| 1. |
- Duits, Flora H., et al.
(author)
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The cerebrospinal fluid "Alzheimer profile": Easily said, but what does it mean?
- 2014
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In: Alzheimer's & Dementia. - : Elsevier. - 1552-5260 .- 1552-5279. ; 10:6, s. 713-723
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Journal article (peer-reviewed)abstract
- Background: We aimed to identify the most useful definition of the "cerebrospinal fluid Alzheimer profile," based on amyloid-beta(1-42) (A beta(42)), total tau, and phosphorylated tau (p-tau), for diagnosis and prognosis of Alzheimers disease (AD). Methods: We constructed eight Alzheimer profiles with previously published combinations, including regression formulas and simple ratios. We compared their diagnostic accuracy and ability to predict dementia due to AD in 1385 patients from the Amsterdam Dementia Cohort. Results were validated in an independent cohort (n = 1442). Results: Combinations outperformed individual biomarkers. Based on the sensitivity of the best performing regression formulas, cutoffs were chosen at 0.52 for the tau/A beta(42) ratio and 0.08 for the p-tau/A beta(42) ratio. Ratios performed similar to formulas (sensitivity, 91%-93%; specificity, 81%-84%). The same combinations best predicted cognitive decline in mild cognitive impairment patients. Validation confirmed these results, especially regarding the tau/A beta(42) ratio. Conclusions: A tau/A beta(42) ratio of greater than0.52 constitutes a robust cerebrospinal fluid Alzheimer profile. We recommend using this ratio to combine biomarkers.
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| 2. |
- Eisenberg, Tobias, et al.
(author)
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Cardioprotection and lifespan extension by the natural polyamine spermidine
- 2016
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 22:12, s. 1428-1438
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Journal article (peer-reviewed)abstract
- Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease.
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| 3. |
- Engert, Andreas, et al.
(author)
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The European Hematology Association Roadmap for European Hematology Research : a consensus document
- 2016
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In: Haematologica. - Pavia, Italy : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 101:2, s. 115-208
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Journal article (peer-reviewed)abstract
- The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at (sic)23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.
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| 4. |
- Glatzel, Pieter, et al.
(author)
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Electronic Structural Changes of Mn in the Oxygen-Evolving Complex of Photosystem II during the Catalytic Cycle
- 2013
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In: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 52:10, s. 5642-5644
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Journal article (peer-reviewed)abstract
- The oxygen-evolving complex (OEC) in photosystem II (PS II) was studied in the S-0 through S-3 states using 1s2p resonant inelastic X-ray scattering spectroscopy. The spectral changes of the OEC during the S-state transitions are subtle, indicating that the electrons are strongly delocalized throughout the cluster. The result suggests that, in addition to the Mn ions, ligands are also playing an important role in the redox reactions. A series of Mn-IV coordination complexes were compared, particularly with the PS II S-3 state spectrum to understand its oxidation state. We find strong variations of the electronic structure within the series of Mn-IV model systems. The spectrum of the S-3 state best resembles those of the Mn-IV complexes (Mn3Ca2)-Ca-IV and saplnMn(2)(IV)(OH)(2). The current result emphasizes that the assignment of formal oxidation states alone is not sufficient for understanding the detailed electronic structural changes that govern the catalytic reaction in the OEC.
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| 5. |
- Mitzner, Rolf, et al.
(author)
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L-Edge X-ray Absorption Spectroscopy of Dilute Systems Relevant to Metalloproteins Using an X-ray Free-Electron Laser
- 2013
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In: The Journal of Physical Chemistry Letters. - : American Chemical Society (ACS). - 1948-7185. ; 4:21, s. 3641-3647
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Journal article (peer-reviewed)abstract
- L-edge spectroscopy of 3d transition metals provides important electronic structure information and has been used in many fields. However, the use of this method for studying dilute aqueous systems, such as metalloenzymes, has not been prevalent because of severe radiation damage and the lack of suitable detection systems. Here we present spectra from a dilute Mn aqueous solution using a high-transmission zone-plate spectrometer at the Linac Coherent Light Source (LCLS). The spectrometer has been optimized for discriminating the Mn L-edge signal from the overwhelming 0 K-edge background that arises from water and protein itself, and the ultrashort LCLS X-ray pulses can outrun X-ray induced damage. We show that the deviations of the partial-fluorescence yield-detected spectra from the true absorption can be well modeled using the state-dependence of the fluorescence yield, and discuss implications for the application of our concept to biological samples.
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| 6. |
- Mühlemann, Barbara, et al.
(author)
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Diverse variola virus (smallpox) strains were widespread in northern Europe in the Viking Age
- 2020
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In: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 369:6502
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Journal article (peer-reviewed)abstract
- Smallpox, one of the most devastating human diseases, killed between 300 million and 500 million people in the 20th century alone. We recovered viral sequences from 13 northern European individuals, including 11 dated to ~600-1050 CE, overlapping the Viking Age, and reconstructed near-complete variola virus genomes for four of them. The samples predate the earliest confirmed smallpox cases by ~1000 years, and the sequences reveal a now-extinct sister clade of the modern variola viruses that were in circulation before the eradication of smallpox. We date the most recent common ancestor of variola virus to ~1700 years ago. Distinct patterns of gene inactivation in the four near-complete sequences show that different evolutionary paths of genotypic host adaptation resulted in variola viruses that circulated widely among humans.
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| 7. |
- Schroeder, Frank G., et al.
(author)
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The Snowmass UHECR White Paper on Ultra-High-Energy Cosmic Rays
- 2023
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In: EPJ Web of Conferences. - : EDP Sciences. - 2100-014X. ; 283
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Journal article (peer-reviewed)abstract
- This proceeding summarizes the talk given at the opening of the UHECR 2022 conference in L'Aquila on the whitepaper 'Ultra-High-Energy Cosmic Rays: The Intersection of the Cosmic and Energy Frontiers' [Astroparticle Physics 149 (2023) 102819 - arXiv:2205.05845] that has been prepared for the Snow-mass survey in the USA. The whitepaper provides an overview of recent progress and open questions regarding the particle physics and astrophysics related to ultra-high-energy cosmic rays (UHECR) and outlines the connections between the particle and astrophysics aspects of cosmic rays. It also discusses what instrumentation is needed to address the major scientific questions in ultra-high-energy cosmic-ray physics. While the upgraded Pierre Auger Observatory and Telescope Array will remain the workhorses at the highest energies in the current decade, new experiments with significantly higher exposure are needed in the coming decade. Ground arrays featuring simultaneous detection of the position of the shower maximum and the size of the muonic component will enable particle astronomy by measuring the rigidity of individual events. They should be complemented by other detectors maximizing the total exposure. This can be achieved by a few next-generation experiments using the latest developments in detection and analysis techniques: GRAND as a ground-based radio array, and POEMMA as a space-borne stereo fluorescence telescope will feature complementary approaches to provide maximum exposure; IceCube-Gen2 with its surface array, and GCOS aim at increased statistics with high accuracy for particle physics and rigidity-based galactic and extra-galactic astrophysics. While designed to discover the astrophysical cosmic-ray sources at the highest energies, the same experiments also contribute to particle physics, e.g., by studying the muon puzzle in cosmic-ray air showers, and by their discovery potential for exciting new physics, such as certain Dark Matter candidates. With the full whitepaper available as a reference, this proceeding will briefly present the science cases of the experiments, highlighting their individual strengths and outlining how they complement each other.
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| 8. |
- Schroeder, Fritz H., et al.
(author)
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Can dutasteride delay or prevent the progression of prostate cancer in patients with biochemical failure after radical therapy? Rationale and design of the Avodart after Radical Therapy for Prostate Cancer Study
- 2009
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In: BJU International. - 1464-4096. ; 103:5, s. 590-596
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Journal article (peer-reviewed)abstract
- To describe the Avodart after Radical Therapy for prostate cancer Study (ARTS), investigating the use of dutasteride (a dual 5 alpha-reductase inhibitor that suppresses intraprostatic dihydrotestosterone, reduces tumour volume and improves other markers of tumour regression in prostate cancer) to prevent or delay disease progression in patients with biochemical recurrence after therapy with curative intent. An increasing serum prostate-specific antigen (PSA) level after radical prostatectomy (RP) or radiotherapy (RT) is indicative of recurrent prostate cancer and typically pre-dates clinically detectable metastatic disease by several years. ARTS is an ongoing European multicentre trial in which patients are stratified by previous therapy (RP with or without salvage RT vs primary RT) and randomized to double-blind treatment with dutasteride 0.5 mg or placebo once daily for 2 years. Eligible patients will have a PSA doubling time (DT) of 3-24 months. Biochemical recurrence is defined as three increases in PSA level from the nadir, with each increase >= 4 weeks apart and each PSA level >= 0.2 ng/mL, and a final PSA level of >= 0.4 ng/mL (after RP) or >= 2 ng/mL (after primary RT). Study endpoints include time to PSA doubling, time to disease progression, treatment response (PSA decrease or an increase of <= 15% from baseline), changes in PSA and PSADT, and changes in anxiety (Memorial Anxiety Scale for Prostate Cancer). ARTS will be the first study to evaluate the effects of dutasteride on PSADT, disease progression and treatment response in patients with biochemical failure after RP or RT, and should help to elucidate the potential role of dual 5 alpha-reductase inhibition in prostate cancer.
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| 9. |
- Testor, Pierre, et al.
(author)
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OceanGliders: A component of the integrated GOOS
- 2019
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In: Frontiers in Marine Science. - : Frontiers Media SA. - 2296-7745. ; 6
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Research review (peer-reviewed)abstract
- The OceanGliders program started in 2016 to support active coordination and enhancement of global glider activity. OceanGliders contributes to the international efforts of the Global Ocean Observation System (GOOS) for Climate, Ocean Health and Operational Services. It brings together marine scientists and engineers operating gliders around the world: (1) to observe the long-term physical, biogeochemical, and biological ocean processes and phenomena that are relevant for societal applications; and, (2) to contribute to the GOOS through real-time and delayed mode data dissemination. The OceanGliders program is distributed across national and regional observing systems and significantly contributes to integrated, multi-scale and multi-platform sampling strategies. OceanGliders shares best practices, requirements, and scientific knowledge needed for glider operations, data collection and analysis. It also monitors global glider activity and supports the dissemination of glider data through regional and global databases, in real-time and delayed modes, facilitating data access to the wider community. OceanGliders currently supports national, regional and global initiatives to maintian and expand the capabilities and application of gliders to meet key global challenges such as improved measurement of ocean boundary currents, water transformation and storm forecast.
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