| 1. |
- Wendisch, M., et al.
(author)
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Atmospheric and Surface Processes, and Feedback Mechanisms Determining Arctic Amplification: A Review of First Results and Prospects of the (AC)(3) Project
- 2023
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In: Bulletin of the American Meteorological Society. - : American Meteorological Society. - 0003-0007 .- 1520-0477. ; 104:1
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Journal article (peer-reviewed)abstract
- Mechanisms behind the phenomenon of Arctic amplification are widely discussed. To contribute to this debate, the (AC)(3) project was established in 2016 (www.ac3-tr.de/). It comprises modeling and data analysis efforts as well as observational elements. The project has assembled a wealth of ground-based, airborne, shipborne, and satellite data of physical, chemical, and meteorological properties of the Arctic atmosphere, cryosphere, and upper ocean that are available for the Arctic climate research community. Short-term changes and indications of long-term trends in Arctic climate parameters have been detected using existing and new data. For example, a distinct atmospheric moistening, an increase of regional storm activities, an amplified winter warming in the Svalbard and North Pole regions, and a decrease of sea ice thickness in the Fram Strait and of snow depth on sea ice have been identified. A positive trend of tropospheric bromine monoxide (BrO) column densities during polar spring was verified. Local marine/biogenic sources for cloud condensation nuclei and ice nucleating particles were found. Atmospheric-ocean and radiative transfer models were advanced by applying new parameterizations of surface albedo, cloud droplet activation, convective plumes and related processes over leads, and turbulent transfer coefficients for stable surface layers. Four modes of the surface radiative energy budget were explored and reproduced by simulations. To advance the future synthesis of the results, cross-cutting activities are being developed aiming to answer key questions in four focus areas: lapse rate feedback, surface processes, Arctic mixed-phase clouds, and airmass transport and transformation.
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| 2. |
- Payne, T., et al.
(author)
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Prospective analysis of plasma amyloid beta and postoperative delirium in the Interventions for Postoperative Delirium: Biomarker-3 study
- 2023
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In: British Journal of Anaesthesia. - : Elsevier BV. - 0007-0912. ; 130:5, s. 546-556
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Journal article (peer-reviewed)abstract
- Background: The effect of postoperative delirium on the amyloid cascade of Alzheimer's dementia is poorly understood. Using early postoperative plasma biomarkers, we explored whether surgery and delirium are associated with changes in amyloid pathways.Methods: We analysed data from 100 participants in the Interventions for Postoperative Delirium: Biomarker-3 (IPOD-B3) cohort study in the USA (NCT03124303 and NCT01980511), which recruited participants aged >65 yr undergoing non-intracranial surgery. We assessed the relationship between the change in plasma amyloid beta ratio (A(3R; A(342:A(340) and delirium incidence (defined by the 3-Minute Diagnostic Confusion Assessment Method) and severity (quantified by the Delirium Rating Scale-Revised-98, the study's primary outcome). We also tested the relationship between plasma amyloid beta and intraoperative variables.Results: Across all participants, the plasma A(3R increased from the preoperative period to postoperative Day 1 (Wilcoxon P<0.001). However, this increase was not associated with delirium incidence (Wilcoxon P=0.22) or peak severity after adjusting for confounders (log[incidence rate ratio]=0.43; P=0.14). Postoperative Day 1 change in plasma A(3R was not associated with postoperative Day 1 change in plasma tau, neurofilament light, or inflammatory markers (interleukin [IL]-1(3, IL-1Ra, IL-2, IL-4, IL-6, IL-8, IL-10, and IL-12), or with operative time or low intraoperative arterial pressure.Conclusions: Perioperative changes in plasma amyloid do not appear to be associated with postoperative delirium. Our findings do not support associations of dynamic changes in amyloid with postoperative delirium.Clinical trial registration: NCT03124303 and NCT01980511.
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| 3. |
- Taylor, J., et al.
(author)
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Postoperative delirium and changes in the blood–brain barrier, neuroinflammation, and cerebrospinal fluid lactate: a prospective cohort study
- 2022
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In: British Journal of Anaesthesia. - : Elsevier BV. - 0007-0912. ; 129:2, s. 219-230
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Journal article (peer-reviewed)abstract
- Background: Case-control studies have associated delirium with blood–brain barrier (BBB) permeability. However, this approach cannot determine whether delirium is attributable to high pre-existing permeability or to perioperative changes. We tested whether perioperative changes in cerebrospinal fluid/plasma albumin ratio (CPAR) and plasma S100B were associated with delirium severity. Methods: Participants were recruited to two prospective cohort studies of non-intracranial surgery (NCT01980511, NCT03124303, and NCT02926417). Delirium severity was assessed using the Delirium Rating Scale-98. Delirium incidence was diagnosed with the 3D-Confusion Assessment Method (3D-CAM) or CAM-ICU (CAM for the ICU). CSF samples from 25 patients and plasma from 78 patients were analysed for albumin and S100B. We tested associations between change in CPAR (n=11) and S100B (n=61) and delirium, blood loss, CSF interleukin-6 (IL-6), and CSF lactate. Results: The perioperative increase in CPAR and S100B correlated with delirium severity (CPAR ρ=0.78, P=0.01; S100B ρ=0.41, P<0.001), delirium incidence (CPAR P=0.012; S100B P<0.001) and CSF IL-6 (CPAR ρ=0.66 P=0.04; S100B ρ=0.75, P=0.025). Linear mixed-effect analysis also showed that decreased levels of S100B predicted recovery from delirium symptoms (P=0.001). Linear regression demonstrated that change in plasma S100B was independently associated with surgical risk, cardiovascular surgery, blood loss, and hypotension. Blood loss also correlated with CPAR (ρ=0.64, P=0.04), S100B (ρ=0.70, P<0.001), CSF lactate (R=0.81, P=0.01), and peak delirium severity (ρ=0.36, P=0.01). Conclusion: Postoperative delirium is associated with a breakdown in the BBB. This increased permeability is dynamic and associated with a neuroinflammatory and lactate response. Strategies to mitigate blood loss may protect the BBB. © 2022 British Journal of Anaesthesia
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| 4. |
- Fellinger, Joris, et al.
(author)
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Tungsten based divertor development for Wendelstein 7-X
- 2023
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In: Nuclear Materials and Energy. - 2352-1791. ; 37
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Journal article (peer-reviewed)abstract
- Wendelstein 7-X, the world’s largest superconducting stellarator in Greifswald (Germany), started plasma experiments with a water-cooled plasma-facing wall in 2022, allowing for long pulse operation. In parallel, a project was launched in 2021 to develop a W based divertor, replacing the current CFC divertor, to demonstrate plasma performance of a stellarator with a reactor relevant plasma facing materials with low tritium retention. The project consists of two tasks: Based on experience from the previous experimental campaigns and improved physics modelling, the geometry of the plasma-facing surface of the divertor and baffles is optimized to prevent overloads and to improve exhaust. In parallel, the manufacturing technology for a W based target module is qualified. This paper gives a status update of project. It focusses on the conceptual design of a W based target module, the manufacturing technology and its qualification, which is conducted in the framework of the EUROfusion funded WPDIV program. A flat tile design in which a target module is made of a single target element is pursued. The technology must allow for moderate curvatures of the plasma-facing surface to follow the magnetic field lines. The target element is designed for steady state heat loads of 10 MW/m2 (as for the CFC divertor). Target modules of a similar size and weight as for the CFC divertor are assumed (approx. < 0.25 m2 and < 60 kg) using the existing water cooling infrastructure providing 5 l/s and roughly maximum 15 bar pressure drop per module. The main technology under qualification is based on a CuCrZr heat sink made either by additive manufacturing using laser powder bed fusion (LPBF) or by uniaxial diffusion welding of pre-machined forged CuCrZr plates. After heat treatment, the plasma-facing side of the heat sink is covered by W or if feasible by the more ductile WNiFe, preferably by coating or alternatively by hot isostatic pressing W based tiles with a soft OFE-Cu interlayer. Last step is a final machining of the plasma-exposed surface and the interfaces to the water supply lines and supports to correct manufacturing deformations.
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| 5. |
- Olahova, M., et al.
(author)
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POLRMT mutations impair mitochondrial transcription causing neurological disease
- 2021
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Journal article (peer-reviewed)abstract
- While >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase gamma, no mitochondrial phenotypes have been associated with POLRMT, the RNA polymerase responsible for transcription of the mitochondrial genome. Here, we characterise the clinical and molecular nature of POLRMT variants in eight individuals from seven unrelated families. Patients present with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype. Massive parallel sequencing of all subjects identifies recessive and dominant variants in the POLRMT gene. Patient fibroblasts have a defect in mitochondrial mRNA synthesis, but no mtDNA deletions or copy number abnormalities. The in vitro characterisation of the recombinant POLRMT mutants reveals variable, but deleterious effects on mitochondrial transcription. Together, our in vivo and in vitro functional studies of POLRMT variants establish defective mitochondrial transcription as an important disease mechanism. POLRMT is key for transcription of the mitochondrial genome, yet has not been implicated in mitochondrial disease to date. Here, the authors identify mutations in POLRMT in individuals with mitochondrial disease-related phenotypes and characterise underlying defects in mitochondrial transcription.
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| 6. |
- Vollmer, Tino, et al.
(author)
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The intratumoral CXCR3 chemokine system is predictive of chemotherapy response in human bladder cancer
- 2021
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In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 13:576
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Journal article (peer-reviewed)abstract
- Chemotherapy has direct toxic effects on cancer cells; however, long-term cancer control and complete remission are likely to involve CD8+ T cell immune responses. To study the role of CD8+ T cell infiltration in the success of chemotherapy, we examined patients with muscle invasive bladder cancer (MIBC) who were categorized on the basis of the response to neoadjuvant chemotherapy (NAC). We identified the intratumoral CXCR3 chemokine system (ligands and receptor splice variants) as a critical component for tumor eradication upon NAC in MIBC. Through characterization of CD8+ T cells, we found that stem-like T cell subpopulations with abundant CXCR3alt, a variant form of the CXCL11 receptor, responded to CXCL11 in culture as demonstrated by migration and enhanced effector function. In tumor biopsies of patients with MIBC accessed before treatment, CXCL11 abundance correlated with high numbers of tumor-infiltrating T cells and response to NAC. The presence of CXCR3alt and CXCL11 was associated with improved overall survival in MIBC. Evaluation of both CXCR3alt and CXCL11 enabled discrimination between responder and nonresponder patients with MIBC before treatment. We validated the prognostic role of the CXCR3-CXCL11 chemokine system in an independent cohort of chemotherapy-treated and chemotherapy-naïve patients with MIBC from data in TCGA. In summary, our data revealed stimulatory activity of the CXCR3alt-CXCL11 chemokine system on CD8+ T cells that is predictive of chemotherapy responsiveness in MIBC. This may offer immunotherapeutic options for targeted activation of intratumoral stem-like T cells in solid tumors.
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