| 1. |
- Ahmad, Amais, et al.
(författare)
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IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 4 : Prediction accuracy and software comparisons with improved data and modelling strategies
- 2020
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 156, s. 50-63
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Tidskriftsartikel (refereegranskat)abstract
- Oral drug absorption is a complex process depending on many factors, including the physicochemical properties of the drug, formulation characteristics and their interplay with gastrointestinal physiology and biology. Physiological-based pharmacokinetic (PBPK) models integrate all available information on gastro-intestinal system with drug and formulation data to predict oral drug absorption. The latter together with in vitro-in vivo extrapolation and other preclinical data on drug disposition can be used to predict plasma concentration-time profiles in silico. Despite recent successes of PBPK in many areas of drug development, an improvement in their utility for evaluating oral absorption is much needed. Current status of predictive performance, within the confinement of commonly available in vitro data on drugs and formulations alongside systems information, were tested using 3 PBPK software packages (GI-Sim (ver.4.1), Simcyp® Simulator (ver.15.0.86.0), and GastroPlusTM (ver.9.0.00xx)). This was part of the Innovative Medicines Initiative (IMI) Oral Biopharmaceutics Tools (OrBiTo) project.Fifty eight active pharmaceutical ingredients (APIs) were qualified from the OrBiTo database to be part of the investigation based on a priori set criteria on availability of minimum necessary information to allow modelling exercise. The set entailed over 200 human clinical studies with over 700 study arms. These were simulated using input parameters which had been harmonised by a panel of experts across different software packages prior to conduct of any simulation. Overall prediction performance and software packages comparison were evaluated based on performance indicators (Fold error (FE), Average fold error (AFE) and absolute average fold error (AAFE)) of pharmacokinetic (PK) parameters.On average, PK parameters (Area Under the Concentration-time curve (AUC0-tlast), Maximal concentration (Cmax), half-life (t1/2)) were predicted with AFE values between 1.11 and 1.97. Variability in FEs of these PK parameters was relatively high with AAFE values ranging from 2.08 to 2.74. Around half of the simulations were within the 2-fold error for AUC0-tlast and around 90% of the simulations were within 10-fold error for AUC0-tlast. Oral bioavailability (Foral) predictions, which were limited to 19 APIs having intravenous (i.v.) human data, showed AFE and AAFE of values 1.37 and 1.75 respectively. Across different APIs, AFE of AUC0-tlast predictions were between 0.22 and 22.76 with 70% of the APIs showing an AFE > 1. When compared across different formulations and routes of administration, AUC0-tlast for oral controlled release and i.v. administration were better predicted than that for oral immediate release formulations. Average predictive performance did not clearly differ between software packages but some APIs showed a high level of variability in predictive performance across different software packages. This variability could be related to several factors such as compound specific properties, the quality and availability of information, and errors in scaling from in vitro and preclinical in vivo data to human in vivo behaviour which will be explored further. Results were compared with previous similar exercise when the input data selection was carried by the modeller rather than a panel of experts on each in vitro test. Overall, average predictive performance was increased as reflected in smaller AAFE value of 2.8 as compared to AAFE value of 3.8 in case of previous exercise.
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| 2. |
- Ahmed, Laeeq, et al.
(författare)
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Predicting target profiles with confidence as a service using docking scores
- 2020
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Ingår i: Journal of Cheminformatics. - : Springer Nature. - 1758-2946. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Identifying and assessing ligand-target binding is a core component in early drug discovery as one or more unwanted interactions may be associated with safety issues. Contributions: We present an open-source, extendable web service for predicting target profiles with confidence using machine learning for a panel of 7 targets, where models are trained on molecular docking scores from a large virtual library. The method uses conformal prediction to produce valid measures of prediction efficiency for a particular confidence level. The service also offers the possibility to dock chemical structures to the panel of targets with QuickVina on individual compound basis. Results: The docking procedure and resulting models were validated by docking well-known inhibitors for each of the 7 targets using QuickVina. The model predictions showed comparable performance to molecular docking scores against an external validation set. The implementation as publicly available microservices on Kubernetes ensures resilience, scalability, and extensibility.
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| 3. |
- Almgren Bäck, Gunilla, et al.
(författare)
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Speech-to-text intervention to support text production among students with writing difficulties: a single-case study in nordic countries
- 2024
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Ingår i: Disability and Rehabilitation. - 1748-3107 .- 1748-3115. ; , s. 1-20
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Tidskriftsartikel (refereegranskat)abstract
- Studies report that speech-to-text applications (STT) may support students with writing difficulties in text production. However, existing research is sparse, shows mixed results, and lacks information on STT interventions and their applicability in schools. Therefore, this study aimed to investigate whether a systematic and intensive assistive technology intervention focusing on STT can improve text production. A modified multiple-baseline across-subject design was used involving eight middle school students, four Norwegian and four Swedish. Their STT-produced narrative texts were collected during and after the intervention and the productivity, accuracy, and text quality were analysed. Keyboarding was the baseline control condition. The results demonstrated that seven of the eight students increased text productivity and that the proportion of word-level accuracy was maintained or improved. The use of punctuation progressed in participants with poor baseline skills. Most students’ STT-produced texts had at least a similar ratio of meaningfulness and text quality as keyboarding. However, the magnitude of the changes and development patterns varied, with three students showing the most notable impacts. In conclusion, this study’s intervention seemed beneficial in initially instructing STT, and the progress monitoring guided individually adapted future interventions such as balancing productivity and formal language aspects. Removing the spelling barrier with STT provided an opportunity for students to improve their higher-order skills, such as vocabulary diversity and overall text quality. Furthermore, visible progress, such as the ability to produce longer texts, might motivate continued STT usage. However, such development may not always be immediate.
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| 4. |
- Almqvist, Gustaf, et al.
(författare)
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Report of the Benchmark Workshop on Baltic Cod Stocks (WKBALTCOD)
- 2015
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- The ICES Benchmark Workshop on Baltic Cod Stocks (WKBALTCOD), chaired by External Chair Jean-Jacques Maguire, Canada and ICES Chair Marie Storr-Paulsen, Denmark, and attended by two invited external experts Verena Trenkel, France and Meaghan Bryan, USA met in Rostock, Germany, 2–6 March 2015 with 39 participants and six countries represented. The objective of WKBALTCOD was to evaluate the appropriateness of data and methods to determine stock status and investigate meth-ods appropriate to use in the single-stock assessment for the cod stock in SD 22–24 and cod in SD 25–32 in the Baltic. Participants in the workshop were a large group with diverse backgrounds representing the industry, fisheries, NGOs, managers and scientists.The single-stock analytic assessment of the eastern Baltic stock was not accepted by the assessment working group (WGBFAS) in 2014 due to severe problems with the input data. The advice for the eastern Baltic cod was, therefore, based on the ICES approach for data-limited stocks. As an outcome ICES decided to establish a bench-mark for both cod stocks and to scope an integrated assessment for the Baltic cod stocks. The first meeting (WKSIBCA) was therefore meant to introduce the interces-sional work conducted since the assessment working group in April 2014, and to reach some conclusions on how to proceed both in the short term (Benchmark in March 2015) and longer term (2–3 years) and was seen as a data compilation work-shop, there is produced a separate report from this workshop. The WKBALTCOD was the 2nd meeting in the benchmark process and was intended to come up with a final stock assessment method, stock annex and input data for both stocks. As it was not possible to reach conclusive decision on the final model to be used for the east Baltic cod stock during the benchmark meeting and as more work on the preferable models was needed, it was decided by the ACOM leadership to prolong the bench-mark process until the assessment working group meeting in April 2015. This deci-sion has led to a relatively long process partly mixed with the assessment working group WGBFAS.It became clear during the benchmark process that although large effort has been put into explaining the underlying processes leading to the changes in the Baltic ecosys-tem, there is still some lack of understanding of the present situation in the eastern Baltic cod stock. Therefore, it was not possible to reach firm conclusions on the final model to be used and therefore not possible to set reference points. It was decided to continue to explore the most promising models and to continue to improve the input data until the assessment working group started in April.The main challenges still to be solved for the Eastern Baltic cod stock is the quantifi-cation of increased natural mortality and decrease in growth. Through several presentations during the workshop (both WKSIBCA and WKBALTCOD) it became clear that natural mortality very likely has increased in later years, due to decreased condition and increased parasite infection. A decrease in growth also seems plausible duo to a decrease in condition and/or selectivity-induced mortality of the largest in-dividuals. However, as none of these parameters are easily estimated, especially with the severe ageing problems, different model assumptions made the output very shaky.For the western Baltic cod, stock identification issues were examined in area SD 24, the intermediate area: based on otolith characteristics and genetics. Due to the results showing a large proportion of east cod in this area, it was decided to split the catch2 | ICES WKBALTCOD REPORT 2015and survey from SD 24 into either the western or eastern Baltic cod stock. It was pos-sible to derive proportions of eastern and western cod in SD 24 back to the mid-1990s.For the western Baltic cod stock a modelled survey indices was included in the as-sessment covering the western part of SD 24 and Area 22+23 and based on a smoothed ALK.Both cod stocks have in the past used commercial tuning fleet to have a better cov-ered of older age groups. It was decided to abound this time-series duo quality issues such as a limited coverage and problems with technical creeping.WKBALTCOD was not able to explore and define reference points for the Western Baltic cod stock during the meeting due to time constraints, but these were calculated and decided by correspondence after the meeting. The recent protocols on estimation procedures developed by WKMSYREF3 for stocks with a full analytical assessment and for data-limited stocks served as objective guidelines to obtain reference point estimates.
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| 5. |
- Andersen, Sören M., et al.
(författare)
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A scalable route to 5-substituted 3-isoxazolol fibrinolysis inhibitor AZD6564
- 2014
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Ingår i: Organic Process Research & Development. - : American Chemical Society (ACS). - 1083-6160 .- 1520-586X. ; 18:8, s. 952-959
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Tidskriftsartikel (refereegranskat)abstract
- A practical and chromatography-free multikilogram synthesis of a 3-isoxazolol containing antifibrinolytic agent, AZD6564, has been developed in eight steps and 7% overall yield starting from methyl 2-chloroisonicotinate. Highlights in the synthesis are a Negishi coupling and an enzymatic resolution of a racemic ester.
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| 6. |
- Aspholm-Hurtig, Marina, et al.
(författare)
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Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin.
- 2004
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Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 305:5683, s. 519-22
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Tidskriftsartikel (refereegranskat)abstract
- Adherence by Helicobacter pylori increases the risk of gastric disease. Here, we report that more than 95% of strains that bind fucosylated blood group antigen bind A, B, and O antigens (generalists), whereas 60% of adherent South American Amerindian strains bind blood group O antigens best (specialists). This specialization coincides with the unique predominance of blood group O in these Amerindians. Strains differed about 1500-fold in binding affinities, and diversifying selection was evident in babA sequences. We propose that cycles of selection for increased and decreased bacterial adherence contribute to babA diversity and that these cycles have led to gradual replacement of generalist binding by specialist binding in blood group O-dominant human populations.
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| 7. |
- Aspholm, Marina, et al.
(författare)
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Helicobacter pylori adhesion to carbohydrates
- 2006
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Ingår i: Methods in Enzymology. - 0076-6879 .- 1557-7988. ; 417, s. 293-339
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Tidskriftsartikel (refereegranskat)abstract
- Adherence of bacterial pathogens to host tissues contributes to colonization and virulence and typically involves specific interactions between bacterial proteins called adhesins and cognate oligosaccharide (glycan) or protein motifs in the host that are used as receptors. A given pathogen may have multiple adhesins, each specific for a different set of receptors and, potentially, with different roles in infection and disease. This chapter provides strategies for identifying and analyzing host glycan receptors and the bacterial adhesins that exploit them as receptors, with particular reference to adherence of the gastric pathogen Helicobacter pylori.
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| 8. |
- Berg, Alexander, et al.
(författare)
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Axonal Regeneration after Sciatic Nerve Lesion Is Delayed but Complete in GFAP- and Vimentin-Deficient Mice.
- 2013
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 8:11
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Tidskriftsartikel (refereegranskat)abstract
- Peripheral axotomy of motoneurons triggers Wallerian degeneration of injured axons distal to the lesion, followed by axon regeneration. Centrally, axotomy induces loss of synapses (synaptic stripping) from the surface of lesioned motoneurons in the spinal cord. At the lesion site, reactive Schwann cells provide trophic support and guidance for outgrowing axons. The mechanisms of synaptic stripping remain elusive, but reactive astrocytes and microglia appear to be important in this process. We studied axonal regeneration and synaptic stripping of motoneurons after a sciatic nerve lesion in mice lacking the intermediate filament (nanofilament) proteins glial fibrillary acidic protein (GFAP) and vimentin, which are upregulated in reactive astrocytes and Schwann cells. Seven days after sciatic nerve transection, ultrastructural analysis of synaptic density on the somata of injured motoneurons revealed more remaining boutons covering injured somata in GFAP(-/-)Vim(-/-) mice. After sciatic nerve crush in GFAP(-/-)Vim(-/-) mice, the fraction of reinnervated motor endplates on muscle fibers of the gastrocnemius muscle was reduced 13 days after the injury, and axonal regeneration and functional recovery were delayed but complete. Thus, the absence of GFAP and vimentin in glial cells does not seem to affect the outcome after peripheral motoneuron injury but may have an important effect on the response dynamics.
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| 9. |
- Berg, Alexander, et al.
(författare)
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The Extent of Synaptic Stripping of Motoneurons after Axotomy Is Not Correlated to Activation of Surrounding Glia or Downregulation of Postsynaptic Adhesion Molecules
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:3, s. e59647-
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Tidskriftsartikel (refereegranskat)abstract
- Synapse elimination in the adult central nervous system can be modelled by axotomy of spinal motoneurons which triggers removal of synapses from the cell surface of lesioned motoneurons by processes that remain elusive. Proposed candidate mechanisms are removal of synapses by reactive microglia and astrocytes, based on the remarkable activation of these cell types in the vicinity of motoneurons following axon lesion, and/or decreased expression of synaptic adhesion molecules in lesioned motoneurons. In the present study, we investigated glia activation and adhesion molecule expression in motoneurons in two mouse strains with deviant patterns of synapse elimination following axotomy. Mice deficient in complement protein C3 display a markedly reduced loss of synapses from axotomized motoneurons, whereas mice with impaired function of major histocompatibility complex (MHC) class Ia display an augmented degree of stripping after axotomy. Activation of microglia and astrocytes was assessed by semiquantative immunohistochemistry for Iba 1 (microglia) and GFAP (astrocytes), while expression of synaptic adhesion molecules was determined by in situ hybridization. In spite of the fact that the two mouse strains display very different degrees of synapse elimination, no differences in terms of glial activation or in the downregulation of the studied adhesion molecules (SynCAM1, neuroligin-2,-3 and netrin G-2 ligand) could be detected. We conclude that neither glia activation nor downregulation of synaptic adhesion molecules are correlated to the different extent of the synaptic stripping in the two studied strains. Instead the magnitude of the stripping event is most likely a consequence of a precise molecular signaling, which at least in part is mediated by immune molecules.
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| 10. |
- Berg, Björn, et al.
(författare)
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Late stage pine litter decomposition : Relationship to litter N, Mn, and acid unhydrolyzable residue (AUR) concentrations and climatic factors
- 2015
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Ingår i: Forest Ecology and Management. - : Elsevier BV. - 0378-1127 .- 1872-7042. ; 358, s. 41-47
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this paper is to evaluate relationships between decomposition rates of Scots pine (Pinus sylvestris) and lodgepole pine (Pinus contorta var. contorta) needle litter in the late stage of decomposition (>30% accumulated mass loss), and the progressively changing concentrations of manganese (Mn), nitrogen (N), and acid unhydrolyzable residue (AUR), as well as mean annual temperature (MAT) and mean annual precipitation (MAP). Using available long-term decomposition studies on pine needle litter in a climate gradient in Sweden, we calculated annual mass loss and related to concentrations of Mn, N, and AUR at the start of each one-year period as well as to MAT and MAP. We investigated these relationships for (i) all data on annual mass loss combined and (ii) annual mass loss for five different decomposition categories as defined by accumulated mass loss. We found highly significant, negative, and dominant relationships between annual mass loss and N (R2=0.39) and AUR (R2=0.39), a slight but significant positive relationship to Mn (R2=0.08) and a significant negative relationship to MAT (R2=0.06). The relationships were dynamic, and changed with accumulated mass loss. The rate-dampening effect of N decreased to be a rate-enhancing effect at c. 60-80% accumulated mass loss. A similar trend was found for AUR, becoming rate-enhancing at 70-80% accumulated mass loss. For Scots pine needle litter the effect of MAT on mass loss decreased with increasing accumulated mass loss and changed to a rate-dampening effect at c. 50-70% accumulated mass loss. Mn showed a stimulating effect on mass loss rate in all categories whereas MAP showed no effect in this mainly boreal climatic gradient. The current approach indicates a method for detailed studies of rate-regulating factors for litter decomposition.
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| 11. |
- Berg, Björn, 1943-, et al.
(författare)
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Magnesium dynamics in decomposing foliar litter - a synthesis
- 2021
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Ingår i: Geoderma. - : Elsevier. - 0016-7061 .- 1872-6259. ; 382
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Tidskriftsartikel (refereegranskat)abstract
- We synthesized available data for magnesium (Mg) dynamics in newly shed and decomposing foliar litter of mainly pine (Pinus) species, Norway spruce (Picea abies), and birch (Betula) species. Using original, measured data from 40 stands organized in climatic gradients we intended to determine patterns of Mg concentration and net release vs accumulated mass loss of the litter. This synthesis is likely the first synthesis of Mg dynamics in decomposing litter.In paired stands, litter of both Norway spruce and lodgepole pine (Pinus contorta) had higher Mg concentrations than Scots pine (Pinus silvestris), with concentrations in Norway spruce litter even twice as high.In decomposing litter, Mg concentrations followed a quadratic (X2-X) function vs accumulated mass loss and consequently had minima, different for Norway spruce and Scots pine litter. Out of 68 decomposition studies 53 gave minimum concentration. The Mg minimum concentration during decomposition was positively related to initial Mg concentration for Scots pine and Scots pine plus lodgepole pine but not for Norway spruce. The increase in concentration suggests that after the minimum Mg was temporarily limiting.For Norway spruce litter there was a relationship between minimum concentration of Mg and the limit value. There was no such relationship for Scots pine and not for the combined pine data.Magnesium net release started directly after the incubation and was linear to accumulated mass loss of litter, giving a slope coefficient (release rate) for each study. The net release rate was linear to initial Mg concentration and all studies combined gave a negative linear relationship.
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| 12. |
- Berg, Jan O., 1937-
(författare)
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På spaning efter en svensk modell : Idéer och vägval i arbetsgivarpolitiken 1897-1909
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The period saw the founding of the first Swedish employers´ associations as a reaction to the preceding decades´ growth of industrial trade unions. Conflicting ideas fought about supremacy. Not only was the fight carried out across the social dividing line separating workers from the bourgeoisie, but also between groups on either side: hawks versus doves among employers; revolutionaries versus reformers among workers. The study uses an actor perspective, comparing three leading industrialists in their particular roles as employers. It analyzes the development of ideas over the period studied, using minutes from meetings, company memos, letters, speeches and newspapers as primary sources. In addition, it is action-orientated and analyzes major labour conflicts that were fought and agreements that were reached. It applies a split vision, taking into regard the contemporary views and actions of the labour unions. Its perspective moves between the individual, the company and the organizational levels, with the primary aim to see what changes in the traditional patriarchal employer policies that were considered and to what extent such changes were realized. A major result is the evidence of the irreconcilable views on the subject of strike breakers/loyal workers -- two conflicting terms for one phenomenon that indicate a gap between two different sets of values. Differing views among employers on how to relate to this gap caused frictions in the years 1906-09. The outcome of the general strike in 1909 ended in a harsh employer organizations policy for more than the two following decades. It was replaced by the mutual spirit, later known as the Swedish Model, materialized in the Saltsjöbaden general agreements of 1938.
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| 13. |
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| 14. |
- Berg, Staffan, et al.
(författare)
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Comparison of co-existing forestry and reindeer husbandry value chains in northern Sweden
- 2016
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Ingår i: Silva Fennica. - : Finnish Society of Forest Science. - 0037-5330 .- 2242-4075. ; 50
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Tidskriftsartikel (refereegranskat)abstract
- Forestry in Mala, northern Sweden, coexists with other land uses. Reindeer husbandry is in the area for centuries and requires large areas of grazing land. Competing land uses may threaten the Mala Sami village. The aim of the study was to evaluate increased consideration in forest management towards 1) reindeer husbandry, 2) nature and 3) a combination of the two. These scenarios were compared with forest management as it was in 2009. Results indicate that all three scenarios lead to a decrease in annual harvesting volumes of 0.2 to 0.4 million m(3). Forest industry dominated the economic viability in the area. Forest management adapted to the needs of reindeer husbandry resulted in less potential for yearly harvest, employment and profits from forest industry. On the other hand, it led to an increase in growing stock and consequently the potential for carbon sequestration over time. Indeed the increased sequestration would compensate for all fossil emissions of carbon from the Forest Wood Chain (FWC). The nature scenario had minor effects on economic result and on the emissions of fossil carbon. The combined scenario gave a reduced economic performance for the FWC. A scenario based on forest management accommodating the needs of reindeer husbandry gave the best economic result for the reindeer chain, due to high survival rate of the reindeer. However the economic importance of reindeer husbandry in the region was small compared to the FWC. Results from scenario analysis could serve as a platform for mutual understanding between stakeholders.
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| 15. |
- Berg, Staffan, et al.
(författare)
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Considerations in the developability of peptides for oral administration when formulated together with transient permeation enhancers
- 2022
-
Ingår i: International Journal of Pharmaceutics. - : Elsevier. - 0378-5173 .- 1873-3476. ; 628
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Tidskriftsartikel (refereegranskat)abstract
- This paper reviews many of the properties of a peptide that need to be considered prior to development as an oral dosage form when co-formulated with a permeation enhancer to improve oral bioavailability, including the importance and implications of peptide half-life on variability in pharmacokinetic profiles. Clinical consider-ations in terms of food and drug-drug interactions are also discussed. The paper further gives a brief overview how permeation enhancers overcome barriers that limit oral absorption of peptides and thereby improve their oral bioavailability, albeit bioavailabilities are still low single digit and variability is high.
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| 16. |
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| 17. |
- Berg, Staffan, et al.
(författare)
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Evaluation in pig of an intestinal administration device for oral peptide delivery
- 2023
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Ingår i: Journal of Controlled Release. - : Elsevier. - 0168-3659 .- 1873-4995. ; 353, s. 792-801
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Tidskriftsartikel (refereegranskat)abstract
- The bioavailability of peptides co-delivered with permeation enhancers following oral administration remains low and highly variable. Two factors that may contribute to this are the dilution of the permeation enhancer in the intestinal fluid, as well as spreading of the released permeation enhancer and peptide in the lumen by intestinal motility. In this work we evaluated an Intestinal Administration Device (IAD) designed to reduce the luminal dilution of drug and permeation enhancer, and to minimize movement of the dosage form in the intestinal lumen. To achieve this, the IAD utilizes an expanding design that holds immediate release mini tablets and places these in contact with the intestinal epithelium, where unidirectional drug release can occur. The expanding conformation limits movement of the IAD in the intestinal tract, thereby enabling drug release at a single focal point in the intestine. A pig model was selected to study the ability of the IAD to promote intestinal absorption of the peptide MEDI7219 formulated together with the permeation enhancer sodium caprate. We compared the IAD to intestinally administered enteric coated capsules and an intestinally administered solution. The IAD restricted movement of the immediate release tablets in the small intestine and histological evaluation of the mucosa indicated that high concentrations of sodium caprate were achieved. Despite significant effect of the permeation enhancer on the integrity of the intestinal epithelium, the bioavailability of MEDI7219 was of the same order of magnitude as that achieved with the solution and enteric coated capsule formulations (2.5–3.8%). The variability in plasma concentrations of MEDI7219 were however lower when delivered using the IAD as compared to the solution and enteric coated capsule formulations. This suggests that dosage forms that can limit intestinal dilution and control the position of drug release can be a way to reduce the absorptive variability of peptides delivered with permeation enhancers but do not offer significant benefits in terms of increasing bioavailability.
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| 18. |
- Berg, Staffan, et al.
(författare)
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Impact of Intestinal Concentration and Colloidal Structure on the Permeation-Enhancing Efficiency of Sodium Caprate in the Rat
- 2022
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 19:1, s. 200-212
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Tidskriftsartikel (refereegranskat)abstract
- In this work, we set out to better understand how the permeation enhancer sodium caprate (C10) influences the intestinal absorption of macromolecules. FITC-dextran 4000 (FD4) was selected as a model compound and formulated with 50-300 mM C10. Absorption was studied after bolus instillation of liquid formulation to the duodenum of anesthetized rats and intravenously as a reference, whereafter plasma samples were taken and analyzed for FD4 content. It was found that the AUC and C-max of FD4 increased with increasing C10 concentration. Higher C10 concentrations were associated with an increased and extended absorption but also increased epithelial damage. Depending on the C10 concentration, the intestinal epithelium showed significant recovery already at 60-120 min after administration. At the highest studied C10 concentrations (100 and 300 mM), the absorption of FD4 was not affected by the colloidal structures of C10, with similar absorption obtained when C10 was administered as micelles (pH 8.5) and as vesicles (pH 6.5). In contrast, the FD4 absorption was lower when C10 was administered at 50 mM formulated as micelles as compared to vesicles. Intestinal dilution of C10 and FD4 revealed a trend of decreasing FD4 absorption with increasing intestinal dilution. However, the effect was smaller than that of altering the total administered C10 dose. Absorption was similar when the formulations were prepared in simulated intestinal fluids containing mixed micelles of bile salts and phospholipids and in simple buffer solution. The findings in this study suggest that in order to optimally enhance the absorption of macromolecules, high (>= 100 mM) initial intestinal C10 concentrations are likely needed and that both the concentration and total dose of C10 are important parameters.
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| 19. |
- Berg, Staffan, et al.
(författare)
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In Vitro and In Vivo Evaluation of 3D Printed Capsules with Pressure Triggered Release Mechanism for Oral Peptide Delivery
- 2021
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Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 110:1, s. 228-238
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Tidskriftsartikel (refereegranskat)abstract
- In this study a 3D printed capsule designed to break from the physiological pressures in the antropyloric region was evaluated for its ability to deliver the synthetic octapeptide octreotide in beagle dogs when co-formulated with the permeation enhancer sodium caprate. The pressure sensitive capsules were compared to traditional enteric coated hard gelatin capsules and enteric coated tablets. Paracetamol, which is completely absorbed in dogs, was included in the formulations and used as an absorption marker to give information about the in vivo performance of the dosage forms. The pressure sensitive capsules released drug in 50% of the dogs. In the cases where drug was released, there was no difference in octreotide bioavailability or C-max compared to the enteric coated dosage forms. When comparing all dosage forms, a correlation was seen between paracetamol C-max and octreotide bioavailability, suggesting that a high drug release rate may be beneficial for peptide absorption when delivered together with sodium caprate. (C) 2020 Published by Elsevier Inc.
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| 20. |
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| 21. |
- Berg, Staffan, et al.
(författare)
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Kollagring i den skogsindustriella sektorn i Sverige
- 2002
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Trätek och SkogForsk har tillsammans fått uppdraget av Statens Energimyndighet att beräkna kollagringen i den skogsindustriella sektorn i Sverige. För att beskriva skogens och dess produkters roll som kolsänka, och därmed positiva påverkan på CO2 och växthusgaser i atmosfären, har här beräkningssätt föreslagna av IPCC (Intergovernmental Panel on Climate Chage) använts. Resultaten är baserade på data från FAO och Riksskogstaxeringen.
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| 22. |
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| 23. |
- Berg, Staffan
(författare)
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Oral delivery of macromolecules formulated with permeation enhancers
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Therapeutic macromolecules including peptides, proteins, and nucleotide-based ones (such as antisense oligonucleotides and RNAs) have great potential as drug candidates. One drawback is that they typically need to be administered parenterally via subcutaneous, intramuscular or intravenous injections. Patients and healthcare professionals, however, generally prefer medicines that are taken orally. Absorption of therapeutic macromolecules after oral administration is unfortunately limited due to their instability in the gastrointestinal tract, as well as their poor permeability across the mucosa, owing to their large and hydrophilic nature.Different formulation approaches can improve the absorption of macromolecules after oral administration. Permeation enhancers are the most studied technology for this purpose, and has resulted in two approved products. Yet despite many years of studying permeation enhancers, the bioavailability in clinical studies remains low and highly variable. Because of this, the use of permeation enhancers is currently limited to potent compounds with wide safety margins and long half-lives. Increasing the bioavailability and reducing variability thereof, would allow a wider range of drug candidates to be delivered using this formulation technology.This thesis aims to improve the understanding of the low and variable absorption of solid dosage forms containing permeation enhancers. It includes studies on the absorption of different macromolecules co-delivered with the permeation enhancer sodium caprate (C10) in three pre-clinical models. To investigate the impact of intestinal C10 concentration, formulations with increasing C10 concentrations were administered to the upper small intestine of rats. C10 was rapidly absorbed and for the proteolytically stable macromolecules, a strong correlation between the C10 concentration and their bioavailability was observed. Furthermore, FITC-dextrans displayed an increase in both the initial rate and duration of absorption. In contrast, only the duration of increased absorption was prolonged for MEDI7219. Histological evaluation of the intestinal mucosa indicated that macromolecule absorption was correlated with erosion of the epithelium. On the basis of these results in rat, solid dosage forms designed to release C10 and peptide in high concentrations were studied in both pig and dog. A dosage form that achieved highly localized release showed promise in decreasing the absorptive variability of a model peptide.
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| 24. |
- Björnham, Oscar, 1976-
(författare)
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A study of bacterial adhesion on a single-cell level by means of force measuring optical tweezers and simulations
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The intriguing world of microbiology is nowadays accessible for detailed exploration at a single–molecular level. Optical tweezers are a novel instrument that allows for non–invasive manipulation of single cells by the sole use of laser light and operates on the nano– and micrometer scale which corresponds to the same length scale as living cells. Moreover, forces within the field of microbiology are typically in the picoNewton range which is in accordance with the capability of force measuring optical tweezers systems. Both these conformabilities imply that force measuring optical tweezers is suitable for studies of single living cells. This thesis focuses on the mechanisms of bacterial attachments to host cells which constitute the first step in bacterial infection processes. Bacteria bind specifically to host receptors by means of adhesins that are expressed either directly on the bacterial membrane or on micrometer–long adhesion organelles that are called pili. The properties of single adhesin–receptor bonds that mediate adherence of the bacterium Helicobacter pylori are first examined at various acidities. Further on, biomechanical properties of P pili expressed by Escherichia coli are presented to which computer simulations, that capture the complex kinetics of the pili structure and precisely replicate measured data, are applied. Simulations are found to be a powerful tool for investigations of adhesive attributes of binding systems and are utilized in the analyses of the specific binding properties of P pili on a single–pilus level. However, bacterial binding systems generally involve a multitude of adhesin–receptor bonds. To explore bacterial attachments, the knowledge from single–pilus studies is brought into a full multipili attachment scenario which is analyzed by means of theoretical treatments and simulations. The results are remarkable in several aspects. Not only is it found that the intrinsic properties of P pili are composed in an optimal combination to promote strong multipili bindings. The properties of the pili structure itself are also found to be optimized with respect to its in vivo environment. Indeed, the true meaning of the attributes derived at a single–pilus level cannot be unraveled until a multipili–binding system is considered. Whereas detailed studies are presented for the helix–like P pili expressed by Gram–negative Escherichia coli, conceptual studies are presented for the open coil–like T4 pili expressed by Gram–positive Streptococcus pneumoniae. The structural and adhesive properties of these two types of pili differ considerably. These dissimilarities have far–reaching consequences on the adhesion possibilities at both single–pilus and multipili levels which are discussed qualitatively. Moreover, error analyses of conventional data processing methods in dynamic force spectroscopy as well as development of novel analysis methods are presented. These findings provide better understanding of how to perform refined force measurements on single adhesion organelles as well as how to improve the analyses of measurement data to obtain accurate parameter values of biomechanical entities. In conclusion, this thesis comprises a study of bacterial adhesion organelles and the way they cooperate to establish efficient attachment systems that can successfully withstand strong external forces that acts upon bacteria. Such systems can resist, for instance, rinsing effects and thereby allow bacteria to colonize their host. By understanding the complexity, and thereby possible weaknesses, of bacterial attachments, new targets for combating bacterial infections can be identified.
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| 25. |
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| 26. |
- Bugaytsova, Jeanna, et al.
(författare)
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pH regulated H. pylori adherence : implications for persistent infection and disease
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Helicobacter pylori’s BabA adhesin binds strongly to gastric mucosal ABH/Leb glycans on the stomach epithelium and overlying mucus, materials continuously shed into the acidic gastric lumen. Here we report that this binding is acid labile, acid inactivation is fully reversible; and acid lability profiles vary with BabA sequence and correlate with disease patterns. Isogenic H. pylori strains from the gastric antrum and more acidic corpus were identified that differed in acid lability of receptor binding and in sequence near BabA’s carbohydrate binding domain. We propose that reversible acid inactivation of receptor binding helps H. pylori avoid clearance by mucosal shedding, and that strain differences in acid lability affect tissue tropism and the spectrum of associated gastric diseases.
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| 27. |
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| 28. |
- Efe, Cumali, et al.
(författare)
-
Tacrolimus and Mycophenolate Mofetil as Second-Line Therapies for Pediatric Patients with Autoimmune Hepatitis
- 2018
-
Ingår i: Digestive Diseases and Sciences. - : SPRINGER. - 0163-2116 .- 1573-2568. ; 63:5, s. 1348-1354
-
Tidskriftsartikel (refereegranskat)abstract
- We studied the efficacy and safety of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy in pediatric patients with autoimmune hepatitis (AIH) who were intolerant or non-responders to standard therapy (corticosteroid and azathioprine). We performed a retrospective study of data from 13 centers in Europe, USA, and Canada. Thirty-eight patients (< 18 years old) who received second-line therapy (18 MMF and 20 tacrolimus), for a median of 72 months (range 8-182) were evaluated. Patients were categorized into two groups: Group 1 (n = 17) were intolerant to corticosteroid or azathioprine, and group 2 (n = 21) were non-responders to standard therapy. Overall complete response rates were similar in patients treated with MMF and tacrolimus (55.6 vs. 65%, p = 0.552). In group 1, MMF and tacrolimus maintained a biochemical remission in 88.9 and 87.5% of patients, respectively (p = 0.929). More patients in group 2 given tacrolimus compared to MMF had a complete response, but the difference was not statistically significant (50.0 vs. 22.2%, p = 0.195). Biochemical remission was achieved in 71.1% (27/38) of patients by tacrolimus and/or MMF. Decompensated cirrhosis was more commonly seen in MMF and/or tacrolimus non-responders than in responders (45.5 vs. 7.4%, p = 0.006). Five patients who received second-line therapy (2 MMF and 3 tacrolimus) developed side effects that led to therapy withdrawal. Long-term therapy with MMF or tacrolimus was generally well tolerated by pediatric patients with AIH. Both MMF and tacrolimus had excellent efficacy in patients intolerant to corticosteroid or azathioprine. Tacrolimus might be more effective than MMF in patients failing previous therapy.
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| 29. |
- Emeh, Prosper, et al.
(författare)
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Experiences and Translatability of In Vitro and In Vivo Models to Evaluate Caprate as a Permeation Enhancer
- 2024
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 21:1, s. 313-324
-
Tidskriftsartikel (refereegranskat)abstract
- Transient permeation enhancers (PEs) have been widely used to improve the oral absorption of macromolecules. During pharmaceutical development, the correct selection of the macromolecule, PE, and the combination needs to be made to maximize oral bioavailability and ensure successful clinical development. Various in vitro and in vivo methods have been investigated to optimize this selection. In vitro methods are generally preferred by the pharmaceutical industry to reduce the use of animals according to the "replacement, reduction, and refinement" principle commonly termed "3Rs," and in vitro methods typically have a higher throughput. This paper compares two in vitro methods that are commonly used within the pharmaceutical industry, being Caco-2 and an Ussing chamber, to two in vivo models, being in situ intestinal instillation to rats and in vivo administration via an endoscope to pigs. All studies use solution formulation of sodium caprate, which has been widely used as a PE, and two macromolecules, being FITC-dextran 4000 Da and MEDI7219, a GLP-1 receptor agonist peptide. The paper shares our experiences of using these models and the challenges with the in vitro models in mimicking the processes occurring in vivo. The paper highlights the need to consider these differences when translating data generated using these in vitro models for evaluating macromolecules, PE, and combinations thereof for enabling oral delivery.
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| 30. |
- Gradin, Per A., et al.
(författare)
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Measurement of the Power Distribution in a Single Disc Refiner
- 1999
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Ingår i: Journal of Pulp and Paper Science. - 0826-6220. ; 25:11, s. 384-387
-
Tidskriftsartikel (refereegranskat)abstract
- A vital parameter in the production of mechanical pulp through refining is the energy consumption. Until recently, the pulping industry has focused on the total energy consumed, without a full understanding of how this energy is distributed in the refiners. In this paper two methods are suggested by which it is possible to estimate the energy supplied at an arbitrary point along the disc radius on refiner segments. The methods are based on instrumented bar with strain gauges. In the first method, a bar is slotted so that the sensor can be viewed as consisting of a number of cantilever beams separated by slots. In the second method, the sensor consists of one continuous bar along the disc radius. The sensors are calibrated such that influence coefficients are obtained for the slotted case and an influence function is obtained for the continuous one. The tangential forces are obtained directly in the first method, while in the second they are given by an integral equation which can be solved numerically. From the knowledge of the tangential force the power distribution can be calculated. Experimental results from the use of the slotted sensor are also given.
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| 31. |
- Gradin, Per, et al.
(författare)
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Measuring forces in a refiner plate gap
- 2011
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Ingår i: Proceedings of International Mechanical Pulping Conference. - 9787501982516 ; , s. 81-83
-
Konferensbidrag (refereegranskat)
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| 32. |
- Gradin, Per, et al.
(författare)
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Measuring Tangential Forces in a Pulp Refiner : A Novel Approach
- 2016
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Ingår i: Experimental techniques (Westport, Conn.). - : Springer Science and Business Media LLC. - 0732-8818 .- 1747-1567. ; 40:2, s. 789-793
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Tidskriftsartikel (refereegranskat)abstract
- To get some insight into the processes that are active during the refining of wood, the tangential force distribution in the plate gap is of interest. Over the years several designs of force sensors have been developed for this purpose. One drawback with these designs is that each sensormeasures forces over quite a small area such that in order to cover the whole disc with a reasonably good resolution, many sensors have to be used. Also, there are problems to protect the active parts of the sensors from the harsh environment in the plate gap. In this paper a different concept is presented, in that the sensor is continuous and consists of a hollow radial bar equipped with strain gages on the inside. The force sensor was calibrated before mounting by loading it with a known load in the tangential direction and in different positions while measuring the strains in the points where the gages are located. This makes it possible to determine the so-called influence (or Green) functions. Knowing these it is possible to determine the tangential force distribution from strain values measured during operation of the refiner. Guidelines for doing this are presented together with a detailed description of the load sensor and some experimental results.
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| 33. |
- Hossain, Md Shakhawath, et al.
(författare)
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Aggregation Behavior of Medium Chain Fatty Acids Studied by Coarse-Grained Molecular Dynamics Simulation
- 2019
-
Ingår i: AAPS PharmSciTech. - : SPRINGER. - 1530-9932. ; 20
-
Tidskriftsartikel (refereegranskat)abstract
- Medium chain fatty acids (MCFA) are digestion products of lipid-rich food and lipid-based formulations, and they are used as transient permeability enhancers in formulation of poorly permeable compounds. These molecules may promote drug absorption by several different processes, including solubilization, increased membrane fluidity, and increased paracellular transport through opening of the tight junctions. Therefore, understanding the aggregation behavior of MCFAs is important. A number of studies have measured the critical micelle concentration (CMC) of MCFAs experimentally. However, CMC is highly dependent on system conditions like pH, temperature, and the ionic strength of the buffer used in different experimental techniques. In this study, we investigated the aggregation behavior of four different MCFAs using the coarse-grained molecular dynamics (CG-MD) simulations with the purpose to explore if CG-MD can be used to study MCFA interactions occurring in water. The ratio of deprotonated and non-charged MCFA molecules were manipulated to assess aggregation behavior under different pH conditions and within the box sizes of 22x22x44nm(3) and 44nm(3) for 1s. CMCs were calculated by performing CG-MD simulations with an increasing number of MCFAs. The resulting aggregate size distribution and number of free MCFA molecules were used to determine the CMC. The CMCs from simulations for C-8, C-10, and C-12 were 1.8-3.5-fold lower than the respective CMCs determined experimentally by the Wilhelmy method. However, the variation of MCFA aggregate sizes and morphologies at different pH conditions is consistent with previous experimental observation. Overall, this study suggests that CG-MD is suitable for studying colloidal systems including various MCFAs.
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| 34. |
- Ingvarsson, Jens, et al.
(författare)
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Rubella virus seropositivity after infection or vaccination as a risk factor for multiple sclerosis
- 2024
-
Ingår i: European Journal of Neurology. - : John Wiley & Sons. - 1351-5101 .- 1468-1331.
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Multiple sclerosis (MS) is a demyelinating disease affecting millions of people worldwide. Hereditary susceptibility and environmental factors contribute to disease risk. Infection with Epstein–Barr virus (EBV) and human herpesvirus 6A (HHV-6A) have previously been associated with MS risk. Other neurotropic viruses, such as rubella virus (RV), are possible candidates in MS aetiopathogenesis, but previous results are limited and conflicting.Methods: In this nested case–control study of biobank samples in a Swedish cohort, we analysed the serological response towards RV before the clinical onset of MS with a bead-based multiplex assay in subjects vaccinated and unvaccinated towards RV. The association between RV seropositivity and MS risk was analysed with conditional logistic regression.Results: Seropositivity towards RV was associated with an increased risk of MS for unvaccinated subjects, even when adjusting for plausible confounders including EBV, HHV-6A, cytomegalovirus and vitamin D (adjusted odds ratio [AOR] = 4.0, 95% confidence interval [CI] 1.8–8.8). Cases also had stronger antibody reactivity towards rubella than controls, which was not seen for other neurotropic viruses such as herpes simplex or varicella zoster. Furthermore, we observed an association between RV seropositivity and MS in vaccinated subjects. However, this association was not significant when adjusting for the aforementioned confounders (AOR = 1.7, 95% CI 1.0–2.9).Conclusions: To our knowledge, these are the first reported associations between early RV seropositivity and later MS development. This suggests a broadening of the virus hypothesis in MS aetiology, where molecular mimicry between rubella epitopes and human central nervous system molecules could be an attractive possible mechanism.
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| 35. |
- Jouybari, Nima Fallah, et al.
(författare)
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An investigation of forces on a representative surface in a pulp flow through rotating and non-rotating grooves
- 2023
-
Ingår i: Journal of the Brazilian Society of Mechanical Sciences and Engineering. - : Springer. - 1678-5878 .- 1806-3691. ; 45:5
-
Tidskriftsartikel (refereegranskat)abstract
- Softwood pulp flow in rotating and non-rotating grooves is numerically simulated in the present study to investigate the fluid flow and the forces acting on a representative surface mounted in the groove. The viscosity of softwood pulp with various consistencies is available from the measurements reported in the literature providing the opportunity to examine the effects of fiber consistency on the velocity and pressure distribution within the groove. The simulations are carried out in OpenFOAM for different values of gap thickness, angular velocity and radial positions from which the pressure coefficient and shear forces values are obtained. It is found that the shear forces within the gap increase linearly with the angular velocity for all fiber consistencies investigated and in both grooves. Also, this behavior can be successfully predicted by modeling the gap flow as a Couette flow in a two-dimensional channel. Meanwhile, a more detailed analysis of the flow kinetic energy close to the stagnation point using Bernoulli’s principle is carried out to provide a better understanding of the pressure coefficient variation with angular velocity in the non-rotating groove. A comparison of pressure coefficients obtained numerically with those calculated by considering the compression effects revealed that the comparison effects are dominating in the pulp flow within the groove.
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| 36. |
- Kabir, Mohammad, 1974, et al.
(författare)
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A Test Vehicle for RF/DC Evaluation and Destructive Testing Of Vertically Grown Nanostructures (VGCNS)
- 2011
-
Ingår i: Proceedings of the NT11 International Conference on the Science and Application of Nanotubes, Cambridge, UK, July 10-16, 2011.
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- We have developed an RF test vehicle suitable for measuring DC and microwave performance of vertically grown carbon nanostructures (VGCNS) as via-interconnects. A first version of the interconnect test vehicles devices were designed, fabricated and characterized. The RF small signal (S-parameter) and large signal measurements show that carbon nanofibres can be used as interconnects in microwave circuit, even for power devices. The design of test vehicle employs a three metal layer concept, forming sequentially the ground, signal and device under test structures for characterization in a microstrip configuration. The structures as such consisted of interconnects of dimensions ranging from 50 nm to 100 µm diameter made of VGCNS. In the first version of the interconnect test vehicles, the interconnects were made of carbon nanofibers grown at 450 C. From SEM measurement we found that the resulting height was around 1.5-2 µm. Epoxy polymer SU-8 was employed by spinning on the device and a subsequent etch back process was carried out to open up the tip of the fibres to connect to consecutive interconnects with the third metallisation layer. After growing the nanofibres, it was observed, using SEM, that interconnect sizes smaller than 10 µm diameter suffered from parasitic growth and therefore the effective device dimension deviated from the initial design. We carried out small signal measurements using a vector network analyser for frequency ranging from 1 to 25 GHz, in order to characterise the transmission and reflection/absorption of the devices as function of their diameter size. The large signal evaluation was performed by measuring the gain compression of the devices. In addition destructive tests, aiming at testing the current carrying capability of the interconnect, have also been performed.The resistivity of interconnects was measured to vary varies from 0.2 µΩ·mm-1.3 mΩ·mm. Apparently, the device performance is considerably influenced by the fill factor of the interconnect with VGCNS. Small variations in fill factor (in %) provided a large variations in device resistivity. Furthermore, it was also observed that the resistance drops at higher power levels. RF conductivity of interconnects ranges from 5x10^3 S/m to 7x10^5 S/m. The average input power before interconnect destruction is larger than 25W with effective device diameter ranging from 3 µm to 100 µm interconnects. In addition, the average gain compression before interconnect destruction was found to be 0.6 dB. It was not possible to extract the conductivity value of an individual nanofiber using comparison to simulation data, since the devices might have suffered from parasitic growth as well as pinhole metal diffusion during top metal contact formation. This certainly affects the actual device dimension and properties. Nevertheless, the proof of concept of design and manufacturing a test vehicle for RF measurements of vertically grown nanostructures was achieved. We will report the findings and anomalies in the measured devices. Further improvement is expected in the coming test vehicle version.
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| 37. |
- Lampa, Samuel, et al.
(författare)
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Predicting off-target binding profiles with confidence using Conformal Prediction
- 2018
-
Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- Ligand-based models can be used in drug discovery to obtain an early indication of potential off-target interactions that could be linked to adverse effects. Another application is to combine such models into a panel, allowing to compare and search for compounds with similar profiles. Most contemporary methods and implementations however lack valid measures of confidence in their predictions, and only providing point predictions. We here describe the use of conformal prediction for predicting off-target interactions with models trained on data from 31 targets in the ExCAPE dataset, selected for their utility in broad early hazard assessment. Chemicals were represented by the signature molecular descriptor and support vector machines were used as the underlying machine learning method. By using conformal prediction, the results from predictions come in the form of confidence p-values for each class. The full pre-processing and model training process is openly available as scientific workflows on GitHub, rendering it fully reproducible. We illustrate the usefulness of the methodology on a set of compounds extracted from DrugBank. The resulting models are published online and are available via a graphical web interface and an OpenAPI interface for programmatic access.
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| 38. |
- Lapins, Maris, et al.
(författare)
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A confidence predictor for logD using conformal regression and a support-vector machine
- 2018
-
Ingår i: Journal of Cheminformatics. - : Springer Science and Business Media LLC. - 1758-2946. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- Lipophilicity is a major determinant of ADMET properties and overall suitability of drug candidates. We have developed large-scale models to predict water-octanol distribution coefficient (logD) for chemical compounds, aiding drug discovery projects. Using ACD/logD data for 1.6 million compounds from the ChEMBL database, models are created and evaluated by a support-vector machine with a linear kernel using conformal prediction methodology, outputting prediction intervals at a specified confidence level. The resulting model shows a predictive ability of [Formula: see text] and with the best performing nonconformity measure having median prediction interval of [Formula: see text] log units at 80% confidence and [Formula: see text] log units at 90% confidence. The model is available as an online service via an OpenAPI interface, a web page with a molecular editor, and we also publish predictive values at 90% confidence level for 91 M PubChem structures in RDF format for download and as an URI resolver service.
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| 39. |
- Lindblom, Rickard P. F., et al.
(författare)
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Complement receptor 2 is up regulated in the spinal cord following nerve root injury and modulates the spinal cord response
- 2015
-
Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Activation of the complement system has been implicated in both acute and chronic states of neurodegeneration. However, a detailed understanding of this complex network of interacting components is still lacking. Methods: Large-scale global expression profiling in a rat F2(DAxPVG) intercross identified a strong cis-regulatory influence on the local expression of complement receptor 2 (Cr2) in the spinal cord after ventral root avulsion (VRA). Expression of Cr2 in the spinal cord was studied in a separate cohort of DA and PVG rats at different time-points after VRA, and also following sciatic nerve transection (SNT) in the same strains. Consequently, Cr2(-/-) mice and Wt controls were used to further explore the role of Cr2 in the spinal cord following SNT. The in vivo experiments were complemented by astrocyte and microglia cell cultures. Results: Expression of Cr2 in naive spinal cord was low but strongly up regulated at 5-7 days after both VRA and SNT. Levels of Cr2 expression, as well as astrocyte activation, was higher in PVG rats than DA rats following both VRA and SNT. Subsequent in vitro studies proposed astrocytes as the main source of Cr2 expression. A functional role for Cr2 is suggested by the finding that transgenic mice lacking Cr2 displayed increased loss of synaptic nerve terminals following nerve injury. We also detected increased levels of soluble CR2 (sCR2) in the cerebrospinal fluid of rats following VRA. Conclusions: These results demonstrate that local expression of Cr2 in the central nervous system is part of the axotomy reaction and is suggested to modulate subsequent complement mediated effects.
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| 40. |
- Lindblom, Rickard P. F., et al.
(författare)
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Unbiased expression mapping identifies a link between the complement and cholinergic systems in the rat central nervous system
- 2014
-
Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 192:3, s. 1138-1153
-
Tidskriftsartikel (refereegranskat)abstract
- The complement system is activated in a wide spectrum of CNS diseases and is suggested to play a role in degenerative phenomena such as elimination of synaptic terminals. Still, little is known of mechanisms regulating complement activation in the CNS. Loss of synaptic terminals in the spinal cord after an experimental nerve injury is increased in the inbred DA strain compared with the PVG strain and is associated with expression of the upstream complement components C1q and C3, in the absence of membrane attack complex activation and neutrophil infiltration. To further dissect pathways regulating complement expression, we performed genome-wide expression profiling and linkage analysis in a large F2(DA × PVG) intercross, which identified quantitative trait loci regulating expression of C1qa, C1qb, C3, and C9. Unlike C1qa, C1qb, and C9, which all displayed distinct coregulation with different cis-regulated C-type lectins, C3 was regulated in a coexpression network immediately downstream of butyrylcholinesterase. Butyrylcholinesterase hydrolyses acetylcholine, which exerts immunoregulatory effects partly through TNF-α pathways. Accordingly, increased C3, but not C1q, expression was demonstrated in rat and mouse glia following TNF-α stimulation, which was abrogated in a dose-dependent manner by acetylcholine. These findings demonstrate new pathways regulating CNS complement expression using unbiased mapping in an experimental in vivo system. A direct link between cholinergic activity and complement activation is supported by in vitro experiments. The identification of distinct pathways subjected to regulation by naturally occurring genetic variability is of relevance for the understanding of disease mechanisms in neurologic conditions characterized by neuronal injury and complement activation.
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| 41. |
- Lindholm, Eva-Lotta, et al.
(författare)
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Skörd av skogsbränslen i ett livscykelperspektiv
- 2010
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Efterfrågan på biobränslen ökar och utvecklingen drivs av både nationella och internationella mål att sänka utsläppen av växthusgaser samt att minska beroendet av fossil energi. Det har emellertid visat sig att inte all användning av bioenergi leder till minskade utsläpp av växthusgaser. För att säkerställa olika energisystems potential att minska utsläppen av växthusgaser behöver de jämföras med ett lämpligt fossilt referenssystem. I den här studien studerades skörd av grot (grenar och toppar) och stubbar i ett livscykelperspektiv för att identifiera system för skörd av skogsbränsle som relativt den producerade bränslemängden orsakar så små miljöeffekter som möjligt samtidigt som insatsenergi är liten. Användandet av skogsbränsle kan ses som en tidigareläggning av utsläpp av koldioxid jämfört med ett referensfall där biomassan lämnas kvar i skogen för att förmultna. Tidsperspektivet är därför betydelsefullt för hur förlusten av markkol ska beräknas för skogsbränsle som GROT och stubbar. För att beräkna den minskade inlagringen i markkol modellerades två granbestånd, ett i södra Sverige och ett i norra Sverige. Referensmarkanvändningen var skogsskötsel utan skörd av skogsbränslen. Två olika beräkningssätt användes för att beräknad den minskade inlagringen (i) medelvärde för kollagerförändringen över en tidsperiod samt (ii) lagerförändring mellan två tidpunkter. Tre olika tidsperspektiv utvärderades, 20 år, en omloppstid (118 år respektive 77 år) samt två eller tre omlopp (231 år och 240 år). Det senare för att kunna jämföra resultaten från bestånden i södra och norra Sverige. Resultaten visar att storleken på den minskade inlagringen i markkol per hektar beror av beräkningsmetodik, tidsperspektiv, skördeintensitet, områdets produktivitet och skördad resurs, d.v.s. stubbar eller grot. Utsläpp av växthusgaser från hela skogsbränslekedjan inklusive minskad inlagring av markkol ger olika resultat beroende på vilket beräkningssätt som används för markkol, lagerförändring mellan två tidpunkter (6-10 g CO2-ekv/MJ bränsle) eller skillnad i medelkolförråd mellan två tidpunkter (11-42 g CO2-ekv/MJ bränsle). Utsläppsminskning (d.v.s. klimatnyttan) genom att ersätta fossil energi med skogsbränslen beräknades. Det antogs att skogsbränslen användes i kraftvärmeverk och genom att allokera 52 % av miljöbelastningen på elen baserat på alternativallokeringsmetoden antogs elen ersätta elektricitet från kolkondenskraftverk samt naturgaskraftverk (kombikondens). Förutom de faktorer som påverkar inlagring i markkol beror skogsbränslens klimatnytta av effektiviteten i användningen, tillämpad fördelningsmetod av miljöbelastning och vilken energisort som ersätts. Den insatsenergi som behövts för att skörda, transportera och förädla skogsbränslet beräknades till 2–5 % av energin i det bränsle som levereras. Arbetet visar att effekterna av grot- och stubbskörd är fördelaktiga jämfört med fossilbaserade alternativ när det gäller såväl insatsenergi som utsläpp av klimatgaser på lång sikt. Insatsenergi är mycket liten och säkerställd medan de långsiktiga klimateffekterna är något osäkra som ett resultat av brist på kunskap när det gäller bland annat effekter av omrörning i skogsmarken vid stubblyftning. Studien indikerar alltså att skörd av grot i studerade systemtyper bör tillämpas om hänsyn tas till enbart insatsenergi och växthusgaseffekter. För stubbars växthusgasbalans krävs mer kunskap om vilken betydelse stubbskördens omrörning av marken har på nedbrytning av organiskt material. Skördetekniken av stubbar kan vara betydelsefull för växthusgasbalansen för stubbar. Studien behandlar inte andra effekter, exempelvis på biologisk mångfald eller skogens upplevelsevärde. Vid en samlad bedömning av om/var/hur grot- och stubbskörd bör tillämpas måste en helhetsbedömning ske där samtliga effekter inkluderas
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| 44. |
- Olafsdottir, Steingerdur, 1972, et al.
(författare)
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Young children's screen habits are associated with consumption of sweetened beverages independently of parental norms.
- 2014
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Ingår i: International journal of public health. - : Springer Science and Business Media LLC. - 1661-8564 .- 1661-8556. ; 59:1, s. 67-75
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: This study investigated the associations between children's screen habits and their consumption of sweetened beverages. Because parents might be disposed to regulate their child's screen and dietary habits in a similar direction, our specific aim was to examine whether these associations were independent of parental norms. METHODS: In the Swedish sample of the European Identification and prevention of dietary and lifestyle-induced health effects in children and infants (IDEFICS) study, parents filled in questionnaires about their 2 to 9-year-old children's (n=1,733) lifestyle and diets. RESULTS: Associations between screen habits and sweetened beverage consumption were found independent of parental norms regarding sweetened beverages. A longitudinal analysis revealed that sweetened beverage consumption at 2-year follow-up was predicted by exposure to commercial TV at baseline (OR 1.4, 95% CI 1.1-1.9). Cross-sectional analysis showed that the likelihood of consuming sweetened beverages at least 1-3 times per week increased for each hour/day watching television (OR 1.5, 95% CI 1.2-1.9), and for being exposed to commercials (OR 1.6, 95% CI 1.3-2.1). TV viewing time and commercial exposure contributed to the associations independently of each other. CONCLUSIONS: The results strengthen the assumption that it is possible to influence children's dietary habits through their TV habits.
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| 45. |
- Regber, Susann, et al.
(författare)
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Parenting styles and treatment of adolescents with obesity
- 2007
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Ingår i: Pediatr Nurs. - Pitman, NJ : Anthony J. Jannetti Inc. - 0097-9805. ; 33:1, s. 21-8
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Tidskriftsartikel (refereegranskat)abstract
- Professional caregivers have an important task in building a trusting relationship with parents and adolescents and in supporting parents in their parental roles. Our clinical experience of some 300 adolescents with obesity between 9 and 18 years of age and their parents has convinced us that consideration of parenting styles is fundamental in the treatment of children and adolescents with obesity. Typical case situations supporting the significance of parenting styles and illustrating the relationships between parents and adolescents with obesity can be identified. Group sessions with parents are the preferred mode for discussing typical parenting issues in the management of obese adolescents. The purpose of this paper is to describe different parenting styles, and to present a set of typical case situations and treatment strategies for nurses working with adolescents with obesity.
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| 46. |
- Roos, Carl, et al.
(författare)
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In Vivo Mechanisms of Intestinal Drug Absorption from Aprepitant Nanoformulations
- 2017
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 14:12, s. 4233-4242
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Tidskriftsartikel (refereegranskat)abstract
- Over recent decades there has been an increase in the proportion of BCS class II and IV drug candidates in industrial drug development. To overcome the biopharmaceutical challenges associated with the less favorable properties of solubility and/or intestinal permeation of these substances, the development of formulations containing nanosuspensions of the drugs has been suggested. The intestinal absorption of aprepitant from two nanosuspensions (20 mu M and 200 mu M total concentrations) in phosphate buffer, one nanosuspension (200 mu M) in fasted-state simulated intestinal fluid (FaSSIF), and one solution (20 mu M) in FaSSIF was investigated in the rat single-pass intestinal perfusion model. The disappearance flux from the lumen (J(disapp)) was faster for formulations containing a total concentration of aprepitant of 200 mu M than for those containing 20 mu M, but was unaffected by the presence of vesicles. The flux into the systemic circulation (J(app)) and, subsequently, the effective diffusion constant (D-eff) were calculated using the plasma concentrations. J(app) was, like J(disapp), faster for the formulations containing higher total concentrations of aprepitant, but was also faster for those containing vesicles (ratios of 2 and 1.5). This suggests that aprepitant is retained in the lumen when presented as nanoparticles in the absence of vesicles. In conclusion, increased numbers of nanoparticles and the presence of vesicles increased the rate of transport and availability of aprepitant in plasma. This effect can be attributed to an increased rate of mass transport through the aqueous boundary layer (ABL) adjacent to the gut wall.
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| 48. |
- Zelano, Johan, et al.
(författare)
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SynCAM1 expression correlates with restoration of central synapses on spinal motoneurons after two different models of peripheral nerve injury
- 2009
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Ingår i: Journal of Comparative Neurology. - : Wiley. - 0021-9967 .- 1096-9861. ; 517:5, s. 670-82
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Tidskriftsartikel (refereegranskat)abstract
- SynCAM1 and neuroligins (NLGs) are adhesion molecules that govern synapse formation in vitro. In vivo, the molecules are expressed during synaptogenesis, and altered NLG function is linked to synapse dysfunction in autism. Less is known about SynCAM1 and NLGs in adult synapse remodeling. CNS synapse elimination occurs after peripheral nerve injury, which causes a transient decrease in synapse number on spinal motoneurons. Here we have studied the expression of SynCAM1 and NLGs in relation to changes in synaptic covering on spinal motoneurons. We performed sciatic nerve transection (SNT) or crush (SNC), axotomy models that result in poor or good conditions for axon regeneration, respectively. The two lesions resulted in similar synapse elimination and in poor (SNT) and good (SNC) return of synapses after 70 days. Functional recovery was good after SNC but absent after SNT. SynCAM1 mRNA decreased after 14 days in both models and was restored 70 days after SNC, but not after SNT. NLG2 and -3 mRNAs decreased to a smaller degree after SNC than after SNT. Synaptophysin immunoreactivity correlated with SynCAM1 mRNA 70 days after SNT and NLG2 mRNA 70 days after SNC. Surprisingly, an inverse correlation was seen between NLG3 mRNA and Vglut2, a marker for excitatory synapses, 70 days after SNT. We conclude that 1) SynCAM1 mRNA levels seem to reflect the loss and restoration of synapses on motoneurons, 2) down-regulation of NLGs is not a prerequisite for synapse elimination, and 3) expression of SynCAM1 and NLGs is regulated by different mechanisms during regeneration.
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| 49. |
- Åberg, Anna, et al.
(författare)
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Helicobacter pylori adapts to chronic infection and gastric disease via ph-responsive baba-mediated adherence
- 2017
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Ingår i: Cell Host and Microbe. - : Elsevier BV. - 1931-3128 .- 1934-6069. ; 21:3, s. 376-389
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Tidskriftsartikel (refereegranskat)abstract
- The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease.
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