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| 2. |
- Adoue, Veronique, et al.
(author)
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Allelic expression mapping across cellular lineages to establish impact of non-coding SNPs
- 2014
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In: Molecular Systems Biology. - : EMBO. - 1744-4292 .- 1744-4292. ; 10:10, s. 754-
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Journal article (peer-reviewed)abstract
- Most complex disease-associated genetic variants are located in non-coding regions and are therefore thought to be regulatory in nature. Association mapping of differential allelic expression (AE) is a powerful method to identify SNPs with direct cis-regulatory impact (cis-rSNPs). We used AE mapping to identify cis-rSNPs regulating gene expression in 55 and 63 HapMap lymphoblastoid cell lines from a Caucasian and an African population, respectively, 70 fibroblast cell lines, and 188 purified monocyte samples and found 40-60% of these cis-rSNPs to be shared across cell types. We uncover a new class of cis-rSNPs, which disrupt footprint-derived de novo motifs that are predominantly bound by repressive factors and are implicated in disease susceptibility through overlaps with GWAS SNPs. Finally, we provide the proof-of-principle for a new approach for genome-wide functional validation of transcription factor-SNP interactions. By perturbing NFκB action in lymphoblasts, we identified 489 cis-regulated transcripts with altered AE after NFκB perturbation. Altogether, we perform a comprehensive analysis of cis-variation in four cell populations and provide new tools for the identification of functional variants associated to complex diseases.
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| 3. |
- Aleman, Soo, et al.
(author)
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A Risk for Hepatocellular Carcinoma Persists Long-term After Sustained Virologic Response in Patients With Hepatitis C-Associated Liver Cirrhosis
- 2013
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In: Clinical Infectious Diseases. - : Oxford University Press (OUP). - 1537-6591 .- 1058-4838. ; 57:2, s. 230-236
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Journal article (peer-reviewed)abstract
- Background. The long-term effect of sustained virologic response (SVR) to antiviral therapy on the risk of developing hepatocellular carcinoma (HCC), liver complications, liver-related death, and overall death in hepatitis C virus (HCV)-infected patients with liver cirrhosis is not fully known. Methods. These risks were evaluated during long-term follow-up in 351 patients with HCV-related cirrhosis. One hundred ten patients with SVR, 193 with non-SVR, and 48 who were untreated were included in a multicenter cohort that was initiated in 2001 and prospectively followed up for a mean of 5.3 (SD, 2.8) years. Complementary follow-up data from national registries were used to minimize the loss of patients during follow-up. Results. Six patients with SVR developed HCC at 0.04, 0.64, 2.4, 7.4, 7.4, and 7.6 years, respectively, after achieving SVR. The incidences of HCC, any liver complication, liver-related death, and overall death per 100 person-years were significantly lower in SVR time with 1.0, 0.9, 0.7, and 1.9, compared to 2.3, 3.2, 3.0, and 4.1 in non-SVR and 4.0, 4.9, 4.5, and 5.1 in untreated time. The long-term consequences did not decline significantly after >3 years versus during the first 3 years of follow-up. Conclusions. The risk for HCC, liver decompensation, and death in patients with liver cirrhosis related to HCV was markedly reduced after SVR, but a long-term risk of developing HCC remains for up to 8 years. Cirrhotic patients with HCV who achieve SVR should therefore maintain long-term surveillance for HCC. Future studies aimed to better identify those with remaining long-term risk for HCC are needed.
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| 4. |
- Carlsson, Christer, et al.
(author)
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Consensus in distributed soft environments
- 1992
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In: European Journal of Operational Research. - : Elsevier. - 0377-2217 .- 1872-6860. ; 61:1-2, s. 165-185
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Journal article (peer-reviewed)abstract
- This paper studies the problem of formalizing consensus reaching within a set of decision makers trying to find and agree upon a mutual decision. Decision makers produce their individual rankings, using their own pet decision schemas. Thus consensus reaching relies only on the aggregation of individual decisions rather than on individual decision procedures. The aggregation of the individual rankings is supported by an advising monitor which tries to contract the decision makers into a mutual decision through soft enforcement. Convergence to consensus then depends upon the decision makers' willingness to compromise. We use a topological approach to consensus where we can measure distances between decision makers. Within the approach we can also model the trade-off between a degree of consensus and a strength of majority.
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| 5. |
- Carlsson, Tony
(author)
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Hepatitis C virus kinetics during antiviral treatment
- 2004
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Doctoral thesis (other academic/artistic)abstract
- It is estimated that 170 million individuals have chronic hepatitis C virus (HCV) infection, whereof 20-30% will develop end stage liver disease within 20-30 years. Antiviral therapy can stop this deterioration and clear the infection in 40-80% of the patients depending on treatment and HCV genotype. Suboptimal therapy, however, is likely to promote selection of resistance and emergence of escape mutants and an unfavourable treatment outcome. We studied the early HCV RNA kinetics during different antiviral treatment schemes and correlated the early viral decay to the eventual virological outcome with regard to the different genotypes. In paper I the addition of amantadine to IFN and ribavirin during 24 weeks treatment of 10 former responder/relapsers and 13 non-responders to standard IFN and ribavirin combination therapy was found to have only limited beneficial effect. At end of treatment, only one previous non-responder and 5 previous response/relapsers were HCV RNA negative but only one former response/relapser had sustained response. In paper II a more pronounced viral decline was seen with induction therapy, when standard IFN was given as mono-therapy daily initially during treatment, as compared to when it was given as standard dosing three times a week (t.i.w.). This difference persisted during the initial 12 weeks for patients infected with genotype 1, but was not maintained from day 14 and onwards for patients infected with genotype non-1. Eighty percent of patients in the induction group versus 16% in the standard t.i.w. group achieved undetectable HCV RNA levels (<600 IU/mL) at week 12 (p<0.05). In paper IV IFN induction mono-therapy resulted in a more pronounced HCV RNA decline at weeks 4, 8, and 12 compared to standard treatment. Most sustained responders were found to have a >3 log10 drop in serum HCV RNA levels week 4. Addition of ribavirin after 12 weeks IFN mono-therapy in two non-responders reverted them to sustained responders. In paper III IFN induction therapy, in combination with ribavirin during treatment of naive patients, also resulted in a small but significantly more pronounced HCV RNA decline compared to standard dosing, in genotype non-1 infected patients but only day 2 and 7 during treatment, in contrast to what was found when IFN mono-therapy was given when this difference was more pronounced. The mean HCV RNA decline from baseline already day 1 was significantly greater in patients who became sustained virological responders as compared to non-responders. Hence, all sustained responders had a viral load decline of minimum 0.7 log (79%) after the first dose of standard IFN, whereas a lack of such response predicted a non-response. In paper V pegylated-IFN alpha-2a (peg-IFN) was used in combination with ribavirin in naive patients. No difference in the decline of HCV RNA levels was noted between responders and non-responders after the first treatment day. At week 1 and week 4, however, sustained responders had a significantly more pronounced drop in HCV RNA levels as compared to response/relapsers and non-responders. Hence, the HCV RNA decline day 1 could not be used for prediction of response to peg-IFN treatment. At week 1, however, a positive predictive value of 92% was noted for a final virological sustained response in the subgroup of patients who had achieved a 2 log10 drop in HCV RNA levels. The best time point for prediction of a non-response was week 12 when a negative predictive value of 92% was noted in patients who did not meet this criterion.
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| 6. |
- Ek, Staffan, et al.
(author)
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A 28-nm FD-SOI 115-fs Jitter PLL-Based LO System for 24-30-GHz Sliding-IF 5G Transceivers
- 2018
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In: IEEE Journal of Solid-State Circuits. - 0018-9200. ; 53:7, s. 1988-2000
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Journal article (peer-reviewed)abstract
- A system for local oscillator (LO) signal generation in 5G millimeter-wave (mmW) multi-antenna transceivers is presented. The system is modular with one phase locked loop (PLL) per antenna element transceiver, and a test circuit implemented in 28-nm fully depleted silicon on insulator (FD-SOI) CMOS features two such PLLs and a 491.52 MHz crystal oscillator (XO) generating a common frequency reference. A fractional-N architecture is employed to achieve high-frequency resolution, and the quantization noise is reduced using a novel frequency divider, which achieves full integer resolution while still using a pre-scaler. The system covers the 3rd Generation Partnership Project (3GPP) bands n257 and n258, achieved by a digital coarse tuning of the voltage-controlled oscillator (VCO). The chip area of each PLL is 0.11 mm², and 0.029 mm² for the XO. The total power consumption of the system is 35 mW, where each PLL consumes 15.4 mW and the XO consumes 0.84 mW. The total rms jitter from 20-kHz to 500-MHz offset for a 26-GHz carrier is just 115 fs, corresponding to an FOMj of -244 dB, which is the best reported figure for a fractional-N PLL above 15 GHz. The error-vector magnitude (EVM) due to phase noise is -34.6 dBc using an orthogonal frequency-division multiplexing (OFDM) signal with 120-kHz sub-carrier spacing, sufficient to support 256 QAM.
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| 7. |
- Fagerberg, Tony, et al.
(author)
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A large molecular size fraction of riverine high molecular weight dissolved organic matter (HMW DOM) stimulates growth of the harmful dinoflagellate Alexandrium minutum
- 2009
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In: Harmful Algae. - : Elsevier BV. - 1878-1470 .- 1568-9883. ; 8:6, s. 823-831
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Journal article (peer-reviewed)abstract
- An increase in the concentration of riverine dissolved organic matter (DOM) has been observed during the last decades, and this material can stimulate marine plankton in coastal waters with significant freshwater input. We studied the effect of two size fractions of riverine high molecular weight dissolved organic matter (HMW DOM), isolated with tangential ultrafiltration, on the harmful dinoflagellate Alexandrium minutum and a natural isolate of marine bacteria under laboratory conditions. Both A. minutum and bacteria grew significantly better with the low MW DOM compared to both the high MW DOM fraction and controls (no DOM additions). This experiment demonstrates that the harmful algae A. minutum and bacteria benefit from larger molecules of river HMW DOM, and highlights the potential of A. minutum to utilize organic nitrogen from large DOM molecules. This ability may enhance their likelihood of success in estuaries/costal waters with a humic rich freshwater input, especially when the relative amount of large molecules within DOM is more pronounced.
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| 8. |
- Fagerberg, Tony, et al.
(author)
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Molecular size of riverine dissolved organic matter influences coastal phytoplankton communities
- 2010
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In: Marine Ecology - Progress Series. - : Inter-Research Science Center. - 1616-1599 .- 0171-8630. ; 409, s. 17-25
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Journal article (peer-reviewed)abstract
- Dissolved organic matter (DOM) concentrations in many northern European freshwater systems have been increasing during the past decades. DOM affects the marine plankton community where rivers discharge into the sea. Large DOM molecules have been suggested to be more available to aquatic plankton than smaller ones due to their more recent origin in the degradation process. In this study, we investigated the effect of riverine DOM molecular size on coastal plankton with the hypothesis that nitrogen associated with large molecules stimulates the plankton more than nitrogen in smaller molecules. Three size fractions of riverine DOM were isolated with tangential ultrafiltration and introduced at similar nitrogen concentrations to mesocosms with a natural coastal marine plankton community under nitrogen limiting conditions. The results show that growth of bacteria and dinoflagellates, but not diatoms, was stimulated by addition of large DOM molecules. Even though organic nitrogen concentrations tended to decrease more in large DOM treatments compared to smaller DOM treatments, no significant differences were detected. However, proteolytic enzyme activities were elevated in treatments with the largest DOM molecules, suggesting that more organic nitrogen was utilized in this treatment. We suggest that input of larger river DOM molecules to nitrogen limited coastal systems may influence the composition of the coastal phytoplankton community in favour of dinoflagellates.
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| 9. |
- Jephson, Therese, et al.
(author)
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Dependency of dinoflagellate vertical migration on salinity stratification
- 2011
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In: Aquatic Microbial Ecology. - : Inter-Research Science Center. - 0948-3055 .- 1616-1564. ; 63:3, s. 255-264
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Journal article (peer-reviewed)abstract
- Increasing precipitation and surface water temperature due to global change may strengthen the salinity gradient in coastal regions, which could influence the behaviour of dinoflagellate migration. We studied diel vertical migration (DVM) behaviour in the dinoflagellates Prorocentrum minimum and Heterocapsa triquetra using vertically stratified laboratory columns with 3 different salinity gradients (difference of 6, 11 and 16 psu). With nutrient-depleted conditions at the surface, and with nutrients added below the halocline, P. minimum remained mainly concentrated in the bottom water, while H. triquetra performed DVM under all 3 salinity treatments. H. triquetra migrated through a salinity difference of 6 and 11 psu, concentrated at the surface at noon, then migrated to the nutrient-rich bottom water during the night. A salinity gradient of 16, however, stopped H. triquetra cells from moving through the gradient and resulted in a concentration of cells in the cline during the night. At midday, cells were again found at the surface. P. minimum and H. triquetra grown in 4 different salinities (10, 15, 20, 26 psu) and at 3 different temperatures (10, 15, 20 degrees C) showed higher specific growth rates with increasing temperature only in the 2 highest salinity treatments. At 10 degrees C, specific growth rates were not affected by different salinities.
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| 10. |
- Jephson, Therese, et al.
(author)
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Dominant impact of water exchange and disruption of stratification on dinoflagellate vertical distribution
- 2012
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In: Estuarine, Coastal and Shelf Science. - : Elsevier BV. - 1096-0015 .- 0272-7714. ; 112, s. 198-206
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Journal article (peer-reviewed)abstract
- The vertical positions of four dinoflagellate species in three 48 h periods in late summer in a Swedish fjord (the Gullmar Fjord) reflect changes to the depth of the halocline. During stable, stratified conditions, the chlorophyll a maximum exhibited a diurnal migration pattern, which was disrupted when the halocline was forced closer to the surface by the inflow of more saline water. While conditions were stable, all studied dinoflagellate species were most abundant below the halocline at 06:00 in contrast to the other times of the day when the highest cell concentrations were above the halocline, indicating diurnal vertical migration. However, when wind-induced inflow of more saline water forced the halocline closer to the surface, these patterns were disrupted and there was no sign of diurnal vertical migration. Despite this, there was a vertical heterogeneity in the distribution of dinoflagellates with Dinophysis spp. found mainly above the halocline, while Ceratium spp. also occurred in high cell numbers below the halocline. We acknowledge the importance of representative resolution when sampling in the field, both in time and concerning vertical resolution. (C) 2012 Elsevier Ltd. All rights reserved.
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