IPF patients in this CUP setting where most patients were not treatment naive. Our data are in agreement with the previously published data. (C) 2016 The Author(s) Published by S. Karger AG, Base

Influence of Biopsy Technique on Molecular Genetic Tumor Characterization in Non-Small Cell Lung Cancer—The Prospective, Randomized, Single-Blinded, Multicenter PROFILER Study Protocol

The detection of molecular alterations is crucial for the individualized treatment of advanced non-small cell lung cancer (NSCLC). Missing targetable alterations may have a major impact on patient’s progression free and overall survival. Although laboratory testing for molecular alterations has continued to improve; little is known about how biopsy technique affects the detection rate of different mutations. In the retrospective study detection rate of epidermal growth factor (EGFR) mutations in tissue extracted by bronchoscopic cryobiopsy (CB was significantly higher compared to other standard biopsy techniques. This prospective, randomized, multicenter, single blinded study evaluates the accuracy of molecular genetic characterization of NSCLC for different cell sampling techniques. Key inclusion criteria are suspected lung cancer or the suspected relapse of known NSCLC that is bronchoscopically visible. Patients will be randomized, either to have a CB or a bronchoscopic forceps biopsy (FB). If indicated, a transbronchial needle aspiration (TBNA) of suspect lymph nodes will be performed. Blood liquid biopsy will be taken before tissue biopsy. The primary endpoint is the detection rate of molecular genetic alterations in NSCLC, using CB and FB. Secondary endpoints are differences in the combined detection of molecular genetic alterations between FB and CB, TBNA and liquid biopsy. This trial plans to recruit 540 patients, with 178 evaluable patients per study cohort. A histopathological and molecular genetic evaluation will be performed by the affiliated pathology departments of the national network for genomic medicine in lung cancer (nNGM), Germany. We will compare the diagnostic value of solid tumor tissue, lymph node cells and liquid biopsy for the molecular genetic characterization of NSCLC. This reflects a real world clinical setting, with potential direct impact on both treatment and survival

Identification of transcriptional networks responding to pyrroloquinoline quinone dietary supplementation and their influence on thioredoxin expression, and the JAK/STAT and MAPK pathways

PQQ (pyrroloquinoline quinone) improves energy utilization and reproductive performance when added to rodent diets devoid of PQQ. In the present paper we describe changes in gene expression patterns and transcriptional networks that respond to dietary PQQ restriction or pharmacological administration. Rats were fed diets either deficient in PQQ (PQQ−) or supplemented with PQQ (approx. 6 nmol of PQQ/g of food; PQQ+). In addition, groups of rats were either repleted by administering PQQ to PQQ− rats (1.5 mg of PQQ intraperitoneal/kg of body weight at 12 h intervals for 36 h; PQQ−/+) or partially depleted by feeding the PQQ− diet to PQQ+ rats for 48 h (PQQ+/−). RNA extracted from liver and a Codelink® UniSet Rat I Bioarray system were used to assess gene transcript expression. Of the approx. 10000 rat sequences and control probes analysed, 238 were altered at the P<0.01 level by feeding on the PQQ− diet for 10 weeks. Short-term PQQ depletion resulted in changes in 438 transcripts (P<0.01). PQQ repletion reversed the changes in transcript expression caused by PQQ deficiency and resulted in an alteration of 847 of the total transcripts examined (P<0.01). Genes important for cellular stress (e.g. thioredoxin), mitochondriogenesis, cell signalling [JAK (Janus kinase)/STAT (signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) pathways] and transport were most affected. qRT-PCR (quantitative real-time PCR) and functional assays aided in validating such processes as principal targets. Collectively, the results provide a mechanistic basis for previous functional observations associated with PQQ deficiency or PQQ administered in pharmacological amounts