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| 2. |
- Henstrom, M., et al.
(författare)
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Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome
- 2018
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Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 67:2, s. 263-270
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Tidskriftsartikel (refereegranskat)abstract
- Objective IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucraseisomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. Design We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p. Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. Results CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case-control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). Conclusions SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.
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| 3. |
- Mancina, Rosellina Margherita, et al.
(författare)
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PSD3 downregulation confers protection against fatty liver disease.
- 2022
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 4:1, s. 60-75
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Tidskriftsartikel (refereegranskat)abstract
- Fatty liver disease (FLD) is a growing health issue with burdening unmet clinical needs. FLD has a genetic component but, despite the common variants already identified, there is still a missing heritability component. Using a candidate gene approach, we identify a locus (rs71519934) at the Pleckstrin and Sec7 domain-containing 3 (PSD3) gene resulting in a leucine to threonine substitution at position 186 of the protein (L186T) that reduces susceptibility to the entire spectrum of FLD in individuals at risk. PSD3 downregulation by short interfering RNA reduces intracellular lipid content in primary human hepatocytes cultured in two and three dimensions, and in human and rodent hepatoma cells. Consistent with this, Psd3 downregulation by antisense oligonucleotides in vivo protects against FLD in mice fed a non-alcoholic steatohepatitis-inducing diet. Thus, translating these results to humans, PSD3 downregulation might be a future therapeutic option for treating FLD.
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| 4. |
- Wohlfarth, C., et al.
(författare)
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miR-16 and miR-103 impact 5-HT4 receptor signalling and correlate with symptom profile in irritable bowel syndrome
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Serotonin 5-HT4 receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT4R selective drug intervention has been proven beneficial in subgroups of patients. We identified a single nucleotide polymorphism (SNP) (rs201253747) c.*61 T > C within the 5-HT4 receptor gene HTR4 to be predominantly present in diarrhoea-IBS patients (IBS-D). It affects a binding site for the miR-16 family and miR-103/miR-107 within the isoforms HTR4b/i and putatively impairs HTR4 expression. Subsequent miRNA-profiling revealed downregulation of miR-16 and miR-103 in the jejunum of IBS-D patients correlating with symptoms. In vitro assays confirmed expression regulation via three 3'UTR binding sites. The novel isoform HTR4b_2 lacking two of the three miRNA binding sites escapes miR-16/103/107 regulation in SNP carriers. We provide the first evidence that HTR4 expression is fine-tuned by miRNAs, and that this regulation is impaired either by the SNP c.*61 T > C or by diminished levels of miR-16 and miR-103 suggesting that HTR4 might be involved in the development of IBS-D.
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| 5. |
- Aidemark, Mari, et al.
(författare)
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Trichoderma viride cellulase induces resistance to the antibiotic pore-forming peptide alamethicin associated with changes in the plasma membrane lipid composition of tobacco BY-2 cells
- 2010
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Ingår i: Bmc Plant Biology. - : Springer Science and Business Media LLC. - 1471-2229. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alamethicin is a membrane-active peptide isolated from the beneficial root-colonising fungus Trichoderma viride. This peptide can insert into membranes to form voltage-dependent pores. We have previously shown that alamethicin efficiently permeabilises the plasma membrane, mitochondria and plastids of cultured plant cells. In the present investigation, tobacco cells (Nicotiana tabacum L. cv Bright Yellow-2) were pre-treated with elicitors of defence responses to study whether this would affect permeabilisation. Results: Oxygen consumption experiments showed that added cellulase, already upon a limited cell wall digestion, induced a cellular resistance to alamethicin permeabilisation. This effect could not be elicited by xylanase or bacterial elicitors such as flg22 or elf18. The induction of alamethicin resistance was independent of novel protein synthesis. Also, the permeabilisation was unaffected by the membrane-depolarising agent FCCP. As judged by lipid analyses, isolated plasma membranes from cellulase-pretreated tobacco cells contained less negatively charged phospholipids ( PS and PI), yet higher ratios of membrane lipid fatty acid to sterol and to protein, as compared to control membranes. Conclusion: We suggest that altered membrane lipid composition as induced by cellulase activity may render the cells resistant to alamethicin. This induced resistance could reflect a natural process where the plant cells alter their sensitivity to membrane pore-forming agents secreted by Trichoderma spp. to attack other microorganisms, and thus adding to the beneficial effect that Trichoderma has for plant root growth. Furthermore, our data extends previous reports on artificial membranes on the importance of lipid packing and charge for alamethicin permeabilisation to in vivo conditions.
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| 6. |
- Alifier, Marek, et al.
(författare)
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Cardiac Surgery is Associated with Biomarker Evidence of Neuronal Damage.
- 2020
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 74:4, s. 1211-1220
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Tidskriftsartikel (refereegranskat)abstract
- Anesthesia and surgery is commonly associated with central nervous system sequelae and cognitive symptoms, which may be caused by neuronal injury. Neuronal injury can be monitored by plasma concentrations of the neuronal biomarkers tau and neurofilament light protein (NFL). Currently, there are no studies examining whether neuronal injury varies between surgical procedures.Our aim was to investigate if neuronal damage is more frequent after cardiac than after otolaryngeal surgery, as estimated by tau and NFL concentrations in plasma.Blood samples were drawn before, during, and after surgery and concentrations of tau, NFL, Aβ40, and Aβ42 were measured in 25 patients undergoing cardiac surgery (9 off-pump and 16 on-pump) and 26 patients undergoing otolaryngeal surgery.Tau increased during surgery (1752%, p=0.0001) and NFL rose seven days post-surgery (1090%, p<0.0001) in patients undergoing cardiac surgery; even more in patients on-pump than off-pump. No changes were observed in patients undergoing otolaryngeal surgery and only minor fluctuations were observed for Aβ40 and Aβ42.Cardiac surgery is associated with neuronal injury, which is aggravated by extracorporeal circulation. Analyses of NFL and tau in blood may guide development of surgical procedures to minimize neuronal damage, and may also be used in longitudinal clinical studies to assess the relationship of surgery with future neurocognitive impairment or dementia.
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| 8. |
- Andreasson, Emma, et al.
(författare)
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Expression of reactive oxygen species in reflux disease
- 2011
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Ingår i: Gastrointestinal Endoscopy. - Rijeka, Croatia : InTech. - 9789533073859 ; , s. 79-90
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Background: High levels of nitric oxide (NO) are formed when nitrite in swallowed saliva meets acidic refluxates in the distal esophagus. In inflamed tissue with production of reactive-oxygen-species (ROS) it is reasonable to assume that luminal NO will react with particularly superoxide and form the extremely labile oxidising compound peroxynitrite. Such oxidative species have potential roles in all steps of carcinogenesis. The aim of the present study is to elucidate the presence of radical producing enzymes, and elucidate the histological changes and number of inflammatory cells in human esophageal mucosa. Material and Methods: Biopsies from healthy volunteers and patients with erosive reflux disease (ERD) were analysed for myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS) and NADPH oxidase, well as the expression of inflammatory markers IL1β and IL6 by western blot technique. Expression of nitrotyrosine was used as an indicator of peroxynitrite activity, thus mirroring the foregoing radical formation. A histological evaluation of inflammation and a morphometric investigation were performed on mucosal specimens. Results: Expression of MPO and nitrotyrosine formation was up regulated in the ERD-patients compared healthy controls. No significant differences in expression of iNOS, NADPH oxidase, IL1β or IL6 were detected. No signs of active inflammation, defined as presence of inflammatory cells were observed, whereas histological signs of erosive mucosal disease were confirmed in the esophageal mucosa. Conclusion: There were clear signs of increased radical forming capacity in the epithelium despite absence of histological inflammation, in association to ERD. During acidified refluxes, epithelial ROS production in combination with luminal NO formation, may constitute aggravated factors in the carcinogenic process.
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| 9. |
- Andreasson, Jesper, 1977-, et al.
(författare)
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Perceptions of gender equality and engaged fatherhood among young fathers: parenthood and the welfare state in Sweden and the UK
- 2023
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Ingår i: Families, Relationships and Societies. - : Policy Press. - 2046-7435 .- 2046-7443. ; 12:3, s. 323-340
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Tidskriftsartikel (refereegranskat)abstract
- This article presents analyses from an international empirical study of young fatherhood in Sweden and the UK to interrogate how welfare contexts and family policies shape young fathers’ views of parenthood. Our analyses demonstrate that despite differences in constructions of young fatherhood, whereby young parenthood is problematised in UK family policy, more so than in Sweden, young fathers in both countries express an encouraging commitment to contemporary cultural imperatives for engaged fatherhood. However, differences in welfare and parental leave systems have a clear influence on the extent to which the young men in the respective countries fulfil their parental commitments and act as local agents of change in the wider social project of gender equality. We argue that while policy processes and discourses in support of young parenthood and gender equality are currently treated as disparate concerns, their articulations with one another may instead be seen as complementary and symbiotic.
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