| 1741. |
- Lepp, Håkan, 1977-
(författare)
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Experimental studies of proton translocation reactions in biological systems : Electrogenic events in heme-copper oxidases
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Terminal heme-copper oxidases (HCuOs) are transmembrane proteins that catalyze the final step in the respiratory chain - the reduction of O2 to H2O, coupled to energy conservation by generation of an electrochemical proton gradient. The most extensively investigated of the HCuOs are the aa3-type oxidases, to which cytochrome c oxidase (CytcO) belongs, which uses energy released in the O2-reduction for proton pumping. The bacterial nitric oxide reductases (NORs) have been identified as divergent members of the HCuO-superfamily and are involved in the denitrification pathway where they catalyze the reduction of NO to NO2. Although as exergonic as O2-reduction, this reaction is completely non-electrogenic. Among the traditional HCuOs, the cbb3-type oxidases are the closest relatives to the NORs and as such provide a link between the aa3 oxidases and the NORs. The cbb3 oxidases have been shown to pump protons with nearly the same efficiency as the aa3 oxidases, despite low sequence similarity.This thesis is focused on measurements of membrane potential generating reactions during catalysis in the CytcO and the cbb3 oxidase from Rhodobacter sphaeroides, and the NOR from Paracoccus denitrificans, using a time resolved electrometric technique. The pH dependence of the membrane potential generation in CytcO showed that only one proton is taken up and that no protons are pumped, at high pH. An additional kinetic phase was also detected at high pH that presumably originates to from charge-transfer within the K-pathway. Possible reasons for uncoupling, and the extent of charge-transfer, were studied using structural variants of CytcO. The measurements established that electrons and protons are taken up from the same side of the membrane in NOR. In addition, the directionality for proton uptake in cbb3 oxidase appeared to be dependent on the choice of substrate while proton pumping was indicated to occur only during O2-reduction.
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| 1742. |
- Lerouge, Frederic, et al.
(författare)
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In vivo targeting and multimodal imaging of cerebral amyloid-beta aggregates using hybrid GdF3 nanoparticles
- 2022
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Ingår i: Nanomedicine. - : FUTURE MEDICINE LTD. - 1743-5889 .- 1748-6963. ; 17:29, s. 2173-2187
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To propose a new multimodal imaging agent targeting amyloid-beta (A beta) plaques in Alzheimers disease. Materials & methods: A new generation of hybrid contrast agents, based on gadolinium fluoride nanoparticles grafted with a pentameric luminescent-conjugated polythiophene, was designed, extensively characterized and evaluated in animal models of Alzheimers disease through MRI, two-photon microscopy and synchrotron x-ray phase-contrast imaging. Results & conclusion: Two different grafting densities of luminescent-conjugated polythiophene were achieved while preserving colloidal stability and fluorescent properties, and without affecting biodistribution. In vivo brain uptake was dependent on the blood-brain barrier status. Nevertheless, multimodal imaging showed successful A beta targeting in both transgenic mice and A beta fibril-injected rats.
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| 1743. |
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| 1744. |
- Levin, Anna, et al.
(författare)
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Framväxten av en diagnos--synen på psykiska krigsreaktioner under 1900-talet med fokus på FN-svenskarna i Kongo 1960 - 64
- 2005
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Ingår i: Svensk medicinhistorisk tidskrift. - 1402-9871. ; 9:1, s. 163-186
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Tidskriftsartikel (refereegranskat)abstract
- Psychiatric casualties among soldiers constitute an inevitable part of modem warfare. For the past hundred years Medicine and Society have shown a growing interest in the combat reactions. The focus has shifted from an organic one towards a psychological and psychiatric perspective. Cultural, social, economical and political forces have influenced the scientific development from the Shell shock to Posttraumatic Stress Disorder. The aims of this literature review are to describe how military psychiatry has viewed combat reactions and in what way this has affected civil psychiatry and medicine in general, and also to follow the development of the diagnosis PTSD. Furthermore, one aim was to study the events in Congo in 1961 when Swedish UN-soldiers participated in combat. The military and associated psychiatrists has by different means tried to prevent and treat psychiatric casualties, but the knowledge was constantly forgotten and the principles of PIE-treatment (proximity, immediacy, expectancy) had to be reinvented over and over again. The experiences of military psychiatry have in some aspect enriched medical science but did also raise questions. Many factors seem to have interacted in the creation of PTSD and this diagnosis is still being questioned and debated. In 1961 PTSD did not exist and according to a follow-up study by Kettner the Swedish soldiers who suffered psychological combat reaction did not differ significantly from the rest, except that they were younger. This study has shown that the dilemma of either serving the demands of war or the individual is a common feature among military psychiatrists. Second, during the last decades there has been a convergence trend of military psychiatry and civil catastrophe psychiatry. The military psychiatry is now part of the socio-medical movement of psyhcotraumatology. Finally, for every war since World War I physicians and psychiatrists have had to relearn the importance of PIE-treatment.
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| 1745. |
- LeVine III, Harry, et al.
(författare)
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Reporters of amyloid structural polymorphism
- 2014
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Ingår i: Bio-nanoimaging. - London : Academic Press. - 9780123944313 ; , s. 69-79
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Misfolding of proteins induced by environmental conditions or by the presence of destabilizing mutations often triggers squestration (aggresome formation) or cellular removal (unfolded protein response (UPR), autophagy) intracellular responses. Extracellular aggregates are phagocytosed or endocytosed by macrophages in the periphery and microglia and astrocytes in the brain and central nervous system. In some cases a highly stable altemative assembly structure, an amyloid fibril, is formed that is highly resistant to degadation and thus accumulates.
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| 1746. |
- Li, Jing, et al.
(författare)
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An obligatory role for neurotensin in high-fat-diet-induced obesity
- 2016
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 533, s. 411-415
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Tidskriftsartikel (refereegranskat)abstract
- Obesity and its associated comorbidities (for example, diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually and are among the most prevalent and challenging conditions confronting the medical profession. Neurotensin (NT; also known as NTS), a 13-amino-acid peptide predominantly localized in specialized enteroendocrine cells of the small intestine and released by fat ingestion, facilitates fatty acid translocation in rat intestine, and stimulates the growth of various cancers. The effects of NT are mediated through three known NT receptors (NTR1, 2 and 3; also known as NTSR1, 2, and NTSR3, respectively). Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality; however, a role for NT as a causative factor in these diseases is unknown. Here we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates fatty acid absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3 (also known as sortilin). Consistent with the findings in mice, expression of NT in Drosophila midgut enteroendocrine cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.
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| 1747. |
- Li, Lizhen, 1977, et al.
(författare)
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Protective role of reactive astrocytes in brain ischemia.
- 2008
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Ingår i: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 28:3, s. 468-81
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Tidskriftsartikel (refereegranskat)abstract
- Reactive astrocytes are thought to protect the penumbra during brain ischemia, but direct evidence has been lacking due to the absence of suitable experimental models. Previously, we generated mice deficient in two intermediate filament (IF) proteins, glial fibrillary acidic protein (GFAP) and vimentin, whose upregulation is the hallmark of reactive astrocytes. GFAP(-/-)Vim(-/-) mice exhibit attenuated posttraumatic reactive gliosis, improved integration of neural grafts, and posttraumatic regeneration. Seven days after middle cerebral artery (MCA) transection, infarct volume was 210 to 350% higher in GFAP(-/-)Vim(-/-) than in wild-type (WT) mice; GFAP(-/-), Vim(-/-) and WT mice had the same infarct volume. Endothelin B receptor (ET(B)R) immunoreactivity was strong on cultured astrocytes and reactive astrocytes around infarct in WT mice but undetectable in GFAP(-/-)Vim(-/-) astrocytes. In WT astrocytes, ET(B)R colocalized extensively with bundles of IFs. GFAP(-/-)Vim(-/-) astrocytes showed attenuated endothelin-3-induced blockage of gap junctions. Total and glutamate transporter-1 (GLT-1)-mediated glutamate transport was lower in GFAP(-/-)Vim(-/-) than in WT mice. DNA array analysis and quantitative real-time PCR showed downregulation of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of tissue plasminogen activator. Thus, reactive astrocytes have a protective role in brain ischemia, and the absence of astrocyte IFs is linked to changes in glutamate transport, ET(B)R-mediated control of gap junctions, and PAI-1 expression.
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| 1748. |
- Li, Sherly X., et al.
(författare)
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Interaction between genes and macronutrient intake on the risk of developing type 2 diabetes : systematic review and findings from European Prospective Investigation into Cancer (EPIC)-InterAct
- 2017
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Ingår i: American Journal of Clinical Nutrition. - : American society for nutrition. - 0002-9165 .- 1938-3207. ; 106:1, s. 263-275
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Forskningsöversikt (refereegranskat)abstract
- Background: Gene-diet interactions have been reported to contribute to the development of type 2 diabetes (T2D). However, to our knowledge, few examples have been consistently replicated to date. Objective: We aimed to identify existing evidence for genemacronutrient interactions and T2D and to examine the reported interactions in a large-scale study. Design: We systematically reviewed studies reporting genemacronutrient interactions and T2D. We searched the MEDLINE, Human Genome Epidemiology Network, and WHO International Clinical Trials Registry Platform electronic databases to identify studies published up to October 2015. Eligibility criteria included assessment of macronutrient quantity (e.g., total carbohydrate) or indicators of quality (e. g., dietary fiber) by use of self-report or objective biomarkers of intake. Interactions identified in the review were subsequently examined in the EPIC (European Prospective Investigation into Cancer)-InterAct case-cohort study (n = 21,148, with 9403 T2D cases; 8 European countries). Prentice-weighted Cox regression was used to estimate countryspecific HRs, 95% CIs, and P-interaction values, which were then pooled by random-effects meta-analysis. A primary model was fitted by using the same covariates as reported in the published studies, and a second model adjusted for additional covariates and estimated the effects of isocaloric macronutrient substitution. Results: Thirteen observational studies met the eligibility criteria (n < 1700 cases). Eight unique interactions were reported to be significant between macronutrients [carbohydrate, fat, saturated fat, dietary fiber, and glycemic load derived from self-report of dietary intake and circulating n-3 (v-3) polyunsaturated fatty acids] and genetic variants in or near transcription factor 7-like 2 (TCF7L2), gastric inhibitory polypeptide receptor (GIPR), caveolin 2 (CAV2), and peptidase D (PEPD) (P-interaction, 0.05). We found no evidence of interaction when we tried to replicate previously reported interactions. In addition, no interactions were detected in models with additional covariates. Conclusions: Eight gene-macronutrient interactions were identified for the risk of T2D from the literature. These interactions were not replicated in the EPIC-InterAct study, which mirrored the analyses undertaken in the original reports. Our findings highlight the importance of independent replication of reported interactions.
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| 1749. |
- Li, Sherly X, et al.
(författare)
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Interplay between genetic predisposition, macronutrient intake and type 2 diabetes incidence: analysis within EPIC-InterAct across eight European countries.
- 2018
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 61:6, s. 1325-1332
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Tidskriftsartikel (refereegranskat)abstract
- Gene-macronutrient interactions may contribute to the development of type 2 diabetes but research evidence to date is inconclusive. We aimed to increase our understanding of the aetiology of type 2 diabetes by investigating potential interactions between genes and macronutrient intake and their association with the incidence of type 2 diabetes.We investigated the influence of interactions between genetic risk scores (GRSs) for type 2 diabetes, insulin resistance and BMI and macronutrient intake on the development of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a prospective case-cohort study across eight European countries (N = 21,900 with 9742 incident type 2 diabetes cases). Macronutrient intake was estimated from diets reported in questionnaires, including proportion of energy derived from total carbohydrate, protein, fat, plant and animal protein, saturated, monounsaturated and polyunsaturated fat and dietary fibre. Using multivariable-adjusted Cox regression, we estimated country-specific interaction results on the multiplicative scale, using random-effects meta-analysis. Secondary analysis used isocaloric macronutrient substitution.No interactions were identified between any of the three GRSs and any macronutrient intake, with low-to-moderate heterogeneity between countries (I2 range 0-51.6%). Results were similar using isocaloric macronutrient substitution analyses and when weighted and unweighted GRSs and individual SNPs were examined.Genetic susceptibility to type 2 diabetes, insulin resistance and BMI did not modify the association between macronutrient intake and incident type 2 diabetes. This suggests that macronutrient intake recommendations to prevent type 2 diabetes do not need to account for differences in genetic predisposition to these three metabolic conditions.
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| 1750. |
- Liang, B., et al.
(författare)
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The autoantibody response to cyclic citrullinated collagen type II peptides in rheumatoid arthritis
- 2019
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Ingår i: Rheumatology. - Oxford : NLM (Medline). - 1462-0324 .- 1462-0332. ; 58:9, s. 1623-1633
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The detection of anti-citrullinated peptide antibodies (ACPAs) is a serological hallmark of RA. Autoantibodies reactive with collagen type II (CII) are present in RA sera and synovial fluid and are potentially pathogenic. Here, we investigate the prevalence and specificity of the autoantibody responses to defined citrullinated cyclic peptides derived from CII in a China RA cohort. METHODS: Using bead-based multiplex assay, we examined the presence of autoantibodies binding to 54 cyclic 17-mer citrullinated CII peptides, encompassing all citrullinate epitopes in CII, and the corresponding unmodified peptides in 415 RA patients, in addition to 304 patients with OA. Furthermore, the autoantibody responses to a selected set of 10 cyclic citrullinated peptides were also examined in 203 healthy individuals. RESULTS: Autoantibody responses to cyclic citrullinated CII peptides were higher in RA patients as compared with OA patients or healthy individuals, whereas little or negligible antibody responses to cyclic unmodified CII peptides were observed. Interestingly, several novel citrullinated CII epitopes were identified. Antibodies to these novel citrullinated CII epitopes showed not only substantial overlapping reactivities but also had unique specificities. CONCLUSION: We found a high prevalence of autoantibodies against cyclic citrullinated CII in the sera of patients in a China RA cohort. The present study revealed heterogeneous binding patterns against novel citrullinated CII epitopes, which may help to stratify RA patients into different subgroups.
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