| 1. |
- Jansen, Willemijn J, et al.
(author)
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Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.
- 2015
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In: JAMA. - : American Medical Association (AMA). - 1538-3598 .- 0098-7484. ; 313:19, s. 1924-38
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Journal article (peer-reviewed)abstract
- Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies.
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| 2. |
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| 3. |
- Grigoriev, Igor, 1984-
(author)
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Turbulence modeling of compressible flows with large density variation
- 2016
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Doctoral thesis (other academic/artistic)abstract
- In this study we highlight the influence of mean dilatation and mean density gradient on the Reynolds stress modeling of compressible, heat-releasing and supercritical turbulent flows.Firstly, the modeling of the rapid pressure-strain correlation has been extended to self-consistently account for the influence of mean dilatation.Secondly, an algebraic model for the turbulent density flux has been developed and coupled to the tensor equationfor Reynolds stress anisotropy via a 'local mean acceleration',a generalization of the buoyancy force.We applied the resulting differential Reynolds stress model (DRSM) and the corresponding explicit algebraic Reynolds stress model (EARSM) to homogeneously sheared and compressed or expanded two-dimensional mean flows. Both formulations have shown that our model preserves the realizability of the turbulence, meaning that the Reynolds stresses do not attain unphysical values, unlike earlier approaches. Comparison with rapid distortion theory (RDT) demonstrated that the DRSM captures the essentials of the transient behaviour of the diagonal anisotropies and gives good predictions of the turbulence kinetic energy.A general three-dimensional solution to the coupled EARSM has been formulated. In the case of turbulent flow in de Laval nozzle we investigated the influence of compressibility effects and demonstrated that the different calibrations lead to different turbulence regimes but with retained realizability. We calibrated our EARSM against a DNS of combustion in a wall-jet flow. Correct predictions of turbulent density fluxes have been achieved and essential features of the anisotropy behaviour have been captured.The proposed calibration keeps the model free of singularities for the cases studied. In addition, we have applied the EARSM to the investigation of supercritical carbon dioxide flow in an annulus. The model correctly captured mean enthalpy, temperature and density as well as the turbulence shear stress. Hence, we consider the model as a useful tool for the analysis of a wide range of compressible flows with large density variation.
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| 4. |
- Jansen, Willemijn J, et al.
(author)
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Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia.
- 2018
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In: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 75:1, s. 84-95
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Journal article (peer-reviewed)abstract
- Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials.To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia.This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017.Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype.Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P=.16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P<.001) and low MMSE (mean difference, 14% [95% CI, 12%-17%], P<.001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years.Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.
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| 5. |
- Jansen, Willemijn J, et al.
(author)
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Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.
- 2022
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In: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 79:3, s. 228-243
-
Journal article (peer-reviewed)abstract
- One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.Alzheimer disease biomarkers detected on PET or in CSF.Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.Among the 19097 participants (mean [SD] age, 69.1 [9.8] years; 10148 women [53.1%]) included, 10139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P=.04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P=.004), subjective cognitive decline (9%; 95% CI, 3%-15%; P=.005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P=.004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P=.18).This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.
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| 6. |
- Mattsson, Niklas, et al.
(author)
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Prevalence of the apolipoprotein E epsilon 4 allele in amyloid beta positive subjects across the spectrum of Alzheimers disease
- 2018
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In: Alzheimer's & Dementia. - : ELSEVIER SCIENCE INC. - 1552-5260 .- 1552-5279. ; 14:7, s. 913-924
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Journal article (peer-reviewed)abstract
- Introduction: Apolipoprotein E (APOE) epsilon 4 is the major genetic risk factor for Alzheimers disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid beta(A beta) pathology. Methods: We included 3451 A beta+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE epsilon 4 prevalence in relation to age, sex, education, and geographical location. Results: The APOE epsilon 4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in A beta+ cognitively normal and A beta+ mild cognitive impairment (P amp;lt;.05) but not in A beta+ AD dementia (P =.66). The prevalence was highest in Northern Europe but did not vary by sex or education. Discussion: The APOE E4 prevalence in AD was higher than that in previous studies, which did not require presence of A beta pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location. (C) 2018 the Alzheimers Association. Published by Elsevier Inc. All rights reserved.
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| 7. |
- Mattsson, Niklas, et al.
(author)
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Prevalence of the apolipoprotein E ε4 allele in amyloid β positive subjects across the spectrum of Alzheimer's disease
- 2018
-
In: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 14:7, s. 913-924
-
Journal article (peer-reviewed)abstract
- Introduction: Apolipoprotein E (APOE) ε4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid β (Aβ) pathology. Methods: We included 3451 Aβ+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE ε4 prevalence in relation to age, sex, education, and geographical location. Results: The APOE ε4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in Aβ+ cognitively normal and Aβ+ mild cognitive impairment (P <.05) but not in Aβ+ AD dementia (P =.66). The prevalence was highest in Northern Europe but did not vary by sex or education. Discussion: The APOE ε4 prevalence in AD was higher than that in previous studies, which did not require presence of Aβ pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location.
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| 8. |
- Vos, Stephanie J. B., et al.
(author)
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Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage
- 2015
-
In: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 138:5, s. 1327-1338
-
Journal article (peer-reviewed)abstract
- Three sets of research criteria are available for diagnosis of Alzheimer's disease in subjects with mild cognitive impairment: the International Working Group-1, International Working Group-2, and National Institute of Aging-Alzheimer Association criteria. We compared the prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage according to these criteria. Subjects with mild cognitive impairment (n = 1607), 766 of whom had both amyloid and neuronal injury markers, were recruited from 13 cohorts. We used cognitive test performance and available biomarkers to classify subjects as prodromal Alzheimer's disease according to International Working Group-1 and International Working Group-2 criteria and in the high Alzheimer's disease likelihood group, conflicting biomarker groups (isolated amyloid pathology or suspected non-Alzheimer pathophysiology), and low Alzheimer's disease likelihood group according to the National Institute of Ageing-Alzheimer Association criteria. Outcome measures were the proportion of subjects with Alzheimer's disease at the mild cognitive impairment stage and progression to Alzheimer's disease-type dementia. We performed survival analyses using Cox proportional hazards models. According to the International Working Group-1 criteria, 850 (53%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 50% compared to 21% for subjects without prodromal Alzheimer's disease. According to the International Working Group-2 criteria, 308 (40%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 61% compared to 22% for subjects without prodromal Alzheimer's disease. According to the National Institute of Ageing-Alzheimer Association criteria, 353 (46%) subjects were in the high Alzheimer's disease likelihood group, 49 (6%) in the isolated amyloid pathology group, 220 (29%) in the suspected non-Alzheimer pathophysiology group, and 144 (19%) in the low Alzheimer's disease likelihood group. The 3-year progression rate to Alzheimer's disease-type dementia was 59% in the high Alzheimer's disease likelihood group, 22% in the isolated amyloid pathology group, 24% in the suspected non-Alzheimer pathophysiology group, and 5% in the low Alzheimer's disease likelihood group. Our findings support the use of the proposed research criteria to identify Alzheimer's disease at the mild cognitive impairment stage. In clinical settings, the use of both amyloid and neuronal injury markers as proposed by the National Institute of Ageing-Alzheimer Association criteria offers the most accurate prognosis. For clinical trials, selection of subjects in the National Institute of Ageing-Alzheimer Association high Alzheimer's disease likelihood group or the International Working Group-2 prodromal Alzheimer's disease group could be considered.
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| 9. |
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| 10. |
- Abbott, Benjamin, et al.
(author)
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Using multi-tracer inference to move beyond single-catchment ecohydrology
- 2016
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In: Earth-Science Reviews. - : Elsevier BV. - 0012-8252 .- 1872-6828. ; 160, s. 19-42
-
Journal article (peer-reviewed)abstract
- Protecting or restoring aquatic ecosystems in the face of growing anthropogenic pressures requires an understanding of hydrological and biogeochemical functioning across multiple spatial and temporal scales. Recent technological and methodological advances have vastly increased the number and diversity of hydrological, biogeochemical, and ecological tracers available, providing potentially powerful tools to improve understanding of fundamental problems in ecohydrology, notably: 1. Identifying spatially explicit flowpaths, 2. Quantifying water residence time, and 3. Quantifying and localizing biogeochemical transformation. In this review, we synthesize the history of hydrological and biogeochemical theory, summarize modem tracer methods, and discuss how improved understanding of flowpath, residence time, and biogeochemical transformation can help ecohydrology move beyond description of site-specific heterogeneity. We focus on using multiple tracers with contrasting characteristics (crossing proxies) to infer ecosystem functioning across multiple scales. Specifically, we present how crossed proxies could test recent ecohydrological theory, combining the concepts of hotspots and hot moments with the Damkohler number in what we call the HotDam framework.
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| 11. |
- Adalbjörnsson, Stefan Ingi, et al.
(author)
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Estimating Periodicities in Symbolic Sequences Using Sparse Modeling
- 2015
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In: IEEE Transactions on Signal Processing. - 1053-587X. ; 63:8, s. 2142-2150
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Journal article (peer-reviewed)abstract
- In this paper, we propose a method for estimating statistical periodicities in symbolic sequences. Different from other common approaches used for the estimation of periodicities of sequences of arbitrary, finite, symbol sets, that often map the symbolic sequence to a numerical representation, we here exploit a likelihood-based formulation in a sparse modeling framework to represent the periodic behavior of the sequence. The resulting criterion includes a restriction on the cardinality of the solution; two approximate solutions are suggested—one greedy and one using an iterative convex relaxation strategy to ease the cardinality restriction. The performance of the proposed methods are illustrated using both simulated and real DNA data, showing a notable performance gain as compared to other common estimators.
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| 12. |
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| 13. |
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| 14. |
- Audet, Joachim, et al.
(author)
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Forest streams are important sources for nitrous oxide emissions - Nitrous oxide emissions from Swedish streams
- 2020
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In: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 26, s. 629-641
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Journal article (peer-reviewed)abstract
- Streams and river networks are increasingly recognized as significant sources for the greenhouse gas nitrous oxide (N2O). N2O is a transformation product of nitrogenous compounds in soil, sediment and water. Agricultural areas are considered a particular hotspot for emissions because of the large input of nitrogen (N) fertilizers applied on arable land. However, there is little information on N2O emissions from forest streams although they constitute a major part of the total stream network globally. Here, we compiled N2O concentration data from low-order streams (~1,000 observations from 172 stream sites) covering a large geographical gradient in Sweden from the temperate to the boreal zone and representing catchments with various degrees of agriculture and forest coverage. Our results showed that agricultural and forest streams had comparable N2O concentrations of 1.6 +/- 2.1 and 1.3 +/- 1.8 mu g N/L, respectively (mean +/- SD) despite higher total N (TN) concentrations in agricultural streams (1,520 +/- 1,640 vs. 780 +/- 600 mu g N/L). Although clear patterns linking N2O concentrations and environmental variables were difficult to discern, the percent saturation of N2O in the streams was positively correlated with stream concentration of TN and negatively correlated with pH. We speculate that the apparent contradiction between lower TN concentration but similar N2O concentrations in forest streams than in agricultural streams is due to the low pH (<6) in forest soils and streams which affects denitrification and yields higher N2O emissions. An estimate of the N2O emission from low-order streams at the national scale revealed that ~1.8 x 10(9) g N2O-N are emitted annually in Sweden, with forest streams contributing about 80% of the total stream emission. Hence, our results provide evidence that forest streams can act as substantial N2O sources in the landscape with 800 x 10(9) g CO2-eq emitted annually in Sweden, equivalent to 25% of the total N2O emissions from the Swedish agricultural sector.
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| 15. |
- Audet, Joachim, et al.
(author)
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Nitrous oxide emissions from streams in a Swedish agricultural catchment
- 2017
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In: Agriculture, Ecosystems & Environment. - : Elsevier BV. - 0167-8809 .- 1873-2305. ; 236, s. 295-303
-
Journal article (peer-reviewed)abstract
- Excess nitrogen fertiliser in agricultural soils might be leached to streams and converted to the greenhouse gas nitrous oxide (N2O). To assess the importance of N2O emissions from agricultural streams, concentration dynamics and emissions N2O emissions in streams were investigated in a 32 km2 lowland agricultural catchment located in Sweden. Dissolved N2O concentration was measured at nine occasions between December 2014 and August 2015 at nine stream stations. The stream stations represented sub-catchments with different land use characteristics with agricultural land use ranging from 0 to 63% of the area. Stream N2O percentage saturation ranged 40-2701% and showed large spatial and temporal variations. Statistical analysis using mixed models revealed that N2O concentration was significantly linked to nitrate concentration in the stream water, to the percentage arable land in the sub catchments as well as to the stream water discharge. Using two empirical equations to estimate the N2O emissions showed that streams were generally a source of N2O to the atmosphere (mean 108 and 175 mu g N m(-2) h(-1) with first and second equation). The catchment scale estimate of N2O stream emissions was compared to the estimate obtained using IPCC guidelines linking N fertilisation inputs and leaching to N2O emissions. The comparison suggested that N2O stream emission calculated using the IPCC methodology might be underestimated. A coarse estimate suggests that N2O stream emissions represent about 4% of the total N2O emissions from N-fertiliser at the catchment scale. Hence while streams covered only 0.1% of the catchment area they were of disproportionate importance as a source of N2O to the atmosphere.
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| 16. |
- Bartesaghi, Stefano, et al.
(author)
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Thermogenic Activity of UCP1 in Human White Fat-Derived Beige Adipocytes.
- 2015
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In: Molecular endocrinology (Baltimore, Md.). - : The Endocrine Society. - 1944-9917 .- 0888-8809. ; 29, s. 130-139
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Journal article (peer-reviewed)abstract
- Heat-producing beige/brite (brown-in-white) adipocytes in white adipose tissue have the potential to suppress metabolic disease in mice and hold great promise for the treatment of obesity and type 2 diabetes in humans. Here, we demonstrate that human adipose-derived stromal/progenitor cells (hASCs) from sc white adipose tissue can be efficiently converted into beige adipocytes. Upon pharmacological activation of PPARγ, hASC-derived adipocytes activated beige fat-selective genes and a brown/beige fat-selective electron transport chain gene program. Importantly, hASC-derived beige fat cells displayed the bioenergetic characteristics of genuine brown fat cells, including a capacity for increased respiratory uncoupling in response to β-adrenergic agonists. Furthermore, knock-down experiments reveal that the thermogenic capacity of human beige fat cells was entirely dependent on the presence of uncoupling protein 1. In summary, this study reveals that hASCs can be readily differentiated into beige adipocytes that, upon activation, undergo uncoupling protein 1-dependent thermogenesis.
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| 17. |
- Baungaard, M., et al.
(author)
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RANS simulation of a wind turbine wake in the neutral atmospheric pressure-driven boundary layer
- 2023
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In: Proceedings 8th Wake Conference 2023. - : IOP Publishing.
-
Conference paper (peer-reviewed)abstract
- Reynolds-averaged Navier-Stokes (RANS) simulations of a single wind turbine wake in the neutral atmospheric pressure-driven boundary layer (PDBL) are conducted and compared to RANS simulations with inflow based on the more traditional log-law. The latter is valid in the neutral atmospheric surface layer (ASL), while the PDBL is a better representation of the whole atmospheric boundary layer (ABL). It is found that the wake results of the two types of simulations become more similar for increasing ABL height to rotor diameter ratio. In fact, the ASL is shown to be a special asymptotic case of the PDBL. The RANS simulations are also compared to a large-eddy simulation (LES) PDBL case, where it is found that both the ASL and PDBL RANS simulations compare well with the reference LES data in the wake region, while the RANS PDBL compares better with the data in the upper region of the domain.
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| 18. |
- Baungaard, Mads, et al.
(author)
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Wind turbine wake simulation with explicit algebraic Reynolds stress modeling
- 2022
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In: Wind Energy Science. - : Copernicus GmbH. - 2366-7443 .- 2366-7451. ; 7:5, s. 1975-2002
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Journal article (peer-reviewed)abstract
- Reynolds-averaged Navier-Stokes (RANS) simulations of wind turbine wakes are usually conducted with two-equation turbulence models based on the Boussinesq hypothesis; these are simple and robust but lack the capability of predicting various turbulence phenomena. Using the explicit algebraic Reynolds stress model (EARSM) of Wallin and Johans son (2000) can alleviate some of these deficiencies while still being numerically robust and only slightly more computationally expensive than the traditional two-equation models. The model implementation is verified with the homogeneous shear flow, half-channel flow, and square duct flow cases, and subsequently full three-dimensional wake simulations are run and analyzed. The results are compared with reference large-eddy simulation (LES) data, which show that the EARSM especially improves the prediction of turbulence anisotropy and turbulence intensity but that it also predicts less Gaussian wake profile shapes.
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| 19. |
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| 20. |
- Bengtsson, Viveca Wallin, et al.
(author)
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Periodontitis related to cardiovascular events and mortality : a long-time longitudinal study
- 2021
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In: Clinical Oral Investigations. - : Springer Science and Business Media Deutschland GmbH. - 1432-6981 .- 1436-3771. ; 25:6, s. 4085-4095
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Journal article (peer-reviewed)abstract
- Objective: The present study assessed if individuals ≥ 60 years of age with periodontitis are more likely to develop stroke or ischemic heart diseases, or at a higher risk of death for 17 years. Material and methods: At baseline individuals ≥ 60 received a dental examination including a panoramic radiograph. Periodontitis was defined as having ≥ 30% sites with ≥ 5-mm distance from the cementoenamel junction to the marginal bone level. Medical records were annually reviewed from 2001 to 2018. Findings from the medical records identifying an ICD-10 code of stroke and ischemic heart diseases or death were registered. Results: Associations between periodontitis and incidence of ischemic heart disease were found in this 17-year follow-up study in all individuals 60–93 years (HR: 1.5, CI: 1.1–2.1, p = 0.017), in women (HR: 2.1, CI: 1.3–3.4, p = 0.002), and in individuals 78–96 years (HR: 1.7, CI: 1.0–2.6, p = 0.033). Periodontitis was associated with mortality in all individuals (HR: 1.4, CI: 1.2–1.8, p = 0.002), specifically in men (HR: 1.5, CI: 1.1–1.9, p = 0.006) or in ages 60–72 years (HR: 2.2, CI: 1.5–3.2, p = 0.000). Periodontitis was more prevalent among men (OR: 1.8, CI: 1.3–2.4, p = 0.000). Conclusions: Individuals with periodontitis have an increased risk for future events of ischemic heart diseases and death. Clinical relevance: Improving periodontal health in older individuals may reduce overall mortality and ischemic heart diseases. Both dental and medical professionals should be aware of the associations and ultimately cooperate. © 2021, The Author(s).
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| 21. |
- Bergström, Anna, et al.
(author)
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Health system context and implementation of evidence-based practices-development and validation of the Context Assessment for Community Health (COACH) tool for low- and middle-income settings
- 2015
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In: Implementation Science. - : Springer Science and Business Media LLC. - 1748-5908. ; 10
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Journal article (peer-reviewed)abstract
- Background: The gap between what is known and what is practiced results in health service users not benefitting from advances in healthcare, and in unnecessary costs. A supportive context is considered a key element for successful implementation of evidence-based practices (EBP). There were no tools available for the systematic mapping of aspects of organizational context influencing the implementation of EBPs in low- and middle-income countries (LMICs). Thus, this project aimed to develop and psychometrically validate a tool for this purpose. Methods: The development of the Context Assessment for Community Health (COACH) tool was premised on the context dimension in the Promoting Action on Research Implementation in Health Services framework, and is a derivative product of the Alberta Context Tool. Its development was undertaken in Bangladesh, Vietnam, Uganda, South Africa and Nicaragua in six phases: (1) defining dimensions and draft tool development, (2) content validity amongst in-country expert panels, (3) content validity amongst international experts, (4) response process validity, (5) translation and (6) evaluation of psychometric properties amongst 690 health workers in the five countries. Results: The tool was validated for use amongst physicians, nurse/midwives and community health workers. The six phases of development resulted in a good fit between the theoretical dimensions of the COACH tool and its psychometric properties. The tool has 49 items measuring eight aspects of context: Resources, Community engagement, Commitment to work, Informal payment, Leadership, Work culture, Monitoring services for action and Sources of knowledge. Conclusions: Aspects of organizational context that were identified as influencing the implementation of EBPs in high-income settings were also found to be relevant in LMICs. However, there were additional aspects of context of relevance in LMICs specifically Resources, Community engagement, Commitment to work and Informal payment. Use of the COACH tool will allow for systematic description of the local healthcare context prior implementing healthcare interventions to allow for tailoring implementation strategies or as part of the evaluation of implementing healthcare interventions and thus allow for deeper insights into the process of implementing EBPs in LMICs.
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| 22. |
- Bergström, Anna, 1983-, et al.
(author)
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Knowledge translation in Uganda : a qualitative study of Ugandan midwives' and managers' perceived relevance of the sub-elements of the context cornerstone in the PARIHS framework
- 2012
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In: Implementation Science. - : BioMed Central (BMC). - 1748-5908. ; 7
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Journal article (peer-reviewed)abstract
- BACKGROUND: A large proportion of the annual 3.3 million neonatal deaths could be averted if there was a high uptake of basic evidence-based practices. In order to overcome this 'know-do' gap, there is an urgent need for in-depth understanding of knowledge translation (KT). A major factor to consider in the successful translation of knowledge into practice is the influence of organizational context. A theoretical framework highlighting this process is Promoting Action on Research Implementation in Health Services (PARIHS). However, research linked to this framework has almost exclusively been conducted in high-income countries. Therefore, the objective of this study was to examine the perceived relevance of the subelements of the organizational context cornerstone of the PARIHS framework, and also whether other factors in the organizational context were perceived to influence KT in a specific low-income setting.METHODS: This qualitative study was conducted in a district of Uganda, where focus group discussions and semi-structured interviews were conducted with midwives (n = 18) and managers (n = 5) within the catchment area of the general hospital. The interview guide was developed based on the context sub-elements in the PARIHS framework (receptive context, culture, leadership, and evaluation). Interviews were transcribed verbatim, followed by directed content analysis of the data.RESULTS: The sub-elements of organizational context in the PARIHS framework--i.e., receptive context, culture, leadership, and evaluation--also appear to be relevant in a low-income setting like Uganda, but there are additional factors to consider. Access to resources, commitment and informal payment, and community involvement were all perceived to play important roles for successful KT.CONCLUSIONS: In further development of the context assessment tool, assessing factors for successful implementation of evidence in low-income settings--resources, community involvement, and commitment and informal payment--should be considered for inclusion. For low-income settings, resources are of significant importance, and might be considered as a separate subelement of the PARIHS framework as a whole.
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| 23. |
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| 24. |
- Bhattacherjee, Arnab, et al.
(author)
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Coupled Folding-Binding in a Hydrophobic/Polar Protein Model: Impact of Synergistic Folding and Disordered Flanks
- 2012
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In: Biophysical Journal. - : Elsevier BV. - 1542-0086 .- 0006-3495. ; 102:3, s. 569-578
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Journal article (peer-reviewed)abstract
- Coupled folding-binding is central to the function of many intrinsically disordered proteins, yet not fully understood. With a continuous three-letter protein model, we explore the free-energy landscape of pairs of interacting sequences and how it is impacted by 1), variations in the binding mechanism; and 2), the addition of disordered flanks to the binding region. In particular, we focus on two sequences, one with 16 and one with 35 amino acids, which make a stable dimeric three-helix bundle at low temperatures. Three distinct binding mechanisms are realized by altering the stabilities of the individual monomers: docking, coupled folding-binding of a single α-helix, and synergistic folding and binding. Compared to docking, the free-energy barrier for binding is reduced when the single α-helix is allowed to fold upon binding, but only marginally. A greater reduction is found for synergistic folding, which in addition results in a binding transition state characterized by very few interchain contacts. Disordered flanking chain segments attached to the α-helix sequence can, despite a negligible impact on the dimer stability, lead to a downhill free-energy surface in which the barrier for binding is eliminated.
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| 25. |
- Bhattacherjee, Arnab, et al.
(author)
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Exploring Protein-Peptide Binding Specificity through Computational Peptide Screening.
- 2013
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In: PLoS Computational Biology. - : Public Library of Science (PLoS). - 1553-7358. ; 9:10
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Journal article (peer-reviewed)abstract
- The binding of short disordered peptide stretches to globular protein domains is important for a wide range of cellular processes, including signal transduction, protein transport, and immune response. The often promiscuous nature of these interactions and the conformational flexibility of the peptide chain, sometimes even when bound, make the binding specificity of this type of protein interaction a challenge to understand. Here we develop and test a Monte Carlo-based procedure for calculating protein-peptide binding thermodynamics for many sequences in a single run. The method explores both peptide sequence and conformational space simultaneously by simulating a joint probability distribution which, in particular, makes searching through peptide sequence space computationally efficient. To test our method, we apply it to 3 different peptide-binding protein domains and test its ability to capture the experimentally determined specificity profiles. Insight into the molecular underpinnings of the observed specificities is obtained by analyzing the peptide conformational ensembles of a large number of binding-competent sequences. We also explore the possibility of using our method to discover new peptide-binding pockets on protein structures.
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| 26. |
- Campeau, Audrey, et al.
(author)
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Multiple sources and sinks of dissolved inorganic carbon across Swedish streams, refocusing the lens of stable C isotopes
- 2017
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
-
Journal article (peer-reviewed)abstract
- It is well established that stream dissolved inorganic carbon (DIC) fluxes play a central role in the global C cycle, yet the sources of stream DIC remain to a large extent unresolved. Here, we explore large-scale patterns in delta C-13-DIC from streams across Sweden to separate and further quantify the sources and sinks of stream DIC. We found that stream DIC is governed by a variety of sources and sinks including biogenic and geogenic sources, CO2 evasion, as well as in-stream processes. Although soil respiration was the main source of DIC across all streams, a geogenic DIC influence was identified in the northernmost region. All streams were affected by various degrees of atmospheric CO2 evasion, but residual variance in delta C-13-DIC also indicated a significant influence of in-stream metabolism and anaerobic processes. Due to those multiple sources and sinks, we emphasize that simply quantifying aquatic DIC fluxes will not be sufficient to characterise their role in the global C cycle.
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| 27. |
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| 28. |
- Cedergren, Stefan, et al.
(author)
-
What is Performance in Complex Product Development?
- 2008
-
In: Proceedings of the R&D Management Conference. 2008.
-
Conference paper (peer-reviewed)abstract
- The process of developing new products is one of the key business processes in a company, especially technology intensive ones. In order to continuously improve this capability of developing new products it is important to be able to measure the performance in the product development process. The dilemma though is that there are no good performance measurements available within complex product development. One reason, as argued in presented research may be the lack of a holistic perception of performance within the development process. Data from a five case explorative study including 49 semi-structured open interviews regarding performance within complex product development is presented and analyzed. The results clearly indicate a need for further development of the perception of performance by managers and decision makers within the process of developing complex products. To meet this need, a Product Development Organizational Performance Model (PDOPM) is proposed, consisting of three generic levels of activities: Product strategy, Project management, and Product activities. These generic activities are modelled in accordance with the IDEF0 making it possible to conceptually reason about uncertainty, effectiveness, and efficiency at each activity level. Further, the term product development efficacy is introduced to describe the capability of identifying or creating a market opportunity and being able to develop and deliver a product fulfilling exactly what was identified as the market opportunity. High performance in product development is achieved when there is efficacy throughout the complete product development portfolio.
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| 29. |
- Chan, Hue Sun, et al.
(author)
-
Cooperativity, Local-Nonlocal Coupling, and Nonnative Interactions: Principles of Protein Folding from Coarse-Grained Models
- 2011
-
In: Annual Review of Physical Chemistry. - : Annual Reviews. - 1545-1593 .- 0066-426X. ; 62, s. 301-326
-
Research review (peer-reviewed)abstract
- Coarse-grained, self-contained polymer models are powerful tools in the study of protein folding. They are also essential to assess predictions from less rigorous theoretical approaches that lack an explicit-chain representation. Here we review advances in coarse-grained modeling of cooperative protein folding, noting in particular that the Levinthal paradox was raised in response to the experimental discovery of two-state-like folding in the late 1960s, rather than to the problem of conformational search per se. Comparisons between theory and experiment indicate a prominent role of desolvation barriers in cooperative folding, which likely emerges generally from a coupling between local conformational preferences and nonlocal packing interactions. Many of these principles have been elucidated by native-centric models, wherein nonnative interactions may be treated perturbatively. We discuss these developments as well as recent applications of coarse-grained chain modeling to knotted proteins and to intrinsically disordered proteins.
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| 30. |
- Chirumalla, Koteshwar, Associate Professor, et al.
(author)
-
Circular Business Models for the Electric Vehicle Battery Second Life : Navigating Battery Ecosystem Actors Towards Circularity
- 2024
-
Reports (other academic/artistic)abstract
- The electrification of vehicles has become a critical means to achieve climate-neutral transportation. As more electric vehicles (EV) are adopted, an increasing number of lithiumion batteries will be utilized, inevitably experiencing capacity degradation over time. Retaining the value of these retired batteries through remanufacturing, reusing, and repurposing to create a second life holds significant environmental and economic benefits. However, many companies within the battery ecosystem struggle to capitalize on this opportunity due to a lack of business insight and suitable business models tailored to their operational contexts.The ReCreate (Second Life Management of Electric Vehicle Batteries) research project was initiated to address these industrial needs through close collaboration with selected companies in the battery ecosystem. The project aims to define appropriate circular business models, methods, and processes to guide battery ecosystem actors in developing and implementing electric vehicle battery second life solutions, thereby advancing circularity around batteries and climate-neutral objectives. This handbook represents the culmination of three years of research within the ReCreate project. Its purpose is to present a simplified and practical overview of project outcomes across a series of key chapters. Comprising six chapters, the handbook will begin by discussing barriers and enablers, followed by circular business models and battery ecosystem management. It will then delve into design principles and performance monitoring guidelines, concluding with an integrated framework for second life and circular solutions for EV batteries. Each chapter briefly presents the main findings of the theme and concludes with discussion questions. The discussion questions include suggestions for relevant templates for workshops, and all templates are conveniently provided in the appendix for practical application. These templates serve as boundary objects, offering a starting point for internal and external cross-functional and cross-organizational dialogues within the electric vehicle battery ecosystem. They facilitate discussions and collaborations among various stakeholders, fostering alignment and synergy in developing circular business models for the second life of EV batteries. By facilitating reflection on current business strategies, needs, and pain points, the handbook aims to aid in the definition of future second life business strategies. We anticipate that this handbook will serve as a valuable resource for actors within the EV battery ecosystem, supporting their journey towards climate-neutral transportation.
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| 31. |
- Crippa, Simone, 1980-
(author)
-
Accurate physical and numerical modeling of complex vortex phenomena over delta wings
- 2006
-
Licentiate thesis (other academic/artistic)abstract
- With this contribution to the AVT-113/VFE-2 task group it was possible to prove the feasibility of high Reynolds number CFD computations to resolve and thus better understand the peculiar dual vortex system encountered on the VFE-2 blunt leading edge delta wing. Initial investigations into this phenomenon seemed to undermine the hypothesis, that the formation of the inner vortex system relies on the laminar state of the boundary layer at separation onset. As a result of this research, this initial hypothesis had to be expanded to account also for high Reynolds number cases, where a laminar boundary layer status at separation onset could be excluded. Furthermore, the data published in the same context shows evidence of secondary separation under the inner primary vortex. This further supports the supposition of a different generation mechanism of the inner vortical system other than a pure development out of a possibly laminar separation bubble. The unsteady computations performed on numerical grids with different levels of refinement led furthermore to the establishment of internal guidelines specific to the DES approach.
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| 32. |
- Criten, Sladjana, et al.
(author)
-
Oral health status among 60-year-old individuals born in 1941-1943 and 1954-1955 and 81-year-old individuals born in 1922-1924 and 1933-1934, respectively : a cross-sectional study
- 2022
-
In: Clinical Oral Investigations. - : Springer Berlin/Heidelberg. - 1432-6981 .- 1436-3771. ; :11, s. 6733-6742
-
Journal article (peer-reviewed)abstract
- Objective This study aimed to analyze the oral health status of four different birth cohorts: two cohorts of 60-year-olds born in 1941-1943 and 1954-1955 and 2 cohorts of 81-year-olds born in 1920-1922 and 1933-1934. Material and methods The study was based on data from an ongoing longitudinal population project, The Swedish National Study on Aging and Care (SNAC). Oral health status was repeatedly examined clinically and radiographically in 2001-2003 and 2014-2015, including 60- and 81-year-olds, in total 412 individuals. Statistical analyses were performed using independent-samples t test and Pearson's chi(2) test. Results More individuals were dentate in 2014-2015 compared to 2001-2003 in the two age groups: 60 and 81 years (p < 0.001 for both). The mean number of teeth increased in the 60-year-olds from 24.2 to 27.0 and in the 81-year-olds from 14.3 to 20.2. The numbers of at least one intact tooth increased for both age groups (p < 0.001 and p < 0.004, respectively). In the age groups 81 years, there was an increase in having at least one PPD >= 6 mm (p < 0.016) and bone loss >= 5 mm (p < 0.029) between the two examinations. No such differences were found in the age groups of 60 years. Conclusion Over 13 years, oral health improved for both 60- and 81-year-old age groups. The most significant changes were in the 81-year-olds where oral health had improved except for periodontal status.
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| 33. |
- Dahl, Kenneth, et al.
(author)
-
Good manufacturing procedure production of [18 F]SynVesT-1, a radioligand for in vivo positron emission tomography imaging of synaptic vesicle glycoprotein 2A.
- 2022
-
In: Journal of labelled compounds & radiopharmaceuticals. - : Wiley. - 1099-1344 .- 0362-4803. ; 65:12, s. 315-322
-
Journal article (peer-reviewed)abstract
- [18 F]SynVesT-1 (also known as [18 F]SDM-8 or [18 F]MNI-1126) is a potent and selective synaptic vesicle glycoprotein 2 (SV2A) positron emission tomography (PET) imaging agent. In order to fulfill the increasing clinical demand of an 18 F-labeled SV2A PET ligand, we have developed a fully automated procedure to provide a sterile and pyrogen-free good manufacturing procedure (GMP)-compliant product of [18 F]SynVesT-1 suitable for clinical studies in humans. [18 F]SynVesT-1 is synthesized via a rapid copper-mediated radiofluorination protocol. The procedure was developed and established on a commercially available module, TracerMaker (ScanSys Laboratorieteknik ApS, Copenhagen, Denmark), a synthesis platform originally developed to conduct carbon-11 radiochemistry. From ~130GBq (end-of-bombardment), our newly developed procedure enabled us to prepare [18 F]SynVesT-1 in an isolated radioactivity yield of 14,220±800MBq (n=3), which corresponds to a radiochemical yield (RCY) of 19.5±0.5%. The radiochemical purity (RCP) and enantiomeric purity of each of the final formulated batches exceeded 98%. The overall synthesis time was 90min and the molar activity was 330±60GBq/μmol (8.9±1.6Ci/μmol). The produced [18 F]SynVesT-1 was stable over 8h at room temperature and is suitable for in vivo PET imaging studies in human subjects.
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| 34. |
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| 35. |
- Downs, Louise M., et al.
(author)
-
A Frameshift Mutation in Golden Retriever Dogs with Progressive Retinal Atrophy Endorses SLC4A3 as a Candidate Gene for Human Retinal Degenerations
- 2011
-
In: PLoS one. - : Public Library of Science (PLoS). - 1932-6203. ; 6:6, s. e21452-
-
Journal article (peer-reviewed)abstract
- Progressive retinal atrophy (PRA) in dogs, the canine equivalent of retinitis pigmentosa (RP) in humans, is characterised by vision loss due to degeneration of the photoreceptor cells in the retina, eventually leading to complete blindness. It affects more than 100 dog breeds, and is caused by numerous mutations. RP affects 1 in 4000 people in the Western world and 70% of causal mutations remain unknown. Canine diseases are natural models for the study of human diseases and are becoming increasingly useful for the development of therapies in humans. One variant, prcd-PRA, only accounts for a small proportion of PRA cases in the Golden Retriever (GR) breed. Using genome-wide association with 27 cases and 19 controls we identified a novel PRA locus on CFA37 (p(raw) = 1.94x10(-10), p(genome) = 1.0x10(-5)), where a 644 kb region was homozygous within cases. A frameshift mutation was identified in a solute carrier anion exchanger gene (SLC4A3) located within this region. This variant was present in 56% of PRA cases and 87% of obligate carriers, and displayed a recessive mode of inheritance with full penetrance within those lineages in which it segregated. Allele frequencies are approximately 4% in the UK, 6% in Sweden and 2% in France, but the variant has not been found in GRs from the US. A large proportion of cases (approximately 44%) remain unexplained, indicating that PRA in this breed is genetically heterogeneous and caused by at least three mutations. SLC4A3 is important for retinal function and has not previously been associated with spontaneously occurring retinal degenerations in any other species, including humans.
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| 36. |
- Dyrby, Tim B, et al.
(author)
-
Segmentation of age-related white matter changes in a clinical multi-center study.
- 2008
-
In: NeuroImage. - : Elsevier BV. - 1053-8119. ; 41:2, s. 335-45
-
Journal article (peer-reviewed)abstract
- Age-related white matter changes (WMC) are thought to be a marker of vascular pathology, and have been associated with motor and cognitive deficits. In the present study, an optimized artificial neural network was used as an automatic segmentation method to produce probabilistic maps of WMC in a clinical multi-center study. The neural network uses information from T1- and T2-weighted and fluid attenuation inversion recovery (FLAIR) magnetic resonance (MR) scans, neighboring voxels and spatial location. Generalizability of the neural network was optimized by including the Optimal Brain Damage (OBD) pruning method in the training stage. Six optimized neural networks were produced to investigate the impact of different input information on WMC segmentation. The automatic segmentation method was applied to MR scans of 362 non-demented elderly subjects from 11 centers in the European multi-center study Leukoaraiosis And Disability (LADIS). Semi-manually delineated WMC were used for validating the segmentation produced by the neural networks. The neural network segmentation demonstrated high consistency between subjects and centers, making it a promising technique for large studies. For WMC volumes less than 10 ml, an increasing discrepancy between semi-manual and neural network segmentation was observed using the similarity index (SI) measure. The use of all three image modalities significantly improved cross-center generalizability compared to neural networks using the FLAIR image only. Expert knowledge not available to the neural networks was a minor source of discrepancy, while variation in MR scan quality constituted the largest source of error.
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| 37. |
- Elfwen, Ludvig, et al.
(author)
-
Direct or subacute coronary angiography in out-of-hospital cardiac arrest (DISCO)-An initial pilot-study of a randomized clinical trial
- 2019
-
In: Resuscitation. - : ELSEVIER IRELAND LTD. - 0300-9572 .- 1873-1570. ; 139, s. 253-261
-
Journal article (peer-reviewed)abstract
- Background: The clinical importance of immediate coronary angiography, with potentially subsequent percutaneous coronary intervention (PCI), in out-of-hospital cardiac arrest (OHCA) patients without ST-elevation on the ECG is unclear. In this study, we assessed feasibility and safety aspects of performing immediate coronary angiography in a pre-specified pilot phase of the 'DIrect or Subacute Coronary angiography in Out-of-hospital cardiac arrest' (DISCO) randomized controlled trial (ClinicalTrials.gov ID: NCT02309151). Methods: Resuscitated bystander witnessed OHCA patients > 18 years without ST-elevation on the ECG were randomized to immediate coronary angiography versus standard of care. Event times, procedure related adverse events and safety variables within 7 days were recorded. Results: In total, 79 patients were randomized to immediate angiography (n = 39) or standard of care (n = 40). No major differences in baseline characteristics between the groups were found. There were no differences in the proportion of bleedings and renal failure. Three patients randomized to immediate angiography and six patients randomized to standard care died within 24 h. The median time from EMS arrival to coronary angiography was 135 min in the immediate angiography group. In patients randomized to immediate angiography a culprit lesion was found in 14/38 (36.8%) and PCI was performed in all these patients. In 6/40 (15%) patients randomized to standard of care, coronary angiography was performed before the stipulated 3 days. Conclusion: In this out-of-hospital cardiac arrest population without ST-elevation, randomization to a strategy to perform immediate coronary angiography was feasible although the time window of 120 min from EMS arrival at the scene of the arrest to start of coronary angiography was not achieved. No significant safety issues were reported.
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| 38. |
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| 39. |
- Ewers, Michael, et al.
(author)
-
Increased CSF-BACE 1 activity is associated with ApoE-epsilon 4 genotype in subjects with mild cognitive impairment and Alzheimer's disease.
- 2008
-
In: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 131:Pt 5, s. 1252-8
-
Journal article (peer-reviewed)abstract
- The Apolipoprotein (ApoE) epsilon 4 allele is a major genetic risk factor of Alzheimer's disease, and may affect the production of amyloid beta (A beta(1-42)). Recently, we have shown that beta-secretase (BACE 1) activity can be reliably detected within the brain and human CSF. Here, we have examined an association between the ApoE genotype and CSF-levels of BACE 1 activity in Alzheimer's disease and mild cognitive impairment (MCI). A total of 148 subjects were included: 60 Alzheimer's disease patients, 51 MCI subjects and 37 elderly healthy controls. The CSF-levels of A beta(1-42), BACE 1 activity and BACE protein were measured in all of these subjects. The differences between ApoE-epsilon 4 carriers and ApoE-epsilon 4 non-carriers in these CSF-based measures were determined controlling for gender, age and MMSE score. The ApoE-epsilon 4 genotype was associated with increased BACE 1 activity in both Alzheimer's disease (P = 0.03) and MCI (P = 0.04) subjects. Levels of A beta(1-42) were decreased in ApoE-epsilon 4 carriers in MCI (P = 0.004) but not Alzheimer's disease subjects. This study is the first to demonstrate the association between ApoE-epsilon 4 and CSF-BACE 1 activity in MCI and Alzheimer's disease subjects. The assessment of BACE 1 in CSF may provide a sensitive measure to detect in vivo alterations in the amyloidogenic processing potentially modified by the ApoE genotype.
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| 40. |
- Favrin, Giorgio, et al.
(author)
-
Folding of a small helical protein using hydrogen bonds and hydrophobicity forces.
- 2002
-
In: Proteins. - : Wiley. - 0887-3585. ; 47:2, s. 99-105
-
Journal article (peer-reviewed)abstract
- A reduced protein model with five to six atoms per amino acid and five amino acid types is developed and tested on a three-helix-bundle protein, a 46-amino acid fragment from staphylococcal protein A. The model does not rely on the widely used Go approximation, which ignores non-native interactions. We find that the collapse transition is considerably more abrupt for the protein A sequence than for random sequences with the same composition. The chain collapse is found to be at least as fast as helix formation. Energy minimization restricted to the thermodynamically favored topology gives a structure that has a root-mean-square deviation of 1.8 A from the native structure. The sequence-dependent part of our potential is pairwise additive. Our calculations suggest that fine-tuning this potential by parameter optimization is of limited use.
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| 41. |
- Favrin, Giorgio, et al.
(author)
-
Sequence-based study of two related proteins with different folding behaviors
- 2004
-
In: Proteins. - : Wiley. - 0887-3585. ; 54:1, s. 8-12
-
Journal article (peer-reviewed)abstract
- Z(SPA-1) is an engineered protein that binds to its parent, the three-helix-bundle Z domain of staphylococcal protein A. Uncomplexed Z(SPA-1) shows a reduced helix content and a melting behavior that is less cooperative, compared with the wild-type Z domain. Here we show that the difference in folding behavior between these two sequences can be partly understood in terms of an off-lattice model with 5-6 atoms per amino acid and a minimalistic potential, in which folding is driven by backbone hydrogen bonding and effective hydrophobic attraction. (C) 2003 Wiley-Liss, Inc.
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| 42. |
- Favrin, Giorgio, et al.
(author)
-
Two-state folding over a weak free-energy barrier
- 2003
-
In: Biophysical Journal. - 1542-0086. ; 85:3, s. 1457-1465
-
Journal article (peer-reviewed)abstract
- We present a Monte Carlo study of a model protein with 54 amino acids that folds directly to its native three-helix-bundle state without forming any well-defined intermediate state. The free-energy barrier separating the native and unfolded states of this protein is found to be weak, even at the folding temperature. Nevertheless, we find that melting curves to a good approximation can be described in terms of a simple two-state system, and that the relaxation behavior is close to single exponential. The motion along individual reaction coordinates is roughly diffusive on timescales beyond the reconfiguration time for a single helix. A simple estimate based on diffusion in a square-well potential predicts the relaxation time within a factor of two.
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| 43. |
- Feigin, Valery L., et al.
(author)
-
Global, regional, and national burden of neurological disorders, 1990–2016 : a systematic analysis for the Global Burden of Disease Study 2016
- 2019
-
In: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 18:5, s. 459-480
-
Journal article (peer-reviewed)abstract
- Background: Neurological disorders are increasingly recognised as major causes of death and disability worldwide. The aim of this analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 is to provide the most comprehensive and up-to-date estimates of the global, regional, and national burden from neurological disorders.Methods: We estimated prevalence, incidence, deaths, and disability-adjusted life-years (DALYs; the sum of years of life lost [YLLs] and years lived with disability [YLDs]) by age and sex for 15 neurological disorder categories (tetanus, meningitis, encephalitis, stroke, brain and other CNS cancers, traumatic brain injury, spinal cord injury, Alzheimer's disease and other dementias, Parkinson's disease, multiple sclerosis, motor neuron diseases, idiopathic epilepsy, migraine, tension-type headache, and a residual category for other less common neurological disorders) in 195 countries from 1990 to 2016. DisMod-MR 2.1, a Bayesian meta-regression tool, was the main method of estimation of prevalence and incidence, and the Cause of Death Ensemble model (CODEm) was used for mortality estimation. We quantified the contribution of 84 risks and combinations of risk to the disease estimates for the 15 neurological disorder categories using the GBD comparative risk assessment approach.Findings: Globally, in 2016, neurological disorders were the leading cause of DALYs (276 million [95% UI 247–308]) and second leading cause of deaths (9·0 million [8·8–9·4]). The absolute number of deaths and DALYs from all neurological disorders combined increased (deaths by 39% [34–44] and DALYs by 15% [9–21]) whereas their age-standardised rates decreased (deaths by 28% [26–30] and DALYs by 27% [24–31]) between 1990 and 2016. The only neurological disorders that had a decrease in rates and absolute numbers of deaths and DALYs were tetanus, meningitis, and encephalitis. The four largest contributors of neurological DALYs were stroke (42·2% [38·6–46·1]), migraine (16·3% [11·7–20·8]), Alzheimer's and other dementias (10·4% [9·0–12·1]), and meningitis (7·9% [6·6–10·4]). For the combined neurological disorders, age-standardised DALY rates were significantly higher in males than in females (male-to-female ratio 1·12 [1·05–1·20]), but migraine, multiple sclerosis, and tension-type headache were more common and caused more burden in females, with male-to-female ratios of less than 0·7. The 84 risks quantified in GBD explain less than 10% of neurological disorder DALY burdens, except stroke, for which 88·8% (86·5–90·9) of DALYs are attributable to risk factors, and to a lesser extent Alzheimer's disease and other dementias (22·3% [11·8–35·1] of DALYs are risk attributable) and idiopathic epilepsy (14·1% [10·8–17·5] of DALYs are risk attributable).Interpretation: Globally, the burden of neurological disorders, as measured by the absolute number of DALYs, continues to increase. As populations are growing and ageing, and the prevalence of major disabling neurological disorders steeply increases with age, governments will face increasing demand for treatment, rehabilitation, and support services for neurological disorders. The scarcity of established modifiable risks for most of the neurological burden demonstrates that new knowledge is required to develop effective prevention and treatment strategies.Funding: Bill & Melinda Gates Foundation.
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| 44. |
- Follin, Elna, et al.
(author)
-
In silico peptide-binding predictions of passerine MHC class I reveal similarities across distantly related species, suggesting convergence on the level of protein function.
- 2013
-
In: Immunogenetics. - : Springer Science and Business Media LLC. - 1432-1211 .- 0093-7711. ; 65:4, s. 299-311
-
Journal article (peer-reviewed)abstract
- The major histocompatibility complex (MHC) genes are the most polymorphic genes found in the vertebrate genome, and they encode proteins that play an essential role in the adaptive immune response. Many songbirds (passerines) have been shown to have a large number of transcribed MHC class I genes compared to most mammals. To elucidate the reason for this large number of genes, we compared 14 MHC class I alleles (α1-α3 domains), from great reed warbler, house sparrow and tree sparrow, via phylogenetic analysis, homology modelling and in silico peptide-binding predictions to investigate their functional and genetic relationships. We found more pronounced clustering of the MHC class I allomorphs (allele specific proteins) in regards to their function (peptide-binding specificities) compared to their genetic relationships (amino acid sequences), indicating that the high number of alleles is of functional significance. The MHC class I allomorphs from house sparrow and tree sparrow, species that diverged 10 million years ago (MYA), had overlapping peptide-binding specificities, and these similarities across species were also confirmed in phylogenetic analyses based on amino acid sequences. Notably, there were also overlapping peptide-binding specificities in the allomorphs from house sparrow and great reed warbler, although these species diverged 30 MYA. This overlap was not found in a tree based on amino acid sequences. Our interpretation is that convergent evolution on the level of the protein function, possibly driven by selection from shared pathogens, has resulted in allomorphs with similar peptide-binding repertoires, although trans-species evolution in combination with gene conversion cannot be ruled out.
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| 45. |
- Forouzanfar, Mohammad H, et al.
(author)
-
Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013 : a systematic analysis for the Global Burden of Disease Study 2013.
- 2015
-
In: The Lancet. - 0140-6736 .- 1474-547X. ; 386:10010, s. 2287-2323
-
Journal article (peer-reviewed)abstract
- BACKGROUND: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.METHODS: Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk-outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990-2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol.FINDINGS: All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8-58·5) of deaths and 41·6% (40·1-43·0) of DALYs. Risks quantified account for 87·9% (86·5-89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa.INTERPRETATION: Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks.FUNDING: Bill & Melinda Gates Foundation.
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| 46. |
- Franke, M., et al.
(author)
-
Assessment of explicit algebraic Reynolds-stress turbulence models in aerodynamic computations
- 2005
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In: Aerospace Science and Technology. - : Elsevier BV. - 1270-9638 .- 1626-3219. ; 9:7, s. 573-581
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Journal article (peer-reviewed)abstract
- In the aerodynamic industrial design process, the use of numerical simulation, including viscous effects, is of ever increasing importance. As simple, standard Boussinesq-viscosity turbulence models have proven insufficient to correctly predict complex flow situations, attention is drawn to more reliable approaches towards the modelling of turbulence. This work aims at assessing the potential of Explicit Algebraic Reynolds Stress Models (EARSM) for application-oriented aerodynamic computations. To this end, two different EARSM are investigated on a variety of configurations in sub- and transonic steady flow, ranging from 2D aerofoils to 3D wing/body-configurations. Is is demonstrated that an increased over-all simulation quality is achieved. Thus, while their overhead with respect to standard linear approaches remains limited, EARSM constitute a valuable extension to the model range available to the aerodynamic design engineer.
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| 47. |
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| 48. |
- Gatski, T. B., et al.
(author)
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Extending the weak-equilibrium condition for algebraic Reynolds stress models to rotating and curved flows
- 2004
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In: Journal of Fluid Mechanics. - 0022-1120 .- 1469-7645. ; 518, s. 147-155
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Journal article (peer-reviewed)abstract
- Weis & Hutter (J. Fluid Mech. vol. 476, 2003, p. 63) obtained an implicit algebraic Reynolds stress model from a differential Reynolds stress transport equation valid in an arbitrarily rotating time-dependent coordinate frame (relative to an inertial system). Although the form of this implicit algebraic equation differed from previous implicit forms, its correctness was argued based on the objective tensor form of the implicit algebraic equation. It is shown here that such conclusions based on simple coordinate frame transformations are incomplete, and that additional considerations taking into account flow rotation and curvature, for example, are necessary. By properly accounting for both the arbitrary motions of the observer coordinate frame as well as the motion of the flow itself, it is shown that previous formulations and application of the weak-equilibrium condition are correct in contrast to the results of Weis Hutter.
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| 49. |
- Giesecke, Peter, et al.
(author)
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All-cause and cardiovascular mortality risk after surgery versus radioiodine treatment for hyperthyroidism
- 2018
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In: British Journal of Surgery. - : John Wiley & Sons. - 0007-1323 .- 1365-2168. ; 105:3, s. 279-286
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Journal article (peer-reviewed)abstract
- BACKGROUND: Little is known about the long-term side-effects of different treatments for hyperthyroidism. The few studies previously published on the subject either included only women or focused mainly on cancer outcomes. This register study compared the impact of surgery versus radioiodine on all-cause and cause-specific mortality in a cohort of men and women.METHODS: Healthcare registers were used to find hyperthyroid patients over 35 years of age who were treated with radioiodine or surgery between 1976 and 2000. Comparisons between treatments were made to assess all-cause and cause-specific deaths to 2013. Three different statistical methods were applied: Cox regression, propensity score matching and inverse probability weighting.RESULTS: Of the 10 992 patients included, 10 250 had been treated with radioiodine (mean age 65·1 years; 8668 women, 84·6 per cent) and 742 had been treated surgically (mean age 44·1 years; 633 women, 85·3 per cent). Mean duration of follow-up varied between 16·3 and 22·3 years, depending on the statistical method used. All-cause mortality was significantly lower among surgically treated patients, with a hazard ratio of 0·82 in the regression analysis, 0·80 in propensity score matching and 0·85 in inverse probability weighting. This was due mainly to lower cardiovascular mortality in the surgical group. Men in particular seemed to benefit from surgery compared with radioiodine treatment.CONCLUSION: Compared with treatment with radioiodine, surgery for hyperthyroidism is associated with a lower risk of all-cause and cardiovascular mortality in the long term. This finding was more evident among men.
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| 50. |
- Giesecke, Peter, et al.
(author)
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Increased Cardiovascular Mortality and Morbidity in Patients Treated for Toxic Nodular Goiter Compared to Graves' Disease and Nontoxic Goiter
- 2017
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In: Thyroid. - : Mary Ann Liebert. - 1050-7256 .- 1557-9077. ; 27:7, s. 878-885
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Journal article (peer-reviewed)abstract
- BACKGROUND: Previous research has suggested an increased risk of death and cardiovascular disease in patients treated for hyperthyroidism. However, studies on this subject are heterogeneous, often based on old data, or have not considered the impact that treatment for hyperthyroidism might have on cardiovascular risk. It is also unclear whether long-term prognosis differs between Graves' disease and toxic nodular goiter. The aim of this study was to use a very large cohort built on recent data to assess whether improvements in cardiovascular care might have changed the prognosis over time. The study also investigated the impact of different etiologies of hyperthyroidism.METHODS: This was an observational register study for the period 1976-2012, with subjects followed for a median period of 18.4 years. Study patients were Stockholm residents treated for Graves' disease or toxic nodular goiter with either radioactive iodine or surgery (N = 12,239). This group was compared to Stockholm residents treated for nontoxic goiter (N = 3685), with adjustments made for age, sex, comorbidities, and time of treatment. Comparisons were also made to the general population of Stockholm. Outcomes were assessed in terms of all-cause and cardiovascular mortality as well as cardiovascular morbidity.RESULTS: The hazard ratios (HR) for all-cause mortality and for cardiovascular mortality were 1.27 [confidence interval (CI) 1.20-1.35] and 1.29 [CI 1.17-1.42], respectively, for hyperthyroid patients compared to those with nontoxic goiter. For cardiovascular morbidity, the HR was 1.12 [CI 1.06-1.18]. Patients aged ≥45 years who were treated for toxic nodular goiter were generally at greater risk than others, and those included from the year 1990 and onwards were at greater risk than those included earlier. Increased all-cause mortality, as well as cardiovascular mortality and morbidity, were also seen in comparisons with the general population.CONCLUSIONS: This is the first large study to indicate that the long-term risk of death and cardiovascular disease in hyperthyroid subjects is due to the hyperthyroidism itself and not an effect of confounding introduced by its treatment. Much of the excess risk is confined to individuals treated for toxic nodular goiter. Despite advances in cardiovascular care during recent decades, hyperthyroidism is still a diagnosis associated with increased cardiovascular morbidity and mortality.
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