Micromachined Capacitive Long-Range Displacement Sensor for Nano-Positioning of Microactuator systems

This thesis is about a “Micromachined capacitive long-range displacement sensor for nano-positioning of microactuator systems”. Possible applications of such microsystems are found in future probe-based datastorage, scanning probe microscopy, microbiology, optical lens manipulation, microgrippers and microrobots, etc. These applications require positioning with nanometer precision over a long range (ten’s of micrometers) and benefit from further miniaturization and the application of sub-mm sized Micro Electro Mechanical Systems (MEMS). In many cases open-loop operation is not sufficient and a form of system control is required to combine nanometer accuracy with a large dynamic range and to obtain better system performance. In order to make such systems both economically viable as well as compact, on-chip position sensing appears to be a requirement. The aim is therefore, to obtain optimal performance through an integration of sensor and actuator with micromachining fabrication technology without additional micro assembly

Granulocyte concentrates: Prolonged functional capacity during storage in the presence of phenotypic changes

Background Granulocyte transfusion has been proposed as a bridging therapy for patients with prolonged p

Severe congenital neutropenia in a multigenerational family with a novel neutrophil elastase (ELANE) mutation

We have analysed a family with nine congenital neutropenia patients in four generations, several of which we have studied in a long-term follow-up of over 25 years. The patients were mild to severe neutropenic and suffered from various recurrent bacterial infections. Mutations in the genes ELANE, CSF3R and GFI1 have been reported in patients with autosomal dominant congenital neutropenias. Using a small-scale linkage analysis with markers around the ELANE, CSF3R, CSF3 and GFI1 genes, we were able to determine that the disease segregated with markers around the ELANE gene. We identified a novel mutation in the ELANE gene in all of the affected family members that was not present in any of the healthy family members. The mutation leads to an A28S missense mutation in the mature protein. None of these patients developed leukaemia. This is the first truly multigenerational family with mutations in ELANE as unambiguous cause of severe congenital neutropenia SCN

Resonant two-site tunnelling dynamics of bosons in a tilted optical superlattice

We study the non-equilibrium dynamics of a 1D Bose-Hubbard model in a gradient potential and a superlattice, beginning from a deep Mott insulator regime with an average filling of one particle per site. Studying a quench that is near resonance to tunnelling of the particles over two lattice sites, we show how a spin model emerges consisting of two coupled Ising chains that are coupled by interaction terms in a staggered geometry. We compare and contrast the behavior in this case with that in a previously studied case where the resonant tunnelling was over a single site. Using optimized tensor network techniques to calculate finite temperature behavior of the model, as well as finite size scaling for the ground state, we conclude that the universality class of the phase transition for the coupled chains is that of a tricritical Ising point. We also investigate the out-of-equilibrium dynamics after the quench in the vicinity of the resonance and compare dynamics with recent experiments realized without the superlattice geometry. This model is directly realizable in current experiments, and reflects a new general way to realize spin models with ultracold atoms in optical lattices.Comment: 12 pages, 6 figure

Dynamics of Transcription Regulation in Human Bone Marrow Myeloid Differentiation to Mature Blood Neutrophils.

Neutrophils are short-lived blood cells that play a critical role in host defense against infections. To better comprehend neutrophil functions and their regulation, we provide a complete epigenetic overview, assessing important functional features of their differentiation stages from bone marrow-residing progenitors to mature circulating cells. Integration of chromatin modifications, methylation, and transcriptome dynamics reveals an enforced regulation of differentiation, for cellular functions such as release of proteases, respiratory burst, cell cycle regulation, and apoptosis. We observe an early establishment of the cytotoxic capability, while the signaling components that activate these antimicrobial mechanisms are transcribed at later stages, outside the bone marrow, thus preventing toxic effects in the bone marrow niche. Altogether, these data reveal how the developmental dynamics of the chromatin landscape orchestrate the daily production of a large number of neutrophils required for innate host defense and provide a comprehensive overview of differentiating human neutrophils

Evidence-based pharmacotherapy of panic disorder: an update

The evidence-based pharmacotherapy of panic disorder continues to evolve. This paper reviews data on first-line pharmacotherapy, evidence for maintenance treatment, and management options for treatment-refractory patients. A Medline search of research on pharmacotherapy was undertaken, and a previous systematic review on the evidence-based pharmacotherapy of panic disorder was updated. Selective serotonin reuptake inhibitors remain a first-line pharmacotherapy of panic disorder, with the serotonin noradrenaline reuptake inhibitor venlafaxine also an acceptable early option. Temporary co-administration of benzodiazepines can be considered. Maintenance treatment reduces relapse rates, but further research to determine optimal duration is needed. For patients not responding to first-line agents several pharmacotherapy options are available, but there is a notable paucity of data on the optimal choice. © 2011 CINP

Sodium stibogluconate and CD47-SIRPa blockade overcome resistance of anti-CD20–opsonized B cells to neutrophil killing

Anti-CD20 antibodies such as rituximab are broadly used to treat B-cell malignancies. These antibodies can induce various effector functions, including immune cell-mediated antibody-dependent cellular cytotoxicity (ADCC). Neutrophils can induce ADCC toward solid cancer cells by trogoptosis, a cytotoxic mechanism known to be dependent on trogocytosis. However, neutrophils seem to be incapable of killing rituximab-opsonized B-cell lymphoma cells. Nevertheless, neutrophils do trogocytose rituximab-opsonized B-cell lymphoma cells, but this only reduces CD20 surface expression and is thought to render tumor cells therapeutically resistant to further rituximab-dependent destruction. Here, we demonstrate that resistance of B-cell lymphoma cells toward neutrophil killing can be overcome by a combination of CD47-SIRPa checkpoint blockade and sodium stibogluconate (SSG), an anti-leishmaniasis drug and documented inhibitor of the tyrosine phosphatase SHP-1. SSG enhanced neutrophil-mediated ADCC of solid tumor cells but enabled trogoptotic killing of B-cell lymphoma cells by turning trogocytosis from a mechanism that contributes to resistance into a cytotoxic anti-cancer mechanism. Tumor cell killing in the presence of SSG required both antibody opsonization of the target cells and disruption of CD47-SIRPa interactions. These results provide a more detailed understanding of the role of neutrophil trogocytosis in antibody-mediated destruction of B cells and clues on how to further optimize antibody therapy of B-cell malignancies

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation