| 1. |
- Zamora, Juan Carlos, et al.
(författare)
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Considerations and consequences of allowing DNA sequence data as types of fungal taxa
- 2018
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Ingår i: IMA Fungus. - : INT MYCOLOGICAL ASSOC. - 2210-6340 .- 2210-6359. ; 9:1, s. 167-185
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Tidskriftsartikel (refereegranskat)abstract
- Nomenclatural type definitions are one of the most important concepts in biological nomenclature. Being physical objects that can be re-studied by other researchers, types permanently link taxonomy (an artificial agreement to classify biological diversity) with nomenclature (an artificial agreement to name biological diversity). Two proposals to amend the International Code of Nomenclature for algae, fungi, and plants (ICN), allowing DNA sequences alone (of any region and extent) to serve as types of taxon names for voucherless fungi (mainly putative taxa from environmental DNA sequences), have been submitted to be voted on at the 11th International Mycological Congress (Puerto Rico, July 2018). We consider various genetic processes affecting the distribution of alleles among taxa and find that alleles may not consistently and uniquely represent the species within which they are contained. Should the proposals be accepted, the meaning of nomenclatural types would change in a fundamental way from physical objects as sources of data to the data themselves. Such changes are conducive to irreproducible science, the potential typification on artefactual data, and massive creation of names with low information content, ultimately causing nomenclatural instability and unnecessary work for future researchers that would stall future explorations of fungal diversity. We conclude that the acceptance of DNA sequences alone as types of names of taxa, under the terms used in the current proposals, is unnecessary and would not solve the problem of naming putative taxa known only from DNA sequences in a scientifically defensible way. As an alternative, we highlight the use of formulas for naming putative taxa (candidate taxa) that do not require any modification of the ICN.
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| 2. |
- Islam, Md. Koushikul, et al.
(författare)
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Anti-Rift Valley fever virus activity in vitro, pre-clinical pharmacokinetics and oral bioavailability of benzavir-2, a broad-acting antiviral compound
- 2018
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Rift Valley fever virus (RVFV) is a mosquito-borne hemorrhagic fever virus affecting both humans and animals with severe morbidity and mortality and is classified as a potential bioterror agent due to the possible aerosol transmission. At present there is no human vaccine or antiviral therapy available. Thus, there is a great need to develop new antivirals for treatment of RVFV infections. Benzavir-2 was previously identified as potent inhibitor of human adenovirus, herpes simplex virus type 1, and type 2. Here we assess the anti-RVFV activity of benzavir-2 together with four structural analogs and determine pre-clinical pharmacokinetic parameters of benzavir-2. In vitro, benzavir-2 efficiently inhibited RVFV infection, viral RNA production and production of progeny viruses. In vitro, benzavir-2 displayed satisfactory solubility, good permeability and metabolic stability. In mice, benzavir-2 displayed oral bioavailability with adequate maximum serum concentration. Oral administration of benzavir-2 formulated in peanut butter pellets gave high systemic exposure without any observed toxicity in mice. To summarize, our data demonstrated potent anti-RVFV activity of benzavir-2 in vitro together with a promising pre-clinical pharmacokinetic profile. This data support further exploration of the antiviral activity of benzavir-2 in in vivo efficacy models that may lead to further drug development for human use.
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| 3. |
- Ladds, Marcus J. G. W., et al.
(författare)
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A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.
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| 4. |
- Ladds, Marcus J. G. W., et al.
(författare)
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Autophagic flux blockage by accumulation of weakly basic tenovins leads to elimination of B-Raf mutant tumour cells that survive vemurafenib
- 2018
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- Tenovin-6 is the most studied member of a family of small molecules with antitumour activity in vivo. Previously, it has been determined that part of the effects of tenovin-6 associate with its ability to inhibit SirT1 and activate p53. However, tenovin-6 has also been shown to modulate autophagic flux. Here we show that blockage of autophagic flux occurs in a variety of cell lines in response to certain tenovins, that autophagy blockage occurs regardless of the effect of tenovins on SirT1 or p53, and that this blockage is dependent on the aliphatic tertiary amine side chain of these molecules. Additionally, we evaluate the contribution of this tertiary amine to the elimination of proliferating melanoma cells in culture. We also demonstrate that the presence of the tertiary amine is sufficient to lead to death of tumour cells arrested in G1 phase following vemurafenib treatment. We conclude that blockage of autophagic flux by tenovins is necessary to eliminate melanoma cells that survive B-Raf inhibition and achieve total tumour cell kill and that autophagy blockage can be achieved at a lower concentration than by chloroquine. This observation is of great relevance as relapse and resistance are frequently observed in cancer patients treated with B-Raf inhibitors.
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| 5. |
- Mauri, G., et al.
(författare)
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Neutron reflectometry with the Multi-Blade B-10-based detector
- 2018
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Ingår i: Proceedings of the Royal Society. Mathematical, Physical and Engineering Sciences. - : The Royal Society. - 1364-5021 .- 1471-2946. ; 474:2216
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Tidskriftsartikel (refereegranskat)abstract
- The Multi-Blade is a boron-10-based gaseous detector developed for neutron reflectometry instruments at the European Spallation Source in Sweden. The main challenges for neutron reflectometry detectors are the instantaneous counting rate and spatial resolution. The Multi-Blade has been tested on the CRISP reflectometer at the ISIS Neutron and Muon Source in the UK. A campaign of scientific measurements has been performed to study the Multi-Blade response in real instrumental conditions. The results of these tests are discussed in this paper.
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| 6. |
- Ouriques, Raquel, et al.
(författare)
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Thinking strategically about knowledge management in agile software development
- 2018
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Ingår i: Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics). - Cham : Springer Verlag. - 0302-9743 .- 1611-3349. - 9783030036720 ; 11271 LNCS, s. 389-395
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Konferensbidrag (refereegranskat)abstract
- Agile methodologies gave teams more autonomy regarding planning tasks and executing them. As a result, coordination gets more flexible, but much relevant knowledge remains undocumented and inside teams’ borders, due to informal communication and reduced development documentation. Since knowledge plays an essential role in software development, it is important to have effective knowledge management (KM) practices that contribute to a better knowledge resource allocation. Several KM practices have been reported in empirical studies in Agile Software Development (ASD). However, these practices are not evaluated regarding its effectiveness or how do they affect product quality. Besides, the studies do not demonstrate connections between the KM practices in the project level and the strategic level. The lack of connection between these levels can result in deviations from the company’s corporate strategy, wasted resources and irrelevant knowledge acquisition. This paper discusses how the strategic management can contribute to an integrated approach to KM in ASD; considering the organizational structure and the corporate strategy. Based on this discussion, we propose research areas that may help with planning KM strategies that can have their effectiveness measured and contribute to product quality. © Springer Nature Switzerland AG 2018.
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| 7. |
- Papaevangelou, T., et al.
(författare)
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ESS nBLM : Beam loss monitors based on fast neutron detection
- 2018
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Ingår i: HB2018 - Proceedings of the 61st ICFA Advanced Beam Dynamics Workshop on High-Intensity and High-Brightness Hadron Beams. - 9783954502028 ; , s. 404-409
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Konferensbidrag (refereegranskat)abstract
- A new type of Beam Loss Monitor (BLM) system is being developed for use in the European Spallation Source (ESS) linac, primarily aiming to cover the low energy part (proton energies between 3-100 MeV). In this region of the linac, typical BLM detectors based on charged particle detection (i.e. Ionization Chambers) are not appropriate because the expected particle fields will be dominated by neutrons and photons. Another issue is the photon background due to the RF cavities, which is mainly due to field emission from the electrons from the cavity walls, resulting in bremsstrahlung photons. The idea for the ESS neutron sensitive BLM system (ESS nBLM) is to use Micromegas detectors specially designed to be sensitive to fast neutrons and insensitive to low energy photons (X and gammas). In addition, the detectors must be insensitive to thermal neutrons, because those neutrons may not be directly correlated to beam losses. The appropriate configuration of the Micromegas operating conditions will allow excellent timing, intrinsic photon background suppression and individual neutron counting, extending thus the dynamic range to very low particle fluxes.
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| 8. |
- Piscitelli, F., et al.
(författare)
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Characterization of the Multi-Blade 10B-based detector at the CRISP reflectometer at ISIS for neutron reflectometry at ESS
- 2018
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Ingår i: Journal of Instrumentation. - : IOP PUBLISHING LTD. - 1748-0221. ; 13:5
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Tidskriftsartikel (refereegranskat)abstract
- The Multi-Blade is a Boron-10-based gaseous thermal neutron detector developed to face the challenge arising in neutron reflectometry at neutron sources. Neutron reflectometers are challenging instruments in terms of instantaneous counting rate and spatial resolution. This detector has been designed according to the requirements given by the reflectometers at the European Spallation Source (ESS) in Sweden. The Multi-Blade has been installed and tested on the CRISP reflectometer at the ISIS neutron and muon source in U.K.. The results on the detailed detector characterization are discussed in this manuscript.
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| 9. |
- Safari, Reza, et al.
(författare)
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Impedance Matching for VSC-HVDC Damping Controller Gain Selection
- 2018
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Ingår i: IEEE Transactions on Power Systems. - 0885-8950.
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Tidskriftsartikel (refereegranskat)abstract
- The impedance matching concept is employed in this paper to select the optimum gain of a VSC-HVDC damping controller. The damping controller of the DC link is based on control of active power in proportion to the difference in local frequency at the VSC-HVDC converter stations. To explain impedance matching, the small-disturbance electro-mechanical dynamics of a power system is transformed to an equivalent LC-circuit. The VSC-HVDC damping controller corresponds to introducing a resistor in the circuit model. Using impedance matching to select resistor value in the circuit model is equivalent to selecting damping controller gain that gives maximum damping ratio. An analytical derivation is conducted for a linearized model of a generic two-area power system, including an expression for the optimum gain. It is also shown how the concept may be employed without a circuit model and that the optimum value is hardly affected by changes in power flow. Then the performance of the proposed approach in multi-mode test systems and with nonlinearities is evaluated using dynamic simulations in DIgSILENT PowerFactory. The results show that impedance matching maximizes the targeted mode damping ratio while non-targeted modes are not negatively impacted.
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| 10. |
- Skogh, Anna, et al.
(författare)
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An imidazole based H-Phe-Phe-NH2 peptidomimetic with anti-allodynic effect in spared nerve injury mice
- 2018
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 28:14, s. 2446-2450
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Tidskriftsartikel (refereegranskat)abstract
- The dipeptide amide H-Phe-Phe-NH2 (1) that previously was identified as a ligand for the substance P 1-7 (SP1-7) binding site exerts intriguing results in animal models of neuropathic pain after central but not after peripheral administration. The dipeptide 1 is derived from stepwise modifications of the anti-nociceptive heptapeptide SP1-7 and the tetrapeptide endomorphin-2 that is also binding to the SP1-7 site. We herein report a strong anti-allodynic effect of a new H-Phe-Phe-NH2 peptidomimetic (4) comprising an imidazole ring as a bioisosteric element, in the spare nerve injury (SNI) mice model after peripheral administration. Peptidomimetic 4 was stable in plasma, displayed a fair membrane permeability and a favorable neurotoxic profile. Moreover, the effective dose (ED50) of 4 was superior as compared to gabapentin and morphine that are used in clinic.
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