Explorations of water oxidation catalysis in explicit solvent

In the search for sustainable energy solutions, the idea of artificial photosynthesis has been proposed as an approach with which to use water and sunlight to produce hydrogen. Key in the development of hydrogen production technologies is the splitting of water using a water oxidation catalyst. In this thesis, the water splitting catalytic process was investigated using a number of different computational techniques. Computationally, the water splitting catalytic process has traditionally been considered statically as a number of snapshots, and in vacuum. The traditional approaches also often include a number of correction factors for the charge carriers in the reaction. But because catalytic processes are dynamic, a novel approach was also developed in this thesis. With this approach, one can examine the dynamic transition from one catalytic intermediate to another, in a fully solvated environment. In optimising water oxidation catalysts it is important to consider the interaction with the surrounding environment, and how this can impact the catalytic reaction. Furthermore, in the new approach all the charge carriers–protons and electrons–are included in a dynamic simulation. These techniques give us a better idea of the things needed in the optimisation of water oxidation catalysts.This research was financed by Leiden University, and co-financed by the Dutch Ministry of Economic Affairs as part of the BioSolar Cells research project C1.9. The use of supercomputer facilities was sponsored by NWO Exact and Natural SciencesSolid state NMR/Biophysical Organic Chemistr

Brain aromatase activity and plasma testosterone levels are elevated in aggressive male mice during early ontogeny

Testosterone (T) and estradiol (E(2)) are involved in intraspecific aggressive behavior. Both steroids exert their effects on behavior via the hypothalamus and the amygdala (Am) of the central nervous system (CNS). In these brain areas T is converted to E(2), by the enzyme aromatase. Both the levels of brain aromatase activity (AA) and the effects of T and E(2) on aggressive behavior in adulthood depend on steroidal organization of the CNS during ontogeny. In this study we measured plasma T and in vitro brain AA of male fetuses and neonates derived from two strains of wild house mice, which had been genetically selected for aggression, based upon attack latency. There were no differences in preoptic area (POA) AA levels between selection lines on either embryonic day (E) 17 or 18, or the day after birth (day 1). In the non-aggressive long attack latency (LAL) males the POA AA increases with age, i.e. was higher on E18 than on E17, which is correlated with brain weight (BrW). This was in contrast to aggressive short attack latency (SAL) fetuses, which only showed a slight, but not significant difference between embryonic days or, a correlation with BrW. Neonatally, the POA AA of LAL males tended to decrease in contrast to SAL males. However, SAL neonates had a higher AA in the amygdala (Am) than LAL neonates, whereas no differences exist in the anterior hypothalamus. Thus, a differential brain AA distribution exists in SAL and LAL pups. At day 1 SAL: males show higher AA in the Am than in the hypothalamus (POA + AH), whereas in the LAL strain the AA did not differ between these brain areas. In the LAL males plasma T levels decreased from E17 to day 1, whereas the SAL neonates (day 1) exhibited higher circulating T concentrations than LAL neonates. These results suggest a T-independent aromatase induction prenatally in both selection lines, whereas neonatally the higher plasma T level in the SAL line coincides with higher AA levels:in the Am. Accordingly, a differential pattern of E(2) formation exists in the brains of the two selection lines during ontogeny. The variation in circulating T and maximal brain E(2) formation around birth might result in a differential organization of adult CNS sensitivity to sex steroids and accordingly differences in aggressive behavior.</p

Introducing a closed system approach for the investigation of chemical steps involving proton and electron transfer; as illustrated by a copper-based water oxidation catalyst

Solid state NMR/Biophysical Organic Chemistr

Comparison of LISA and Atom Interferometry for Gravitational Wave Astronomy in Space

One of the atom interferometer gravitational wave missions proposed by Dimopoulos et al.1 in 2008 was called AGIS-Sat. 2. It had a suggested gravitational wave sensitivity set by the atom state detection shot noise level that started at 1 mHz, was comparable to LISA sensitivity from 1 to about 20 mHz, and had better sensitivity from 20 to 500 mHz. The separation between the spacecraft was 1,000 km, with atom interferometers 200 m long and shades from sunlight used at each end. A careful analysis of many error sources was included, but requirements on the time-stability of both the laser wavefront aberrations and the atom temperatures in the atom clouds were not investigated. After including these considerations, the laser wavefront aberration stability requirement to meet the quoted sensitivity level is about 1\times10-8 wavelengths, and is far tighter than for LISA. Also, the temperature fluctuations between atom clouds have to be less than 1 pK. An alternate atom interferometer GW mission in Earth orbit called AGIS-LEO with 30 km satellite separation has been suggested recently. The reduction of wavefront aberration noise by sending the laser beam through a high-finesse mode-scrubbing optical cavity is discussed briefly, but the requirements on such a cavity are not given. Unfortunately, such an Earth-orbiting mission seems to be considerably more difficult to design than a non-geocentric mission and does not appear to have comparably attractive scientific goals.Comment: Submitted to Proc. 46th Rencontres de Moriond: Gravitational Waves and Experimental Gravity, March 20 - 27, 2011, La Thuile, Ital

Energetic Effects of a Closed System Approach Including Explicit Proton and Electron Acceptors as Demonstrated by a Mononuclear Ruthenium Water Oxidation Catalyst

Solid state NMR/Biophysical Organic Chemistr

The USCT reference database

Ultrasound Computer Tomography (USCT) is an emerging technology mostly aimed at breast cancer imaging. Following the idea of open science a USCT reference database is established with open and easy to use data and code interfaces. The aim is to promote and facilitate the exchange of available reconstruction algorithms and raw data sets from different USCT devices throughout the growing USCT community. Additionally, the feedback about data and system architecture of the scientists working on reconstruction methods will be published online to help to drive further development of the various measurement setups

The role of surgery for stage I non-small cell lung cancer in octogenarians in the era of stereotactic body radiotherapy in the Netherlands

ObjectivesResection is the standard treatment for stage I non-small cell lung cancer (NSCLC) in operable patients. Stereotactic body radiotherapy (SBRT) is recommended for inoperable patients. A shift from surgery to SBRT is expected in elderly patients due to increased frailty and competing risks. We assessed the current influence of age on treatment decision-making and overall survival (OS).Materials and methodsWe performed a retrospective cohort study using data from patients with clinical stage I NSCLC diagnosed in 2012–2016 and treated with lobectomy, segmentectomy, wedge resection, or SBRT, retrieved from the Netherlands Cancer Registry. Patient characteristics and OS were compared between SBRT and (sub)lobar resection for patients aged 18−79 and ≥80 years.Results and Conclusion8764 patients treated with lobectomy (n = 4648), segmentectomy (n = 122), wedge resection (n = 272), or SBRT (n = 3722) were included. In 2012–2016, SBRT was increasingly used for octogenarians and younger patients from 75.3% to 83.7% and from 30.8% to 43.2%, respectively. Five-year OS in the whole population was 70% after surgery versus 39% after SBRT and 50% versus 27% in octogenarians. After correction for age, gender, year of diagnosis, and clinical T-stage, OS was equal after lobectomy and SBRT in the first 2 years after diagnosis. However, after >2 years, OS was better after lobectomy than after SBRT.SBRT is the prevailing treatment in octogenarians with stage I NSCLC. While surgery is associated with better OS than SBRT, factors other than treatment modality (e.g. comorbidity) may have had a significant impact on survival. The wider application of SBRT in octogenarians likely reflects the frailty of this group. Registries and trials are required to identify key determinants of frailty in this specific population to improve patient selection for surgery or SBRT.Stem cells & developmental biolog

Metabolic blood profile and response to treatment with the pyruvate kinase activator mitapivat in patients with sickle cell disease

Mitapivat is an investigational, oral, small-molecule allosteric activator of pyruvate kinase (PK). PK is a regulatory glycolytic enzyme that is key in providing the red blood cell (RBC) with sufficient amounts of adenosine triphosphate (ATP). In sickle cell disease (SCD), decreased 2,3-DPG levels increase the oxygen affinity of hemoglobin, thereby preventing deoxygenation and polymerization of sickle hemoglobin. The PK activator mitapivat has been shown to decrease levels of 2,3-DPG and increase levels of ATP in RBCs in patients with SCD. In this phase 2, investigator-initiated, open-label study (https://www.clinicaltrialsregister.eu/ NL8517; EudraCT 2019-003438-18), untargeted metabolomics was used to explore the overall metabolic effects of 8-week treatment with mitapivat in the dose-finding period. In total, 1773 unique metabolites were identified in dried blood spots of whole blood from ten patients with SCD and 42 healthy controls (HCs). The metabolic phenotype of patients with SCD revealed alterations in 139/1773 (7.8%) metabolites at baseline when compared to HCs (false discovery rate-adjusted p &lt; 0.05), including increases of (derivatives of) polyamines, purines, and acyl carnitines. Eight-week treatment with mitapivat in nine patients with SCD altered 85/1773 (4.8%) of the total metabolites and 18/139 (12.9%) of the previously identified altered metabolites in SCD (unadjusted p &lt; 0.05). Effects were observed on a broad spectrum of metabolites and were not limited to glycolytic intermediates. Our results show the relevance of metabolic profiling in SCD, not only to unravel potential pathophysiological pathways and biomarkers in multisystem diseases but also to determine the effect of treatment.</p

Electrochemical and Spectroscopic Study of Mononuclear Ruthenium Water Oxidation Catalysts: A Combined Experimental and Theoretical Investigation

Solid state NMR/Biophysical Organic Chemistr

Metabolic blood profile and response to treatment with the pyruvate kinase activator mitapivat in patients with sickle cell disease

Mitapivat is an investigational, oral, small-molecule allosteric activator of pyruvate kinase (PK). PK is a regulatory glycolytic enzyme that is key in providing the red blood cell (RBC) with sufficient amounts of adenosine triphosphate (ATP). In sickle cell disease (SCD), decreased 2,3-DPG levels increase the oxygen affinity of hemoglobin, thereby preventing deoxygenation and polymerization of sickle hemoglobin. The PK activator mitapivat has been shown to decrease levels of 2,3-DPG and increase levels of ATP in RBCs in patients with SCD. In this phase 2, investigator-initiated, open-label study (https://www.clinicaltrialsregister.eu/ NL8517; EudraCT 2019-003438-18), untargeted metabolomics was used to explore the overall metabolic effects of 8-week treatment with mitapivat in the dose-finding period. In total, 1773 unique metabolites were identified in dried blood spots of whole blood from ten patients with SCD and 42 healthy controls (HCs). The metabolic phenotype of patients with SCD revealed alterations in 139/1773 (7.8%) metabolites at baseline when compared to HCs (false discovery rate-adjusted p &lt; 0.05), including increases of (derivatives of) polyamines, purines, and acyl carnitines. Eight-week treatment with mitapivat in nine patients with SCD altered 85/1773 (4.8%) of the total metabolites and 18/139 (12.9%) of the previously identified altered metabolites in SCD (unadjusted p &lt; 0.05). Effects were observed on a broad spectrum of metabolites and were not limited to glycolytic intermediates. Our results show the relevance of metabolic profiling in SCD, not only to unravel potential pathophysiological pathways and biomarkers in multisystem diseases but also to determine the effect of treatment.</p