| 1. |
- Holleboom, Adriaan G, et al.
(författare)
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Heterozygosity for a Loss-of-Function Mutation in GALNT2 Improves Plasma Triglyceride Clearance in Man
- 2011
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Ingår i: Cell Metabolism. - : Elsevier. - 1550-4131 .- 1932-7420. ; 14:6, s. 811-8
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have identified GALNT2 as a candidate gene in lipid metabolism, but it is not known how the encoded enzyme ppGalNAc-T2, which contributes to the initiation of mucin-type O-linked glycosylation, mediates this effect. In two probands with elevated plasma high-density lipoprotein cholesterol and reduced triglycerides, we identified a mutation in GALNT2. It is shown that carriers have improved postprandial triglyceride clearance, which is likely attributable to attenuated glycosylation of apolipoprotein (apo) C-III, as observed in their plasma. This protein inhibits lipoprotein lipase (LPL), which hydrolyses plasma triglycerides. We show that an apoC-III-based peptide is a substrate for ppGalNAc-T2 while its glycosylation by the mutant enzyme is impaired. In addition, neuraminidase treatment of apoC-III which removes the sialic acids from its glycan chain decreases its potential to inhibit LPL. Combined, these data suggest that ppGalNAc-T2 can affect lipid metabolism through apoC-III glycosylation, thereby establishing GALNT2 as a lipid-modifying gene.
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| 2. |
- Abbasi, Rasha, et al.
(författare)
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IceCube search for neutrinos from GRB 221009A
- 2023
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Ingår i: Proceedings of 38th International Cosmic Ray Conference (ICRC 2023). - : Sissa Medialab Srl.
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Konferensbidrag (refereegranskat)abstract
- GRB 221009A is the brightest Gamma Ray Burst (GRB) ever observed. The observed extremelyhigh flux of high and very-high-energy photons provide a unique opportunity to probe the predictedneutrino counterpart to the electromagnetic emission. We have used a variety of methods to searchfor neutrinos in coincidence with the GRB over several time windows during the precursor, promptand afterglow phases of the GRB. MeV scale neutrinos are studied using photo-multiplier ratescalers which are normally used to search for galactic core-collapse supernovae neutrinos. GeVneutrinos are searched starting with DeepCore triggers. These events don’t have directionallocalization, but instead can indicate an excess in the rate of events. 10 GeV - 1 TeV and >TeVneutrinos are searched using traditional neutrino point source methods which take into accountthe direction and time of events with DeepCore and the entire IceCube detector respectively. The>TeV results include both a fast-response analysis conducted by IceCube in real-time with timewindows of T0 − 1 to T0 + 2 hours and T0 ± 1 day around the time of GRB 221009A, as well asan offline analysis with 3 new time windows up to a time window of T0 − 1 to T0 + 14 days, thelongest time period we consider. The combination of observations by IceCube covers 9 ordersof magnitude in neutrino energy, from MeV to PeV, placing upper limits across the range forpredicted neutrino emission.
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| 3. |
- Fahrer, Jörg, et al.
(författare)
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Cytolethal distending toxin (CDT) is a radiomimetic agent and induces persistent levels of DNA double-strand breaks in human fibroblasts
- 2014
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Ingår i: DNA Repair. - : Elsevier. - 1568-7864 .- 1568-7856. ; 18, s. 31-43
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Tidskriftsartikel (refereegranskat)abstract
- Cytolethal distending toxin (CDT) is a unique genotoxin produced by several pathogenic bacteria. The tripartite protein toxin is internalized into mammalian cells via endocytosis followed by retrograde transport to the ER. Upon translocation into the nucleus, CDT catalyzes the formation of DNA double-strand breaks (DSBs) due to its intrinsic endonuclease activity. In the present study, we compared the DNA damage response (DDR) in human fibroblasts triggered by recombinant CDT to that of ionizing radiation (IR), a well-known DSB inducer. Furthermore, we dissected the pathways involved in the detection and repair of CDT-induced DNA lesions. qRT-PCR array-based mRNA and western blot analyses showed a partial overlap in the DDR pattern elicited by CDT and IR, with strong activation of both the ATM-Chk2 and the ATR-Chk1 axis. In line with its in vitro DNase I-like activity on plasmid DNA, neutral and alkaline Comet assay revealed predominant induction of DSBs in CDT-treated fibroblasts, whereas irradiation of cells generated higher amounts of SSBs and alkali-labile sites. Using confocal microscopy, the dynamics of the DSB surrogate marker γ-H2AX was monitored after pulse treatment with CDT or IR. In contrast to the fast induction and disappearance of γ-H2AX-foci observed in irradiated cells, the number of γ-H2AX-foci induced by CDT were formed with a delay and persisted. 53BP1 foci were also generated following CDT treatment and co-localized with γ-H2AX foci. We further demonstrated that ATM-deficient cells are very sensitive to CDT-induced DNA damage as reflected by increased cell death rates with concomitant cleavage of caspase-3 and PARP-1. Finally, we provided novel evidence that both homologous recombination (HR) and non-homologous end joining (NHEJ) protect against CDT-elicited DSBs. In conclusion, the findings suggest that CDT functions as a radiomimetic agent and, therefore, is an attractive tool for selectively inducing persistent levels of DSBs and unveiling the associated cellular responses.
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| 4. |
- Fischer, Hubertus, et al.
(författare)
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Palaeoclimate constraints on the impact of 2 °C anthropogenic warming and beyond
- 2018
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Ingår i: Nature Geoscience. - : Springer Science and Business Media LLC. - 1752-0894 .- 1752-0908. ; 11:7, s. 474-485
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Tidskriftsartikel (refereegranskat)abstract
- Over the past 3.5 million years, there have been several intervals when climate conditions were warmer than during the pre-industrial Holocene. Although past intervals of warming were forced differently than future anthropogenic change, such periods can provide insights into potential future climate impacts and ecosystem feedbacks, especially over centennial-to-millennial timescales that are often not covered by climate model simulations. Our observation-based synthesis of the understanding of past intervals with temperatures within the range of projected future warming suggests that there is a low risk of runaway greenhouse gas feedbacks for global warming of no more than 2 °C. However, substantial regional environmental impacts can occur. A global average warming of 1–2 °C with strong polar amplification has, in the past, been accompanied by significant shifts in climate zones and the spatial distribution of land and ocean ecosystems. Sustained warming at this level has also led to substantial reductions of the Greenland and Antarctic ice sheets, with sea-level increases of at least several metres on millennial timescales. Comparison of palaeo observations with climate model results suggests that, due to the lack of certain feedback processes, model-based climate projections may underestimate long-term warming in response to future radiative forcing by as much as a factor of two, and thus may also underestimate centennial-to-millennial-scale sea-level rise.
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| 5. |
- Fritz, Johannes
(författare)
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The notion of 'authorship' under EU law-who can be an author and what makes one an author? An analysis of the legislative framework and case law
- 2024
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Ingår i: Journal of Intellectual Property Law & Practice. - 1747-1532 .- 1747-1540.
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Tidskriftsartikel (refereegranskat)abstract
- The question of who an author can be, and what makes one an author, has once again come to the fore with the rise of Artificial Intelligence (AI). Such a concept, in particular the requirements of authorship, is not defined in the European Union (EU) legislation though. Additionally, no referral regarding the notion of authorship has yet reached the Court of Justice of the European Union (CJEU).This article analyses the legislation and case law of the CJEU to identify the elements needed for defining ‘authorship’. The analysis of international copyright law and the EU legislation shows that an author must generally be a human. Examining existing CJEU case law further provides indications of what makes someone an author. The creator must (i) exercise their creative freedom by monitoring and executing the preparation, realization and finalization of the work and (ii) express their creative act with a general authorial intent.Ultimately, the article attempts to rationalize these findings to advance its own definition. Accordingly, it is shown that an author is a human who, at least to a specific extent, is exercising a subjective judgment in the composition of a work and has control of its execution. This definition has the advantage of including objective and subjective criteria, allowing the assessment of cases involving multiple authors and technical aids. Regarding AI, it helps to clarify the level and type of human involvement required for an output to be considered a work of human authorship and therefore be potentially protected by copyright.
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| 6. |
- Gauld, Jethro G., et al.
(författare)
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Hotspots in the grid : Avian sensitivity and vulnerability to collision risk from energy infrastructure interactions in Europe and North Africa
- 2022
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Ingår i: Journal of Applied Ecology. - : John Wiley & Sons. - 0021-8901 .- 1365-2664. ; 59:6, s. 1496-1512
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Tidskriftsartikel (refereegranskat)abstract
- Wind turbines and power lines can cause bird mortality due to collision or electrocution. The biodiversity impacts of energy infrastructure (EI) can be minimised through effective landscape-scale planning and mitigation. The identification of high-vulnerability areas is urgently needed to assess potential cumulative impacts of EI while supporting the transition to zero carbon energy. We collected GPS location data from 1,454 birds from 27 species susceptible to collision within Europe and North Africa and identified areas where tracked birds are most at risk of colliding with existing EI. Sensitivity to EI development was estimated for wind turbines and power lines by calculating the proportion of GPS flight locations at heights where birds were at risk of collision and accounting for species' specific susceptibility to collision. We mapped the maximum collision sensitivity value obtained across all species, in each 5 x 5 km grid cell, across Europe and North Africa. Vulnerability to collision was obtained by overlaying the sensitivity surfaces with density of wind turbines and transmission power lines. Results: Exposure to risk varied across the 27 species, with some species flying consistently at heights where they risk collision. For areas with sufficient tracking data within Europe and North Africa, 13.6% of the area was classified as high sensitivity to wind turbines and 9.4% was classified as high sensitivity to transmission power lines. Sensitive areas were concentrated within important migratory corridors and along coastlines. Hotspots of vulnerability to collision with wind turbines and transmission power lines (2018 data) were scattered across the study region with highest concentrations occurring in central Europe, near the strait of Gibraltar and the Bosporus in Turkey. Synthesis and applications. We identify the areas of Europe and North Africa that are most sensitive for the specific populations of birds for which sufficient GPS tracking data at high spatial resolution were available. We also map vulnerability hotspots where mitigation at existing EI should be prioritised to reduce collision risks. As tracking data availability improves our method could be applied to more species and areas to help reduce bird-EI conflicts.
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| 7. |
- Miyazaki, Akira, 1986-, et al.
(författare)
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Millimeter-Wave WISP Search with Coherent Light-Shining-Through-a-Wall Toward the STAX Project
- 2024
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Ingår i: Annalen der Physik. - : John Wiley & Sons. - 0003-3804 .- 1521-3889. ; 536:1
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Tidskriftsartikel (refereegranskat)abstract
- A dark photon is one of the simplest extensions of the Standard Model of particle physics and can be a dark matter candidate. Dark photons kinetically mix with ordinary photons. The mass range from 10(-4) to 10(-3) eV of such dark photons is underconstrained by laboratory-based experiments and a new search is therefore motivated. In this mass range, dark photons behave like waves rather than particles and the corresponding electromagnetic waves are in the millimeter-wave range. The technical difficulties of the millimeter waves have prevented so far dark photon experiments in this mass range. The use of coherent millimeter waves to search for dark photons in a Light-Shining-through-a-Wall (LSW) experiment is proposed. The merits and limitations of coherent wave detection are clarified and the potential of single photon sensors at microwaves is investigated. Development of millimeter-wave technology is not only limited to dark photons. Technically, an experiment for dark photons by using electromagnetic waves resembles that for axions, another light dark matter candidate, with static magnetic fields. This paper represents an essential step toward axion LSW in the millimeter-wave range (Sub-THz-AXion experiment; STAX) as a potential successor of an on-going experiment in infrared.
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| 8. |
- Miyazaki, Akira, 1986-, et al.
(författare)
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Proof-of-principle of the ultra-narrowband detection scheme at 30 GHz toward weakly interacting slim particle search
- 2021
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- A coherent detection scheme was tested for dark photons and axion search with millimeter waves. It was shown that relative bandwidth of 169 μHz can be achieved at the center frequency of 30 GHz by commercial equipment. This is in principle a lock-in amplifier at 30 GHz. With a low noise amplifier, thermal noise can be reduced down to 1.36 X 10-24 with one and half hours data taking and the expected signal was locked within one bin of 169 μHz resolution bandwidth by using the standard 10 MHz reference line. This will lead to a new search of dark photons in the mass range, which is complementary to any previous experiments and a future upgrade project of ALPS-II. Although a fully quantum mechanical argument will be necessary to quantify the ultimate limit of this coherent detection scheme, the use of a state-of-the-art phase-locked gyrotron and superconducting quantum sensors would lead to further improvement of millimeter-wave dark photon and axion searches.
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| 9. |
- Palica, Katarzyna, 1992-, et al.
(författare)
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α-Aminophosphonate inhibitors of metallo-β-lactamases NDM-1 and VIM-2
- 2023
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Ingår i: RSC Medicinal Chemistry. - : Royal Society of Chemistry. - 2632-8682. ; 14:11, s. 2277-2300
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Tidskriftsartikel (refereegranskat)abstract
- The upswing of antibiotic resistance is an escalating threat to human health. Resistance mediated by bacterial metallo-β-lactamases is of particular concern as these enzymes degrade β-lactams, our most frequently prescribed class of antibiotics. Inhibition of metallo-β-lactamases could allow the continued use of existing β-lactam antibiotics, such as penicillins, cephalosporins and carbapenems, whose applicability is becoming ever more limited. The design, synthesis, and NDM-1, VIM-2, and GIM-1 inhibitory activities (IC50 4.1–506 μM) of a series of novel non-cytotoxic α-aminophosphonate-based inhibitor candidates are presented herein. We disclose the solution NMR spectroscopic and computational investigation of their NDM-1 and VIM-2 binding sites and binding modes. Whereas the binding modes of the inhibitors are similar, VIM-2 showed a somewhat higher conformational flexibility, and complexed a larger number of inhibitor candidates in more varying binding modes than NDM-1. Phosphonate-type inhibitors may be potential candidates for development into therapeutics to combat metallo-β-lactamase resistant bacteria.
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| 10. |
- Schroeder, Fritz H., et al.
(författare)
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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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Ingår i: BJU International. - 1464-4096. ; 103:5, s. 590-596
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Tidskriftsartikel (refereegranskat)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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