| 1. |
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| 2. |
- Tabiri, S, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 3. |
- Bravo, L, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 4. |
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| 5. |
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| 6. |
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| 7. |
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| 8. |
- Glasbey, JC, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 9. |
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| 10. |
- Dey, Lankeswar, et al.
(författare)
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Authenticating the Presence of a Relativistic Massive Black Hole Binary in OJ 287 Using Its General Relativity Centenary Flare : Improved Orbital Parameters
- 2018
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 866:1
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Tidskriftsartikel (refereegranskat)abstract
- Results from regular monitoring of relativistic compact binaries like PSR 1913+16 are consistent with the dominant (quadrupole) order emission of gravitational waves (GWs). We show that observations associated with the binary black hole (BBH) central engine of blazar OJ 287 demand the inclusion of gravitational radiation reaction effects beyond the quadrupolar order. It turns out that even the effects of certain hereditary contributions to GW emission are required to predict impact flare timings of OJ 287. We develop an approach that incorporates this effect into the BBH model for OJ 287. This allows us to demonstrate an excellent agreement between the observed impact flare timings and those predicted from ten orbital cycles of the BBH central engine model. The deduced rate of orbital period decay is nine orders of magnitude higher than the observed rate in PSR 1913+16, demonstrating again the relativistic nature of OJ 287's central engine. Finally, we argue that precise timing of the predicted 2019 impact flare should allow a test of the celebrated black hole no-hair theorem at the 10% level.
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| 11. |
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| 12. |
- Imai, Y., et al.
(författare)
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Identification of oxidative stress and toll-like receptor 4 signaling as a key pathway of acute lung injury
- 2008
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Ingår i: Cell. - : Elsevier BV. - 1097-4172 .- 0092-8674. ; 133:2, s. 235-249
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Tidskriftsartikel (refereegranskat)abstract
- Multiple lung pathogens such as chemical agents, H5N1 avian flu, or SARS cause high lethality due to acute respiratory distress syndrome. Here we report that Toll-like receptor 4 (TLR4) mutant mice display natural resistance to acid-induced acute lung injury (ALI). We show that TLR4-TRIF-TRAF6 signaling is a key disease pathway that controls the severity of ALI. The oxidized phospholipid (OxPL) OxPAPC was identified to induce lung injury and cytokine production by lung macrophages via TLR4-TRIF. We observed OxPL production in the lungs of humans and animals infected with SARS, Anthrax, or H5N1. Pulmonary challenge with an inactivated H5N1 avian influenza virus rapidly induces ALI and OxPL formation in mice. Loss of TLR4 or TRIF expression protects mice from H5N1-induced ALI. Moreover, deletion of ncf1, which controls ROS production, improves the severity of H5N1-mediated ALI. Our data identify oxidative stress and innate immunity as key lung injury pathways that control the severity of ALI.
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| 13. |
- Neely, G Gregory, et al.
(författare)
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A Genome-wide Drosophila Screen for Heat Nociception Identifies alpha 2 delta 3 as an Evolutionarily Conserved Pain Gene
- 2010
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Ingår i: Cell. - : Elsevier Science B.V., Amsterdam.. - 0092-8674 .- 1097-4172. ; 143:4, s. 628-638
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Tidskriftsartikel (refereegranskat)abstract
- Worldwide, acute, and chronic pain affects 20% of the adult population and represents an enormous financial and emotional burden. Using genome-wide neuronal-specific RNAi knockdown in Drosophila, we report a global screen for an innate behavior and identify hundreds of genes implicated in heat nociception, including the alpha 2 delta family calcium channel subunit straightjacket (stj). Mice mutant for the stj ortholog CACNA2D3 (alpha 2 delta 3) also exhibit impaired behavioral heat pain sensitivity. In addition, in humans, alpha 2 delta 3 SNP variants associate with reduced sensitivity to acute noxious heat and chronic back pain. Functional imaging in alpha 2 delta 3 mutant mice revealed impaired transmission of thermal pain-evoked signals from the thalamus to higher-order pain centers. Intriguingly, in alpha 2 delta 3 mutant mice, thermal pain and tactile stimulation triggered strong cross-activation, or synesthesia, of brain regions involved in vision, olfaction, and hearing.
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| 14. |
- Pirozhkov, A. S., et al.
(författare)
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Diagnostic of laser contrast using target reflectivity
- 2009
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Ingår i: Applied Physics Letters. - : AIP Publishing. - 0003-6951 .- 1077-3118. ; 94:24
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Tidskriftsartikel (refereegranskat)abstract
- Using three different laser systems, we demonstrate a convenient and simple plasma based diagnostic of the contrast of high-power short-pulse lasers. The technique is based on measuring the specular reflectivity from a solid target. The reflectivity remains high even at relativistic intensities above 10(19) W/cm(2) in the case of a high-contrast prepulse-free laser. On the contrary, the specular reflectivity drops with increasing intensities in the case of systems with insufficient contrast due to beam breakup and increased absorption caused by preplasma.
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| 15. |
- Turcu, I. C. E., et al.
(författare)
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HIGH FIELD PHYSICS AND QED EXPERIMENTS AT ELI-NP
- 2016
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Ingår i: Romanian Reports on Physics. - 1221-1451 .- 1841-8759. ; 68, s. S145-S231
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Tidskriftsartikel (refereegranskat)abstract
- ELI-NP facility will enable for the first time the use of two 10 PW laser beams for quantum electrodynamics (QED) experiments. The first beam will accelerate electrons to relativistic energies. The second beam will subject relativistic electrons to the strong electromagnetic field generating QED processes: intense gamma ray radiation and electron-positron pair formation. The laser beams will be focused to intensities above 10(21) Wcm(-2) and reaching 10(22)-10(23) Wcm(-2) for the first time. We propose to use this capability to investigate new physical phenomena at the interfaces of plasma, nuclear and particle physics at ELI-NP. This High Power Laser System Technical Design Report (HPLS-TDR2) presents the experimental area E6 at ELI-NP for investigating high field physics and quantum electrodynamics and the production of electron-positron-pairs and of energetic gamma-rays. The scientific community submitted 12 commissioning runs for E6 interaction chamber with two 10 PW laser beams and one proposal for the CETAL interaction chamber with 1 PW laser. The proposals are representative of the international high field physics community being written by 48 authors from 14 European and US organizations. The proposals are classified according to the science area investigated into: Radiation Reaction Physics: Classical and Quantum; Compton and Thomson Scattering Physics: Linear and Non Linear Regimes; QED in Vacuum; Atoms in Extreme Fields. Two pump-probe colliding 10 PW laser beams are proposed for the E6 interaction chamber. The focused pump laser beam accelerates the electrons to relativistic energies. The accelerated electron bunches interact with the very high electro-magnetic field of the focused probe laser beam. We propose two main types of experiments with: (a) gas targets in which the pump laser-beam is focused by a long focal length mirror and drives a wakefield in which the electron bunch is accelerated to multi-GeV energies and then exposed to the EM field of the probe laser which is tightly focused; (b) solid targets in which both the pump and probe laser beams are focused on the solid target, one accelerating the electrons in the solid and the other, delayed, providing the high electric field to which the relativistic electrons are subjected. We propose four main focusing configurations for the pump and probe laser beams, two for each type of target: counter-propagating 10 PW focused laser beams and the two 10 PW laser beams focused in the same direction. For solid targets we propose an additional configuration with plasma-mirror on the pump laser beam: the plasma mirror placed between the focusing mirror and target. It is proposed that the 10 PW laser beams will have polarization control and focus control by means of adaptive optics. Initially only one 10 PW may have polarization control and adaptive optics. In order to accommodate the two laser beams and diagnostics the proposed interaction chamber is quasi-octagonal with a diameter of 4.5 m. A large electron-spectrometer is proposed for multi-GeV electrons. Other diagnostics are requested for: gamma-rays, electrons and positrons, protons and ions, plasma characterization, transmitted and reflected laser beam. Targets will be provided by the ELI-NP Target Laboratory or purchased. The E6 experiments and diagnostics will benefit from the ELI-NP Electronics Laboratory, the Workshop and the Optics Laboratory. In order to ensure radiation-protection, a large beam-dump is planned for both multi-GeV electrons and multi-100 MeV protons.
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| 16. |
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| 17. |
- Martson, A-G, et al.
(författare)
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How to design a study to evaluate therapeutic drug monitoring in infectious diseases?
- 2020
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Ingår i: Clinical Microbiology and Infection. - : Elsevier BV. - 1198-743X .- 1469-0691. ; 26:8, s. 1008-1016
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Forskningsöversikt (refereegranskat)abstract
- Background: Therapeutic drug monitoring (TDM) is a tool to personalize and optimize dosing by measuring the drug concentration and subsequently adjusting the dose to reach a target concentration or exposure. The evidence to support TDM is however often ranked as expert opinion. Limitations in study design and sample size have hampered definitive conclusions of the potential added value of TDM.Objectives: We aim to give expert opinion and discuss the main points and limitations of available data from antibiotic TDM trials and emphasize key elements for consideration in design of future clinical studies to quantify the benefits of TDM.Sources: The sources were peer-reviewed publications, guidelines and expert opinions from the field of TDM.Content: This review focuses on key aspects of antimicrobial TDM study design: describing the rationale for a TDM study, assessing the exposure of a drug, assessing susceptibility of pathogens and selecting appropriate clinical endpoints. Moreover we provide guidance on appropriate study design.
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| 18. |
- Meredith, Jere E, et al.
(författare)
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Characterization of novel CSF Tau and ptau biomarkers for Alzheimer's disease.
- 2013
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 8:10
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral spinal fluid (CSF) Aβ42, tau and p181tau are widely accepted biomarkers of Alzheimer's disease (AD). Numerous studies show that CSF tau and p181tau levels are elevated in mild-to-moderate AD compared to age-matched controls. In addition, these increases might predict preclinical AD in cognitively normal elderly. Despite their importance as biomarkers, the molecular nature of CSF tau and ptau is not known. In the current study, reverse-phase high performance liquid chromatography was used to enrich and concentrate tau prior to western-blot analysis. Multiple N-terminal and mid-domain fragments of tau were detected in pooled CSF with apparent sizes ranging from <20 kDa to ~40 kDa. The pattern of tau fragments in AD and control samples were similar. In contrast, full-length tau and C-terminal-containing fragments were not detected. To quantify levels, five tau ELISAs and three ptau ELISAs were developed to detect different overlapping regions of the protein. The discriminatory potential of each assay was determined using 20 AD and 20 age-matched control CSF samples. Of the tau ELISAs, the two assays specific for tau containing N-terminal sequences, amino acids 9-198 (numbering based on tau 441) and 9-163, exhibited the most significant differences between AD and control samples. In contrast, CSF tau was not detected with an ELISA specific for a more C-terminal region (amino acids 159-335). Significant discrimination was also observed with ptau assays measuring amino acids 159-p181 and 159-p231. Interestingly, the discriminatory potential of p181 was reduced when measured in the context of tau species containing amino acids 9-p181. Taken together, these results demonstrate that tau in CSF occurs as a series of fragments and that discrimination of AD from control is dependent on the subset of tau species measured. These assays provide novel tools to investigate CSF tau and ptau as biomarkers for other neurodegenerative diseases.
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| 19. |
- Orthofer, M, et al.
(författare)
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Identification of ALK in Thinness
- 2020
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Ingår i: Cell. - : Elsevier BV. - 1097-4172 .- 0092-8674. ; 181:6, s. 1246-
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Tidskriftsartikel (refereegranskat)
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| 20. |
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| 21. |
- Xu, M. H., et al.
(författare)
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Enhancement of ion generation in femtosecond ultraintense laser-foil interactions by defocusing
- 2012
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Ingår i: Applied Physics Letters. - : AIP Publishing. - 0003-6951 .- 1077-3118. ; 100:8
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Tidskriftsartikel (refereegranskat)abstract
- A simple method to enhance ion generation with femtosecond ultraintense lasers is demonstrated experimentally by defocusing laser beams on target surface. When the laser is optimally defocused, we find that the population of medium and low energy protons from ultra-thin foils is increased significantly while the proton cutoff energy is almost unchanged. In this way, the total proton yield can be enhanced by more than 1 order, even though the peak laser intensity drops. The depression of the amplified spontaneous emission (ASE) effect and the population increase of moderate-energy electrons are believed to be the main reasons for the effective enhancement. (C) 2012 American Institute of Physics. [doi:10.1063/1.3688027]
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| 22. |
- Alfirevic, A., et al.
(författare)
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Phenotype Standardization for Statin-Induced Myotoxicity
- 2014
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 96:4, s. 470-476
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Forskningsöversikt (refereegranskat)abstract
- Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.
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| 23. |
- Alfredsson, Joakim, et al.
(författare)
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Predicting the risk of bleeding during dual antiplatelet therapy after acute coronary syndromes
- 2017
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Ingår i: Heart. - : BMJ PUBLISHING GROUP. - 1355-6037 .- 1468-201X. ; 103:15, s. 1168-1176
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Dual antiplatelet therapy (DAPT) with aspirin + a P2Y12 inhibitor is recommended for at least 12 months for patients with acute coronary syndrome (ACS), with shorter durations considered for patients with increased bleeding risk. However, there are no decision support tools available to predict an individual patients bleeding risk during DAPT treatment in the post-ACS setting. Methods To develop a longitudinal bleeding risk prediction model, we analysed 9240 patients with unstable angina/non-ST segment elevation myocardial infarction (NSTEMI) from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial, who were managed without revascularisation and treated with DAPT for a median of 14.8 months. Results We identified 10 significant baseline predictors of non-coronary artery bypass grafting (CABG)-related Global Use of Strategies to Open Occluded Arteries (GUSTO) severe/life-threatening/moderate bleeding: age, sex, weight, NSTEMI (vs unstable angina), angiography performed before randomisation, prior peptic ulcer disease, creatinine, systolic blood pressure, haemoglobin and treatment with beta-blocker. The five significant baseline predictors of Thrombolysis In Myocardial Infarction (TIMI) major or minor bleeding included age, sex, angiography performed before randomisation, creatinine and haemoglobin. The models showed good predictive accuracy with Therneaus C-indices: 0.78 (SE=0.024) for the GUSTO model and 0.67 (SE=0.023) for the TIMI model. Internal validation with bootstrapping gave similar C-indices of 0.77 and 0.65, respectively. External validation demonstrated an attenuated C-index for the GUSTO model (0.69) but not the TIMI model (0.68). Conclusions Longitudinal bleeding risks during treatment with DAPT in patients with ACS can be reliably predicted using selected baseline characteristics. The TRILOGY ACS bleeding models can inform riskbenefit considerations regarding the duration of DAPT following ACS.
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| 24. |
- Brenner, C. M., et al.
(författare)
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Dependence of laser accelerated protons on laser energy following the interaction of defocused, intense laser pulses with ultra-thin targets
- 2011
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Ingår i: Laser and Particle Beams. - 0263-0346. ; 29:3, s. 345-351
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Tidskriftsartikel (refereegranskat)abstract
- The scaling of the flux and maximum energy of laser-driven sheath-accelerated protons has been investigated as a function of laser pulse energy in the range of 15-380 mJ at intensities of 10(16)-10(18) W/cm(2). The pulse duration and target thickness were fixed at 40 fs and 25 nm, respectively, while the laser focal spot size and drive energy were varied. Our results indicate that while the maximum proton energy is dependent on the laser energy and laser spot diameter, the proton flux is primarily related to the laser pulse energy under the conditions studied here. Our measurements show that increasing the laser energy by an order of magnitude results in a more than 500-fold increase in the observed proton flux. Whereas, an order of magnitude increase in the laser intensity generated by decreasing the laser focal spot size, at constant laser energy, gives rise to less than a tenfold increase in observed proton flux.
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| 25. |
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| 26. |
- Green, J. S., et al.
(författare)
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Enhanced proton flux in the MeV range by defocused laser irradiation
- 2010
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Ingår i: New Journal of Physics. - : IOP Publishing. - 1367-2630. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Thin Al foils (50 nm and 6 mu m) were irradiated at intensities of up to 2x10(19) W cm(-2) using high contrast (10(8)) laser pulses. Ion emission from the rear of the targets was measured using a scintillator-based Thomson parabola and beam sampling 'footprint' monitor. The variation of the ion spectra and beam profile with focal spot size was systematically studied. The results show that while the maximum proton energy is achieved around tight focus for both target thicknesses, as the spot size increases the ion flux at lower energies is seen to peak at significantly increased spot sizes. Measurements of the proton footprint, however, show that the off-axis proton flux is highest at tight focus, indicating that a previously identified proton deflection mechanism may alter the on-axis spectrum. One-dimensional particle-in-cell modelling of the experiment supports our hypothesis that the observed change in spectra with focal spot size is due to the competition of two effects: decrease in laser intensity and an increase in proton emission area.
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| 27. |
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| 28. |
- Neely, K E, et al.
(författare)
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Activation domain-mediated targeting of the SWI/SNF complex to promoters stimulates transcription from nucleosome arrays
- 1999
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Ingår i: Molecular Cell. - 1097-2765 .- 1097-4164. ; 4:4, s. 649-655
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Tidskriftsartikel (refereegranskat)abstract
- The yeast SWI/SNF complex is required for the transcription of several yeast genes and has been shown to alter nucleosome structure in an ATP-dependent reaction. In this study, we show that the complex stimulated in vitro transcription from nucleosome templates in an activation domain-dependent manner. Transcription stimulation by SWI/SNF required an activation domain with which it directly interacts. The acidic activation domains of VP16, Gcn4, Swi5, and Hap4 interacted directly with the purified SWI/SNF complex and with the SWI/SNF complex in whole-cell extracts. The similarity of activation domain interactions and transcriptional stimulation between SWI/SNF and the SAGA histone acetyltransferase complex may account for their apparent overlapping functions in vivo.
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| 29. |
- Sindi, S., et al.
(författare)
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Multimodal Preventive Trial for Alzheimer’s Disease : MIND-ADmini Pilot Trial Study Design and Progress
- 2022
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Ingår i: The Journal of Prevention of Alzheimer's Disease. - : Serdi-Editions. - 2274-5807 .- 2426-0266. ; 9:1, s. 30-39
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Tidskriftsartikel (refereegranskat)abstract
- Background: Interventions simultaneously targeting multiple risk factors and mechanisms are most likely to be effective in preventing cognitive impairment. This was indicated in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) testing a multidomain lifestyle intervention among at-risk individuals. The importance of medical food at the early symptomatic disease stage, prodromal Alzheimer’s disease (AD), was emphasized in the LipiDiDiet trial. The feasibility and effects of multimodal interventions in prodromal AD are unclear. Objectives: To evaluate the feasibility of an adapted FINGER-based multimodal lifestyle intervention, with or without medical food, among individuals with prodromal AD. Methods: MIND-ADmini is a multinational proof-of-concept 6-month randomized controlled trial (RCT), with four trial sites (Sweden, Finland, Germany, France). The trial targeted individuals with prodromal AD defined using the International Working Group-1 criteria, and with vascular or lifestyle-related risk factors. The parallel-group RCT includes three arms: 1) multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management and social stimulation); 2) multimodal lifestyle intervention+medical food (Fortasyn Connect); and 3) regular health advice/ care (control group). Primary outcomes are feasibility and adherence. Secondary outcomes are adherence to the individual intervention domains and healthy lifestyle changes. Results: Screening began on 28 September 2017 and was completed on 21 May 2019. Altogether 93 participants were randomized and enrolled. The intervention proceeded as planned. Conclusions: For the first time, this pilot trial tests the feasibility and adherence to a multimodal lifestyle intervention, alone or combined with medical food, among individuals with prodromal AD. It can serve as a model for combination therapy trials (non-pharma, nutrition-based and/or pharmacological interventions).
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| 30. |
- Tricoci, Pierluigi, et al.
(författare)
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Effects of genetic variation in protease activated receptor 4 after an acute coronary syndrome : Analysis from the TRACER trial
- 2018
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Ingår i: Blood Cells, Molecules & Diseases. - : Elsevier BV. - 1079-9796 .- 1096-0961. ; 72, s. 37-43
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Tidskriftsartikel (refereegranskat)abstract
- Variation in platelet response to thrombin may affect the safety and efficacy of PAR antagonism. The Thr120 variant of the common single nucleotide polymorphism (SNP) rs773902 in the protease-activated receptor (PAR) 4 gene is associated with higher platelet aggregation compared to the Ala120 variant. We investigated the relationship between the rs773902 SNP with major bleeding and ischemic events, safety, and efficacy of PAR1 inhibition in 6177 NSTE ACS patients in the TRACER trial. There was a lower rate of GUSTO moderate/severe bleeding in patients with the Thr120 variant. The difference was driven by a lower rate in the smaller homozygous group (recessive model, HR 0.13 [0.02-0.92] P= 0.042). No significant differences were observed in the ischemic outcomes. The excess in bleeding observed with PAR1 inhibition was attenuated in patients with the Thr120 variant, but the interactions were not statistically significant. In summary, lower major bleeding rates were observed in the overall TRACER cohort with the hyperreactive PAR4 Thr120 variant. The increase in bleeding with vorapaxar was attenuated with the Thr120 variant, but we could not demonstrate an interaction with PAR1 inhibition. These findings warrant further exploration, including those of African ancestry where the A allele (Thr120) frequency is similar to 65%.
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| 31. |
- Wallberg, A. E., et al.
(författare)
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Histone acetyltransferase complexes can mediate transcriptional activation by the major glucocorticoid receptor activation domain
- 1999
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Ingår i: Molecular and Cellular Biology. - : American Society for Microbiology. - 0270-7306 .- 1098-5549. ; 19:9, s. 5952-5959
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have shown that the Ada adapter proteins are important for glucocorticoid receptor (GR)-mediated gene activation in yeast. The N- terminal transactivation domain of GR, τ1, is dependent upon Ada2, Ada3, and Gcn5 for transactivation in vitro and in vivo. Using in vitro techniques, we demonstrate that the GR-τ1 interacts directly with the native Ada containing histone acetyltransferase (HAT) complex SAGA but not the related Ada complex. Mutations in τ1 that reduce τ1 transactivation activity in vivo lead to a reduced binding of τ1 to the SAGA complex and conversely, mutations increasing the transactivation activity of τ1 lead to an increased binding of τ1 to SAGA. In addition, the Ada-independent NuA4 HAT complex also interacts with τ1. GAIA-τ1-driven transcription from chromatin templates is stimulated by SAGA and NuA4 in an acetyl coenzyme A-dependent manner. Low- activity τ1 mutants reduce SAGA- and NuA4-stimulated transcription while high-activity τ1 mutants increase transcriptional activation, specifically from chromatin templates. Our results demonstrate that the targeting of native HAT complexes by the GR-τ1 activation domain mediates transcriptional stimulation from chromatin templates.
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| 32. |
- Wallberg, A E, et al.
(författare)
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Recruitment of the SWI-SNF chromatin remodeling complex as a mechanism of gene activation by the glucocorticoid receptor tau 1 activation domain
- 2000
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Ingår i: Molecular and Cellular Biology. - 0270-7306 .- 1098-5549. ; 20:6, s. 2004-2013
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Tidskriftsartikel (refereegranskat)abstract
- The SWI-SNF complex has been shown to alter nucleosome conformation in an ATP-dependent manner, leading to increased accessibility of nucleosomal DNA to transcription factors. In this study, we show that the SWI-SNF complex can potentiate the activity of the glucocorticoid receptor (GR) through the N-terminal transactivation domain, tau 1, in both yeast and mammalian cells. GR-sl can directly interact with purified SWI-SNF complex, and mutations in tau 1 that affect the transactivation activity in vivo also directly affect tau 1 interaction with SWI-SNF. Furthermore, the SWI-SNF complex can stimulate tau 1-driven transcription from chromatin templates in vitro, Taken together, these results support a model in which the GR can directly recruit the SWI-SNF complex to target promoters during glucocorticoid-dependent gene activation. We also provide evidence that the SWI-SNF and SAGA complexes represent independent pathways of tau 1-mediated activation but play overlapping roles that are able to compensate for one another under some conditions.
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| 33. |
- Chan, Mark Y., et al.
(författare)
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Temporal biomarker profiling reveals longitudinal changes in risk of death or myocardial infarction in Non-ST-segment elevation acute coronary syndrome
- 2017
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 63:7, s. 1214-1226
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There are conflicting data on whether changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hs-CRP) concentrations between time points (delta NT-proBNP and hs-CRP) are associated with a change in prognosis. METHODS: We measured NT-proBNP and hs-CRP at 3 time points in 1665 patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). Cox proportional hazards was applied to the delta between temporal measurements to determine the continuous association with cardiovascular events. Effect estimates for delta NT-proBNP and hs-CRP are presented per 40% increase as the basic unit of temporal change. RESULTS: Median NT-proBNP was 370.0 (25th, 75th percentiles, 130.0, 996.0), 340.0 (135.0, 875.0), and 267.0 (111.0, 684.0) ng/L; and median hs-CRP was 4.6 (1.7, 13.1), 1.9 (0.8, 4.5), and 1.8 (0.8, 4.4) mg/L at baseline, 30 days, and 6 months, respectively. The deltas between baseline and 6 months were the most prognostically informative. Every 40% increase of delta NTproBNP (baseline to 6 months) was associated with a 14% greater risk of cardiovascular death (adjusted hazard ratio (HR) 1.14, 95% CI, 1.03-1.27) and with a 14% greater risk of all-cause death (adjusted HR 1.14, 95% CI, 1.04 -1.26), while every 40% increase of delta hs- CRP (baseline to 6 months) was associated with a 9% greater risk of the composite end point (adjusted HR 1.09, 95% CI, 1.02-1.17) and a 10% greater risk of myocardial infarction (adjusted HR 1.10, 95%, CI 1.00 -1.20). CONCLUSIONS: Temporal changes in NT-proBNP and hs-CRP are quantitatively associated with future cardiovascular events, supporting their role in dynamic risk stratification of NSTEACS.
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| 34. |
- Cherniack, Martin, et al.
(författare)
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Syndromes from segmental vibration and nerve entrapment : observations on case definitions for carpal tunnel syndrome
- 2008
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Ingår i: International Archives of Occupational and Environmental Health. - Berlin : Springer-Vlg. - 0340-0131 .- 1432-1246. ; 81:5, s. 661-669
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The purpose of this paper is to assess the overlap and stability of two different case definitions of carpal tunnel syndrome CTS. The analysis considers the association between different case definitions and objective tests (sensory nerve conduction velocities, SNCVs and vibrotactile perception thresholds, TTS), and the natural history of CTS, in the context of two vibration-exposed cohorts. Methods: Clinical CTS cases were defined in two ways: (1) by the study physician using fixed criteria, and; (2) by questionnaire and hand diagram. SNCV in median and ulnar nerves was measured for digital, transpalmar, and transcarpal segments, and conventionally as from wrist-digit. Skin temperature was assessed as a point measurement by thermistor and regionally by thermal imaging. VTTs were determined at the bilateral fingertips of the third and fifth digits using a tactometer meeting the requirements of ISO 13091-1 (ISO 2001). The subjects were cohorts of shipyard workers in 2001 and 2004, and dental hygienists in 2002 and 2004. Results: Results are reported for 214 shipyard workers in 2001 and 135 in 2004, and for 94 dental hygienists in 2002 and 66 in 2004. In 2001, 50% of shipyard workers were diagnosed as CTS cases by at least one of the diagnostic schemes, but only 20% were positive by both criteria. Among study physician diagnosed cases, 64% were CTS negative in 2001, 76% were negative in 2004, 13% were positive in both years, 22% became negative after being positive, and 11% became positive after being negative. For only study physician diagnosed CTS did VTTs differ between cases differ and non-cases in digit 3; there was no such distinction in digit 5. The dental hygienists had little CTS. Conclusion: Clinical case definitions of CTS based on diagrams and self-assessment, and clinical evaluation have limited overlap. Combining clinical criteria to create a more narrow or specific case definition of CTS does not appear to predict SNCV. The natural history of CTS suggests a protean disorder with considerable flux in case status over time.
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| 35. |
- Cherniack, Martin, et al.
(författare)
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The effect of different warming methods on sensory nerve conduction velocity in shipyard workers occupationally exposed to hand-arm vibration.
- 2008
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Ingår i: International archives of occupational and environmental health. - : Springer Science and Business Media LLC. - 1432-1246 .- 0340-0131. ; 81:8, s. 1045-58
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Segmental sensory nerve conduction velocity (SNCV) was measured from the wrists to the hands and digits in a population of 134 (126 men and 8 women) vibration-exposed shipyard workers following systemic warming using a bicycle ergometer. Results were compared to earlier nerve conduction tests, identical in execution, except that the warming process was segmental and cutaneous. The study was designed to investigate whether SNCVs, which were selectively slow in the fingers after segmental cutaneous (skin surface) warming, would be affected differently by systemic warming. METHODS: Wrist-palm, palm-proximal digit, and digital sensory nerve segments were assessed antidromically by stimulating at the wrist with recording electrodes placed distally. The same subjects were cutaneously warmed in 2001 to >or=31 degrees C and were systemically warmed 28 months later in 2004 by ramped sustained exercise to 100 W for 12 min. Skin temperatures were measured by traditional thermistry and by infrared thermal images taken over the hand and wrist surfaces. RESULTS: When systemic warming was compared to segmental cutaneous warming, SNCVs were increased by 15.1% in the third digit and 20.4% in the fifth digit of the dominant hand. Respective increases in the non-dominant hand were 11.0% and 19.4%. A strong association between increased surface skin temperature and faster SNCV, which had been observed after segmental cutaneous warming, was largely eliminated for both digit and palmar anatomic segments after systemic warming. Significant differences in SNCV between vibration-exposed and non-exposed workers, which had been observed after segmental cutaneous warming, were eliminated after systemic warming. Systemic warming had only a small effect on the wrist-palm (transcarpal) segmental SNCVs. CONCLUSIONS: Reduced SNCV in the digits was observed in vibration-exposed and non-exposed workers. Substituting exercise-induced systemic warming for segmental cutaneous warming significantly increased SNCV in the digits and appeared to reduce differences in SNCV between vibration-exposed and non-exposed workers. These findings persisted despite a substantial time interval between tests, during which the subjects continued to work. There may be more general implications for diagnosing clinical conditions in industrial workers, such as the carpal tunnel syndrome and the hand-arm vibration syndrome.
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| 36. |
- Cherniack, Martin, et al.
(författare)
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The Hand-Arm Vibration International Consortium (HAVIC) : prospective studies on the relationship between power tool exposure and health effects.
- 2007
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Ingår i: Journal of Occupational and Environmental Medicine. - 1076-2752 .- 1536-5948. ; 49:3, s. 289-301
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The Hand-Arm Vibration International Consortium (HAVIC) is a collaboration of investigators from Europe and North America studying health effects from hand-arm vibration (HAV). Features include prospective design, cross-cohort exposure, and health assessment methods. METHODS: Two new cohorts (dental hygienists and dental hygiene students), two existing cohorts (Finnish forest workers, and Swedish truck cab assemblers), and a previous population (US shipyard workers) are included. Instruments include surveys, quantitative medical tests, physical examination, and work simulation and data logging to assess exposure. New methods were developed for nerve conduction and data logging. RESULTS: Findings on the relationship between nerve conduction and skin temperature in HAV-exposed subjects resulted in a new approach to subject warming. CONCLUSIONS: Integrating established cohorts has advantages over de novo cohort construction. Complex laboratory tests can be successfully adapted for field use.
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| 37. |
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| 38. |
- Clarke, R. J., et al.
(författare)
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Detection of short lived radioisotopes as a fast diagnostic for intense laser-solid interactions
- 2006
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Ingår i: Applied Physics Letters. - : AIP Publishing. - 0003-6951 .- 1077-3118. ; 89:14
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Tidskriftsartikel (refereegranskat)abstract
- As a diagnostic of high-intensity laser interactions (> 10(19) W cm(-2)), the detection of radioactive isotopes is regularly used for the characterization of proton, neutron, ion, and photon beams. This involves sample removal from the interaction chamber and time consuming post shot analysis using NaI coincidence counting or Ge detectors. This letter describes the use of in situ detectors to measure laser-driven (p,n) reactions in Al-27 as an almost real-time diagnostic for proton acceleration. The produced Si-27 isotope decays with a 4.16 s half-life by the predominantly beta+ emission, producing a strong 511 keV annihilation peak. (c) 2006 American Institute of Physics.
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| 39. |
- Coury, M., et al.
(författare)
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Influence of laser irradiated spot size on energetic electron injection and proton acceleration in foil targets
- 2012
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Ingår i: Applied Physics Letters. - : AIP Publishing. - 0003-6951 .- 1077-3118. ; 100:7
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Tidskriftsartikel (refereegranskat)abstract
- The influence of irradiated spot size on laser energy coupling to electrons, and subsequently to protons, in the interaction of intense laser pulses with foil targets is investigated experimentally. Proton acceleration is characterized for laser intensities ranging from 2 x 10(18) - 6 x 10(20) W/cm(2), by (1) variation of the laser energy for a fixed irradiated spot size, and (2) by variation of the spot size for a fixed energy. At a given laser pulse intensity, the maximum proton energy is higher under defocus illumination compared to tight focus and the results are explained in terms of geometrical changes to the hot electron injection. (C) 2012 American Institute of Physics. [doi:10.1063/1.3685615]
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| 40. |
- Coury, M., et al.
(författare)
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Injection and transport properties of fast electrons in ultraintense laser-solid interactions
- 2013
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Ingår i: Physics of Plasmas. - : AIP Publishing. - 1070-664X .- 1089-7674. ; 20:4
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Tidskriftsartikel (refereegranskat)abstract
- Fast electron injection and transport in solid foils irradiated by sub-picosecond-duration laser pulses with peak intensity equal to 4 x 10(20)W/cm(2) is investigated experimentally and via 3D simulations. The simulations are performed using a hybrid-particle-in-cell (PIC) code for a range of fast electron beam injection conditions, with and without inclusion of self-generated resistive magnetic fields. The resulting fast electron beam transport properties are used in rear-surface plasma expansion calculations to compare with measurements of proton acceleration, as a function of target thickness. An injection half-angle of similar to 50 degrees - 70 degrees is inferred, which is significantly larger than that derived from previous experiments under similar conditions. (C) 2013 American Institute of Physics. [http://dx.doi.org/10.1063/1.4799726]
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| 41. |
- Foerster, Sunniva, et al.
(författare)
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In vitro antimicrobial combination testing of and evolution of resistance to the first-in-class spiropyrimidinetrione zoliflodacin combined with six therapeutically relevant antimicrobials for Neisseria gonorrhoeae
- 2019
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Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press. - 0305-7453 .- 1460-2091. ; 74:12, s. 3521-3529
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Resistance in Neisseria gonorrhoeae to all gonorrhoea therapeutic antimicrobials has emerged. Novel therapeutic antimicrobials are imperative and the first-in-class spiropyrimidinetrione zoliflodacin appears promising. Zoliflodacin could be introduced in dual antimicrobial therapies to prevent the emergence and/or spread of resistance. We investigated the in vitro activity of and selection of resistance to zoliflodacin alone and in combination with six gonorrhoea therapeutic antimicrobials against N. gonorrhoeae.METHODS: The international gonococcal reference strains WHO F (WT) and WHO O, WHO V and WHO X (strains with different AMR profiles) were examined. Zoliflodacin was evaluated alone or combined with ceftriaxone, cefixime, spectinomycin, gentamicin, tetracycline, cethromycin or sitafloxacin in chequerboard assays, time-kill curve analysis and selection-of-resistance studies.RESULTS: Zoliflodacin alone or in combination with all six antimicrobials showed rapid growth inhibition against all examined strains. The time-kill curve analysis indicated that tetracycline or cethromycin combined with zoliflodacin can significantly decrease the zoliflodacin kill rate in vitro. The frequency of selected zoliflodacin-resistance mutations was low when evaluated as a single agent and further reduced for all antimicrobial combinations. All resistant mutants contained the GyrB mutations D429N, K450T or K450N, resulting in zoliflodacin MICs of 0.5-4 mg/L.CONCLUSIONS: Zoliflodacin, alone or in combination with sexually transmitted infection therapeutic antimicrobials, rapidly kills gonococci with infrequent resistance emergence. Zoliflodacin remains promising for gonorrhoea oral monotherapy and as part of dual antimicrobial therapy with low resistance emergence potential. A Phase III trial evaluating efficacy and safety of zoliflodacin for uncomplicated gonorrhoea treatment is planned in 2019.
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| 42. |
- Gray, R. J., et al.
(författare)
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Laser pulse propagation and enhanced energy coupling to fast electrons in dense plasma gradients
- 2014
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Ingår i: New Journal of Physics. - : IOP Publishing. - 1367-2630. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Laser energy absorption to fast electrons during the interaction of an ultra-intense (10(20) Wcm(-2)), picosecond laser pulse with a solid is investigated, experimentally and numerically, as a function of the plasma density scale length at the irradiated surface. It is shown that there is an optimum density gradient for efficient energy coupling to electrons and that this arises due to strong self-focusing and channeling driving energy absorption over an extended length in the preformed plasma. At longer density gradients the laser filaments, resulting in significantly lower overall energy coupling. As the scale length is further increased, a transition to a second laser energy absorption process is observed experimentally via multiple diagnostics. The results demonstrate that it is possible to significantly enhance laser energy absorption and coupling to fast electrons by dynamically controlling the plasma density gradient.
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| 43. |
- Hagström, Emil, et al.
(författare)
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Association Between Very Low Levels of High-Density Lipoprotein Cholesterol and Long-term Outcomes of Patients With Acute Coronary Syndrome Treated Without Revascularization : Insights From the TRILOGY ACS Trial
- 2016
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Ingår i: Clinical Cardiology. - : Wiley. - 0160-9289 .- 1932-8737. ; 39:6, s. 329-337
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Tidskriftsartikel (refereegranskat)abstract
- Background: Low levels of high-density lipoprotein cholesterol (HDL-C; < 40 mg/dL) are associated with increased risk of cardiovascular events, but it is unclear whether lower thresholds (< 30 mg/dL) are associated with increased hazard.Hypothesis: Very low levels of HDL-C may provide prognostic information in acute coronary syndrome (ACS) patients treated medically without revascularization.Methods: We examined data from 9064/9326 ACS patients enrolled in the TRILOGY ACS trial. Participants were randomized to clopidogrel or prasugrel plus aspirin. Study treatments continued for 6 to 30 months. Relationships between baseline HDL-C and the composite of cardiovascular death, myocardial infarction (MI), or stroke, and individual endpoints of death (cardiovascular and all-cause), MI, and stroke, adjusted for baseline characteristics through 30 months, were analyzed. The HDL-C was evaluated as a dichotomous variable-very low (< 30 mg/dL) vs higher (>= 30 mg/dL)-and continuously.Results: Median baseline HDL-C was 42mg/dL (interquartile range, 34-49mg/dL) with little variation over time. Frequency of the composite endpoint was similar for very low vs higher baseline HDL-C, with no risk difference between groups (hazard ratio [ HR]: 1.13, 95% confidence interval [ CI]: 0.95-1.34). Similar findings were seen for MI and stroke. However, risks for cardiovascular (HR: 1.42, 95% CI: 1.13-1.78) and all-cause death (HR: 1.36, 95% CI: 1.11-1.67) were higher in patients with very low baseline HDL-C.Conclusions: Medically managed ACS patients with very low baseline HDL-C levels have higher risk of long-term cardiovascular and all-cause death but similar risks for nonfatal ischemic outcomes vs patients with higher baseline HDL-C.
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| 44. |
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| 45. |
- Ivory, Chris, et al.
(författare)
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Leadership of Business Schools : Perceptions, Priorities and Predicaments (Executive Briefing)
- 2008
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- UK business schools have grown rapidly over the last forty years. They account for a substantial proportion of students and overall income (especially from overseas), with one in seven undergraduates and one in five postgraduates studying business and management related subjects. Underlying this robust picture, where business schools are integral to their universities’ successes, some interesting issues arise about the future for business schools and particularly the leadership pipeline. This report focuses on business schools and how like other schools within universities face a challenging, complex and ambiguous future and there appears to be a limited pool of candidates applying to become deans.
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| 46. |
- Ivory, Chris, et al.
(författare)
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The Future of Business School Faculty (Executive Briefing
- 2007
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- The UK business schools are threatened by a potential shortage of faculty. Not only that but business schools face significant challenges within retention and development with data suggesting that there are worrying shortfalls in amounts of PhD students graduating and taking up faculty positions. The research reveals that a key part of devising a successful talent strategy is to understand the business school faculty shortage and the strategies for addressing it in the context of the different types of activity that business schools engage in.
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| 47. |
- Lowenstern, Angela, et al.
(författare)
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Platelet-related biomarkers and their response to inhibition with aspirin and p2y12-receptor antagonists in patients with acute coronary syndrome
- 2017
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Ingår i: Journal of Thrombosis and Thrombolysis. - : Springer Science and Business Media LLC. - 0929-5305 .- 1573-742X. ; 44:2, s. 145-153
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Tidskriftsartikel (refereegranskat)abstract
- The PLATelet inhibition and patient Outcomes (PLATO) trial showed that treatment with ticagrelor reduced the rate of death due to vascular causes, myocardial infarction and stroke when compared to clopidogrel in patients with ST-elevation or non-ST-elevation acute coronary syndrome (ACS). While the comparative benefit of ticagrelor over clopidogrel increased over time, event rates accrued in both groups during the study period. The purpose of our biomarker-based exploratory analysis was to determine whether long-term platelet inhibition may be associated with platelet adaptation. A sample of 4000 participants from the PLATO trial also consented to participate in a prospectively designed biomarker substudy. Blood samples were procured at baseline, immediately prior to hospital discharge and at 1 and 6 months. Markers of platelet activity, including platelet count, serum CD40-ligand and soluble P-selectin were analyzed. Mean levels were compared at discharge, 1 and 6 months following study drug initiation-first for all patients and subsequently stratified by treatment group. A linear mixed model was used to estimate the short-term change rate (baseline to 1 month) and long-term change rate (1-6 months) for each biomarker. A Cox proportional hazards model was used to calculate hazard ratios for each change in biomarker over the two time periods examined: baseline to 1 month and 1 to 6 months. Prior to randomized treatment (baseline), sCD40 ligand and sP-selectin levels were elevated above the normal range of the assay (0.39 and 33.5 A μg/L, respectively). The mean level of each biomarker was significantly different at 1 month compared to baseline (p < 0.0001). When stratified by treatment group, at 1 month patients treated with ticagrelor had a larger increase in platelet count compared to those treated with clopidogrel (p < 0.0001). Similarly, when comparing biomarker levels for all patients at 6 months with those at 1 month, each differed significantly (p < 0.05). There was no significant difference between treatment groups during this time period. The rate of change for both platelet count and sP-selectin were significantly different between baseline and 1 month when compared to the 1 to 6-month time period (p < 0.0001). When comparing treatment groups, the rate of increase in platelets from baseline to 1 month was greater for patients treated with ticagrelor (p < 0.0001). This was no longer observed in the 1 to 6-month interval. Using a Cox proportional hazard model, the increase in platelet count from 1 to 6 months was associated with ischemic-thrombotic events, while sCD40 ligand decrease from 1 to 6 months was associated with hemorrhagic events. There were no differences between treatment groups for the associations with clinical endpoints. Dynamic changes in platelet count, sCD-40 ligand and sP-selectin occur over time among patients with ACS. Platelet-directed therapy with a P2Y12 receptor inhibitor in combination with aspirin modestly impacts the expression of these biomarkers. Platelet count and sCD40 ligand may offer modest overall predictive value for future ischemic-thrombotic or hemorrhagic clinical events, respectively. The existence of a platelet adaptome and its overall clinical significance among patients at risk for thrombotic events will require a more in-depth and platelet-biology specific investigation.
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| 48. |
- MacLellan, D. A., et al.
(författare)
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Annular Fast Electron Transport in Silicon Arising from Low-Temperature Resistivity
- 2013
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Ingår i: Physical Review Letters. - 1079-7114. ; 111:9
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Tidskriftsartikel (refereegranskat)abstract
- Fast electron transport in Si, driven by ultraintense laser pulses, is investigated experimentally and via 3D hybrid particle-in-cell simulations. A transition from a Gaussian-like to an annular fast electron beam profile is demonstrated and explained by resistively generated magnetic fields. The results highlight the potential to completely transform the beam transport pattern by tailoring the resistivity-temperature profile at temperatures as low as a few eV.
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| 49. |
- MacLellan, D A, et al.
(författare)
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Tunable mega-ampere electron current propagation in solids by dynamic control of lattice melt.
- 2014
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Ingår i: Physical Review Letters. - 1079-7114. ; 113:18
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Tidskriftsartikel (refereegranskat)abstract
- The influence of lattice-melt-induced resistivity gradients on the transport of mega-ampere currents of fast electrons in solids is investigated numerically and experimentally using laser-accelerated protons to induce isochoric heating. Tailoring the heating profile enables the resistive magnetic fields which strongly influence the current propagation to be manipulated. This tunable laser-driven process enables important fast electron beam properties, including the beam divergence, profile, and symmetry to be actively tailored, and without recourse to complex target manufacture.
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| 50. |
- McCusker, Gillian Young, et al.
(författare)
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Evaluating Arctic clouds modelled with the Unified Model and Integrated Forecasting System
- 2023
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Ingår i: Atmospheric Chemistry And Physics. - 1680-7316 .- 1680-7324. ; 23:8, s. 4819-4847
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Tidskriftsartikel (refereegranskat)abstract
- By synthesising remote-sensing measurements made in the central Arctic into a model-gridded Cloudnet cloud product, we evaluate how well the Met Office Unified Model (UM) and the European Centre for Medium-Range Weather Forecasting (ECMWF) Integrated Forecasting System (IFS) capture Arctic clouds and their associated interactions with the surface energy balance and the thermodynamic structure of the lower troposphere. This evaluation was conducted using a 4-week observation period from the Arctic Ocean 2018 expedition, where the transition from sea ice melting to freezing conditions was measured. Three different cloud schemes were tested within a nested limited-area model (LAM) configuration of the UM – two regionally operational single-moment schemes (UM_RA2M and UM_RA2T) and one novel double-moment scheme (UM_CASIM-100) – while one global simulation was conducted with the IFS, utilising its default cloud scheme (ECMWF_IFS).Consistent weaknesses were identified across both models, with both the UM and IFS overestimating cloud occurrence below 3 km. This overestimation was also consistent across the three cloud configurations used within the UM framework, with >90 % mean cloud occurrence simulated between 0.15 and 1 km in all the model simulations. However, the cloud microphysical structure, on average, was modelled reasonably well in each simulation, with the cloud liquid water content (LWC) and ice water content (IWC) comparing well with observations over much of the vertical profile. The key microphysical discrepancy between the models and observations was in the LWC between 1 and 3 km, where most simulations (all except UM_RA2T) overestimated the observed LWC.Despite this reasonable performance in cloud physical structure, both models failed to adequately capture cloud-free episodes: this consistency in cloud cover likely contributes to the ever-present near-surface temperature bias in every simulation. Both models also consistently exhibited temperature and moisture biases below 3 km, with particularly strong cold biases coinciding with the overabundant modelled cloud layers. These biases are likely due to too much cloud-top radiative cooling from these persistent modelled cloud layers and were consistent across the three UM configurations tested, despite differences in their parameterisations of cloud on a sub-grid scale. Alarmingly, our findings suggest that these biases in the regional model were inherited from the global model, driving a cause–effect relationship between the excessive low-altitude cloudiness and the coincident cold bias. Using representative cloud condensation nuclei concentrations in our double-moment UM configuration while improving cloud microphysical structure does little to alleviate these biases; therefore, no matter how comprehensive we make the cloud physics in the nested LAM configuration used here, its cloud and thermodynamic structure will continue to be overwhelmingly biased by the meteorological conditions of its driving model.
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