Unidirektionale Schaltprozesse auf Basis von cyclischen Pseudopeptiden

Zusammenfassung Das Gebiet der synthetischen molekularen Schalter und Motoren wächst seit einigen Jahren stetig an. Auf der Natur beruhend können die heutigen Systeme hingegen noch nicht mit ihren natürlichen Vorbildern konkurrieren. Allerdings gelang es bisher erfolgreich, unidirektionale Schalter und Motoren zu entwickeln, deren Bewegung gezielt gesteuert werden kann und somit die Grundlage schaffen, um auf molekularer Ebene Arbeit zu verrichten. In dieser Arbeit wird auf die Entwicklung neuer unidirektionaler Systeme und ihrer Schaltprozesse eingegangen. Im ersten Teil wurde die Anwendung von Biphenylsystemen als Grundelement für unidirektionale Schalter untersucht. Bei diesen sollte mittels energetischer Diskriminierung ein Konformer stabilisiert werden, um auf diesem Wege prinzipiell einen unidirektionalen Bewegungsablauf zu ermöglichen. Zusammenfassend konnte die Konformation der drei Biphenylsysteme 1, 2 und 3 bestimmt, sowie die Vergrößerung des Diederwinkels der Biarylbindungsachse im Vergleich mit (P)-1 bei den Systemen (P)-3 und (P)-4 erfolgreich realisiert werden. Beruhend auf den Biphenylverbindungen sollte somit eine unidirektionale Schaltung von ähnlichen Systemen möglich sein. Im zweiten Teil dieser Arbeit wurde sich mit den unidirektionalen Redoxschaltern (P)-1 und (P)-26 (Abbildung 1.2) beschäftigt. Das System (P)-1 sowie dessen Referenz 33 wurden bereits teilweise in einer vorangegangen Arbeit untersucht.[21] Hier sollten ergänzend die elektrochemischen Untersuchungen vorgenommen werden. Die Schaltung der beiden Systeme 33 und 1 Systeme konnte unter gleichzeitiger Aufnahme von UV-Spektren betrachtet werden. Die Schaltung der Systeme konnte somit erfolgreich nachgewiesen werden. Die spektroelektrochemische Untersuchung konnten sowohl für das Referenzsystem 27 als auch für den Disulfidschalter (P)-26 nicht durchgeführt werden, da als Arbeitselektrode in diesem Fall nur ein Platin-Netz zur Verfügung stand und Sulfide beziehungsweise Thiole an diesen zur irreversiblen Adsorption neigen. Der dritte Teil dieser Arbeit beinhaltete die Synthese und Untersuchung neuer Säure/Base-Schalter. Zu diesem Zweck wurden Methoxy- und Hydroxyphenylpyridinsysteme gewählt. Es konnten drei verschiedene Systeme sowie die entsprechenden Referenzen erfolgreich synthetisiert und der Schaltprozess nachgewiesen werden

Exhaled nitric oxide during infancy as a risk factor for asthma and airway hyperreactivity

Childhood asthma is often characterised by elevated exhaled nitric oxide (eNO), decreased lung function, increased airway reactivity and atopy; however, our understanding of when these phenotypic airway characteristics develop remains unclear. This study evaluated whether eNO, lung function, airway reactivity and immune characteristics during infancy are risk factors of asthma at age 5 years. Infants with eczema, enrolled prior to wheezy illness (n=116), had eNO, spirometry, airway reactivity and allergen sensitisation assessed at entry to the study and repeated at age 5 years (n=90). Increasing eNO at entry was associated with an increased risk of asthma (p=0.037) and increasing airway reactivity (p=0.015) at age 5 years. Children with asthma at 5 years of age had a greater increase in eNO between infancy and age 5 years compared with those without asthma (p=0.002). Egg sensitisation at entry was also associated with an increased risk of asthma (p=0.020), increasing eNO (p = 0.002) and lower forced expiratory flows (p=0.029) as a 5 year-old. Our findings suggest that, among infants at high risk for developing asthma, eNO early in life may provide important insights into the subsequent risk of asthma and its airway characteristics

The regulation of miRNAs by reconstituted high-density lipoproteins in diabetes-impaired angiogenesis

Diabetic vascular complications are associated with impaired ischaemia-driven angiogenesis. We recently found that reconstituted high-density lipoproteins (rHDL) rescue diabetes-impaired angiogenesis. microRNAs (miRNAs) regulate angiogenesis and are transported within HDL to sites of injury/repair. The role of miRNAs in the rescue of diabetes-impaired angiogenesis by rHDL is unknown. Using a miRNA array, we found that rHDL inhibits hsa-miR-181c-5p expression in vitro and using a hsa-miR-181c-5p mimic and antimiR identify a novel anti-angiogenic role for miR-181c-5p. miRNA expression was tracked over time post-hindlimb ischaemic induction in diabetic mice. Early post-ischaemia when angiogenesis is important, rHDL suppressed hindlimb mmu-miR-181c-5p. mmu-miR-181c-5p was not detected in the plasma or within HDL, suggesting rHDL specifically targets mmu-miR-181c-5p at the ischaemic site. Three known angiogenic miRNAs (mmu-miR-223-3p, mmu-miR-27b-3p, mmu-miR-92a-3p) were elevated in the HDL fraction of diabetic rHDL-infused mice early post-ischaemia. This was accompanied by a decrease in plasma levels. Only mmu-miR-223-3p levels were elevated in the hindlimb 3 days post-ischaemia, indicating that rHDL regulates mmu-miR-223-3p in a time-dependent and site-specific manner. The early regulation of miRNAs, particularly miR-181c-5p, may underpin the rescue of diabetes-impaired angiogenesis by rHDL and has implications for the treatment of diabetes-related vascular complications

Antenatal corticosteriods decrease forced vital capacity in infants born fullterm

Antenatal corticosteroids (ACS) administration to pregnant women for threatened preterm labor is standard obstetric care to reduce neonatal respiratory distress syndrome and the associated respiratory morbidity. While ACS stimulates surfactant production in the fetal lung, the effects of ACS upon the subsequent growth and development of the lung are unclear. Follow-up studies outside of the neonatal period have been primarily limited to spirometry, and most subjects evaluated were born prematurely. To our knowledge, no study has assessed both airway and parenchymal function in infants or adults following ACS exposure. We hypothesized that ACS impairs lung growth and performed infant pulmonary function testing, which included spirometry, alveolar volume (VA ) and lung diffusion (DL ). As a pilot study, we limited our assessment to infants whose mothers received ACS for threatened preterm labor, but then proceeded to full term delivery. This approach evaluated a more homogenous population and eliminated the confounding effects of preterm birth. We evaluated 36 full-term infants between 4 to 12 months of age; 17 infants had ACS exposure and 19 infants had no ACS exposure. Infants exposed to ACS had a significantly lower forced vital capacity compared with non-ACS exposed infants (250 vs 313 mL; P = .0075). FEV0.5 tended to be lower for the ACS exposed group (205 vs 237 mL; P = .075). VA and DL did not differ between the two groups. These findings suggest that ACS may impair subsequent growth of the lung parenchyma

Retinoic Acid Functions as a Key GABAergic Differentiation Signal in the Basal Ganglia

Retinoic acid (RA) is essential for the generation of GABAergic inhibitory neurons in the mouse forebrain, and RA treatment of embryonic stem cells induces the production of GABAergic neurons

Toward unidirectional switches: 2-(2-Hydroxyphenyl)pyridine and 2-(2-methoxyphenyl)pyridine derivatives as pH-triggered pivots

The pH-induced switching process of 2-(2-hydroxyphenyl)pyridine and 2-(2-methoxyphenyl)pyridine derivatives was investigated with the help of UV spectroscopy. Quantum chemical calculations at the B3LYP/6-31G* level of theory were performed to show that in the case of 2-(2-methoxyphenyl)-3-methylpyridine and 2-(2-hydroxyphenyl)-3-methylpyridine the rotation during the switching process proceeds unidirectionally at the molecular level. If a 2-(2-methoxyphenyl)pyridine derivative is fixed to a chiral cyclopeptidic scaffold, a unidirectional progress of the rotation is achieved macroscopically

Membrane and Capillary Components of Lung Diffusion in Infants with Bronchopulmonary Dysplasia

RATIONALE: Autopsied lungs of infants with bronchopulmonary dysplasia (BPD) demonstrate impaired alveolar development with larger and fewer alveoli, which is consistent with our previous physiologic findings of lower pulmonary diffusing capacity of the lung for carbon monoxide (DL(CO)) in infants and toddlers with BPD compared with healthy controls born at full term (FT). However, it is not known whether the decreased DL(CO) in infants with BPD results from a reduction in both components of DL(CO): pulmonary membrane diffusing capacity (D(M)) and Vc. OBJECTIVES: We hypothesized that impairment of alveolar development in BPD results in a decrease in both D(M) and Vc components of DlCO but that the D(M)/Vc ratio would not differ between the BPD and FT groups. METHODS: DL(CO) was measured under conditions of room air and high inspired oxygen (90%), which enabled D(M) and Vc to be calculated. MEASUREMENTS AND MAIN RESULTS: D(M) and Vc increased with increasing body length; however, infants with BPD had significantly lower D(M) and Vc than FT subjects after adjustment for race, sex, body length, and corrected age. In contrast to D(M) and Vc, the D(M)/Vc ratio remained constant with increasing body length and did not differ for infants with BPD and FT subjects. CONCLUSIONS: Our findings are consistent with infants with BPD having impaired alveolar development with fewer but larger alveoli, as well as a reduced Vc

Forced expiratory flows and diffusion capacity in infants born from mothers with pre‐eclampsia

Rationale: Animal models suggest pre-eclampsia (Pre-E) affects alveolar development, but data from humans are lacking. Objective: Assess the impact of Pre-E on airway function, diffusion capacity, and respiratory morbidity in preterm and term infants born from mothers with Pre-E. Methods: Infants born from mothers with and without Pre-E were recruited for this study; term and preterm infants were included in both cohorts. Respiratory morbidity in the first 12 months of life was assessed through monthly phone surveys. Raised volume rapid thoracoabdominal compression and measurement of diffusion capacity of the lung to carbon monoxide (DLCO) were performed at 6 months corrected age. Measurements and main results: There were 146 infants in the Pre-E cohort and 143 in the control cohort. The Pre-E cohort was further divided into nonsevere (N = 41) and severe (N = 105) groups. There was no significant difference in DLCO and DLCO/alveolar volume among the three groups. Forced vital capacity was similar among the three groups, but the nonsevere Pre-E group had significantly higher forced expiratory flows than the other two groups. After adjusting for multiple covariates including prematurity, the severe Pre-E group had a lower risk for wheezing in the first year of life compared to the other two groups. Conclusions: Pre-E is not associated with reduced DLCO, lower forced expiratory flows, or increased wheezing in the first year of life. These results differ from animal models and highlight the complex relationships between Pre-E and lung function and respiratory morbidity in human infants