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| 6. |
- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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| 7. |
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| 8. |
- Calander, Ann-Marie, 1957, et al.
(författare)
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Impact of staphylococcal protease expression on the outcome of infectious arthritis
- 2004
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Ingår i: Microbes Infect. - : Elsevier BV. - 1286-4579. ; 6:2, s. 202-6
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Tidskriftsartikel (refereegranskat)abstract
- The exoproteases of Staphylococcus aureus have been proposed as virulence factors during S. aureus infections. To investigate this, we used the wild-type S. aureus strain 8325-4 and its mutants devoid of aureolysin, serine protease, and cysteine protease, respectively, in a well-established model of septic arthritis in mice. The inactivation of the exoprotease genes did not affect the frequency or the severity of joint disease. We conclude that in the model of haematogenously spread staphylococcal arthritis, the bacterial proteases studied do not act as virulence factors.
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| 16. |
- Reddy, N, et al.
(författare)
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Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors
- 2023
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Ingår i: Antibiotics (Basel, Switzerland). - : MDPI AG. - 2079-6382. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- Virulent Enterobacterale strains expressing serine and metallo-β-lactamases (MBL) genes have emerged responsible for conferring resistance to hard-to-treat infectious diseases. One strategy that exists is to develop β-lactamase inhibitors to counter this resistance. Currently, serine β-lactamase inhibitors (SBLIs) are in therapeutic use. However, an urgent global need for clinical metallo-β-lactamase inhibitors (MBLIs) has become dire. To address this problem, this study evaluated BP2, a novel beta-lactam-derived β-lactamase inhibitor, co-administered with meropenem. According to the antimicrobial susceptibility results, BP2 potentiates the synergistic activity of meropenem to a minimum inhibitory concentration (MIC) of ≤1 mg/L. In addition, BP2 is bactericidal over 24 h and safe to administer at the selected concentrations. Enzyme inhibition kinetics showed that BP2 had an apparent inhibitory constant (Kiapp) of 35.3 µM and 30.9 µM against New Delhi Metallo-β-lactamase (NDM-1) and Verona Integron-encoded Metallo-β-lactamase (VIM-2), respectively. BP2 did not interact with glyoxylase II enzyme up to 500 µM, indicating specific (MBL) binding. In a murine infection model, BP2 co-administered with meropenem was efficacious, observed by the >3 log10 reduction in K. pneumoniae NDM cfu/thigh. Given the promising pre-clinical results, BP2 is a suitable candidate for further research and development as an (MBLI).
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| 17. |
- Reddy, N, et al.
(författare)
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Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors
- 2023
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Ingår i: Antibiotics (Basel, Switzerland). - : MDPI AG. - 2079-6382. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- Virulent Enterobacterale strains expressing serine and metallo-β-lactamases (MBL) genes have emerged responsible for conferring resistance to hard-to-treat infectious diseases. One strategy that exists is to develop β-lactamase inhibitors to counter this resistance. Currently, serine β-lactamase inhibitors (SBLIs) are in therapeutic use. However, an urgent global need for clinical metallo-β-lactamase inhibitors (MBLIs) has become dire. To address this problem, this study evaluated BP2, a novel beta-lactam-derived β-lactamase inhibitor, co-administered with meropenem. According to the antimicrobial susceptibility results, BP2 potentiates the synergistic activity of meropenem to a minimum inhibitory concentration (MIC) of ≤1 mg/L. In addition, BP2 is bactericidal over 24 h and safe to administer at the selected concentrations. Enzyme inhibition kinetics showed that BP2 had an apparent inhibitory constant (Kiapp) of 35.3 µM and 30.9 µM against New Delhi Metallo-β-lactamase (NDM-1) and Verona Integron-encoded Metallo-β-lactamase (VIM-2), respectively. BP2 did not interact with glyoxylase II enzyme up to 500 µM, indicating specific (MBL) binding. In a murine infection model, BP2 co-administered with meropenem was efficacious, observed by the >3 log10 reduction in K. pneumoniae NDM cfu/thigh. Given the promising pre-clinical results, BP2 is a suitable candidate for further research and development as an (MBLI).
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| 22. |
- Almhöjd, Ulrica S., et al.
(författare)
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Analysis of carious dentine using FTIR and ToF-SIMS.
- 2014
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Ingår i: Journal of Oral Health and Dental Management. - 1583-5588. ; 13:3, s. 735-744
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Apart from the Maillard reaction, other processes, such as esterification, take place in carious tissue. The aim of the present study was to analyse sound and carious dentine in terms of ester groups and their reaction with hydrazine derivate using Fourier Transform Infrared Spectroscopy (FTIR) and Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS). Carious and sound dentine from human premolars were excavated in three series (Experimental Parts I-III) and separated into inner and outer layers of carious dentine. The excavated tooth material was analysed with FTIR (Part I). Carious and sound dentine were also exposed to different chemical treatments and analysed with FTIR-Attenuated Total Reflectance (FTIR-ATR; Part II) and ToF-SIMS (Part III). The FTIR absorption spectra showed that the carious tissue contained ester groups, not detected in sound dentine. The results also indicated a higher occurrence of ester groups in the inner dental caries layer than in the outer ones. Potential binding to these ester groups by hydrazine derivative was observed after different chemical treatments with both FTIR-ATR and ToF-SIMS. The results of the present study revealed ester groups unique to the carious dentine which, after reaction with hydrazine derivative, form a covalent bond not found in sound dentine. The staining of carious unique groups would be clinically helpful in detection and prevention unnecessary removal of sound dentine.
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| 23. |
- Altaib, Mohamed S., et al.
(författare)
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Synthesis and NMR elucidation of novel pentacycloundecane-based peptides
- 2010
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Ingår i: Magnetic Resonance in Chemistry. - : Wiley. - 0749-1581 .- 1097-458X. ; 48:6, s. 435-442
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Tidskriftsartikel (refereegranskat)abstract
- The synthesis and NMR elucidation of two novel pentacycloundecane (PCU)-based peptides are reported. The PCU cage amino acids were synthesised as racemates and the incorporation of the cage amino acid with (S)-natural amino acids produced diastereomeric peptides. The diastereomeric 'cage' peptides were separated using preparative HPLC and the NMR elucidation of these PCU containing peptides are reported for the first time. The H-1 and C-13 NMR spectra showed series of overlapping signals of the cage skeleton and that of the peptide, making it extremely difficult to resolve the structure using one-dimensional NMR techniques only. The use of two-dimensional NMR techniques proved to be a highly effective tool in overcoming this problem.
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| 25. |
- Amini, A., et al.
(författare)
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Determination of Ephedrine, Pseudo-Ephedrine and Caffeine in a Dietary Product by Capillary Electrophoresis
- 2006
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Ingår i: Chromatographia. - : Springer Science and Business Media LLC. - 0009-5893 .- 1612-1112. ; 63:3/4, s. 143-148
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Tidskriftsartikel (refereegranskat)abstract
- This paper reports the determination of caffeine, ephedrine and pseudo-ephedrine in a dietary product by two rapid and simple methods utilising capillary electrophoresis (CE). The solutes were extracted from the product using 0.2 M HCl and determined by CE with background electrolytes containing 7.5% highly sulfated-β-cyclodextrin (7–11 sulfate groups per β-CD molecule) at pH 2.5 and pH 7.6. Determination of ephedrine and pseudo-ephedrine was accomplished at pH 2.5 with the anode at the detection side of the capillary whereas caffeine was quantified at pH 7.6 with a normal electrophoresis polarity mode. Triethanolamine was added to the running buffer at pH 2.5 in order to reverse the electroosmotic flow (EOF) and thereby speed up the separation of ephedrine and pseudo-ephedrine.
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| 27. |
- ARUP, U, et al.
(författare)
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Lavar
- 2005
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Ingår i: Gärdenfors, U (red.): Rödlistade arter i Sverige 2005, ArtDatabanken, SLU, Uppsala.
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Forskningsöversikt (refereegranskat)
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| 28. |
- Arvidsson, Andreas, et al.
(författare)
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Stroke induces widespread changes of gene expression for glial cell line-derived neurotrophic factor family receptors in the adult rat brain
- 2001
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Ingår i: Neuroscience. - 1873-7544. ; 106:1, s. 27-41
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Tidskriftsartikel (refereegranskat)abstract
- Gene expression for glial cell line-derived neurotrophic factor (GDNF) family ligands and receptors was analyzed with in situ hybridization after two focal ischemic insults of different severities. Focal ischemia was induced in rats by either 30 min or 2 h of middle cerebral artery occlusion (MCAO), causing damage to the striatum only, or involving also the parietal cortex, respectively. We found modest, transient elevation of GDNF mRNA in the dentate granule cell layer. In addition, the number of GDNF mRNA-expressing cells increased in the cortex and striatum after 2 h or 30 min of MCAO, respectively. No changes of neurturin or persephin mRNA expression were detected. Both c-Ret and GFRalpha1 mRNA levels were markedly increased in the ipsilateral cortex outside the ischemic lesion at 6-24 h after the 2-h insult, whereas GFRalpha2 expression was decreased in cortical areas both within and outside the lesion. Similar increases of c-Ret and GFRalpha1 mRNA levels were detected in the striatum, and to a lesser extent, in the cortex following 30 min of MCAO. The 2-h insult also gave rise to transient increases of c-Ret and GFRalpha1 mRNA in hippocampal subregions. Thirty minutes and 2 h of MCAO lead to elevated c-Ret, and GFRalpha1 or GFRalpha2 mRNA expression, respectively, in the ipsilateral ventroposterolateral thalamic nucleus. Both insults induced increased levels of GFRalpha1 mRNA in the subventricular zone of the lateral ventricle.Our data indicate major changes of GDNF family signaling in the forebrain, regulated mainly through altered receptor levels, in the post-ischemic phase. These changes could enhance neuroprotective and neuroregenerative responses both to endogenous and exogenous GDNF ligands.
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| 31. |
- Arvidsson, D, et al.
(författare)
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Randomized clinical trial comparing 5-year recurrence rate after laparoscopic versus Shouldice repair of primary inguinal hernia
- 2005
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Ingår i: British Journal of Surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 92:9, s. 1085-1091
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Tidskriftsartikel (refereegranskat)abstract
- Background: The Shouldice technique is the 'gold standard' of open non-mesh hernia repair. The aim of this study was to compare 5-year recurrence rates after Shouldice and laparoscopic transabdominal preperitoneal patch (TAPP) repair for primary inguinal hernia. Method: Men with a primary unilateral inguinal hernia were randomized to either Shouldice or TAPP operation. An independent observer scored the surgeons' performance. Follow-up comprised clinical examination after 1 year, a questionnaire after 2 and 3 years, and a clinical examination after 5 years. Results: Between February 1993 and March 1996, 1183 patients were included. Nine hundred and twenty patients were followed for 5 years, 454 in the TAPP group and 466 in the Shouldice group. Recurrences were evenly distributed between groups throughout the follow-up period. The cumulative recurrence rate after 5 years was 6.6 per cent in the TAPP group and 6.7 per cent in the Shouldice group. Postoperative pain was a risk factor for recurrence after Shouldice operation but not after TAPP repair. There was a correlation between a low surgeon's performance score and recurrence. Conclusion: The 5-year recurrence rate is acceptable, with no difference between TAPP and Shouldice repair. Poor operative performance resulted in a higher recurrence rate. The TAPP operation represents an excellent alternative for primary inguinal hernia repair.
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| 32. |
- Arvidsson, Elin, et al.
(författare)
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Exercise training and physiological responses to acute stress: study protocol and methodological considerations of a randomised controlled trial
- 2018
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Ingår i: BMJ Open Sport & Exercise Medicine. - : BMJ. - 2055-7647. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: This paper describes the protocol and methodological prerequisites for a randomised controlled exercise intervention. Selected baseline data from the study are also presented, demonstrating some methodological challenges related to exercise intervention trials. The aim of the trial was to study the effects of exercise training on physiological responses to acute psychosocial stress in untrained individuals. Methods: Individuals with a low level of physical activity were invited to participate in an exercise intervention lasting for 6 months. A total of 119 participants were included and went through a peak oxygen uptake test and a psychosocial stress test at baseline. Adrenocorticotropic hormone (ACTH) and cortisol were measured in connection to the stress test to identify the physiological response. Results: Almost 90% of the participants reported themselves as untrained, but results from the objectively measured oxygen uptake did not seem to correspond to the reported sedentary lifestyle. The primary outcome measures at baseline varied between individuals. The mean change from pre-test to peak value was 214% for ACTH and 94% for cortisol. Of these, 13 individuals did not respond in ACTH and/or and cortisol. Discussion: Supposedly untrained individuals seeking participation in an exercise intervention might not be as untrained as they report, a methodological consideration of importance when evaluating the effects of training. Another important consideration is related to the primary outcome measure, which should be measurable and possible to affect. Absence of reaction at baseline means that changes can only be detected as an increased reaction.
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| 33. |
- Arvidsson, E, et al.
(författare)
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Forebrain NgR1 Overexpression Impairs DA Release Suggesting Synergy of Local and Global Synaptic Plasticity Mechanisms
- 2020
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Ingår i: Frontiers in synaptic neuroscience. - : Frontiers Media SA. - 1663-3563. ; 12, s. 545854-
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Tidskriftsartikel (refereegranskat)abstract
- Structural synaptic reorganizations needed to permanently embed novel memories in the brain involve complex plasticity-enhancing and plasticity-inhibiting systems. Increased neural activity is linked to rapid downregulation of Nogo receptor 1 (NgR1), needed to allow local structural synaptic plasticity. This local regulation of plasticity is thought to be moderated by global systems, such as the ascending cholinergic and monoaminergic systems, adding significance to locally increased neural activity. Here we address the reverse possibility that the global systems may also be influenced by the status of local plasticity. Using NgR1-overexpressing mice, with impaired plasticity and long-term memory, we measured the ability to release dopamine (DA), implicated in regulating plasticity and memory. In vivo chronoamperometric recording with high temporal and spatial resolution revealed severe impairment of potassium chloride (KCl)-induced increase of extracellular DA in the dorsal striatum of mice overexpressing NgR1 in forebrain neurons. A similar, but lesser, impairment of DA release was seen following amphetamine delivery. In contrast, potassium chloride-evoked DA release in NgR1 knockout (KO) mice led to increased levels of extracellular DA. That NgR1 can impair DA signaling, thereby further dampening synaptic plasticity, suggests a new role for NgR1 signaling, acting in synergy with DA signaling to control synaptic plasticity.Significance Statement:The inverse correlation between local NgR1 levels and magnitude of KCl-inducible amounts of DA release in the striatum reinforces the rule of NgR1 as a regulator of structural synaptic plasticity and suggests synergy between local and global plasticity regulating systems.
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| 37. |
- Arvidsson, Louise, et al.
(författare)
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Fat, sugar and water intakes among families from the IDEFICS intervention and control groups: first observations from I.Family
- 2015
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Ingår i: Obesity Reviews. - : Wiley. - 1467-7881 .- 1467-789X. ; 16:Suppl. 2, s. 127-137
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe objective of this paper is to investigate differences in diets of families in intervention versus control communities 5years after the Identification and Prevention of Dietary- and Lifestyle-Induced Health Effects in Children and Infants intervention ended. MethodsAltogether, 4,691 families from the I.Family study with at least one participating parent and one child are included in this analysis. Diet quality indicators, defined as propensities to consume fat, sugar, water and fruit and vegetables, are calculated from a 59-item food frequency questionnaire. Multilevel linear models with random intercepts for study centre are used to determine whether mean diet indicators, calculated at the family level, differed as a function of previous exposure to the intervention. ResultsFamilies in the intervention communities reported a significantly lower sugar propensity (19.8% vs. 20.7% of total food items, p<0.01) and a higher water propensity (47.3% vs. 46.0% of total beverages, p<0.05) compared with families in the control communities, while fat and fruit and vegetables propensities were similar. No significant diet differences between intervention and control children were present at the Identification and Prevention of Dietary- and Lifestyle-Induced Health Effects in Children and Infants baseline. DiscussionThis result indicates better diet quality in intervention families, which was not present in children when their diets were assessed before the intervention, and gives some cause for optimism regarding the sustainability of some aspects of the diet intervention.
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| 40. |
- Arvidsson-Lenner, R, et al.
(författare)
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Glycaemic index
- 2004
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Ingår i: Scandinavian Journal of Food and Nutrition. - : Informa UK Limited. - 1748-2976. ; 48:2, s. 84-94
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Tidskriftsartikel (refereegranskat)abstract
- The glycaemic index (GI) concept is based on the difference in blood glucose response after ingestion of the same amount of carbohydrates from different foods, and possible implications of these differences for health, performance and well-being. GI is defined as the incremental blood glucose area (0-2 h) following ingestion of 50 g of available carbohydrates in the test product as a percentage of the corresponding area following an equivalent amount of carbohydrate from a reference product. A high GI is generally accompanied by a high insulin response. The glycaemic load (GL) is the GI×the amount (g) of carbohydrate in the food/100. Many factors affect the GI of foods, and GI values in published tables are indicative only, and cannot be applied directly to individual foods. Properly determined GI values for individual foods have been used successfully to predict the glycaemic response of a meal, while table values have not. An internationally recognised method for GI determination is available, and work is in progress to improve inter- and intra-laboratory performance. Some epidemiological studies and intervention studies indicate that low GI diets may favourably influence the risk of chronic diseases such as diabetes and coronary heart disease, although further well-controlled studies are needed for more definite conclusions. Low GI diets have been demonstrated to improve the blood glucose control, LDL-cholesterol and a risk factor for thrombosis in intervention studies with diabetes patients, but the effect in free-living conditions remains to be shown. The impact of GI in weight reduction and maintenance as well as exercise performance also needs further investigation. The GI concept should be applied only to foods providing at least 15 g and preferably 20 g of available carbohydrates per normal serving, and comparisons should be kept within the same food group. For healthy people, the significance of GI is still unclear and general labelling is therefore not recommended. If introduced, labelling should be product-specific and considered on a case-by-case basis.
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| 50. |
- Arvidsson, Per, et al.
(författare)
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Exploring the Antibacterial and Hemolytic Activity of Shorter- and Longer-Chain B-, a,B-, and y-Peptides, and of B-Peptides from B2-3-Aza- and B3-2-Methylidene-amino Acids Bearing Proteinogenic Side Chains - A Survey
- 2005
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Ingår i: Chemistry & Biodiversity. ; 2, s. 401-420
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Tidskriftsartikel (refereegranskat)abstract
- The antibacterial activities of 31 different b-, mixed a/B-, and y-peptides, as well as of B-peptides derived from B2-3-aza- and B3-2-methylidene-amino acids were assayed against six pathogens (Enterococcus faecails, STaphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa), and the results were compared with literature data. The interaction of these peptides with mammalian cells, as modeled by measuring the hemolysis of human erythrocytes, was also investigated. In addition to those peptides designed to fold into amphiphilic helical conformations with positive charges on one face of the helix, one new peptide with hemolytic activity was detected within the sample set. Moreover, it was demontrated that neither cationic peptides used for membrane translocation (B3-oligoarginines), nor mixeda/B- or y-peptides with somatostatin-mimicking activities display unwanted hemolytic activity.
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