An infrared/submillimetre perspective on Active Galactic Nuclei

This thesis presents a Far Infrared / submillimeter view on local Active Galactic Nuclei (AGN). Two aspects are discussed: the potential to detect the molecular torus through high rotational transitions in CO, and the driving of molecular outflows. High-J CO lines arise from dense and warm regions, and could therefore trace the gas around AGN that is hold responsible for absorbing the X-rays from the AGN. Whether this is possible with lines as high as CO(40-39), was tested on the nearby Compton-thick AGN NGC 1068. A deep observation with the Photodetector Array Camera and Spectrometer (PACS) onboard the Herschel Space Observatory resulted in a non-detection of CO(40-39). A radiative transfer model of X-ray dominated regions clarifies the non-detection: with an X-ray input spectrum typical of AGN, the CO(40-39) line only reaches the detection limit at a column density N_H = 10^25 cm^-2. If any dust is present in the gas, it will absorb the CO(40-39) emission over such a large column density. Very high CO rotational lines are therefore not ideal tracers of AGN tori. The second topic concerns galaxy-scale molecular outflows in local Ultra Luminous Infrared Galaxies (ULIRGs). The 22 ULIRGs in our sample are gas-rich mergers with active star formation and AGN activity. Most of these sources have fast (> 1000 km/s) outflows as detected in OH 119 micrometer, thought to be AGN-driven based on their high velocity and their relation between outflow velocity and AGN luminosity. Here it is investigated whether these outflows are traced well through broad wings in the [CII] fine structure line at 158 micrometer. Fourteen out of 22 objects show broad wings in [CII]. Taking only those objects with an outflow detected in both [CII] and OH119, we find a trend between two outflow velocities, as well as between the outflow masses derived from both tracers. We conclude that [CII] is a good tracer of molecular outflows. This is particularly useful at high redshift, where other tracers like OH119 and CO(1-0) are harder to observe. IRAS F08572+3915 is one of the ULIRGs which has a particularly fast and massive molecular outflow. It is studied here in more detail, using high spatial resolution observations of CO(1-0) which were taken with NOEMA (formerly known as Plateau de Bure Interferometer). We find that the source hosts a biconical outflow, aligned with the kinematic major axis of the disk. Possibly the outflow is coplanar, stripping gas off the disk. Spatially resolved observations of Na I D, H alpha and warm H2 show that the atomic and ionized gas overlap with the molecular outflow. The CO observations also reveal a second outflow, at about 6 kpc from the galaxy. If this is an AGN-driven outflow as well, it would imply AGN variability over time-scales of a few megayears. The outflow is slowing down at a rate of ~300 km/s/kpc, perhaps as result of gravitational pull and the absence of a driving mechanism

Phase-Controlled Synthesis of Ruthenium and Palladium Nanocrystals

The utility of noble-metal nanocrystals in applications ranging from catalysis to biomedical applications has increased with the ability to finely tune their shapes and sizes. In particular, the catalytic activity of the nanocrystals is strongly affected by their shape, as this parameter is directly related to the atomic arrangement on the surface. Another way to alter the surface atomic arrangement is through changing the crystal structure (or phase) of the nanocrystal, a property known as polymorphism. A powerful method to achieve such control over the crystal structure is through template-directed growth to obtain metastable core-shell nanocrystals. In this dissertation, I present a number of studies delving into the mechanistic details behind template-directed phase control for Pd and Ru, alongside an evaluation of their catalytic properties. First, the importance of particle size on successful template-directed deposition was demonstrated through deposition of Ru on 12-, 18-, 22-, and 26-nm Pd nanoplates, where small nanoplates resulted in fcc-Ru shells, while the larger ones gave hcp-Ru overgrowth. The size dependence was ascribed to a trade-off between the bulk and surface energies that changed with particle size. On small nanoplates, the high proportion of total surface area coming from the side faces makes it favorable to grow fcc-Ru, which deposits smoothly on the side facets (low surface energy) at the expense of forming a metastable phase (high bulk energy). For large nanoplates, only a small proportion of the surface area comes from the side, promoting the growth of hcp-Ru as the resulting jagged side faces (high surface energy) could be compensated by the formation of a thermodynamically stable phase (low bulk energy). To further elucidate the mechanistic details involved in phase-controlled synthesis, the influence of the template’s shape was investigated next. When Ru was deposited on 8-25 nm Pd cubic nanocrystals, the Ru shell took an fcc phase, but on 14-26 nm Pd octahedral nanocrystals, the Ru was deposited as fcc on the small templates before reverting to hcp on the larger ones. The {100} facets displayed on cubic templates forced the Ru to take the fcc phase due to a symmetry mismatch between the facets of the fcc¬-Pd template and hcp-Ru, while on octahedral templates, the displayed {111} facets could be symmetrically aligned with either hcp- or fcc-Ru, allowing for the overgrowth of either crystal structure. Thus, on octahedral templates, the crystal structure depends on particle size and it is determined by the balance of surface and bulk energies. With an improved understanding of template-directed phase control, this method could be extended to obtain hcp-Pd deposition on an hcp¬-Ru template. Under careful control of the reaction conditions, Pd could be deposited on an hcp-Ru template in either the standard fcc phase, or in a novel, metastable hcp phase. It was essential to slow down the reduction rate of the Pd precursor in order to obtain phase-controlled Pd. The ability to control the crystal structure of noble-metal nanocrystals, coupled with a mechanistic understanding of this process, will enable the development of nanostructured materials with unique properties through rational and deterministic syntheses.Ph.D

The carbon footprint of NL astronomy in 2019

Science Communication and Societ

Systemic Signature of the Lung Response to Respiratory Syncytial Virus Infection

Respiratory Syncytial Virus is a frequent cause of severe bronchiolitis in children. To improve our understanding of systemic host responses to RSV, we compared BALB/c mouse gene expression responses at day 1, 2, and 5 during primary RSV infection in lung, bronchial lymph nodes, and blood. We identified a set of 53 interferon-associated and innate immunity genes that give correlated responses in all three murine tissues. Additionally, we identified blood gene signatures that are indicative of acute infection, secondary immune response, and vaccine-enhanced disease, respectively. Eosinophil-associated ribonucleases were characteristic for the vaccine-enhanced disease blood signature. These results indicate that it may be possible to distinguish protective and unfavorable patient lung responses via blood diagnostics

IL1RL1 Gene Variants and Nasopharyngeal IL1RL-a Levels Are Associated with Severe RSV Bronchiolitis: A Multicenter Cohort Study

Targets for intervention are required for respiratory syncytial virus (RSV) bronchiolitis, a common disease during infancy for which no effective treatment exists. Clinical and genetic studies indicate that IL1RL1 plays an important role in the development and exacerbations of asthma. Human IL1RL1 encodes three isoforms, including soluble IL1RL1-a, that can influence IL33 signalling by modifying inflammatory responses to epithelial damage. We hypothesized that IL1RL1 gene variants and soluble IL1RL1-a are associated with severe RSV bronchiolitis.We studied the association between RSV and 3 selected IL1RL1 single-nucleotide polymorphisms rs1921622, rs11685480 or rs1420101 in 81 ventilated and 384 non-ventilated children under 1 year of age hospitalized with primary RSV bronchiolitis in comparison to 930 healthy controls. Severe RSV infection was defined by need for mechanical ventilation. Furthermore, we examined soluble IL1RL1-a concentration in nasopharyngeal aspirates from children hospitalized with primary RSV bronchiolitis. An association between SNP rs1921622 and disease severity was found at the allele and genotype level (p = 0.011 and p = 0.040, respectively). In hospitalized non-ventilated patients, RSV bronchiolitis was not associated with IL1RL1 genotypes. Median concentrations of soluble IL1RL1-a in nasopharyngeal aspirates were >20-fold higher in ventilated infants when compared to non-ventilated infants with RSV (median [and quartiles] 9,357 [936-15,528] pg/ml vs. 405 [112-1,193] pg/ml respectively; p<0.001).We found a genetic link between rs1921622 IL1RL1 polymorphism and disease severity in RSV bronchiolitis. The potential biological role of IL1RL1 in the pathogenesis of severe RSV bronchiolitis was further supported by high local concentrations of IL1RL1 in children with most severe disease. We speculate that IL1RL1a modifies epithelial damage mediated inflammatory responses during RSV bronchiolitis and thus may serve as a novel target for intervention to control disease severity

Real-world palbociclib effectiveness in patients with metastatic breast cancer: Focus on neutropenia-related treatment modification strategies and clinical outcomes

INTRODUCTION: In addition to clinical trials, real-world data is needed to verify the effectiveness of the CDK 4/6 inhibitor palbociclib. The primary aim was to examine real-world variation in treatment modification strategies for neutropenia and its relation to progression-free survival (PFS). The secondary aim was to assess if there is a gap between real-world and clinical trial outcomes. MATERIALS AND METHODS: In this multicenter, retrospective observational cohort study 229 patients were analyzed who started palbociclib and fulvestrant as second- or later-line therapy for HR-positive, HER2-negative metastatic breast cancer in the Santeon hospital group in the Netherlands between September 2016 and December 2019. Data were manually retrieved from patients' electronic medical records. PFS was examined using the Kaplan-Meier method to compare neutropenia-related treatment modification strategies within the first three months after neutropenia grade 3 - 4 occurred, as well as patients' eligibility to have participated in the PALOMA-3 clinical trial or not. RESULTS: Even though treatment modification strategies differed from those in PALOMA-3 (dose interruptions: 26 vs 54%, cycle delays: 54 vs 36%, and dose reductions: 39 vs 34%), these did not influence PFS. Patients who were PALOMA-3 ineligible experienced a shorter median PFS than those who were eligible (10.2 vs. 14.1 months; HR 1.52; 95% CI 1.12 - 2.07). An overall longer median PFS was found compared to PALOMA-3 (11.6 vs. 9.5 months; HR 0.70; 95% CI 0.54 - 0.90). CONCLUSION: This study suggests no impact of neutropenia-related treatment modifications on PFS and confirms inferior outcomes outside clinical trial eligibility

Consensus molecular subtype classification of colorectal adenomas

Consensus molecular subtyping is an RNA expression-based classification system for colorectal cancer (CRC). Genomic alterations accumulate during CRC pathogenesis, including the premalignant adenoma stage, leading to changes in RNA expression. Only a minority of adenomas progress to malignancies, a transition that is associated with specific DNA copy number aberrations or microsatellite instability (MSI). We aimed to investigate whether colorectal adenomas can already be stratified into consensus molecular subtype (CMS) classes, and whether specific CMS classes are related to the presence of specific DNA copy number aberrations associated with progression to malignancy. RNA sequencing was performed on 62 adenomas and 59 CRCs. MSI status was determined with polymerase chain reaction-based methodology. DNA copy number was assessed by low-coverage DNA sequencing (n = 30) or array-comparative genomic hybridisation (n = 32). Adenomas were classified into CMS classes together with CRCs from the study cohort and from The Cancer Genome Atlas (n = 556), by use of the established CMS classifier. As a result, 54 of 62 (87%) adenomas were classified according to the CMS. The CMS3 ‘metabolic subtype’, which was least common among CRCs, was most prevalent among adenomas (n = 45; 73%). One of the two adenomas showing MSI was classified as CMS1 (2%), the ‘MSI immune’ subtype. Eight adenomas (13%) were classified as the ‘canonical’ CMS2. No adenomas were classified as the ‘mesenchymal’ CMS4, consistent with the fact that adenomas lack invasion-associated stroma. The distribution of the CMS classes among adenomas was confirmed in an independent series. CMS3 was enriched with adenomas at low risk of progressing to CRC, whereas relatively more high-risk adenomas were observed in CMS2. We conclude that adenomas can be stratified into the CMS classes. Considering that CMS1 and CMS2 expression signatures may mark adenomas at increased risk of progression, the distribution of the CMS classes among adenomas is consistent with the proportion of adenomas expected to progress to CRC

Rh@Au Core–Shell Nanocrystals with the Core in Tensile Strain and the Shell in Compressive Strain

Bimetallic nanocrystals provide a versatile platform for utilizing the desired characteristics of two different elements within one particle. Core–shell nanocrystals, in particular, have found widespread use in catalysis by providing an ability to leverage the strains arising from the lattice mismatch between the core and the shell. However, large (>5%) lattice mismatch tends to result in nonepitaxial growth and lattice defects in an effort to release the strain. Herein, we report the epitaxial growth of Au on Rh cubic seeds under mild reaction conditions to generate Rh@Au truncated octahedra featuring a lattice mismatch of 7.2%. Key to the success was the use of small (4.5 nm) Rh cubes as seeds, which could homogeneously distribute the tensile strain arising from the epitaxial growth of a conformal, compressively strained Au shell. Further, delicate tuning of kinetic parameters through the introduction of NaOH and KBr into the synthesis allowed for a unique nucleation pattern that led to centrally located cores and a narrow size distribution for the product. A thorough investigation of the various possible highly strained morphologies was conducted to gain a full understanding of the system