| 1. |
- Frazier-Wood, Alexis C., et al.
(författare)
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Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses
- 2016
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Ingår i: Nature Genetics. - : Nature Research (part of Springer Nature). - 1061-4036 .- 1546-1718. ; 48, s. 624-
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Tidskriftsartikel (refereegranskat)abstract
- Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (vertical bar(p) over cap vertical bar approximate to 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
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| 2. |
- Bjoreland, Anders, et al.
(författare)
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Liquid ionization chamber calibrated gel dosimetry in conformal stereotactic radiotherapy of brain lesions
- 2008
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 1651-226X .- 0284-186X. ; 47:6, s. 1099-1109
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Tidskriftsartikel (refereegranskat)abstract
- Hypofractionated conformal stereotactic radiotherapy (HCSRT) is an established method of treating brain lesions such as arteriovenous malformations (AVMs) and brain metastases. The aim of this study was to investigate the reliability of treatment plans in the terms of dose distribution and absorbed dose for HCSRT. Methods and materials. Treatment plans for three different clinical intracerebral targets, AVMs, were transferred to a CT study of a spherical water filled phantom simulating the human head and recalculated for the phantom geometry using a standard treatment planning system utilizing a pencil beam algorithm for dose calculation. The calculated absorbed dose, relative three dimensional (3D) dose distribution and dose conformity were investigated using gel dosimetry normalized to liquid ionization chamber (LIC) measurements. Results. The measured absorbed dose to the dose reference point was found to be within 2% of the calculated dose for all three targets. The measured dose distribution was found to be within 3% and 2 mm of the calculated dose for more than 93% of all points in the target volume for all three targets. Conclusions. The results show that the investigated standard treatment planning system can correctly predict the absorbed dose and dose distribution in different types of intracerebral targets and that the treatment can be delivered according to the plan.
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| 3. |
- Khalili, Bita, et al.
(författare)
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Associations between common genetic variants and income provide insights about the socioeconomic health gradient
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We conducted a genome-wide association study (GWAS) on income among individuals of European descent and leveraged the results to investigate the socio-economic health gradient (N=668,288). We found 162 genomic loci associated with a common genetic factor underlying various income measures, all with small effect sizes. Our GWAS-derived polygenic index captures 1 - 4% of income variance, with only one-fourth attributed to direct genetic effects. A phenome-wide association study using this polygenic index showed reduced risks for a broad spectrum of diseases, including hypertension, obesity, type 2 diabetes, coronary atherosclerosis, depression, asthma, and back pain. The income factor showed a substantial genetic correlation (0.92, s.e. = .006) with educational attainment (EA). Accounting for EA's genetic overlap with income revealed that the remaining genetic signal for higher income related to better mental health but reduced physical health benefits and increased participation in risky behaviours such as drinking and smoking.
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| 4. |
- Kullander, Sven, 1952-, et al.
(författare)
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Chalinochromis cyanophleps, a new species of cichlid fish (Teleostei: Cichlidae) from Lake Tanganyika
- 2014
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Ingår i: Zootaxa. - : Magnolia Press. - 1175-5326 .- 1175-5334. ; 3790:3, s. 425-438
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Tidskriftsartikel (refereegranskat)abstract
- Chalinochromis cyanophleps is described from nine specimens, the largest 129 mm SL, from Namansi. It differs fromother species of Chalinochromis in plain trunk colouration, absence of black stripes on the head, relatively narrow lips, presence of tricuspid jaw teeth, and presence of five rather than four dentary lateralis foramina. The blue iridescent stripe below the eye is shared with other lamprologin cichlids, but is broader and more conspicuous in C. cyanophleps. Chalinochromis cyanophleps occurs at depths between 6 and 45 m in rocky habitats along the Tanzanian coast of Lake Tanganyika,from Mvuna Island south to Kalala Island, a stretch of about 90 km. Field observations were made of specimens up to 18 cm total length. The COI DNA barcode sequence differs by 1.8% from that of C. popelini.
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| 5. |
- Kullander, Sven, 1952-, et al.
(författare)
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Description of Neolamprologus timidus, new species, and review of N. furcifer from Lake Tanganyika (Teleostei: Cichlidae)
- 2013
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Ingår i: Ichthyological Exploration of Freshwaters. - München : Verlag Dr. Friedrich Pfeil. - 0936-9902. ; 24:4, s. 301-328
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Tidskriftsartikel (refereegranskat)abstract
- Neolamprologus timidus, new species, is described from Ulwile Island and adjacent localities on the Tanzanian coast of Lake Tanganyika. The species was observed or collected along about 100 km of coastline from KolwePoint, Cape Mpimbwe, south to Kisi Island. It is distinguished from the most similar species, N. furcifer, by presenceof scales on most of the cheek, long pectoral fin and pelvic fin with the second ray longer than the first. Neolamprologus timidus is sympatric with N. furcifer at Kolwe Point and south to Kampempa Point, and at Lupitaand Ulwile Islands south to Kisi Island, but N. furcifer is otherwise absent from the range of N. timidus. Two morphologically distinct forms are recognized in N. furcifer. Samples of N. furcifer from Ulwile Island and slightly more southern localities possess a caudal fin with rounded lobes and long middle rays, appearing onlyslightly emarginate. Samples of N. furcifer from Udachi and nearby localities possess pointed caudal-fin lobeswith greatly elongated streamers, similar to N. timidus and to N. furcifer from other parts of Lake Tanganyika, including the type specimens from the southern part of the lake. The variation in caudal-fin shape may be an expression of character displacement as it occurs in the area of sympatry between N. timidus and N. furcifer. MitochondrialDNA sequences are nearly identical in samples of N. furcifer with pointed or rounded caudal fin. A molecular phylogenetic analysis of a large set of lamprologin cichlids using two mitochondrial genes corroborates earlier analyses and places N. furcifer and N. timidus in different clades with different species of Neolamprologus, Julidochromis, Chalinochromis, and Telmatochromis despite sharing a unique combination of fin and bodyshape, and colour pattern. A 4648 base-pair multiloci analysis of a smaller number of species using fragments ofthree mitochondrial and two nuclear genes resolves N. furcifer and N. timidus in sister clades, but the N. timidus clade also includes Telmatochromis brachygnathus, and N. furcifer is sister species of Chalinochromis brichardi.
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| 6. |
- Pousette, Anders, 1959, et al.
(författare)
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Informationssäkerhetskultur i praktiken: Populärvetenskaplig sammanfattning
- 2023
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Projektet Informationssäkerhetskultur i praktiken har finansierats av MSB under åren 2019–2024 med syftet att förklara och belysa hur informationssäkerhetskulturen i organisationer kan förändras till det bättre. Fokus har varit på olika sätt att mäta och förändra kulturen. Projektet har genomförts av forskare i tre organisationer. Upplägget är tvärvetenskapligt med forskare specialiserade inom ämnen såsom fredsstudier, statsvetenskap, informatik, psykologi och cyberförsvar. Det tvärvetenskapliga angreppssättet har, förutom de resultat som presenteras i denna rapport, inneburit stort kunskapsutbyte mellan forskare i projektet och förbättrat deras förståelse för de problem och dilemman som kopplas till hantering av informationssäkerhetskulturer. Projektets forskningsplan inkluderade flera datainsamlingsinsatser och interventioner i samhällsviktiga organisationer. Eftersom kunskap om en organisations informationssäkerhet kan missbrukas av illasinnade aktörer förutsatte projektet stort förtroende och engagemang från dessa organisationer. Det krävde också förtroende och engagemang från enskilda individer inom dessa organisationer som förväntades delta i studierna. Den pandemi som drabbade världen i början av projektet innebar att många av de planer som gjorts behövde justeras och förändras. Organisationer och personer som trots detta valt att stödja studien förtjänar därför ett tack utöver det vanliga. Stort tack!
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| 7. |
- Ronquist, Fredrik, et al.
(författare)
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Completing Linnaeus’s inventory of the Swedish insect fauna: only 5,000 species left?
- 2020
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:3
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Tidskriftsartikel (refereegranskat)abstract
- Despite more than 250 years of taxonomic research, we still have only a vague idea about the true size and composition of the faunas and floras of the planet. Many biodiversity inventories provide limited insight because they focus on a small taxonomic subsample or a tiny geographic area. Here, we report on the size and composition of the Swedish insect fauna, thought to represent roughly half of the diversity of multicellular life in one of the largest European countries. Our results are based on more than a decade of data from the Swedish Taxonomy Initiative and its massive inventory of the country’s insect fauna, the Swedish Malaise Trap Project The fauna is considered one of the best known in the world, but the initiative has nevertheless revealed a surprising amount of hidden diversity: more than 3,000 new species (301 new to science) have been documented so far. Here, we use three independent methods to analyze the true size and composition of the fauna at the family or subfamily level: (1) assessments by experts who have been working on the most poorly known groups in the fauna; (2) estimates based on the proportion of new species discovered in the Malaise trap inventory; and (3) extrapolations based on species abundance and incidence data from the inventory. For the last method, we develop a new estimator, the combined non-parametric estimator, which we show is less sensitive to poor coverage of the species pool than other popular estimators. The three methods converge on similar estimates of the size and composition of the fauna, suggesting that it comprises around 33,000 species. Of those, 8,600 (26%) were unknown at the start of the inventory and 5,000 (15%) still await discovery. We analyze the taxonomic and ecological composition of the estimated fauna, and show that most of the new species belong to Hymenoptera and Diptera groups that are decomposers or parasitoids. Thus, current knowledge of the Swedish insect fauna is strongly biased taxonomically and ecologically, and we show that similar but even stronger biases have distorted our understanding of the fauna in the past. We analyze latitudinal gradients in the size and composition of known European insect faunas and show that several of the patterns contradict the Swedish data, presumably due to similar knowledge biases. Addressing these biases is critical in understanding insect biomes and the ecosystem services they provide. Our results emphasize the need to broaden the taxonomic scope of current insect monitoring efforts, a task that is all the more urgent as recent studies indicate a possible worldwide decline in insect faunas.
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| 8. |
- Smith, Jennifer A, et al.
(författare)
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Genome-wide association study identifies 74 loci associated with educational attainment
- 2016
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Ingår i: Nature (London). - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 533:7604, s. 539-542
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Tidskriftsartikel (refereegranskat)abstract
- Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
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| 9. |
- Ahlbäck Öberg, Shirin, 1964-, et al.
(författare)
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MOOCs-studenter bildar B-laget
- 2013
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Ingår i: Upsala Nya Tidning. - Uppsala : AB Upsala Nya Tidning. - 1104-0173. ; :17/6
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Tidskriftsartikel (populärvet., debatt m.m.)
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| 10. |
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| 11. |
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| 12. |
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| 13. |
- Alattar, Abdul Ghani, et al.
(författare)
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Recombinant alpha(1)-Microglobulin (rA1M) Protects against Hematopoietic and Renal Toxicity, Alone and in Combination with Amino Acids, in a Lu-177-DOTATATE Mouse Radiation Model
- 2023
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Ingår i: Biomolecules. - 2218-273X. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- Lu-177-DOTATATE peptide receptor radionuclide therapy (PRRT) is used clinically to treat metastasized or unresectable neuroendocrine tumors (NETs). Although Lu-177-DOTATATE is mostly well tolerated in patients, bone marrow suppression and long-term renal toxicity are still side effects that should be considered. Amino acids are often used to minimize renal radiotoxicity, however, they are associated with nausea and vomiting in patients. alpha (1)-microglobulin (A1M) is an antioxidant with heme- and radical-scavenging abilities. A recombinant form (rA1M) has previously been shown to be renoprotective in preclinical models, including in PRRT-induced kidney damage. Here, we further investigated rA1M's renal protective effect in a mouse Lu-177-DOTATATE model in terms of administration route and dosing regimen and as a combined therapy with amino acids (Vamin). Moreover, we investigated the protective effect of rA1M on peripheral blood and bone marrow cells, as well as circulatory biomarkers. Intravenous (i.v.) administration of rA1M reduced albuminuria levels and circulatory levels of the oxidative stress-related protein fibroblast growth factor-21 (FGF-21). Dual injections of rA1M (i.e., at 0 and 24 h post-Lu-177-DOTATATE administration) preserved bone marrow cellularity and peripheral blood reticulocytes. Administration of Vamin, alone or in combination with rA1M, did not show any protection of bone marrow cellularity or peripheral reticulocytes. In conclusion, this study suggests that rA1M, administered i.v. for two consecutive days in conjunction with Lu-177-DOTATATE, may reduce hematopoietic and kidney toxicity during PRRT with Lu-177-DOTATATE.
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| 14. |
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| 15. |
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| 16. |
- Almby, Kristina E., et al.
(författare)
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Effects of Gastric Bypass Surgery on the Brain : Simultaneous Assessment of Glucose Uptake, Blood Flow, Neural Activity, and Cognitive Function During Normo- and Hypoglycemia
- 2021
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 70:6, s. 1265-1277
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Tidskriftsartikel (refereegranskat)abstract
- While Roux-en-Y gastric bypass (RYGB) surgery in obese individuals typically improves glycemic control and prevents diabetes, it also frequently causes asymptomatic hypoglycemia. Previous work showed attenuated counterregulatory responses following RYGB. The underlying mechanisms as well as the clinical consequences are unclear. In this study, 11 subjects without diabetes with severe obesity were investigated pre- and post-RYGB during hyperinsulinemic normo-hypoglycemic clamps. Assessments were made of hormones, cognitive function, cerebral blood flow by arterial spin labeling, brain glucose metabolism by F-18-fluorodeoxyglucose (FDG) positron emission tomography, and activation of brain networks by functional MRI. Post- versus presurgery, we found a general increase of cerebral blood flow but a decrease of total brain FDG uptake during normoglycemia. During hypoglycemia, there was a marked increase in total brain FDG uptake, and this was similar for post- and presurgery, whereas hypothalamic FDG uptake was reduced during hypoglycemia. During hypoglycemia, attenuated responses of counterregulatory hormones and improvements in cognitive function were seen postsurgery. In early hypoglycemia, there was increased activation post- versus presurgery of neural networks in brain regions implicated in glucose regulation, such as the thalamus and hypothalamus. The results suggest adaptive responses of the brain that contribute to lowering of glycemia following RYGB, and the underlying mechanisms should be further elucidated.
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| 17. |
- Altraja, Alan, et al.
(författare)
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Expression of laminins in the airways in various types of asthmatic patients: A morphometric study
- 1996
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Ingår i: American Journal of Respiratory Cell and Molecular Biology. - 1044-1549 .- 1535-4989. ; 15:4, s. 482-488
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Tidskriftsartikel (refereegranskat)abstract
- Laminins (Ln) are crucial in airway morphogenesis. Because they are able to interact with inflammatory cells, they are likely to participate in inflammation accompanied by airway structural remodeling in asthma. Taking biopsies and using immunohistochemistry and quantitative image analysis, we characterized the distribution of Ln chains alpha 1, alpha 2, and beta 2 in the bronchial mucosa of patients with seasonal (n = 17), early occupational (n = 8), and chronic asthma (n = 16) for comparison with that of normal controls (n = 8). In all asthmatic patients, both Ln chains alpha 1 and beta 2 were confined to the superficial margin of the basement membrane (BM), blood vessels, and smooth muscle. The thickness of Ln beta 2 expression in BM was significantly greater in patients with chronic (1.9 +/- 0.1 microns; P < 0.001) and occupational asthma (1.7 +/- 0.1 microns; P < 0.05) than in controls (0.4 +/- 0.3 microns). Only in patients with occupational asthma was the thickness of the Ln alpha 1 layer (2.3 +/- 0.2 microns; mean +/- SEM) significantly different from that in controls (1.4 +/- 0.5 microns; P < 0.05). There was no immunoreactivity for the Ln alpha 2 chain in controls or patients with mild asthma, but in clinically severe chronic asthma we found a discontinuous staining along the epithelial margin of the BM. Since Ln chains alpha 2 and beta 2 appear to function only during morphogenesis, increased expression of these Ln chains in adult asthma patients suggests accelerated tissue turnover in the airways, possibly as a result of airway inflammation in asthma.
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| 18. |
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| 19. |
- Andersson, Bodil, et al.
(författare)
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Combining Keystroke Logging with Eye Tracking
- 2006
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Ingår i: Writing and Digital Media. - 1572-6304. - 0080448631 ; 17, s. 166-172
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Bokkapitel (refereegranskat)abstract
- This chapter describes the successful development of a new methodology for studying on-line writing. The text-logging tool ScriptLog has been combined with the eyetracking technology iView X HED HT, in order to enhance the study of the interplay between writing, monitoring and revision. Data on the distribution of visual attention during writing help determining to what extent pauses are used for monitoring. The complexity of the experimental settings, and the expertise needed for interpreting the eye-tracking data make this a method suitable mainly for laboratory settings. The chapter also introduces an analysis tool that merges data from ScriptLog and iView and thus helps the researcher to organise and analyse the vast amount of data produced.
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| 20. |
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| 21. |
- Andersson, Martin, et al.
(författare)
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Betydelsen av unga och växande företag : En politik för ett mer dynamiskt näringsliv
- 2024
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Rapport (populärvet., debatt m.m.)abstract
- Syftet med denna rapport är att studera betydelsen av unga växande företag i Sverige underperioden 2003 till 2022. Vi studerar relationen mellan tillväxt i antal anställda och företagensålder och storlek med hjälp av registerdata över svenska privata aktiebolag. Mer specifiktbesvarar vi följande frågeställningar: Vilken betydelse har de unga företagen för jobbtillväxten i Sverige? Hur har nyföretagande och unga snabbväxande företag utvecklats över tid? Bör politiken fokusera på att stimulera framväxt av nya företag i Sverige och vilkareformer är effektiva för att utveckla ett dynamiskt näringsliv i Sverige med fler ungaväxande företag?
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| 22. |
- Andersson, Malin E, 1978, et al.
(författare)
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Signs of neuroaxonal injury in preeclampsia-A case control study.
- 2021
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 16:2
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral injury is a common cause of maternal mortality due to preeclampsia and is challenging to predict and diagnose. In addition, there are associations between previous preeclampsia and stroke, dementia and epilepsy later in life. The cerebral biomarkers S100B, neuron specific enolase, (NSE), tau protein and neurofilament light chain (NfL) have proven useful as predictors and diagnostic tools in other neurological disorders. This case-control study sought to determine whether cerebral biomarkers were increased in cerebrospinal fluid (CSF) as a marker of cerebral origin and potential cerebral injury in preeclampsia and if concentrations in CSF correlated to concentrations in plasma.CSF and blood at delivery from 15 women with preeclampsia and 15 women with normal pregnancies were analysed for the cerebral biomarkers S100B, NSE, tau protein and NfL by Simoa and ELISA based methods. MRI brain was performed after delivery and for women with preeclampsia also at six months postpartum.Women with preeclampsia demonstrated increased CSF- and plasma concentrations of NfL and these concentrations correlated to each other. CSF concentrations of NSE and tau were decreased in preeclampsia and there were no differences in plasma concentrations of NSE and tau between groups. For S100B, serum concentrations in preeclampsia were increased but there was no difference in CSF concentrations of S100B between women with preeclampsia and normal pregnancy.NfL emerges as a promising circulating cerebral biomarker in preeclampsia and increased CSF concentrations point to a neuroaxonal injury in preeclampsia, even in the absence of clinically evident neurological complications.
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| 23. |
- Andersson, Magnus, et al.
(författare)
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Fiskbestånd och miljö i hav och sötvatten : Resurs- och miljööversikt 2012
- 2012
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Detta är den nionde utgåvan av den samlade översikten över fisk- och kräftdjursbeståndens status i våra vatten. Kunskap om fiskbestånden och miljön är en förutsättning för att utnyttjandet av fiskresurserna skall bli bärkraftigt. För svenska vattenområden beskrivs miljöutvecklingen i ett ekosystemsperspektiv, dels för att tydliggöra fiskens ekologiska roll och beskriva yttre miljöfaktorer som påverkar fiskbestånden, dels för att belysa fiskets effekter på miljön.Fiskbestånd och miljö i hav och sötvatten är utarbetad av Sveriges lantbruksuniversitet (SLU), Institutionen för akvatiska resurser (SLU Aqua), på uppdrag av Havs- och vattenmyndigheten. Rapporten sammanfattar utveckling och beståndsstatus för de kommersiellt viktigaste fisk- och kräftdjursarterna i våra vatten. Bedömningar och förvaltningsråd är baserade på Internationella Havsforskningsrådets (ICES) rådgivning, SLU Aquas nationella och regionala provfiskedata, samt yrkesfiskets rapportering.
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| 24. |
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| 25. |
- Andersson, Thord, et al.
(författare)
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Consistent intensity inhomogeneity correction in water-fat MRI
- 2015
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Ingår i: Journal of Magnetic Resonance Imaging. - : Wiley-Blackwell. - 1053-1807 .- 1522-2586. ; 42:2
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To quantitatively and qualitatively evaluate the water-signal performance of the consistent intensity inhomogeneity correction (CIIC) method to correct for intensity inhomogeneitiesMETHODS: Water-fat volumes were acquired using 1.5 Tesla (T) and 3.0T symmetrically sampled 2-point Dixon three-dimensional MRI. Two datasets: (i) 10 muscle tissue regions of interest (ROIs) from 10 subjects acquired with both 1.5T and 3.0T whole-body MRI. (ii) Seven liver tissue ROIs from 36 patients imaged using 1.5T MRI at six time points after Gd-EOB-DTPA injection. The performance of CIIC was evaluated quantitatively by analyzing its impact on the dispersion and bias of the water image ROI intensities, and qualitatively using side-by-side image comparisons.RESULTS: CIIC significantly ( P1.5T≤2.3×10-4,P3.0T≤1.0×10-6) decreased the nonphysiological intensity variance while preserving the average intensity levels. The side-by-side comparisons showed improved intensity consistency ( Pint≤10-6) while not introducing artifacts ( Part=0.024) nor changed appearances ( Papp≤10-6).CONCLUSION: CIIC improves the spatiotemporal intensity consistency in regions of a homogenous tissue type.
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| 26. |
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| 27. |
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| 28. |
- Arvidson, Markus
(författare)
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Den fabricerande människan : Om bedrägeri som vardaglig interaktionsform
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The present dissertation takes the multi-faceted phenomenon of deception as its point of departure. The aim is to make a case for deception as a social phenomenon, and to frame theoretically and define the skills and abilities that make deception possible.A theoretical model based on a number of ideal types is constructed. The purpose of the model is to differentiate particular aspects of deception, and the model is illustrated with examples of actions of more or less well-known impostors. The examples were collected from a variety of sources, such as autobiographies and television programs.As a first step, the legal definition of deception, i.e. fraud, and statistics on crimes of deception in Sweden are presented. Different theoretical approaches are also discussed; deception as a personality trait, and deception as communication and interaction.In order to illuminate the social dimensions, it is emphasized that deception constitutes a particular type of relationship between deceiver and deceivee. This particular form of interaction exploits elementary forms, and it is also asymmetrical in terms of the intentions of the parties involved.The concept of social competence is used to describe the skills and abilities required for successful acts of deception. It is argued that the social competence of deceivers consists of three types: strategic, normative, and dramaturgic competencies. The strategic competency involves being goal-rational and strategic, for example, the ability to predict the actions of the potential addressee. In the normative competency, norms and reference to norms are used strategically. The dramaturgic competency represents an operationalization and enactment of the two other competencies, and resembles the preparation and performance of an actor.The different contexts in which deception can occur are also discussed. A preliminary typology is presented, with the aim of demonstrating the difficulties in drawing clear lines between various types of deception. The extended approach to deception also means that it can be viewed as a part of everyday social interaction.Finally, some thoughts on deception in the light of societal changes are presented. It is argued that the increasing demands on people to promote themselves in various ways in today’s society can be perceived as an invitation to deception and fabrication. These demands can generate feelings of inferiority and a fear of eventually being unmasked as an impostor, or a phony.
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| 29. |
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| 30. |
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| 31. |
- Astrand, Per, et al.
(författare)
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A three-year follow-up report of a comparative study of ITI Dental Implants and Bråemark System implants in the treatment of the partially edentulous maxilla.
- 2004
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Ingår i: Clin Implant Dent Relat Res. - 1523-0899. ; 6:3, s. 130-41
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Many longitudinal studies of different implant systems have been published but few controlled randomized investigations have been reported. A 1-year report of a comparative study of ITI Dental Implant System implants (Straumann AG, Waldenburg, Switzerland) and Branemark System implants (Nobel Biocare AB, Gothenburg, Sweden) has been published by the present authors. This paper is a 3-year follow-up of that randomized study. PURPOSE: The aim of the study was to compare the outcome of fixed partial prostheses supported by ITI or Branemark implants. The outcome was evaluated primarily in terms of survival rates and changes in marginal bone level. MATERIAL AND METHODS: The study group comprised 28 patients with anterior residual dentition in the maxilla. The patients were provided with two to four implants on each side of the dentition and were randomly allocated to Branemark implants or ITI implants; 77 ITI implants and 73 Branemark implants were inserted. After 6 months abutment connections were made to both ITI and Branemark implants. All patients were provided with fixed partial prostheses of gold-ceramic. The patients were followed up annually with clinical and radiographic examinations for 3 years RESULTS: Two Branemark implants and two ITI implants were lost. The Branemark implants were lost before loading whereas the ITI implants were lost because of periimplantitis. The survival rate for both groups was 97.3%. The mean marginal bone level of the Branemark implants was situated 1.8 mm from the reference point at both the baseline and the 3-year examinations. The corresponding values for the ITI implants were 1.4 mm at baseline and 1.3 mm after 3 years. There was no significant difference between the implant systems with regard to bone level or bone level change. A steady state of the marginal bone level was calculated to have been reached after 3 years for 95.5% of the Branemark implants and 87.1% of the ITI implants. Periimplantitis (infection including pus and bone loss) was observed with seven ITI implants but with none of the Branemark implants. This difference was statistically significant. CONCLUSIONS: No statistically significant differences were found between the implants studied, except for the frequency of periimplantitis, which was higher for the ITI implants. The survival rates were high, and the marginal bone loss was small for both systems.
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| 32. |
- Averfalk, Helge, 1988-, et al.
(författare)
-
Klimatgaser i Halland – en målinriktad analys med framtidsperspektiv
- 2014
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Rapporten innehåller en analys av utsläppen av de sex klimatgaserna i Halland mellan 1990 och 2011, en skattning vad som kommer att genomföras till 2020 och förslag till åtgärder för att kunna leverera utsläppsreduktioner efter 2020. Resultaten visar att de halländska utsläppen har minskat med 20 procent sedan 1990, målet om 27 procent lägre utsläpp till 2020 kommer troligen att uppnås, transporter och jordbruk måste kunna leverera utsläppsreduktioner efter 2020, regionala plan- och styrdokument måste i större utsträckning kunna kvantifiera framtida utsläppsreduktioner samt att det behövs ett regionalt kompetenscenter i Halland för att länet ska kunna leverera utsläppsreduktioner i framtiden.
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| 33. |
- Baison, J., et al.
(författare)
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Genetic control of tracheid properties in Norway spruce wood
- 2020
-
Ingår i: Scientific Reports. - : Nature Research. - 2045-2322. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- Through the use of genome-wide association studies (GWAS) mapping it is possible to establish the genetic basis of phenotypic trait variation. Our GWAS study presents the first such effort in Norway spruce (Picea abies (L). Karst.) for the traits related to wood tracheid characteristics. The study employed an exome capture genotyping approach that generated 178 101 Single Nucleotide Polymorphisms (SNPs) from 40 018 probes within a population of 517 Norway spruce mother trees. We applied a least absolute shrinkage and selection operator (LASSO) based association mapping method using a functional multi-locus mapping approach, with a stability selection probability method as the hypothesis testing approach to determine significant Quantitative Trait Loci (QTLs). The analysis has provided 30 significant associations, the majority of which show specific expression in wood-forming tissues or high ubiquitous expression, potentially controlling tracheids dimensions, their cell wall thickness and microfibril angle. Among the most promising candidates based on our results and prior information for other species are: Picea abies BIG GRAIN 2 (PabBG2) with a predicted function in auxin transport and sensitivity, and MA_373300g0010 encoding a protein similar to wall-associated receptor kinases, which were both associated with cell wall thickness. The results demonstrate feasibility of GWAS to identify novel candidate genes controlling industrially-relevant tracheid traits in Norway spruce. © 2020, The Author(s).
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| 34. |
- Baison, John, et al.
(författare)
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Genome-Wide Association Study (GWAS) identified novel candidate loci affecting wood formation in Norway spruce
- 2019
-
Ingår i: The Plant Journal. - : Wiley. - 0960-7412 .- 1365-313X. ; 100:1, s. 83-100
-
Tidskriftsartikel (refereegranskat)abstract
- Norway spruce is a boreal forest tree species of significant ecological and economic importance. Hence there is a strong imperative to dissect the genetics underlying important wood quality traits in the species. We performed a functional Genome-Wide Association Study (GWAS) of 17 wood traits in Norway spruce using 178101 single-nucleotide polymorphisms (SNPs) generated from exome genotyping of 517 mother trees. The wood traits were defined using functional modelling of wood properties across annual growth rings.We applied a LASSO based association mapping method using a functional multi-locus mapping approach that utilizes latent traits, with a stability selection probability method as the hypothesis testing approach to determine significant Quantitative Trait Loci (QTLs). The analysis provided 52 significant SNPs from 39 candidate genes, including genes previously implicated in wood formation and tree growth in spruce and other species. Our study represents a multi-locus GWAS for complex wood traits in Norway spruce. The results advance our understanding of the genetics influencing wood traits and identifies candidate genes for future functional studies.
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| 35. |
- Baison, John, et al.
(författare)
-
Genome-wide association study identified novel candidate loci affecting wood formation in Norway spruce
- 2019
-
Ingår i: The Plant Journal. - : John Wiley & Sons. - 0960-7412 .- 1365-313X. ; 100:1, s. 83-100
-
Tidskriftsartikel (refereegranskat)abstract
- Norway spruce is a boreal forest tree species of significant ecological and economic importance. Hence there is a strong imperative to dissect the genetics underlying important wood quality traits in the species. We performed a functional genome-wide association study (GWAS) of 17 wood traits in Norway spruce using 178 101 single nucleotide polymorphisms (SNPs) generated from exome genotyping of 517 mother trees. The wood traits were defined using functional modelling of wood properties across annual growth rings. We applied a Least Absolute Shrinkage and Selection Operator (LASSO-based) association mapping method using a functional multilocus mapping approach that utilizes latent traits, with a stability selection probability method as the hypothesis testing approach to determine a significant quantitative trait locus. The analysis provided 52 significant SNPs from 39 candidate genes, including genes previously implicated in wood formation and tree growth in spruce and other species. Our study represents a multilocus GWAS for complex wood traits in Norway spruce. The results advance our understanding of the genetics influencing wood traits and identifies candidate genes for future functional studies.
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| 36. |
- Becker, Joel, et al.
(författare)
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Resource profile and user guide of the Polygenic Index Repository
- 2021
-
Ingår i: Nature Human Behaviour. - : Nature Research (part of Springer Nature). - 2397-3374. ; 51:6, s. 694-695
-
Tidskriftsartikel (refereegranskat)abstract
- Polygenic indexes (PGIs) are DNA-based predictors. Their value for research in many scientific disciplines is growing rapidly. As a resource for researchers, we used a consistent methodology to construct PGIs for 47 phenotypes in 11 datasets. To maximize the PGIs’ prediction accuracies, we constructed them using genome-wide association studies—some not previously published—from multiple data sources, including 23andMe and UK Biobank. We present a theoretical framework to help interpret analyses involving PGIs. A key insight is that a PGI can be understood as an unbiased but noisy measure of a latent variable we call the ‘additive SNP factor’. Regressions in which the true regressor is this factor but the PGI is used as its proxy therefore suffer from errors-in-variables bias. We derive an estimator that corrects for the bias, illustrate the correction, and make a Python tool for implementing it publicly available. © 2021, The Author(s), under exclusive licence to Springer Nature Limited.
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| 37. |
- Bergkvist, Magnus, et al.
(författare)
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TM-AFM Threshold Analysis of Macromolecular Orientation : A Study of the Orientation of IgG and IgE on Mica Surfaces
- 1998
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Ingår i: Journal of Colloid and Interface Science. - : Elsevier BV. - 0021-9797 .- 1095-7103. ; 206:2, s. 475-481
-
Tidskriftsartikel (refereegranskat)abstract
- Adsorption and orientation properties of two different types of immunoglobulin molecules on derivatized and native mica surfaces were investigated using TM-AFM. The analyses included height measurements at two different pH values and a new technique, presented here as threshold analysis, which displays the outer mantle shape of an adsorbed protein. A major difference in preferential orientation is observed upon comparing the adsorption of the two proteins onto the different surfaces. The characteristics of both the adsorbed immunoglobulin and the surface are important for any preferential orientation of the adsorbed protein.
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| 38. |
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| 39. |
- Bergström, Gunnar, et al.
(författare)
-
Acceptanskriterier för repor och intryck i plaströr Accpetance criteria for scratches and indentations in plastic pipes
- 2009
-
Rapport (refereegranskat)abstract
- Development of materials and laying techniques have arisen the question how scratches and indentations in plastics pipes affect the strength and technical lifetime of pipelines. Scratches may occur both in the manufacturing of the pipes, in connection with the installation and subsequent maintenance. The problems in assessing the failure risk from scratches and indentations are similar for pipes used in gas and water distribution and in district heating applications. Therefore, a broad effort to identify the risks in relation to current pipe materials is technically and economically justified. The project has aimed to evaluate the effect of scratches and indentations on the technical lifetime of plastics pipes and to present criteria for maximum allowable depth of scratches and indentations. The study on pressure pipes focused on the conditions for scratched polyethylene pipes to achieve a lifetime of 50 years. It is noted that a scratch damage can not be judged solely on the basis of its depth and sharpness. To assess the impact of the scratch on the serviceability of the pipe, consideration must also be taken to the material from which the pipe was made and the safety factor used in the design. Extensive pressure tests show that pipes made of modern materials can withstand surface scratches to a higher degree than pipes of older materials. For pipes made of modern bimodal PE80 and PE100 materials, scratches up to 10% depth may be accepted without reduction of rated pressure. However, for pipes of older material, a reduction in pressure may be required already at smaller scratches. The study also indicates that for the same relative scratch depth, a greater reduction in pressure is required with increasing pipe dimension. The study on the non pressure pipes shows that the studied polypropylene pipes resist both deep scratches combined with ovalization and large indentations without any cracks penetrating the pipe wall. However, the extent and development of crazing and surface cracking vary with scratch depth, deformation level and material. The test pipes were subjected to extreme conditions very rarely or never occurring in practice. This suggests that small scratches at moderate ovalization and realistic indentations in temperatures around room temperature do not affect the lifetime of the pipes. One objective of the project was to develop a method for the evaluation of the scratch resistance of a pipe. In the proposed test method the force needed to produce a specified scratch is measured. This force is used as a relative measure of the scratch resistance of a pipe material when compared to other materials. In order to assess to what extent a scratch affects the lifetime of the pipe, the depth of the scratch must be estimated with reasonable accuracy. Since the scratch in many cases is found on existing pipelines the method must be suited for field use. To achieve that a simple instrument for scratch depth measurements was made and evaluated.
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| 40. |
- Bergström, Gunnar, et al.
(författare)
-
Accpetance criteria for scratches and indentations in plastic pipes
- 2009
-
Rapport (refereegranskat)abstract
- Development of materials and laying techniques have arisen the question how scratches and indentations in plastics pipes affect the strength and technical lifetime of pipelines. Scratches may occur both in the manufacturing of the pipes, in connection with the installation and subsequent maintenance. The problems in assessing the failure risk from scratches and indentations are similar for pipes used in gas and water distribution and in district heating applications. Therefore, a broad effort to identify the risks in relation to current pipe materials is technically and economically justified. The project has aimed to evaluate the effect of scratches and indentations on the technical lifetime of plastics pipes and to present criteria for maximum allowable depth of scratches and indentations. The study on pressure pipes focused on the conditions for scratched polyethylene pipes to achieve a lifetime of 50 years. It is noted that a scratch damage can not be judged solely on the basis of its depth and sharpness. To assess the impact of the scratch on the serviceability of the pipe, consideration must also be taken to the material from which the pipe was made and the safety factor used in the design. Extensive pressure tests show that pipes made of modern materials can withstand surface scratches to a higher degree than pipes of older materials. For pipes made of modern bimodal PE80 and PE100 materials, scratches up to 10% depth may be accepted without reduction of rated pressure. However, for pipes of older material, a reduction in pressure may be required already at smaller scratches. The study also indicates that for the same relative scratch depth, a greater reduction in pressure is required with increasing pipe dimension. The study on the non pressure pipes shows that the studied polypropylene pipes resist both deep scratches combined with ovalization and large indentations without any cracks penetrating the pipe wall. However, the extent and development of crazing and surface cracking vary with scratch depth, deformation level and material. The test pipes were subjected to extreme conditions very rarely or never occurring in practice. This suggests that small scratches at moderate ovalization and realistic indentations in temperatures around room temperature do not affect the lifetime of the pipes. One objective of the project was to develop a method for the evaluation of the scratch resistance of a pipe. In the proposed test method the force needed to produce a specified scratch is measured. This force is used as a relative measure of the scratch resistance of a pipe material when compared to other materials. In order to assess to what extent a scratch affects the lifetime of the pipe, the depth of the scratch must be estimated with reasonable accuracy. Since the scratch in many cases is found on existing pipelines the method must be suited for field use. To achieve that a simple instrument for scratch depth measurements was made and evaluated.
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| 41. |
- Bernesson, Sven, et al.
(författare)
-
Energieffektivisering i lantbruket : en litteraturstudie med fokus på svenska förhållanden
- 2023
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Inom jordbruket används stora mängder energi. Det finns dock möjlighet att effektivisera och reducera energianvändningen på många ställen inom de olika produktionsgrenarna. Även användningen av indirekt energi är stor inom jordbruket, vilket medför att effektivare användning av förnödenheter med flera insatsvaror leder till energisparande. Då flertalet studier som gjorts över energianvändningen och möjligheter till energieffektivisering är ganska gamla, och jordbruket under senare år genomgått en stor strukturomvandling mot allt större enheter samtidigt som mycket ny teknik utvecklats, finns ett behov av mera djupgående studier inom området.Syftet med den här studien är att sammanställa tillgänglig litteratur om energieffektivisering inom lantbruket. Fokus är på svenska förhållanden.I studien ingår åtgärder inom både fältarbeten och animalieproduktion. Inom fältarbeten har åtgärder såsom optimering och planering av arbetet för att minska körning och transporter stor betydelse. Arbetsstrategi, underhåll och skötsel av maskiner är viktigt, liksom investeringar i de energieffektivaste maskinerna. Inom animalieproduktion och byggnader kan åtgärderna ofta delas in i tre nivåer: den första nivån är inställningar, skötsel och underhåll såsom rengöring och planering m.m. som handlar om beteende; den andra nivån handlar om ombyggnad och komplettering av utrustning; och den tredje nivån innebär åtgärder som kräver större investeringar, såsom byte av system. Detta gäller bland annat för utfodring, mjölkning, gödselhantering, belysning och spannmålstorkning. Precisionsstyrning kan komma in som en typ av fjärde nivå inom både animalieproduktion och fältarbeten.Inom fältarbeten kan stora mängder energi sparas in genom att reducera jordbearbetningen. Framöver kan elektrifiering och automatiseringen av fältarbetena leda till betydande energibesparingar.Inom mjölkning, gödselhantering, uppvärmning, ventilation, belysning och spannmålstorkning finns en mängd åtgärder som tillsammans kan leda till betydande energibesparingar. Även i gårdsverkstäder kan mycket energi sparas in om dessa planeras och utformas på ett bra sätt, särskilt om de används mycket under den kalla årstiden.Inom jordbruket används stora mängder indirekt energi, bunden till förnödenheter såsom konstgödsel, foder, ensilageplast och drivmedel men även i mindre grad bekämpningsmedel, maskiner, byggmaterial, transporter, produktionsanläggningar, kalk och utsäde.I lantbruket utgör energianvändningen en del av mera omfattande system, vilka interagerar och påverkar varandra på en mängd olika sätt. Åtgärder för att reducera energianvändningen behöver därför normalt utvärderas med ett systemperspektiv.
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| 42. |
- Björkman, Sven, et al.
(författare)
-
Thermic and tremorogenic effects of thyroliberin (TRH) in reserpine-treated mice--the non-involvement of GABA-ergic mechanisms.
- 1981
-
Ingår i: Journal of Pharmacy and Pharmacology (JPP). - : Oxford University Press (OUP). - 0022-3573 .- 2042-7158. ; 33:9, s. 580-585
-
Tidskriftsartikel (refereegranskat)abstract
- Administration of thyroliberin (TRH) to reserpinized mice causes tremor and counteracts the hypothermia in a dose-dependent fashion. The thyroliberin response is inhibited by gamma-hydroxybutyric acid (GHB) and baclofen, but not by other, more specific GABA-ergic agents, such as THIP, gamma-acetylenic GABA, and sodium valproate. Picrotoxin neither potentiates nor inhibits the thyroliberin actions. Nor are the thyroliberin effects dependent on cholinergic, monoaminergic or histaminergic mechanisms. The results repudiate a current hypothesis, that the peptide actions may be mediated by GABA-ergic pathways in the brain.
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| 43. |
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| 44. |
- Bouchene, Salim, 1984-, et al.
(författare)
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A Whole-Body Physiologically Based Pharmacokinetic Model for Colistin and Colistin Methanesulfonate in Rat
- 2018
-
Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 123:4, s. 407-422
-
Tidskriftsartikel (refereegranskat)abstract
- Colistin is a polymyxin antibiotic used to treat patients infected with multidrug-resistant Gram-negative bacteria (MDR-GNB). The objective of this work was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model to predict tissue distribution of colistin in rat. The distribution of a drug in a tissue is commonly characterized by its tissue-to-plasma partition coefficient, K-p. Colistin and its prodrug, colistin methanesulfonate (CMS) K-p priors, were measured experimentally from rat tissue homogenates or predicted in silico. The PK parameters of both compounds were estimated fitting invivo their plasma concentration-time profiles from six rats receiving an i.v. bolus of CMS. The variability in the data was quantified by applying a nonlinear mixed effect (NLME) modelling approach. A WB-PBPK model was developed assuming a well-stirred and perfusion-limited distribution in tissue compartments. Prior information on tissue distribution of colistin and CMS was investigated following three scenarios: K-p was estimated using in silico K-p priors (I) or K-p was estimated using experimental K-p priors (II) or K-p was fixed to the experimental values (III). The WB-PBPK model best described colistin and CMS plasma concentration-time profiles in scenario II. Colistin-predicted concentrations in kidneys in scenario II were higher than in other tissues, which was consistent with its large experimental K-p prior. This might be explained by a high affinity of colistin for renal parenchyma and active reabsorption into the proximal tubular cells. In contrast, renal accumulation of colistin was not predicted in scenario I. Colistin and CMS clearance estimates were in agreement with published values. The developed model suggests using experimental priors over in silico K-p priors for kidneys to provide a better prediction of colistin renal distribution. Such models might serve in drug development for interspecies scaling and investigate the impact of disease state on colistin disposition.
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| 45. |
- Bouchene, Salim, 1984-, et al.
(författare)
-
A Whole-Body Physiologically Based Pharmacokinetic-Pharmacodynamic (WBPBPK-PD) Model for Colistin in Critically Ill Patients
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Objectives: Colistin is used as a salvage therapy for multidrug-resistant Gram-negative bacterial infections and administered as a prodrug, colistimethate sodium (CMS). Characterizing distribution of colistin at the site of infection is important to optimize bacterial killing. The aims of this analysis were (i) to apply a whole-body physiologically based pharmacokinetic (WPBPK) model structure to describe the pharmacokinetics (PK) of CMS and colistin in critically ill patients and (ii) to predict colistin concentration-time courses and bacterial killing in target tissues combining the WBPBPK model with a semi-mechanistic pharmacokinetic-pharmacodynamic (PKPD) model.Methods: 27 critically ill patients treated with colistin were included in the analysis. A WBPBPK model previously developed in rat was applied to describe CMS and colistin PK data. The model was used to predict tissue concentrations in lungs, skin, blood and kidneys to drive a semi-mechanistic PKPD model on a wild-type (ATCC 27853) or a meropenem-resistant (AUR552) clinical strain P. aeruginosa to predict bacterial killing following the original dosing regimen and by replacing the original initial dose with a loading dose of 9MU.Results: The plasma data were reasonably well described by the WBPBPK model for both CMS and colistin with a slight overprediction at the 1st occasion. High exposure was predicted in kidneys comparable to what had been predicted in previous studies, in rat and healthy subjects. Bacterial load was quickly cleared for both the ATCC 27853 and ARU552 strains in all tissues and at a higher extend in kidney tissue, for all dosing scenarios.Conclusion: The WPBPK model was able to adequately describe the PK of CMS and colistin in critically ill patients. The combination of the predicted PK profiles in tissues of interest with a PKPD model was able to predict the bactericidal effect of colistin at target sites.
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| 46. |
- Bouchene, Salim, 1984-, et al.
(författare)
-
Application of a whole-body physiologically based pharmacokinetic model to describe the plasma and urine disposition of colistin and colistin methanesulfonate (CMS) in healthy volunteers
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Objectives: The primary aim of this work was to develop a whole-body physiologically based pharmacokinetic (WBPBPK) model to describe CMS and colistin disposition in human plasma and urine. The secondary aim of this analysis was to use the WBPBPK model to predict CMS and colistin tissue distribution in typical individuals with different pathophysiological changes and receiving different dosing regimens.Methods: Twelve healthy males were included in the analysis. They received a single dose of 80 mg CMS (1 million unit) through a 1-h intravenous infusion. Venous blood was collected between 0 and 18 h post dose. Fractionated urine samples were collected between 0 and 24 h after dose. A WBPBPK model initially developed in rat was further detailed with the addition of a specific urinary tract (UT) model. The Kp values of CMS and colistin were estimated for all tissues using experimental Kp prior values from rat tissue homogenates.Results: The model adequately described CMS and colistin concentrations over time in plasma and in urine. A shared first order elimination rate constant was estimated to depict the hydrolysis of CMS in plasma and tissues. A separate hydrolysis rate constant for CMS was estimated in urine, and was lower than in plasma and tissues. A shared non-renal elimination rate constant of colistin was estimated in plasma and in tissues. CMS and colistin disposition in urine was well characterized by the UT model. The tubular reabsorption of colistin was best described by a saturable model estimating the colistin affinity constant, KM. Non-specific binding of colistin in the UT lumen was accounted for using a linear relationship.Conclusion: The WBPBPK developed in this study characterized plasma and urine PK of CMS and colistin in human well. This model was used as a new framework to predict colistin exposure in the tissues of interest under different physiological conditions. The model can be easily refined when new data are available and can be combined to PKPD models to increase the understanding of the concentration-effect relationship at target sites.
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| 47. |
- Bouchene, Salim, et al.
(författare)
-
Development of a Whole-Body Physiologically Based Pharmacokinetic Model for Colistin and Colistin methanesulfonate (CMS) in Rat
-
Tidskriftsartikel (refereegranskat)abstract
- Colistin is a polymyxin antibiotic which is used to treat patients infected with multidrug resistant Gram negative bacteria (MDR-GNB). The objective of this work was to develop a whole-body physiologically based pharmacokinetic (WBPBPK) model in rat for colistin and its prodrug, CMS. The Kp prior values of colisin and CMS used in the WBPBPK model were either measured ex vivo in rat tissue homogenates or calculated using an in silico model. The PK parameters were estimated fitting plasma concentrations from rats receiving an i.v. bolus of CMS. In the WBPBPK model, the tissue distribution was assumed to be well-stirred and perfusion-limited. Three scenarios were investigated: estimating the Kp values using in silico Kp prior values (I), estimating the Kp values using the Kp prior values from ex vivo experiments (II) and fixing the Kp values to the experimental ex vivo Kp values (III). The WBPBPK model well described CMS and colistin plasma concentration-time profiles. Colistin Kp values in kidneys were higher than in the other tissues. The predicted concentrations in tissue were highest for kidneys and brain which might be due to a high affinity for these tissues and/or active transport processes that remain poorly elucidated. The clearance estimates of CMS and colistin were in agreement with previously reported values in the literature. The model developed in this study might be a valuable tool in drug development to understand the disposition of colistin or new polymyxin candidates as well as to guide for optimal dosing regimens.
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| 48. |
- Bouchene, Salim, 1984-, et al.
(författare)
-
Development of an interspecies whole-body physiologically based pharmacokinetic (WBPBPK) model for colistin methanesulfonate (CMS) and colistin in five animal species and evaluation of its predictive ability in human
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background and purposeColistin is a last-line antibiotic administered as the prodrug colistin methanesulfonate (CMS) for the treatment of multidrug resistant Gram-negative bacterial infections. Whole-body physiologically based pharmacokinetic (WBPBPK) models are valuable tools to understand and characterize drug disposition, predict tissue distribution and interpret exposure-response relationship. The aim of this work was to develop a WBPBPK model for colistin and CMS in five animal species and evaluate the utility of the model for predicting colistin and CMS disposition in human.MethodsA nonlinear mixed-effects WBPBPK model previously developed in rats was extended to describe CMS and colistin plasma data of animals from 5 different species (40 mice, 6 rats, 3 rabbits, 3 baboons and 2 pigs) that had received single doses of CMS. CMS renal clearance and hydrolysis to colistin were allometrically scaled based on glomerular filtration rate (GFR) and tissue volumes, respectively. For the non-renal colistin clearance, three scaling models were evaluated: volume based allometric scaling, volume and maximum lifespan potential (MLP) based allometric scaling, and estimation of specie-specific parameters. Tissue concentrations were predicted for all species. The WBPBPK model was then used to predict human plasma concentrations, which were compared to observed human plasma PK data extracted from literature.ResultsThe description of the plasma PK of CMS and colistin in mice, rats, rabbits, baboons and pigs was satisfactory. The volume and MLP based allometric scaling of the non-renal clearance of colistin was best at characterizing colistin concentration-time course, even if a misprediction remained in pigs. In human however, allometric scaling without MLP was closest to the observed data, with satisfactory prediction of the CMS plasma profiles and a slight overprediction of colistin plasma PK profiles.ConclusionsInterspecies WBPBPK models were developed to describe the disposition of CMS and colistin across five animal species and human plasma concentrations of CMS and colistin were predicted in the right ranges.
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| 49. |
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| 50. |
- Braekeveldt, Noémie, et al.
(författare)
-
Patient-derived xenograft models reveal intratumor heterogeneity and temporal stability in neuroblastoma
- 2018
-
Ingår i: Cancer Research. - 0008-5472. ; 78:20, s. 5958-5969
-
Tidskriftsartikel (refereegranskat)abstract
- Patient-derived xenografts (PDX) and the Avatar, a single PDX mirroring an individual patient, are emerging tools in preclinical cancer research. However, the consequences of intratumor heterogeneity for PDX modeling of biomarkers, target identification, and treatment decisions remain underexplored. In this study, we undertook serial passaging and comprehensive molecular analysis of neuroblastoma orthotopic PDXs, which revealed strong intrinsic genetic, transcriptional, and phenotypic stability for more than 2 years. The PDXs showed preserved neuroblastoma-associated gene signatures that correlated with poor clinical outcome in a large cohort of patients with neuroblastoma. Furthermore, we captured spatial intratumor heterogeneity using ten PDXs from a single high-risk patient tumor. We observed diverse growth rates, transcriptional, proteomic, and phosphoproteomic profiles. PDX-derived transcriptional profiles were associated with diverse clinical characteristics in patients with high-risk neuroblastoma. These data suggest that high-risk neuroblastoma contains elements of both temporal stability and spatial intratumor heterogeneity, the latter of which complicates clinical translation of personalized PDX-Avatar studies into preclinical cancer research.
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