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1.
  • Abe, K., et al. (författare)
  • J-PARC Neutrino Beamline Upgrade Technical Design Report
  • 2019
  • Rapport (refereegranskat)abstract
    • In this document, technical details of the upgrade plan of the J-PARC neutrino beamline for the extension of the T2K experiment are described. T2K has proposed to accumulate data corresponding to 2×1022 protons-on-target in the next decade, aiming at an initial observation of CP violation with 3σ or higher significance in the case of maximal CP violation. Methods to increase the neutrino beam intensity, which are necessary to achieve the proposed data increase, are described.
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  • Blunden, Jessica, et al. (författare)
  • State of the Climate in 2012
  • 2013
  • Ingår i: Bulletin of The American Meteorological Society - (BAMS). - 0003-0007 .- 1520-0477. ; 94:8, s. S1-S258
  • Tidskriftsartikel (refereegranskat)abstract
    • For the first time in serveral years, the El Nino-Southern Oscillation did not dominate regional climate conditions around the globe. A weak La Ni a dissipated to ENSOneutral conditions by spring, and while El Nino appeared to be emerging during summer, this phase never fully developed as sea surface temperatures in the eastern conditions. Nevertheless, other large-scale climate patterns and extreme weather events impacted various regions during the year. A negative phase of the Arctic Oscillation from mid-January to early February contributed to frigid conditions in parts of northern Africa, eastern Europe, and western Asia. A lack of rain during the 2012 wet season led to the worst drought in at least the past three decades for northeastern Brazil. Central North America also experienced one of its most severe droughts on record. The Caribbean observed a very wet dry season and it was the Sahel's wettest rainy season in 50 years. Overall, the 2012 average temperature across global land and ocean surfaces ranked among the 10 warmest years on record. The global land surface temperature alone was also among the 10 warmest on record. In the upper atmosphere, the average stratospheric temperature was record or near-record cold, depending on the dataset. After a 30-year warming trend from 1970 to 1999 for global sea surface temperatures, the period 2000-12 had little further trend. This may be linked to the prevalence of La Ni a-like conditions during the 21st century. Heat content in the upper 700 m of the ocean remained near record high levels in 2012. Net increases from 2011 to 2012 were observed at 700-m to 2000-m depth and even in the abyssal ocean below. Following sharp decreases in to the effects of La Ni a, sea levels rebounded to reach records highs in 2012. The increased hydrological cycle seen in recent years continued, with more evaporation in drier locations and more precipitation in rainy areas. In a pattern that has held since 2004, salty areas of the ocean surfaces and subsurfaces were anomalously salty on average, while fresher areas were anomalously fresh. Global tropical cyclone activity during 2012 was near average, with a total of 84 storms compared with the 1981-2010 average of 89. Similar to 2010 and 2011, the North Atlantic was the only hurricane basin that experienced above-normal activity. In this basin, Sandy brought devastation to Cuba and parts of the eastern North American seaboard. All other basins experienced either near-or below-normal tropical cyclone activity. Only three tropical cyclones reached Category 5 intensity-all in Bopha became the only storm in the historical record to produce winds greater than 130 kt south of 7 N. It was also the costliest storm to affect the Philippines and killed more than 1000 residents. Minimum Arctic sea ice extent in September and Northern Hemisphere snow cover extent in June both reached new record lows. June snow cover extent is now declining at a faster rate (-17.6% per decade) than September sea ice extent (-13.0% per decade). Permafrost temperatures reached record high values in northernmost Alaska. A new melt extent record occurred on 11-12 July on the Greenland ice sheet; 97% of the ice sheet showed some form of melt, four times greater than the average melt for this time of year. The climate in Antarctica was relatively stable overall. The largest maximum sea ice extent since records begain in 1978 was observed in September 2012. In the stratosphere, warm air led to the second smallest ozone hole in the past two decades. Even so, the springtime ozone layer above Antarctica likely will not return to its early 1980s state until about 2060. Following a slight decline associated with the global 2 emissions from fossil fuel combustion and cement production reached a record 9.5 +/- 0.5 Pg C in 2011 and a new record of 9.7 +/- 0.5 Pg C is estimated for 2012. Atmospheric CO2 concentrations increased by 2.1 ppm in 2012, to 392.6 ppm. In spring 2012, 2 concentration exceeded 400 ppm at 7 of the 13 Arctic observation sites. Globally, other greenhouse gases including methane and nitrous oxide also continued to rise in concentration and the combined effect now represents a 32% increase in radiative forcing over a 1990 baseline. Concentrations of most ozone depleting substances continued to fall.
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4.
  • Adcox, K, et al. (författare)
  • PHENIX detector overview
  • 2003
  • Ingår i: Nuclear Instruments & Methods in Physics Research. Section A: Accelerators, Spectrometers, Detectors, and Associated Equipment. - 0167-5087. ; 499:2-3, s. 469-479
  • Tidskriftsartikel (refereegranskat)abstract
    • The PHENIX detector is designed to perform a broad study of A-A, p-A, and p-p collisions to investigate nuclear matter under extreme conditions. A wide variety of probes, sensitive to all timescales, are used to study systematic variations with species and energy as well as to measure the spin structure of the nucleon. Designing for the needs of the heavy-ion and polarized-proton programs has produced a detector with unparalleled capabilities. PHENIX measures electron and muon pairs, photons, and hadrons with excellent energy and momentum resolution. The detector consists of a large number of subsystems that are discussed in other papers in this volume. The overall design parameters of the detector are presented. (C) 2002 Elsevier Science B.V. All rights reserved.
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  • Verra, L., et al. (författare)
  • Controlled Growth of the Self-Modulation of a Relativistic Proton Bunch in Plasma
  • 2022
  • Ingår i: Physical Review Accelerators and Beams. - : American Physical Society. - 2469-9888. ; 25:7
  • Tidskriftsartikel (refereegranskat)abstract
    • A long, narrow, relativistic charged particle bunch propagating in plasma is subject to the self -modulation (SM) instability. We show that SM of a proton bunch can be seeded by the wakefields driven by a preceding electron bunch. SM timing reproducibility and control are at the level of a small fraction of the modulation period. With this seeding method, we independently control the amplitude of the seed wakefields with the charge of the electron bunch and the growth rate of SM with the charge of the proton bunch. Seeding leads to larger growth of the wakefields than in the instability case.
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6.
  • Sachdev, P. S., et al. (författare)
  • STROKOG (stroke and cognition consortium): An international consortium to examine the epidemiology, diagnosis, and treatment of neurocognitive disorders in relation to cerebrovascular disease
  • 2017
  • Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 7, s. 11-23
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction The Stroke and Cognition consortium (STROKOG) aims to facilitate a better understanding of the determinants of vascular contributions to cognitive disorders and help improve the diagnosis and treatment of vascular cognitive disorders (VCD). Methods Longitudinal studies with ≥75 participants who had suffered or were at risk of stroke or TIA and which evaluated cognitive function were invited to join STROKOG. The consortium will facilitate projects investigating rates and patterns of cognitive decline, risk factors for VCD, and biomarkers of vascular dementia. Results Currently, STROKOG includes 25 (21 published) studies, with 12,092 participants from five continents. The duration of follow-up ranges from 3months to 21years. Discussion Although data harmonization will be a key challenge, STROKOG is in a unique position to reuse and combine international cohort data and fully explore patient level characteristics and outcomes. STROKOG could potentially transform our understanding of VCD and have a worldwide impact on promoting better vascular cognitive outcomes. © 2016 The Authors
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  • Ovadia, C., et al. (författare)
  • Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis
  • 2021
  • Ingår i: Lancet Gastroenterology & Hepatology. - : Elsevier BV. - 2468-1253. ; 6:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes. Methods In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 mu mol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495. Findings The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67.8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0.7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0.6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1.04, 95% CI 0.35-3.07; p=0.95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0.29, 95% CI 0.04-2.42; p=0.25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1.28, 95% CI 0.86-1.91; p=0.22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0.60, 0.39-0.91; p=0.016). Interpretation Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment. Copyright (C) 2021 The Authors(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
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  • Lyons, A, et al. (författare)
  • Outcomes of etravirine-based antiretroviral treatment in treatment-experienced children and adolescents living with HIV in Europe and Thailand
  • 2022
  • Ingår i: Antiviral therapy. - : SAGE Publications. - 2040-2058 .- 1359-6535. ; 27:3, s. 13596535221092182-
  • Tidskriftsartikel (refereegranskat)abstract
    • Etravirine (ETR) is approved as a component of second or third-line antiretroviral treatment (ART) for children living with HIV. We assessed the outcomes of ETR-based ART in children in routine care in Europe and Thailand. Methods Data on children aged <18 years at ETR start were pooled from 17 observational cohorts. Characteristics at ETR start, immunological and virological outcomes at 12 months, discontinuations, adverse events (AEs) and serious adverse events (SAEs) were described. Follow-up was censored at ETR discontinuation, death or last visit. Results 177 children ever received ETR. At ETR start, median [IQR] age was 15 [12,16] years, CD4 count 480 [287, 713] cells/mm3, 70% had exposure to ≥3 ART classes and 20% had viral load (VL) <50 copies/mL. 95% received ETR in combination with ≥1 potent drug class, mostly protease inhibitor-based regimens. Median time on ETR was 24 [7, 48] months. Amongst those on ETR at 12 months ( n=141), 69% had VL<50 copies/mL. Median CD4 increase since ETR start ( n=83) was 147 [16, 267] cells/mm3. Overall, 81 (46%) discontinued ETR by last follow-up. Median time to discontinuation was 23 [8, 47] months. Common reasons for discontinuation were treatment simplification (19%), treatment failure (16%) and toxicity (12%). Eight children (5%) had AEs causally associated with ETR, all dermatological/hypersensitivity reactions. Two were SAEs, both Stevens–Johnson Syndrome in children on regimens containing ETR and darunavir and were causally related to either drugs; both resolved following ART discontinuation. Conclusion Children receiving ETR were predominantly highly treatment-experienced, over two-thirds were virally suppressed at 12 months.
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11.
  • Ovadia, C., et al. (författare)
  • Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses
  • 2019
  • Ingår i: The Lancet. - : Elsevier BV. - 0140-6736. ; 393:10174, s. 899-909
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcomes, but the association with the concentration of specific biochemical markers is unclear. We aimed to quantify the adverse perinatal effects of intrahepatic cholestasis of pregnancy in women with increased serum bile acid concentrations and determine whether elevated bile acid concentrations were associated with the risk of stillbirth and preterm birth. Methods We did a systematic review by searching PubMed, Web of Science, and Embase databases for studies published from database inception to June 1, 2018, reporting perinatal outcomes for women with intrahepatic cholestasis of pregnancy when serum bile acid concentrations were available. Inclusion criteria were studies defining intrahepatic cholestasis of pregnancy based upon pruritus and elevated serum bile acid concentrations, with or without raised liver aminotransferase concentrations. Eligible studies were case-control, cohort, and population-based studies, and randomised controlled trials, with at least 30 participants, and that reported bile acid concentrations and perinatal outcomes. Studies at potential higher risk of reporter bias were excluded, including case reports, studies not comprising cohorts, or successive cases seen in a unit; we also excluded studies with high risk of bias from groups selected (eg, a subgroup of babies with poor outcomes were explicitly excluded), conference abstracts, and Letters to the Editor without clear peer review. We also included unpublished data from two UK hospitals. We did a random effects meta-analysis to determine risk of adverse perinatal outcomes. Aggregate data for maternal and perinatal outcomes were extracted from case-control studies, and individual patient data (IPD) were requested from study authors for all types of study (as no control group was required for the IPD analysis) to assess associations between biochemical markers and adverse outcomes using logistic and stepwise logistic regression. This study is registered with PROSPERO, number CRD42017069134. Findings We assessed 109 full-text articles, of which 23 studies were eligible for the aggregate data meta-analysis (5557 intrahepatic cholestasis of pregnancy cases and 165 136 controls), and 27 provided IPD (5269 intrahepatic cholestasis of pregnancy cases). Stillbirth occurred in 45 (0.83%) of 4936 intrahepatic cholestasis of pregnancy cases and 519 (0.32%) of 163 947 control pregnancies (odds ratio [OR] 1.46 [95% CI 0.73-2.89]; I-2 = 59.8%). In singleton pregnancies, stillbirth was associated with maximum total bile acid concentration (area under the receiver operating characteristic curve [ROC AUC]) 0.83 [95% CI 0.74-0.92]), but not alanine aminotransferase (ROC AUC 0.46 [0.35-0.57]). For singleton pregnancies, the prevalence of stillbirth was three (0.13%; 95% CI 0.02-0.38) of 2310 intrahepatic cholestasis of pregnancy cases in women with serum total bile acids of less than 40 mu mol/L versus four (0.28%; 0.08-0.72) of 1412 cases with total bile acids of 40-99 mu mol/L (hazard ratio [HR] 2.35 [95% CI 0.52-10.50]; p=0.26), and versus 18 (3.44%; 2.05-5.37) of 524 cases for bile acids of 100 mu mol/L or more (HR 30.50 [8.83-105.30]; p<0.0001). Interpretation The risk of stillbirth is increased in women with intrahepatic cholestasis of pregnancy and singleton pregnancies when serum bile acids concentrations are of 100 mu mol/L or more. Because most women with intrahepatic cholestasis of pregnancy have bile acids below this concentration, they can probably be reassured that the risk of stillbirth is similar to that of pregnant women in the general population, provided repeat bile acid testing is done until delivery. Funding Tommy's, ICP Support, UK National Institute of Health Research, Wellcome Trust, and Genesis Research Trust. Copyright (c) 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
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  • Abu-Hayyeh, S., et al. (författare)
  • Prognostic and Mechanistic Potential of Progesterone Sulfates in Intrahepatic Cholestasis of Pregnancy and Pruritus Gravidarum
  • 2016
  • Ingår i: Hepatology. - : Ovid Technologies (Wolters Kluwer Health). - 0270-9139 .- 1527-3350. ; 63:4, s. 1287-1298
  • Tidskriftsartikel (refereegranskat)abstract
    • A challenge in obstetrics is to distinguish pathological symptoms from those associated with normal changes of pregnancy, typified by the need to differentiate whether gestational pruritus of the skin is an early symptom of intrahepatic cholestasis of pregnancy (ICP) or due to benign pruritus gravidarum. ICP is characterized by raised serum bile acids and complicated by spontaneous preterm labor and stillbirth. A biomarker for ICP would be invaluable for early diagnosis and treatment and to enable its differentiation from other maternal diseases. Three progesterone sulfate compounds, whose concentrations have not previously been studied, were newly synthesized and assayed in the serum of three groups of ICP patients and found to be significantly higher in ICP at 9-15 weeks of gestation and prior to symptom onset (group 1 cases/samples: ICP n = 35/80, uncomplicated pregnancy = 29/100), demonstrating that all three progesterone sulfates are prognostic for ICP. Concentrations of progesterone sulfates were associated with itch severity and, in combination with autotaxin, distinguished pregnant women with itch that would subsequently develop ICP from pruritus gravidarum (group 2: ICP n = 41, pruritus gravidarum n = 14). In a third group of first-trimester samples all progesterone sulfates were significantly elevated in serum from low-risk asymptomatic women who subsequently developed ICP (ICP/uncomplicated pregnancy n = 54/51). Finally, we show mechanistically that progesterone sulfates mediate itch by evoking a Tgr5-dependent scratch response in mice. Conclusion: Our discovery that sulfated progesterone metabolites are a prognostic indicator for ICP will help predict onset of ICP and distinguish it from benign pruritus gravidarum, enabling targeted obstetric care to a high-risk population. Delineation of a progesterone sulfate-TGR5 pruritus axis identifies a therapeutic target for itch management in ICP.
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  • Luo, Yiqi, et al. (författare)
  • Toward more realistic projections of soil carbon dynamics by Earth system models
  • 2016
  • Ingår i: Global Biogeochemical Cycles. - 0886-6236. ; 30:1, s. 40-56
  • Tidskriftsartikel (refereegranskat)abstract
    • Soil carbon (C) is a critical component of Earth system models (ESMs), and its diverse representations are a major source of the large spread across models in the terrestrial C sink from the third to fifth assessment reports of the Intergovernmental Panel on Climate Change (IPCC). Improving soil C projections is of a high priority for Earth system modeling in the future IPCC and other assessments. To achieve this goal, we suggest that (1) model structures should reflect real-world processes, (2) parameters should be calibrated to match model outputs with observations, and (3) external forcing variables should accurately prescribe the environmental conditions that soils experience. First, most soil C cycle models simulate C input from litter production and C release through decomposition. The latter process has traditionally been represented by first-order decay functions, regulated primarily by temperature, moisture, litter quality, and soil texture. While this formulation well captures macroscopic soil organic C (SOC) dynamics, better understanding is needed of their underlying mechanisms as related to microbial processes, depth-dependent environmental controls, and other processes that strongly affect soil C dynamics. Second, incomplete use of observations in model parameterization is a major cause of bias in soil C projections from ESMs. Optimal parameter calibration with both pool- and flux-based data sets through data assimilation is among the highest priorities for near-term research to reduce biases among ESMs. Third, external variables are represented inconsistently among ESMs, leading to differences in modeled soil C dynamics. We recommend the implementation of traceability analyses to identify how external variables and model parameterizations influence SOC dynamics in different ESMs. Overall, projections of the terrestrial C sink can be substantially improved when reliable data sets are available to select the most representative model structure, constrain parameters, and prescribe forcing fields.
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  • Thompson, Robin N., et al. (författare)
  • Key questions for modelling COVID-19 exit strategies
  • 2020
  • Ingår i: Proceedings of the Royal Society of London. Biological Sciences. - : The Royal Society. - 0962-8452 .- 1471-2954. ; 287:1932
  • Tidskriftsartikel (refereegranskat)abstract
    • Combinations of intense non-pharmaceutical interventions (lockdowns) were introduced worldwide to reduce SARS-CoV-2 transmission. Many governments have begun to implement exit strategies that relax restrictions while attempting to control the risk of a surge in cases. Mathematical modelling has played a central role in guiding interventions, but the challenge of designing optimal exit strategies in the face of ongoing transmission is unprecedented. Here, we report discussions from the Isaac Newton Institute 'Models for an exit strategy' workshop (11-15 May 2020). A diverse community of modellers who are providing evidence to governments worldwide were asked to identify the main questions that, if answered, would allow for more accurate predictions of the effects of different exit strategies. Based on these questions, we propose a roadmap to facilitate the development of reliable models to guide exit strategies. This roadmap requires a global collaborative effort from the scientific community and policymakers, and has three parts: (i) improve estimation of key epidemiological parameters; (ii) understand sources of heterogeneity in populations; and (iii) focus on requirements for data collection, particularly in low-to-middle-income countries. This will provide important information for planning exit strategies that balance socio-economic benefits with public health.
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  • Zeng, Z. Z., et al. (författare)
  • A reversal in global terrestrial stilling and its implications for wind energy production
  • 2019
  • Ingår i: Nature Climate Change. - : Springer Science and Business Media LLC. - 1758-678X .- 1758-6798. ; 9:12, s. 979-985
  • Tidskriftsartikel (refereegranskat)abstract
    • Wind power, a rapidly growing alternative energy source, has been threatened by reductions in global average surface wind speed, which have been occurring over land since the 1980s, a phenomenon known as global terrestrial stilling. Here, we use wind data from in situ stations worldwide to show that the stilling reversed around 2010 and that global wind speeds over land have recovered. We illustrate that decadal-scale variations of near-surface wind are probably determined by internal decadal ocean-atmosphere oscillations, rather than by vegetation growth and/or urbanization as hypothesized previously. The strengthening has increased potential wind energy by 17 +/- 2% for 2010 to 2017, boosting the US wind power capacity factor by similar to 2.5% and explains half the increase in the US wind capacity factor since 2010. In the longer term, the use of ocean-atmosphere oscillations to anticipate future wind speeds could allow optimization of turbines for expected speeds during their productive life spans.
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21.
  • Zhou, Jinyuan, et al. (författare)
  • Review and consensus recommendations on clinical APT-weighted imaging approaches at 3T : Application to brain tumors
  • 2022
  • Ingår i: Magnetic Resonance in Medicine. - : Wiley. - 1522-2594 .- 0740-3194. ; 88:2, s. 546-574
  • Tidskriftsartikel (refereegranskat)abstract
    • Amide proton transfer-weighted (APTw) MR imaging shows promise as a biomarker of brain tumor status. Currently used APTw MRI pulse sequences and protocols vary substantially among different institutes, and there are no agreed-on standards in the imaging community. Therefore, the results acquired from different research centers are difficult to compare, which hampers uniform clinical application and interpretation. This paper reviews current clinical APTw imaging approaches and provides a rationale for optimized APTw brain tumor imaging at 3 T, including specific recommendations for pulse sequences, acquisition protocols, and data processing methods. We expect that these consensus recommendations will become the first broadly accepted guidelines for APTw imaging of brain tumors on 3 T MRI systems from different vendors. This will allow more medical centers to use the same or comparable APTw MRI techniques for the detection, characterization, and monitoring of brain tumors, enabling multi-center trials in larger patient cohorts and, ultimately, routine clinical use.
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22.
  • Boger, E., et al. (författare)
  • Systems Pharmacology Approach for Prediction of Pulmonary and Systemic Pharmacokinetics and Receptor Occupancy of Inhaled Drugs
  • 2016
  • Ingår i: CPT. - : Wiley. - 2163-8306. ; 5:4, s. 201-210
  • Tidskriftsartikel (refereegranskat)abstract
    • Pulmonary drug disposition after inhalation is complex involving mechanisms, such as regional drug deposition, dissolution, and mucociliary clearance. This study aimed to develop a systems pharmacology approach to mechanistically describe lung disposition in rats and thereby provide an integrated understanding of the system. When drug-and formulation-specific properties for the poorly soluble drug fluticasone propionate were fed into the model, it proved predictive of the pharmacokinetics and receptor occupancy after intravenous administration and nose-only inhalation. As the model clearly distinguishes among drug-specific, formulation-specific, and system-specific properties, it was possible to identify key determinants of pulmonary selectivity of receptor occupancy of inhaled drugs: slow particle dissolution and slow drug-receptor dissociation. Hence, it enables assessment of factors for lung targeting, including molecular properties, formulation, as well as the physiology of the animal species, thereby providing a general framework for rational drug design and facilitated translation of lung targeting from animal to man.
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23.
  • Fuselier, S. A., et al. (författare)
  • High-density O+ in Earth's outer magnetosphere and its effect on dayside magnetopause magnetic reconnection
  • 2019
  • Ingår i: Journal of Geophysical Research - Space Physics. - : AMER GEOPHYSICAL UNION. - 2169-9380 .- 2169-9402. ; 124:12, s. 10257-10269
  • Tidskriftsartikel (refereegranskat)abstract
    • The warm plasma cloak is a source of magnetospheric plasma that contain significant O+. When the O+ density in the magnetosphere near the magnetopause is >0.2 cm(-3) and the H+ density is <1.5 cm(-3), then O+ dominates the magnetospheric ion mass density by more than a factor of 2. A survey is conducted of such O+-rich warm plasma cloak intervals and their effect on reconnection at the Earth's magnetopause. The survey uses data from the Magnetospheric Multiscale mission (MMS) and the results are compared and combined with a previous survey of the warm plasma cloak. Overall, the warm plasma cloak and the O+-rich warm plasma cloak reduce the magnetopause reconnection rate by >20% due to mass-loading only about 2% to 4% of the time. However, during geomagnetic storms, O+ dominates the mass density of the warm plasma cloak and these mass densities are very high. Therefore, a separate study is conducted to determine the effect of the warm plasma cloak on magnetopause reconnection during geomagnetically disturbed times. This study shows that the warm plasma cloak reduces the reconnection rate significantly about 25% of the time during disturbed conditions.
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24.
  • Fuselier, S. A., et al. (författare)
  • Mass Loading the Earth's Dayside Magnetopause Boundary Layer and Its Effect on Magnetic Reconnection
  • 2019
  • Ingår i: Geophysical Research Letters. - : AMER GEOPHYSICAL UNION. - 0094-8276 .- 1944-8007. ; 46:12, s. 6204-6213
  • Tidskriftsartikel (refereegranskat)abstract
    • When the interplanetary magnetic field is northward for a period of time, O+ from the high-latitude ionosphere escapes along reconnected magnetic field lines into the dayside magnetopause boundary layer. Dual-lobe reconnection closes these field lines, which traps O+ and mass loads the boundary layer. This O+ is an additional source of magnetospheric plasma that interacts with magnetosheath plasma through magnetic reconnection. This mass loading and interaction is illustrated through analysis of a magnetopause crossing by the Magnetospheric Multiscale spacecraft. While in the O+-rich boundary layer, the interplanetary magnetic field turns southward. As the Magnetospheric Multiscale spacecraft cross the high-shear magnetopause, reconnection signatures are observed. While the reconnection rate is likely reduced by the mass loading, reconnection is not suppressed at the magnetopause. The high-latitude dayside ionosphere is therefore a source of magnetospheric ions that contributes often to transient reduction in the reconnection rate at the dayside magnetopause.
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25.
  • Gore, Andrea C., et al. (författare)
  • EDC-2 : The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals
  • 2015
  • Ingår i: Endocrine reviews. - : Oxford University Press. - 0163-769X .- 1945-7189. ; 36:6, s. E1-E150
  • Forskningsöversikt (refereegranskat)abstract
    • The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community about how environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, and epigenetic changes, thereby producing effects in exposed individuals as well as their descendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in a range that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings can be much better translated to human health. Armed with this information, researchers, physicians, and other healthcare providers can guide regulators and policymakers as they make responsible decisions.
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26.
  • Gore, Andrea C., et al. (författare)
  • Executive Summary to EDC-2 : The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals
  • 2015
  • Ingår i: Endocrine reviews. - : Oxford University Press. - 0163-769X .- 1945-7189. ; 36:6, s. 593-602
  • Forskningsöversikt (refereegranskat)abstract
    • This Executive Summary to the Endocrine Society's second Scientific Statement on environmental endocrine-disrupting chemicals (EDCs) provides a synthesis of the key points of the complete statement. The full Scientific Statement represents a comprehensive review of the literature on seven topics for which there is strong mechanistic, experimental, animal, and epidemiological evidence for endocrine disruption, namely: obesity and diabetes, female reproduction, male reproduction, hormone-sensitive cancers in females, prostate cancer, thyroid, and neurodevelopment and neuroendocrine systems. EDCs such as bisphenol A, phthalates, pesticides, persistent organic pollutants such as polychlorinated biphenyls, polybrominated diethyl ethers, and dioxins were emphasized because these chemicals had the greatest depth and breadth of available information. The Statement also included thorough coverage of studies of developmental exposures to EDCs, especially in the fetus and infant, because these are critical life stages during which perturbations of hormones can increase the probability of a disease or dysfunction later in life. A conclusion of the Statement is that publications over the past 5 years have led to a much fuller understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability. These findings will prove useful to researchers, physicians, and other healthcare providers in translating the science of endocrine disruption to improved public health.
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27.
  • Haaland, S., et al. (författare)
  • Estimation of cold plasma outflow during geomagnetic storms
  • 2015
  • Ingår i: Journal of Geophysical Research - Space Physics. - 2169-9380 .- 2169-9402. ; 120:12, s. 10622-10639
  • Tidskriftsartikel (refereegranskat)abstract
    • Low-energy ions of ionospheric origin constitute a significant contributor to the magnetospheric plasma population. Measuring cold ions is difficult though. Observations have to be done at sufficiently high altitudes and typically in regions of space where spacecraft attain a positive charge due to solar illumination. Cold ions are therefore shielded from the satellite particle detectors. Furthermore, spacecraft can only cover key regions of ion outflow during segments of their orbit, so additional complications arise if continuous longtime observations, such as during a geomagnetic storm, are needed. In this paper we suggest a new approach, based on a combination of synoptic observations and a novel technique to estimate the flux and total outflow during the various phases of geomagnetic storms. Our results indicate large variations in both outflow rates and transport throughout the storm. Prior to the storm main phase, outflow rates are moderate, and the cold ions are mainly emanating from moderately sized polar cap regions. Throughout the main phase of the storm, outflow rates increase and the polar cap source regions expand. Furthermore, faster transport, resulting from enhanced convection, leads to a much larger supply of cold ions to the near-Earth region during geomagnetic storms.
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28.
  • Kretzschmar, A., et al. (författare)
  • Reversing hydrology : quantifying the temporal aggregation effect of catchment rainfall estimation using sub-hourly data
  • 2016
  • Ingår i: HYDROLOGY RESEARCH. - : IWA Publishing. - 1998-9563 .- 0029-1277 .- 2224-7955. ; 47:3, s. 630-645
  • Tidskriftsartikel (refereegranskat)abstract
    • Inferred rainfall sequences generated by a novel method of inverting a continuous time transfer function show a smoothed profile when compared to the observed rainfall, however, streamflow generated using the inferred catchment rainfall is almost identical to observed streamflow (R-t(2) > 97%). This paper compares the effective rainfall inferred by the regularised inversion process (termed inferred effective rainfall (IER)) proposed by the authors with effective rainfall derived from the observed catchment rainfall (termed observed effective rainfall (OER)) in both time and frequency domains in order to confirm that, by using the dominant catchment dynamics in the inversion process, the main characteristics of catchment rainfall are being captured by the IER estimates. Estimates of the resolution of the IER are found in the time domain by comparison with aggregated sequences of OER, and in the frequency domain by comparing the amplitude spectra of observed and IER. The temporal resolution of the rainfall estimates is affected by the slow time constant of the catchment, reflecting the presence of slow hydrological pathways, for example, aquifers, and by the rainfall regime, for example, dominance of convective or frontal rainfall. It is also affected by the goodness-of-fit of the original forward rainfall-streamflow model.
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29.
  • Li, Yu-Xuan, et al. (författare)
  • Quantification of Cold-Ion Beams in a Magnetic Reconnection Jet
  • 2021
  • Ingår i: Frontiers in Astronomy and Space Sciences. - : Frontiers Media S.A.. - 2296-987X. ; 8
  • Tidskriftsartikel (refereegranskat)abstract
    • Cold (few eV) ions of ionospheric origin are widely observed in the lobe region of Earth's magnetotail and can enter the ion jet region after magnetic reconnection is triggered in the magnetotail. Here, we investigate a magnetotail crossing with cold ions in one tailward and two earthward ion jets observed by the Magnetospheric Multiscale (MMS) constellation of spacecraft. Cold ions co-existing with hot plasma-sheet ions form types of ion velocity distribution functions (VDFs) in the three jets. In one earthward jet, MMS observe cold-ion beams with large velocities parallel to the magnetic fields, and we perform quantitative analysis on the ion VDFs in this jet. The cold ions, together with the hot ions, are reconnection outflow ions and are a minor population in terms of number density inside this jet. The average bulk speed of the cold-ion beams is approximately 38% larger than that of the hot plasma-sheet ions. The cold-ion beams inside the explored jet are about one order of magnitude colder than the hot plasma-sheet ions. These cold-ion beams could be accelerated by the Hall electric field in the cold ion diffusion region and the shrinking magnetic field lines through the Fermi effect.
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30.
  • Ma, Y., et al. (författare)
  • Measurement batch differences and between-batch conversion of Alzheimer's disease cerebrospinal fluid biomarker values
  • 2021
  • Ingår i: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. - : Wiley. - 2352-8729. ; 13:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction Batch differences in cerebrospinal fluid (CSF) biomarker measurement can introduce bias into analyses for Alzheimer's disease studies. We evaluated and adjusted for batch differences using statistical methods. Methods A total of 792 CSF samples from 528 participants were assayed in three batches for 12 biomarkers and 3 biomarker ratios. Batch differences were assessed using Bland-Altman plot, paired t test, Pitman-Morgan test, and linear regression. Generalized linear models were applied to convert CSF values between batches. Results We found statistically significant batch differences for all biomarkers and ratios, except that neurofilament light was comparable between batches 1 and 2. The conversion models generally had high R-2 except for converting P-tau between batches 1 and 3. Discussion Between-batch conversion allows harmonized CSF values to be used in the same analysis. Such method may be applied to adjust for other sources of variability in measuring CSF or other types of biomarkers.
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31.
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32.
  • Saller, T., et al. (författare)
  • A case series on the value of tau and neurofilament protein levels to predict and detect delirium in cardiac surgery patients
  • 2019
  • Ingår i: Biomedical Papers-Olomouc. - : Palacky University Olomouc. - 1213-8118 .- 1804-7521. ; 163:3, s. 241-246
  • Tidskriftsartikel (refereegranskat)abstract
    • Background. Delirium following cardiac surgery is a relevant complication in the majority of elderly patients but its prediction is challenging. Cardiopulmonary bypass, essential for many interventions in cardiac surgery, is responsible for a severe inflammatory response leading to neuroinflammation and subsequent delirium. Neurofilament light protein (NfL) and tau protein (tau) are specific biomarkers to detect neuroaxonal injury as well as glial fibrillary acidic protein (GFAP), a marker of astrocytic activation. Methods. We thought to examine the perioperative course of these markers in a case series of each three cardiac surgery patients under off-pump cardiac arterial bypass without evolving delirium (OPCAB-NDEL), patients with a procedure under cardio-pulmonary bypass (CPB) without delirium (CPB-NDEL) and delirium after a CPB procedure (CPB-DEL). Delirium was diagnosed by the Confusion Assessment Method for the ICU and chart reviews. Results. We observed increased preoperative levels of tau in patients with later delirium, whereas values of NfL and GFAP did not differ. In the postoperative course, all biomarkers increased multi-fold. NfL levels sharply increased in patients with CPB reaching the highest levels in the CPB-DEL group. Conclusion. Tau and NfL might be of benefit to identify patients in cardiac surgery at risk for delirium and to detect patients with the postoperative emergence of delirium.
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33.
  • Schalekamp-Timmermans, Sarah, et al. (författare)
  • Fetal sex-specific differences in gestational age at delivery in pre-eclampsia : A meta-analysis
  • 2017
  • Ingår i: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 46:2, s. 632-642
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Pre-eclampsia (PE) is a major pregnancy disorder complicating up to 8% of pregnancies. Increasing evidence indicates a sex-specific interplay between the mother, placenta and fetus. This may lead to different adaptive mechanisms during pregnancy. Methods: We performed an individual participant data meta-analysis to determine associations of fetal sex and PE, with specific focus on gestational age at delivery in PE. This was done on 219 575 independent live-born singleton pregnancies, with a gestational age at birth between 22.0 and 43.0 weeks of gestation, from 11 studies participating in a worldwide consortium of international research groups focusing on pregnancy. Results: Of the women, 9033 (4.1%) experienced PE in their pregnancy and 48.8% of the fetuses were feMale versus 51.2% Male. No differences in the feMale/Male distribution were observed with respect to term PE (delivered > 37 weeks). Preterm PE (delivered < 37 weeks) was slightly more prevalent among pregnancies with a feMale fetus than in pregnancies with a Male fetus [odds ratio (OR) 1.11, 95% confidence interval (CI) 1.02-1.21]. Very preterm PE (delivered < 34 weeks) was even more prevalent among pregnancies with a feMale fetus as compared with pregnancies with a Male fetus (OR 1.36, 95% CI 1.17-1.59). Conclusions: Sexual dimorphic differences in the occurrence of PE exist, with preterm PE being more prevalent among pregnancies with a feMale fetus as compared with pregnancies with a Male fetus and with no differences with respect to term PE.
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34.
  • Shaffer, Carrie L., et al. (författare)
  • Peptidomimetic Small Molecules Disrupt Type IV Secretion System Activity in Diverse Bacterial Pathogens
  • 2016
  • Ingår i: mBio. - 2161-2129 .- 2150-7511. ; 7:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Bacteria utilize complex type IV secretion systems (T4SSs) to translocate diverse effector proteins or DNA into target cells. Despite the importance of T4SSs in bacterial pathogenesis, the mechanism by which these translocation machineries deliver cargo across the bacterial envelope remains poorly understood, and very few studies have investigated the use of synthetic molecules to disrupt T4SS-mediated transport. Here, we describe two synthetic small molecules (C10 and KSK85) that disrupt T4SS-dependent processes in multiple bacterial pathogens. Helicobacter pylori exploits a pilus appendage associated with the cag T4SS to inject an oncogenic effector protein (CagA) and peptidoglycan into gastric epithelial cells. In H. pylori, KSK85 impedes biogenesis of the pilus appendage associated with the cag T4SS, while C10 disrupts cag T4SS activity without perturbing pilus assembly. In addition to the effects in H. pylori, we demonstrate that these compounds disrupt interbacterial DNA transfer by conjugative T4SSs in Escherichia coli and impede vir T4SS-mediated DNA delivery by Agrobacterium tumefaciens in a plant model of infection. Of note, C10 effectively disarmed dissemination of a derepressed IncF plasmid into a recipient bacterial population, thus demonstrating the potential of these compounds in mitigating the spread of antibiotic resistance determinants driven by conjugation. To our knowledge, this study is the first report of synthetic small molecules that impair delivery of both effector protein and DNA cargos by diverse T4SSs. IMPORTANCE Many human and plant pathogens utilize complex nanomachines called type IV secretion systems (T4SSs) to transport proteins and DNA to target cells. In addition to delivery of harmful effector proteins into target cells, T4SSs can disseminate genetic determinants that confer antibiotic resistance among bacterial populations. In this study, we sought to identify compounds that disrupt T4SS-mediated processes. Using the human gastric pathogen H. pylori as a model system, we identified and characterized two small molecules that prevent transfer of an oncogenic effector protein to host cells. We discovered that these small molecules also prevented the spread of antibiotic resistance plasmids in E. coli populations and diminished the transfer of tumor-inducing DNA from the plant pathogen A. tumefaciens to target cells. Thus, these compounds are versatile molecular tools that can be used to study and disarm these important bacterial machines.
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35.
  • Toledo-Redondo, S., et al. (författare)
  • Impacts of Ionospheric Ions on Magnetic Reconnection and Earth's Magnetosphere Dynamics
  • 2021
  • Ingår i: Reviews of geophysics. - : John Wiley & Sons. - 8755-1209 .- 1944-9208. ; 59:3
  • Forskningsöversikt (refereegranskat)abstract
    • Ionospheric ions (mainly H+, He+, and O+) escape from the ionosphere and populate the Earth's magnetosphere. Their thermal energies are usually low when they first escape the ionosphere, typically a few electron volt to tens of electron volt, but they are energized in their journey through the magnetosphere. The ionospheric population is variable, and it makes significant contributions to the magnetospheric mass density in key regions where magnetic reconnection is at work. Solar wind—magnetosphere coupling occurs primarily via magnetic reconnection, a key plasma process that enables transfer of mass and energy into the near-Earth space environment. Reconnection leads to the triggering of magnetospheric storms, auroras, energetic particle precipitation and a host of other magnetospheric phenomena. Several works in the last decades have attempted to statistically quantify the amount of ionospheric plasma supplied to the magnetosphere, including the two key regions where magnetic reconnection occurs: the dayside magnetopause and the magnetotail. Recent in situ observations by the Magnetospheric Multiscale spacecraft and associated modeling have advanced our current understanding of how ionospheric ions alter the magnetic reconnection process, including its onset and efficiency. This article compiles the current understanding of the ionospheric plasma supply to the magnetosphere. It reviews both the quantification of these sources and their effects on the process of magnetic reconnection. It also provides a global description of how the ionospheric ion contribution modifies the way the solar wind couples to the Earth's magnetosphere and how these ions modify the global dynamics of the near-Earth space environment.Plain Language SummaryAbove the neutral atmosphere, space is filled with charged particles, which are tied to the Earth's magnetic field. The particles come from two sources, the solar wind and the Earth's upper atmosphere. Most of the solar wind particles are deflected by the Earth´s magnetic field, but some can penetrate into near-Earth space. The ionized layer of the upper atmosphere is continuously ejecting particles into space, which have low energies and are difficult to measure. We investigate the relative importance of the two charged particle sources for the dynamics of plasma processes in near-Earth space. In particular, we consider the effects of these sources in magnetic reconnection. Magnetic reconnection allows initially separated plasma regions to become magnetically connected and mix, and converts magnetic energy to kinetic energy of charged particles. Magnetic reconnection is the main driver of geomagnetic activity in the near-Earth space, and is responsible for the release of energy that drives a variety of space weather effects. We highlight the fact that plasma from the ionized upper atmosphere contributes a significant part of the density in the key regions where magnetic reconnection is at work, and that this contribution is larger when the geomagnetic activity is high.
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36.
  • Wardlaw, JM, et al. (författare)
  • Protocol for the perfusion and angiography imaging sub-study of the Third International Stroke Trial (IST-3) of alteplase treatment within six-hours of acute ischemic stroke
  • 2015
  • Ingår i: International journal of stroke : official journal of the International Stroke Society. - : SAGE Publications. - 1747-4949. ; 10:6, s. 956-968
  • Tidskriftsartikel (refereegranskat)abstract
    • Intravenous thrombolysis with recombinant tissue Plasminogen Activator improves outcomes in patients treated early after stroke but at the risk of causing intracranial hemorrhage. Restricting recombinant tissue Plasminogen Activator use to patients with evidence of still salvageable tissue, or with definite arterial occlusion, might help reduce risk, increase benefit and identify patients for treatment at late time windows. Aims To determine if perfusion or angiographic imaging with computed tomography or magnetic resonance help identify patients who are more likely to benefit from recombinant tissue Plasminogen Activator in the context of a large multicenter randomized trial of recombinant tissue Plasminogen Activator given within six-hours of onset of acute ischemic stroke, the Third International Stroke Trial. Design Third International Stroke Trial is a prospective multicenter randomized controlled trial testing recombinant tissue Plasminogen Activator (0·9 mg/kg, maximum dose 90 mg) started up to six-hours after onset of acute ischemic stroke, in patients with no clear indication for or contraindication to recombinant tissue Plasminogen Activator. Brain imaging (computed tomography or magnetic resonance) was mandatory pre-randomization to exclude hemorrhage. Scans were read centrally, blinded to treatment and clinical information. In centers where perfusion and/or angiography imaging were used routinely in stroke, these images were also collected centrally, processed and assessed using validated visual scores and computational measures. Study outcomes The primary outcome in Third International Stroke Trial is alive and independent (Oxford Handicap Score 0–2) at 6 months; secondary outcomes are symptomatic and fatal intracranial hemorrhage, early and late death. The perfusion and angiography study additionally will examine interactions between recombinant tissue Plasminogen Activator and clinical outcomes, infarct growth and recanalization in the presence or absence of perfusion lesions and/or arterial occlusion at presentation. The study is registered ISRCTN25765518.
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37.
  • Wheeler, A. J., et al. (författare)
  • Roof cavity dust as an exposure proxy for extreme air pollution events
  • 2020
  • Ingår i: Chemosphere. - : Elsevier BV. - 0045-6535. ; 244
  • Tidskriftsartikel (refereegranskat)abstract
    • Understanding exposure to air pollution during extreme events such as fire emergencies is critical for assessing their potential health impacts. However, air pollution emergencies often affect places without a network of air quality monitoring and characterising exposure retrospectively is methodologically challenging due to the complex behaviour of smoke and other air pollutants. Here we test the potential of roof cavity (attic) dust to act as a robust household-level exposure proxy, using a major air pollution event associated with a coal mine fire in the Latrobe Valley, Australia, as an illustrative study. To assess the relationship between roof cavity dust composition and mine fire exposure, we analysed the elemental and polycyclic aromatic hydrocarbon composition of roof cavity dust (<150 mu m) from 39 homes along a gradient of exposure to the mine fire plume. These homes were grouped into 12 zones along this exposure gradient: eight zones across Morwell, where mine fire impacts were greatest, and four in other Latrobe Valley towns at increasing distance from the fire. We identified two elements-barium and magnesium-as 'chemical markers' that show a clear and theoretically grounded relationship with the brown coal mine fire plume exposure. This relationship is robust to the influence of plausible confounders and contrasts with other, non-mine fire related elements, which showed distinct and varied distributional patterns. We conclude that targeted components of roof cavity dust can be a useful empirical marker of household exposure to severe air pollution events and their use could support epidemiological studies by providing spatially-resolved exposure estimates post-event. (C) 2019 Elsevier Ltd. All rights reserved.
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38.
  • Zhang, G. F., et al. (författare)
  • Rapid urbanization induced daily maximum wind speed decline in metropolitan areas: A case study in the Yangtze River Delta (China)
  • 2022
  • Ingår i: Urban Climate. - : Elsevier BV. - 2212-0955. ; 43
  • Tidskriftsartikel (refereegranskat)abstract
    • Wind extremes cause many environmental and natural hazard related problems globally, particularly in heavily populated metropolitan areas. However, the underlying causes of maximum wind speed variability in urbanized regions remain largely unknown. Here, we investigated how rapid urbanization in the Yangtze River Delta (YRD), China, impacted daily maximum wind speed (DMWS) between 1990 and 2015, based on near-surface (10 m height) DMWS observations, reanalysis datasets, and night-time lighting data (a proxy for urbanization). The station observation shows that annual DMWS in the YRD significantly (p < 0.05) declined during 1990-2015, by -0.209 m s(-1) decade(-1), while slightly (p > 0.1) positive trends were found in NCEP-NCAR1 (+0.048 m s(-1) decade(-1)) and ERA5 (+0.027 m s(-1) decade(-1)). An increasing divergence between the reanalysis output and the station observation since 2005 was found, and those stations located in areas with high rates of urbanization show the strongest negative annual DMWS trend, implying the key role of urbanization in weakening DMWS. This finding is supported by sensitivity experiments conducted using a regional climate model (RegCM4) forced with both 1990 and 2015 land-use and land-cover (LULC) data, where the simulated DMWS using the 2015 LULC data was lower than that simulated using the 1990 LULC data.
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39.
  • Alm, Love, et al. (författare)
  • MMS Observations of Multiscale Hall Physics in the Magnetotail
  • 2019
  • Ingår i: Geophysical Research Letters. - : AMER GEOPHYSICAL UNION. - 0094-8276 .- 1944-8007.
  • Tidskriftsartikel (refereegranskat)abstract
    • We present Magnetospheric Multiscale mission (MMS) observations of Hall physics in the magnetotail, which compared to dayside Hall physics is a relatively unexplored topic. The plasma consists of electrons, moderately cold ions (T similar to 1.5 keV) and hot ions (T similar to 20 keV). MMS can differentiate between the cold ion demagnetization region and hot ion demagnetization regions, which suggests that MMS was observing multiscale Hall physics. The observed Hall electric field is compared with a generalized Ohm's law, accounting for multiple ion populations. The cold ion population, despite its relatively high initial temperature, has a significant impact on the Hall electric field. These results show that multiscale Hall physics is relevant over a much larger temperature range than previously observed and is relevant for the whole magnetosphere as well as for other astrophysical plasma.
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40.
  • Andersson, Robert, et al. (författare)
  • Dose-response-time modelling - Second generation turnover model with integral feedback control
  • 2015
  • Ingår i: Proceedings of the 24th Annual meeting of the Population Approach Group in Europe, PAGE2015.
  • Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
    • Objectives: To demonstrate the utility of a dose-response-time (DRT) model using a large preclinical biomarker dataset of nicotinic acid (NiAc) induced changes on free fatty acids (FFA).Methods: Data were collected from studies where different rates, routes, and modes of NiAc provocations on the FFA time course had been tested [1]. All information of the exposure were excluded in order to use a DRT approach. Different models structures, describing the biophase kinetics, were assessed and quantitatively and qualitatively compared. The modeled biophase drug amount was assumed to act as the `driving force`of an inhibitory Imax-model which acted on the turnover of FFA. An integral feedback controller was used to model the slow adaptation process that forces FFA levels back to baseline values under long-term NiAc provocations. Finally, new numerical algorithms were applied, which rely on sensitivity equations to robustly and efficiently compute the gradients of the approximate population likelihood function in mixed-effects modelling [2].Results: The DRT model successfully captured the behaviour of all FFA time courses. The model predicted 90% adaptation within four days of constant-rate infusions of NiAc, using rates that lead to therapeutic concentrations. High consistency of the pharmacodynamic parameters was shown when compared to an exposure-driven study by Tapani et al. [3].Conclusions: The versatility of the DRT approach was shown by successfully fitting a DRT model to all FFA time courses. Different feedback mechanisms were described, using moderator compartments and integral feedback control. The consistency in the pharmacodynamic parameters, when comparing to an exposure-driven approach, demonstrates the utility of DRT analysis in a wider context.References:[1] Ahlström C. Modelling of tolerance and rebound in normal and diseased rats. Dissertation, University of Gothenburg. 2011.[2] Almquist J, Leander J, Jirstrand M. Using sensitivity equations for computing gradients of the FOCE and FOCEI approximations to the population likelihood. J Pharmacokin Pharmacodyn. 2015.[3] Tapani S, Almquist J, Leander J, Ahlström C, Peletier LA, Jirstrand M, Gabrielsson J. Joint feedback analysis modeling of nonesterified fatty acids in obese Zucker rats and normal Sprague-Dawley rats after different routes of administration of nicotinic acid. J Pharm Sci. 2014.
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41.
  • Brochet, Mathieu, et al. (författare)
  • Phosphoinositide metabolism links cGMP-dependent protein kinase G to essential Ca²⁺ signals at key decision points in the life cycle of malaria parasites
  • 2014
  • Ingår i: PLoS biology. - : Public Library of Science. - 1544-9173 .- 1545-7885. ; 12:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Many critical events in the Plasmodium life cycle rely on the controlled release of Ca²⁺ from intracellular stores to activate stage-specific Ca²⁺-dependent protein kinases. Using the motility of Plasmodium berghei ookinetes as a signalling paradigm, we show that the cyclic guanosine monophosphate (cGMP)-dependent protein kinase, PKG, maintains the elevated level of cytosolic Ca²⁺ required for gliding motility. We find that the same PKG-dependent pathway operates upstream of the Ca²⁺ signals that mediate activation of P. berghei gametocytes in the mosquito and egress of Plasmodium falciparum merozoites from infected human erythrocytes. Perturbations of PKG signalling in gliding ookinetes have a marked impact on the phosphoproteome, with a significant enrichment of in vivo regulated sites in multiple pathways including vesicular trafficking and phosphoinositide metabolism. A global analysis of cellular phospholipids demonstrates that in gliding ookinetes PKG controls phosphoinositide biosynthesis, possibly through the subcellular localisation or activity of lipid kinases. Similarly, phosphoinositide metabolism links PKG to egress of P. falciparum merozoites, where inhibition of PKG blocks hydrolysis of phosphatidylinostitol (4,5)-bisphosphate. In the face of an increasing complexity of signalling through multiple Ca²⁺ effectors, PKG emerges as a unifying factor to control multiple cellular Ca²⁺ signals essential for malaria parasite development and transmission.
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42.
  • Edwards, Mark G., et al. (författare)
  • Giving voice to values : A new perspective on ethics in globalised organisational environments
  • 2011
  • Ingår i: Ethical models and applications of globalization. - Hershey, PA : IGI Global. - 9781613503324 - 1613503326 - 9781613503331 ; , s. 160-185
  • Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
    • This chapter presents a multilevel approach to the practical expression of core values and ethical commitments in a globalised world. GVV is an innovative approach to business ethics that offers a way of implementing and expressing ethical values at the micro, meso, and macro levels of social interaction. In this chapter we describe the GVV approach and show how it can be applied both theoretically and practically to the task of expressing our shared values from the personal all the way to the global level of ethical concerns.
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43.
  • Edwards, Mark G., et al. (författare)
  • Voicing possibilities : A performative approach to the theory and practice of ethics in a globalised world
  • 2015
  • Ingår i: Handbook of research on business ethics and corporate responsibilities. - Hershey, PA : IGI Global. - 9781466674776 - 1466674768 - 9781466674769 ; , s. 249-275
  • Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
    • Business ethics is witnessing the emergence of new activity-based, communicative approaches to ethics theory and pedagogy that go beyond the conventional normative-descriptive distinction. The authors call this emergent approach "performative ethics" and recognise it as a fundamentally innovative new orientation towards theorising and teaching ethics. They apply this notion of performative ethics to the topic of sustainability, and illustrate their discussion using "Giving Voice to Values" (GVV). GVV is an innovative approach that focuses on implementing ethical values and how they might be expressed at multiple levels of organisational life. The challenge of intergenerational sustainability requires a multilevel orientation to the practical expression of core values in a globalised world. To illustrate this, the authors present three short case studies and explore them from a GVV perspective. They show how GVV can be applied, both theoretically and practically, to the task of expressing and acting on shared values for developing sustaining and sustainable personal, organisational, and global futures.
  •  
44.
  • Edwards, Mark G., et al. (författare)
  • Voicing possibilities : A performative approach to the theory and practice of ethics in a globalised world
  • 2016
  • Ingår i: Leadership and personnel management. - Hersey, PA : IGI Global. - 9781466696259 - 1466696249 - 9781466696242 ; , s. 1955-1981
  • Bokkapitel (refereegranskat)abstract
    • Business ethics is witnessing the emergence of new activity-based, communicative approaches to ethics theory and pedagogy that go beyond the conventional normative-descriptive distinction. The authors call this emergent approach "performative ethics" and recognise it as a fundamentally innovative new orientation towards theorising and teaching ethics. They apply this notion of performative ethics to the topic of sustainability, and illustrate their discussion using "Giving Voice to Values" (GVV). GVV is an innovative approach that focuses on implementing ethical values and how they might be expressed at multiple levels of organisational life. The challenge of intergenerational sustainability requires a multilevel orientation to the practical expression of core values in a globalised world. To illustrate this, the authors present three short case studies and explore them from a GVV perspective. They show how GVV can be applied, both theoretically and practically, to the task of expressing and acting on shared values for developing sustaining and sustainable personal, organisational, and global futures.
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45.
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46.
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47.
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48.
  • Geenes, V., et al. (författare)
  • The Reversed Feto-Maternal Bile Acid Gradient in Intrahepatic Cholestasis of Pregnancy Is Corrected by Ursodeoxycholic Acid
  • 2014
  • Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder associated with an increased risk of adverse fetal outcomes. It is characterised by raised maternal serum bile acids, which are believed to cause the adverse outcomes. ICP is commonly treated with ursodeoxycholic acid (UDCA). This study aimed to determine the fetal and maternal bile acid profiles in normal and ICP pregnancies, and to examine the effect of UDCA treatment. Matched maternal and umbilical cord serum samples were collected from untreated ICP (n = 18), UDCA-treated ICP (n = 46) and uncomplicated pregnancy (n = 15) cases at the time of delivery. Nineteen individual bile acids were measured using HPLC-MS/MS. Maternal and fetal serum bile acids are significantly raised in ICP compared with normal pregnancy (p = <0.0001 and <0.05, respectively), predominantly due to increased levels of conjugated cholic and chenodeoxycholic acid. There are no differences between the umbilical cord artery and cord vein levels of the major bile acid species. The feto-maternal gradient of bile acids is reversed in ICP. Treatment with UDCA significantly reduces serum bile acids in the maternal compartment (p = <0.0001), thereby reducing the feto-maternal transplacental gradient. UDCA-treatment does not cause a clinically important increase in lithocholic acid (LCA) concentrations. ICP is associated with significant quantitative and qualitative changes in the maternal and fetal bile acid pools. Treatment with UDCA reduces the level of bile acids in both compartments and reverses the qualitative changes. We have not found evidence to support the suggestion that UDCA treatment increases fetal LCA concentrations to deleterious levels.
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49.
  • Manna, L. B., et al. (författare)
  • Enzymatic quantification of total serum bile acids as a monitoring strategy for women with intrahepatic cholestasis of pregnancy receiving ursodeoxycholic acid treatment: a cohort study
  • 2019
  • Ingår i: Bjog-an International Journal of Obstetrics and Gynaecology. - : Wiley. - 1470-0328 .- 1471-0528. ; 126:13, s. 1633-1640
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective To evaluate enzymatic total serum bile acid quantification as a monitoring strategy for women with intrahepatic cholestasis of pregnancy (ICP) treated with ursodeoxycholic acid (UDCA). Design Cohort. Setting One UK university hospital. Population 29 ICP cases treated with UDCA. Methods Serial samples were collected prospectively throughout gestation. Total serum bile acids were measured enzymatically and individual bile acids by high-performance liquid chromatography-tandem mass spectrometry. Data were log-transformed and analysed with random effects generalised least square regression. Main outcome measures The relationship between enzymatic total bile acid measurements and individual bile acid concentrations after UDCA treatment. Results In untreated women, cholic acid was the principal bile acid (51%) and UDCA concentrations were <0.5%, whereas UDCA constituted 60% (IQR 43-69) of serum bile acids following treatment and cholic acid fell to <20%. Changes in the total bile acid measurement reflected similar alterations in the concentrations of the pathologically elevated bile acids, e.g. a two-fold increase in enzymatic total bile acids is accompanied by approximately a two-fold increase in cholic acid and chenodeoxycholic acid at most UDCA doses (P < 0.001). Most of the effects of UDCA on cholic acid occur in the first week of treatment (60% relative reduction, P = 0.025, 95% CI 0.2-0.9, from 10 micromol/l (4.7-17.6) to 3.5 micromol/l (1.4-7.5). Conclusion Ursodeoxycholic acid becomes the main component of the bile acid measurement after treatment. Enzymatic total bile acid assays are good predictors of both cholic acid and chenodeoxycholic acid, the primary bile acids that are raised prior to treatment. Tweetable abstract Ursodeoxycholic acid constitutes approximately 60% of the bile acid measurement and reduces pathological cholic acid in treated women.
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