| 1. |
- Do, Ron, et al.
(författare)
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Common variants associated with plasma triglycerides and risk for coronary artery disease
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1345-
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Tidskriftsartikel (refereegranskat)abstract
- Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
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| 2. |
- Egeblad, Louise, et al.
(författare)
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Structural and functional studies of the human phosphoribosyltransferase domain containing protein 1
- 2010
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Ingår i: The FEBS Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 277:23, s. 4920-30
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Tidskriftsartikel (refereegranskat)abstract
- Human hypoxanthine-guanine phosphoribosyltransferase (HPRT) (EC 2.4.2.8) catalyzes the conversion of hypoxanthine and guanine to their respective nucleoside monophosphates. Human HPRT deficiency as a result of genetic mutations is linked to both Lesch-Nyhan disease and gout. In the present study, we have characterized phosphoribosyltransferase domain containing protein 1 (PRTFDC1), a human HPRT homolog of unknown function. The PRTFDC1 structure has been determined at 1.7 Å resolution with bound GMP. The overall structure and GMP binding mode are very similar to that observed for HPRT. Using a thermal-melt assay, a nucleotide metabolome library was screened against PRTFDC1 and revealed that hypoxanthine and guanine specifically interacted with the enzyme. It was subsequently confirmed that PRTFDC1 could convert these two bases into their corresponding nucleoside monophosphate. However, the catalytic efficiency (k(cat)/K(m)) of PRTFDC1 towards hypoxanthine and guanine was only 0.26% and 0.09%, respectively, of that of HPRT. This low activity could be explained by the fact that PRTFDC1 has a Gly in the position of the proposed catalytic Asp of HPRT. In PRTFDC1, a water molecule at the position of the aspartic acid side chain position in HPRT might be responsible for the low activity observed by acting as a weak base. The data obtained in the present study indicate that PRTFDC1 does not have a direct catalytic role in the nucleotide salvage pathway.
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| 3. |
- Johansson, Håkan, et al.
(författare)
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Practicing empty talk - Compliance and resistance to normative control among caseworkers in the Swedish Public Employment Service
- 2022
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Ingår i: Sociologisk Forskning. - : Sociologisk Forskning, Swedish Sociological Association. - 0038-0342 .- 2002-066X. ; 59:3, s. 299-320
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Tidskriftsartikel (refereegranskat)abstract
- This article draws on theories of normative control and critical management studies to investigate caseworkers’ strategies in correspondence to a new leadership philosophy in the Swedish Public Employment Service called self-leadership. Based on 43 interviews and observations at two local offices, we find that managerial models are arbitrary and cause uncertainty at the local level as caseworkers both comply and resist managerial talk of self-leadership. Based on a distinction between types of and grounds for strategic responses, we identify four subject positions defined as “personal embracement”, “personal detachment”, “professional recognition” and “professional dismissal”. The study shows that newly employed comply through practices of personal embracement, while senior employees resist based on professional dismissal. The article concludes that caseworkers are not docile bodies, who adjust to managerial talk, but derive their identity, engagement and esteem linked to a shared-work identity as organisational professionals. This demonstrates the relevance of closing the gap between street-level bureaucracy and critical management studies to further explore the tension between governing “employees” or “professionals” in contemporary public welfare governance.
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| 4. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 5. |
- Speliotes, Elizabeth K., et al.
(författare)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 6. |
- Willer, Cristen J., et al.
(författare)
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Discovery and refinement of loci associated with lipid levels
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1274-1283
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Tidskriftsartikel (refereegranskat)abstract
- Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 x 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
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| 7. |
- Andersson, Gerhard, Professor, 1988-, et al.
(författare)
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Individually tailored Internet-delivered cognitive-behavioral therapy for survivors of intimate partner violence : A randomized controlled pilot trial
- 2021
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Ingår i: Internet Interventions. - : Elsevier BV. - 2214-7829. ; 26
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Tidskriftsartikel (refereegranskat)abstract
- Intimate partner violence (IPV) is a serious public health concern worldwide and defined as behavior performed by spouses or other intimate partners that causes physical, sexual, or psychological harm. Internet-delivered cognitive-behavioral therapy (ICBT) may be particularly useful for survivors of IPV for several reasons, including barriers pertaining to limited community recourses and treatment availability, safety concerns, and issues of stigma, guilt and shame, which may prevent members of this population from seeking help via face-to-face interactions. However, Internet interventions are lacking. The primary aim of the present randomized controlled pilot trial was to explore the feasibility of ICBT as guided self-help individually tailored to the predominant symptomatology of PTSD or depression in survivors of IPV. A second aim was to conduct a preliminary evaluation exploring the short- and long-term effects of the treatment in comparison to a waitlist control condition. Results showed that the treatment was feasible. Attrition rate was low (9.4%), and participants were satisfied with treatment. However, treatment adherence was moderate in terms of completed modules (62.5%). Results of the preliminary evaluation of treatment effects showed large and statistically significant between-group effect sizes (Cohen's d = 0.86–1.08) on some measures of PTSD and depression at post assessment, favoring the treatment condition. However, there were no effects on other measures. At follow-up assessment, when the control condition had received delayed treatment, there were large and statistically significant within-group effect sizes (d = 0.96–1.48) on measures of PTSD, depression and anxiety, and small effects (d = 0.48) on a measure of quality of life. The results of the present pilot study are promising and warrant further research on ICBT for this population.
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| 8. |
- Arvidsson, Ida, et al.
(författare)
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Apyrase decreases phage induction and Shiga toxin release from E. coli O157:H7 and has a protective effect during infection
- 2022
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Ingår i: Gut microbes. - : Informa UK Limited. - 1949-0976 .- 1949-0984. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli (EHEC) cause gastrointestinal infection and, in severe cases, hemolytic uremic syndrome which may lead to death. There is, to-date, no therapy for this infection. Stx induces ATP release from host cells and ATP signaling mediates its cytotoxic effects. Apyrase cleaves and neutralizes ATP and its effect on Stx and EHEC infection was therefore investigated. Apyrase decreased bacterial RecA and dose-dependently decreased toxin release from E. coli O157:H7 in vitro, demonstrated by reduced phage DNA and protein levels. The effect was investigated in a mouse model of E. coli O157:H7 infection. BALB/c mice infected with Stx2-producing E. coli O157:H7 were treated with apyrase intraperitoneally, on days 0 and 2 post-infection, and monitored for 11 days. Apyrase-treated mice developed disease two days later than untreated mice. Untreated infected mice lost significantly more weight than those treated with apyrase. Apyrase-treated mice exhibited less colonic goblet cell depletion and apoptotic cells, as well as lower fecal ATP and Stx2, compared to untreated mice. Apyrase also decreased platelet aggregation induced by co-incubation of human platelet-rich-plasma with Stx2 and E. coli O157 lipopolysaccharide in the presence of collagen. Thus, apyrase had multiple protective effects, reducing RecA levels, stx2 and toxin release from EHEC, reducing fecal Stx2 and protecting mouse intestinal cells, as well as decreasing platelet activation, and could thereby delay the development of disease.
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