| 1. |
- Eriksson, Leif A., 1964-, et al.
(författare)
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Tetrazole derivatives as cytochrome p450 inhibitors
- 2019
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Patent (populärvet., debatt m.m.)abstract
- According to the invention there is provided a compound of formula I, wherein R1 and R2 have meanings given in the description, which compounds are useful in the treatment of skin disorders and other diseases.
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| 2. |
- Rohin Rajan, Meenu, et al.
(författare)
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Comparative analysis of obesity-related cardiometabolic and renal biomarkers in human plasma and serum.
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- The search for biomarkers associated with obesity-related diseases is ongoing, but it is not clear whether plasma and serum can be used interchangeably in this process. Here we used high-throughput screening to analyze 358 proteins and 76 lipids, selected because of their relevance to obesity-associated diseases, in plasma and serum from age- and sex-matched lean and obese humans. Most of the proteins/lipids had similar concentrations in plasma and serum, but a subset showed significant differences. Notably, a key marker of cardiovascular disease PAI-1 showed a difference in concentration between the obese and lean groups only in plasma. Furthermore, some biomarkers showed poor correlations between plasma and serum, including PCSK9, an important regulator of cholesterol homeostasis. Collectively, our results show that the choice of biofluid may impact study outcome when screening for obesity-related biomarkers and we identify several markers where this will be the case.
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| 3. |
- Lind, Marcus, et al.
(författare)
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Thrombomodulin as a marker for bleeding complications during warfarin treatment
- 2009
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Ingår i: Archives of Internal Medicine. - : American Medical Association (AMA). - 0003-9926 .- 1538-3679. ; 169:13, s. 1210-1215
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The major adverse effect of warfarin treatment is hemorrhage. Several risk factors for bleeding complications are also risk factors for thromboembolic events, making the clinical decision to initiate or withhold anticoagulant treatment difficult. Specific markers that solely identify patients at high risk of bleeding would have great clinical impact. This study aimed to test if thrombomodulin (TM) concentrations were associated with bleeding complications, cardiovascular events, or mortality in long-term anticoagulant-treated patients. METHODS: In a longitudinal cohort study we followed up 719 patients receiving warfarin treatment for a mean duration of 4.2 years. All bleeding complications causing hospitalization were registered and classified. Soluble TM antigen (sTM) concentration in plasma was measured with an enzyme-linked immunosorbent assay method. RESULTS: During the follow-up time, 113 clinically relevant bleeding events and 73 major bleeding events occurred. Increased concentration of sTM was associated with both clinically relevant bleeding and major bleeding events after adjustment for age. In the multivariable models, hazard ratios for the highest tertiles compared with the lowest were 2.29 (95% confidence interval, 1.35-3.89) and 2.33 (95% confidence interval, 1.21-4.48), respectively. No association between sTM concentration and nonfatal ischemic cardiovascular events or all-cause mortality was found. CONCLUSIONS: Increased levels of sTM are associated with bleeding complications during warfarin treatment but not with cardiovascular events or all-cause mortality. Soluble TM antigen concentration has potential as a new specific marker to identify patients at high risk of bleeding during warfarin treatment.
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| 4. |
- Norinder, Ulf, 1956-, et al.
(författare)
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Multitask Modeling with Confidence Using Matrix Factorization and Conformal Prediction
- 2019
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Ingår i: Journal of Chemical Information and Modeling. - Washington : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 59:4, s. 1598-1604
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Tidskriftsartikel (refereegranskat)abstract
- Multitask prediction of bioactivities is often faced with challenges relating to the sparsity of data and imbalance between different labels. We propose class conditional (Mondrian) conformal predictors using underlying Macau models as a novel approach for large scale bioactivity prediction. This approach handles both high degrees of missing data and label imbalances while still producing high quality predictive models. When applied to ten assay end points from PubChem, the models generated valid models with an efficiency of 74.0-80.1% at the 80% confidence level with similar performance both for the minority and majority class. Also when deleting progressively larger portions of the available data (0-80%) the performance of the models remained robust with only minor deterioration (reduction in efficiency between 5 and 10%). Compared to using Macau without conformal prediction the method presented here significantly improves the performance on imbalanced data sets.
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| 5. |
- Erdtman, Edvin, et al.
(författare)
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Modelling the behavior of 5-aminolevulinic acid and its alkyl esters in a lipid bilayer
- 2008
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Ingår i: Chemical Physics Letters. - Amsterdam : North-Holland Publishing Co. - 0009-2614 .- 1873-4448. ; 463:1-3, s. 178-182
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Tidskriftsartikel (refereegranskat)abstract
- 5-Aminolevulinic acid (5ALA) and ester derivates thereof are used as prodrugs in photodynamic therapy (PDT). The behavior of 5ALA and three esters of 5ALA in a DPPC lipid bilayer is investigated. In particular, the methyl ester displays a very different free energy profile, where the highest barrier is located in the region with highest lipid density, while the others have their peak in the middle of the membrane, and also displays a considerably lower permeability coefficient than neutral 5ALA and the ethyl ester. The zwitterion of 5ALA has the highest permeability constant, but a significant free energy minimum in the polar head-group region renders an accumulation in this region.
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| 6. |
- Frøbert, Anne Mette, et al.
(författare)
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Hypothyroidism in hibernating brown bears
- 2023
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Ingår i: Thyroid Research. - : BioMed Central (BMC). - 1756-6614. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Brown bears hibernate throughout half of the year as a survival strategy to reduce energy consumption during prolonged periods with scarcity of food and water. Thyroid hormones are the major endocrine regulators of basal metabolic rate in humans. Therefore, we aimed to determine regulations in serum thyroid hormone levels in hibernation compared to the active state to investigate if these are involved in the adaptions for hibernation.We used electrochemiluminescence immunoassay to quantify total triiodothyronine (T3) and thyroxine (T4) levels in hibernation and active state in paired serum samples from six subadult Scandinavian brown bears. Additionally, we determined regulations in the liver mRNA levels of three major thyroid hormone-binding proteins; thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin, by analysis of previously published grizzly bear RNA sequencing data.We found that bears were hypothyroid when hibernating with T4 levels reduced to less than 44% (P = 0.008) and T3 levels reduced to less than 36% (P = 0.016) of those measured in the active state. In hibernation, mRNA levels of TBG and albumin increased to 449% (P = 0.031) and 121% (P = 0.031), respectively, of those measured in the active state. TTR mRNA levels did not change.Hibernating bears are hypothyroid and share physiologic features with hypothyroid humans, including decreased basal metabolic rate, bradycardia, hypothermia, and fatigue. We speculate that decreased thyroid hormone signaling is a key mediator of hibernation physiology in bears. Our findings shed light on the translational potential of bear hibernation physiology to humans for whom a similar hypometabolic state could be of interest in specific conditions.
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| 7. |
- Hellgren, Mikko, 1972-, et al.
(författare)
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Enrichment of ligands with molecular dockings and subsequent characterization for human alcohol dehydrogenase 3
- 2010
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Ingår i: CELLULAR AND MOLECULAR LIFE SCIENCES. - : Springer Science Business Media. - 1420-682X .- 1420-9071. ; 67:17, s. 3005-3015
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol dehydrogenase 3 (ADH3) has been assigned a role in nitric oxide homeostasis due to its function as an S-nitrosoglutathione reductase. As altered S-nitrosoglutathione levels are often associated with disease, compounds that modulate ADH3 activity might be of therapeutic interest. We performed a virtual screening with molecular dockings of more than 40,000 compounds into the active site of human ADH3. A novel knowledge-based scoring method was used to rank compounds, and several compounds that were not known to interact with ADH3 were tested in vitro. Two of these showed substrate activity (9-decen-1-ol and dodecyltetraglycol), where calculated binding scoring energies correlated well with the logarithm of the k (cat)/K (m) values for the substrates. Two compounds showed inhibition capacity (deoxycholic acid and doxorubicin), and with these data three different lines for specific inhibitors for ADH3 are suggested: fatty acids, glutathione analogs, and cholic acids.
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| 8. |
- Kardeby, Caroline, 1989-, et al.
(författare)
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Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα
- 2019
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 3:3, s. 275-287
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Tidskriftsartikel (refereegranskat)abstract
- Fucoidans are sulfated fucose-based polysaccharides that activate platelets and have pro- and anticoagulant effects; thus, they may have therapeutic value. In the present study, we show that 2 synthetic sulfated α-l-fucoside-pendant glycopolymers (with average monomeric units of 13 and 329) and natural fucoidans activate human platelets through a Src- and phosphatidylinositol 3-kinase (PI3K)-dependent and Syk-independent signaling cascade downstream of the platelet endothelial aggregation receptor 1 (PEAR1). Synthetic glycopolymers and natural fucoidan stimulate marked phosphorylation of PEAR1 and Akt, but not Syk. Platelet aggregation and Akt phosphorylation induced by natural fucoidan and synthetic glycopolymers are blocked by a monoclonal antibody to PEAR1. Direct binding of sulfated glycopolymers to epidermal like growth factor (EGF)-like repeat 13 of PEAR1 was shown by avidity-based extracellular protein interaction screen technology. In contrast, synthetic glycopolymers and natural fucoidans activate mouse platelets through a Src- and Syk-dependent pathway regulated by C-type lectin-like receptor 2 (CLEC-2) with only a minor role for PEAR1. Mouse platelets lacking the extracellular domain of GPIbα and human platelets treated with GPIbα-blocking antibodies display a reduced aggregation response to synthetic glycopolymers. We found that synthetic sulfated glycopolymers bind directly to GPIbα, substantiating that GPIbα facilitates the interaction of synthetic glycopolymers with CLEC-2 or PEAR1. Our results establish PEAR1 as the major signaling receptor for natural fucose-based polysaccharides and synthetic glycopolymers in human, but not in mouse, platelets. Sulfated α-l-fucoside-pendant glycopolymers are unique tools for further investigation of the physiological role of PEAR1 in platelets and beyond.
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| 9. |
- Kruse, Robert, et al.
(författare)
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Colloid centrifugation removes seminal plasma and cholesterol from boar spermatozoa
- 2011
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Ingår i: Reproduction, Fertility and Development. - : CSIRO Publishing. - 1031-3613 .- 1448-5990. ; 23, s. 858-865
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Tidskriftsartikel (refereegranskat)abstract
- The objective of the present study was to investigate the effect of Single-Layer Centrifugation (SLC) on boar spermatozoa, namely the effect of removal of seminal plasma proteins and cholesterol from the surface of spermatozoa. The presence of porcine seminal plasma proteins I and II (PSP-I/PSP-II) before and after SLC was studied using immunofluorescence, whereas the removal of cholesterol was shown qualitatively by thin-layer chromatography (TLC). Finally, the integrity of the sperm plasma membrane was observed by electron microscopy. It was shown that the seminal plasma proteins PSP-I and -II were removed from spermatozoa during SLC but could be restored by adding seminal plasma to the SLC-selected sperm samples. Some cholesterol was also lost from the spermatozoa during SLC but the plasma membrane itself appeared to be morphologically intact. Further studies are underway to examine the relevance of these findings to boar sperm cryopreservation and sperm fertility.
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| 10. |
- Nilsson, Ola, 1970-
(författare)
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Behandling av akondroplasi är på väg – kan ge nya möjligheter : [New treatments for achondroplasia may be efficacious in other forms of short stature]
- 2021
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Ingår i: Läkartidningen. - : Läkartidningen Förlag AB. - 0023-7205 .- 1652-7518. ; 118
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Tidskriftsartikel (refereegranskat)abstract
- Achondroplasia is the most common form of monogenic skeletal dysplasia and is caused by activating mutations in fibroblast growth factor receptor 3 (FGFR3) resulting in exaggerated MAPK signaling in the growth cartilage chondrocytes and thus reduced growth. C-type natriuretic peptide (CNP) stimulates growth by inhibiting MAPK signaling in growth plate cartilage. Several new treatments that target these pathways are currently in clinical trials for the treatment of achondroplasia. A recent phase 3 clinical trial confirmed near normal growth rate in children with achondroplasia during treatment with vosoritide, a CNP analogue with a prolonged half-life. Vosoritide is currently being evaluated for approval by the EMA. Treatments that enable normalization of growth in children with achondroplasia may soon be available. It is likely that some of these treatments also will increase growth in other forms of short stature.
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