| 31. |
- Engdahl, Cecilia, et al.
(författare)
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The Rift Valley Fever virus protein NSm and putative cellular protein interactions
- 2012
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Ingår i: Virology Journal. - 1743-422X. ; 9, s. 139-
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Tidskriftsartikel (refereegranskat)abstract
- Rift Valley Fever is an infectious viral disease and an emerging problem in many countries of Africa and on the Arabian Peninsula. The causative virus is predominantly transmitted by mosquitoes and high mortality and abortion rates characterize outbreaks in animals while symptoms ranging from mild to life-threatening encephalitis and hemorrhagic fever are noticed among infected humans. For a better prevention and treatment of the infection, an increased knowledge of the infectious process of the virus is required. The focus of this work was to identify protein-protein interactions between the non-structural protein (NSm), encoded by the M-segment of the virus, and host cell proteins. This study was initiated by screening approximately 26 million cDNA clones of a mouse embryonic cDNA library for interactions with the NSm protein using a yeast two-hybrid system. We have identified nine murine proteins that interact with NSm protein of Rift Valley Fever virus, and the putative protein-protein interactions were confirmed by growth selection procedures and beta-gal activity measurements. Our results suggest that the cleavage and polyadenylation specificity factor subunit 2 (Cpsf2), the peptidyl-prolyl cistrans isomerase (cyclophilin)-like 2 protein (Ppil2), and the synaptosome-associated protein of 25 kDa (SNAP-25) are the most promising targets for the NSm protein of the virus during an infection.
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| 32. |
- Engström, Elisabet, et al.
(författare)
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Auditory event-related potentials and mismatch negativity in children with hearing loss using hearing aids or cochlear implants : A three-year follow-up study
- 2021
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Ingår i: International Journal of Pediatric Otorhinolaryngology. - : Elsevier. - 0165-5876 .- 1872-8464. ; 140
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The primary aim was to examine how event-related potentials (ERPs) and mismatch negativity (MMN) change and develop over time among children with hearing loss (HL) using hearing aids (HAs) or cochlear implants (CIs). Children with normal hearing (NH) were tested as a reference group.Methods: This three-year follow-up study included 13 children with sensorineural HL (SNHL); 7 children using bilateral HAs and 6 children using CIs; and 10 children with NH as a reference group. ERPs were recorded at baseline and after three years. At time for the original study the children were approximately 5-8 years old and at the follow-up study 8-11 years old. ERP recordings and data processing were identical in both sessions. A standard stimulus alternated with five different deviants (gap, intensity, pitch, location and duration), presented in a pseudorandom sequence, thus following the multi-feature paradigm, Optimum-1. MMN was calculated from the average ERP of each deviant minus the standard stimuli. Repeated measures ANOVA was used for the statistical analyses and the results were based on samples within a specific time interval; 80-224 ms.Results: There was a statistically significant difference in the obligatory responses between the NH and HA groups at baseline, but this difference disappeared after three years in our follow-up study. The children with HA also showed a significant difference in mean ERP at baseline compared to follow-up, and significant differences between the deviants at follow-up but not at baseline. This suggests an improvement over time among the children with HAs. On the other hand, the children with CIs did not differ from the NH children at baseline, but after three years their mean ERP was significantly lower compared to both the children with HA and NH, indicating a reduced development of the central auditory system in this age span among the children with CIs. Regarding MMN, there was an interaction between the duration deviant and time for the children with HA, also indicating a possible improvement over time among the HA children.Conclusions: This three-year follow-up study shows neurophysiological differences between children with HL and children with NH. The results suggest a delay in the central auditory processing among the HA children compared to children with NH, but a possible catch-up, over time, and this potential may be worth to be utilized. Regarding the CI children, similar improvement in this age span is missing, meaning there are differences between the subgroups of children with HL, i.e. the children with HAs vs. CIs. The results highlight the importance of distinguishing between subgroups of children with HL in further research.
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| 33. |
- Engström, Elisabet, et al.
(författare)
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Computer-assisted reading intervention for children with hearing impairment using cochlear implants : Effects on auditory event-related potentials and mismatch negativity
- 2020
-
Ingår i: International Journal of Pediatric Otorhinolaryngology. - : Elsevier. - 0165-5876 .- 1872-8464. ; 137
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The primary aim was to find out whether a computer-assisted reading intervention program with a phonic approach can affect event-related (ERPs) and mismatch negativity (MMN) in hearing impaired (HI) children using cochlear implants (CIs).METHODS: This study involved a test group of 15 HI children with CIs and a control group of 14 normal hearing (NH) children. The children were 4 years and 10 months to 8 years and 1 month old. ERPs were recorded immediately before and after 4 weeks of training with a computer-assisted reading intervention, GraphoGame. A multi-feature paradigm, Optimum-1, was used, i.e. a standard stimulus alternated with five different deviants: gap intensity, pitch, location and duration. MMN was calculated from the mean amplitude ERP of each deviant minus the standard stimulus response in a specific time interval, 80 - 224 ms. Repeated measures ANOVA was used for the statistical analysis.RESULTS: The results did not show any significant changes with the computerassisted training in the ERPs and MMNs among the HI children with CIs. The presence of both MMN and a positive mismatch response (pMMR), which might reflect an immaturity, complicates interpreting the results in this age group. Individually, there was a mix of MMNs and pMMRs among all participants, pre and post training, and the change of each deviant after intervention was not predictable.CONCLUSIONS: There are no significant changes in ERP or MMN after intervention, however lack of significances must be interpreted with caution. Besides the presence of both MMNs and pMMRs, only modest changes are to be expected on an individual basis and small samples hinder making statistical conclusions regarding the training's effects. The study contributes to some more descriptive pieces of ERPs and MMNs among the HI children with CIs. The issues of MMN and pMMR are highlighted.
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| 34. |
- Engström, Elisabet, et al.
(författare)
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Computer-assisted reading intervention for children with sensorineural hearing loss using hearing aids : Effects on auditory event-related potentials and mismatch negativity
- 2019
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Ingår i: International Journal of Pediatric Otorhinolaryngology. - : Elsevier. - 0165-5876 .- 1872-8464. ; 117, s. 17-25
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The primary aim was to investigate whether computer-assisted reading intervention somehow can affect event-related potentials (ERP) and mismatch negativity (MMN) in hearing impaired (HI) children with hearing aids (HAs) and normal hearing (NH) children.METHODS: The study included 15 HI children with sensorineural hearing loss (SNHL) using bilateral HAs and 14 NH children as a reference group; all children between the ages of 5 and 8. A multi-feature MMN-paradigm, Optimum-1, with a standard stimulus alternating with 5 different deviants was used. ERPs were recorded pre and post intervention, i.e. one month of repeatedly computer-assisted training (GraphoGame). MMN was calculated from the average ERP of each deviant minus standard. Data were based on samples within a specific time interval, 80-224 ms, and repeated measures ANOVA was used to analyze possible interactions.RESULTS: There was a significant difference between groups before training, though, the mean obligatory responses or MMN was not statistically significantly different before versus after training, neither among the NH nor the HI children. Further, the HI children did generally achieve lower levels in GraphoGame compared to the NH children. Altogether, our findings indicate differences between the groups and that training may affect the neurophysiological processing in the brain, gaining the HI children. Both MMN and positive mismatch response (pMMR) were seen among both the HA and NH children, irrespective to deviant type. Individually, changes of the MMN and pMMR after training seem unpredictable.CONCLUSION: There are statistically significant differences in both the obligatory responses in ERP and the MMNs between the NH and HI groups before the computer-assisted training. Though, these differences disappear after the intervention. This suggests possible training effects regarding the central auditory processing among the HI children.
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| 35. |
- Evangelou, Evangelos, et al.
(författare)
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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
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Tidskriftsartikel (refereegranskat)abstract
- High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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| 36. |
- Fall, Tove, et al.
(författare)
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The Role of Adiposity in Cardiometabolic Traits : A Mendelian Randomization Analysis
- 2013
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 10:6, s. e1001474-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. Methods and Findings: We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age-and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001). Conclusions: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
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| 37. |
- Flannick, Jason, et al.
(författare)
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Data Descriptor : Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
- 2017
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Ingår i: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
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| 38. |
- Flannick, Jason, et al.
(författare)
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Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 46:4, s. 357-357
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Tidskriftsartikel (refereegranskat)abstract
- Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ∼150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
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| 39. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 40. |
- Folkersen, Lasse, et al.
(författare)
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Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease
- 2017
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Ingår i: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- Recent advances in highly multiplexed immunoassays have allowed systematic large-scale measurement of hundreds of plasma proteins in large cohort studies. In combination with genotyping, such studies offer the prospect to 1) identify mechanisms involved with regulation of protein expression in plasma, and 2) determine whether the plasma proteins are likely to be causally implicated in disease. We report here the results of genome-wide association (GWA) studies of 83 proteins considered relevant to cardiovascular disease (CVD), measured in 3,394 individuals with multiple CVD risk factors. We identified 79 genome-wide significant (p<5e-8) association signals, 55 of which replicated at P<0.0007 in separate validation studies (n = 2,639 individuals). Using automated text mining, manual curation, and network-based methods incorporating information on expression quantitative trait loci (eQTL), we propose plausible causal mechanisms for 25 trans-acting loci, including a potential post-translational regulation of stem cell factor by matrix metalloproteinase 9 and receptor-ligand pairs such as RANK-RANK ligand. Using public GWA study data, we further evaluate all 79 loci for their causal effect on coronary artery disease, and highlight several potentially causal associations. Overall, a majority of the plasma proteins studied showed evidence of regulation at the genetic level. Our results enable future studies of the causal architecture of human disease, which in turn should aid discovery of new drug targets.
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