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Institute
Low energy beam transport (LEBT) for a future heavy ion driven inertial fusion (HIDIF [1]) facility is a crucial point using a Bi+ beam of 40 mA at 156 keV. High space charge forces (generalised perveance K=3.6*10-3) restrict the use of electrostatic focussing systems. On the other hand magnetic lenses using space charge compensation suffer from the low particle velocity. Additionally the emittance requirements are very high in order to avoid particle losses in the linac and at ring injection [2]. urthermore source noise and rise time of space charge compensation [3] might enhance particle losses and emittance. Gabor lenses [4] using a continuous space charge cloud for focussing could be a serious alternative to conventional LEBT systems. They combine strong cylinder symmetric focussing with partly space charge compensation and low emittance growth due to lower non linear fields. A high tolerance against source noise and current fluctuations and reduced investment costs are other possible advantages. The proof of principle has already been shown [5, 6]. To broaden the experiences an experimental program was started. Therefrom the first experimental results using a double Gabor lens (DGPL, see fig. 1 ) LEBT system for transporting an high perveance Xe+ beam will be presented and the results of numerical simulations will be shown.
Investigation of the focus shift due to compensation process for low energy ion beam transport
(2000)
In magnetic Low Energy Beam Transport (LEBT) sections space charge compensation helps to enhance the transportable beam current and to reduce emittance growth due to space charge forces. For pulsed beams the time neccesary to establish space charge compensation is of great interest for beam transport. Particularly with regard to beam injection into the first accelerator section (e.g. RFQ) investigation of effects on shift of the beam focus due to space charge compensation are very important. The achieved results helps to obviate a mismatch into the first RFQ. To investigate the space charge compensation due to residual gas ionization, time resolved measurements using pulsed ion beams were performed at the LEBT system at the IAP and at the CEA-Saclay injektion line. A residual gas ion energy analyser (RGIA) equiped with a channeltron was used to measure the potential destribution as a function of time to estimate the rise time of compensation. For time resolved measurements (delta t min=50ns) of the radial density profile of the ion beam a CCD-camera was applied. The measured data were used in a numerical simulation of selfconsistant eqilibrium states of the beam plasma [1] to determine plasma parameters such as the density, the temperature, the kinetic and potential energy of the compensation electrons as a function of time. Measurements were done using focused proton beams (10keV, 2mA at IAP and 92keV, 62mA at CEA-Saclay) to get a better understanding of the influence of the compensation process. An interpretation of the acquired data and the achieved results will be presented.
High perveance negative ion beams with low emittance are essential for several next generation particle accelerators (i. g. spallation sources like ESS [1] and SNS [2]). The extraction and transport of these beams have intrinsic difficulties different from positive ion beams. Limitation of beam current and emittance growth have to be avoided. To fulfill the requirements of those projects a detailed knowledge of the physics of beam formation the interaction of the H- with the residual gas and transport is substantial. A compact cesium free H- volume source delivering a low energy high perveance beam (6.5 keV, 2.3 mA, perveance K= 0.0034) has been built to study the fundamental physics of beam transport and will be integrated into the existing LEBT section in the near future. First measurements of the interaction between the ion beam and the residual gas will be presented together with the experimental set up and preliminary results.
High perveance negative ion beams with low emittance are essential for several next generation particle accelerators (i. g. spallation sources like ESS [1] and SNS [2]). The extraction and transport of these beams have intrinsic difficulties different from positive ion beams. Limitation of beam current and emittance growth have to be avoided. To fulfill the requirements of those projects a detailed knowledge of the physics of beam formation the interaction of the H- with the residual gas and transport is substantial. A compact cesium free H- volume source delivering a low energy high perveance beam (6.5 keV, 2.3 mA, perveance K= 0.0034) has been built to study the fundamental physics of beam transport and will be integrated into the existing LEBT section in the near future. First measurements of the interaction between the ion beam and the residual gas will be presented together with the experimental set up and preliminary results.
The knowledge of the build up time of space charge compensation (SCC) and the investigation of the compensation process is of main interest for low energy beam transport of pulsed high perveance ion beams under space charge compensated conditions. To investigate experimentally the rise of compensation an LEBT system consisting of a pulsed ion source, two solenoids and a drift tube as diagnostic section has been set up. The beam potential has been measured time resolved by a residual gas ion energy analyser (RGA). A numerical simulation for the calculation of self-consistent equilibrium states of the beam plasma has been developed to determine plasma parameters which are difficult measure directly. The results of the simulation has been compared with the measured data to investigate the behavior of the compensation electrons as a function of time. The acquired data shows that the theoretical rise time of space charge compensation is by a factor of two shorter than the build up time determined experimentally. In view of description the process of SCC an interpretation of the gained results is given.
The determination of the beam emittance using conventional destructive methods suffers from two main disadvantages. The interaction between the ion beam and the measurement device produces a high amount of secondary particles. Those particles interact with the beam and can change the transport properties of the accelerator. Particularly in the low energy section of high current accelerators like proposed for IFMIF, heavy ion inertial fusion devices (HIDIF) and spallation sources (ESS, SNS) the power deposited on the emittance measurement device can lead to extensive heat on the detector itself and can destruct or at least dejust the device (slit or grit for example). CCD camera measurements of the incident light emitted from interaction of beam ions with residual gas are commonly used for determination of the beam emittance. Fast data acquisition and high time resolution are additional features of such a method. Therefore a matrix formalism is used to derive the emittance from the measured profile of the beam [1,2] which does not take space charge effects and emittance growth into account. A new method to derive the phase space distribution of the beam from a single CCD camera image using statistical numerical methods will be presented together with measurements. The results will be compared with measurements gained from a conventional Allison type (slit-slit) emittance measurement device.
For investigation of space charge compensation process due to residual gas ionization and the experimentally study of the rise of compensation, a Low Energy Beam Transport (LEBT) system consisting of an ion source, two solenoids, a decompensation electrode to generate a pulsed decompensated ion beam and a diagnostic section was set up. The potentials at the beam axis and the beam edge were ascertained from time resolved measurements by a residual gas ion energy analyzer. A numerical simulation of self-consistent equilibrium states of the beam plasma has been developed to determine plasma parameters which are difficult to measure directly. The temporal development of the kinetic and potential energy of the compensation electrons has been analyzed by using the numerically gained results of the simulation. To investigate the compensation process the distribution and the losses of the compensation electrons were studied as a function of time. The acquired data show that the theoretical estimated rise time of space charge compensation neglecting electron losses is shorter than the build up time determined experimentally. To describe the process of space charge compensation an interpretation of the achieved results is given.
A LEBT system consisting of an ion source, two solenoids, and a diagnostic section has been set up to investigate the space charge compensation process due to residual gas ionization [1] and to study experimentally the rise of compensation. To gain the radial beam potential distribution time resolved measurements of the residual gas ion energy distribution were carried out using a Hughes Rojanski analyzer [2,3]. To measure the radial density profile of the ion beam a CCD-camera performed time resolved measurements, which allow an estimation the rise time of compensation. Further the dynamic effect of the space charge compensation on the beam transport was shown. A numerical simulation under assumption of selfconsistent states [4] of the beam plasma has been used to determine plasma parameters such as the radial density profile and the temperature of the electrons. The acquired data show that the theoretical estimated rise time of space charge compensation neglecting electron losses is shorter than the build up time determined experimentally. An interpretation of the achieved results is given.
Influence of space charge fluctuations on the low energy beam transport of high current ion beams
(2000)
For future high current ion accelerators like SNS, ESS or IFMIF the beam behaviour in low energy beam transport sections is dominated by space charge forces. Therefore space charge fluctuations (e. g. source noise) can drastically influence the beam transport properties of the low energy beam transport section. Losses of beam ions and emittance growth are the most severe problems. For electrostatic transport systems either a LEBT design has to be found which is insensitive to variations of the space charge or the origin of the fluctuations has to be eliminated. For space charge compensated transport as proposed for ESS and IFMIF the situation is different: No major influence on beam transport is expected for fluctuations below a cut-off frequency given by the production rate of the compensation particles. Above this frequency the fluctuations can not be compensated by particle production alone, but redistributions of the compensation particles helps to compensate the influence of the fluctuations. Above a second cut-off frequency given by the density and the temperature of the compensation particles their redistribution is too slow to reduce the influence of the space charge fluctuations. Transport simulations for the IFMIF injector including space charge fluctuations will be presented together with a determination of the cut-off frequencies. The results will be compared with measurements of the rise time of space charge compensation.
Objectives: We explore the importance of SARS-CoV-2 sentinel surveillance testing in primary care during a regional COVID-19 outbreak in Austria.
Design: Prospective cohort study.
Setting: A single sentinel practice serving 22 829 people in the ski-resort of Schladming-Dachstein.
Participants: All 73 patients presenting with mild-to-moderate flu-like symptoms between 24 February and 03 April, 2020.
Intervention: Nasopharyngeal sampling to detect SARS-CoV-2 using real-time reverse transcriptase-quantitative PCR (RT-qPCR).
Outcome measures: We compared RT-qPCR at presentation with confirmed antibody status. We split the outbreak in two parts, by halving the period from the first to the last case, to characterise three cohorts of patients with confirmed infection: early acute (RT-qPCR reactive) in the first half; and late acute (reactive) and late convalescent (non-reactive) in the second half. For each cohort, we report the number of cases detected, the accuracy of RT-qPCR, the duration and variety of symptoms, and the number of viral clades present.
Results: Twenty-two patients were diagnosed with COVID-19 (eight early acute, seven late acute and seven late convalescent), 44 patients tested SARS-CoV-2 negative and 7 were excluded. The sensitivity of RT-qPCR was 100% among all acute cases, dropping to 68.1% when including convalescent. Test specificity was 100%. Mean duration of symptoms for each group were 2 days (range 1–4) among early acute, 4.4 days (1–7) among late acute and 8 days (2–12) among late convalescent. Confirmed infection was associated with loss of taste. Acute infection was associated with loss of taste, nausea/vomiting, breathlessness, sore throat and myalgia; but not anosmia, fever or cough. Transmission clusters of three viral clades (G, GR and L) were identified.
Conclusions: RT-qPCR testing in primary care can rapidly and accurately detect SARS-CoV-2 among people with flu-like illness in a heterogeneous viral outbreak. Targeted testing in primary care can support national sentinel surveillance of COVID-19.
We report the first measurements of 1,1,1,2,3,3,3-heptafluoropropane (HFC-227ea), a substitute for ozone depleting compounds, in remote regions of the atmosphere and present evidence for its rapid growth. Observed mixing ratios ranged from below 0.01 ppt in deep firn air to 0.59 ppt in the northern mid-latitudinal upper troposphere. Firn air samples collected in Greenland were used to reconstruct a history of atmospheric abundance. Year-on-year increases were deduced, with acceleration in the growth rate from 0.026 ppt per year in 2000 to 0.057 ppt per year in 2007. Upper tropospheric air samples provide evidence for a continuing growth until late 2009. Fur- thermore we calculated a stratospheric lifetime of 370 years from measurements of air samples collected on board high altitude aircraft and balloons. Emission estimates were determined from the reconstructed atmospheric trend and suggest that current "bottom-up" estimates of global emissions for 2005 are too high by more than a factor of three.
We report the first measurements of 1,1,1,2,3,3,3-heptafluoropropane (HFC-227ea), a substitute for ozone depleting compounds, in air samples originating from remote regions of the atmosphere and present evidence for its accelerating growth. Observed mixing ratios ranged from below 0.01 ppt in deep firn air to 0.59 ppt in the current northern mid-latitudinal upper troposphere. Firn air samples collected in Greenland were used to reconstruct a history of atmospheric abundance. Year-on-year increases were deduced, with acceleration in the growth rate from 0.029 ppt per year in 2000 to 0.056 ppt per year in 2007. Upper tropospheric air samples provide evidence for a continuing growth until late 2009. Furthermore we calculated a stratospheric lifetime of 370 years from measurements of air samples collected on board high altitude aircraft and balloons. Emission estimates were determined from the reconstructed atmospheric trend and suggest that current "bottom-up" estimates of global emissions for 2005 are too high by a factor of three.
Global response of diacylglycerol kinase towards substrate binding observed by 2D and 3D MAS NMR
(2019)
Escherichia coli diacylglycerol kinase (DGK) is an integral membrane protein, which catalyses the ATP-dependent phosphorylation of diacylglycerol (DAG) to phosphatic acid (PA). It is a unique trimeric enzyme, which does not share sequence homology with typical kinases. It exhibits a notable complexity in structure and function despite of its small size. Here, chemical shift assignment of wild-type DGK within lipid bilayers was carried out based on 3D MAS NMR, utilizing manual and automatic analysis protocols. Upon nucleotide binding, extensive chemical shift perturbations could be observed. These data provide evidence for a symmetric DGK trimer with all of its three active sites concurrently occupied. Additionally, we could detect that the nucleotide substrate induces a substantial conformational change, most likely directing DGK into its catalytic active form. Furthermore, functionally relevant interprotomer interactions are identified by DNP-enhanced MAS NMR in combination with site-directed mutagenesis and functional assays.
Light‐induced activation of biomolecules by uncaging of photolabile protection groups has found many applications for triggering biochemical reactions with minimal perturbations directly within cells. Such an approach might also offer unique advantages for solid‐state NMR experiments on membrane proteins for initiating reactions within or at the membrane directly within the closed MAS rotor. Herein, we demonstrate that the integral membrane protein E. coli diacylglycerol kinase (DgkA), which catalyzes the phosphorylation of diacylglycerol, can be controlled by light under MAS‐NMR conditions. Uncaging of NPE‐ATP or of lipid substrate NPE‐DOG by in situ illumination triggers its enzymatic activity, which can be monitored by real‐time 31P‐MAS NMR. This proof‐of‐concept illustrates that combining MAS‐NMR with uncaging strategies and illumination methods offers new possibilities for controlling biochemical reactions at or within lipid bilayers.
Aims: SARS-CoV-2 infection is associated with adverse outcomes in patients with cardiovascular disease. Here, we analyzed whether specific biomarkers predict the clinical course of COVID-19 in patients with cardiovascular comorbidities. Methods and results: We enrolled 2147 patients with SARS-CoV-2 infection which were included in the Lean European Open Survey on SARS-CoV‑2 (LEOSS)-registry from March to June 2020. Clinical data and laboratory values were collected and compared between patients with and without cardiovascular comorbidities in different clinical stages of the disease. Predictors for mortality were calculated using multivariate regression analysis. We show that patients with cardiovascular comorbidities display significantly higher markers of myocardial injury and thrombo-inflammatory activation already in the uncomplicated phase of COVID-19. In multivariate analysis, elevated levels of troponin [OR 1.54; (95% CI 1.22–1.96), p < 0.001)], IL-6 [OR 1.69 (95% CI 1.26–2.27), p < 0.013)], and CRP [OR 1.32; (95% CI 1.1–1.58), p < 0.003)] were predictors of mortality in patients with COVID-19. Conclusion: Patients with cardiovascular comorbidities show elevated markers of thrombo-inflammatory activation and myocardial injury, which predict mortality, already in the uncomplicated phase of COVID-19. Starting targeted anti-inflammatory therapy and aggressive anticoagulation already in the uncomplicated phase of the disease might improve outcomes after SARS-CoV-2 infection in patients with cardiovascular comorbidities.
Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting.
Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators.
Results: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm).
Conclusions: Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.
Objective: Establishment of an immunocompetent mouse model representing the typical progressive stages observed in malignant human gliomas for the in vivo evaluation of novel target-specific regimens.
Methods: Isolated clones from tumours that arose spontaneously in GFAP-v-src transgenic mice were used to develop a transplantable brain tumour model in syngeneic B6C3F1 mice. STAT3 protein was knocked down by infection of tumour cells with replication-defective lentivirus encoding STAT3-siRNA. Apoptosis is designed to be induced by soluble recombinant TRAIL + chemical Bcl-2/Bcl-xL inhibitors.
Results: Striatal implantation of 105 mouse tumour cells resulted in the robust development of microscopically (2 – 3 mm) infiltrating malignant gliomas. Immunohistochemically, the gliomas displayed the astroglial marker GFAP and the oncogenic form of STAT3 (Tyr-705-phosphorylated) which is found in many malignancies including gliomas. Phosphorylated STAT3 was particularly prominent in the nucleus but was also found at the plasma membrane of peripherally infiltrating glioma cells. To evaluate the role of STAT3 in tumour progression, we stably expressed siRNA against STAT3 in several murine glioma cell lines. The effect of STAT3 depletion on proliferation, invasion and survival will be first assessed in vitro and subsequently after transplantation in vivo. Upstream and downstream components of the STAT3 signalling pathway as well as possible non-specific side effects of STAT3-siRNA expression after lentiviral infection will be examined, too.
Conclusions: Its high rate of engraftment, its similarity to the malignant glioma of origin, and its rapid locally invasive growth should make this murine model useful in testing novel therapies for malignant gliomas.
The function of the p53 transcription factor family is dependent on several folded domains. In addition to a DNA-binding domain, members of this family contain an oligomerization domain. p63 and p73 also contain a C-terminal Sterile α-motif domain. Inhibition of most transcription factors is difficult as most of them lack deep pockets that can be targeted by small organic molecules. Genetic knock-out procedures are powerful in identifying the overall function of a protein, but they do not easily allow one to investigate roles of individual domains. Here we describe the characterization of Designed Ankyrin Repeat Proteins (DARPins) that were selected as tight binders against all folded domains of p63. We determine binding affinities as well as specificities within the p53 protein family and show that DARPins can be used as intracellular inhibitors for the modulation of transcriptional activity. By selectively inhibiting DNA binding of the ΔNp63α isoform that competes with p53 for the same promoter sites, we show that p53 can be reactivated. We further show that inhibiting the DNA binding activity stabilizes p63, thus providing evidence for a transcriptionally regulated negative feedback loop. Furthermore, the ability of DARPins to bind to the DNA-binding domain and the Sterile α-motif domain within the dimeric-only and DNA-binding incompetent conformation of TAp63α suggests a high structural plasticity within this special conformation. In addition, the developed DARPins can also be used to specifically detect p63 in cell culture and in primary tissue and thus constitute a very versatile research tool for studying the function of p63.
DNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2
(2023)
More than 1600 human transcription factors orchestrate the transcriptional machinery to control gene expression and cell fate. Their function is conveyed through intrinsically disordered regions (IDRs) containing activation or repression domains but lacking quantitative structural ensemble models prevents their mechanistic decoding. Here we integrate single-molecule FRET and NMR spectroscopy with molecular simulations showing that DNA binding can lead to complex changes in the IDR ensemble and accessibility. The C-terminal IDR of pioneer factor Sox2 is highly disordered but its conformational dynamics are guided by weak and dynamic charge interactions with the folded DNA binding domain. Both DNA and nucleosome binding induce major rearrangements in the IDR ensemble without affecting DNA binding affinity. Remarkably, interdomain interactions are redistributed in complex with DNA leading to variable exposure of two activation domains critical for transcription. Charged intramolecular interactions allowing for dynamic redistributions may be common in transcription factors and necessary for sensitive tuning of structural ensembles.
Background: Nitric oxide synthase 1 adaptor protein (NOS1AP; previously named CAPON) is linked to the glutamatergic postsynaptic density through interaction with neuronal nitric oxide synthase (nNOS). NOS1AP and its interaction with nNOS have been associated with several mental disorders. Despite the high levels of NOS1AP expression in the hippocampus and the relevance of this brain region in glutamatergic signalling as well as mental disorders, a potential role of hippocampal NOS1AP in the pathophysiology of these disorders has not been investigated yet.
Methods: To uncover the function of NOS1AP in hippocampus, we made use of recombinant adeno-associated viruses to overexpress murine full-length NOS1AP or the NOS1AP carboxyterminus in the hippocampus of mice. We investigated these mice for changes in gene expression, neuronal morphology, and relevant behavioural phenotypes.
Findings: We found that hippocampal overexpression of NOS1AP markedly increased the interaction of nNOS with PSD-95, reduced dendritic spine density, and changed dendritic spine morphology at CA1 synapses. At the behavioural level, we observed an impairment in social memory and decreased spatial working memory capacity.
Interpretation: Our data provide a mechanistic explanation for a highly selective and specific contribution of hippocampal NOS1AP and its interaction with the glutamatergic postsynaptic density to cross-disorder pathophysiology. Our findings allude to therapeutic relevance due to the druggability of this molecule.
Hybrid robust deep and shallow semantic processing for creativity support in document production
(2004)
The research performed in the DeepThought project (http://www.project-deepthought.net) aims at demonstrating the potential of deep linguistic processing if added to existing shallow methods that ensure robustness. Classical information retrieval is extended by high precision concept indexing and relation detection. We use this approach to demonstrate the feasibility of three ambitious applications, one of which is a tool for creativity support in document production and collective brainstorming. This application is described in detail in this paper. Common to all three applications, and the basis for their development is a platform for integrated linguistic processing. This platform is based on a generic software architecture that combines multiple NLP components and on robust minimal recursive semantics (RMRS) as a uniform representation language.