Supramolekular organisierte Farbstoffe: Synthese und Charakterisierung flüssigkristalliner Isatin- und Indigo-Derivate

Die geordnete Ausrichtung von Materie auf molekularer Ebene ist Basis zahlreicher technologischer Anwendungen. Flüssigkristalle nehmen aufgrund ihrer einzigartigen Kombination aus Anisotropie und hoher molekularer Dynamik dabei eine besondere Position ein. Durch Einbringen funktioneller Molekülbereiche, wie z.B. Chromophore in die molekulare Struktur eines Mesogens können zusätzliche, anisotrope Effekte erzielt werden. Unter diesem Gesichtspunkt wird zunächst ein effizientes Konzept zur Synthese flüssigkristalliner Indigo-Derivate aus entsprechenden Isatin-Vorstufen präsentiert. Im ersten Teil dieser Arbeit wird dessen hohe Diversitätsorientierung anhand der Synthese einer Vielzahl unterschiedlicher Verbindungen unter Beweis gestellt. Einige der im Rahmen dieser Arbeit synthetisierten Isatin-Derivate zeigen selbst flüssigkristalline Phasen, die in Anbetracht der molekularen Gestalt interessante Effekte aufweisen könnten. Der zweite Teil widmet sich daher der Untersuchung der flüssigkristallinen Isatin-Derivate. Es werden zwei mögliche Modelle supramolekularer Anordnungen vorgestellt und deren physikalische Implikationen diskutiert. Die Befunde an einer großen Vielfalt verschiedener Isatin-Derivate werden in Hinblick auf diese Modelle erörtert. Im dritten Teil werden die Untersuchungen eines weiten Strukturraums von Indigo-Derivaten mit einer hohen Diversität flüssigkristalliner Phasen präsentiert. Dabei wurde eine Reihe von Substanzen mit ungewöhnlich stark ausfallendem photochromen Effekt entdeckt, deren Verhalten eingehend beschrieben wird. Anhand der molekularen Geometrie aus Kristallstrukturen verschiedener Indigo-Derivate wird das Auftreten bzw. Ausbleiben flüssigkristalliner Eigenschaften für bestimmte Substitutionsmuster begründet. Einige der im Rahmen dieser Arbeit entdeckten flüssigkristallinen Phasen sind sehr außergewöhnlich und werden daher detaillierter diskutiert. Es wird dabei ein einfaches Modell der supramolekularen Orientierung vorgestellt. Letztlich werden die zur supramolekularen Organisation von Isatin- und Indigo-Derivaten gesammelten Ergebnisse zusammengefasst und ein konkreter Ausblick auf Basis dieser Erkenntnisse geliefert

Non-specific abdominal pain and air pollution: a novel association.

We studied whether short-term exposure to air pollution was associated with non-specific abdominal pain in epidemiologic and animal studies. Patients visiting the emergency department with non-specific abdominal pain were identified in Edmonton (1992 to 2002, n = 95,173) and Montreal (1997 to 2002, n = 25,852). We calculated the daily concentrations for ozone (O(3)), nitrogen dioxide (NO(2)), sulfur dioxide (SO(2)), carbon monoxide (CO), and particles <10 (PM(10)) or <2.5 (PM(2.5)) µm. A case crossover study design was used to estimate the odds ratio (OR) and 95% confidence interval (CI) associated with an increase in the interquartile range of the air pollutants. We investigated differential effects by age and sex. Mice were gavaged with urban particle extracts. In animal models, colonic motility was tested, and visceral abdominal pain was measured using a writhing test, and behavioral response to oil of mustard and neostigmine. Motility and pain was measured acutely (1.5 hours after gavage) and chronically (7-days and 21-days after gavage). Emergency department visits for non-specific abdominal pain were primarily by women between the ages of 15-24 years. Individuals aged 15 to 24 years were at increased risk of non-specific abdominal pain in Edmonton (same day CO: OR = 1.04, 95% CI = 1.02-1.06; and NO(2): OR = 1.06, 95% CI = 1.03-1.09). The risk of air pollution among 15-24 year olds in Montreal was significantly positive (same day CO: OR = 1.11, 95% CI = 1.05-1.17; NO(2): OR = 1.09, 95% CI = 1.01-1.16; SO(2): OR = 1.17, 95% CI = 1.10-1.25; PM(2.5): OR = 1.09, 95% CI = 1.04-1.15). Abdominal pain was increased by an acute gavage of pollution extract but not to chronic exposure to pollutants. Colonic transit was delayed following chronic but not acute exposure with the pollutants. Epidemiological and animal data suggest that short-term exposure to air pollution may trigger non-specific abdominal pain in young individuals

Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of a disease spectrum with shared clinical, genetic and pathological features. These include near ubiquitous pathological inclusions of the RNA-binding protein (RBP) TDP-43, and often the presence of a GGGGCC expansion in the C9ORF72 (C9) gene. Previously, we reported that the sequestration of hnRNP H altered the splicing of target transcripts in C9ALS patients (Conlon et al., 2016). Here, we show that this signature also occurs in half of 50 postmortem sporadic, non-C9 ALS/FTD brains. Furthermore, and equally surprisingly, these ‘like-C9’ brains also contained correspondingly high amounts of insoluble TDP-43, as well as several other disease-related RBPs, and this correlates with widespread global splicing defects. Finally, we show that the like-C9 sporadic patients, like actual C9ALS patients, were much more likely to have developed FTD. We propose that these unexpected links between C9 and sporadic ALS/FTD define a common mechanism in this disease spectrum

Invasive characteristics of human prostatic epithelial cells: understanding the metastatic process

Prostate cancer has a predilection to metastasise to the bone marrow stroma (BMS) by an as yet uncharacterised mechanism. We have defined a series of coculture models of invasion, which simulate the blood/BMS boundary and allow the elucidation of the signalling and mechanics of trans-endothelial migration within the complex bone marrow environment. Confocal microscopy shows that prostate epithelial cells bind specifically to bone marrow endothelial-to-endothelial cell junctions and initiate endothelial cell retraction. Trans-endothelial migration proceeds via an epithelial cell pseudopodial process, with complete epithelial migration occurring after 232±43 min. Stromal-derived factor-1 (SDF-1)/CXCR4 signalling induced PC-3 to invade across a basement membrane although the level of invasion was 3.5-fold less than invasion towards BMS (P=0.0007) or bone marrow endothelial cells (P=0.004). Maximal SDF-1 signalling of invasion was completely inhibited by 10 μM of the SDF-1 inhibitor T140. However, 10 μM T140 only reduced invasion towards BMS and bone marrow endothelial cells by 59% (P=0.001) and 29% (P=0.011), respectively. This study highlights the need to examine the potential roles of signalling molecules and/or inhibitors, not just in single-cell models but in coculture models that mimic the complex environment of the bone marrow