The effect of the alkali-metal cation (Li+, Na+, K+, and Cs+) on the non-Nernstian pH shift of the Pt(554) and Pt(533) step-associated voltammetric peak is elucidated over a wide pH window (1-13),... Show moreThe effect of the alkali-metal cation (Li+, Na+, K+, and Cs+) on the non-Nernstian pH shift of the Pt(554) and Pt(533) step-associated voltammetric peak is elucidated over a wide pH window (1-13), through computation and experiment. In conjunction with our previously reported study on Pt(553), the non-Nernstian pH shift of the step-induced peak is found to be independent of the step density and the step orientation. In our prior work, we explained the sharp peak as due to the exchange between adsorbed hydrogen and hydroxyl along the step and the non-Nernstian shift as a result of the adsorption of an alkali-metal cation and its subsequent weakening of hydroxyl adsorption. Our density functional theory results support this same mechanism on Pt(533) and capture the effect of alkali-metal cation identity and alkali cation coverage well, where increasing electrolyte pH and cation concentration leads to increased cation coverage and a greater weakening effect on hydroxide adsorption. This work paints a consistent picture for the mechanism of these effects, expanding our fundamental understanding of the electrode/electrolyte interface and practical ability to control hydrogen and hydroxyl adsorption thermodynamics via the electrolyte composition, important for improving fuel cell and electrolyzer performance. Show less
By investigating the interaction between different types of nucleases (i.e. nicking versus cleaving), donor DNA structures and target chromatin environments, this thesis provides important insights... Show moreBy investigating the interaction between different types of nucleases (i.e. nicking versus cleaving), donor DNA structures and target chromatin environments, this thesis provides important insights into how to improve the three crucial parameters of genome editing: efficiency, specificity and fidelity. The work presented in this thesis expand the range of possibilities for high-fidelity genetic manipulation of human cells. Show less
This work deals with the interconversions of various nitrogen-containing compounds on Pt(111) and Pt(100) electrodes in contact with acidic solutions of nitrate. Via its reduction, nitrate acts... Show moreThis work deals with the interconversions of various nitrogen-containing compounds on Pt(111) and Pt(100) electrodes in contact with acidic solutions of nitrate. Via its reduction, nitrate acts merely as the source of adsorbed nitrogen-containing intermediates, which then undergo complex oxidative or reductive transformations depending on the electrode potential. Nitrate reduction to ammonium is structure sensitive on Pt(111) and Pt(100) because it is mediated by *NO, the adsorption and reactivity of which is also structure sensitive. Accordingly, previous knowledge from *NO electrochemistry is useful to streamline nitrate reduction and elaborate a comprehensive picture of nitrogen-cycle electrocatalysis. Our overall conclusion for nitrate reduction is that the complete conversion to ammonium under prolonged electrolysis is possible only if the reduction of nitrate to nitric oxide, and the reduction of nitric oxide to ammonium are feasible at the applied potential. Among the two surfaces studied here, this condition is fulfilled by Pt(111) in a narrow potential region. (C) 2018 Elsevier Ltd. All rights reserved. Show less
Chen, X.; Orriols, M.; Laghmani, E.; Hoogeboom, A.; Hogen-Esch, A.; Hiemstra, P.; ... ; Wagenaar, G. 2017
Bronchopulmonary dysplasia is the most common complication when premature birth occurs at less than 28 weeks gestational age. The general aim of this thesis is to explore the therapeutic... Show moreBronchopulmonary dysplasia is the most common complication when premature birth occurs at less than 28 weeks gestational age. The general aim of this thesis is to explore the therapeutic potential of interventions in signaling pathways, involved in lung development and oxidative stress-induced lung injury, to prevent or attenuate BPD in a neonatal rat model, in which experimental BPD is induced by exposure to hyperoxia. The therapeutic potential of the targeting compounds of signaling pathways was investigated by studying their beneficial effects on contributing factors to severe experimental BPD pathology, including aberrant alveolar and vascular development, inflammation, fibrosis, coagulation, vascular remodeling, pulmonary arterial hypertension and right ventricular hypertrophy. We found ⑴angiotensin II type 2 receptor ligand PD123319 attenuates hyperoxia-induced lung and heart injury at a low dose in newborn rats; ⑵ Metformin attenuates hyperoxia-induced lung injury in neonatal rats by reducing the inflammatory response; ⑶ Deficiency or inhibition of lysophosphatidic acid receptor 1 protects against hyperoxia-induced lung injury in neonatal rats; ⑷Adult lysophosphatidic acid receptor 1-deficient rats with hyperoxia-induced neonatal chronic lung disease are protected against lipopolysaccharide-induced acute lung injury; ⑸ Bone morphogenetic protein 9 protects against neonatal hyperoxia-induced impairment of alveolarization and pulmonary inflammation. Show less
The GABAergic system has been implicated in the pathogenesis of various anxiety disorders. Pharmacological treatments, like benzodiazepines, have been proven to target the GABA(A) receptors and... Show moreThe GABAergic system has been implicated in the pathogenesis of various anxiety disorders. Pharmacological treatments, like benzodiazepines, have been proven to target the GABA(A) receptors and exert quick-onset anxiolytic effect in anxiety patients. However, the side effects of these non-selective GABA(A)ergic compounds, such as sedation, postural imbalance, or potential abuse, limit their use for clinical anxiolysis. Based on the understanding of benzodiazepines’ mechanism of action, the emergence of α2,3 subtype-selective GABA(A) modulator is expected to provide a novel pharmacological approach that alleviates anxiety symptoms but spares the common undesired side effects. Most of these compounds are still in early clinical development, in which stage proof-of-mechanism studies are usually performed in healthy volunteers. The findings from our studies consistently present a similar pattern in the pharmacodynamic effect profiles of the α2,3 subtype-selective GABA(A) modulators versus those of the non-selective full GABA(A) agonist, lorazepam. Future application of anxiogenic symptom provocation models that combine subjective measurements and/or neuroendocrine biomarker assays may provide further construct validity for clinical anxiolytic effects of α2,3 subtype-selective GABA(A) modulators. Also, such findings are expected to provide insights into the translation of preclinical pharmacological properties of α2,3-subtype-selective GABA(A)ergic compounds to clinical effects in anxiety patients through human pharmacology studies. Show less
